{"ID":91427,"post_author":"9412100","post_date":"2020-07-07 16:50:35","post_date_gmt":"0000-00-00 00:00:00","post_content":"","post_title":"LIMSjournal - Summer 2020","post_excerpt":"","post_status":"draft","comment_status":"closed","ping_status":"closed","post_password":"","post_name":"","to_ping":"","pinged":"","post_modified":"2020-07-07 16:50:35","post_modified_gmt":"2020-07-07 20:50:35","post_content_filtered":"","post_parent":0,"guid":"https:\/\/www.limsforum.com\/?post_type=ebook&p=91427","menu_order":0,"post_type":"ebook","post_mime_type":"","comment_count":"0","filter":"","_ebook_metadata":{"enabled":"on","private":"0","guid":"2D49E5D2-73ED-4DB7-8161-7AE6E626D53B","title":"LIMSjournal - Summer 2020","subtitle":"Volume 6, Issue 2","cover_theme":"nico_21","cover_image":"https:\/\/www.limsforum.com\/wp-content\/plugins\/rdp-ebook-builder\/pl\/cover.php?cover_style=nico_21&subtitle=Volume+6%2C+Issue+2&editor=Shawn+Douglas&title=LIMSjournal+-+Summer+2020&title_image=https%3A%2F%2Fs3.limsforum.com%2Fwww.limsforum.com%2Fwp-content%2Fuploads%2FFig2_Bhattacharya_AIMSPubHlth2019_6-3.png&publisher=LabLynx+Press","editor":"Shawn Douglas","publisher":"LabLynx Press","author_id":"26","image_url":"","items":{"1b738084b45b445282479ac65a72296b_type":"article","1b738084b45b445282479ac65a72296b_title":"Wrangling environmental exposure data: Guidance for getting the best information from your laboratory measurements (Udesky et al. 2019)","1b738084b45b445282479ac65a72296b_url":"https:\/\/www.limswiki.org\/index.php\/Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements","1b738084b45b445282479ac65a72296b_plaintext":"\n\n\t\t\n\t\t\t\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t\n\n\t\t\t\tJournal:Wrangling environmental exposure data: Guidance for getting the best information from your laboratory measurements\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t\tFrom LIMSWiki\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\tJump to: navigation, search\n\n\t\t\t\t\t\n\t\t\t\t\tFull article title\n \nWrangling environmental exposure data: Guidance for getting the best information from your laboratory measurementsJournal\n \nEnvironmental HealthAuthor(s)\n \nUdesky, Julia O.; Dodson, Robin E.; Perovich, Laura J.; Rudel, Ruthann A.Author affiliation(s)\n \nSilent Spring Institute, MIT Media LabPrimary contact\n \nEmail: Use journal website to contactYear published\n \n2019Volume and issue\n \n18Article #\n \n99DOI\n \n10.1186\/s12940-019-0537-8ISSN\n \n1476-069XDistribution license\n \nCreative Commons Attribution 4.0 InternationalWebsite\n \nhttps:\/\/ehjournal.biomedcentral.com\/articles\/10.1186\/s12940-019-0537-8Download\n \nhttps:\/\/ehjournal.biomedcentral.com\/track\/pdf\/10.1186\/s12940-019-0537-8 (PDF)\n\nContents\n\n1 Abstract \n2 Background \n3 About the wrangling guide \n4 Study design \n\n4.1 What can we measure and how? \n\n4.1.1 Chemical identities \n4.1.2 Matrix \n4.1.3 Method \n4.1.4 Quantification method \n4.1.5 Sensitivity of the method \n\n\n4.2 How to minimize sample contamination? \n4.3 How will the lab report the data? \n\n4.3.1 Chemical identities \n4.3.2 Reporting limits \n4.3.3 Amount \n\n\n\n\n5 Study implementation \n\n5.1 What QA\/QC is needed? \n\n5.1.1 Spiked samples and certified reference material \n5.1.2 Surrogate recovery standards \n5.1.3 Blanks \n5.1.4 Duplicates \n5.1.5 Analytical batches \n\n\n\n\n6 Data interpretation \n\n6.1 What was measured? \n\n6.1.1 Chemical identities \n\n\n6.2 Were there trends over time? \n\n6.2.1 Analytical batches \n\n\n6.3 Is the method accurate? \n\n6.3.1 Spiked samples and certified reference material \n\n\n6.4 Were there problems with certain samples? \n\n6.4.1 Surrogate recovery standards \n\n\n6.5 Is there evidence of contamination or analytical bias? \n\n6.5.1 Blanks \n\n\n6.6 How precise are these measurements? \n\n6.6.1 Duplicates \n\n\n6.7 Publication: How do we tell others about our data? \n\n\n7 Conclusion \n8 Abbreviations \n9 Supplementary information \n10 Acknowledgements \n\n10.1 Contributions \n10.2 Funding \n10.3 Competing interests \n\n\n11 References \n12 Notes \n\n\n\nAbstract \nBackground: Environmental health and exposure researchers can improve the quality and interpretation of their chemical measurement data, avoid spurious results, and improve analytical protocols for new chemicals by closely examining lab and field quality control (QC) data. Reporting QC data along with chemical measurements in biological and environmental samples allows readers to evaluate data quality and appropriate uses of the data (e.g., for comparison to other exposure studies, association with health outcomes, use in regulatory decision-making). However many studies do not adequately describe or interpret QC assessments in publications, leaving readers uncertain about the level of confidence in the reported data. One potential barrier to both QC implementation and reporting is that guidance on how to integrate and interpret QC assessments is often fragmented and difficult to find, with no centralized repository or summary. In addition, existing documents are typically written for regulatory scientists rather than environmental health researchers, who may have little or no experience in analytical chemistry.\nObjectives: We discuss approaches for implementing quality assurance\/quality control (QA\/QC) in environmental exposure measurement projects and describe our process for interpreting QC results and drawing conclusions about data validity.\nDiscussion: Our methods build upon existing guidance and years of practical experience collecting exposure data and analyzing it in collaboration with contract and university laboratories, as well as the Centers for Disease Control and Prevention. With real examples from our data, we demonstrate problems that would not have come to light had we not engaged with our QC data and incorporated field QC samples in our study design. Our approach focuses on descriptive analyses and data visualizations that have been compatible with diverse exposure studies, with sample sizes ranging from tens to hundreds of samples. Future work could incorporate additional statistically grounded methods for larger datasets with more QC samples.\nConclusions: This guidance, along with example table shells, graphics, and some sample R code, provides a useful set of tools for getting the best information from valuable environmental exposure datasets and enabling valid comparison and synthesis of exposure data across studies.\nKeywords: exposure science, environmental epidemiology, environmental chemicals, environmental monitoring, quality assurance\/quality control (QA\/QC), data validation, exposure measurement, measurement error\n\nBackground \nChemical measurements play a critical role in the study of links between the environment and health, yet many researchers in this field receive little if any training in analytical chemistry. The growing interest in measuring and evaluating health effects of co-exposure to a multitude of chemicals[1][2] makes this gap in training increasingly problematic, as the task at hand becomes ever-more complicated (i.e., analyzing for more and for new chemicals of concern). If steps are not taken throughout samples collection and analysis to minimize and characterize likely sources of measurement error, the impact on the interpretation of these valuable measurements can vary along the spectrum from false negative to false positive, as we will illustrate with real examples from our own data.\nSome important considerations when measuring and interpreting environmental chemical exposures have been discussed in other peer-reviewed articles or official guidance documents. For example, a recent document from the Environmental Protection Agency (EPA) provides citizen scientists with guidance on how to develop a field measurement program, including planning for the collection of quality control (QC) samples.[3] The Centers for Disease Control and Prevention (CDC) also gives guidance related to collection, storage, and shipment of biological samples for analysis of environmental chemicals or nutritional factors.[4] To assess the quality of already-collected data, LaKind et al. (2014) developed a tool to evaluate epidemiologic studies that use biomonitoring data on short-lived chemicals, with a focus on critical elements of study design such as choice of analytical and sampling methods.[5] The tool was recently incorporated into \u201cExpoQual,\u201d a framework for assessing suitability of both measured and modeled exposure data for a given use (\u201cfit-for-purpose\u201d).[6] Other useful guidance has been published, for example on automated quality assurance\/quality control (QA\/QC) processes for sensors collecting continuous streams of environmental data[7] and for establishing an overall data management plan, including documentation of metadata and strategies for data storage.[8]\nDespite these helpful documents, there is still a lack of readily accessible, practical guidance on how to interpret and use the results of both field and laboratory QC checks to qualify exposure datasets (i.e., flag results for certain compounds or certain samples that are imprecise, estimated, or potentially over- or under-reported), and this gap is reflected in the environmental health literature. While the vast majority of environmental health studies report robust findings based on high-quality measurements, questions about measure validity have led to confusion and lack of confidence in some topic areas. For example, a number of studies have measured rapidly metabolized chemicals such as phthalates and bisphenol A (BPA) in blood or other non-urine matrices, despite the fact that urine is the preferred matrix for these chemicals. Phthalates and BPA are present at higher levels in urine and, when the proper metabolites are measured, there is less concern about contamination from external sources, including contamination from plastics during specimen collection.[9]\nMore commonly, however, exposure studies simply do not adequately report on QA\/QC or describe how QC results informed reporting and interpretation of the data. In the context of systematic review and weight of evidence approaches, not reporting on QA\/QC may result in a study being given less weight. For example, the risk of bias tool employed in case studies of the Navigation Guide method for systematic review includes reporting of certain QA\/QC results in its criteria for a \u201clow risk of bias\u201d rating (e.g., reference Lam et al.[10]). When we applied the Navigation Guide's QA\/QC criterion to 30 studies of biological or environmental measurements that we included in a recent review of environmental exposures and breast cancer[11], we found that more than half either did not report QA\/QC details that were required for a \u201clow risk of bias\u201d assessment, or if they did report QA\/QC, they did not interpret or use them adequately to inform the analysis (e.g., reported poor precision but did not discuss how\/whether this could affect findings) (see Additional file 1 for details). Similarly, when LaKind et al. applied their study quality assessment tool to epidemiologic literature on BPA and neurodevelopmental and respiratory health, they found that QA\/QC issues related to contamination and analyte stability were not well-reported.[12] Of note, several of the studies in our breast cancer review that did not provide adequate QA\/QC information had their samples analyzed at the CDC Environmental Health Laboratory. It is helpful to include summaries of QA\/QC assessments in published work, even if researchers are using a well-established lab, because this provides a useful standard for comparing QA\/QC in other studies.\nOver many years of collecting and interpreting environmental exposure data, we have developed a standard approach for (1) using field and laboratory QA\/QC to validate and qualify chemical measurement data for environmental samples and (2) presenting our QC findings in our research publications (e.g., reference Rudel et al.[13]). These methods are based on data validation procedures from the EPA, Army Corps of Engineers, and U.S. Geological Survey[14][15][16][17], as well as the guidance of the many experienced chemists with whom we have collaborated. In this commentary, we compile our methods into a practical guide, focusing on how to use the information to make decisions about data usability and how to make the information transparent in publications. Our guide is organized in three sections, presenting questions to consider during study design, implementation, and data analysis. We describe key elements of QA\/QC, including for assessing precision, accuracy, and sample contamination, and we include suggested graphics (Additional files 2 and 4), and table shells (Additional file 2) that clearly present QC data, emphasizing how it may affect interpretation of study measurements. Minimizing and characterizing potential errors requires close collaboration between the researchers who may have designed the study and plan to analyze the data and the chemists performing the analysis. As such, our guidance also includes example correspondence (Additional file 2) to help establish this relationship at the start of a project.\nWe present a detailed approach based on our own studies, acknowledging that this is an example, not a one-size-fits-all approach. Every study is unique and some will require specialized quality assessment not covered here. Still, we anticipate that many environmental health scientists will find this example to be a useful framework for building their own processes.\n\nAbout the wrangling guide \nOur guide is organized by a series of questions that we ask when we start a new study, and then ask again when we receive measurement data from the lab. Key QA\/QC concepts are introduced in the section on study design, and they are more thoroughly addressed in sections concerning study implementation and data interpretation.\nNot every question is relevant to every study; for example, researchers working with a lab to develop a new analytical method will need to focus more on method validation and quality control than those using a well-established method and credentialed lab. Still, controlling for issues related to sample collection and transport remain important in the latter scenario, as does variation in method performance and\/or sources of contamination when samples are analyzed at the laboratory in multiple batches. Our guidance is most relevant to targeted organic chemical analyses, which use liquid or gas chromatography, often in combination with mass spectrometry, to determine whether a pre-defined set of chemicals are present in samples. QA\/QC approaches for non-targeted methods, where tentative identities are established by matching to a library of mass spectra such as the National Institute of Standards and Technology (NIST) database[18], are addressed elsewhere.[19]\nThis guide is not a set of rules, but rather establishes a framework for evaluating and reporting QC data for chemical measurements in environmental or biological samples. While it may be most useful to environmental health scientists who have little or no experience in analytical chemistry, we hope that researchers with a range of experience will find it helpful to consult our approach for evaluating and presenting QC data in publications.\nBecause the number of QC samples available is often limited by budgetary constraints, many of the methods we use rely on visualization and conservative action (i.e., removing chemicals from our dataset or qualifying their interpretation unless there is evidence that the analytical method was accurate and precise) rather than on statistical methods. Whether statistical methods are incorporated or not, tabulating, visualizing, and communicating about QA\/QC for environmental exposure measurements is important in order to reveal systematic error in the laboratory[20] or in the field, supporting future use of the data.[6]\n\nStudy design \nWhat can we measure and how? \nOne of our first priorities when designing a new study is to consult with a chemist to establish an analyte list and method for analysis.\n\nChemical identities \nGiven the complexity of chemical synonyms, it is helpful to be as specific as possible when communicating about the chemicals to be analyzed. One approach is to send the lab a list of the chemical names (avoiding the use of trade names, which can be imprecise), Chemical Abstracts Service (CAS) numbers, and configurations (e.g., branched or linear, if relevant) of all desired analytes (see Additional file 1 for example correspondence). For biomonitoring, it is also important to determine if the parent chemical or metabolites will be targeted.\n\nMatrix \nAnother consideration in developing the analyte list is what type of samples are available (if working with stored samples) or will be collected. As discussed previously, certain biological matrices are preferred over others for measurement, depending on the chemicals (e.g., reference Calafat et al.[9]). Matrix type is also relevant for environmental samples; for example, physical chemical properties like the octanol air partitioning coefficient inform whether an analyte is more likely to be found in air or dust.[21]\n\nMethod \nThe process of determining a final list of analytes will differ depending on whether the lab has an established method or is developing a new method, and whether it is targeted to a few chemicals with similar structure versus many chemicals with different properties (different polarities, solubilities, etc.). Targeting a broad suite of chemicals may limit the degree of precision and accuracy that can be achieved for each individual chemical, and the lab may need to invest substantial effort to develop a multi-residue method\u2014that is, a method that can analyze for many chemicals at once\u2014and determine a final list of target chemicals with acceptable method performance. In any case, a new method should be validated to characterize performance measures\u2014precision, accuracy, expected quantitation and method detection limits, and the range of concentrations that can be quantitated with demonstrated precision and accuracy\u2014before analyzing study samples. If the lab already has an established method for the chemicals of interest, the research team should review method performance measures to ensure they are consistent with study objectives.\n\nQuantification method \nThe method of quantification affects the types of QC data that are expected from the lab. Three common approaches include external calibration, internal calibration and isotope dilution (a form of internal calibration). External calibration, where the response (i.e., chromatogram peak) from the sample is compared to the response from calibration standards containing known amounts of the analytes of interest, is a simple method that can be used for a variety of different analyses. However, results can be influenced by interference from other chemicals present in the sample matrix and resulting fluctuations in the analytical instrument response.[22] With internal calibration, on the other hand, one or more labeled compounds\u2014either one of the targeted analytes or a closely related compound\u2014are added to each of the samples just before they are injected into the instrument for analysis and used to correct for variation in the instrument response. The internal standard must be similar to the target compounds in physical chemical properties (e.g., a labeled polychlorinated biphenyl should not be used to represent a brominated diphenyl ether). Finally, for isotope dilution methods\u2014which are the most accurate\u2014labeled isotopes for each of the target compounds are added to samples prior to extraction. Additional internal standards are added to the samples just prior to injection to monitor loss of the labeled isotopes, and the analytical software then corrects for loss during sample extraction and for effects of the sample matrix (e.g., presence of other compounds in the sample that interfere with the analysis).[22] Many laboratories that analyze chemical levels in blood, urine, or tissues (e.g., the CDC National Exposure Research Laboratory) use isotope dilution quantification. However, isotopically labeled standards are not available for every compound and may be cost-prohibitive. If quantification is by internal or external calibration, researchers will likely need to review and report more extensive QC data from the lab compared to when using isotope dilution, as discussed in the section on study implementation.\n\nSensitivity of the method \nAnother important factor in selecting a method is to make sure it is sensitive enough to detect the anticipated concentrations in the field samples (samples submitted to the lab) down to levels that are relevant to the research question. For example, commercial labs measuring environmental chemicals may establish reporting limits to meet the needs of occupational or regulatory safety compliance testing; these limits may be much higher than levels that are meaningful for research questions about general population exposure and could result in most data being reported as non-detect or qualified as estimated and imprecise. On the other hand, lower reporting limits generally translate to more expensive testing, so researchers have the opportunity to balance sensitivity and cost.\n\nHow to minimize sample contamination? \nThere are ample opportunities for sample contamination during collection, storage, shipment, and analysis, especially when targeting ubiquitous chemicals commonly encountered in consumer products, home and office furnishings, or laboratory equipment. An important aspect of method validation is to check for contamination of samples during field activities, from collection containers, during transport and storage, and during laboratory extraction and analysis (see discussion of blanks in the section on study implementation). The CDC\u2019s guidance on sample collection and management identifies some possible sources of contamination when analyzing for common chemicals like plastics chemicals, antimicrobials, and preservatives in blood or urine. Key considerations, depending on the particular chemicals being targeted, include selecting appropriate collection containers (e.g., glass containers if analyzing for plastics chemicals), avoiding the use of urine preservatives (e.g., when analyzing for parabens, BPA), and providing adequate instructions to participants collecting their own samples (e.g., avoid using antimicrobial soaps or wipes during collection).[4] As noted previously, contamination can also be minimized in biomonitoring of some chemicals by measuring a metabolite rather than parent chemical, and possibly by measuring a conjugated rather than free form of the metabolite.[9] In some cases, the lab may need to pre-screen collection containers or other sampling materials to see if they contain any target chemicals. For example, when we used polyurethane foam (PUF) sorbent to collect air samples for analysis of flame retardants, plastics chemicals, and preservatives, we asked the lab to pre-screen the PUF matrix for target analytes. Another important precaution was to ship the samplers wrapped in aluminum foil that had been baked in a muffle furnace to ensure it was clean and uncoated.\n\nHow will the lab report the data? \nThree key elements of data typically reported by the lab are the identity of the chemical, the reporting limit for each chemical and sample, and how much of each chemical is present in each sample. Sometimes an additional measure is needed to normalize mass of chemical per sample, for example, grams of urinary creatinine, urine specific gravity, grams of serum lipid, or cubic meters of air (see work by LaKind et al.[5] for discussion of issues related to matrix adjustment and presentation of measurements).\n\nChemical identities \nIt is helpful to request in advance that the lab report CAS numbers and configurations (if relevant) along with chemical names (see Additional files 2 and 3 for example reporting requests).\n\nReporting limits \nCommon terms used by laboratories to discuss reporting limits include \"instrument detection limit\" (IDL), \"method detection limit\" (MDL) and \"limit of quantitation\" (LOQ). The IDL and MDL are both related to the level of an analyte that can be detected with confidence that it is truly present. The IDL captures the smallest true signal (change in instrument response when an analyte is present) that can be distinguished from background noise (variation in the instrument response to blank samples), while the MDL takes into account additional sources of error introduced during sample preparation (e.g., the extraction process, possible concentration or dilution of samples) and thus is higher than the IDL. The MDL is also often referred to as the limit of detection (LOD) or detection limit (DL). The LOQ, on the other hand, describes the lowest mass or concentration that can be detected with confidence in the amount detected. The reporting limit (RL) or method reporting limit (MRL), which is either the lowest value that the lab will report or the lowest value that the lab will report without flagging the data as estimated, is often (but not always) the same as the quantitation limit or LOQ.\nBefore submitting samples for analysis, it is helpful to find out (1) the methods and terminology that the laboratory will use to describe reporting limits (LOD, LOQ, etc.) and (2) whether reporting limits will be consistent within a chemical or whether limits could vary between samples or batches. Equally critical is to clarify how the lab will report non-detects. Several different values could appear in the amount or concentration fields for non-detects, including but not limited to zeroes, the detection limit, the reporting limit, or \u201cND.\u201d\n\nAmount \nAnother important point to discuss in advance with the laboratory is how they will report values for compounds with a confirmed identity but measured at levels below what accurately can be quantitated. For example, when measuring chemicals of emerging interest, we ask laboratories to report estimated values below the RL and we flag them during data analysis. This practice has some limitations[23] but is preferable to falsely reducing variance in the dataset by treating estimated values below the RL as equivalent to non-detects below the detection limit. Non-detects can present significant data analysis challenges, and while a discussion of the best available methods and the problems with common approaches such as substituting the RL, RL\/2, or zero for non-detects is beyond the scope of this commentary, it is a critical issue, and we refer the reader to several helpful resources.Cite error: Invalid <ref> tag;\nrefs with no content must have a name[24][25][26] Reporting estimated values is not standard practice for many laboratories, so it is important to raise this issue early on (see Additional file 2 for example correspondence). If the lab reports data qualifier flags, it may be necessary to clarify the interpretation of those flags, including but not limited to which flags distinguish non-detects from detects above the MRL and estimated values. In other words, it is best not to make assumptions.\n\nStudy implementation \nWhat QA\/QC is needed? \nQA\/QC occurs both inside and outside the analytical laboratory (see Table 1). Field QC samples, namely blanks and duplicates, capture the sum of contamination and measurement error from collection, storage, transport, and laboratory sources. We base the number of QC samples we collect in the field on budget and our sample size, generally aiming for at least 20% QC samples (e.g., if collecting 80 field samples, then collect 16 field QC samples), though a higher percentage is needed in small studies. Lab analysts should be blinded to the identity of field QC samples whenever possible. Maintaining blinding can be challenging, so it is worth putting some thought into sample names (e.g., QC samples should not have obviously different IDs than other samples, should not be labeled with a \u201cD\u201d for duplicate or \u201cB\u201d for blank). Logs retained at the site must contain sufficient information to allow the data analysts to identify field QC samples and sample types.\n\n\n\n\n\n\n\nTable 1. Summary of QC sample types, interpretation, and possible actions\n\n\nQA\/QC concept\n\nMeasure\n\nInterpretation\n\nPossible actions\n\n\nAccuracy\n\n\n\u2022 Surrogate spike recovery in each sample\n\u2022 Certified reference material\r\n\n\u2022 Isotope dilution quantification\r\n\n\n\n\nMeasures whether the analytical method produces accurate quantification for each compound. Matrix spike recovery evaluates matrix effects on accuracy, such as interferences. Isotope dilution is the most rigorous approach to generating accurate measurements in biomonitoring.\n\n\n\n\u2022 Drop compounds with inaccurate quantification from the data analysis, discuss with lab whether improvements can be made for future analyses.\r\n\n\u2022 If problems are modest and batch-specific, include batch as a covariate in regression model.\n\n\n\nExtraction efficiency\n\n\n\u2022 Surrogate spike recovery in each sample\n\n\n\nMeasures\u2014for each field sample\u2014whether the chemical is extracted completely from the sample matrix, (e.g., blood, dust). Isotope dilution approaches capture and correct for differences in extraction efficiency.\n\n\n\n\u2022 Consider dropping samples with poor surrogate recovery from data analysis.\r\n\n\u2022 Consider applying a surrogate correction factor (1\/fraction recovery) if the recovery is consistent (\u00b1 15\u201320% in standard deviation).\n\n\n\nDetection limit\n\n\n\n\nThis is the level above which the lab can detect with confidence that the analyte is present in the sample. Common terms include \"instrument detection limit\" (IDL), \"detection limit\" (DL), \"method detection limit\" (MDL), and \"limit of detection\" (LOD).\n\n\n\n\u2022 See Method reporting limit (MRL)\n\n\n\nQuantitation limit\n\n\n\n\nThis is the level above which the lab can quantify with confidence the amount of chemical in the sample. Common terms include \"practical quantitation limit\" (PQL), \"limit of quantitation\" (LOQ), \"laboratory quantitation level\" (LQL), and \"contract required quantitation limit\" (CRQL).\n\n\n\n\u2022 See Method reporting limit (MRL)\n\n\n\nMethod reporting limit (MRL)\n\n\n\u2022 Levels detected in blanks (lab-blind field blanks, solvent blanks, matrix blanks, storage blanks, other types)\n\n\n\nThis is the level above which the researcher is confident that the reported chemical measurement reflects a signal from the media sampled, considering all sources of measurement error, especially potential contamination during sample collection and handling, as well as in the laboratory.\n\n\n\n\u2022 Determine MRL by comparing the lab limit (quantitation limit, unless not reported, in which case detection limit) to the levels in the blanks for each compound.\r\n\n\u2022 Qualify reported values below the MRL as \u201cestimated.\u201d\n\n\n\nPotential contamination \/ Analytical bias\n\n\n\u2022 Levels detected in blanks (lab-blind field blanks, solvent blanks, matrix blanks, storage blanks, other types)\n\n\n\nMeasures the confidence in accuracy of values reported above the MRL.\n\n\n\n\u2022 If there is evidence of contamination, consider dropping a compound or dropping results for a compound in a particular batch. Additionally, identify the source of contamination (e.g., lab vs. field equipment) to inform future work.\n\u2022 For compounds with consistent contamination in blanks, researchers may correct field sample quantity by subtracting the amount attributed to contamination. This is most important when contamination is significant relative to sample values (e.g., >\u200910%) and for comparisons with external data.\n\n\n\nPrecision\n\n\n\u2022 Relative percent difference (RPD) for side-by-side duplicate samples (lab-blind) or split samples (lab-blind if possible)\n\n\n\nMeasures the reproducibility of field measurements, including analytical variability and sampling variability.\n\n\n\n\u2022 Flag compounds with >\u200930% RPD.\r\n\n\u2022 Consider precision in combination with other QA\/QC when deciding to qualify results.\n\n\n\n\nQC samples prepared in the lab can include spiked samples or certified reference materials (CRMs) for target chemicals to evaluate the accuracy of the analytical method, surrogate compounds added to field samples to estimate recovery during extraction and analysis, and blanks to assess contamination with target chemicals from some source in the laboratory. While laboratories generally conduct rigorous review of their own QC data, considering lab and field QC together can help to identify specific sources of contamination, imprecision, and systematic error. As such, we typically request to review the lab\u2019s raw QC data in conjunction with the field QC data.\n\nSpiked samples and certified reference material \nSpiked samples and CRMs establish the accuracy of the method by assessing the recoveries of known amounts of each target chemical from a clean or representative matrix. A CRM is a matrix comparable to that used for sampling (e.g., drinking water) that has been certified to contain a specific amount of analyte with a well-characterized uncertainty. If CRMs aren\u2019t available, the laboratory can prepare laboratory control samples (LCSs) by spiking known amounts of target chemicals into a clean sample of the matrix of interest, such as a dust wipe, air sampler, purified water, or synthetic urine or blood that has been analyzed and shown to be free of the analytes of interest, or to contain a consistent amount of analytes of interest that can be subtracted from the amounts measured in the spiked sample to calculate a percent recovery. The LCS or CRM\u2014at least one per analytical batch\u2014is run through the same sample preparation, extraction, and analysis as the field samples to capture the accuracy of the complete method; calculating the percent of the known\/spiked amount recovered for each analyte tells us whether the method is accurate in the matrix.\nAnother type of spiked sample, called a matrix spike, can be used to check the extraction efficiency for a complex sampling matrix that may interfere with the analysis. These samples are typically included if there is concern about interference from the sampling matrix, for example, with house dust, soil or sediment samples, consumer products, or biological samples like blood. Instead of recovery from a clean matrix, these QC checks capture recovery from a representative field sample. Here the \u201cmatrix\u201d refers to all elements of the sample other than the targeted analytes; this includes the sampling medium (e.g., dust, PUF, foam) itself as well as any other chemicals present in the sample that might interfere with measurement of target chemicals. A matrix spike can be created, for example, by splitting a representative sample collected in the field and spiking the target analytes into one half prior to extraction and analysis. The recovery of spiked analyte is determined as the amount measured in the spiked sample minus the amount measured in the non-spiked sample divided by the spike amount. A limitation of this approach is that the analytes are spiked in an already dissolved state, so it is possible that the analytes in the environmental matrix would not be extracted as readily from the matrix as the spiked chemicals. Thus, the true extraction efficiency may be lower than represented by the matrix spike.\nFor newly developed methods where performance is not characterized, we request results for all recoveries of spiked samples and\/or CRMs so that we can perform visual checks that have at times revealed systematic problems with the analytical method that were not noted by the lab (see the data interpretation section for further discussion). For well-established methods, and particularly when isotope dilution quantification is used, it is sufficient to request a table summarizing the spike recovery or CRM recovery results (by batch, if relevant) for reporting in publications.\n\nSurrogate recovery standards \nWhereas recoveries from LCSs, matrix spikes, and\/or CRMs tell us about the performance of the method in a clean or representative matrix, surrogate compounds are used to evaluate recoveries from individual samples. Recoveries of surrogate compounds can help identify any individual samples that may have inaccurate quantification, for example due to extraction errors or chemical interferences. Surrogates, like internal standards, are spiked into each sample; however, surrogates are added prior to sample extraction to assess the efficiency of this process. Internal standards, on the other hand, are added after extraction, just prior to injection into the chromatographic system, to account for matrix effects and other variation in the instrument response during analysis. The ideal surrogate is a chemical that is not typically present in the environment but that is representative of the physical and chemical properties of target analytes.[16] It is best to have a representative surrogate for each individual chemical, though when analyzing for numerous chemicals at once with multi-residue methods, cost and time restraints may result in one or a few surrogates being selected to represent a class of compounds. In this case, it is critical that the lab selects an appropriate surrogate.\nFor analyses using external or internal calibration, we ask the lab to provide us with the recovery results for each surrogate in each sample, so that we can flag any samples or compounds that might have had extraction problems. However, if the lab uses isotope dilution quantification, we are less concerned about obtaining this raw data from the laboratory given that the reported results are already automatically corrected for extraction and matrix effects.\n\nBlanks \nCollecting and preparing several types of blank samples helps us to distinguish sources of contamination. Laboratory blanks alert us to possible contamination originating in the lab. These blanks can capture contamination during sample extraction (solvent blanks), from reagents and other materials used in the analytical method (solvent method blanks), or from \u201ctypical\u201d background levels of target analytes present in the sampling matrix (matrix blanks). Field blanks, on the other hand, capture all possible contamination during sample collection and analysis. Field blanks are clean samples (e.g., distilled water, air sampling cartridge detached from pump immediately following calibration) that are transported to the sampling location and exposed to all of the same conditions as the real samples (e.g., the sampler is opened, if applicable) except the actual collection process. We aim for at least 10% of our samples to be field blanks, with an absolute minimum of three field blanks.\nUnfortunately, in some cases there aren\u2019t good options for representative field blanks. For example, field blanks can be created for biomonitoring programs by taking empty collection containers into the field and using purified water or synthetic urine or blood to create a blank.[4] However, important shortcomings of this approach are that (1) it is difficult to capture contamination that can be introduced by sample collection materials such as needles and plastic tubing used to collect blood, (2) water may not perform the same as urine or blood in the extraction and analysis, and (3) the lab will likely be able to identify the field blanks. Similarly, it is difficult to maintain lab blinding when using a \u201cclean\u201d matrix like vacuumed quartz sand as a field blank for vacuumed house dust.\n\nDuplicates \nCollecting side-by-side duplicate samples in the field helps assess the precision of both the sample collection and analytical methods. Duplicate samples can also be created by collecting a single sample and splitting it prior to analysis, which is the only option for biological samples; however, this method only captures the precision of the analysis process[14][17] and could lead to un-blinding of the lab analyst, if for example the split samples are noticeably smaller than others. When planning for duplicate collection, the best practice is to label these samples so that the lab analyst is blinded to duplicate pairs (i.e., use different Sample IDs for the two samples). Ideally, researchers should plan to collect or create (that is, split) one duplicate pair per every 10\u201320 samples collected and spread duplicate pairs across analytical batches.\n\nAnalytical batches \nAnalytical performance can shift over time, and even between multiple extractions or instrument runs within a short time window. Laboratories often analyze samples in multiple batches, that is, sets of field samples and associated laboratory QC samples that are analyzed together in one analytical run. The time between batches can vary from days to months or even years, though ideally this time span is minimized in order to maintain consistent equipment and procedures throughout the study.\nTwo approaches help address batch-to-batch variability: (1) randomizing participant samples between batches by specifying the order and grouping of samples (and blind field QC samples) when submitting samples to the lab (this may require corresponding with the lab to determine the batch size in advance), and (2) running CRMs\u2014such as standard reference material (SRM) from NIST[27]\u2014in each batch of samples in order to characterize drift. When CRMs are not available, another option is for the researcher to prepare identical\/split reference samples. We have done this, for example, by pooling together several urine specimens and making many aliquots of the pool, then including 1\u20132 blinded samples from this pool with each set of samples we send to the lab. If the laboratory analysis is performed in multiple batches, all QC elements should be examined on a batch-specific basis. Not every laboratory will specify whether or not samples were analyzed in batches; it is a good idea to request that a variable for batch be included in the results report.\nIn Additional files 2 and 3, we provide example correspondence for requesting QC data and consistent formatting from the lab.\n\nData interpretation \nWhat was measured? \nChemical identities \nNo amount of QA\/QC can save a dataset from basic misunderstandings about what is being reported. After receiving data, it is helpful to ask the chemists to double check the analyte list (chemical name, CAS, isomer details) against the list of standards used in the analysis, particularly if this information was not included in the report from the lab. It is worthwhile to make this verification even when chemical identities were specified in advance of the analysis, as it is possible that the standard used for analysis was slightly different than planned. Only through this process, for example, did we discover that a lab had accidentally purchased a standard for 2,2,4-trimethyl-1,3-pentanediol isobutyrate rather than 2,2,4-trimethyl-1,3-pentanediol diisobutyrate (two different chemicals).\nTable 2 summarizes some steps for getting acquainted with a new dataset received from the lab. We have also published sample R code on GitHub that may be helpful for getting acquainted with a new dataset, including examining trends in QC and field samples over time.[28]\n\n\n\n\n\n\n\nTable 2. Steps for getting acquainted with your data\n\n\n\n1. Verify chemical identities.\r\n\n\n\u25cb Check CAS number, chemical name, isomer type of reported analytes vs. analytical standards purchased by lab (see Additional file 2 for example correspondence).\r\n\n2. Count (overall and by batch) the number of:\r\n\n\n\u25cb \u201cReal\u201d samples (compare these to the chain of custody that lists the samples submitted for analysis to make sure all submitted samples were analyzed)\r\n\n\u25cb Lab control and\/or matrix spike recoveries\r\n\n\u25cb Reference samples (e.g., CRMs)\r\n\n\u25cb Surrogate spike recoveries\r\n\n\u25cb Blanks (solvent method, field, matrix, other)\r\n\n\u25cb Duplicates\r\n\n3. Examine any data qualifier flags reported by the lab and make sure interpretation is clear.\n\n\n\n\nWere there trends over time? \nAnalytical batches \nExamining results by batch or even by sample run order can reveal trends in QC samples over time, identifying systematic laboratory errors that may be missed by summary statistics or visualizations.[20] Shifts in method performance over time may require batch-specific corrections or dropping or flagging data from certain batches. Notably, a trend in QC sample results over time can be problematic even if they remain within the acceptable limits established by the lab. In our own work, for example, examining our data by analytical batch revealed an upward trend in sample-specific detection limits for some analytes, such that detection limits in later batches were within the range of sample results from earlier batches (Fig. 1). The detection limits in the later batches still met the specifications of our contract with the lab, but it was clear that we would not be able to compare results in the latter two batches to those in the first three. We showed the plot in Fig. 1 to the lab and they agreed to re-analyze the samples in the later batches, which resulted in more consistent detection limits.\n\r\n\n\n\n\n\n\n\n\n\n\n Figure 1. Visualizing urine sample results by analytical batch (data not yet published) revealed that sample-specific detection limits in later batches were higher and in the range of sample results in previous batches. After discussing with the laboratory, samples in later batches were re-analyzed to achieve lower detection limits.\n\n\n\nIs the method accurate? \nSpiked samples and certified reference material \nTable 3 outlines our approach for analyzing LCS or matrix spike recovery or CRM data. The approach is similar for all of these samples. However, one distinction is that if LCS recovery and other QC measures, such as lab blanks (matrix, solvent method, or other) are acceptable, a poor matrix spike recovery (higher or lower than acceptable bounds) can alert chemists to interferences from matrix effects, suggesting steps to address this such as matrix-matched calibration.[17] We typically only use data for analytes that have average LCS, matrix spike and\/or CRM recoveries between 50 and 150%, though this decision criterion can be adjusted based on the needs of the project. If we do retain data for chemicals with spike or CRM recoveries outside of this acceptable range, we note in publications that concentrations in our data may be under- or over-reported.\n\n\n\n\n\n\n\nTable 3. Steps for spiked samples and certified reference material (see Additional file 4 for an example of this approach with real data)\n\n\n\n1. Summarize percent recoveries for each chemical across analytical batches and flag those chemicals with average recoveries outside of a pre-established acceptable range.\r\n\n\n\u25a1 We typically apply an acceptable range of 50\u2013150% recovery for most environmental samples, particularly when we are analyzing for new chemicals or combinations of chemicals for which methods are not well-established. For well-established methods, a more conservative range\u201480-120% recovery\u2014is appropriate.\r\n\n2. Visualize percent recoveries for each chemical across analytical batches to assess consistency.\r\n\n\n\u25a1 If recoveries for a particular chemical or chemicals are consistently out of range (>\u2009150% or\u2009<\u200950%) across multiple batches, this should be discussed with the laboratory analyst.\r\n\n\u25cb If the laboratory analyst agrees that the method was not successful, we drop the chemical(s) from our dataset. We do not report values or include such chemicals in any data analyses.\r\n\n\u25cb If the laboratory analyst can explain the reason for consistent high or low recoveries and has confidence in the ranking and relative values of the reported sample data, the reported values can be used for many data analyses, but it will be difficult to compare with levels from another study.\r\n<\/dd>\n\u25a1 If recoveries from one or a few batches are out of range, we are concerned that results in those batches might be over\/under-estimated compared to the rest. One way to investigate this concern is to look for corresponding systematic differences in sample data (see Additional file 4: Figure S3).\r\n\n\u25cb If field samples have been randomized into batches, we check if the variation in sample results correlates with spiked sample or CRM recoveries by batch. Note: we still go through this step even if we were not able to randomize field samples, but in this case it can be very challenging to distinguish systematic analytical variation from other possible sources of variation in sample results between batches (e.g., if samples in different batches were also collected during different seasons).\r\n\n\u25aa If there are systematic differences (e.g., the sample results for a chemical are higher in the batch where the spike or CRM recovery was high, or if only one batch, the sample results for a chemical with high spike or CRM recovery are much higher than previously reported levels), we consider dropping the chemical results from the affected batches from the dataset. If an identical\/split reference sample was analyzed in each batch, these results can also be helpful to resolve questions about whether and how to use the data in this case.\r\n\n\u25aa If there are no obvious systematic differences, we keep the chemical in our dataset, but flag the results for that chemical in the batch with the out-of-range spiked sample or CRM recovery.\r\n<\/dd><\/dd>\n3. In regards to reporting:\r\n\n\n\u25a1 We note in summary statistics when the average spiked sample or CRM recovery for a particular chemical was out of range.\r\n\n\u25a1 We note whether levels in our study might be systematically over- or under-reported (i.e., because of consistent high or low spiked sample or CRM recoveries). We especially note this if comparing to levels from another study.\r\n\n\u25a1 For chemicals with low\/high recoveries in certain batches, we may perform sensitivity analyses \u2013 for example, by including lab batch as a covariate in regression analyses, though this can be challenging for small datasets.\r\n\n\n\n\nFigure 2 illustrates a case from our own data where the laboratory reported that 1,2,5,6,9,10-Hexabromocyclododecane (HBCD), a brominated flame retardant, was mostly \u201cnot detected,\u201d but the LCS recoveries, which ranged from \u2212\u20092 to 1670% and averaged about 750%, indicated that the method was not able to accurately quantify this chemical. We removed this compound from our dataset and did not report on it. Examining spike recoveries thus prevents us from reporting a chemical as \u201cnot detected,\u201d or from reporting an unreliable detect, if the analytical method is not performing accurately for that compound.\n\r\n\n\n\n\n\n\n\n\n\n\n Figure 2. A. Results for flame retardant HBCD measured in air samples collected in 105 homes. All but three samples were non-detects (open circles). Samples were analyzed in six different analytical batches. B. Summary of laboratory control spike recovery data for HBCD across the six analytical batches shows very poor accuracy and indicates no confidence for this analyte in the indoor air samples.\n\n\n\nA summary of the recovery information should be included in the peer-reviewed manuscript to demonstrate accuracy. See Additional file 2: Tables S1-S2 and Figure S1 for an example of how to present this information.\n\nWere there problems with certain samples? \nSurrogate recovery standards \nWhen isotope dilution quantitation with automatic recovery correction is not employed, we review the surrogate recovery standard data for each individual sample, generally considering 50\u2013150% recovery to be acceptable. Interpretation of an out-of-range surrogate recovery depends both on its direction and on the levels of the associated analytes (i.e., those represented by the surrogate compound) measured in the sample. In samples with low surrogate recoveries, the concern is that if similar target analytes are present in the sample, the measurements will be underestimated\/biased low. For samples with high surrogate recoveries, on the other hand, we can be confident that similar target compounds should be detected if present, but the amount may be overestimated or biased high. If surrogate recoveries are out-of-range in all samples, and particularly if they are also out-of-range in blank samples, this is likely indicative of a broader problem with the analytical method.[16][29] Table 4 outlines our approach for analyzing surrogate recovery data.\n\n\n\n\n\n\n\nTable 4. Steps for surrogates (see Additional file 4 for an example of this approach with real data)\n\n\n\n1. Count high and low recoveries for each surrogate chemical across analytical batches.\n\n\u25a1 We typically apply an acceptable range of 50\u2013150% recovery for most environmental samples, particularly when we are analyzing for new chemicals or combinations of chemicals for which methods are not well-established. For well-established methods, a more conservative range\u201480-120% recovery\u2014would be appropriate.\n2. Identify any sample where all surrogate recoveries were low (e.g., <\u200950%). This suggests a potential problem with the extraction for that sample.\n\n\u25a1 Discuss with lab analyst. Consider dropping sample.\n3. Visualize surrogate recoveries for QC samples (lab blanks, lab control or matrix spikes) across analytical batches. See Additional file 4: Figure S4 for an example.\n\n\u25a1 If these recoveries are out of range, this suggests a larger problem with the analytical method rather than with particular samples. Summarize information about the surrogate recoveries in the QC samples as well as lab control or matrix spike recoveries for the associated chemicals and discuss with lab analyst.\n4. Visualize percent recoveries across all samples for each surrogate, by analytical batch. See Additional file 4: Figure S6 for an example.\n\n\u25a1 Note any trends (upward or downward) in the distribution of surrogate recoveries across batches. Such trends should be discussed with the laboratory analyst, even if all recoveries are in the 50\u2013150% acceptable range (see Fig. 3 for an example).\n\u25a1 If the surrogate is a deuterated version of one of the target chemicals, it can be helpful to compare a plot of the surrogate recoveries by batch to the sample data for the corresponding un-deuterated target chemical by batch. We would be concerned \u2013 and would seek guidance from the lab analyst \u2013 if we saw a trend for the target chemical results that matched the trend in the surrogate recoveries.\n\u25a1 Note if many surrogate recoveries (e.g., more than half) are out of range in a particular lab batch. If yes, flag the results in that batch for the chemical(s) represented by that surrogate.\n5. Visualize sample results flagged by surrogate recoveries. For each individual sample with an out-of-range recovery for a surrogate, flag the results for the chemical(s) associated with that surrogate. Plot all sample data with indicators (e.g., different colors) for whether the representative surrogate for each sample was out of range. See Additional file 4: Figure S7A-D for an example.\n\n\u25a1 Note whether samples with high surrogate recoveries consistently have the highest results for the associated chemical(s).\n\u25cb If yes, we would be concerned that samples with high recoveries are all overestimated. Discuss with lab analyst. Consider applying a surrogate correction factor to sample results (multiplying by 1\/fraction recovery).<\/dd>\n\u25a1 Note whether samples with low surrogate recoveries were consistently non-detects or very low-level detects for the associated chemical(s).\n\u25cb If yes, we would be concerned that samples with low recoveries are all underestimated. Discuss with lab analyst. Note in publications that levels and detection frequencies for associated chemicals might be underestimated.<\/dd>\n6. In regards to reporting:\n\n\u25a1 In summary statistics, we note whether any maximum value is from a sample associated with a high (>\u2009150%) surrogate recovery and note that in this case the maximum might be overestimated. Similarly, if 100% of samples are detects, we also flag the minimum value if it is from a sample associated with a low (<\u200950%) recovery and note that in this case the minimum might be underestimated.\n\u25a1 For any statistical analyses, if possible (i.e., if large enough dataset) we run sensitivity analyses:\n\u25cb Excluding samples with out-of-range surrogate recoveries.\n\u25cb Controlling for lab batch, if surrogates were problematic for a particular batch.<\/dd>\n\n\n\nFigure 3 shows an example where our examination of surrogate recoveries on a batch-specific basis indicated trends in the recoveries over time, even though most remained within the generally acceptable range (50\u2013150%). This plot led to a discussion with the lab analyst, who suggested that stock solutions for surrogate compounds may have concentrated over time as solvent evaporated, until a new stock solution was prepared for the last batch. On the advice of the lab analyst, we looked at trends in the \u201cspike check\u201d\u2014solvent that is spiked with target analytes but not extracted or concentrated\u2014sample recoveries. Spike check recoveries indicated good reproducibility, giving us confidence that the drift in surrogate recoveries did not reflect changes in instrument calibration over time.\n\r\n\n\n\n\n\n\n\n\n\n\n Figure 3. In this example from our data, recoveries of surrogate d4-di-n-butyl-phthalate from air samples showed notable upward and downward trends over time, despite largely staying within the 50\u2013150% acceptable bounds. Here we were examining surrogate recoveries in batches of samples from different studies analyzed at the same laboratory. The last two batches (Sept 2014 and May 2015) were from the same study but collected approximately a year apart per the study design.\n\n\n\nIs there evidence of contamination or analytical bias? \nBlanks \nOnce we have determined that we can accurately measure the target analytes in our sampling matrix, the next step is to ensure that we are confident about whether those target analytes came from the study site or participant\u2014or from somewhere else. Table 5 outlines our approach to reviewing data from blank samples. When it is not straight forward to collect field blanks (e.g., for blood samples), any assessment of contamination introduced from sampling (e.g., pre-screening of collection materials) should be thoroughly described and limitations acknowledged.\n\n\n\n\n\n\n\nTable 5. Steps for blanks (see Additional file 4 for an example of this approach with real data)\n\n\n\n1. Summarize results across all chemicals by blank type (e.g., field blank, solvent method blank, matrix blank, etc.), with non-detects set to zero. For chemicals with no detects in blanks, the MRL will equal the lab reporting limit and none of the subsequent steps in Tables 6 or 7 are needed.\r\n \r\n\nFor chemicals detected in blanks:\r\n \r\n\n2. Visualize levels in blanks by blank type. Set non-detects to \u00bd lab reporting limit and plot by analytical batch.\r\n\n\n\u25a1 Consider whether blank detects are consistent across batches. Note whether detects seem to occur mostly in one type of blank which could indicate a source of contamination in the lab or field.\r\n\n\u25cb If a particular source is suspected, we investigate (talk to lab, look at field logs, etc.).\r\n<\/dd>\n3. Visualize levels in blanks by blank type along with field samples by analytical batch. Set non-detects to \u00bd lab reporting limit.\r\n\n\n\u25a1 Note whether blanks are in range of the samples.\r\n\n\u25a1 If field samples have been randomized into batches, check if variation in sample results correlates with blank results by batch. Note: we still go through this step even when we were not able to randomize field samples, but it is more challenging to distinguish whether contamination is driving differences in sample results in a particular batch or whether other explanations are more likely (e.g., all samples in one batch were collected in a different season or from a particular study site).\n\n\n\nFigure 4 illustrates an example from our study comparing levels of chemicals in air in college dorm rooms before and after students moved in (data not yet published) where field blanks proved particularly crucial. Our first look at the sample data suggested that bis(2-ethylhexyl) phthalate (DEHP), a chemical commonly used in plastics, was present at notably higher levels after students moved in. However, upon further review, we found that DEHP levels in the field blanks were also higher and in the range of the sample data at the post- compared to pre-occupancy time point. At the same time, levels of DEHP in the laboratory blanks (matrix and solvent method) were not elevated. A conversation with the lab revealed that different plastic bags may have been used to transport samples during the later round of sampling (i.e., the post-occupancy sampling). These bags may have contained higher levels of DEHP.\n\r\n\n\n\n\n\n\n\n\n\n\n Figure 4. Phthalate DEHP measured in air in college dorm rooms before and after occupancy (data not yet published). Levels in our samples (purple dots) were higher post- compared to pre-occupancy, but this plot revealed that levels in field blanks (blue dots) were also higher post- compared to pre-occupancy and within the range of field samples. We also saw a matrix blank (green dot) well within the range of the field samples in the pre-occupancy batch. These data suggest DEHP contamination in both batches; for the post-occupancy batch, we hypothesized this might have come from the plastic bags in which the samplers were shipped. We will not report results for this chemical from this study, given the evidence of contamination. LLOQ\u2009=\u2009Lower Limit of Quantitation.\n\n\n\nTypically, we use blanks to qualify values rather than remove measurements from our data. Specifically, we use detected values in field blanks and sometimes other blanks (see Table 6) as a basis to qualify data by raising the method reporting limit (MRL), flagging low values as estimated, until we feel confident in the levels we\u2019re reporting. Values reported by the lab but below the MRL are considered estimated (see Fig. 5 for an example of graphical presentation distinguishing estimated detects below the MRL from true detects above the MRL). In the example of the potentially DEHP-contaminated plastic bags used to transport samples, however, we decided not to report DEHP levels for the post-occupancy samples, given the evidence that contamination might have significantly biased the results in that batch. Unexpected findings, such as a chemical or chemicals detected at much higher levels in a lab blank (matrix, solvent method, or other) than in the field blanks, warrant further investigation. In this case, we might suspect that the lab blank was contaminated by another sample; examining the sample run order (which must be requested from the lab; see example correspondence in Additional file 2) could shed light on whether a very high sample was run directly before the lab blank.\n\r\n\n\n\n\n\n\n\n\n\n\n Figure 5. Example of graphical presentation distinguishing true, estimated, and non-detects. MRL\u2009=\u2009Method Reporting Limit.\n\n\n\n\n\n\n\n\n\nTable 6. Steps for the consideration of raising method reporting limits (MRLs) (see Additional file 4 for an example of this approach with real data)\n\n\n\n1A. For chemicals not detected in blanks, the MRL is equal to the laboratory reporting limit.\r\n\n1B. For each chemical detected in blanks, if there are detects in blanks in all batches, establish the MRL as follows (otherwise proceed to 1C):\r\n\n\n\u25a1 Compare the lab\u2019s reporting limit to the 90th percentile of field blanks (computed with non-detects set to \u00bd lab\u2019s reporting limit). The higher value is the new MRL.\r\n\n\u25cb However, if we observe many detects in other types of blanks (e.g., matrix, solvent), we consider determining the MRL by comparing the lab\u2019s reporting limit to the 90th percentile of ALL blanks (computed with non-detects set to \u00bd lab\u2019s reporting limit). The higher value is the new MRL.\r\n\n\u25cb It can be helpful here to plot sample data with different possible MRLs to gain understanding of precisely what is being achieved by raising the MRL (i.e., are we successfully flagging data that we are not confident in and at the same time leaving data in which we have confidence unqualified?). See Additional file 4: Figure S9, for an example of this type of plot.\r\n<\/dd>\n\u25a1 Note: We use the 90th percentile of the blanks rather than using the maximum value or the mean because the 90th percentile is less sensitive to extreme values and can be estimated for data that are not normally distributed. However if the overall study is small (e.g., in our practice, when we have <\u20095 blanks), we set the MRL equal to the maximum blank mass.\r\n\n1C. For each chemical detected in blanks, if detects in blanks are clustered in one or a few batches:\r\n\n\n\u25a1 If just one extremely problematic batch, consider dropping the sample data from that batch.\r\n\n\u25a1 If multiple field blanks were run in each batch, can consider determining MRL as above but on a batch-specific basis.\r\n\n\u25cb In this case, the way to proceed will very much be a judgment call. Spend time with the data considering various approaches.\r\n<\/dd>\n\u25a1 Data from reference material and duplicate samples can be helpful in deciding which data points should be qualified because they are \u201cin the noise.\u201d\r\n\n2. After determining the MRL, we flag each sample result as follows:\r\n\n\n\u25a1 0 flag\u2009=\u2009measurement reported by the lab as \u201cnon-detect\u201d\r\n\n\u25a1 0.5 flag\u2009=\u2009measurement falls below the MRL. These are considered \u201cestimated detects\u201d\r\n\n\u25a1 1 flag\u2009=\u2009measurement falls above the MRL. These are considered \u201ctrue detects\u201d\r\n\n\u25a1 Note that our data qualifier flags may differ from those used by others. For example, NHANES flags non-detects with a \u201c1\u201d and detects with a \u201c0.\u201d\r\n\n3. Normalize MRL.\r\n\n\n\u25a1 If the MRL is determined on a mass basis but sample results are normalized by some factor, such as sample volume, we compute a sample-specific concentration-based MRL by dividing the mass-based MRL by the sample volume.\r\n\n4. In regards to reporting:\r\n\n\n\u25a1 We do not count estimated values (0.5 flags) as detects when reporting %\u2009>\u2009MRL. We do not use estimated detects to calculate summary statistics such as percentiles (see Table shell S2 in Additional file 2).\r\n\n\u25a1 In summary statistics, we identify any chemicals with greater than 50% estimated detects and add a footnote: \u201cImprecise quantification for more than 50% of detected values.\u201d\r\n\n\u25a1 Graphical presentations should distinguish estimated from true detects (e.g., by plotting as different shapes, see Fig. 5).\r\n\n\u25a1 For reporting in tables, we use median sample volume across samples to convert mass-based MRL to a single concentration-based MRL for each chemical, if applicable.\r\n\n\u25a1 There are different approaches for incorporating estimated or 0.5 flagged values in statistical analyses, including performing analyses weighted by estimates of the measurement precision below the MRL, or using censored regression methods.[23] However any approach that incorporates estimated values is preferable to procedures that substitute with the DL, \u00bd DL, zero, or remove these values, a practice which can introduce bias.[25]\n\n\n\nAfter we establish the MRL for chemicals that are detected in blanks, we are confident that levels in samples above that value are true detects and that they are correctly ranked, but there may still be concern about consistent bias in the actual numeric values being reported, both from contamination in the field or lab or from bias in the analytical method. Consistent bias in levels would not be a major concern for ranking individual exposure or comparing groups within a study but is misleading when comparing to levels reported in other studies. For each chemical, we check for evidence of consistent bias across many blanks and correct concentrations reported in summary tables in our papers to reduce this bias (see Table 7).\n\n\n\n\n\n\n\nTable 7. Steps for blank correction (see Additional file 4 for an example of this approach with real data)\n\n\n\n1. Which blanks to use?\r\n\n\n\u25a1 If detects are spread across all types of blanks (e.g., field, solvent method, matrix), we use all blanks for blank correction. Otherwise we use field blanks. We try to keep our blank correction approach consistent with our MRL approach.\r\n\n2. Which chemicals get corrected?\r\n\n\n\u25a1 If\u2009>\u20095 blanks:\r\n\n\u25cb For each chemical, we use a one-sided one sample sign test (special case of binomial test with p\u2009=\u20090.5) to determine whether the median of blanks is statistically significantly different from zero. True and estimated detects are treated as positive values and non-detects as negative values.\r\n\n\u25aa We blank-correct chemicals with a sign test p-value <\u20090.05.\r\n\n\u25aa However, if the number of blanks is relatively small (10 or fewer) we consider blank correction even when the sign test does not produce a significant result. The sign test does not take into account the magnitude of the levels detected in the blanks nor does it distinguish different types of blanks (i.e., field and lab).\r\n\n\u2022 For example, if we have 3 field blanks and 4 lab blanks, and we see consistent levels detected across all field blanks and all but one lab blank, we would consider blank correcting even though the sign test would produce p\u2009>\u20090.05.\r\n<\/dd><\/dd>\n\u25a1 If\u2009\u2264\u20095 blanks (i.e., for a small dataset):\r\n\n\u25cb With five or fewer blanks, the sign test will never be significant. In this case, we blank-correct chemicals with 100% detects in blanks.\r\n<\/dd>\n3. Blank correction:\r\n\n\n\u25a1 Calculate the median value of the blanks, with non-detects set to \u00bd lab\u2019s reporting limit and using all values (i.e., estimated and true detects).\r\n\n\u25cb It is useful to pause here and assess the value being used for blank correction. Is it based on an estimated value below the MRL? What will be the percent change in the median, comparing the original to the blank-corrected data?\r\n<\/dd>\n\u25a1 Subtract median blank value from all sample results.\r\n\n\u25a1 Subtract median blank value from the MRL (determined as in Table 6).\r\n\n4. In regards to reporting:\r\n\n\n\u25a1 We are explicit about whatever procedure we use to decide whether or not to perform blank correction (sign test or other) and about the statistic (e.g., median, mean) and amount used for correction.\r\n\n\u25a1 Any presentation of measurements (e.g., summary statistics) should use blank-corrected values because they may be compared with measurements in other studies.\r\n\n\u25a1 For statistical analyses such as regression and correlation performed within the dataset, non-blank-corrected data can be used.\n\n\n\nHow precise are these measurements? \nDuplicates \nDuplicate samples indicate whether variation in our data is explained by imprecision. If duplicate samples have high reproducibility, meaning that the relative percent difference between measurements in duplicate samples is less than 30%, it adds to confidence in the field sample results. In fact, excellent precision in duplicate samples can influence a decision about how to treat data for a chemical that has sporadic blank contamination or variable spiked sample or CRM recoveries because it can indicate that the results are reproducible. On the other hand, consistently poor precision for dust wipe samples, for example, has informed our decision to rely more heavily on measured air concentrations as an indicator of home exposure.[30] Table 8 outlines our approach for analyzing duplicate data.\n\n\n\n\n\n\n\nTable 8. Steps for duplicates (see Additional file 4 for an example of this approach with real data)\n\n\n\n1. Compute precision.\r\n\n\n\u25a1 Compute & summarize average relative percent difference (RPD) for duplicate pairs or, if \u22653 side-by-side samples, compute relative standard deviation (RSD):\r\n\n\u25cb If sample results have been normalized (e.g., mass converted to concentration), compute precision with normalized values.\r\n\n\u25cb Compute only for pairs where both samples are detects.\r\n\n\u25cb Also consider precision restricted to pairs where both samples are flagged as \u201ctrue detects\u201d above the MRL.\r\n<\/dd>\n2. Visualize duplicate pairs.\r\n\n\n\u25a1 This is a good point to pause and check your data and to note\/investigate anything that looks unusual (e.g., huge difference in results for two members of a duplicate pair, how tight are detect\/non-detect pairs). See Additional file 4: Figure S10A-D for an example.\r\n\n3. Average duplicates, with non-detects set to lab\u2019s reporting limit.\r\n\n\n\u25a1 Calculate average volume and concentration for each pair. Note, can skip this step if only have mass data, or if results were reported by lab as concentrations, rather than as masses that were then normalized to concentrations.\r\n\n\u25a1 Back calculate new average mass using average volume and average concentration. Or, simply average the duplicate measurements if only have mass data, or if results were reported by lab as concentrations, rather than as masses that were then normalized to concentrations.\r\n\n\u25a1 Compare new average measurement to MRL to determine data qualifier flag.\r\n\n\u25a1 Combine duplicate averages back with rest of data.\r\n\n4. In regards to reporting:\r\n\n\n\u25a1 In publications, we note the range of average RPDs across all chemicals in our QA\/QC discussion. We consider average RPD\u2009<\u200930% to be \u201cgood\u201d precision.\r\n\n\u25a1 If a chemical has sporadic blank contamination or variable spike recoveries, excellent precision can increase our confidence in the field sample results.\n\n\n\nPublication: How do we tell others about our data? \nWhile it is imperative that a researcher has a thorough understanding of the quality of their own data, it is equally important they clearly communicate the results of the QA\/QC review. When we considered the articles included in our recent review of epidemiologic studies of environmental chemicals and breast cancer[11], we identified gaps in reporting and\/or interpretation of QA\/QC data, an issue also noted by LaKind et al..[12] To encourage more regular and consistent reporting of QA\/QC results, in supplementary material we provide examples of the tables and plots (Additional file 2: Tables S3, S4, and Figure S1) we have used to communicate QA\/QC findings in our publications. Consistently publishing QA\/QC findings allows readers to think for themselves about the quality of the data and can inform risk of bias assessments in a systematic review. QA\/QC data also provides a basis for determining whether further analyses of the published data (e.g., comparisons to or pooling with other datasets) are appropriate.\n\nConclusion \nSeveral real examples from our data demonstrate that close examination of lab and field quality control data is worth the effort. By providing a detailed example of how we have processed and drawn conclusions about our own environmental exposure data (Additional file 4), we aim to make our guidelines explicit and straightforward so that others may adopt and build on them.\n\nAbbreviations \nCAS: Chemical Abstracts Service\nCDC: Centers for Disease Control and Prevention\nCRM: Certified reference material\nCRQL: Contract required quantitation limit\nDEHP: Bis(2-ethylhexyl) phthalate\nDL: Detection limit\nEPA: United States Environmental Protection Agency\nHBCD: 1,2,5,6,9,10-Hexabromocyclododecane\nLCS: Laboratory control sample\nLOD: Limit of detection\nLOQ: Limit of quantitation\nLQL: Laboratory quantitation level\nMDL: Method detection limit\nMRL: Method reporting limit\nNIST: National Institute of Standards and Technology\nPQL: Practical quantitation limit\nPUF: Polyurethane foam\nQA\/QC: Quality assurance\/quality control\nQC: Quality control\nRL: Reporting limit\nRPD: Relative percent difference\nRSD: Relative standard deviation\nSRM: Standard reference material\n\nSupplementary information \n Additional file 1: Table S1. Summary of our application of the Navigation Guide Criteria for Low Risk of Bias Assessment for the question \"Were exposure assessment methods robust?\"\n Additional file 2: Section I: Example lab correspondence. Section II: Table S2. Summary statistics table shell. Table S3. Quality assurance and quality control (QA\/QC) summary table shell. Table S4. Findings and actions from review of quality assurance and quality control (QA\/QC) data table shell. Section III: Figure S1. Distribution of surrogate recoveries by study visit\n Additional file 3: Example of report formatting request to send to the lab\n Additional file 4: Example QA\/QC report\nAcknowledgements \nWe thank David Camann, Alice Yau, Marcia Nishioka, Martha McCauley, and Adrian Covaci for helping us make thoughtful decisions about how to interpret our data. We also thank Vincent Bessonneau for helpful discussion and for his valuable comments on a draft of this manuscript. Silent Spring Institute is a scientific research organization dedicated to studying environmental factors in women\u2019s health.\n\nContributions \nRAR, RED, and LP developed the detailed data processing approach provided as an example in this manuscript. JU drafted the manuscript. RAR, RED, and LP critically reviewed and revised the manuscript. All authors read and approved the final manuscript.\n\nFunding \nThis work was funded by the U.S. Department of Housing and Urban Development (Grant No. MAHHU0005\u201312) and by charitable gifts to Silent Spring Institute.\n\nCompeting interests \nThe authors declare that they have no competing interests.\n\nReferences \n\n\n\u2191 Wild, C.P. (2005). \"Complementing the genome with an \"exposome\": the outstanding challenge of environmental exposure measurement in molecular epidemiology\". Cancer Epidemiology, Biomarkers & Preventions 14 (8): 1847\u201350. doi:10.1158\/1055-9965.EPI-05-0456. PMID 16103423.   \n\n\u2191 Carlin, D.J.; Rider, C.V.; Woychik, R. et al. (2013). \"Unraveling the health effects of environmental mixtures: An NIEHS priority\". Environmental Health Perspectives 121 (1): A6\u20138. doi:10.1289\/ehp.1206182. PMC PMC3553446. PMID 23409283. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3553446 .   \n\n\u2191 U.S. Environmental Protection Agency (March 2019). \"Quality Assurance Handbook and Guidance Documents for Citizen Science Projects\". U.S. Environmental Protection Agency. https:\/\/www.epa.gov\/citizen-science\/quality-assurance-handbook-and-guidance-documents-citizen-science-projects . Retrieved 28 May 2019 .   \n\n\u2191 4.0 4.1 4.2 Centers for Disease Control and Preventions (March 2018). \"Improving the Collection and Management of Human Samples Used for Measuring Environmental Chemicals and Nutrition Indicators\" (PDF). Centers for Disease Control and Prevention. https:\/\/www.cdc.gov\/biomonitoring\/pdf\/Human_Sample_Collection-508.pdf . Retrieved 28 May 2019 .   \n\n\u2191 5.0 5.1 LaKind, J.S.; Sobus, J.R.; Goodman, M. et al. (2014). \"A proposal for assessing study quality: Biomonitoring, Environmental Epidemiology, and Short-lived Chemicals (BEES-C) instrument\". Environment International 73: 195\u2013207. doi:10.1016\/j.envint.2014.07.011. PMC PMC4310547. PMID 25137624. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4310547 .   \n\n\u2191 6.0 6.1 LaKind, J.S.; O'Mahony, C.; Armstrong, T. et al. (2019). \"ExpoQual: Evaluating measured and modeled human exposure data\". Environmental Research 171: 302-312. doi:10.1016\/j.envres.2019.01.039. PMID 30708234.   \n\n\u2191 Campbell, J.L.; Rustad, L.E.; Porter, J.H. et al. (2013). \"Quantity is Nothing without Quality: Automated QA\/QC for Streaming Environmental Sensor Data\". BioScience 63 (7): 574\u2013585. doi:10.1525\/bio.2013.63.7.10.   \n\n\u2191 Michener, W.K. (2015). \"Ten Simple Rules for Creating a Good Data Management Plan\". PLoS Computational Biology 11 (10): e1004525. doi:10.1371\/journal.pcbi.1004525. PMC PMC4619636. PMID 26492633. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4619636 .   \n\n\u2191 9.0 9.1 9.2 Calafat, A.M.; Longnecker, M.P.; Koch, H.M. et al. (2015). \"Optimal Exposure Biomarkers for Nonpersistent Chemicals in Environmental Epidemiology\". Environmental Health Perspectives 123 (7): A166\u20138. doi:10.1289\/ehp.1510041. PMC PMC4492274. PMID 26132373. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4492274 .   \n\n\u2191 Lam, J.; Koustas, E.; Sutton, P. et al. (2014). \"The Navigation Guide - Evidence-based medicine meets environmental health: Integration of animal and human evidence for PFOA effects on fetal growth\". Environmental Health Perspectives 122 (10): 1040-51. doi:10.1289\/ehp.1307923. PMC PMC4181930. PMID 24968389. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4181930 .   \n\n\u2191 11.0 11.1 Rodgers, K.M.; Udesky, J.O.; Rudel, R.A. et al. (2018). \"Environmental chemicals and breast cancer: An updated review of epidemiological literature informed by biological mechanisms\". Environmental Research 160: 152\u201382. doi:10.1016\/j.envres.2017.08.045. PMID 28987728.   \n\n\u2191 12.0 12.1 LaKind, J.S.; Goodman, M.; Barr, D.B. et al. (2015). \"Lessons learned from the application of BEES-C: Systematic assessment of study quality of epidemiologic research on BPA, neurodevelopment, and respiratory health\". Environment International 80: 41\u201371. doi:10.1016\/j.envint.2015.03.015. PMID 25884849.   \n\n\u2191 Rudel, R.A.; Dodson, R.E.; Perovich, L.J. et al. (2010). \"Semivolatile endocrine-disrupting compounds in paired indoor and outdoor air in two northern California communities\". Environmental Science & Technology 44 (17): 6583-90. doi:10.1021\/es100159c. PMC PMC2930400. PMID 20681565. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2930400 .   \n\n\u2191 14.0 14.1 Wentworth, N. (28 September 2001). \"Review of Guidance on Data Quality Indicators (EPA QA\/G-5i)\" (PDF). U.S. Environmental Protection Agency. http:\/\/colowqforum.org\/pdfs\/whole-effluent-toxicity\/documents\/g5i-prd.pdf . Retrieved 28 May 2019 .   \n\n\u2191 U.S. Environmental Protection Agency (December 1994). \"Laboratory Data Validation Functional Guidelines For Evaluating Organics Analyses\". U.S. Environmental Protection Agency. https:\/\/nepis.epa.gov\/Exe\/ZyPURL.cgi?Dockey=20012TGE.TXT . Retrieved 28 May 2019 .   \n\n\u2191 16.0 16.1 16.2 U.S. Army Corps of Engineers (30 June 2005). \"Guidance for Evaluating Performance-Based Chemical Data\" (PDF). U.S. Army Corps of Engineers. https:\/\/www.publications.usace.army.mil\/Portals\/76\/Publications\/EngineerManuals\/EM_200-1-10.pdf?ver=2013-09-04-070852-230 . Retrieved 28 May 2019 .   \n\n\u2191 17.0 17.1 17.2 Geboy, N.J.; Engle, M.A. (07 September 2011). \"Quality Assurance and Quality Control of Geochemical Data: A Primer for the Research Scientist\". Open-File Report 2011\u20131187. U.S. Geological Survey. https:\/\/pubs.usgs.gov\/of\/2011\/1187\/ . Retrieved 28 May 2019 .   \n\n\u2191 NIST (19 June 2014). \"NIST Standard Reference Database 1A v17\". https:\/\/www.nist.gov\/srd\/nist-standard-reference-database-1a-v17 . Retrieved 28 May 2019 .   \n\n\u2191 Ulrich, E.M.; Sobus, J.R.; Grulke, C.M. et al. (2019). \"EPA's non-targeted analysis collaborative trial (ENTACT): Genesis, design, and initial findings\". Analytical and Bioanalytical Chemistry 411 (4): 853\u201366. doi:10.1007\/s00216-018-1435-6. PMID 30519961.   \n\n\u2191 20.0 20.1 L\u00f6tsch, J. (2017). \"Data visualizations to detect systematic errors in laboratory assay results\". Pharmacology Research & Perspectives 5 (6): e00369. doi:10.1002\/prp2.369. PMC PMC5723702. PMID 29226627. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5723702 .   \n\n\u2191 Dodson, R.E.; Camann, D.E.; Morello-Frosch, R. et al. (2015). \"Semivolatile organic compounds in homes: Strategies for efficient and systematic exposure measurement based on empirical and theoretical factors\". Environmental Science & Technology 49 (1): 113-22. doi:10.1021\/es502988r. PMC PMC4288060. PMID 25488487. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4288060 .   \n\n\u2191 22.0 22.1 U.S. Environmental Protection Agency (December 2015). \"Method 8000D: Determinative Chromatographic Separations\" (PDF). U.S. Environmental Protection Agency. https:\/\/www.epa.gov\/sites\/production\/files\/2015-12\/documents\/8000d.pdf . Retrieved 16 August 2019 .   \n\n\u2191 23.0 23.1 Helsel, D.R. (2012). Statistics for Censored Environmental Data Using Minitab and R (2nd ed.). Wiley. ISBN 9780470479889.   \n\n\u2191 Helsel, D. (2010). \"Much ado about next to nothing: Incorporating nondetects in science\". Annals of Occupational Hygiene 54 (3): 257-62. doi:10.1093\/annhyg\/mep092. PMID 20032004.   \n\n\u2191 25.0 25.1 Newton, E.; Rudel, R. (2007). \"Estimating correlation with multiply censored data arising from the adjustment of singly censored data\". Environmental Science & Technology 41 (1): 221\u20138. doi:10.1021\/es0608444. PMC PMC2565512. PMID 17265951. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2565512 .   \n\n\u2191 Shoari, N.; Dub\u00e9, J.S. (2018). \"Toward improved analysis of concentration data: Embracing nondetects\". Environmental Toxicology and Chemistry 37 (3): 643-656. doi:10.1002\/etc.4046. PMID 29168890.   \n\n\u2191 NIST. \"SRM Order Request System\". https:\/\/www-s.nist.gov\/srmors\/ . Retrieved 28 May 2019 .   \n\n\u2191 Silent Spring Institute. \"SilentSpringInstitute\/QAQC-Toolkit\". GitHub. https:\/\/github.com\/SilentSpringInstitute\/QAQC-Toolkit . Retrieved 28 May 2019 .   \n\n\u2191 Dawson, B.J.M.; Bennett V, G.L.; Belitz, K. (2008). \"Ground-Water Quality Data in the Southern Sacramento Valley, California, 2005\u2014Results from the California GAMA Program\" (PDF). U.S. Geological Survey. https:\/\/pubs.usgs.gov\/ds\/285\/ds285.pdf . Retrieved 28 May 2019 .   \n\n\u2191 Dodson, R.E.; Udesky, J.O.; Colton, M.D. et al. (2017). \"Chemical exposures in recently renovated low-income housing: Influence of building materials and occupant activities\". Environmental International 109: 114\u201427. doi:10.1016\/j.envint.2017.07.007. PMID 28916131.   \n\n\nNotes \nThis presentation is faithful to the original, with only a few minor changes to presentation, spelling, and grammar. We also added PMCID and DOI when they were missing from the original reference.\n\n\n\n\n\n\nSource: <a rel=\"external_link\" class=\"external\" href=\"https:\/\/www.limswiki.org\/index.php\/Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements\">https:\/\/www.limswiki.org\/index.php\/Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements<\/a>\n\t\t\t\t\tCategories: LIMSwiki journal articles (added in 2020)LIMSwiki journal articles (all)LIMSwiki journal articles on data qualityLIMSwiki journal articles on data visualizationLIMSwiki journal articles on environmental scienceLIMSwiki journal articles on reporting\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\n\t\t\t\t\n\t\t\t\n\t\t\n\t\t\n\t\t\tNavigation menu\n\t\t\t\t\t\n\t\t\tViews\n\n\t\t\t\n\t\t\t\t\n\t\t\t\tJournal\n\t\t\t\tDiscussion\n\t\t\t\tView source\n\t\t\t\tHistory\n\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\n\t\t\t\t\n\t\t\t\tPersonal tools\n\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\t\t\tLog in\n\t\t\t\t\t\t\t\t\t\t\t\t\tRequest account\n\t\t\t\t\t\t\t\t\t\t\t\n\t\t\t\t\n\t\t\t\n\t\t\t\n\t\t\t\t\n\t\t\t\n\t\t\t\t\n\t\tNavigation\n\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\tMain page\n\t\t\t\t\t\t\t\t\t\t\tRecent changes\n\t\t\t\t\t\t\t\t\t\t\tRandom page\n\t\t\t\t\t\t\t\t\t\t\tHelp\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\n\t\t\t\n\t\t\tSearch\n\n\t\t\t\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t \n\t\t\t\t\t\t\n\t\t\t\t\n\n\t\t\t\t\t\t\t\n\t\t\n\t\t\t\n\t\t\tTools\n\n\t\t\t\n\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\tWhat links here\n\t\t\t\t\t\t\t\t\t\t\tRelated changes\n\t\t\t\t\t\t\t\t\t\t\tSpecial pages\n\t\t\t\t\t\t\t\t\t\t\tPermanent link\n\t\t\t\t\t\t\t\t\t\t\tPage information\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\n\t\t\n\t\tPrint\/export\n\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\tCreate a book\n\t\t\t\t\t\t\t\t\t\t\tDownload as PDF\n\t\t\t\t\t\t\t\t\t\t\tDownload as Plain text\n\t\t\t\t\t\t\t\t\t\t\tPrintable version\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\n\t\t\n\t\tSponsors\n\t\t\n\t\t\t \r\n\n\t\r\n\n\t\r\n\n\t\n\t\r\n\n\t\r\n\n\t\n\t\r\n\n \n\t\r\n\n\t\n\t\r\n\n \n\t\n\t\r\n\n\t\n\t\n\t\r\n\n\t\r\n\n\t\r\n\n\t\n\t\r\n\n\t\r\n\t\t\n\t\t\n\t\t\t\n\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t This page was last modified on 14 April 2020, at 01:25.\n\t\t\t\t\t\t\t\t\tThis page has been accessed 5,459 times.\n\t\t\t\t\t\t\t\t\tContent is available under a Creative Commons Attribution-ShareAlike 4.0 International License unless otherwise noted.\n\t\t\t\t\t\t\t\t\tPrivacy policy\n\t\t\t\t\t\t\t\t\tAbout LIMSWiki\n\t\t\t\t\t\t\t\t\tDisclaimers\n\t\t\t\t\t\t\t\n\t\t\n\t\t\n\t\t\n\n","1b738084b45b445282479ac65a72296b_html":"<body class=\"mediawiki ltr sitedir-ltr ns-206 ns-subject page-Journal_Wrangling_environmental_exposure_data_Guidance_for_getting_the_best_information_from_your_laboratory_measurements skin-monobook action-view\">\n<div id=\"rdp-ebb-globalWrapper\">\n\t\t<div id=\"rdp-ebb-column-content\">\n\t\t\t<div id=\"rdp-ebb-content\" class=\"mw-body\" role=\"main\">\n\t\t\t\t<a id=\"rdp-ebb-top\"><\/a>\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t<h1 id=\"rdp-ebb-firstHeading\" class=\"firstHeading\" lang=\"en\">Journal:Wrangling environmental exposure data: Guidance for getting the best information from your laboratory measurements<\/h1>\n\t\t\t\t\n\t\t\t\t<div id=\"rdp-ebb-bodyContent\" class=\"mw-body-content\">\n\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\n\n\t\t\t\t\t<!-- start content -->\n\t\t\t\t\t<div id=\"rdp-ebb-mw-content-text\" lang=\"en\" dir=\"ltr\" class=\"mw-content-ltr\">\n\n\n<h2><span class=\"mw-headline\" id=\"Abstract\">Abstract<\/span><\/h2>\n<p><b>Background<\/b>: <a href=\"https:\/\/www.limswiki.org\/index.php\/Environmental_health\" title=\"Environmental health\" class=\"wiki-link\" data-key=\"b2ad96ed483dfe210a96cc4e44bcdee7\">Environmental health<\/a> and exposure researchers can improve the quality and interpretation of their chemical measurement data, avoid spurious results, and improve analytical protocols for new chemicals by closely examining lab and field <a href=\"https:\/\/www.limswiki.org\/index.php\/Quality_control\" title=\"Quality control\" class=\"wiki-link\" data-key=\"1e0e0c2eb3e45aff02f5d61799821f0f\">quality control<\/a> (QC) data. Reporting QC data along with chemical measurements in biological and environmental <a href=\"https:\/\/www.limswiki.org\/index.php\/Sample_(material)\" title=\"Sample (material)\" class=\"wiki-link\" data-key=\"7f8cd41a077a88d02370c02a3ba3d9d6\">samples<\/a> allows readers to evaluate data quality and appropriate uses of the data (e.g., for comparison to other exposure studies, association with health outcomes, use in regulatory decision-making). However many studies do not adequately describe or interpret QC assessments in publications, leaving readers uncertain about the level of confidence in the reported data. One potential barrier to both QC implementation and reporting is that guidance on how to integrate and interpret QC assessments is often fragmented and difficult to find, with no centralized repository or summary. In addition, existing documents are typically written for regulatory scientists rather than environmental health researchers, who may have little or no experience in analytical chemistry.\n<\/p><p><b>Objectives<\/b>: We discuss approaches for implementing <a href=\"https:\/\/www.limswiki.org\/index.php\/Quality_assurance\" title=\"Quality assurance\" class=\"wiki-link\" data-key=\"2ede4490f0ea707b14456f44439c0984\">quality assurance<\/a>\/quality control (QA\/QC) in environmental exposure measurement projects and describe our process for interpreting QC results and drawing conclusions about data validity.\n<\/p><p><b>Discussion<\/b>: Our methods build upon existing guidance and years of practical experience collecting exposure data and analyzing it in collaboration with contract and university <a href=\"https:\/\/www.limswiki.org\/index.php\/Laboratory\" title=\"Laboratory\" class=\"wiki-link\" data-key=\"c57fc5aac9e4abf31dccae81df664c33\">laboratories<\/a>, as well as the <a href=\"https:\/\/www.limswiki.org\/index.php\/Centers_for_Disease_Control_and_Prevention\" title=\"Centers for Disease Control and Prevention\" class=\"wiki-link\" data-key=\"176aa9c9513251c328d864d1e724e814\">Centers for Disease Control and Prevention<\/a>. With real examples from our data, we demonstrate problems that would not have come to light had we not engaged with our QC data and incorporated field QC samples in our study design. Our approach focuses on descriptive analyses and <a href=\"https:\/\/www.limswiki.org\/index.php\/Data_visualization\" title=\"Data visualization\" class=\"wiki-link\" data-key=\"4a3b86cba74bc7bb7471aa3fc2fcccc3\">data visualizations<\/a> that have been compatible with diverse exposure studies, with sample sizes ranging from tens to hundreds of samples. Future work could incorporate additional statistically grounded methods for larger datasets with more QC samples.\n<\/p><p><b>Conclusions<\/b>: This guidance, along with example table shells, graphics, and some sample <a href=\"https:\/\/www.limswiki.org\/index.php\/R_(programming_language)\" title=\"R (programming language)\" class=\"wiki-link\" data-key=\"1b0aa598f071aca4c5b4ee08d8bb2bde\">R code<\/a>, provides a useful set of tools for getting the best <a href=\"https:\/\/www.limswiki.org\/index.php\/Information\" title=\"Information\" class=\"wiki-link\" data-key=\"6300a14d9c2776dcca0999b5ed940e7d\">information<\/a> from valuable environmental exposure datasets and enabling valid comparison and synthesis of exposure data across studies.\n<\/p><p><b>Keywords<\/b>: exposure science, environmental epidemiology, environmental chemicals, environmental monitoring, quality assurance\/quality control (QA\/QC), data validation, exposure measurement, measurement error\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Background\">Background<\/span><\/h2>\n<p>Chemical measurements play a critical role in the study of links between the environment and health, yet many researchers in this field receive little if any training in analytical chemistry. The growing interest in measuring and evaluating health effects of co-exposure to a multitude of chemicals<sup id=\"rdp-ebb-cite_ref-WildComplem05_1-0\" class=\"reference\"><a href=\"#cite_note-WildComplem05-1\">[1]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-CarlinUnrav13_2-0\" class=\"reference\"><a href=\"#cite_note-CarlinUnrav13-2\">[2]<\/a><\/sup> makes this gap in training increasingly problematic, as the task at hand becomes ever-more complicated (i.e., analyzing for more and for new chemicals of concern). If steps are not taken throughout <a href=\"https:\/\/www.limswiki.org\/index.php\/Sample_(material)\" title=\"Sample (material)\" class=\"wiki-link\" data-key=\"7f8cd41a077a88d02370c02a3ba3d9d6\">samples<\/a> collection and analysis to minimize and characterize likely sources of measurement error, the impact on the interpretation of these valuable measurements can vary along the spectrum from false negative to false positive, as we will illustrate with real examples from our own data.\n<\/p><p>Some important considerations when measuring and interpreting environmental chemical exposures have been discussed in other peer-reviewed articles or official guidance documents. For example, a recent document from the <a href=\"https:\/\/www.limswiki.org\/index.php\/United_States_Environmental_Protection_Agency\" title=\"United States Environmental Protection Agency\" class=\"wiki-link\" data-key=\"877b052e12328aa52f6f7c3f2d56f99a\">Environmental Protection Agency<\/a> (EPA) provides citizen scientists with guidance on how to develop a field measurement program, including planning for the collection of <a href=\"https:\/\/www.limswiki.org\/index.php\/Quality_control\" title=\"Quality control\" class=\"wiki-link\" data-key=\"1e0e0c2eb3e45aff02f5d61799821f0f\">quality control<\/a> (QC) samples.<sup id=\"rdp-ebb-cite_ref-EPAQuality19_3-0\" class=\"reference\"><a href=\"#cite_note-EPAQuality19-3\">[3]<\/a><\/sup> The <a href=\"https:\/\/www.limswiki.org\/index.php\/Centers_for_Disease_Control_and_Prevention\" title=\"Centers for Disease Control and Prevention\" class=\"wiki-link\" data-key=\"176aa9c9513251c328d864d1e724e814\">Centers for Disease Control and Prevention<\/a> (CDC) also gives guidance related to collection, storage, and shipment of biological samples for analysis of environmental chemicals or nutritional factors.<sup id=\"rdp-ebb-cite_ref-CDCImprov18_4-0\" class=\"reference\"><a href=\"#cite_note-CDCImprov18-4\">[4]<\/a><\/sup> To assess the quality of already-collected data, LaKind <i>et al.<\/i> (2014) developed a tool to evaluate <a href=\"https:\/\/www.limswiki.org\/index.php\/Epidemiology\" title=\"Epidemiology\" class=\"wiki-link\" data-key=\"123badb8bf0b37a513182dbcfc3875bc\">epidemiologic<\/a> studies that use biomonitoring data on short-lived chemicals, with a focus on critical elements of study design such as choice of analytical and sampling methods.<sup id=\"rdp-ebb-cite_ref-LaKindAProp14_5-0\" class=\"reference\"><a href=\"#cite_note-LaKindAProp14-5\">[5]<\/a><\/sup> The tool was recently incorporated into \u201cExpoQual,\u201d a framework for assessing suitability of both measured and modeled exposure data for a given use (\u201cfit-for-purpose\u201d).<sup id=\"rdp-ebb-cite_ref-LaKindExpo19_6-0\" class=\"reference\"><a href=\"#cite_note-LaKindExpo19-6\">[6]<\/a><\/sup> Other useful guidance has been published, for example on automated <a href=\"https:\/\/www.limswiki.org\/index.php\/Quality_assurance\" title=\"Quality assurance\" class=\"wiki-link\" data-key=\"2ede4490f0ea707b14456f44439c0984\">quality assurance<\/a>\/quality control (QA\/QC) processes for sensors <a href=\"https:\/\/www.limswiki.org\/index.php\/Environmental_monitoring\" title=\"Environmental monitoring\" class=\"wiki-link\" data-key=\"4671d3cbb4201e1698d0fb44369dc1ea\">collecting<\/a> continuous streams of environmental data<sup id=\"rdp-ebb-cite_ref-CampbellQuant13_7-0\" class=\"reference\"><a href=\"#cite_note-CampbellQuant13-7\">[7]<\/a><\/sup> and for establishing an overall data management plan, including documentation of <a href=\"https:\/\/www.limswiki.org\/index.php\/Metadata\" title=\"Metadata\" class=\"wiki-link\" data-key=\"f872d4d6272811392bafe802f3edf2d8\">metadata<\/a> and strategies for <a href=\"https:\/\/www.limswiki.org\/index.php\/Data_warehouse\" title=\"Data warehouse\" class=\"wiki-link\" data-key=\"ca506499cdf544371c0a0d549ff0e9ee\">data storage<\/a>.<sup id=\"rdp-ebb-cite_ref-MichenerTen15_8-0\" class=\"reference\"><a href=\"#cite_note-MichenerTen15-8\">[8]<\/a><\/sup>\n<\/p><p>Despite these helpful documents, there is still a lack of readily accessible, practical guidance on how to interpret and use the results of both field and <a href=\"https:\/\/www.limswiki.org\/index.php\/Laboratory\" title=\"Laboratory\" class=\"wiki-link\" data-key=\"c57fc5aac9e4abf31dccae81df664c33\">laboratory<\/a> QC checks to qualify exposure datasets (i.e., flag results for certain compounds or certain samples that are imprecise, estimated, or potentially over- or under-reported), and this gap is reflected in the <a href=\"https:\/\/www.limswiki.org\/index.php\/Environmental_health\" title=\"Environmental health\" class=\"wiki-link\" data-key=\"b2ad96ed483dfe210a96cc4e44bcdee7\">environmental health<\/a> literature. While the vast majority of environmental health studies report robust findings based on high-quality measurements, questions about measure validity have led to confusion and lack of confidence in some topic areas. For example, a number of studies have measured rapidly metabolized chemicals such as phthalates and bisphenol A (BPA) in blood or other non-urine matrices, despite the fact that urine is the preferred matrix for these chemicals. Phthalates and BPA are present at higher levels in urine and, when the proper metabolites are measured, there is less concern about contamination from external sources, including contamination from plastics during specimen collection.<sup id=\"rdp-ebb-cite_ref-CalafatOptimal15_9-0\" class=\"reference\"><a href=\"#cite_note-CalafatOptimal15-9\">[9]<\/a><\/sup>\n<\/p><p>More commonly, however, exposure studies simply do not adequately report on QA\/QC or describe how QC results informed reporting and interpretation of the data. In the context of systematic review and weight of evidence approaches, not reporting on QA\/QC may result in a study being given less weight. For example, the risk of bias tool employed in case studies of the Navigation Guide method for systematic review includes reporting of certain QA\/QC results in its criteria for a \u201clow risk of bias\u201d rating (e.g., reference Lam <i>et al.<\/i><sup id=\"rdp-ebb-cite_ref-LamTheNav14_10-0\" class=\"reference\"><a href=\"#cite_note-LamTheNav14-10\">[10]<\/a><\/sup>). When we applied the Navigation Guide's QA\/QC criterion to 30 studies of biological or environmental measurements that we included in a recent review of environmental exposures and breast cancer<sup id=\"rdp-ebb-cite_ref-RodgersEnviro18_11-0\" class=\"reference\"><a href=\"#cite_note-RodgersEnviro18-11\">[11]<\/a><\/sup>, we found that more than half either did not report QA\/QC details that were required for a \u201clow risk of bias\u201d assessment, or if they did report QA\/QC, they did not interpret or use them adequately to inform the analysis (e.g., reported poor precision but did not discuss how\/whether this could affect findings) (see Additional file 1 for details). Similarly, when LaKind <i>et al.<\/i> applied their study quality assessment tool to epidemiologic literature on BPA and neurodevelopmental and respiratory health, they found that QA\/QC issues related to contamination and analyte stability were not well-reported.<sup id=\"rdp-ebb-cite_ref-LaKindLessons15_12-0\" class=\"reference\"><a href=\"#cite_note-LaKindLessons15-12\">[12]<\/a><\/sup> Of note, several of the studies in our breast cancer review that did not provide adequate QA\/QC <a href=\"https:\/\/www.limswiki.org\/index.php\/Information\" title=\"Information\" class=\"wiki-link\" data-key=\"6300a14d9c2776dcca0999b5ed940e7d\">information<\/a> had their samples analyzed at the CDC Environmental Health Laboratory. It is helpful to include summaries of QA\/QC assessments in published work, even if researchers are using a well-established lab, because this provides a useful standard for comparing QA\/QC in other studies.\n<\/p><p>Over many years of collecting and interpreting environmental exposure data, we have developed a standard approach for (1) using field and laboratory QA\/QC to validate and qualify chemical measurement data for environmental samples and (2) presenting our QC findings in our research publications (e.g., reference Rudel <i>et al.<\/i><sup id=\"rdp-ebb-cite_ref-RudelSemi10_13-0\" class=\"reference\"><a href=\"#cite_note-RudelSemi10-13\">[13]<\/a><\/sup>). These methods are based on data validation procedures from the EPA, Army Corps of Engineers, and U.S. Geological Survey<sup id=\"rdp-ebb-cite_ref-WentworthReview01_14-0\" class=\"reference\"><a href=\"#cite_note-WentworthReview01-14\">[14]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-EPALab94_15-0\" class=\"reference\"><a href=\"#cite_note-EPALab94-15\">[15]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-USACEGuidance05_16-0\" class=\"reference\"><a href=\"#cite_note-USACEGuidance05-16\">[16]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-GeboyQuality11_17-0\" class=\"reference\"><a href=\"#cite_note-GeboyQuality11-17\">[17]<\/a><\/sup>, as well as the guidance of the many experienced chemists with whom we have collaborated. In this commentary, we compile our methods into a practical guide, focusing on how to use the information to make decisions about data usability and how to make the information transparent in publications. Our guide is organized in three sections, presenting questions to consider during study design, implementation, and data analysis. We describe key elements of QA\/QC, including for assessing precision, accuracy, and sample contamination, and we include suggested graphics (Additional files 2 and 4), and table shells (Additional file 2) that clearly present QC data, emphasizing how it may affect interpretation of study measurements. Minimizing and characterizing potential errors requires close collaboration between the researchers who may have designed the study and plan to analyze the data and the chemists performing the analysis. As such, our guidance also includes example correspondence (Additional file 2) to help establish this relationship at the start of a project.\n<\/p><p>We present a detailed approach based on our own studies, acknowledging that this is an example, not a one-size-fits-all approach. Every study is unique and some will require specialized quality assessment not covered here. Still, we anticipate that many environmental health scientists will find this example to be a useful framework for building their own processes.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"About_the_wrangling_guide\">About the wrangling guide<\/span><\/h2>\n<p>Our guide is organized by a series of questions that we ask when we start a new study, and then ask again when we receive measurement data from the lab. Key QA\/QC concepts are introduced in the section on study design, and they are more thoroughly addressed in sections concerning study implementation and data interpretation.\n<\/p><p>Not every question is relevant to every study; for example, researchers working with a lab to develop a new analytical method will need to focus more on method validation and quality control than those using a well-established method and credentialed lab. Still, controlling for issues related to sample collection and transport remain important in the latter scenario, as does variation in method performance and\/or sources of contamination when samples are analyzed at the laboratory in multiple batches. Our guidance is most relevant to targeted organic chemical analyses, which use <a href=\"https:\/\/www.limswiki.org\/index.php\/Liquid_chromatography%E2%80%93mass_spectrometry\" title=\"Liquid chromatography\u2013mass spectrometry\" class=\"wiki-link\" data-key=\"d171745b38c8d2ed7d274d2cc13fa1f3\">liquid<\/a> or <a href=\"https:\/\/www.limswiki.org\/index.php\/Gas_chromatography%E2%80%93mass_spectrometry\" title=\"Gas chromatography\u2013mass spectrometry\" class=\"wiki-link\" data-key=\"d7fe02050f81fca3ad7a5845b1879ae2\">gas chromatography<\/a>, often in combination with mass spectrometry, to determine whether a pre-defined set of chemicals are present in samples. QA\/QC approaches for non-targeted methods, where tentative identities are established by matching to a library of mass spectra such as the National Institute of Standards and Technology (NIST) database<sup id=\"rdp-ebb-cite_ref-NISTStandard1Av17_18-0\" class=\"reference\"><a href=\"#cite_note-NISTStandard1Av17-18\">[18]<\/a><\/sup>, are addressed elsewhere.<sup id=\"rdp-ebb-cite_ref-UlrichEPA19_19-0\" class=\"reference\"><a href=\"#cite_note-UlrichEPA19-19\">[19]<\/a><\/sup>\n<\/p><p>This guide is not a set of rules, but rather establishes a framework for evaluating and reporting QC data for chemical measurements in environmental or biological samples. While it may be most useful to environmental health scientists who have little or no experience in analytical chemistry, we hope that researchers with a range of experience will find it helpful to consult our approach for evaluating and presenting QC data in publications.\n<\/p><p>Because the number of QC samples available is often limited by budgetary constraints, many of the methods we use rely on <a href=\"https:\/\/www.limswiki.org\/index.php\/Data_visualization\" title=\"Data visualization\" class=\"wiki-link\" data-key=\"4a3b86cba74bc7bb7471aa3fc2fcccc3\">visualization<\/a> and conservative action (i.e., removing chemicals from our dataset or qualifying their interpretation unless there is evidence that the analytical method was accurate and precise) rather than on statistical methods. Whether statistical methods are incorporated or not, tabulating, visualizing, and communicating about QA\/QC for environmental exposure measurements is important in order to reveal systematic error in the laboratory<sup id=\"rdp-ebb-cite_ref-L.C3.B6tschData17_20-0\" class=\"reference\"><a href=\"#cite_note-L.C3.B6tschData17-20\">[20]<\/a><\/sup> or in the field, supporting future use of the data.<sup id=\"rdp-ebb-cite_ref-LaKindExpo19_6-1\" class=\"reference\"><a href=\"#cite_note-LaKindExpo19-6\">[6]<\/a><\/sup>\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Study_design\">Study design<\/span><\/h2>\n<h3><span class=\"mw-headline\" id=\"What_can_we_measure_and_how.3F\">What can we measure and how?<\/span><\/h3>\n<p>One of our first priorities when designing a new study is to consult with a chemist to establish an analyte list and method for analysis.\n<\/p>\n<h4><span class=\"mw-headline\" id=\"Chemical_identities\">Chemical identities<\/span><\/h4>\n<p>Given the complexity of chemical synonyms, it is helpful to be as specific as possible when communicating about the chemicals to be analyzed. One approach is to send the lab a list of the chemical names (avoiding the use of trade names, which can be imprecise), Chemical Abstracts Service (CAS) numbers, and configurations (e.g., branched or linear, if relevant) of all desired analytes (see Additional file 1 for example correspondence). For biomonitoring, it is also important to determine if the parent chemical or metabolites will be targeted.\n<\/p>\n<h4><span class=\"mw-headline\" id=\"Matrix\">Matrix<\/span><\/h4>\n<p>Another consideration in developing the analyte list is what type of samples are available (if working with stored samples) or will be collected. As discussed previously, certain biological matrices are preferred over others for measurement, depending on the chemicals (e.g., reference Calafat <i>et al.<\/i><sup id=\"rdp-ebb-cite_ref-CalafatOptimal15_9-1\" class=\"reference\"><a href=\"#cite_note-CalafatOptimal15-9\">[9]<\/a><\/sup>). Matrix type is also relevant for environmental samples; for example, physical chemical properties like the octanol air partitioning coefficient inform whether an analyte is more likely to be found in air or dust.<sup id=\"rdp-ebb-cite_ref-DodsonSemi15_21-0\" class=\"reference\"><a href=\"#cite_note-DodsonSemi15-21\">[21]<\/a><\/sup>\n<\/p>\n<h4><span class=\"mw-headline\" id=\"Method\">Method<\/span><\/h4>\n<p>The process of determining a final list of analytes will differ depending on whether the lab has an established method or is developing a new method, and whether it is targeted to a few chemicals with similar structure versus many chemicals with different properties (different polarities, solubilities, etc.). Targeting a broad suite of chemicals may limit the degree of precision and accuracy that can be achieved for each individual chemical, and the lab may need to invest substantial effort to develop a multi-residue method\u2014that is, a method that can analyze for many chemicals at once\u2014and determine a final list of target chemicals with acceptable method performance. In any case, a new method should be validated to characterize performance measures\u2014precision, accuracy, expected quantitation and method detection limits, and the range of concentrations that can be quantitated with demonstrated precision and accuracy\u2014before analyzing study samples. If the lab already has an established method for the chemicals of interest, the research team should review method performance measures to ensure they are consistent with study objectives.\n<\/p>\n<h4><span class=\"mw-headline\" id=\"Quantification_method\">Quantification method<\/span><\/h4>\n<p>The method of quantification affects the types of QC data that are expected from the lab. Three common approaches include external calibration, internal calibration and isotope dilution (a form of internal calibration). External calibration, where the response (i.e., chromatogram peak) from the sample is compared to the response from calibration standards containing known amounts of the analytes of interest, is a simple method that can be used for a variety of different analyses. However, results can be influenced by interference from other chemicals present in the sample matrix and resulting fluctuations in the analytical instrument response.<sup id=\"rdp-ebb-cite_ref-EPAMethod8000D_22-0\" class=\"reference\"><a href=\"#cite_note-EPAMethod8000D-22\">[22]<\/a><\/sup> With internal calibration, on the other hand, one or more labeled compounds\u2014either one of the targeted analytes or a closely related compound\u2014are added to each of the samples just before they are injected into the instrument for analysis and used to correct for variation in the instrument response. The internal standard must be similar to the target compounds in physical chemical properties (e.g., a labeled polychlorinated biphenyl should not be used to represent a brominated diphenyl ether). Finally, for isotope dilution methods\u2014which are the most accurate\u2014labeled isotopes for each of the target compounds are added to samples prior to extraction. Additional internal standards are added to the samples just prior to injection to monitor loss of the labeled isotopes, and the analytical software then corrects for loss during sample extraction and for effects of the sample matrix (e.g., presence of other compounds in the sample that interfere with the analysis).<sup id=\"rdp-ebb-cite_ref-EPAMethod8000D_22-1\" class=\"reference\"><a href=\"#cite_note-EPAMethod8000D-22\">[22]<\/a><\/sup> Many laboratories that analyze chemical levels in blood, urine, or tissues (e.g., the CDC National Exposure Research Laboratory) use isotope dilution quantification. However, isotopically labeled standards are not available for every compound and may be cost-prohibitive. If quantification is by internal or external calibration, researchers will likely need to review and report more extensive QC data from the lab compared to when using isotope dilution, as discussed in the section on study implementation.\n<\/p>\n<h4><span class=\"mw-headline\" id=\"Sensitivity_of_the_method\">Sensitivity of the method<\/span><\/h4>\n<p>Another important factor in selecting a method is to make sure it is sensitive enough to detect the anticipated concentrations in the field samples (samples submitted to the lab) down to levels that are relevant to the research question. For example, commercial labs measuring environmental chemicals may establish reporting limits to meet the needs of occupational or regulatory safety compliance testing; these limits may be much higher than levels that are meaningful for research questions about general population exposure and could result in most data being reported as non-detect or qualified as estimated and imprecise. On the other hand, lower reporting limits generally translate to more expensive testing, so researchers have the opportunity to balance sensitivity and cost.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"How_to_minimize_sample_contamination.3F\">How to minimize sample contamination?<\/span><\/h3>\n<p>There are ample opportunities for sample contamination during collection, storage, shipment, and analysis, especially when targeting ubiquitous chemicals commonly encountered in consumer products, home and office furnishings, or laboratory equipment. An important aspect of method validation is to check for contamination of samples during field activities, from collection containers, during transport and storage, and during laboratory extraction and analysis (see discussion of blanks in the section on study implementation). The CDC\u2019s guidance on sample collection and management identifies some possible sources of contamination when analyzing for common chemicals like plastics chemicals, antimicrobials, and preservatives in blood or urine. Key considerations, depending on the particular chemicals being targeted, include selecting appropriate collection containers (e.g., glass containers if analyzing for plastics chemicals), avoiding the use of urine preservatives (e.g., when analyzing for parabens, BPA), and providing adequate instructions to participants collecting their own samples (e.g., avoid using antimicrobial soaps or wipes during collection).<sup id=\"rdp-ebb-cite_ref-CDCImprov18_4-1\" class=\"reference\"><a href=\"#cite_note-CDCImprov18-4\">[4]<\/a><\/sup> As noted previously, contamination can also be minimized in biomonitoring of some chemicals by measuring a metabolite rather than parent chemical, and possibly by measuring a conjugated rather than free form of the metabolite.<sup id=\"rdp-ebb-cite_ref-CalafatOptimal15_9-2\" class=\"reference\"><a href=\"#cite_note-CalafatOptimal15-9\">[9]<\/a><\/sup> In some cases, the lab may need to pre-screen collection containers or other sampling materials to see if they contain any target chemicals. For example, when we used polyurethane foam (PUF) sorbent to collect air samples for analysis of flame retardants, plastics chemicals, and preservatives, we asked the lab to pre-screen the PUF matrix for target analytes. Another important precaution was to ship the samplers wrapped in aluminum foil that had been baked in a muffle furnace to ensure it was clean and uncoated.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"How_will_the_lab_report_the_data.3F\">How will the lab report the data?<\/span><\/h3>\n<p>Three key elements of data typically reported by the lab are the identity of the chemical, the reporting limit for each chemical and sample, and how much of each chemical is present in each sample. Sometimes an additional measure is needed to normalize mass of chemical per sample, for example, grams of urinary creatinine, urine specific gravity, grams of serum lipid, or cubic meters of air (see work by LaKind <i>et al.<\/i><sup id=\"rdp-ebb-cite_ref-LaKindAProp14_5-1\" class=\"reference\"><a href=\"#cite_note-LaKindAProp14-5\">[5]<\/a><\/sup> for discussion of issues related to matrix adjustment and presentation of measurements).\n<\/p>\n<h4><span class=\"mw-headline\" id=\"Chemical_identities_2\">Chemical identities<\/span><\/h4>\n<p>It is helpful to request in advance that the lab report CAS numbers and configurations (if relevant) along with chemical names (see Additional files 2 and 3 for example reporting requests).\n<\/p>\n<h4><span class=\"mw-headline\" id=\"Reporting_limits\">Reporting limits<\/span><\/h4>\n<p>Common terms used by laboratories to discuss reporting limits include \"instrument detection limit\" (IDL), \"method detection limit\" (MDL) and \"limit of quantitation\" (LOQ). The IDL and MDL are both related to the level of an analyte that can be detected with confidence that it is truly present. The IDL captures the smallest true signal (change in instrument response when an analyte is present) that can be distinguished from background noise (variation in the instrument response to blank samples), while the MDL takes into account additional sources of error introduced during sample preparation (e.g., the extraction process, possible concentration or dilution of samples) and thus is higher than the IDL. The MDL is also often referred to as the limit of detection (LOD) or detection limit (DL). The LOQ, on the other hand, describes the lowest mass or concentration that can be detected with confidence in the <i>amount<\/i> detected. The reporting limit (RL) or method reporting limit (MRL), which is either the lowest value that the lab will report or the lowest value that the lab will report without flagging the data as estimated, is often (but not always) the same as the quantitation limit or LOQ.\n<\/p><p>Before submitting samples for analysis, it is helpful to find out (1) the methods and terminology that the laboratory will use to describe reporting limits (LOD, LOQ, etc.) and (2) whether reporting limits will be consistent within a chemical or whether limits could vary between samples or batches. Equally critical is to clarify how the lab will report non-detects. Several different values could appear in the amount or concentration fields for non-detects, including but not limited to zeroes, the detection limit, the reporting limit, or \u201cND.\u201d\n<\/p>\n<h4><span class=\"mw-headline\" id=\"Amount\">Amount<\/span><\/h4>\n<p>Another important point to discuss in advance with the laboratory is how they will report values for compounds with a confirmed identity but measured at levels below what accurately can be quantitated. For example, when measuring chemicals of emerging interest, we ask laboratories to report estimated values below the RL and we flag them during data analysis. This practice has some limitations<sup id=\"rdp-ebb-cite_ref-HelselStat12_23-0\" class=\"reference\"><a href=\"#cite_note-HelselStat12-23\">[23]<\/a><\/sup> but is preferable to falsely reducing variance in the dataset by treating estimated values below the RL as equivalent to non-detects below the detection limit. Non-detects can present significant data analysis challenges, and while a discussion of the best available methods and the problems with common approaches such as substituting the RL, RL\/2, or zero for non-detects is beyond the scope of this commentary, it is a critical issue, and we refer the reader to several helpful resources.<strong class=\"error mw-ext-cite-error\">Cite error: Invalid <code><ref><\/code> tag;\nrefs with no content must have a name<\/strong><sup id=\"rdp-ebb-cite_ref-HelselMuchAdo10_24-0\" class=\"reference\"><a href=\"#cite_note-HelselMuchAdo10-24\">[24]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-NewtonEstim07_25-0\" class=\"reference\"><a href=\"#cite_note-NewtonEstim07-25\">[25]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ShoariToward18_26-0\" class=\"reference\"><a href=\"#cite_note-ShoariToward18-26\">[26]<\/a><\/sup> Reporting estimated values is not standard practice for many laboratories, so it is important to raise this issue early on (see Additional file 2 for example correspondence). If the lab reports data qualifier flags, it may be necessary to clarify the interpretation of those flags, including but not limited to which flags distinguish non-detects from detects above the MRL and estimated values. In other words, it is best not to make assumptions.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Study_implementation\">Study implementation<\/span><\/h2>\n<h3><span class=\"mw-headline\" id=\"What_QA.2FQC_is_needed.3F\">What QA\/QC is needed?<\/span><\/h3>\n<p>QA\/QC occurs both inside and outside the analytical laboratory (see Table 1). Field QC samples, namely blanks and duplicates, capture the sum of contamination and measurement error from collection, storage, transport, and laboratory sources. We base the number of QC samples we collect in the field on budget and our sample size, generally aiming for at least 20% QC samples (e.g., if collecting 80 field samples, then collect 16 field QC samples), though a higher percentage is needed in small studies. Lab analysts should be blinded to the identity of field QC samples whenever possible. Maintaining blinding can be challenging, so it is worth putting some thought into sample names (e.g., QC samples should not have obviously different IDs than other samples, should not be labeled with a \u201cD\u201d for duplicate or \u201cB\u201d for blank). Logs retained at the site must contain sufficient information to allow the data analysts to identify field QC samples and sample types.\n<\/p>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table class=\"wikitable\" border=\"1\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\" colspan=\"4\"><b>Table 1.<\/b> Summary of QC sample types, interpretation, and possible actions\n<\/td><\/tr>\n<tr>\n<th style=\"padding-left:10px; padding-right:10px;\">QA\/QC concept\n<\/th>\n<th style=\"padding-left:10px; padding-right:10px;\">Measure\n<\/th>\n<th style=\"padding-left:10px; padding-right:10px;\">Interpretation\n<\/th>\n<th style=\"padding-left:10px; padding-right:10px;\">Possible actions\n<\/th><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>Accuracy<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">\n<p>\u2022 Surrogate spike recovery in each sample\n\u2022 Certified reference material<br \/>\n\u2022 Isotope dilution quantification<br \/>\n<\/p>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">\n<p>Measures whether the analytical method produces accurate quantification for each compound. Matrix spike recovery evaluates matrix effects on accuracy, such as interferences. Isotope dilution is the most rigorous approach to generating accurate measurements in biomonitoring.\n<\/p>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">\n<p>\u2022 Drop compounds with inaccurate quantification from the data analysis, discuss with lab whether improvements can be made for future analyses.<br \/>\n\u2022 If problems are modest and batch-specific, include batch as a covariate in regression model.\n<\/p>\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>Extraction efficiency<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">\n<p>\u2022 Surrogate spike recovery in each sample\n<\/p>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">\n<p>Measures\u2014for each field sample\u2014whether the chemical is extracted completely from the sample matrix, (e.g., blood, dust). Isotope dilution approaches capture and correct for differences in extraction efficiency.\n<\/p>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">\n<p>\u2022 Consider dropping samples with poor surrogate recovery from data analysis.<br \/>\n\u2022 Consider applying a surrogate correction factor (1\/fraction recovery) if the recovery is consistent (\u00b1 15\u201320% in standard deviation).\n<\/p>\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>Detection limit<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">\n<p>This is the level above which the lab can detect with confidence that the analyte is present in the sample. Common terms include \"instrument detection limit\" (IDL), \"detection limit\" (DL), \"method detection limit\" (MDL), and \"limit of detection\" (LOD).\n<\/p>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">\n<p>\u2022 See <i>Method reporting limit (MRL)<\/i>\n<\/p>\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>Quantitation limit<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">\n<p>This is the level above which the lab can quantify with confidence the amount of chemical in the sample. Common terms include \"practical quantitation limit\" (PQL), \"limit of quantitation\" (LOQ), \"laboratory quantitation level\" (LQL), and \"contract required quantitation limit\" (CRQL).\n<\/p>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">\n<p>\u2022 See <i>Method reporting limit (MRL)<\/i>\n<\/p>\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>Method reporting limit (MRL)<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">\n<p>\u2022 Levels detected in blanks (lab-blind field blanks, solvent blanks, matrix blanks, storage blanks, other types)\n<\/p>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">\n<p>This is the level above which the researcher is confident that the reported chemical measurement reflects a signal from the media sampled, considering all sources of measurement error, especially potential contamination during sample collection and handling, as well as in the laboratory.\n<\/p>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">\n<p>\u2022 Determine MRL by comparing the lab limit (quantitation limit, unless not reported, in which case detection limit) to the levels in the blanks for each compound.<br \/>\n\u2022 Qualify reported values below the MRL as \u201cestimated.\u201d\n<\/p>\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>Potential contamination \/ Analytical bias<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">\n<p>\u2022 Levels detected in blanks (lab-blind field blanks, solvent blanks, matrix blanks, storage blanks, other types)\n<\/p>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">\n<p>Measures the confidence in accuracy of values reported above the MRL.\n<\/p>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">\n<p>\u2022 If there is evidence of contamination, consider dropping a compound or dropping results for a compound in a particular batch. Additionally, identify the source of contamination (e.g., lab vs. field equipment) to inform future work.\n\u2022 For compounds with consistent contamination in blanks, researchers may correct field sample quantity by subtracting the amount attributed to contamination. This is most important when contamination is significant relative to sample values (e.g., >\u200910%) and for comparisons with external data.\n<\/p>\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>Precision<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">\n<p>\u2022 Relative percent difference (RPD) for side-by-side duplicate samples (lab-blind) or split samples (lab-blind if possible)\n<\/p>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">\n<p>Measures the reproducibility of field measurements, including analytical variability and sampling variability.\n<\/p>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">\n<p>\u2022 Flag compounds with >\u200930% RPD.<br \/>\n\u2022 Consider precision in combination with other QA\/QC when deciding to qualify results.\n<\/p>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>QC samples prepared in the lab can include spiked samples or certified reference materials (CRMs) for target chemicals to evaluate the accuracy of the analytical method, surrogate compounds added to field samples to estimate recovery during extraction and analysis, and blanks to assess contamination with target chemicals from some source in the laboratory. While laboratories generally conduct rigorous review of their own QC data, considering lab and field QC together can help to identify specific sources of contamination, imprecision, and systematic error. As such, we typically request to review the lab\u2019s raw QC data in conjunction with the field QC data.\n<\/p>\n<h4><span class=\"mw-headline\" id=\"Spiked_samples_and_certified_reference_material\">Spiked samples and certified reference material<\/span><\/h4>\n<p>Spiked samples and CRMs establish the accuracy of the method by assessing the recoveries of known amounts of each target chemical from a clean or representative matrix. A CRM is a matrix comparable to that used for sampling (e.g., drinking water) that has been certified to contain a specific amount of analyte with a well-characterized uncertainty. If CRMs aren\u2019t available, the laboratory can prepare laboratory control samples (LCSs) by spiking known amounts of target chemicals into a clean sample of the matrix of interest, such as a dust wipe, air sampler, purified water, or synthetic urine or blood that has been analyzed and shown to be free of the analytes of interest, or to contain a consistent amount of analytes of interest that can be subtracted from the amounts measured in the spiked sample to calculate a percent recovery. The LCS or CRM\u2014at least one per analytical batch\u2014is run through the same sample preparation, extraction, and analysis as the field samples to capture the accuracy of the complete method; calculating the percent of the known\/spiked amount recovered for each analyte tells us whether the method is accurate in the matrix.\n<\/p><p>Another type of spiked sample, called a matrix spike, can be used to check the extraction efficiency for a complex sampling matrix that may interfere with the analysis. These samples are typically included if there is concern about interference from the sampling matrix, for example, with house dust, soil or sediment samples, consumer products, or biological samples like blood. Instead of recovery from a clean matrix, these QC checks capture recovery from a representative field sample. Here the \u201cmatrix\u201d refers to all elements of the sample other than the targeted analytes; this includes the sampling medium (e.g., dust, PUF, foam) itself as well as any other chemicals present in the sample that might interfere with measurement of target chemicals. A matrix spike can be created, for example, by splitting a representative sample collected in the field and spiking the target analytes into one half prior to extraction and analysis. The recovery of spiked analyte is determined as the amount measured in the spiked sample minus the amount measured in the non-spiked sample divided by the spike amount. A limitation of this approach is that the analytes are spiked in an already dissolved state, so it is possible that the analytes in the environmental matrix would not be extracted as readily from the matrix as the spiked chemicals. Thus, the true extraction efficiency may be lower than represented by the matrix spike.\n<\/p><p>For newly developed methods where performance is not characterized, we request results for all recoveries of spiked samples and\/or CRMs so that we can perform visual checks that have at times revealed systematic problems with the analytical method that were not noted by the lab (see the data interpretation section for further discussion). For well-established methods, and particularly when isotope dilution quantification is used, it is sufficient to request a table summarizing the spike recovery or CRM recovery results (by batch, if relevant) for reporting in publications.\n<\/p>\n<h4><span class=\"mw-headline\" id=\"Surrogate_recovery_standards\">Surrogate recovery standards<\/span><\/h4>\n<p>Whereas recoveries from LCSs, matrix spikes, and\/or CRMs tell us about the performance of the method in a clean or representative matrix, surrogate compounds are used to evaluate recoveries from individual samples. Recoveries of surrogate compounds can help identify any individual samples that may have inaccurate quantification, for example due to extraction errors or chemical interferences. Surrogates, like internal standards, are spiked into each sample; however, surrogates are added prior to sample extraction to assess the efficiency of this process. Internal standards, on the other hand, are added after extraction, just prior to injection into the <a href=\"https:\/\/www.limswiki.org\/index.php\/Chromatography\" title=\"Chromatography\" class=\"wiki-link\" data-key=\"2615535d1f14c6cffdfad7285999ad9d\">chromatographic<\/a> system, to account for matrix effects and other variation in the instrument response during analysis. The ideal surrogate is a chemical that is not typically present in the environment but that is representative of the physical and chemical properties of target analytes.<sup id=\"rdp-ebb-cite_ref-USACEGuidance05_16-1\" class=\"reference\"><a href=\"#cite_note-USACEGuidance05-16\">[16]<\/a><\/sup> It is best to have a representative surrogate for each individual chemical, though when analyzing for numerous chemicals at once with multi-residue methods, cost and time restraints may result in one or a few surrogates being selected to represent a class of compounds. In this case, it is critical that the lab selects an appropriate surrogate.\n<\/p><p>For analyses using external or internal calibration, we ask the lab to provide us with the recovery results for each surrogate in each sample, so that we can flag any samples or compounds that might have had extraction problems. However, if the lab uses isotope dilution quantification, we are less concerned about obtaining this raw data from the laboratory given that the reported results are already automatically corrected for extraction and matrix effects.\n<\/p>\n<h4><span class=\"mw-headline\" id=\"Blanks\">Blanks<\/span><\/h4>\n<p>Collecting and preparing several types of blank samples helps us to distinguish sources of contamination. Laboratory blanks alert us to possible contamination originating in the lab. These blanks can capture contamination during sample extraction (solvent blanks), from reagents and other materials used in the analytical method (solvent method blanks), or from \u201ctypical\u201d background levels of target analytes present in the sampling matrix (matrix blanks). Field blanks, on the other hand, capture all possible contamination during sample collection and analysis. Field blanks are clean samples (e.g., distilled water, air sampling cartridge detached from pump immediately following calibration) that are transported to the sampling location and exposed to all of the same conditions as the real samples (e.g., the sampler is opened, if applicable) except the actual collection process. We aim for at least 10% of our samples to be field blanks, with an absolute minimum of three field blanks.\n<\/p><p>Unfortunately, in some cases there aren\u2019t good options for representative field blanks. For example, field blanks can be created for biomonitoring programs by taking empty collection containers into the field and using purified water or synthetic urine or blood to create a blank.<sup id=\"rdp-ebb-cite_ref-CDCImprov18_4-2\" class=\"reference\"><a href=\"#cite_note-CDCImprov18-4\">[4]<\/a><\/sup> However, important shortcomings of this approach are that (1) it is difficult to capture contamination that can be introduced by sample collection materials such as needles and plastic tubing used to collect blood, (2) water may not perform the same as urine or blood in the extraction and analysis, and (3) the lab will likely be able to identify the field blanks. Similarly, it is difficult to maintain lab blinding when using a \u201cclean\u201d matrix like vacuumed quartz sand as a field blank for vacuumed house dust.\n<\/p>\n<h4><span class=\"mw-headline\" id=\"Duplicates\">Duplicates<\/span><\/h4>\n<p>Collecting side-by-side duplicate samples in the field helps assess the precision of both the sample collection and analytical methods. Duplicate samples can also be created by collecting a single sample and splitting it prior to analysis, which is the only option for biological samples; however, this method only captures the precision of the analysis process<sup id=\"rdp-ebb-cite_ref-WentworthReview01_14-1\" class=\"reference\"><a href=\"#cite_note-WentworthReview01-14\">[14]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-GeboyQuality11_17-1\" class=\"reference\"><a href=\"#cite_note-GeboyQuality11-17\">[17]<\/a><\/sup> and could lead to un-blinding of the lab analyst, if for example the split samples are noticeably smaller than others. When planning for duplicate collection, the best practice is to label these samples so that the lab analyst is blinded to duplicate pairs (i.e., use different Sample IDs for the two samples). Ideally, researchers should plan to collect or create (that is, split) one duplicate pair per every 10\u201320 samples collected and spread duplicate pairs across analytical batches.\n<\/p>\n<h4><span class=\"mw-headline\" id=\"Analytical_batches\">Analytical batches<\/span><\/h4>\n<p>Analytical performance can shift over time, and even between multiple extractions or instrument runs within a short time window. Laboratories often analyze samples in multiple batches, that is, sets of field samples and associated laboratory QC samples that are analyzed together in one analytical run. The time between batches can vary from days to months or even years, though ideally this time span is minimized in order to maintain consistent equipment and procedures throughout the study.\n<\/p><p>Two approaches help address batch-to-batch variability: (1) randomizing participant samples between batches by specifying the order and grouping of samples (and blind field QC samples) when submitting samples to the lab (this may require corresponding with the lab to determine the batch size in advance), and (2) running CRMs\u2014such as standard reference material (SRM) from NIST<sup id=\"rdp-ebb-cite_ref-NIST_SRM_27-0\" class=\"reference\"><a href=\"#cite_note-NIST_SRM-27\">[27]<\/a><\/sup>\u2014in each batch of samples in order to characterize drift. When CRMs are not available, another option is for the researcher to prepare identical\/split reference samples. We have done this, for example, by pooling together several urine specimens and making many aliquots of the pool, then including 1\u20132 blinded samples from this pool with each set of samples we send to the lab. If the laboratory analysis is performed in multiple batches, all QC elements should be examined on a batch-specific basis. Not every laboratory will specify whether or not samples were analyzed in batches; it is a good idea to request that a variable for batch be included in the results report.\n<\/p><p>In Additional files 2 and 3, we provide example correspondence for requesting QC data and consistent formatting from the lab.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Data_interpretation\">Data interpretation<\/span><\/h2>\n<h3><span class=\"mw-headline\" id=\"What_was_measured.3F\">What was measured?<\/span><\/h3>\n<h4><span class=\"mw-headline\" id=\"Chemical_identities_3\">Chemical identities<\/span><\/h4>\n<p>No amount of QA\/QC can save a dataset from basic misunderstandings about what is being reported. After receiving data, it is helpful to ask the chemists to double check the analyte list (chemical name, CAS, isomer details) against the list of standards used in the analysis, particularly if this information was not included in the report from the lab. It is worthwhile to make this verification even when chemical identities were specified in advance of the analysis, as it is possible that the standard used for analysis was slightly different than planned. Only through this process, for example, did we discover that a lab had accidentally purchased a standard for 2,2,4-trimethyl-1,3-pentanediol isobutyrate rather than 2,2,4-trimethyl-1,3-pentanediol diisobutyrate (two different chemicals).\n<\/p><p>Table 2 summarizes some steps for getting acquainted with a new dataset received from the lab. We have also published sample <a href=\"https:\/\/www.limswiki.org\/index.php\/R_(programming_language)\" title=\"R (programming language)\" class=\"wiki-link\" data-key=\"1b0aa598f071aca4c5b4ee08d8bb2bde\">R code<\/a> on GitHub that may be helpful for getting acquainted with a new dataset, including examining trends in QC and field samples over time.<sup id=\"rdp-ebb-cite_ref-GH_QAQC_28-0\" class=\"reference\"><a href=\"#cite_note-GH_QAQC-28\">[28]<\/a><\/sup>\n<\/p>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table class=\"wikitable\" border=\"1\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\" colspan=\"1\"><b>Table 2.<\/b> Steps for getting acquainted with your data\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">\n<p>1. Verify chemical identities.<br \/>\n<\/p>\n<dl><dd>\u25cb Check CAS number, chemical name, isomer type of reported analytes vs. analytical standards purchased by lab (see Additional file 2 for example correspondence).<br \/><\/dd><\/dl>\n<p>2. Count (overall and by batch) the number of:<br \/>\n<\/p>\n<dl><dd>\u25cb \u201cReal\u201d samples (compare these to the chain of custody that lists the samples submitted for analysis to make sure all submitted samples were analyzed)<br \/><\/dd>\n<dd>\u25cb Lab control and\/or matrix spike recoveries<br \/><\/dd>\n<dd>\u25cb Reference samples (e.g., CRMs)<br \/><\/dd>\n<dd>\u25cb Surrogate spike recoveries<br \/><\/dd>\n<dd>\u25cb Blanks (solvent method, field, matrix, other)<br \/><\/dd>\n<dd>\u25cb Duplicates<br \/><\/dd><\/dl>\n<p>3. Examine any data qualifier flags reported by the lab and make sure interpretation is clear.\n<\/p>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<h3><span class=\"mw-headline\" id=\"Were_there_trends_over_time.3F\">Were there trends over time?<\/span><\/h3>\n<h4><span class=\"mw-headline\" id=\"Analytical_batches_2\">Analytical batches<\/span><\/h4>\n<p>Examining results by batch or even by sample run order can reveal trends in QC samples over time, identifying systematic laboratory errors that may be missed by summary statistics or visualizations.<sup id=\"rdp-ebb-cite_ref-L.C3.B6tschData17_20-1\" class=\"reference\"><a href=\"#cite_note-L.C3.B6tschData17-20\">[20]<\/a><\/sup> Shifts in method performance over time may require batch-specific corrections or dropping or flagging data from certain batches. Notably, a trend in QC sample results over time can be problematic even if they remain within the acceptable limits established by the lab. In our own work, for example, examining our data by analytical batch revealed an upward trend in sample-specific detection limits for some analytes, such that detection limits in later batches were within the range of sample results from earlier batches (Fig. 1). The detection limits in the later batches still met the specifications of our contract with the lab, but it was clear that we would not be able to compare results in the latter two batches to those in the first three. We showed the plot in Fig. 1 to the lab and they agreed to re-analyze the samples in the later batches, which resulted in more consistent detection limits.\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig1_Udesky_EnviroHealth2019_18.png\" class=\"image wiki-link\" data-key=\"7c45041ee3dad50868448a9fd03c5504\"><img alt=\"Fig1 Udesky EnviroHealth2019 18.png\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/7\/76\/Fig1_Udesky_EnviroHealth2019_18.png\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Figure 1.<\/b> Visualizing urine sample results by analytical batch (data not yet published) revealed that sample-specific detection limits in later batches were higher and in the range of sample results in previous batches. After discussing with the laboratory, samples in later batches were re-analyzed to achieve lower detection limits.<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<h3><span class=\"mw-headline\" id=\"Is_the_method_accurate.3F\">Is the method accurate?<\/span><\/h3>\n<h4><span class=\"mw-headline\" id=\"Spiked_samples_and_certified_reference_material_2\">Spiked samples and certified reference material<\/span><\/h4>\n<p>Table 3 outlines our approach for analyzing LCS or matrix spike recovery or CRM data. The approach is similar for all of these samples. However, one distinction is that if LCS recovery and other QC measures, such as lab blanks (matrix, solvent method, or other) are acceptable, a poor matrix spike recovery (higher or lower than acceptable bounds) can alert chemists to interferences from matrix effects, suggesting steps to address this such as matrix-matched calibration.<sup id=\"rdp-ebb-cite_ref-GeboyQuality11_17-2\" class=\"reference\"><a href=\"#cite_note-GeboyQuality11-17\">[17]<\/a><\/sup> We typically only use data for analytes that have average LCS, matrix spike and\/or CRM recoveries between 50 and 150%, though this decision criterion can be adjusted based on the needs of the project. If we do retain data for chemicals with spike or CRM recoveries outside of this acceptable range, we note in publications that concentrations in our data may be under- or over-reported.\n<\/p>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table class=\"wikitable\" border=\"1\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\" colspan=\"1\"><b>Table 3.<\/b> Steps for spiked samples and certified reference material (see Additional file 4 for an example of this approach with real data)\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">\n<p>1. Summarize percent recoveries for each chemical across analytical batches and flag those chemicals with average recoveries outside of a pre-established acceptable range.<br \/>\n<\/p>\n<dl><dd>\u25a1 We typically apply an acceptable range of 50\u2013150% recovery for most environmental samples, particularly when we are analyzing for new chemicals or combinations of chemicals for which methods are not well-established. For well-established methods, a more conservative range\u201480-120% recovery\u2014is appropriate.<br \/><\/dd><\/dl>\n<p>2. Visualize percent recoveries for each chemical across analytical batches to assess consistency.<br \/>\n<\/p>\n<dl><dd>\u25a1 If recoveries for a particular chemical or chemicals are consistently out of range (>\u2009150% or\u2009<\u200950%) across multiple batches, this should be discussed with the laboratory analyst.<br \/>\n<dl><dd>\u25cb If the laboratory analyst agrees that the method was not successful, we drop the chemical(s) from our dataset. We do not report values or include such chemicals in any data analyses.<br \/><\/dd>\n<dd>\u25cb If the laboratory analyst can explain the reason for consistent high or low recoveries and has confidence in the ranking and relative values of the reported sample data, the reported values can be used for many data analyses, but it will be difficult to compare with levels from another study.<br \/><\/dd><\/dl><\/dd>\n<dd>\u25a1 If recoveries from one or a few batches are out of range, we are concerned that results in those batches might be over\/under-estimated compared to the rest. One way to investigate this concern is to look for corresponding systematic differences in sample data (see Additional file 4: Figure S3).<br \/>\n<dl><dd>\u25cb If field samples have been randomized into batches, we check if the variation in sample results correlates with spiked sample or CRM recoveries by batch. Note: we still go through this step even if we were not able to randomize field samples, but in this case it can be very challenging to distinguish systematic analytical variation from other possible sources of variation in sample results between batches (e.g., if samples in different batches were also collected during different seasons).<br \/>\n<dl><dd>\u25aa If there are systematic differences (e.g., the sample results for a chemical are higher in the batch where the spike or CRM recovery was high, or if only one batch, the sample results for a chemical with high spike or CRM recovery are much higher than previously reported levels), we consider dropping the chemical results from the affected batches from the dataset. If an identical\/split reference sample was analyzed in each batch, these results can also be helpful to resolve questions about whether and how to use the data in this case.<br \/><\/dd>\n<dd>\u25aa If there are no obvious systematic differences, we keep the chemical in our dataset, but flag the results for that chemical in the batch with the out-of-range spiked sample or CRM recovery.<br \/><\/dd><\/dl><\/dd><\/dl><\/dd><\/dl>\n<p>3. In regards to reporting:<br \/>\n<\/p>\n<dl><dd>\u25a1 We note in summary statistics when the average spiked sample or CRM recovery for a particular chemical was out of range.<br \/><\/dd>\n<dd>\u25a1 We note whether levels in our study might be systematically over- or under-reported (i.e., because of consistent high or low spiked sample or CRM recoveries). We especially note this if comparing to levels from another study.<br \/><\/dd>\n<dd>\u25a1 For chemicals with low\/high recoveries in certain batches, we may perform sensitivity analyses \u2013 for example, by including lab batch as a covariate in regression analyses, though this can be challenging for small datasets.<br \/><\/dd><\/dl>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>Figure 2 illustrates a case from our own data where the laboratory reported that 1,2,5,6,9,10-Hexabromocyclododecane (HBCD), a brominated flame retardant, was mostly \u201cnot detected,\u201d but the LCS recoveries, which ranged from \u2212\u20092 to 1670% and averaged about 750%, indicated that the method was not able to accurately quantify this chemical. We removed this compound from our dataset and did not report on it. Examining spike recoveries thus prevents us from reporting a chemical as \u201cnot detected,\u201d or from reporting an unreliable detect, if the analytical method is not performing accurately for that compound.\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig2_Udesky_EnviroHealth2019_18.png\" class=\"image wiki-link\" data-key=\"4eb9abfcc733822a69be87a04a4894cc\"><img alt=\"Fig2 Udesky EnviroHealth2019 18.png\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/6\/67\/Fig2_Udesky_EnviroHealth2019_18.png\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Figure 2.<\/b> <b>A.<\/b> Results for flame retardant HBCD measured in air samples collected in 105 homes. All but three samples were non-detects (open circles). Samples were analyzed in six different analytical batches. <b>B.<\/b> Summary of laboratory control spike recovery data for HBCD across the six analytical batches shows very poor accuracy and indicates no confidence for this analyte in the indoor air samples.<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>A summary of the recovery information should be included in the peer-reviewed manuscript to demonstrate accuracy. See Additional file 2: Tables S1-S2 and Figure S1 for an example of how to present this information.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Were_there_problems_with_certain_samples.3F\">Were there problems with certain samples?<\/span><\/h3>\n<h4><span class=\"mw-headline\" id=\"Surrogate_recovery_standards_2\">Surrogate recovery standards<\/span><\/h4>\n<p>When isotope dilution quantitation with automatic recovery correction is not employed, we review the surrogate recovery standard data for each individual sample, generally considering 50\u2013150% recovery to be acceptable. Interpretation of an out-of-range surrogate recovery depends both on its direction and on the levels of the associated analytes (i.e., those represented by the surrogate compound) measured in the sample. In samples with low surrogate recoveries, the concern is that if similar target analytes are present in the sample, the measurements will be underestimated\/biased low. For samples with high surrogate recoveries, on the other hand, we can be confident that similar target compounds should be detected if present, but the amount may be overestimated or biased high. If surrogate recoveries are out-of-range in all samples, and particularly if they are also out-of-range in blank samples, this is likely indicative of a broader problem with the analytical method.<sup id=\"rdp-ebb-cite_ref-USACEGuidance05_16-2\" class=\"reference\"><a href=\"#cite_note-USACEGuidance05-16\">[16]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-DawsonGround08_29-0\" class=\"reference\"><a href=\"#cite_note-DawsonGround08-29\">[29]<\/a><\/sup> Table 4 outlines our approach for analyzing surrogate recovery data.\n<\/p>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table class=\"wikitable\" border=\"1\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\" colspan=\"1\"><b>Table 4.<\/b> Steps for surrogates (see Additional file 4 for an example of this approach with real data)\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">\n<p>1. Count high and low recoveries for each surrogate chemical across analytical batches.\n<\/p>\n<dl><dd>\u25a1 We typically apply an acceptable range of 50\u2013150% recovery for most environmental samples, particularly when we are analyzing for new chemicals or combinations of chemicals for which methods are not well-established. For well-established methods, a more conservative range\u201480-120% recovery\u2014would be appropriate.<\/dd><\/dl>\n<p>2. Identify any sample where all surrogate recoveries were low (e.g., <\u200950%). This suggests a potential problem with the extraction for that sample.\n<\/p>\n<dl><dd>\u25a1 Discuss with lab analyst. Consider dropping sample.<\/dd><\/dl>\n<p>3. Visualize surrogate recoveries for QC samples (lab blanks, lab control or matrix spikes) across analytical batches. See Additional file 4: Figure S4 for an example.\n<\/p>\n<dl><dd>\u25a1 If these recoveries are out of range, this suggests a larger problem with the analytical method rather than with particular samples. Summarize information about the surrogate recoveries in the QC samples as well as lab control or matrix spike recoveries for the associated chemicals and discuss with lab analyst.<\/dd><\/dl>\n<p>4. Visualize percent recoveries across all samples for each surrogate, by analytical batch. See Additional file 4: Figure S6 for an example.\n<\/p>\n<dl><dd>\u25a1 Note any trends (upward or downward) in the distribution of surrogate recoveries across batches. Such trends should be discussed with the laboratory analyst, even if all recoveries are in the 50\u2013150% acceptable range (see Fig. 3 for an example).<\/dd>\n<dd>\u25a1 If the surrogate is a deuterated version of one of the target chemicals, it can be helpful to compare a plot of the surrogate recoveries by batch to the sample data for the corresponding un-deuterated target chemical by batch. We would be concerned \u2013 and would seek guidance from the lab analyst \u2013 if we saw a trend for the target chemical results that matched the trend in the surrogate recoveries.<\/dd>\n<dd>\u25a1 Note if many surrogate recoveries (e.g., more than half) are out of range in a particular lab batch. If yes, flag the results in that batch for the chemical(s) represented by that surrogate.<\/dd><\/dl>\n<p>5. Visualize sample results flagged by surrogate recoveries. For each individual sample with an out-of-range recovery for a surrogate, flag the results for the chemical(s) associated with that surrogate. Plot all sample data with indicators (e.g., different colors) for whether the representative surrogate for each sample was out of range. See Additional file 4: Figure S7A-D for an example.\n<\/p>\n<dl><dd>\u25a1 Note whether samples with high surrogate recoveries consistently have the highest results for the associated chemical(s).\n<dl><dd>\u25cb If yes, we would be concerned that samples with high recoveries are all overestimated. Discuss with lab analyst. Consider applying a surrogate correction factor to sample results (multiplying by 1\/fraction recovery).<\/dd><\/dl><\/dd>\n<dd>\u25a1 Note whether samples with low surrogate recoveries were consistently non-detects or very low-level detects for the associated chemical(s).\n<dl><dd>\u25cb If yes, we would be concerned that samples with low recoveries are all underestimated. Discuss with lab analyst. Note in publications that levels and detection frequencies for associated chemicals might be underestimated.<\/dd><\/dl><\/dd><\/dl>\n<p>6. In regards to reporting:\n<\/p>\n<dl><dd>\u25a1 In summary statistics, we note whether any maximum value is from a sample associated with a high (>\u2009150%) surrogate recovery and note that in this case the maximum might be overestimated. Similarly, if 100% of samples are detects, we also flag the minimum value if it is from a sample associated with a low (<\u200950%) recovery and note that in this case the minimum might be underestimated.<\/dd>\n<dd>\u25a1 For any statistical analyses, if possible (i.e., if large enough dataset) we run sensitivity analyses:\n<dl><dd>\u25cb Excluding samples with out-of-range surrogate recoveries.<\/dd>\n<dd>\u25cb Controlling for lab batch, if surrogates were problematic for a particular batch.<\/dd><\/dl><\/dd><\/dl>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>Figure 3 shows an example where our examination of surrogate recoveries on a batch-specific basis indicated trends in the recoveries over time, even though most remained within the generally acceptable range (50\u2013150%). This plot led to a discussion with the lab analyst, who suggested that stock solutions for surrogate compounds may have concentrated over time as solvent evaporated, until a new stock solution was prepared for the last batch. On the advice of the lab analyst, we looked at trends in the \u201cspike check\u201d\u2014solvent that is spiked with target analytes but not extracted or concentrated\u2014sample recoveries. Spike check recoveries indicated good reproducibility, giving us confidence that the drift in surrogate recoveries did not reflect changes in instrument calibration over time.\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig3_Udesky_EnviroHealth2019_18.png\" class=\"image wiki-link\" data-key=\"971a40c05b98c675e3b36d74d15a49c2\"><img alt=\"Fig3 Udesky EnviroHealth2019 18.png\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/7\/74\/Fig3_Udesky_EnviroHealth2019_18.png\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Figure 3.<\/b> In this example from our data, recoveries of surrogate d4-di-n-butyl-phthalate from air samples showed notable upward and downward trends over time, despite largely staying within the 50\u2013150% acceptable bounds. Here we were examining surrogate recoveries in batches of samples from different studies analyzed at the same laboratory. The last two batches (Sept 2014 and May 2015) were from the same study but collected approximately a year apart per the study design.<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<h3><span class=\"mw-headline\" id=\"Is_there_evidence_of_contamination_or_analytical_bias.3F\">Is there evidence of contamination or analytical bias?<\/span><\/h3>\n<h4><span class=\"mw-headline\" id=\"Blanks_2\">Blanks<\/span><\/h4>\n<p>Once we have determined that we can accurately measure the target analytes in our sampling matrix, the next step is to ensure that we are confident about whether those target analytes came from the study site or participant\u2014or from somewhere else. Table 5 outlines our approach to reviewing data from blank samples. When it is not straight forward to collect field blanks (e.g., for blood samples), any assessment of contamination introduced from sampling (e.g., pre-screening of collection materials) should be thoroughly described and limitations acknowledged.\n<\/p>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table class=\"wikitable\" border=\"1\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\" colspan=\"1\"><b>Table 5.<\/b> Steps for blanks (see Additional file 4 for an example of this approach with real data)\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">\n<p>1. Summarize results across all chemicals by blank type (e.g., field blank, solvent method blank, matrix blank, etc.), with non-detects set to zero. For chemicals with no detects in blanks, the MRL will equal the lab reporting limit and none of the subsequent steps in Tables 6 or 7 are needed.<br \/> <br \/>\nFor chemicals detected in blanks:<br \/> <br \/>\n2. Visualize levels in blanks by blank type. Set non-detects to \u00bd lab reporting limit and plot by analytical batch.<br \/>\n<\/p>\n<dl><dd>\u25a1 Consider whether blank detects are consistent across batches. Note whether detects seem to occur mostly in one type of blank which could indicate a source of contamination in the lab or field.<br \/>\n<dl><dd>\u25cb If a particular source is suspected, we investigate (talk to lab, look at field logs, etc.).<br \/><\/dd><\/dl><\/dd><\/dl>\n<p>3. Visualize levels in blanks by blank type along with field samples by analytical batch. Set non-detects to \u00bd lab reporting limit.<br \/>\n<\/p>\n<dl><dd>\u25a1 Note whether blanks are in range of the samples.<br \/><\/dd>\n<dd>\u25a1 If field samples have been randomized into batches, check if variation in sample results correlates with blank results by batch. Note: we still go through this step even when we were not able to randomize field samples, but it is more challenging to distinguish whether contamination is driving differences in sample results in a particular batch or whether other explanations are more likely (e.g., all samples in one batch were collected in a different season or from a particular study site).<\/dd><\/dl>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>Figure 4 illustrates an example from our study comparing levels of chemicals in air in college dorm rooms before and after students moved in (data not yet published) where field blanks proved particularly crucial. Our first look at the sample data suggested that bis(2-ethylhexyl) phthalate (DEHP), a chemical commonly used in plastics, was present at notably higher levels after students moved in. However, upon further review, we found that DEHP levels in the field blanks were also higher and in the range of the sample data at the post- compared to pre-occupancy time point. At the same time, levels of DEHP in the laboratory blanks (matrix and solvent method) were not elevated. A conversation with the lab revealed that different plastic bags may have been used to transport samples during the later round of sampling (i.e., the post-occupancy sampling). These bags may have contained higher levels of DEHP.\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig4_Udesky_EnviroHealth2019_18.png\" class=\"image wiki-link\" data-key=\"1b8fb792a04220877bf0b4aeec957a5b\"><img alt=\"Fig4 Udesky EnviroHealth2019 18.png\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/9\/9e\/Fig4_Udesky_EnviroHealth2019_18.png\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Figure 4.<\/b> Phthalate DEHP measured in air in college dorm rooms before and after occupancy (data not yet published). Levels in our samples (purple dots) were higher post- compared to pre-occupancy, but this plot revealed that levels in field blanks (blue dots) were also higher post- compared to pre-occupancy and within the range of field samples. We also saw a matrix blank (green dot) well within the range of the field samples in the pre-occupancy batch. These data suggest DEHP contamination in both batches; for the post-occupancy batch, we hypothesized this might have come from the plastic bags in which the samplers were shipped. We will not report results for this chemical from this study, given the evidence of contamination. LLOQ\u2009=\u2009Lower Limit of Quantitation.<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>Typically, we use blanks to qualify values rather than remove measurements from our data. Specifically, we use detected values in field blanks and sometimes other blanks (see Table 6) as a basis to qualify data by raising the method reporting limit (MRL), flagging low values as estimated, until we feel confident in the levels we\u2019re reporting. Values reported by the lab but below the MRL are considered estimated (see Fig. 5 for an example of graphical presentation distinguishing estimated detects below the MRL from true detects above the MRL). In the example of the potentially DEHP-contaminated plastic bags used to transport samples, however, we decided not to report DEHP levels for the post-occupancy samples, given the evidence that contamination might have significantly biased the results in that batch. Unexpected findings, such as a chemical or chemicals detected at much higher levels in a lab blank (matrix, solvent method, or other) than in the field blanks, warrant further investigation. In this case, we might suspect that the lab blank was contaminated by another sample; examining the sample run order (which must be requested from the lab; see example correspondence in Additional file 2) could shed light on whether a very high sample was run directly before the lab blank.\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig5_Udesky_EnviroHealth2019_18.png\" class=\"image wiki-link\" data-key=\"9d3ea2922fdad1696aa196128cdc0346\"><img alt=\"Fig5 Udesky EnviroHealth2019 18.png\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/1\/1d\/Fig5_Udesky_EnviroHealth2019_18.png\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Figure 5.<\/b> Example of graphical presentation distinguishing true, estimated, and non-detects. MRL\u2009=\u2009Method Reporting Limit.<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table class=\"wikitable\" border=\"1\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\" colspan=\"1\"><b>Table 6.<\/b> Steps for the consideration of raising method reporting limits (MRLs) (see Additional file 4 for an example of this approach with real data)\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">\n<p>1A. For chemicals not detected in blanks, the MRL is equal to the laboratory reporting limit.<br \/>\n1B. For each chemical detected in blanks, if there are detects in blanks in all batches, establish the MRL as follows (otherwise proceed to 1C):<br \/>\n<\/p>\n<dl><dd>\u25a1 Compare the lab\u2019s reporting limit to the 90th percentile of field blanks (computed with non-detects set to \u00bd lab\u2019s reporting limit). The higher value is the new MRL.<br \/>\n<dl><dd>\u25cb However, if we observe many detects in other types of blanks (e.g., matrix, solvent), we consider determining the MRL by comparing the lab\u2019s reporting limit to the 90th percentile of ALL blanks (computed with non-detects set to \u00bd lab\u2019s reporting limit). The higher value is the new MRL.<br \/><\/dd>\n<dd>\u25cb It can be helpful here to plot sample data with different possible MRLs to gain understanding of precisely what is being achieved by raising the MRL (i.e., are we successfully flagging data that we are not confident in and at the same time leaving data in which we have confidence unqualified?). See Additional file 4: Figure S9, for an example of this type of plot.<br \/><\/dd><\/dl><\/dd>\n<dd>\u25a1 Note: We use the 90th percentile of the blanks rather than using the maximum value or the mean because the 90th percentile is less sensitive to extreme values and can be estimated for data that are not normally distributed. However if the overall study is small (e.g., in our practice, when we have <\u20095 blanks), we set the MRL equal to the maximum blank mass.<br \/><\/dd><\/dl>\n<p>1C. For each chemical detected in blanks, if detects in blanks are clustered in one or a few batches:<br \/>\n<\/p>\n<dl><dd>\u25a1 If just one extremely problematic batch, consider dropping the sample data from that batch.<br \/><\/dd>\n<dd>\u25a1 If multiple field blanks were run in each batch, can consider determining MRL as above but on a batch-specific basis.<br \/>\n<dl><dd>\u25cb In this case, the way to proceed will very much be a judgment call. Spend time with the data considering various approaches.<br \/><\/dd><\/dl><\/dd>\n<dd>\u25a1 Data from reference material and duplicate samples can be helpful in deciding which data points should be qualified because they are \u201cin the noise.\u201d<br \/><\/dd><\/dl>\n<p>2. After determining the MRL, we flag each sample result as follows:<br \/>\n<\/p>\n<dl><dd>\u25a1 0 flag\u2009=\u2009measurement reported by the lab as \u201cnon-detect\u201d<br \/><\/dd>\n<dd>\u25a1 0.5 flag\u2009=\u2009measurement falls below the MRL. These are considered \u201cestimated detects\u201d<br \/><\/dd>\n<dd>\u25a1 1 flag\u2009=\u2009measurement falls above the MRL. These are considered \u201ctrue detects\u201d<br \/><\/dd>\n<dd>\u25a1 Note that our data qualifier flags may differ from those used by others. For example, NHANES flags non-detects with a \u201c1\u201d and detects with a \u201c0.\u201d<br \/><\/dd><\/dl>\n<p>3. Normalize MRL.<br \/>\n<\/p>\n<dl><dd>\u25a1 If the MRL is determined on a mass basis but sample results are normalized by some factor, such as sample volume, we compute a sample-specific concentration-based MRL by dividing the mass-based MRL by the sample volume.<br \/><\/dd><\/dl>\n<p>4. In regards to reporting:<br \/>\n<\/p>\n<dl><dd>\u25a1 We do not count estimated values (0.5 flags) as detects when reporting %\u2009>\u2009MRL. We do not use estimated detects to calculate summary statistics such as percentiles (see Table shell S2 in Additional file 2).<br \/><\/dd>\n<dd>\u25a1 In summary statistics, we identify any chemicals with greater than 50% estimated detects and add a footnote: \u201cImprecise quantification for more than 50% of detected values.\u201d<br \/><\/dd>\n<dd>\u25a1 Graphical presentations should distinguish estimated from true detects (e.g., by plotting as different shapes, see Fig. 5).<br \/><\/dd>\n<dd>\u25a1 For reporting in tables, we use median sample volume across samples to convert mass-based MRL to a single concentration-based MRL for each chemical, if applicable.<br \/><\/dd>\n<dd>\u25a1 There are different approaches for incorporating estimated or 0.5 flagged values in statistical analyses, including performing analyses weighted by estimates of the measurement precision below the MRL, or using censored regression methods.<sup id=\"rdp-ebb-cite_ref-HelselStat12_23-1\" class=\"reference\"><a href=\"#cite_note-HelselStat12-23\">[23]<\/a><\/sup> However any approach that incorporates estimated values is preferable to procedures that substitute with the DL, \u00bd DL, zero, or remove these values, a practice which can introduce bias.<sup id=\"rdp-ebb-cite_ref-NewtonEstim07_25-1\" class=\"reference\"><a href=\"#cite_note-NewtonEstim07-25\">[25]<\/a><\/sup><\/dd><\/dl>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>After we establish the MRL for chemicals that are detected in blanks, we are confident that levels in samples above that value are true detects and that they are correctly ranked, but there may still be concern about consistent bias in the actual numeric values being reported, both from contamination in the field or lab or from bias in the analytical method. Consistent bias in levels would not be a major concern for ranking individual exposure or comparing groups within a study but is misleading when comparing to levels reported in other studies. For each chemical, we check for evidence of consistent bias across many blanks and correct concentrations reported in summary tables in our papers to reduce this bias (see Table 7).\n<\/p>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table class=\"wikitable\" border=\"1\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\" colspan=\"1\"><b>Table 7.<\/b> Steps for blank correction (see Additional file 4 for an example of this approach with real data)\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">\n<p>1. Which blanks to use?<br \/>\n<\/p>\n<dl><dd>\u25a1 If detects are spread across all types of blanks (e.g., field, solvent method, matrix), we use all blanks for blank correction. Otherwise we use field blanks. We try to keep our blank correction approach consistent with our MRL approach.<br \/><\/dd><\/dl>\n<p>2. Which chemicals get corrected?<br \/>\n<\/p>\n<dl><dd>\u25a1 If\u2009>\u20095 blanks:<br \/>\n<dl><dd>\u25cb For each chemical, we use a one-sided one sample sign test (special case of binomial test with p\u2009=\u20090.5) to determine whether the median of blanks is statistically significantly different from zero. True and estimated detects are treated as positive values and non-detects as negative values.<br \/>\n<dl><dd>\u25aa We blank-correct chemicals with a sign test p-value <\u20090.05.<br \/><\/dd>\n<dd>\u25aa However, if the number of blanks is relatively small (10 or fewer) we consider blank correction even when the sign test does not produce a significant result. The sign test does not take into account the magnitude of the levels detected in the blanks nor does it distinguish different types of blanks (i.e., field and lab).<br \/><\/dd>\n<dd>\u2022 For example, if we have 3 field blanks and 4 lab blanks, and we see consistent levels detected across all field blanks and all but one lab blank, we would consider blank correcting even though the sign test would produce p\u2009>\u20090.05.<br \/><\/dd><\/dl><\/dd><\/dl><\/dd>\n<dd>\u25a1 If\u2009\u2264\u20095 blanks (i.e., for a small dataset):<br \/>\n<dl><dd>\u25cb With five or fewer blanks, the sign test will never be significant. In this case, we blank-correct chemicals with 100% detects in blanks.<br \/><\/dd><\/dl><\/dd><\/dl>\n<p>3. Blank correction:<br \/>\n<\/p>\n<dl><dd>\u25a1 Calculate the median value of the blanks, with non-detects set to \u00bd lab\u2019s reporting limit and using all values (i.e., estimated and true detects).<br \/>\n<dl><dd>\u25cb It is useful to pause here and assess the value being used for blank correction. Is it based on an estimated value below the MRL? What will be the percent change in the median, comparing the original to the blank-corrected data?<br \/><\/dd><\/dl><\/dd>\n<dd>\u25a1 Subtract median blank value from all sample results.<br \/><\/dd>\n<dd>\u25a1 Subtract median blank value from the MRL (determined as in Table 6).<br \/><\/dd><\/dl>\n<p>4. In regards to reporting:<br \/>\n<\/p>\n<dl><dd>\u25a1 We are explicit about whatever procedure we use to decide whether or not to perform blank correction (sign test or other) and about the statistic (e.g., median, mean) and amount used for correction.<br \/><\/dd>\n<dd>\u25a1 Any presentation of measurements (e.g., summary statistics) should use blank-corrected values because they may be compared with measurements in other studies.<br \/><\/dd>\n<dd>\u25a1 For statistical analyses such as regression and correlation performed within the dataset, non-blank-corrected data can be used.<\/dd><\/dl>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<h3><span class=\"mw-headline\" id=\"How_precise_are_these_measurements.3F\">How precise are these measurements?<\/span><\/h3>\n<h4><span class=\"mw-headline\" id=\"Duplicates_2\">Duplicates<\/span><\/h4>\n<p>Duplicate samples indicate whether variation in our data is explained by imprecision. If duplicate samples have high reproducibility, meaning that the relative percent difference between measurements in duplicate samples is less than 30%, it adds to confidence in the field sample results. In fact, excellent precision in duplicate samples can influence a decision about how to treat data for a chemical that has sporadic blank contamination or variable spiked sample or CRM recoveries because it can indicate that the results are reproducible. On the other hand, consistently poor precision for dust wipe samples, for example, has informed our decision to rely more heavily on measured air concentrations as an indicator of home exposure.<sup id=\"rdp-ebb-cite_ref-DodsonChem17_30-0\" class=\"reference\"><a href=\"#cite_note-DodsonChem17-30\">[30]<\/a><\/sup> Table 8 outlines our approach for analyzing duplicate data.\n<\/p>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table class=\"wikitable\" border=\"1\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\" colspan=\"1\"><b>Table 8.<\/b> Steps for duplicates (see Additional file 4 for an example of this approach with real data)\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">\n<p>1. Compute precision.<br \/>\n<\/p>\n<dl><dd>\u25a1 Compute & summarize average relative percent difference (RPD) for duplicate pairs or, if \u22653 side-by-side samples, compute relative standard deviation (RSD):<br \/>\n<dl><dd>\u25cb If sample results have been normalized (e.g., mass converted to concentration), compute precision with normalized values.<br \/><\/dd>\n<dd>\u25cb Compute only for pairs where both samples are detects.<br \/><\/dd>\n<dd>\u25cb Also consider precision restricted to pairs where both samples are flagged as \u201ctrue detects\u201d above the MRL.<br \/><\/dd><\/dl><\/dd><\/dl>\n<p>2. Visualize duplicate pairs.<br \/>\n<\/p>\n<dl><dd>\u25a1 This is a good point to pause and check your data and to note\/investigate anything that looks unusual (e.g., huge difference in results for two members of a duplicate pair, how tight are detect\/non-detect pairs). See Additional file 4: Figure S10A-D for an example.<br \/><\/dd><\/dl>\n<p>3. Average duplicates, with non-detects set to lab\u2019s reporting limit.<br \/>\n<\/p>\n<dl><dd>\u25a1 Calculate average volume and concentration for each pair. Note, can skip this step if only have mass data, or if results were reported by lab as concentrations, rather than as masses that were then normalized to concentrations.<br \/><\/dd>\n<dd>\u25a1 Back calculate new average mass using average volume and average concentration. Or, simply average the duplicate measurements if only have mass data, or if results were reported by lab as concentrations, rather than as masses that were then normalized to concentrations.<br \/><\/dd>\n<dd>\u25a1 Compare new average measurement to MRL to determine data qualifier flag.<br \/><\/dd>\n<dd>\u25a1 Combine duplicate averages back with rest of data.<br \/><\/dd><\/dl>\n<p>4. In regards to reporting:<br \/>\n<\/p>\n<dl><dd>\u25a1 In publications, we note the range of average RPDs across all chemicals in our QA\/QC discussion. We consider average RPD\u2009<\u200930% to be \u201cgood\u201d precision.<br \/><\/dd>\n<dd>\u25a1 If a chemical has sporadic blank contamination or variable spike recoveries, excellent precision can increase our confidence in the field sample results.<\/dd><\/dl>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<h3><span class=\"mw-headline\" id=\"Publication:_How_do_we_tell_others_about_our_data.3F\">Publication: How do we tell others about our data?<\/span><\/h3>\n<p>While it is imperative that a researcher has a thorough understanding of the quality of their own data, it is equally important they clearly communicate the results of the QA\/QC review. When we considered the articles included in our recent review of epidemiologic studies of environmental chemicals and breast cancer<sup id=\"rdp-ebb-cite_ref-RodgersEnviro18_11-1\" class=\"reference\"><a href=\"#cite_note-RodgersEnviro18-11\">[11]<\/a><\/sup>, we identified gaps in reporting and\/or interpretation of QA\/QC data, an issue also noted by LaKind <i>et al.<\/i>.<sup id=\"rdp-ebb-cite_ref-LaKindLessons15_12-1\" class=\"reference\"><a href=\"#cite_note-LaKindLessons15-12\">[12]<\/a><\/sup> To encourage more regular and consistent reporting of QA\/QC results, in supplementary material we provide examples of the tables and plots (Additional file 2: Tables S3, S4, and Figure S1) we have used to communicate QA\/QC findings in our publications. Consistently publishing QA\/QC findings allows readers to think for themselves about the quality of the data and can inform risk of bias assessments in a systematic review. QA\/QC data also provides a basis for determining whether further analyses of the published data (e.g., comparisons to or pooling with other datasets) are appropriate.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Conclusion\">Conclusion<\/span><\/h2>\n<p>Several real examples from our data demonstrate that close examination of lab and field quality control data is worth the effort. By providing a detailed example of how we have processed and drawn conclusions about our own environmental exposure data (Additional file 4), we aim to make our guidelines explicit and straightforward so that others may adopt and build on them.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Abbreviations\">Abbreviations<\/span><\/h2>\n<p><b>CAS<\/b>: Chemical Abstracts Service\n<\/p><p><b>CDC<\/b>: Centers for Disease Control and Prevention\n<\/p><p><b>CRM<\/b>: Certified reference material\n<\/p><p><b>CRQL<\/b>: Contract required quantitation limit\n<\/p><p><b>DEHP<\/b>: Bis(2-ethylhexyl) phthalate\n<\/p><p><b>DL<\/b>: Detection limit\n<\/p><p><b>EPA<\/b>: United States Environmental Protection Agency\n<\/p><p><b>HBCD<\/b>: 1,2,5,6,9,10-Hexabromocyclododecane\n<\/p><p><b>LCS<\/b>: Laboratory control sample\n<\/p><p><b>LOD<\/b>: Limit of detection\n<\/p><p><b>LOQ<\/b>: Limit of quantitation\n<\/p><p><b>LQL<\/b>: Laboratory quantitation level\n<\/p><p><b>MDL<\/b>: Method detection limit\n<\/p><p><b>MRL<\/b>: Method reporting limit\n<\/p><p><b>NIST<\/b>: National Institute of Standards and Technology\n<\/p><p><b>PQL<\/b>: Practical quantitation limit\n<\/p><p><b>PUF<\/b>: Polyurethane foam\n<\/p><p><b>QA\/QC<\/b>: Quality assurance\/quality control\n<\/p><p><b>QC<\/b>: Quality control\n<\/p><p><b>RL<\/b>: Reporting limit\n<\/p><p><b>RPD<\/b>: Relative percent difference\n<\/p><p><b>RSD<\/b>: Relative standard deviation\n<\/p><p><b>SRM<\/b>: Standard reference material\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Supplementary_information\">Supplementary information<\/span><\/h2>\n<ul><li> <b><a rel=\"external_link\" class=\"external text\" href=\"https:\/\/static-content.springer.com\/esm\/art%3A10.1186%2Fs12940-019-0537-8\/MediaObjects\/12940_2019_537_MOESM1_ESM.pdf\" target=\"_blank\">Additional file 1<\/a><\/b>: Table S1. Summary of our application of the Navigation Guide Criteria for Low Risk of Bias Assessment for the question \"Were exposure assessment methods robust?\"<\/li><\/ul>\n<ul><li> <b><a rel=\"external_link\" class=\"external text\" href=\"https:\/\/static-content.springer.com\/esm\/art%3A10.1186%2Fs12940-019-0537-8\/MediaObjects\/12940_2019_537_MOESM2_ESM.pdf\" target=\"_blank\">Additional file 2<\/a><\/b>: Section I: Example lab correspondence. Section II: Table S2. Summary statistics table shell. Table S3. Quality assurance and quality control (QA\/QC) summary table shell. Table S4. Findings and actions from review of quality assurance and quality control (QA\/QC) data table shell. Section III: Figure S1. Distribution of surrogate recoveries by study visit<\/li><\/ul>\n<ul><li> <b><a rel=\"external_link\" class=\"external text\" href=\"https:\/\/static-content.springer.com\/esm\/art%3A10.1186%2Fs12940-019-0537-8\/MediaObjects\/12940_2019_537_MOESM3_ESM.xls\" target=\"_blank\">Additional file 3<\/a><\/b>: Example of report formatting request to send to the lab<\/li><\/ul>\n<ul><li> <b><a rel=\"external_link\" class=\"external text\" href=\"https:\/\/static-content.springer.com\/esm\/art%3A10.1186%2Fs12940-019-0537-8\/MediaObjects\/12940_2019_537_MOESM4_ESM.pdf\" target=\"_blank\">Additional file 4<\/a><\/b>: Example QA\/QC report<\/li><\/ul>\n<h2><span class=\"mw-headline\" id=\"Acknowledgements\">Acknowledgements<\/span><\/h2>\n<p>We thank David Camann, Alice Yau, Marcia Nishioka, Martha McCauley, and Adrian Covaci for helping us make thoughtful decisions about how to interpret our data. We also thank Vincent Bessonneau for helpful discussion and for his valuable comments on a draft of this manuscript. Silent Spring Institute is a scientific research organization dedicated to studying environmental factors in women\u2019s health.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Contributions\">Contributions<\/span><\/h3>\n<p>RAR, RED, and LP developed the detailed data processing approach provided as an example in this manuscript. JU drafted the manuscript. RAR, RED, and LP critically reviewed and revised the manuscript. All authors read and approved the final manuscript.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Funding\">Funding<\/span><\/h3>\n<p>This work was funded by the U.S. Department of Housing and Urban Development (Grant No. MAHHU0005\u201312) and by charitable gifts to Silent Spring Institute.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Competing_interests\">Competing interests<\/span><\/h3>\n<p>The authors declare that they have no competing interests.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"References\">References<\/span><\/h2>\n<div class=\"reflist references-column-width\" style=\"-moz-column-width: 30em; -webkit-column-width: 30em; column-width: 30em; list-style-type: decimal;\">\n<ol class=\"references\">\n<li id=\"cite_note-WildComplem05-1\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-WildComplem05_1-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Wild, C.P. (2005). \"Complementing the genome with an \"exposome\": the outstanding challenge of environmental exposure measurement in molecular epidemiology\". <i>Cancer Epidemiology, Biomarkers & Preventions<\/i> <b>14<\/b> (8): 1847\u201350. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1158%2F1055-9965.EPI-05-0456\" target=\"_blank\">10.1158\/1055-9965.EPI-05-0456<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/16103423\" target=\"_blank\">16103423<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Complementing+the+genome+with+an+%22exposome%22%3A+the+outstanding+challenge+of+environmental+exposure+measurement+in+molecular+epidemiology&rft.jtitle=Cancer+Epidemiology%2C+Biomarkers+%26+Preventions&rft.aulast=Wild%2C+C.P.&rft.au=Wild%2C+C.P.&rft.date=2005&rft.volume=14&rft.issue=8&rft.pages=1847%E2%80%9350&rft_id=info:doi\/10.1158%2F1055-9965.EPI-05-0456&rft_id=info:pmid\/16103423&rfr_id=info:sid\/en.wikipedia.org:Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-CarlinUnrav13-2\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-CarlinUnrav13_2-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Carlin, D.J.; Rider, C.V.; Woychik, R. et al. (2013). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3553446\" target=\"_blank\">\"Unraveling the health effects of environmental mixtures: An NIEHS priority\"<\/a>. <i>Environmental Health Perspectives<\/i> <b>121<\/b> (1): A6\u20138. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1289%2Fehp.1206182\" target=\"_blank\">10.1289\/ehp.1206182<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC3553446\/\" target=\"_blank\">PMC3553446<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/23409283\" target=\"_blank\">23409283<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3553446\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3553446<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Unraveling+the+health+effects+of+environmental+mixtures%3A+An+NIEHS+priority&rft.jtitle=Environmental+Health+Perspectives&rft.aulast=Carlin%2C+D.J.%3B+Rider%2C+C.V.%3B+Woychik%2C+R.+et+al.&rft.au=Carlin%2C+D.J.%3B+Rider%2C+C.V.%3B+Woychik%2C+R.+et+al.&rft.date=2013&rft.volume=121&rft.issue=1&rft.pages=A6%E2%80%938&rft_id=info:doi\/10.1289%2Fehp.1206182&rft_id=info:pmc\/PMC3553446&rft_id=info:pmid\/23409283&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC3553446&rfr_id=info:sid\/en.wikipedia.org:Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-EPAQuality19-3\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-EPAQuality19_3-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">U.S. Environmental Protection Agency (March 2019). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.epa.gov\/citizen-science\/quality-assurance-handbook-and-guidance-documents-citizen-science-projects\" target=\"_blank\">\"Quality Assurance Handbook and Guidance Documents for Citizen Science Projects\"<\/a>. U.S. Environmental Protection Agency<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.epa.gov\/citizen-science\/quality-assurance-handbook-and-guidance-documents-citizen-science-projects\" target=\"_blank\">https:\/\/www.epa.gov\/citizen-science\/quality-assurance-handbook-and-guidance-documents-citizen-science-projects<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 28 May 2019<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Quality+Assurance+Handbook+and+Guidance+Documents+for+Citizen+Science+Projects&rft.atitle=&rft.aulast=U.S.+Environmental+Protection+Agency&rft.au=U.S.+Environmental+Protection+Agency&rft.date=March+2019&rft.pub=U.S.+Environmental+Protection+Agency&rft_id=https%3A%2F%2Fwww.epa.gov%2Fcitizen-science%2Fquality-assurance-handbook-and-guidance-documents-citizen-science-projects&rfr_id=info:sid\/en.wikipedia.org:Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-CDCImprov18-4\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-CDCImprov18_4-0\">4.0<\/a><\/sup> <sup><a href=\"#cite_ref-CDCImprov18_4-1\">4.1<\/a><\/sup> <sup><a href=\"#cite_ref-CDCImprov18_4-2\">4.2<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation web\">Centers for Disease Control and Preventions (March 2018). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.cdc.gov\/biomonitoring\/pdf\/Human_Sample_Collection-508.pdf\" target=\"_blank\">\"Improving the Collection and Management of Human Samples Used for Measuring Environmental Chemicals and Nutrition Indicators\"<\/a> (PDF). Centers for Disease Control and Prevention<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.cdc.gov\/biomonitoring\/pdf\/Human_Sample_Collection-508.pdf\" target=\"_blank\">https:\/\/www.cdc.gov\/biomonitoring\/pdf\/Human_Sample_Collection-508.pdf<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 28 May 2019<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Improving+the+Collection+and+Management+of+Human+Samples+Used+for+Measuring+Environmental+Chemicals+and+Nutrition+Indicators&rft.atitle=&rft.aulast=Centers+for+Disease+Control+and+Preventions&rft.au=Centers+for+Disease+Control+and+Preventions&rft.date=March+2018&rft.pub=Centers+for+Disease+Control+and+Prevention&rft_id=https%3A%2F%2Fwww.cdc.gov%2Fbiomonitoring%2Fpdf%2FHuman_Sample_Collection-508.pdf&rfr_id=info:sid\/en.wikipedia.org:Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-LaKindAProp14-5\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-LaKindAProp14_5-0\">5.0<\/a><\/sup> <sup><a href=\"#cite_ref-LaKindAProp14_5-1\">5.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">LaKind, J.S.; Sobus, J.R.; Goodman, M. et al. (2014). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4310547\" target=\"_blank\">\"A proposal for assessing study quality: Biomonitoring, Environmental Epidemiology, and Short-lived Chemicals (BEES-C) instrument\"<\/a>. <i>Environment International<\/i> <b>73<\/b>: 195\u2013207. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.envint.2014.07.011\" target=\"_blank\">10.1016\/j.envint.2014.07.011<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC4310547\/\" target=\"_blank\">PMC4310547<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/25137624\" target=\"_blank\">25137624<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4310547\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4310547<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=A+proposal+for+assessing+study+quality%3A+Biomonitoring%2C+Environmental+Epidemiology%2C+and+Short-lived+Chemicals+%28BEES-C%29+instrument&rft.jtitle=Environment+International&rft.aulast=LaKind%2C+J.S.%3B+Sobus%2C+J.R.%3B+Goodman%2C+M.+et+al.&rft.au=LaKind%2C+J.S.%3B+Sobus%2C+J.R.%3B+Goodman%2C+M.+et+al.&rft.date=2014&rft.volume=73&rft.pages=195%E2%80%93207&rft_id=info:doi\/10.1016%2Fj.envint.2014.07.011&rft_id=info:pmc\/PMC4310547&rft_id=info:pmid\/25137624&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC4310547&rfr_id=info:sid\/en.wikipedia.org:Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-LaKindExpo19-6\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-LaKindExpo19_6-0\">6.0<\/a><\/sup> <sup><a href=\"#cite_ref-LaKindExpo19_6-1\">6.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">LaKind, J.S.; O'Mahony, C.; Armstrong, T. et al. (2019). \"ExpoQual: Evaluating measured and modeled human exposure data\". <i>Environmental Research<\/i> <b>171<\/b>: 302-312. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.envres.2019.01.039\" target=\"_blank\">10.1016\/j.envres.2019.01.039<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/30708234\" target=\"_blank\">30708234<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=ExpoQual%3A+Evaluating+measured+and+modeled+human+exposure+data&rft.jtitle=Environmental+Research&rft.aulast=LaKind%2C+J.S.%3B+O%27Mahony%2C+C.%3B+Armstrong%2C+T.+et+al.&rft.au=LaKind%2C+J.S.%3B+O%27Mahony%2C+C.%3B+Armstrong%2C+T.+et+al.&rft.date=2019&rft.volume=171&rft.pages=302-312&rft_id=info:doi\/10.1016%2Fj.envres.2019.01.039&rft_id=info:pmid\/30708234&rfr_id=info:sid\/en.wikipedia.org:Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-CampbellQuant13-7\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-CampbellQuant13_7-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Campbell, J.L.; Rustad, L.E.; Porter, J.H. et al. (2013). \"Quantity is Nothing without Quality: Automated QA\/QC for Streaming Environmental Sensor Data\". <i>BioScience<\/i> <b>63<\/b> (7): 574\u2013585. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1525%2Fbio.2013.63.7.10\" target=\"_blank\">10.1525\/bio.2013.63.7.10<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Quantity+is+Nothing+without+Quality%3A+Automated+QA%2FQC+for+Streaming+Environmental+Sensor+Data&rft.jtitle=BioScience&rft.aulast=Campbell%2C+J.L.%3B+Rustad%2C+L.E.%3B+Porter%2C+J.H.+et+al.&rft.au=Campbell%2C+J.L.%3B+Rustad%2C+L.E.%3B+Porter%2C+J.H.+et+al.&rft.date=2013&rft.volume=63&rft.issue=7&rft.pages=574%E2%80%93585&rft_id=info:doi\/10.1525%2Fbio.2013.63.7.10&rfr_id=info:sid\/en.wikipedia.org:Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-MichenerTen15-8\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-MichenerTen15_8-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Michener, W.K. (2015). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4619636\" target=\"_blank\">\"Ten Simple Rules for Creating a Good Data Management Plan\"<\/a>. <i>PLoS Computational Biology<\/i> <b>11<\/b> (10): e1004525. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1371%2Fjournal.pcbi.1004525\" target=\"_blank\">10.1371\/journal.pcbi.1004525<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC4619636\/\" target=\"_blank\">PMC4619636<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/26492633\" target=\"_blank\">26492633<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4619636\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4619636<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Ten+Simple+Rules+for+Creating+a+Good+Data+Management+Plan&rft.jtitle=PLoS+Computational+Biology&rft.aulast=Michener%2C+W.K.&rft.au=Michener%2C+W.K.&rft.date=2015&rft.volume=11&rft.issue=10&rft.pages=e1004525&rft_id=info:doi\/10.1371%2Fjournal.pcbi.1004525&rft_id=info:pmc\/PMC4619636&rft_id=info:pmid\/26492633&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC4619636&rfr_id=info:sid\/en.wikipedia.org:Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-CalafatOptimal15-9\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-CalafatOptimal15_9-0\">9.0<\/a><\/sup> <sup><a href=\"#cite_ref-CalafatOptimal15_9-1\">9.1<\/a><\/sup> <sup><a href=\"#cite_ref-CalafatOptimal15_9-2\">9.2<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Calafat, A.M.; Longnecker, M.P.; Koch, H.M. et al. (2015). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4492274\" target=\"_blank\">\"Optimal Exposure Biomarkers for Nonpersistent Chemicals in Environmental Epidemiology\"<\/a>. <i>Environmental Health Perspectives<\/i> <b>123<\/b> (7): A166\u20138. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1289%2Fehp.1510041\" target=\"_blank\">10.1289\/ehp.1510041<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC4492274\/\" target=\"_blank\">PMC4492274<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/26132373\" target=\"_blank\">26132373<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4492274\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4492274<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Optimal+Exposure+Biomarkers+for+Nonpersistent+Chemicals+in+Environmental+Epidemiology&rft.jtitle=Environmental+Health+Perspectives&rft.aulast=Calafat%2C+A.M.%3B+Longnecker%2C+M.P.%3B+Koch%2C+H.M.+et+al.&rft.au=Calafat%2C+A.M.%3B+Longnecker%2C+M.P.%3B+Koch%2C+H.M.+et+al.&rft.date=2015&rft.volume=123&rft.issue=7&rft.pages=A166%E2%80%938&rft_id=info:doi\/10.1289%2Fehp.1510041&rft_id=info:pmc\/PMC4492274&rft_id=info:pmid\/26132373&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC4492274&rfr_id=info:sid\/en.wikipedia.org:Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-LamTheNav14-10\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-LamTheNav14_10-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Lam, J.; Koustas, E.; Sutton, P. et al. (2014). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4181930\" target=\"_blank\">\"The Navigation Guide - Evidence-based medicine meets environmental health: Integration of animal and human evidence for PFOA effects on fetal growth\"<\/a>. <i>Environmental Health Perspectives<\/i> <b>122<\/b> (10): 1040-51. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1289%2Fehp.1307923\" target=\"_blank\">10.1289\/ehp.1307923<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC4181930\/\" target=\"_blank\">PMC4181930<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/24968389\" target=\"_blank\">24968389<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4181930\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4181930<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=The+Navigation+Guide+-+Evidence-based+medicine+meets+environmental+health%3A+Integration+of+animal+and+human+evidence+for+PFOA+effects+on+fetal+growth&rft.jtitle=Environmental+Health+Perspectives&rft.aulast=Lam%2C+J.%3B+Koustas%2C+E.%3B+Sutton%2C+P.+et+al.&rft.au=Lam%2C+J.%3B+Koustas%2C+E.%3B+Sutton%2C+P.+et+al.&rft.date=2014&rft.volume=122&rft.issue=10&rft.pages=1040-51&rft_id=info:doi\/10.1289%2Fehp.1307923&rft_id=info:pmc\/PMC4181930&rft_id=info:pmid\/24968389&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC4181930&rfr_id=info:sid\/en.wikipedia.org:Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-RodgersEnviro18-11\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-RodgersEnviro18_11-0\">11.0<\/a><\/sup> <sup><a href=\"#cite_ref-RodgersEnviro18_11-1\">11.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Rodgers, K.M.; Udesky, J.O.; Rudel, R.A. et al. (2018). \"Environmental chemicals and breast cancer: An updated review of epidemiological literature informed by biological mechanisms\". <i>Environmental Research<\/i> <b>160<\/b>: 152\u201382. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.envres.2017.08.045\" target=\"_blank\">10.1016\/j.envres.2017.08.045<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/28987728\" target=\"_blank\">28987728<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Environmental+chemicals+and+breast+cancer%3A+An+updated+review+of+epidemiological+literature+informed+by+biological+mechanisms&rft.jtitle=Environmental+Research&rft.aulast=Rodgers%2C+K.M.%3B+Udesky%2C+J.O.%3B+Rudel%2C+R.A.+et+al.&rft.au=Rodgers%2C+K.M.%3B+Udesky%2C+J.O.%3B+Rudel%2C+R.A.+et+al.&rft.date=2018&rft.volume=160&rft.pages=152%E2%80%9382&rft_id=info:doi\/10.1016%2Fj.envres.2017.08.045&rft_id=info:pmid\/28987728&rfr_id=info:sid\/en.wikipedia.org:Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-LaKindLessons15-12\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-LaKindLessons15_12-0\">12.0<\/a><\/sup> <sup><a href=\"#cite_ref-LaKindLessons15_12-1\">12.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">LaKind, J.S.; Goodman, M.; Barr, D.B. et al. (2015). \"Lessons learned from the application of BEES-C: Systematic assessment of study quality of epidemiologic research on BPA, neurodevelopment, and respiratory health\". <i>Environment International<\/i> <b>80<\/b>: 41\u201371. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.envint.2015.03.015\" target=\"_blank\">10.1016\/j.envint.2015.03.015<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/25884849\" target=\"_blank\">25884849<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Lessons+learned+from+the+application+of+BEES-C%3A+Systematic+assessment+of+study+quality+of+epidemiologic+research+on+BPA%2C+neurodevelopment%2C+and+respiratory+health&rft.jtitle=Environment+International&rft.aulast=LaKind%2C+J.S.%3B+Goodman%2C+M.%3B+Barr%2C+D.B.+et+al.&rft.au=LaKind%2C+J.S.%3B+Goodman%2C+M.%3B+Barr%2C+D.B.+et+al.&rft.date=2015&rft.volume=80&rft.pages=41%E2%80%9371&rft_id=info:doi\/10.1016%2Fj.envint.2015.03.015&rft_id=info:pmid\/25884849&rfr_id=info:sid\/en.wikipedia.org:Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-RudelSemi10-13\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-RudelSemi10_13-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Rudel, R.A.; Dodson, R.E.; Perovich, L.J. et al. (2010). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2930400\" target=\"_blank\">\"Semivolatile endocrine-disrupting compounds in paired indoor and outdoor air in two northern California communities\"<\/a>. <i>Environmental Science & Technology<\/i> <b>44<\/b> (17): 6583-90. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1021%2Fes100159c\" target=\"_blank\">10.1021\/es100159c<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC2930400\/\" target=\"_blank\">PMC2930400<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/20681565\" target=\"_blank\">20681565<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2930400\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2930400<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Semivolatile+endocrine-disrupting+compounds+in+paired+indoor+and+outdoor+air+in+two+northern+California+communities&rft.jtitle=Environmental+Science+%26+Technology&rft.aulast=Rudel%2C+R.A.%3B+Dodson%2C+R.E.%3B+Perovich%2C+L.J.+et+al.&rft.au=Rudel%2C+R.A.%3B+Dodson%2C+R.E.%3B+Perovich%2C+L.J.+et+al.&rft.date=2010&rft.volume=44&rft.issue=17&rft.pages=6583-90&rft_id=info:doi\/10.1021%2Fes100159c&rft_id=info:pmc\/PMC2930400&rft_id=info:pmid\/20681565&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC2930400&rfr_id=info:sid\/en.wikipedia.org:Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-WentworthReview01-14\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-WentworthReview01_14-0\">14.0<\/a><\/sup> <sup><a href=\"#cite_ref-WentworthReview01_14-1\">14.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation web\">Wentworth, N. (28 September 2001). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/colowqforum.org\/pdfs\/whole-effluent-toxicity\/documents\/g5i-prd.pdf\" target=\"_blank\">\"Review of <i>Guidance on Data Quality Indicators (EPA QA\/G-5i)<\/i>\"<\/a> (PDF). U.S. Environmental Protection Agency<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/colowqforum.org\/pdfs\/whole-effluent-toxicity\/documents\/g5i-prd.pdf\" target=\"_blank\">http:\/\/colowqforum.org\/pdfs\/whole-effluent-toxicity\/documents\/g5i-prd.pdf<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 28 May 2019<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Review+of+%27%27Guidance+on+Data+Quality+Indicators+%28EPA+QA%2FG-5i%29%27%27&rft.atitle=&rft.aulast=Wentworth%2C+N.&rft.au=Wentworth%2C+N.&rft.date=28+September+2001&rft.pub=U.S.+Environmental+Protection+Agency&rft_id=http%3A%2F%2Fcolowqforum.org%2Fpdfs%2Fwhole-effluent-toxicity%2Fdocuments%2Fg5i-prd.pdf&rfr_id=info:sid\/en.wikipedia.org:Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-EPALab94-15\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-EPALab94_15-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">U.S. Environmental Protection Agency (December 1994). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/nepis.epa.gov\/Exe\/ZyPURL.cgi?Dockey=20012TGE.TXT\" target=\"_blank\">\"Laboratory Data Validation Functional Guidelines For Evaluating Organics Analyses\"<\/a>. U.S. Environmental Protection Agency<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/nepis.epa.gov\/Exe\/ZyPURL.cgi?Dockey=20012TGE.TXT\" target=\"_blank\">https:\/\/nepis.epa.gov\/Exe\/ZyPURL.cgi?Dockey=20012TGE.TXT<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 28 May 2019<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Laboratory+Data+Validation+Functional+Guidelines+For+Evaluating+Organics+Analyses&rft.atitle=&rft.aulast=U.S.+Environmental+Protection+Agency&rft.au=U.S.+Environmental+Protection+Agency&rft.date=December+1994&rft.pub=U.S.+Environmental+Protection+Agency&rft_id=https%3A%2F%2Fnepis.epa.gov%2FExe%2FZyPURL.cgi%3FDockey%3D20012TGE.TXT&rfr_id=info:sid\/en.wikipedia.org:Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-USACEGuidance05-16\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-USACEGuidance05_16-0\">16.0<\/a><\/sup> <sup><a href=\"#cite_ref-USACEGuidance05_16-1\">16.1<\/a><\/sup> <sup><a href=\"#cite_ref-USACEGuidance05_16-2\">16.2<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation web\">U.S. Army Corps of Engineers (30 June 2005). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.publications.usace.army.mil\/Portals\/76\/Publications\/EngineerManuals\/EM_200-1-10.pdf?ver=2013-09-04-070852-230\" target=\"_blank\">\"Guidance for Evaluating Performance-Based Chemical Data\"<\/a> (PDF). U.S. Army Corps of Engineers<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.publications.usace.army.mil\/Portals\/76\/Publications\/EngineerManuals\/EM_200-1-10.pdf?ver=2013-09-04-070852-230\" target=\"_blank\">https:\/\/www.publications.usace.army.mil\/Portals\/76\/Publications\/EngineerManuals\/EM_200-1-10.pdf?ver=2013-09-04-070852-230<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 28 May 2019<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Guidance+for+Evaluating+Performance-Based+Chemical+Data&rft.atitle=&rft.aulast=U.S.+Army+Corps+of+Engineers&rft.au=U.S.+Army+Corps+of+Engineers&rft.date=30+June+2005&rft.pub=U.S.+Army+Corps+of+Engineers&rft_id=https%3A%2F%2Fwww.publications.usace.army.mil%2FPortals%2F76%2FPublications%2FEngineerManuals%2FEM_200-1-10.pdf%3Fver%3D2013-09-04-070852-230&rfr_id=info:sid\/en.wikipedia.org:Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-GeboyQuality11-17\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-GeboyQuality11_17-0\">17.0<\/a><\/sup> <sup><a href=\"#cite_ref-GeboyQuality11_17-1\">17.1<\/a><\/sup> <sup><a href=\"#cite_ref-GeboyQuality11_17-2\">17.2<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation web\">Geboy, N.J.; Engle, M.A. (07 September 2011). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/pubs.usgs.gov\/of\/2011\/1187\/\" target=\"_blank\">\"Quality Assurance and Quality Control of Geochemical Data: A Primer for the Research Scientist\"<\/a>. <i>Open-File Report 2011\u20131187<\/i>. U.S. Geological Survey<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/pubs.usgs.gov\/of\/2011\/1187\/\" target=\"_blank\">https:\/\/pubs.usgs.gov\/of\/2011\/1187\/<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 28 May 2019<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Quality+Assurance+and+Quality+Control+of+Geochemical+Data%3A+A+Primer+for+the+Research+Scientist&rft.atitle=Open-File+Report+2011%E2%80%931187&rft.aulast=Geboy%2C+N.J.%3B+Engle%2C+M.A.&rft.au=Geboy%2C+N.J.%3B+Engle%2C+M.A.&rft.date=07+September+2011&rft.pub=U.S.+Geological+Survey&rft_id=https%3A%2F%2Fpubs.usgs.gov%2Fof%2F2011%2F1187%2F&rfr_id=info:sid\/en.wikipedia.org:Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-NISTStandard1Av17-18\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-NISTStandard1Av17_18-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">NIST (19 June 2014). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.nist.gov\/srd\/nist-standard-reference-database-1a-v17\" target=\"_blank\">\"NIST Standard Reference Database 1A v17\"<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.nist.gov\/srd\/nist-standard-reference-database-1a-v17\" target=\"_blank\">https:\/\/www.nist.gov\/srd\/nist-standard-reference-database-1a-v17<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 28 May 2019<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=NIST+Standard+Reference+Database+1A+v17&rft.atitle=&rft.aulast=NIST&rft.au=NIST&rft.date=19+June+2014&rft_id=https%3A%2F%2Fwww.nist.gov%2Fsrd%2Fnist-standard-reference-database-1a-v17&rfr_id=info:sid\/en.wikipedia.org:Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-UlrichEPA19-19\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-UlrichEPA19_19-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Ulrich, E.M.; Sobus, J.R.; Grulke, C.M. et al. (2019). \"EPA's non-targeted analysis collaborative trial (ENTACT): Genesis, design, and initial findings\". <i>Analytical and Bioanalytical Chemistry<\/i> <b>411<\/b> (4): 853\u201366. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1007%2Fs00216-018-1435-6\" target=\"_blank\">10.1007\/s00216-018-1435-6<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/30519961\" target=\"_blank\">30519961<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=EPA%27s+non-targeted+analysis+collaborative+trial+%28ENTACT%29%3A+Genesis%2C+design%2C+and+initial+findings&rft.jtitle=Analytical+and+Bioanalytical+Chemistry&rft.aulast=Ulrich%2C+E.M.%3B+Sobus%2C+J.R.%3B+Grulke%2C+C.M.+et+al.&rft.au=Ulrich%2C+E.M.%3B+Sobus%2C+J.R.%3B+Grulke%2C+C.M.+et+al.&rft.date=2019&rft.volume=411&rft.issue=4&rft.pages=853%E2%80%9366&rft_id=info:doi\/10.1007%2Fs00216-018-1435-6&rft_id=info:pmid\/30519961&rfr_id=info:sid\/en.wikipedia.org:Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-L.C3.B6tschData17-20\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-L.C3.B6tschData17_20-0\">20.0<\/a><\/sup> <sup><a href=\"#cite_ref-L.C3.B6tschData17_20-1\">20.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">L\u00f6tsch, J. (2017). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5723702\" target=\"_blank\">\"Data visualizations to detect systematic errors in laboratory assay results\"<\/a>. <i>Pharmacology Research & Perspectives<\/i> <b>5<\/b> (6): e00369. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1002%2Fprp2.369\" target=\"_blank\">10.1002\/prp2.369<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC5723702\/\" target=\"_blank\">PMC5723702<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/29226627\" target=\"_blank\">29226627<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5723702\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5723702<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Data+visualizations+to+detect+systematic+errors+in+laboratory+assay+results&rft.jtitle=Pharmacology+Research+%26+Perspectives&rft.aulast=L%C3%B6tsch%2C+J.&rft.au=L%C3%B6tsch%2C+J.&rft.date=2017&rft.volume=5&rft.issue=6&rft.pages=e00369&rft_id=info:doi\/10.1002%2Fprp2.369&rft_id=info:pmc\/PMC5723702&rft_id=info:pmid\/29226627&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC5723702&rfr_id=info:sid\/en.wikipedia.org:Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-DodsonSemi15-21\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-DodsonSemi15_21-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Dodson, R.E.; Camann, D.E.; Morello-Frosch, R. et al. (2015). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4288060\" target=\"_blank\">\"Semivolatile organic compounds in homes: Strategies for efficient and systematic exposure measurement based on empirical and theoretical factors\"<\/a>. <i>Environmental Science & Technology<\/i> <b>49<\/b> (1): 113-22. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1021%2Fes502988r\" target=\"_blank\">10.1021\/es502988r<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC4288060\/\" target=\"_blank\">PMC4288060<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/25488487\" target=\"_blank\">25488487<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4288060\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4288060<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Semivolatile+organic+compounds+in+homes%3A+Strategies+for+efficient+and+systematic+exposure+measurement+based+on+empirical+and+theoretical+factors&rft.jtitle=Environmental+Science+%26+Technology&rft.aulast=Dodson%2C+R.E.%3B+Camann%2C+D.E.%3B+Morello-Frosch%2C+R.+et+al.&rft.au=Dodson%2C+R.E.%3B+Camann%2C+D.E.%3B+Morello-Frosch%2C+R.+et+al.&rft.date=2015&rft.volume=49&rft.issue=1&rft.pages=113-22&rft_id=info:doi\/10.1021%2Fes502988r&rft_id=info:pmc\/PMC4288060&rft_id=info:pmid\/25488487&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC4288060&rfr_id=info:sid\/en.wikipedia.org:Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-EPAMethod8000D-22\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-EPAMethod8000D_22-0\">22.0<\/a><\/sup> <sup><a href=\"#cite_ref-EPAMethod8000D_22-1\">22.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation web\">U.S. Environmental Protection Agency (December 2015). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.epa.gov\/sites\/production\/files\/2015-12\/documents\/8000d.pdf\" target=\"_blank\">\"Method 8000D: Determinative Chromatographic Separations\"<\/a> (PDF). U.S. Environmental Protection Agency<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.epa.gov\/sites\/production\/files\/2015-12\/documents\/8000d.pdf\" target=\"_blank\">https:\/\/www.epa.gov\/sites\/production\/files\/2015-12\/documents\/8000d.pdf<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 16 August 2019<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Method+8000D%3A+Determinative+Chromatographic+Separations&rft.atitle=&rft.aulast=U.S.+Environmental+Protection+Agency&rft.au=U.S.+Environmental+Protection+Agency&rft.date=December+2015&rft.pub=U.S.+Environmental+Protection+Agency&rft_id=https%3A%2F%2Fwww.epa.gov%2Fsites%2Fproduction%2Ffiles%2F2015-12%2Fdocuments%2F8000d.pdf&rfr_id=info:sid\/en.wikipedia.org:Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-HelselStat12-23\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-HelselStat12_23-0\">23.0<\/a><\/sup> <sup><a href=\"#cite_ref-HelselStat12_23-1\">23.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation book\">Helsel, D.R. (2012). <i>Statistics for Censored Environmental Data Using Minitab and R<\/i> (2nd ed.). Wiley. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/International_Standard_Book_Number\" data-key=\"f64947ba21e884434bd70e8d9e60bae6\">ISBN<\/a> 9780470479889.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=book&rft.btitle=Statistics+for+Censored+Environmental+Data+Using+Minitab+and+R&rft.aulast=Helsel%2C+D.R.&rft.au=Helsel%2C+D.R.&rft.date=2012&rft.edition=2nd&rft.pub=Wiley&rft.isbn=9780470479889&rfr_id=info:sid\/en.wikipedia.org:Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-HelselMuchAdo10-24\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-HelselMuchAdo10_24-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Helsel, D. (2010). \"Much ado about next to nothing: Incorporating nondetects in science\". <i>Annals of Occupational Hygiene<\/i> <b>54<\/b> (3): 257-62. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1093%2Fannhyg%2Fmep092\" target=\"_blank\">10.1093\/annhyg\/mep092<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/20032004\" target=\"_blank\">20032004<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Much+ado+about+next+to+nothing%3A+Incorporating+nondetects+in+science&rft.jtitle=Annals+of+Occupational+Hygiene&rft.aulast=Helsel%2C+D.&rft.au=Helsel%2C+D.&rft.date=2010&rft.volume=54&rft.issue=3&rft.pages=257-62&rft_id=info:doi\/10.1093%2Fannhyg%2Fmep092&rft_id=info:pmid\/20032004&rfr_id=info:sid\/en.wikipedia.org:Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-NewtonEstim07-25\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-NewtonEstim07_25-0\">25.0<\/a><\/sup> <sup><a href=\"#cite_ref-NewtonEstim07_25-1\">25.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Newton, E.; Rudel, R. (2007). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2565512\" target=\"_blank\">\"Estimating correlation with multiply censored data arising from the adjustment of singly censored data\"<\/a>. <i>Environmental Science & Technology<\/i> <b>41<\/b> (1): 221\u20138. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1021%2Fes0608444\" target=\"_blank\">10.1021\/es0608444<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC2565512\/\" target=\"_blank\">PMC2565512<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/17265951\" target=\"_blank\">17265951<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2565512\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2565512<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Estimating+correlation+with+multiply+censored+data+arising+from+the+adjustment+of+singly+censored+data&rft.jtitle=Environmental+Science+%26+Technology&rft.aulast=Newton%2C+E.%3B+Rudel%2C+R.&rft.au=Newton%2C+E.%3B+Rudel%2C+R.&rft.date=2007&rft.volume=41&rft.issue=1&rft.pages=221%E2%80%938&rft_id=info:doi\/10.1021%2Fes0608444&rft_id=info:pmc\/PMC2565512&rft_id=info:pmid\/17265951&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC2565512&rfr_id=info:sid\/en.wikipedia.org:Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ShoariToward18-26\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-ShoariToward18_26-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Shoari, N.; Dub\u00e9, J.S. (2018). \"Toward improved analysis of concentration data: Embracing nondetects\". <i>Environmental Toxicology and Chemistry<\/i> <b>37<\/b> (3): 643-656. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1002%2Fetc.4046\" target=\"_blank\">10.1002\/etc.4046<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/29168890\" target=\"_blank\">29168890<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Toward+improved+analysis+of+concentration+data%3A+Embracing+nondetects&rft.jtitle=Environmental+Toxicology+and+Chemistry&rft.aulast=Shoari%2C+N.%3B+Dub%C3%A9%2C+J.S.&rft.au=Shoari%2C+N.%3B+Dub%C3%A9%2C+J.S.&rft.date=2018&rft.volume=37&rft.issue=3&rft.pages=643-656&rft_id=info:doi\/10.1002%2Fetc.4046&rft_id=info:pmid\/29168890&rfr_id=info:sid\/en.wikipedia.org:Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-NIST_SRM-27\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-NIST_SRM_27-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">NIST. <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www-s.nist.gov\/srmors\/\" target=\"_blank\">\"SRM Order Request System\"<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www-s.nist.gov\/srmors\/\" target=\"_blank\">https:\/\/www-s.nist.gov\/srmors\/<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 28 May 2019<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=SRM+Order+Request+System&rft.atitle=&rft.aulast=NIST&rft.au=NIST&rft_id=https%3A%2F%2Fwww-s.nist.gov%2Fsrmors%2F&rfr_id=info:sid\/en.wikipedia.org:Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-GH_QAQC-28\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-GH_QAQC_28-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Silent Spring Institute. <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/github.com\/SilentSpringInstitute\/QAQC-Toolkit\" target=\"_blank\">\"SilentSpringInstitute\/QAQC-Toolkit\"<\/a>. <i>GitHub<\/i><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/github.com\/SilentSpringInstitute\/QAQC-Toolkit\" target=\"_blank\">https:\/\/github.com\/SilentSpringInstitute\/QAQC-Toolkit<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 28 May 2019<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=SilentSpringInstitute%2FQAQC-Toolkit&rft.atitle=GitHub&rft.aulast=Silent+Spring+Institute&rft.au=Silent+Spring+Institute&rft_id=https%3A%2F%2Fgithub.com%2FSilentSpringInstitute%2FQAQC-Toolkit&rfr_id=info:sid\/en.wikipedia.org:Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-DawsonGround08-29\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-DawsonGround08_29-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Dawson, B.J.M.; Bennett V, G.L.; Belitz, K. (2008). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/pubs.usgs.gov\/ds\/285\/ds285.pdf\" target=\"_blank\">\"Ground-Water Quality Data in the Southern Sacramento Valley, California, 2005\u2014Results from the California GAMA Program\"<\/a> (PDF). U.S. Geological Survey<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/pubs.usgs.gov\/ds\/285\/ds285.pdf\" target=\"_blank\">https:\/\/pubs.usgs.gov\/ds\/285\/ds285.pdf<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 28 May 2019<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Ground-Water+Quality+Data+in+the+Southern+Sacramento+Valley%2C+California%2C+2005%E2%80%94Results+from+the+California+GAMA+Program&rft.atitle=&rft.aulast=Dawson%2C+B.J.M.%3B+Bennett+V%2C+G.L.%3B+Belitz%2C+K.&rft.au=Dawson%2C+B.J.M.%3B+Bennett+V%2C+G.L.%3B+Belitz%2C+K.&rft.date=2008&rft.pub=U.S.+Geological+Survey&rft_id=https%3A%2F%2Fpubs.usgs.gov%2Fds%2F285%2Fds285.pdf&rfr_id=info:sid\/en.wikipedia.org:Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-DodsonChem17-30\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-DodsonChem17_30-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Dodson, R.E.; Udesky, J.O.; Colton, M.D. et al. (2017). \"Chemical exposures in recently renovated low-income housing: Influence of building materials and occupant activities\". <i>Environmental International<\/i> <b>109<\/b>: 114\u201427. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.envint.2017.07.007\" target=\"_blank\">10.1016\/j.envint.2017.07.007<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/28916131\" target=\"_blank\">28916131<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Chemical+exposures+in+recently+renovated+low-income+housing%3A+Influence+of+building+materials+and+occupant+activities&rft.jtitle=Environmental+International&rft.aulast=Dodson%2C+R.E.%3B+Udesky%2C+J.O.%3B+Colton%2C+M.D.+et+al.&rft.au=Dodson%2C+R.E.%3B+Udesky%2C+J.O.%3B+Colton%2C+M.D.+et+al.&rft.date=2017&rft.volume=109&rft.pages=114%E2%80%9427&rft_id=info:doi\/10.1016%2Fj.envint.2017.07.007&rft_id=info:pmid\/28916131&rfr_id=info:sid\/en.wikipedia.org:Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<\/ol><\/div>\n<h2><span class=\"mw-headline\" id=\"Notes\">Notes<\/span><\/h2>\n<p>This presentation is faithful to the original, with only a few minor changes to presentation, spelling, and grammar. We also added PMCID and DOI when they were missing from the original reference.\n<\/p>\n<!-- \nNewPP limit report\nCached time: 20200707205108\nCache expiry: 86400\nDynamic content: false\nCPU time usage: 0.645 seconds\nReal time usage: 2.021 seconds\nPreprocessor visited node count: 23955\/1000000\nPreprocessor generated node count: 37971\/1000000\nPost\u2010expand include size: 199183\/2097152 bytes\nTemplate argument size: 66981\/2097152 bytes\nHighest expansion depth: 18\/40\nExpensive parser function count: 0\/100\n-->\n\n<!-- \nTransclusion expansion time report (%,ms,calls,template)\n100.00% 500.826 1 - -total\n 84.97% 425.575 1 - Template:Reflist\n 70.87% 354.943 30 - Template:Citation\/core\n 50.01% 250.472 18 - Template:Cite_journal\n 21.99% 110.149 11 - Template:Cite_web\n 8.29% 41.498 45 - Template:Citation\/identifier\n 7.66% 38.341 1 - Template:Infobox_journal_article\n 7.28% 36.443 1 - Template:Infobox\n 4.91% 24.584 80 - Template:Infobox\/row\n 3.97% 19.866 32 - Template:Citation\/make_link\n-->\n\n<!-- Saved in parser cache with key limswiki:pcache:idhash:11880-0!*!0!!en!5!* and timestamp 20200707205106 and revision id 39011\n -->\n<\/div><div class=\"printfooter\">Source: <a rel=\"external_link\" class=\"external\" href=\"https:\/\/www.limswiki.org\/index.php\/Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements\">https:\/\/www.limswiki.org\/index.php\/Journal:Wrangling_environmental_exposure_data:_Guidance_for_getting_the_best_information_from_your_laboratory_measurements<\/a><\/div>\n\t\t\t\t\t\t\t\t\t\t<!-- end content -->\n\t\t\t\t\t\t\t\t\t\t<div class=\"visualClear\"><\/div>\n\t\t\t\t<\/div>\n\t\t\t<\/div>\n\t\t<\/div>\n\t\t<!-- end of the left (by default at least) column -->\n\t\t<div class=\"visualClear\"><\/div>\n\t\t\t\t\t\n\t\t<\/div>\n\t\t\n\n<\/body>","1b738084b45b445282479ac65a72296b_images":["https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/7\/76\/Fig1_Udesky_EnviroHealth2019_18.png","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/6\/67\/Fig2_Udesky_EnviroHealth2019_18.png","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/7\/74\/Fig3_Udesky_EnviroHealth2019_18.png","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/9\/9e\/Fig4_Udesky_EnviroHealth2019_18.png","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/1\/1d\/Fig5_Udesky_EnviroHealth2019_18.png"],"1b738084b45b445282479ac65a72296b_timestamp":1594155066,"5a2f572706bf2e7b99579d5658274a83_type":"article","5a2f572706bf2e7b99579d5658274a83_title":"2019 novel coronavirus disease (COVID-19): Paving the road for rapid detection and point-of-care diagnostics (Nguyen et al. 2020)","5a2f572706bf2e7b99579d5658274a83_url":"https:\/\/www.limswiki.org\/index.php\/Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics","5a2f572706bf2e7b99579d5658274a83_plaintext":"\n\n\t\t\n\t\t\t\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t\n\n\t\t\t\tJournal:2019 novel coronavirus disease (COVID-19): Paving the road for rapid detection and point-of-care diagnostics\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t\tFrom LIMSWiki\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\tJump to: navigation, search\n\n\t\t\t\t\t\n\t\t\t\t\tFull article title\n \n2019 novel coronavirus disease (COVID-19): Paving the road for rapid detection and point-of-care diagnosticsJournal\n \nMicromachinesAuthor(s)\n \nNguyen, Trieu; Bang, Dang Duong; Wolff, AndersAuthor affiliation(s)\n \nTechnical University of DenmarkPrimary contact\n \nEmail: awol at dtu dot dkYear published\n \n2020Volume and issue\n \n11(3)Article #\n \n306DOI\n \n10.3390\/mi11030306ISSN\n \n2072-666XDistribution license\n \nCreative Commons Attribution 4.0 InternationalWebsite\n \nhttps:\/\/www.mdpi.com\/2072-666X\/11\/3\/306\/htmDownload\n \nhttps:\/\/www.mdpi.com\/2072-666X\/11\/3\/306\/pdf (PDF)\n\nContents\n\n1 Abstract \n2 Introduction \n3 The need for a rapid detection method and portable detection devices \n4 A potential candidate for rapid detection of SARS-CoV-2: Loop-mediated isothermal amplification (LAMP) assays in PoC devices \n5 Other important factors in fighting COVID-19 \n6 Acknowledgements \n\n6.1 Author contributions \n6.2 Funding \n6.3 Conflicts of interest \n\n\n7 References \n8 Notes \n\n\n\nAbstract \nWe believe a point-of-care (PoC) device for the rapid detection of the 2019 novel coronavirus (SARS-CoV-2) is crucial and urgently needed. With this perspective, we give suggestions regarding a potential candidate for the rapid detection of the coronavirus disease 2019 (COVID-19), as well as factors for the preparedness and response to the outbreak of COVID-19.\nKeywords: COVID-19, Wuhan, 2019 novel coronavirus, point-of-care detection, SARS-CoV-2, loop-mediated isothermal amplification, LAMP assay, polymerase chain reaction, PCR\n\nIntroduction \nOn January 30, 2020, the World Health Organization (WHO) declared a global public health emergency[1] over the outbreak of a novel coronavirus, called the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (previously \"2019 novel coronavirus\" or \"2019-nCoV\"), which originated in Wuhan City, in the Hubei Province of China. On February 11, WHO officially named the disease the coronavirus disease 2019 (COVID-19).[2] Human-to-human transmission (Figure 1) has been confirmed by WHO and by the Centers for Disease Control and Prevention (CDC) of the United States[3], with evidence of person-to-person transmission from three different cases outside China, namely in the U.S.[4], Germany[5], and Vietnam.[6]\n\r\n\n\n\n\n\n\n\n\n\n\n Figure 1. Illustration of the transmission of various coronaviruses, including SARS-CoV-2.[7] Current studies have suggested that the intermediate carriers may be snakes[8] or pangolins[9], but according to WHO the real source is still unknown.[10][11].\n\n\n\nCOVID-19 has continuously spread to 104 countries; the number of confirmed infections reached 109,343 on March 9, 2020[12], and the death toll in China has overtaken the SARS epidemic of 2002\u20132003 and has risen to 3,100.[2] To slow down the spread of COVID-19, at least 50 million people in China have been placed under lockdown.[13] On March 8, 2020, Italy also undertook the same measures, with the northern part of the country getting placed under lockdown, affecting 16 million people.[14] The reproduction number R0 (i.e., the average number of secondary cases generated by a typical infectious individual) is estimated to be 2.68, and the doubling time is estimated to be 6.4 days.[15]\nThe difference in terminology between \"coronavirus\" and \"SARS-Cov-2\" is detailed in Table 1. \n\n\n\n\n\n\n\nTable 1. Difference between the term \"coronavirus\" and \"SARS-CoV-2\"\n\n\nTerm\n\nDescription\n\n\nCoronavirus (CoV)\n\nA large and diverse family of enveloped, positive-stranded RNA viruses, with a ~26\u201332 kilobase genome.[16] The Coronaviridae cover a broad host range, infecting many mammalian and avian species, and induce upper respiratory, gastrointestinal, hepatic, and central nervous system diseases.[17] In the last few decades, coronaviruses have been shown to be capable of also infecting humans. The outbreak of severe acute respiratory syndrome (SARS) in 2003, and, more recently, Middle East respiratory syndrome (MERS) have proved the lethality of coroanviruses when they cross the species barrier and infect humans.[18]\n\n\nSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2)\n\nA new zoonotic human coronavirus, which was reported and announced by the Chinese Center for Disease Control and Prevention (CCDC) on January 9, 2020.[19] This novel coronavirus can lead to coroanvirus disease 2019 (COVID-19) in humans. In spite of the fact that the initial infected cases have been associated with the Huanan South China Seafood Market, the source of SARS-CoV-2 is still unknown (Figure 1). On January 30, 2020, the WHO declared a global public health emergency regarding the outbreak of COVID-19. On March 11, 2020, WHO declared the outbreak of COVID-19 a pandemic.\n\n\n\nThe need for a rapid detection method and portable detection devices \nThe manifestation of the COVID-19 infection is highly nonspecific, including respiratory symptoms, fever, cough, dyspnea, and viral pneumonia.[20] Thus, diagnostic tests specific to this infection are urgently required to confirm suspected cases, screen patients, and conduct virus surveillance.\nIn this scenario, a point-of-care (PoC) device (i.e., a rapid, robust, and cost-efficient device that can be used onsite and in the field, and which does not necessarily require a trained technician to operate[21]) is crucial for the detection of COVID-19. Figure 2 shows the dramatic impact of early detection of infectious diseases in controlling an outbreak.[22][23][24]\n\r\n\n\n\n\n\n\n\n\n\n\n Figure 2. The dramatic impact of the rapid detection of infectious diseases in controlling and preventing an outbreak (adapted from the works of Ke et al.[22], Isere et al.[23], and Jones et al.[24]).\n\n\n\nSuch a PoC device can be used in (but is not limited to) an emergency situation, such as the Diamond Princess cruise ship case. Recently, it was reported that the Diamond Princess cruise ship had been quarantined in Yokohama, Japan, due to a serious spreading of COVID-19 on the ship, with at least 454 infected cases out of 3,700 passengers and crew (reported by WHO[25], February 17, 2020). The detection of COVID-19 may not have been prompt enough as they did not have enough test kits to diagnose all the passengers on the ship in order to timely respond to the rapid spreading of the disease.[26]\nThe current standard molecular technique that is now being used to detect SARS-CoV-2 is real-time reverse transcription polymerase chain reaction (rRT-PCR). This protocol has been documented and available online on the WHO website since January 17, 2020.[27] The testing procedure includes: (i) specimen collection; (ii) packing (storage) and shipment of the clinical specimens; (iii) (good) communication with the laboratory and providing needed information; (iv) laboratory testing; and (v) reporting the results. This rRT-PCR technique requires sophisticated laboratory equipment that is often located at a central laboratory (Biosafety level 2 or above).[4][27][28] Sample transportation is inevitable. As a consequence, the time required to obtain the results can be up to two or three days. In the case of a public health emergency such as the COVID-19 outbreak, this time-consuming process of sample testing is not only extremely disadvantageous, but also dangerous since the virus needs to be contained. \nAnother concern of PCR testing is that commercial PCR-based methods are expensive, depend upon technical expertise, and the presence of viral RNA or DNA does not always reflect acute disease.[29][30][31] Furthermore, using PCR, codetection with other respiratory viruses is frequently encountered in coronaviruse (CoV) testing, and the contribution of positive CoV PCR results to disease severity is not always explicitly exhibited.[29][30][31] Furthermore, as of February 2, 2020 in the United States, as mentioned in the Interim Guidelines for Collecting, Handling, and Testing Clinical Specimens from Persons Under Investigation (PUIs) for 2019 Novel Coronavirus, diagnostic testing for COVID-19 can be conducted only at the CDC, though from February 4 onwards, COVID-19 tests can also be done at laboratories designated by the CDC. Likewise in China, where the outbreak is ongoing, samples had to be sent to Beijing for testing, as reported on January 31.[32] On February 4, China\u2019s own CDC deployed a mobile biosafety laboratory to Wuhan in the Hubei Province to assist with the response.[33][34] On February 5, an emergency test laboratory (biosafety level 2) run by BGI Group (with global heartquarters in Shenzhen, China) was set up in Wuhan in the Hubei Province to assist the COVID-19 epidemic.[35]\n\nA potential candidate for rapid detection of SARS-CoV-2: Loop-mediated isothermal amplification (LAMP) assays in PoC devices \nIn order to overcome the current time-consuming and laborious detection technique using RT-PCR, an alternative molecular amplification technique should be deployed. Loop-mediated isothermal amplification (LAMP) reaction is a novel nucleic acid amplification technique that amplifies DNA with high specificity, efficiency, and rapidity under isothermal conditions. This method uses a set of four specially designed primers, in combination with a DNA polymerase with strand displacement activity[36] to synthesize target DNA up to 109 copies in less than an hour at a constant temperature of 65 \u00b0C. The final products are stem-loop DNAs with multiple inverted repeats of the target, bearing structures with a cauliflower-like appearance. LAMP has high specificity and sensitivity and is simple to perform; hence, soon after its initial development, it became an enormously popular isothermal amplification method in molecular biology, with applications in pathogen detection. LAMP uses strand-displacement polymerases instead of heat denaturation to generate a single-stranded template. As such, it has the advantage of running at a constant temperature, simultaneously reducing the cumbersomeness of a thermocycler as well as the energy required. LAMP technology is proven to be more stable[37] and more sensitive[38] in detection compared to PCR. Other advantages of LAMP compared to those of PCR are shown in Table 2.\n\n\n\n\n\n\n\nTable 2. Comparison between PCR and loop-mediated isothermal amplification (LAMP) reactions\n\n\nPCR\n\nLAMP\n\n\nThermal cycling: Multiple heating and cooling cycles; hence, bulky and cumbersome\n\nIsothermal and continuous amplification: Smaller, simpler, and therefor portable\n\n\nAlways requires sample concentration and preparation: Time-consuming\n\nMore flexible: For detection of viruses such as influenza[39] or human norovirus, LAMP assay offers one-step detection.[40] Sample preparation steps are simplified.\n\n\nMultiple protocols: Complicated and requires a skilled technician\n\nSingle protocol: Faster\n\n\nReaction hindered by inhibitors\n\nReaction tolerates inhibitors and is more stable\n\n\nDiagnostic sensitivity (95%) is currently reported as lower than LAMP[38][40][41]\n\nDiagnostic sensitivity > 95%\n\n\nTechnique is established\n\nTechnique is still being explored\n\n\n\nWe believe that the LAMP assay could be a potential candidate for the point-of-care device application in the detection of COVID-19. The Veterinary Validation of Point-of-Care Diagnostic Instrument (VIVALDI) project[42] is an example of using LAMP in a point-of-care device for the detection of a zoonotic virus causing respiratory symptoms (such as the strains responsible for Avian influenza). With PoC devices such as the VETPOD (Veterinary, Portable, Onsite Detection), which the VIVALDI project is validating[43], detection time can be less than one hour. Besides PoC devices using disposable polymer chips and LAMP assays, as in the VETPOD, a lateral flow strip (LFS) would also be a suitable candidate for the rapid and on-site detection of COVID-19. A device such as COVID-19 IgM\/IgG Rapid Test of BioMedomics is a good example.[44] The sensitivity of the COVID-19 IgM\/IgG Rapid Test is 88.66%, which is expected to be lower than the sensitivity of tests based on LAMP-reaction assays (>95%). Therefore, a combination of LFS and LAMP into one device could be an excellent candidate for PoC testing of COVID-19.\n\nOther important factors in fighting COVID-19 \nFurthermore, alongside detecting and containing the virus, for the sake of a public health response regarding the dynamics of the outbreak, the socio-economic impact of COVID-19 is equally in urgent need. WHO announced that to fight the further spread of COVID-19, the international community had launched a U.S. $675 million preparedness and response plan to run from February through April 2020.[45] In 2003, the SARS-CoV virus pulled the world\u2019s output down by $50 billion. The early estimation for the cost to the global economy as a result of the outbreak of COVID-19 is about $360 billion.[46] This is because China\u2019s GDP shares were approximately 17% globally as of 2019, which was about four times higher than in 2003, and the confirmed infected cases (at the time of doing the economic estimation, i.e., at the beginning of February 2020) are more than two times larger than the total of SARS. Given that the number of infected cases (109,343 confirmed cases) is currently approximately 14 times larger than SARS cases[47], and that the death toll due to COVID-19 has surpassed that of the SARS epidemic, the economic impact of COVID-19 might be much larger than $360 billion.\nFurthermore, in order to win the battle against this outbreak, information on the epidemiological characteristics, such as the identification of the animal reservoirs[48] (Figure 1) and the risk factor of the disease, is also essential. The intermediate host carrying the disease is important to identify not only for the current epidemic, but also to eliminate a future outbreak. Together with all the aforementioned factors, the race for a vaccination against COVID-19 is equally essential. Although at this stage there is no registered treatment or vaccine for COVID-19, Zhang has recently mentioned some potential interventions[49], such as nutritional interventions (Vitamin A, B, C, D, E, and other trace minerals such as zinc and iron). Due to the high percentage of identicality in the sequence (up to 82% of the genome structure) between SARS-COV-2 and the SARS-CoV virus, immuno-enhancers and other specific treatment that have been applied for SARS could also be considered[49] for treatment of SARS-CoV-2.\n\nAcknowledgements \nAuthor contributions \nConceptualization, T.N.; writing\u2014original draft preparation, T.N.; manuscript revision, T.N, D.D.B., and A.W.; funding acquisition, D.D.B., A.W. All authors have read and agreed to the published version of the manuscript.\n\nFunding \nThis research was funded by the European Union\u2019s Horizon 2020 research and innovation program, the CORONADX project, grant agreement No: 101003562, and the VIVALDI project, grant agreement No: 773422.\n\nConflicts of interest \nThe authors declare no conflict of interest.\n\nReferences \n\n\n\u2191 World Health Organization (31 January 2020). \"Novel Coronavirus (2019-nCoV): Situation Report - 11\" (PDF). World Health Organization. https:\/\/www.who.int\/docs\/default-source\/coronaviruse\/situation-reports\/20200131-sitrep-11-ncov.pdf . Retrieved 13 March 2020 .   \n\n\u2191 2.0 2.1 World Health Organization (08 March 2020). \"Coronavirus disease 2019 (COVID-19): Situation Report - 48\" (PDF). World Health Organization. https:\/\/www.who.int\/docs\/default-source\/coronaviruse\/situation-reports\/20200308-sitrep-48-covid-19.pdf . Retrieved 13 March 2020 .   \n\n\u2191 Centers for Disease Control and Prevention (March 2020). \"How COVID-19 Spreads\". Centers for Disease Control and Prevention. https:\/\/www.cdc.gov\/coronavirus\/2019-ncov\/prevent-getting-sick\/how-covid-spreads.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fcoronavirus%2F2019-ncov%2Fprepare%2Ftransmission.html . Retrieved 13 March 2020 .   \n\n\u2191 4.0 4.1 Holshue, M.L.; DeBolt, C.; Lindquist, S. et al. (2020). \"First Case of 2019 Novel Coronavirus in the United States\". New England Journal of Medicine 382 (10): 929\u201336. doi:10.1056\/NEJMoa2001191. PMC PMC7092802. PMID 32004427. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7092802 .   \n\n\u2191 Rothe, C.; Schunk, M.; Bretzel, G. et al. (2020). \"Transmission of 2019-nCoV Infection from an Asymptomatic Contact in Germany\". New England Journal of Medicine 382 (10): 970\u201371. doi:10.1056\/NEJMc2001468. PMID 32003551.   \n\n\u2191 Phan, L.T.; Nguyen, T.V.; Luong, Q.C. et al. (2020). \"Importation and Human-to-Human Transmission of a Novel Coronavirus in Vietnam\". New England Journal of Medicine 382 (9): 872-874. doi:10.1056\/NEJMc2001272. PMID 31991079.   \n\n\u2191 Enserink, M. (12 February 2020). \"Update: \u2018A bit chaotic.\u2019 Christening of new coronavirus and its disease name create confusion\". Science. https:\/\/www.sciencemag.org\/news\/2020\/02\/bit-chaotic-christening-new-coronavirus-and-its-disease-name-create-confusion . Retrieved 13 March 2020 .   \n\n\u2191 Ji, W.; Wang, W.; Zhao, X. et al. (2020). \"Cross-species transmission of the newly identified coronavirus 2019-nCoV\". Journal of Medical Virology 92 (4): 433-440. doi:10.1002\/jmv.25682. PMID 31967321.   \n\n\u2191 Cyrankoski, D. (07 February 2020). \"Did pangolins spread the China caronavirus to people?\". Nature - News. doi:10.1038\/d41586-020-00364-2. https:\/\/www.nature.com\/articles\/d41586-020-00364-2 .   \n\n\u2191 World Health Organization (March 2020). \"WHO recommendations to reduce risk of transmission of emerging pathogens from animals to humans in live animal markets or animal product markets\". World Health Organization. https:\/\/www.who.int\/health-topics\/coronavirus\/who-recommendations-to-reduce-risk-of-transmission-of-emerging-pathogens-from-animals-to-humans-in-live-animal-markets . Retrieved 13 March 2020 .   \n\n\u2191 Wang, W.; Tang, J.; Wei, F. (2020). \"Updated understanding of the outbreak of 2019 novel coronavirus (2019\u2010nCoV) in Wuhan, China\". Journal of Medical Virology 92 (4): 441\u201347. doi:10.1002\/jmv.25689.   \n\n\u2191 World Health Organization (March 2020). \"Coronavirus disease (COVID-2019) situation reports\". World Health Organization. https:\/\/www.who.int\/emergencies\/diseases\/novel-coronavirus-2019\/situation-reports\/ . Retrieved 09 March 2020 .   \n\n\u2191 Cohen, J.; Kupferschmidt, K. (2020). \"Strategies shift as coronavirus pandemic looms\". Science 367 (6481): 962\u201363. doi:10.1126\/science.367.6481.962. PMID 32108093.   \n\n\u2191 Regan, H. (08 March 2020). \"Italy announces lockdown as global coronavirus cases surpass 105,000\". CNN. https:\/\/edition.cnn.com\/2020\/03\/08\/asia\/coronavirus-covid-19-update-intl-hnk\/index.html . Retrieved 08 March 2020 .   \n\n\u2191 Wu, J.T.; Leung, K.; Leung, G.M. (2020). \"Nowcasting and forecasting the potential domestic and international spread of the 2019-nCoV outbreak originating in Wuhan, China: A modelling study\". Lancet 395 (10225): 689-697. doi:10.1016\/S0140-6736(20)30260-9. PMID 32014114.   \n\n\u2191 Tang, B.; Bragazzi, N.L.; Li, Q. et al. (2020). \"An updated estimation of the risk of transmission of the novel coronavirus (2019-nCov)\". Infectious Disease Modelling 5: 248-255. doi:10.1016\/j.idm.2020.02.001. PMC PMC7029158. PMID 32099934. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7029158 .   \n\n\u2191 Gallagher, T.M.; Buchmeier, M.J. (2001). \"Coronavirus spike proteins in viral entry and pathogenesis\". Virology 279 (2): 371\u20134. doi:10.1006\/viro.2000.0757. PMID 11162792.   \n\n\u2191 Schoeman, D.; Fielding, B.C. (2019). \"Coronavirus envelope protein: Current knowledge\". Virology Journal 16 (1): 69. doi:10.1186\/s12985-019-1182-0. PMC PMC6537279. PMID 31133031. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6537279 .   \n\n\u2191 Gralinski, L.E.; Menechary, V.D. (2020). \"Return of the Coronavirus: 2019-nCoV\". Viruses 12 (2): E135. doi:10.3390\/v12020135. PMC PMC7077245. PMID 31991541. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7077245 .   \n\n\u2191 Huang, C.; Wang, T.; Li, X. et al. (2020). \"Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China\". Lancet 395 (10223): 497\u2013506. doi:10.1016\/S0140-6736(20)30183-5. PMID 31986264.   \n\n\u2191 Nguyen, T.; Zo\u00ebga Andreasen, S.; Wolff, A. et al. (2018). \"From Lab on a Chip to Point of Care Devices: The Role of Open Source Microcontrollers\". Micromachines 9 (8): E403. doi:10.3390\/mi9080403. PMC PMC6187319. PMID 30424336. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6187319 .   \n\n\u2191 22.0 22.1 Ke, C.-M.; Tsai, H.-C.; Chen, Y.-S. et al. (2015). \"Outbreak investigation of pandemic influenza A H1N1 at the emergency department in a medical center in Southern Taiwan\". Journal of Microbiology, Immunology and Infection 48 (2, Suppl. 1): S36. doi:10.1016\/j.jmii.2015.02.051.   \n\n\u2191 23.0 23.1 Isere, E.E.; Fatiregun, A.A.; Ajayi, I.O. (2015). \"An overview of disease surveillance and notification system in Nigeria and the roles of clinicians in disease outbreak prevention and control\". Nigerian Medical Journal 56 (3): 161\u20138. doi:10.4103\/0300-1652.160347. PMC PMC4518330. PMID 26229222. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4518330 .   \n\n\u2191 24.0 24.1 Jones, G.; Le Hello, S.; Jourdan-da Silva, N. et al. (2014). \"The French human Salmonella surveillance system: evaluation of timeliness of laboratory reporting and factors associated with delays, 2007 to 2011\". Euro Surveillance 19 (1): 20664. doi:10.2807\/1560-7917.es2014.19.1.20664. PMID 24434174.   \n\n\u2191 World Health Organization (17 February 2020). \"Coronavirus disease 2019 (COVID-19): Situation Report - 28\" (PDF). World Health Organization. https:\/\/www.who.int\/docs\/default-source\/coronaviruse\/situation-reports\/20200217-sitrep-28-covid-19.pdf . Retrieved 13 March 2020 .   \n\n\u2191 The Japan Times Staff (10 February 2020). \"Coronavirus infection tally on Diamond Princess hits 135 as tests for all passengers eyed\". The Japan Times. https:\/\/www.japantimes.co.jp\/news\/2020\/02\/10\/national\/japan-test-all-passengers-diamond-princess-cruise-ship-coronavirus\/ . Retrieved 10 February 2020 .   \n\n\u2191 27.0 27.1 Corman, V.M.; Landt, O.; Kaiser, M. et al. (2020). \"Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR\". Euro Surveillance 25 (3): 2000045. doi:10.2807\/1560-7917.ES.2020.25.3.2000045. PMC PMC6988269. PMID 31992387. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6988269 .   \n\n\u2191 Chu, D.K.W.; Pan, Y.; Cheng, S.M.S. et al. (2020). \"Molecular Diagnosis of a Novel Coronavirus (2019-nCoV) Causing an Outbreak of Pneumonia\". Clinical Chemistry 66 (4): 549-555. doi:10.1093\/clinchem\/hvaa029. PMC PMC7108203. PMID 32031583. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7108203 .   \n\n\u2191 29.0 29.1 Bruning, A.H.L.; Aatola, H.; Toivola, H. et al. (2020). \"Rapid detection and monitoring of human coronavirus infections\". New Microbes and New Infections 24: 52\u201355. doi:10.1016\/j.nmni.2018.04.007. PMC PMC5986163. PMID 29872531. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5986163 .   \n\n\u2191 30.0 30.1 Gaunt, E.R.; Hardie, A.; Claas, E.C. et al. (2020). \"Epidemiology and clinical presentations of the four human coronaviruses 229E, HKU1, NL63, and OC43 detected over three years using a novel multiplex real-time PCR method\". Journal of Clinical Microbiology 48 (8): 2940-7. doi:10.1128\/JCM.00636-10. PMC PMC2916580. PMID 20554810. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2916580 .   \n\n\u2191 31.0 31.1 Cho, C.H.; Lee, C.K.; Nam, M.H. et al. (2014). \"Evaluation of the AdvanSure real-time RT-PCR compared with culture and Seeplex RV15 for simultaneous detection of respiratory viruses\". Diagnostic Microbiology and Infectious Disease 79 (1): 14\u201318. doi:10.1016\/j.diagmicrobio.2014.01.016. PMID 24582583.   \n\n\u2191 Brueck, H. (30 January 2020). \"There's only one way to know if you have the coronavirus, and it involves machines full of spit and mucus\". Business Insider. https:\/\/www.businessinsider.com\/how-to-know-if-you-have-the-coronavirus-pcr-test-2020-1 . Retrieved 13 March 2020 .   \n\n\u2191 Molteni, M. (04 February 2020). \"The US Fast-Tracked a Coronavirus Test to Speed Up Diagnoses\". Wired. https:\/\/www.wired.com\/story\/the-us-fast-tracked-a-coronavirus-test\/ . Retrieved 13 March 2020 .   \n\n\u2191 Chinese Center for Disease Control and Prevention (04 February 2020). \"\u9a70\u63f4\u6b66\u6c49,\u9ad8\u7b49\u7ea7\u79fb\u52a8\u751f\u7269\u5b89\u5168\u5b9e\u9a8c\u5ba4\u542f\u7a0b\". Chinese Center for Disease Control and Prevention. http:\/\/www.chinacdc.cn\/yw_9324\/202002\/t20200204_212214.html . Retrieved 13 March 2020 .   \n\n\u2191 \"New Emergency Detection Laboratory Run by BGI Starts Trial Operation in Wuhan, Designed to Test 10,000 Samples Daily\". BGI News. BGI. 06 February 2020. https:\/\/www.bgi.com\/global\/company\/news\/new-emergency-detection-laboratory-run-by-bgi-starts-trial-operation-in-wuhan-designed-to-test-10000-samples-daily\/ . Retrieved 13 March 2020 .   \n\n\u2191 Nagamine, K.; Hase, T.; Notomi, T. (2002). \"Accelerated reaction by loop-mediated isothermal amplification using loop primers\". Molecular and Cellular Probes 16 (3): 223-9. doi:10.1006\/mcpr.2002.0415. PMID 12144774.   \n\n\u2191 Francois, P.; Tangomo, M.; Hibbs, J. et al. (2011). \"Robustness of a loop-mediated isothermal amplification reaction for diagnostic applications\". FEMS Immunology and Medical Microbiology 62 (1): 41\u20138. doi:10.1111\/j.1574-695X.2011.00785.x. PMID 21276085.   \n\n\u2191 38.0 38.1 Galvez, L.C.; Barbosa, C.F.C.; Koh, R.B.L. et al. (2020). \"Loop-mediated isothermal amplification (LAMP) assays for the detection of abaca bunchy top virus and banana bunchy top virus in abaca\". Crop Protection 131: 105101. doi:10.1016\/j.cropro.2020.105101.   \n\n\u2191 Ahn, S.J.; Baek, Y.H.; Lloren, K.K.S. et al. (2019). \"Rapid and simple colorimetric detection of multiple influenza viruses infecting humans using a reverse transcriptional loop-mediated isothermal amplification (RT-LAMP) diagnostic platform\". BMC Infectious Diseases 19 (1): 676. doi:10.1186\/s12879-019-4277-8. PMC PMC6669974. PMID 31370782. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6669974 .   \n\n\u2191 40.0 40.1 Jeon, S.B.; Seo, D.J.; Oh, H. et al. (2017). \"Development of one-step reverse transcription loop-mediated isothermal amplification for norovirus detection in oysters\". Food Control 73 (Part B): 1002\u20139. doi:10.1016\/j.foodcont.2016.10.005.   \n\n\u2191 Wang, X.; Seo, D.J.; Lee, M.H. et al. (2014). \"Comparison of conventional PCR, multiplex PCR, and loop-mediated isothermal amplification assays for rapid detection of Arcobacter species\". Journal of Clinical Microbiology 52 (2): 557\u201363. doi:10.1128\/JCM.02883-13. PMC PMC3911361. PMID 24478488. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3911361 .   \n\n\u2191 \"VIVALDI\". DTU Bioengineering, Technical University of Denmark. 2020. https:\/\/www.vivaldi-ia.eu\/ . Retrieved 13 March 2020 .   \n\n\u2191 \"VIVALDI - Research\". DTU Bioengineering, Technical University of Denmark. 2020. https:\/\/www.vivaldi-ia.eu\/Research . Retrieved 13 March 2020 .   \n\n\u2191 \"COVID-19 IgM\/IgG Rapid Test\". BioMedomics, Inc. 2020. https:\/\/www.biomedomics.com\/products\/infectious-disease\/covid-19-rt\/ . Retrieved 13 March 2020 .   \n\n\u2191 World Health Organization (05 February 2020). \"US$675 million needed for new coronavirus preparedness and response global plan\". World Health Organization. https:\/\/www.who.int\/news-room\/detail\/05-02-2020-us-675-million-needed-for-new-coronavirus-preparedness-and-response-global-plan . Retrieved 13 March 2020 .   \n\n\u2191 Raga, S. (05 February 2020). \"Economic vulnerabilities to the coronavirus: Top countries at risk\". ODI Blog. ODI. https:\/\/www.odi.org\/blogs\/16639-economic-vulnerabilities-coronavirus-top-countries-risk . Retrieved 13 March 2020 .   \n\n\u2191 Wang, C.; Horby, P.W.; Hayden, F.G. et al. (2020). \"A novel coronavirus outbreak of global health concern\". Lancet 395 (10223): 470-473. doi:10.1016\/S0140-6736(20)30185-9. PMID 31986257.   \n\n\u2191 Zhou, P.; Yang, X.L.; Wang, X.G. et al. (2020). \"A pneumonia outbreak associated with a new coronavirus of probable bat origin\". Nature 579 (7798): 270\u201373. doi:10.1038\/s41586-020-2012-7. PMC PMC7095418. PMID 32015507. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7095418 .   \n\n\u2191 49.0 49.1 Zhang, L.; Liu, Y. (2020). \"Potential interventions for novel coronavirus in China: A systematic review\". Journal of Medical Virology 95 (2): 479-490. doi:10.1002\/jmv.25707. PMID 32052466.   \n\n\nNotes \nThis presentation is faithful to the original, with only a few minor changes to presentation. In some cases important information was missing from the references, and that information was added. The original article referenced a generic situation report page from the WHO for the Diamond Princess infection numbers; the specific report (#28) is referenced for this version. Similarly, a more specific citation was used in this version for the mentioned VETPOD system. In a few places, \"SARS-CoV-2\" replaced \"COVID-19\" when the authors intended to reference the virus but referenced the disease.\n\n\n\n\n\n\nSource: <a rel=\"external_link\" class=\"external\" href=\"https:\/\/www.limswiki.org\/index.php\/Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\">https:\/\/www.limswiki.org\/index.php\/Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics<\/a>\n\t\t\t\t\tCategories: LIMSwiki journal articles (added in 2020)LIMSwiki journal articles (all)LIMSwiki journal articles on clinical researchLIMSwiki journal articles on epidemiology\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\n\t\t\t\t\n\t\t\t\n\t\t\n\t\t\n\t\t\tNavigation menu\n\t\t\t\t\t\n\t\t\tViews\n\n\t\t\t\n\t\t\t\t\n\t\t\t\tJournal\n\t\t\t\tDiscussion\n\t\t\t\tView source\n\t\t\t\tHistory\n\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\n\t\t\t\t\n\t\t\t\tPersonal tools\n\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\t\t\tLog in\n\t\t\t\t\t\t\t\t\t\t\t\t\tRequest account\n\t\t\t\t\t\t\t\t\t\t\t\n\t\t\t\t\n\t\t\t\n\t\t\t\n\t\t\t\t\n\t\t\t\n\t\t\t\t\n\t\tNavigation\n\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\tMain page\n\t\t\t\t\t\t\t\t\t\t\tRecent changes\n\t\t\t\t\t\t\t\t\t\t\tRandom page\n\t\t\t\t\t\t\t\t\t\t\tHelp\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\n\t\t\t\n\t\t\tSearch\n\n\t\t\t\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t \n\t\t\t\t\t\t\n\t\t\t\t\n\n\t\t\t\t\t\t\t\n\t\t\n\t\t\t\n\t\t\tTools\n\n\t\t\t\n\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\tWhat links here\n\t\t\t\t\t\t\t\t\t\t\tRelated changes\n\t\t\t\t\t\t\t\t\t\t\tSpecial pages\n\t\t\t\t\t\t\t\t\t\t\tPermanent link\n\t\t\t\t\t\t\t\t\t\t\tPage information\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\n\t\t\n\t\tPrint\/export\n\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\tCreate a book\n\t\t\t\t\t\t\t\t\t\t\tDownload as PDF\n\t\t\t\t\t\t\t\t\t\t\tDownload as Plain text\n\t\t\t\t\t\t\t\t\t\t\tPrintable version\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\n\t\t\n\t\tSponsors\n\t\t\n\t\t\t \r\n\n\t\r\n\n\t\r\n\n\t\n\t\r\n\n\t\r\n\n\t\n\t\r\n\n \n\t\r\n\n\t\n\t\r\n\n \n\t\n\t\r\n\n\t\n\t\n\t\r\n\n\t\r\n\n\t\r\n\n\t\n\t\r\n\n\t\r\n\t\t\n\t\t\n\t\t\t\n\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t This page was last modified on 6 April 2020, at 22:47.\n\t\t\t\t\t\t\t\t\tThis page has been accessed 310 times.\n\t\t\t\t\t\t\t\t\tContent is available under a Creative Commons Attribution-ShareAlike 4.0 International License unless otherwise noted.\n\t\t\t\t\t\t\t\t\tPrivacy policy\n\t\t\t\t\t\t\t\t\tAbout LIMSWiki\n\t\t\t\t\t\t\t\t\tDisclaimers\n\t\t\t\t\t\t\t\n\t\t\n\t\t\n\t\t\n\n","5a2f572706bf2e7b99579d5658274a83_html":"<body class=\"mediawiki ltr sitedir-ltr ns-206 ns-subject page-Journal_2019_novel_coronavirus_disease_COVID-19_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics skin-monobook action-view\">\n<div id=\"rdp-ebb-globalWrapper\">\n\t\t<div id=\"rdp-ebb-column-content\">\n\t\t\t<div id=\"rdp-ebb-content\" class=\"mw-body\" role=\"main\">\n\t\t\t\t<a id=\"rdp-ebb-top\"><\/a>\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t<h1 id=\"rdp-ebb-firstHeading\" class=\"firstHeading\" lang=\"en\">Journal:2019 novel coronavirus disease (COVID-19): Paving the road for rapid detection and point-of-care diagnostics<\/h1>\n\t\t\t\t\n\t\t\t\t<div id=\"rdp-ebb-bodyContent\" class=\"mw-body-content\">\n\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\n\n\t\t\t\t\t<!-- start content -->\n\t\t\t\t\t<div id=\"rdp-ebb-mw-content-text\" lang=\"en\" dir=\"ltr\" class=\"mw-content-ltr\">\n\n\n<h2><span class=\"mw-headline\" id=\"Abstract\">Abstract<\/span><\/h2>\n<p>We believe a point-of-care (PoC) device for the rapid detection of the 2019 novel coronavirus (<a href=\"https:\/\/www.limswiki.org\/index.php\/SARS-CoV-2\" title=\"SARS-CoV-2\" class=\"mw-redirect wiki-link\" data-key=\"6c6b78479de2c640028696ed32948526\">SARS-CoV-2<\/a>) is crucial and urgently needed. With this perspective, we give suggestions regarding a potential candidate for the rapid detection of the <a href=\"https:\/\/www.limswiki.org\/index.php\/Coronavirus_disease_2019\" title=\"Coronavirus disease 2019\" class=\"wiki-link\" data-key=\"68331dff29df205bcb39c3ad9599c30c\">coronavirus disease 2019<\/a> (COVID-19), as well as factors for the preparedness and response to the outbreak of COVID-19.\n<\/p><p><b>Keywords<\/b>: COVID-19, Wuhan, 2019 novel coronavirus, point-of-care detection, SARS-CoV-2, loop-mediated isothermal amplification, LAMP assay, polymerase chain reaction, PCR\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Introduction\">Introduction<\/span><\/h2>\n<p>On January 30, 2020, the <a href=\"https:\/\/www.limswiki.org\/index.php\/World_Health_Organization\" title=\"World Health Organization\" class=\"wiki-link\" data-key=\"2a49f1470638d5f579e3f6419e239b03\">World Health Organization<\/a> (WHO) declared a global public health emergency<sup id=\"rdp-ebb-cite_ref-WHONovel11_20_1-0\" class=\"reference\"><a href=\"#cite_note-WHONovel11_20-1\">[1]<\/a><\/sup> over the outbreak of a novel <a href=\"https:\/\/www.limswiki.org\/index.php\/Coronavirus\" title=\"Coronavirus\" class=\"wiki-link\" data-key=\"86c887aaa85c1b2b96fd478c10703204\">coronavirus<\/a>, called the <a href=\"https:\/\/www.limswiki.org\/index.php\/Severe_acute_respiratory_syndrome_coronavirus_2\" title=\"Severe acute respiratory syndrome coronavirus 2\" class=\"wiki-link\" data-key=\"beddd8bfa6022d0f538d26cdefb7df5c\">severe acute respiratory syndrome coronavirus 2<\/a> (SARS-CoV-2) (previously \"2019 novel coronavirus\" or \"2019-nCoV\"), which originated in Wuhan City, in the Hubei Province of China. On February 11, WHO officially named the disease the <a href=\"https:\/\/www.limswiki.org\/index.php\/Coronavirus_disease_2019\" title=\"Coronavirus disease 2019\" class=\"wiki-link\" data-key=\"68331dff29df205bcb39c3ad9599c30c\">coronavirus disease 2019<\/a> (COVID-19).<sup id=\"rdp-ebb-cite_ref-WHOCorona48_20_2-0\" class=\"reference\"><a href=\"#cite_note-WHOCorona48_20-2\">[2]<\/a><\/sup> Human-to-human transmission (Figure 1) has been confirmed by WHO and by the <a href=\"https:\/\/www.limswiki.org\/index.php\/Centers_for_Disease_Control_and_Prevention\" title=\"Centers for Disease Control and Prevention\" class=\"wiki-link\" data-key=\"176aa9c9513251c328d864d1e724e814\">Centers for Disease Control and Prevention<\/a> (CDC) of the United States<sup id=\"rdp-ebb-cite_ref-CDCHow20_3-0\" class=\"reference\"><a href=\"#cite_note-CDCHow20-3\">[3]<\/a><\/sup>, with evidence of person-to-person transmission from three different cases outside China, namely in the U.S.<sup id=\"rdp-ebb-cite_ref-HolshueFirst20_4-0\" class=\"reference\"><a href=\"#cite_note-HolshueFirst20-4\">[4]<\/a><\/sup>, Germany<sup id=\"rdp-ebb-cite_ref-RotheTrans20_5-0\" class=\"reference\"><a href=\"#cite_note-RotheTrans20-5\">[5]<\/a><\/sup>, and Vietnam.<sup id=\"rdp-ebb-cite_ref-PhanImport20_6-0\" class=\"reference\"><a href=\"#cite_note-PhanImport20-6\">[6]<\/a><\/sup>\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig1_Nguyen_Micromachines2020_11-3.png\" class=\"image wiki-link\" data-key=\"4310be325ca3a458c47113b6a669eba0\"><img alt=\"Fig1 Nguyen Micromachines2020 11-3.png\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/7\/7a\/Fig1_Nguyen_Micromachines2020_11-3.png\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Figure 1.<\/b> Illustration of the transmission of various coronaviruses, including SARS-CoV-2.<sup id=\"rdp-ebb-cite_ref-EnserinkUpdate20_7-0\" class=\"reference\"><a href=\"#cite_note-EnserinkUpdate20-7\">[7]<\/a><\/sup> Current studies have suggested that the intermediate carriers may be snakes<sup id=\"rdp-ebb-cite_ref-JiCross20_8-0\" class=\"reference\"><a href=\"#cite_note-JiCross20-8\">[8]<\/a><\/sup> or pangolins<sup id=\"rdp-ebb-cite_ref-CyrankoskiDidPang20_9-0\" class=\"reference\"><a href=\"#cite_note-CyrankoskiDidPang20-9\">[9]<\/a><\/sup>, but according to WHO the real source is still unknown.<sup id=\"rdp-ebb-cite_ref-WHORecomm20_10-0\" class=\"reference\"><a href=\"#cite_note-WHORecomm20-10\">[10]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-WangUpdated20_11-0\" class=\"reference\"><a href=\"#cite_note-WangUpdated20-11\">[11]<\/a><\/sup>.<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>COVID-19 has continuously spread to 104 countries; the number of confirmed infections reached 109,343 on March 9, 2020<sup id=\"rdp-ebb-cite_ref-WHOSitReps20_12-0\" class=\"reference\"><a href=\"#cite_note-WHOSitReps20-12\">[12]<\/a><\/sup>, and the death toll in China has overtaken the SARS epidemic of 2002\u20132003 and has risen to 3,100.<sup id=\"rdp-ebb-cite_ref-WHOCorona48_20_2-1\" class=\"reference\"><a href=\"#cite_note-WHOCorona48_20-2\">[2]<\/a><\/sup> To slow down the spread of COVID-19, at least 50 million people in China have been placed under lockdown.<sup id=\"rdp-ebb-cite_ref-CohenStrat20_13-0\" class=\"reference\"><a href=\"#cite_note-CohenStrat20-13\">[13]<\/a><\/sup> On March 8, 2020, Italy also undertook the same measures, with the northern part of the country getting placed under lockdown, affecting 16 million people.<sup id=\"rdp-ebb-cite_ref-ReganItaly20_14-0\" class=\"reference\"><a href=\"#cite_note-ReganItaly20-14\">[14]<\/a><\/sup> The reproduction number R<sub>0<\/sub> (i.e., the average number of secondary cases generated by a typical infectious individual) is estimated to be 2.68, and the doubling time is estimated to be 6.4 days.<sup id=\"rdp-ebb-cite_ref-WuNow20_15-0\" class=\"reference\"><a href=\"#cite_note-WuNow20-15\">[15]<\/a><\/sup>\n<\/p><p>The difference in terminology between \"coronavirus\" and \"SARS-Cov-2\" is detailed in Table 1. \n<\/p>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table class=\"wikitable\" border=\"1\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\" colspan=\"2\"><b>Table 1.<\/b> Difference between the term \"coronavirus\" and \"SARS-CoV-2\"\n<\/td><\/tr>\n<tr>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">Term\n<\/th>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">Description\n<\/th><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Coronavirus (CoV)\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">A large and diverse family of enveloped, positive-stranded RNA viruses, with a ~26\u201332 kilobase genome.<sup id=\"rdp-ebb-cite_ref-TangAnUpdated20_16-0\" class=\"reference\"><a href=\"#cite_note-TangAnUpdated20-16\">[16]<\/a><\/sup> The <i>Coronaviridae<\/i> cover a broad host range, infecting many mammalian and avian species, and induce upper respiratory, gastrointestinal, hepatic, and central nervous system diseases.<sup id=\"rdp-ebb-cite_ref-GallagherCorona01_17-0\" class=\"reference\"><a href=\"#cite_note-GallagherCorona01-17\">[17]<\/a><\/sup> In the last few decades, coronaviruses have been shown to be capable of also infecting humans. The outbreak of <a href=\"https:\/\/www.limswiki.org\/index.php\/Severe_acute_respiratory_syndrome\" title=\"Severe acute respiratory syndrome\" class=\"wiki-link\" data-key=\"11abe2043ece64ad43ee0052402c5cec\">severe acute respiratory syndrome<\/a> (SARS) in 2003, and, more recently, <a href=\"https:\/\/www.limswiki.org\/index.php\/Middle_East_respiratory_syndrome\" title=\"Middle East respiratory syndrome\" class=\"wiki-link\" data-key=\"6a290adf3ac17e4b8a75ef1ce0b28afd\">Middle East respiratory syndrome<\/a> (MERS) have proved the lethality of coroanviruses when they cross the species barrier and infect humans.<sup id=\"rdp-ebb-cite_ref-SchoemanCorona19_18-0\" class=\"reference\"><a href=\"#cite_note-SchoemanCorona19-18\">[18]<\/a><\/sup>\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">A new zoonotic human coronavirus, which was reported and announced by the Chinese Center for Disease Control and Prevention (CCDC) on January 9, 2020.<sup id=\"rdp-ebb-cite_ref-GralinskiReturn20_19-0\" class=\"reference\"><a href=\"#cite_note-GralinskiReturn20-19\">[19]<\/a><\/sup> This novel coronavirus can lead to coroanvirus disease 2019 (COVID-19) in humans. In spite of the fact that the initial infected cases have been associated with the Huanan South China Seafood Market, the source of SARS-CoV-2 is still unknown (Figure 1). On January 30, 2020, the WHO declared a global public health emergency regarding the outbreak of COVID-19. On March 11, 2020, WHO declared the outbreak of COVID-19 a <a href=\"https:\/\/www.limswiki.org\/index.php\/Pandemic\" title=\"Pandemic\" class=\"wiki-link\" data-key=\"bd9a48e6c6e41b6d603ee703836b01f1\">pandemic<\/a>.\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<h2><span class=\"mw-headline\" id=\"The_need_for_a_rapid_detection_method_and_portable_detection_devices\">The need for a rapid detection method and portable detection devices<\/span><\/h2>\n<p>The manifestation of the COVID-19 infection is highly nonspecific, including respiratory symptoms, fever, cough, dyspnea, and viral pneumonia.<sup id=\"rdp-ebb-cite_ref-HuangClin20_20-0\" class=\"reference\"><a href=\"#cite_note-HuangClin20-20\">[20]<\/a><\/sup> Thus, diagnostic tests specific to this infection are urgently required to confirm suspected cases, screen patients, and conduct virus surveillance.\n<\/p><p>In this scenario, a point-of-care (PoC) device (i.e., a rapid, robust, and cost-efficient device that can be used onsite and in the field, and which does not necessarily require a trained technician to operate<sup id=\"rdp-ebb-cite_ref-NguyenFromLab18_21-0\" class=\"reference\"><a href=\"#cite_note-NguyenFromLab18-21\">[21]<\/a><\/sup>) is crucial for the detection of COVID-19. Figure 2 shows the dramatic impact of early detection of infectious diseases in controlling an outbreak.<sup id=\"rdp-ebb-cite_ref-KeOutbreak15_22-0\" class=\"reference\"><a href=\"#cite_note-KeOutbreak15-22\">[22]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-IsereAnOver15_23-0\" class=\"reference\"><a href=\"#cite_note-IsereAnOver15-23\">[23]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-JonesTheFrench14_24-0\" class=\"reference\"><a href=\"#cite_note-JonesTheFrench14-24\">[24]<\/a><\/sup>\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig2_Nguyen_Micromachines2020_11-3.png\" class=\"image wiki-link\" data-key=\"f36be552f5f9928538a4462eed719206\"><img alt=\"Fig2 Nguyen Micromachines2020 11-3.png\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/b\/be\/Fig2_Nguyen_Micromachines2020_11-3.png\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Figure 2.<\/b> The dramatic impact of the rapid detection of infectious diseases in controlling and preventing an outbreak (adapted from the works of Ke <i>et al.<\/i><sup id=\"rdp-ebb-cite_ref-KeOutbreak15_22-1\" class=\"reference\"><a href=\"#cite_note-KeOutbreak15-22\">[22]<\/a><\/sup>, Isere <i>et al.<\/i><sup id=\"rdp-ebb-cite_ref-IsereAnOver15_23-1\" class=\"reference\"><a href=\"#cite_note-IsereAnOver15-23\">[23]<\/a><\/sup>, and Jones <i>et al.<\/i><sup id=\"rdp-ebb-cite_ref-JonesTheFrench14_24-1\" class=\"reference\"><a href=\"#cite_note-JonesTheFrench14-24\">[24]<\/a><\/sup>).<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>Such a PoC device can be used in (but is not limited to) an emergency situation, such as the Diamond Princess cruise ship case. Recently, it was reported that the Diamond Princess cruise ship had been quarantined in Yokohama, Japan, due to a serious spreading of COVID-19 on the ship, with at least 454 infected cases out of 3,700 passengers and crew (reported by WHO<sup id=\"rdp-ebb-cite_ref-WHOCorona28_20_25-0\" class=\"reference\"><a href=\"#cite_note-WHOCorona28_20-25\">[25]<\/a><\/sup>, February 17, 2020). The detection of COVID-19 may not have been prompt enough as they did not have enough test kits to diagnose all the passengers on the ship in order to timely respond to the rapid spreading of the disease.<sup id=\"rdp-ebb-cite_ref-TJTCorona20_26-0\" class=\"reference\"><a href=\"#cite_note-TJTCorona20-26\">[26]<\/a><\/sup>\n<\/p><p>The current standard molecular technique that is now being used to detect SARS-CoV-2 is real-time <a href=\"https:\/\/www.limswiki.org\/index.php\/Reverse_transcription_polymerase_chain_reaction\" title=\"Reverse transcription polymerase chain reaction\" class=\"wiki-link\" data-key=\"bb69657b45c41e6345baf4c8067c7aa3\">reverse transcription polymerase chain reaction<\/a> (rRT-PCR). This protocol has been documented and available online on the WHO website since January 17, 2020.<sup id=\"rdp-ebb-cite_ref-CormanDetect20_27-0\" class=\"reference\"><a href=\"#cite_note-CormanDetect20-27\">[27]<\/a><\/sup> The testing procedure includes: (i) specimen collection; (ii) packing (storage) and shipment of the clinical specimens; (iii) (good) communication with the <a href=\"https:\/\/www.limswiki.org\/index.php\/Laboratory\" title=\"Laboratory\" class=\"wiki-link\" data-key=\"c57fc5aac9e4abf31dccae81df664c33\">laboratory<\/a> and providing needed information; (iv) laboratory testing; and (v) reporting the results. This rRT-PCR technique requires sophisticated laboratory equipment that is often located at a central laboratory (<a href=\"https:\/\/www.limswiki.org\/index.php\/Biosafety_level\" title=\"Biosafety level\" class=\"wiki-link\" data-key=\"df3da482bc6a095d4f125bcf7fccfc76\">Biosafety level 2<\/a> or above).<sup id=\"rdp-ebb-cite_ref-HolshueFirst20_4-1\" class=\"reference\"><a href=\"#cite_note-HolshueFirst20-4\">[4]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-CormanDetect20_27-1\" class=\"reference\"><a href=\"#cite_note-CormanDetect20-27\">[27]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ChuMolec20_28-0\" class=\"reference\"><a href=\"#cite_note-ChuMolec20-28\">[28]<\/a><\/sup> <a href=\"https:\/\/www.limswiki.org\/index.php\/Sample_(material)\" title=\"Sample (material)\" class=\"wiki-link\" data-key=\"7f8cd41a077a88d02370c02a3ba3d9d6\">Sample<\/a> transportation is inevitable. As a consequence, the time required to obtain the results can be up to two or three days. In the case of a public health emergency such as the COVID-19 outbreak, this time-consuming process of sample testing is not only extremely disadvantageous, but also dangerous since the virus needs to be contained. \n<\/p><p>Another concern of PCR testing is that commercial PCR-based methods are expensive, depend upon technical expertise, and the presence of viral RNA or DNA does not always reflect acute disease.<sup id=\"rdp-ebb-cite_ref-BruningRapid18_29-0\" class=\"reference\"><a href=\"#cite_note-BruningRapid18-29\">[29]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-GauntEpidem10_30-0\" class=\"reference\"><a href=\"#cite_note-GauntEpidem10-30\">[30]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ChoEval14_31-0\" class=\"reference\"><a href=\"#cite_note-ChoEval14-31\">[31]<\/a><\/sup> Furthermore, using PCR, codetection with other respiratory viruses is frequently encountered in coronaviruse (CoV) testing, and the contribution of positive CoV PCR results to disease severity is not always explicitly exhibited.<sup id=\"rdp-ebb-cite_ref-BruningRapid18_29-1\" class=\"reference\"><a href=\"#cite_note-BruningRapid18-29\">[29]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-GauntEpidem10_30-1\" class=\"reference\"><a href=\"#cite_note-GauntEpidem10-30\">[30]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ChoEval14_31-1\" class=\"reference\"><a href=\"#cite_note-ChoEval14-31\">[31]<\/a><\/sup> Furthermore, as of February 2, 2020 in the United States, as mentioned in the <i>Interim Guidelines for Collecting, Handling, and Testing Clinical Specimens from Persons Under Investigation (PUIs) for 2019 Novel Coronavirus<\/i>, diagnostic testing for COVID-19 can be conducted only at the CDC, though from February 4 onwards, COVID-19 tests can also be done at laboratories designated by the CDC. Likewise in China, where the outbreak is ongoing, samples had to be sent to Beijing for testing, as reported on January 31.<sup id=\"rdp-ebb-cite_ref-BrueckThere20_32-0\" class=\"reference\"><a href=\"#cite_note-BrueckThere20-32\">[32]<\/a><\/sup> On February 4, China\u2019s own CDC deployed a mobile biosafety laboratory to Wuhan in the Hubei Province to assist with the response.<sup id=\"rdp-ebb-cite_ref-MolteniTheUS20_33-0\" class=\"reference\"><a href=\"#cite_note-MolteniTheUS20-33\">[33]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-CCDCWuhan20_34-0\" class=\"reference\"><a href=\"#cite_note-CCDCWuhan20-34\">[34]<\/a><\/sup> On February 5, an emergency test laboratory (biosafety level 2) run by BGI Group (with global heartquarters in Shenzhen, China) was set up in Wuhan in the Hubei Province to assist the COVID-19 epidemic.<sup id=\"rdp-ebb-cite_ref-BGINewEmerg20_35-0\" class=\"reference\"><a href=\"#cite_note-BGINewEmerg20-35\">[35]<\/a><\/sup>\n<\/p>\n<h2><span class=\"mw-headline\" id=\"A_potential_candidate_for_rapid_detection_of_SARS-CoV-2:_Loop-mediated_isothermal_amplification_.28LAMP.29_assays_in_PoC_devices\">A potential candidate for rapid detection of SARS-CoV-2: Loop-mediated isothermal amplification (LAMP) assays in PoC devices<\/span><\/h2>\n<p>In order to overcome the current time-consuming and laborious detection technique using RT-PCR, an alternative molecular amplification technique should be deployed. <a href=\"https:\/\/www.limswiki.org\/index.php\/Loop-mediated_isothermal_amplification\" title=\"Loop-mediated isothermal amplification\" class=\"wiki-link\" data-key=\"e71e4c1cfffeaf6781dd13b0ac1cc2a9\">Loop-mediated isothermal amplification<\/a> (LAMP) reaction is a novel <a href=\"https:\/\/www.limswiki.org\/index.php\/Nucleic_acid_test\" title=\"Nucleic acid test\" class=\"wiki-link\" data-key=\"9b850e87cf2257909a3cde1f7ea4dd94\">nucleic acid amplification technique<\/a> that amplifies DNA with high specificity, efficiency, and rapidity under isothermal conditions. This method uses a set of four specially designed primers, in combination with a DNA polymerase with strand displacement activity<sup id=\"rdp-ebb-cite_ref-NagamineAccel02_36-0\" class=\"reference\"><a href=\"#cite_note-NagamineAccel02-36\">[36]<\/a><\/sup> to synthesize target DNA up to 109 copies in less than an hour at a constant temperature of 65 \u00b0C. The final products are stem-loop DNAs with multiple inverted repeats of the target, bearing structures with a cauliflower-like appearance. LAMP has high specificity and sensitivity and is simple to perform; hence, soon after its initial development, it became an enormously popular isothermal amplification method in molecular biology, with applications in pathogen detection. LAMP uses strand-displacement polymerases instead of heat denaturation to generate a single-stranded template. As such, it has the advantage of running at a constant temperature, simultaneously reducing the cumbersomeness of a thermocycler as well as the energy required. LAMP technology is proven to be more stable<sup id=\"rdp-ebb-cite_ref-FrancoisRobust11_37-0\" class=\"reference\"><a href=\"#cite_note-FrancoisRobust11-37\">[37]<\/a><\/sup> and more sensitive<sup id=\"rdp-ebb-cite_ref-GalvezLoop20_38-0\" class=\"reference\"><a href=\"#cite_note-GalvezLoop20-38\">[38]<\/a><\/sup> in detection compared to PCR. Other advantages of LAMP compared to those of PCR are shown in Table 2.\n<\/p>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table class=\"wikitable\" border=\"1\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\" colspan=\"2\"><b>Table 2.<\/b> Comparison between PCR and loop-mediated isothermal amplification (LAMP) reactions\n<\/td><\/tr>\n<tr>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">PCR\n<\/th>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">LAMP\n<\/th><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Thermal cycling: Multiple heating and cooling cycles; hence, bulky and cumbersome\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Isothermal and continuous amplification: Smaller, simpler, and therefor portable\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Always requires sample concentration and preparation: Time-consuming\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">More flexible: For detection of viruses such as influenza<sup id=\"rdp-ebb-cite_ref-AhnRapid19_39-0\" class=\"reference\"><a href=\"#cite_note-AhnRapid19-39\">[39]<\/a><\/sup> or human norovirus, LAMP assay offers one-step detection.<sup id=\"rdp-ebb-cite_ref-JeonDevelop17_40-0\" class=\"reference\"><a href=\"#cite_note-JeonDevelop17-40\">[40]<\/a><\/sup> Sample preparation steps are simplified.\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Multiple protocols: Complicated and requires a skilled technician\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Single protocol: Faster\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Reaction hindered by inhibitors\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Reaction tolerates inhibitors and is more stable\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Diagnostic sensitivity (95%) is currently reported as lower than LAMP<sup id=\"rdp-ebb-cite_ref-GalvezLoop20_38-1\" class=\"reference\"><a href=\"#cite_note-GalvezLoop20-38\">[38]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-JeonDevelop17_40-1\" class=\"reference\"><a href=\"#cite_note-JeonDevelop17-40\">[40]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-WangComp14_41-0\" class=\"reference\"><a href=\"#cite_note-WangComp14-41\">[41]<\/a><\/sup>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Diagnostic sensitivity > 95%\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Technique is established\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Technique is still being explored\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>We believe that the LAMP assay could be a potential candidate for the point-of-care device application in the detection of COVID-19. The Veterinary Validation of Point-of-Care Diagnostic Instrument (VIVALDI) project<sup id=\"rdp-ebb-cite_ref-VIVALDI20_42-0\" class=\"reference\"><a href=\"#cite_note-VIVALDI20-42\">[42]<\/a><\/sup> is an example of using LAMP in a point-of-care device for the detection of a zoonotic virus causing respiratory symptoms (such as the strains responsible for Avian influenza). With PoC devices such as the VETPOD (Veterinary, Portable, Onsite Detection), which the VIVALDI project is validating<sup id=\"rdp-ebb-cite_ref-VIVALDI_VETPOD20_43-0\" class=\"reference\"><a href=\"#cite_note-VIVALDI_VETPOD20-43\">[43]<\/a><\/sup>, detection time can be less than one hour. Besides PoC devices using disposable polymer chips and LAMP assays, as in the VETPOD, a lateral flow strip (LFS) would also be a suitable candidate for the rapid and on-site detection of COVID-19. A device such as COVID-19 IgM\/IgG Rapid Test of BioMedomics is a good example.<sup id=\"rdp-ebb-cite_ref-BioMedomicsCOVID20_44-0\" class=\"reference\"><a href=\"#cite_note-BioMedomicsCOVID20-44\">[44]<\/a><\/sup> The sensitivity of the COVID-19 IgM\/IgG Rapid Test is 88.66%, which is expected to be lower than the sensitivity of tests based on LAMP-reaction assays (>95%). Therefore, a combination of LFS and LAMP into one device could be an excellent candidate for PoC testing of COVID-19.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Other_important_factors_in_fighting_COVID-19\">Other important factors in fighting COVID-19<\/span><\/h2>\n<p>Furthermore, alongside detecting and containing the virus, for the sake of a public health response regarding the dynamics of the outbreak, the socio-economic impact of COVID-19 is equally in urgent need. WHO announced that to fight the further spread of COVID-19, the international community had launched a U.S. $675 million preparedness and response plan to run from February through April 2020.<sup id=\"rdp-ebb-cite_ref-WHO_US675_20_45-0\" class=\"reference\"><a href=\"#cite_note-WHO_US675_20-45\">[45]<\/a><\/sup> In 2003, the SARS-CoV virus pulled the world\u2019s output down by $50 billion. The early estimation for the cost to the global economy as a result of the outbreak of COVID-19 is about $360 billion.<sup id=\"rdp-ebb-cite_ref-RagaEcon20_46-0\" class=\"reference\"><a href=\"#cite_note-RagaEcon20-46\">[46]<\/a><\/sup> This is because China\u2019s GDP shares were approximately 17% globally as of 2019, which was about four times higher than in 2003, and the confirmed infected cases (at the time of doing the economic estimation, i.e., at the beginning of February 2020) are more than two times larger than the total of SARS. Given that the number of infected cases (109,343 confirmed cases) is currently approximately 14 times larger than SARS cases<sup id=\"rdp-ebb-cite_ref-WangANovel20_47-0\" class=\"reference\"><a href=\"#cite_note-WangANovel20-47\">[47]<\/a><\/sup>, and that the death toll due to COVID-19 has surpassed that of the SARS epidemic, the economic impact of COVID-19 might be much larger than $360 billion.\n<\/p><p>Furthermore, in order to win the battle against this outbreak, information on the epidemiological characteristics, such as the identification of the animal reservoirs<sup id=\"rdp-ebb-cite_ref-ZhouAPneumonia20_48-0\" class=\"reference\"><a href=\"#cite_note-ZhouAPneumonia20-48\">[48]<\/a><\/sup> (Figure 1) and the risk factor of the disease, is also essential. The intermediate host carrying the disease is important to identify not only for the current epidemic, but also to eliminate a future outbreak. Together with all the aforementioned factors, the race for a vaccination against COVID-19 is equally essential. Although at this stage there is no registered treatment or vaccine for COVID-19, Zhang has recently mentioned some potential interventions<sup id=\"rdp-ebb-cite_ref-ZhangPotential20_49-0\" class=\"reference\"><a href=\"#cite_note-ZhangPotential20-49\">[49]<\/a><\/sup>, such as nutritional interventions (Vitamin A, B, C, D, E, and other trace minerals such as zinc and iron). Due to the high percentage of identicality in the sequence (up to 82% of the genome structure) between SARS-COV-2 and the SARS-CoV virus, immuno-enhancers and other specific treatment that have been applied for SARS could also be considered<sup id=\"rdp-ebb-cite_ref-ZhangPotential20_49-1\" class=\"reference\"><a href=\"#cite_note-ZhangPotential20-49\">[49]<\/a><\/sup> for treatment of SARS-CoV-2.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Acknowledgements\">Acknowledgements<\/span><\/h2>\n<h3><span class=\"mw-headline\" id=\"Author_contributions\">Author contributions<\/span><\/h3>\n<p>Conceptualization, T.N.; writing\u2014original draft preparation, T.N.; manuscript revision, T.N, D.D.B., and A.W.; funding acquisition, D.D.B., A.W. All authors have read and agreed to the published version of the manuscript.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Funding\">Funding<\/span><\/h3>\n<p>This research was funded by the European Union\u2019s Horizon 2020 research and innovation program, the CORONADX project, grant agreement No: 101003562, and the VIVALDI project, grant agreement No: 773422.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Conflicts_of_interest\">Conflicts of interest<\/span><\/h3>\n<p>The authors declare no conflict of interest.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"References\">References<\/span><\/h2>\n<div class=\"reflist references-column-width\" style=\"-moz-column-width: 30em; -webkit-column-width: 30em; column-width: 30em; list-style-type: decimal;\">\n<ol class=\"references\">\n<li id=\"cite_note-WHONovel11_20-1\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-WHONovel11_20_1-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">World Health Organization (31 January 2020). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.who.int\/docs\/default-source\/coronaviruse\/situation-reports\/20200131-sitrep-11-ncov.pdf\" target=\"_blank\">\"Novel Coronavirus (2019-nCoV): Situation Report - 11\"<\/a> (PDF). World Health Organization<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.who.int\/docs\/default-source\/coronaviruse\/situation-reports\/20200131-sitrep-11-ncov.pdf\" target=\"_blank\">https:\/\/www.who.int\/docs\/default-source\/coronaviruse\/situation-reports\/20200131-sitrep-11-ncov.pdf<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 13 March 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Novel+Coronavirus+%282019-nCoV%29%3A+Situation+Report+-+11&rft.atitle=&rft.aulast=World+Health+Organization&rft.au=World+Health+Organization&rft.date=31+January+2020&rft.pub=World+Health+Organization&rft_id=https%3A%2F%2Fwww.who.int%2Fdocs%2Fdefault-source%2Fcoronaviruse%2Fsituation-reports%2F20200131-sitrep-11-ncov.pdf&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-WHOCorona48_20-2\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-WHOCorona48_20_2-0\">2.0<\/a><\/sup> <sup><a href=\"#cite_ref-WHOCorona48_20_2-1\">2.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation web\">World Health Organization (08 March 2020). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.who.int\/docs\/default-source\/coronaviruse\/situation-reports\/20200308-sitrep-48-covid-19.pdf\" target=\"_blank\">\"Coronavirus disease 2019 (COVID-19): Situation Report - 48\"<\/a> (PDF). World Health Organization<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.who.int\/docs\/default-source\/coronaviruse\/situation-reports\/20200308-sitrep-48-covid-19.pdf\" target=\"_blank\">https:\/\/www.who.int\/docs\/default-source\/coronaviruse\/situation-reports\/20200308-sitrep-48-covid-19.pdf<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 13 March 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Coronavirus+disease+2019+%28COVID-19%29%3A+Situation+Report+-+48&rft.atitle=&rft.aulast=World+Health+Organization&rft.au=World+Health+Organization&rft.date=08+March+2020&rft.pub=World+Health+Organization&rft_id=https%3A%2F%2Fwww.who.int%2Fdocs%2Fdefault-source%2Fcoronaviruse%2Fsituation-reports%2F20200308-sitrep-48-covid-19.pdf&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-CDCHow20-3\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-CDCHow20_3-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Centers for Disease Control and Prevention (March 2020). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.cdc.gov\/coronavirus\/2019-ncov\/prevent-getting-sick\/how-covid-spreads.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fcoronavirus%2F2019-ncov%2Fprepare%2Ftransmission.html\" target=\"_blank\">\"How COVID-19 Spreads\"<\/a>. Centers for Disease Control and Prevention<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.cdc.gov\/coronavirus\/2019-ncov\/prevent-getting-sick\/how-covid-spreads.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fcoronavirus%2F2019-ncov%2Fprepare%2Ftransmission.html\" target=\"_blank\">https:\/\/www.cdc.gov\/coronavirus\/2019-ncov\/prevent-getting-sick\/how-covid-spreads.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fcoronavirus%2F2019-ncov%2Fprepare%2Ftransmission.html<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 13 March 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=How+COVID-19+Spreads&rft.atitle=&rft.aulast=Centers+for+Disease+Control+and+Prevention&rft.au=Centers+for+Disease+Control+and+Prevention&rft.date=March+2020&rft.pub=Centers+for+Disease+Control+and+Prevention&rft_id=https%3A%2F%2Fwww.cdc.gov%2Fcoronavirus%2F2019-ncov%2Fprevent-getting-sick%2Fhow-covid-spreads.html%3FCDC_AA_refVal%3Dhttps%253A%252F%252Fwww.cdc.gov%252Fcoronavirus%252F2019-ncov%252Fprepare%252Ftransmission.html&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-HolshueFirst20-4\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-HolshueFirst20_4-0\">4.0<\/a><\/sup> <sup><a href=\"#cite_ref-HolshueFirst20_4-1\">4.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Holshue, M.L.; DeBolt, C.; Lindquist, S. et al. (2020). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7092802\" target=\"_blank\">\"First Case of 2019 Novel Coronavirus in the United States\"<\/a>. <i>New England Journal of Medicine<\/i> <b>382<\/b> (10): 929\u201336. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1056%2FNEJMoa2001191\" target=\"_blank\">10.1056\/NEJMoa2001191<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC7092802\/\" target=\"_blank\">PMC7092802<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/32004427\" target=\"_blank\">32004427<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7092802\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7092802<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=First+Case+of+2019+Novel+Coronavirus+in+the+United+States&rft.jtitle=New+England+Journal+of+Medicine&rft.aulast=Holshue%2C+M.L.%3B+DeBolt%2C+C.%3B+Lindquist%2C+S.+et+al.&rft.au=Holshue%2C+M.L.%3B+DeBolt%2C+C.%3B+Lindquist%2C+S.+et+al.&rft.date=2020&rft.volume=382&rft.issue=10&rft.pages=929%E2%80%9336&rft_id=info:doi\/10.1056%2FNEJMoa2001191&rft_id=info:pmc\/PMC7092802&rft_id=info:pmid\/32004427&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC7092802&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-RotheTrans20-5\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-RotheTrans20_5-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Rothe, C.; Schunk, M.; Bretzel, G. et al. (2020). \"Transmission of 2019-nCoV Infection from an Asymptomatic Contact in Germany\". <i>New England Journal of Medicine<\/i> <b>382<\/b> (10): 970\u201371. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1056%2FNEJMc2001468\" target=\"_blank\">10.1056\/NEJMc2001468<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/32003551\" target=\"_blank\">32003551<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Transmission+of+2019-nCoV+Infection+from+an+Asymptomatic+Contact+in+Germany&rft.jtitle=New+England+Journal+of+Medicine&rft.aulast=Rothe%2C+C.%3B+Schunk%2C+M.%3B+Bretzel%2C+G.+et+al.&rft.au=Rothe%2C+C.%3B+Schunk%2C+M.%3B+Bretzel%2C+G.+et+al.&rft.date=2020&rft.volume=382&rft.issue=10&rft.pages=970%E2%80%9371&rft_id=info:doi\/10.1056%2FNEJMc2001468&rft_id=info:pmid\/32003551&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-PhanImport20-6\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-PhanImport20_6-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Phan, L.T.; Nguyen, T.V.; Luong, Q.C. et al. (2020). \"Importation and Human-to-Human Transmission of a Novel Coronavirus in Vietnam\". <i>New England Journal of Medicine<\/i> <b>382<\/b> (9): 872-874. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1056%2FNEJMc2001272\" target=\"_blank\">10.1056\/NEJMc2001272<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/31991079\" target=\"_blank\">31991079<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Importation+and+Human-to-Human+Transmission+of+a+Novel+Coronavirus+in+Vietnam&rft.jtitle=New+England+Journal+of+Medicine&rft.aulast=Phan%2C+L.T.%3B+Nguyen%2C+T.V.%3B+Luong%2C+Q.C.+et+al.&rft.au=Phan%2C+L.T.%3B+Nguyen%2C+T.V.%3B+Luong%2C+Q.C.+et+al.&rft.date=2020&rft.volume=382&rft.issue=9&rft.pages=872-874&rft_id=info:doi\/10.1056%2FNEJMc2001272&rft_id=info:pmid\/31991079&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-EnserinkUpdate20-7\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-EnserinkUpdate20_7-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Enserink, M. (12 February 2020). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.sciencemag.org\/news\/2020\/02\/bit-chaotic-christening-new-coronavirus-and-its-disease-name-create-confusion\" target=\"_blank\">\"Update: \u2018A bit chaotic.\u2019 Christening of new coronavirus and its disease name create confusion\"<\/a>. <i>Science<\/i><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.sciencemag.org\/news\/2020\/02\/bit-chaotic-christening-new-coronavirus-and-its-disease-name-create-confusion\" target=\"_blank\">https:\/\/www.sciencemag.org\/news\/2020\/02\/bit-chaotic-christening-new-coronavirus-and-its-disease-name-create-confusion<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 13 March 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Update%3A+%E2%80%98A+bit+chaotic.%E2%80%99+Christening+of+new+coronavirus+and+its+disease+name+create+confusion&rft.atitle=Science&rft.aulast=Enserink%2C+M.&rft.au=Enserink%2C+M.&rft.date=12+February+2020&rft_id=https%3A%2F%2Fwww.sciencemag.org%2Fnews%2F2020%2F02%2Fbit-chaotic-christening-new-coronavirus-and-its-disease-name-create-confusion&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-JiCross20-8\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-JiCross20_8-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Ji, W.; Wang, W.; Zhao, X. et al. (2020). \"Cross-species transmission of the newly identified coronavirus 2019-nCoV\". <i>Journal of Medical Virology<\/i> <b>92<\/b> (4): 433-440. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1002%2Fjmv.25682\" target=\"_blank\">10.1002\/jmv.25682<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/31967321\" target=\"_blank\">31967321<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Cross-species+transmission+of+the+newly+identified+coronavirus+2019-nCoV&rft.jtitle=Journal+of+Medical+Virology&rft.aulast=Ji%2C+W.%3B+Wang%2C+W.%3B+Zhao%2C+X.+et+al.&rft.au=Ji%2C+W.%3B+Wang%2C+W.%3B+Zhao%2C+X.+et+al.&rft.date=2020&rft.volume=92&rft.issue=4&rft.pages=433-440&rft_id=info:doi\/10.1002%2Fjmv.25682&rft_id=info:pmid\/31967321&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-CyrankoskiDidPang20-9\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-CyrankoskiDidPang20_9-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Cyrankoski, D. (07 February 2020). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.nature.com\/articles\/d41586-020-00364-2\" target=\"_blank\">\"Did pangolins spread the China caronavirus to people?\"<\/a>. <i>Nature - News<\/i>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1038%2Fd41586-020-00364-2\" target=\"_blank\">10.1038\/d41586-020-00364-2<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.nature.com\/articles\/d41586-020-00364-2\" target=\"_blank\">https:\/\/www.nature.com\/articles\/d41586-020-00364-2<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Did+pangolins+spread+the+China+caronavirus+to+people%3F&rft.atitle=Nature+-+News&rft.aulast=Cyrankoski%2C+D.&rft.au=Cyrankoski%2C+D.&rft.date=07+February+2020&rft_id=info:doi\/10.1038%2Fd41586-020-00364-2&rft_id=https%3A%2F%2Fwww.nature.com%2Farticles%2Fd41586-020-00364-2&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-WHORecomm20-10\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-WHORecomm20_10-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">World Health Organization (March 2020). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.who.int\/health-topics\/coronavirus\/who-recommendations-to-reduce-risk-of-transmission-of-emerging-pathogens-from-animals-to-humans-in-live-animal-markets\" target=\"_blank\">\"WHO recommendations to reduce risk of transmission of emerging pathogens from animals to humans in live animal markets or animal product markets\"<\/a>. World Health Organization<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.who.int\/health-topics\/coronavirus\/who-recommendations-to-reduce-risk-of-transmission-of-emerging-pathogens-from-animals-to-humans-in-live-animal-markets\" target=\"_blank\">https:\/\/www.who.int\/health-topics\/coronavirus\/who-recommendations-to-reduce-risk-of-transmission-of-emerging-pathogens-from-animals-to-humans-in-live-animal-markets<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 13 March 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=WHO+recommendations+to+reduce+risk+of+transmission+of+emerging+pathogens+from+animals+to+humans+in+live+animal+markets+or+animal+product+markets&rft.atitle=&rft.aulast=World+Health+Organization&rft.au=World+Health+Organization&rft.date=March+2020&rft.pub=World+Health+Organization&rft_id=https%3A%2F%2Fwww.who.int%2Fhealth-topics%2Fcoronavirus%2Fwho-recommendations-to-reduce-risk-of-transmission-of-emerging-pathogens-from-animals-to-humans-in-live-animal-markets&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-WangUpdated20-11\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-WangUpdated20_11-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Wang, W.; Tang, J.; Wei, F. (2020). \"Updated understanding of the outbreak of 2019 novel coronavirus (2019\u2010nCoV) in Wuhan, China\". <i>Journal of Medical Virology<\/i> <b>92<\/b> (4): 441\u201347. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1002%2Fjmv.25689\" target=\"_blank\">10.1002\/jmv.25689<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Updated+understanding+of+the+outbreak+of+2019+novel+coronavirus+%282019%E2%80%90nCoV%29+in+Wuhan%2C+China&rft.jtitle=Journal+of+Medical+Virology&rft.aulast=Wang%2C+W.%3B+Tang%2C+J.%3B+Wei%2C+F.&rft.au=Wang%2C+W.%3B+Tang%2C+J.%3B+Wei%2C+F.&rft.date=2020&rft.volume=92&rft.issue=4&rft.pages=441%E2%80%9347&rft_id=info:doi\/10.1002%2Fjmv.25689&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-WHOSitReps20-12\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-WHOSitReps20_12-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">World Health Organization (March 2020). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.who.int\/emergencies\/diseases\/novel-coronavirus-2019\/situation-reports\/\" target=\"_blank\">\"Coronavirus disease (COVID-2019) situation reports\"<\/a>. World Health Organization<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.who.int\/emergencies\/diseases\/novel-coronavirus-2019\/situation-reports\/\" target=\"_blank\">https:\/\/www.who.int\/emergencies\/diseases\/novel-coronavirus-2019\/situation-reports\/<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 09 March 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Coronavirus+disease+%28COVID-2019%29+situation+reports&rft.atitle=&rft.aulast=World+Health+Organization&rft.au=World+Health+Organization&rft.date=March+2020&rft.pub=World+Health+Organization&rft_id=https%3A%2F%2Fwww.who.int%2Femergencies%2Fdiseases%2Fnovel-coronavirus-2019%2Fsituation-reports%2F&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-CohenStrat20-13\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-CohenStrat20_13-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Cohen, J.; Kupferschmidt, K. (2020). \"Strategies shift as coronavirus pandemic looms\". <i>Science<\/i> <b>367<\/b> (6481): 962\u201363. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1126%2Fscience.367.6481.962\" target=\"_blank\">10.1126\/science.367.6481.962<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/32108093\" target=\"_blank\">32108093<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Strategies+shift+as+coronavirus+pandemic+looms&rft.jtitle=Science&rft.aulast=Cohen%2C+J.%3B+Kupferschmidt%2C+K.&rft.au=Cohen%2C+J.%3B+Kupferschmidt%2C+K.&rft.date=2020&rft.volume=367&rft.issue=6481&rft.pages=962%E2%80%9363&rft_id=info:doi\/10.1126%2Fscience.367.6481.962&rft_id=info:pmid\/32108093&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ReganItaly20-14\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-ReganItaly20_14-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Regan, H. (08 March 2020). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/edition.cnn.com\/2020\/03\/08\/asia\/coronavirus-covid-19-update-intl-hnk\/index.html\" target=\"_blank\">\"Italy announces lockdown as global coronavirus cases surpass 105,000\"<\/a>. <i>CNN<\/i><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/edition.cnn.com\/2020\/03\/08\/asia\/coronavirus-covid-19-update-intl-hnk\/index.html\" target=\"_blank\">https:\/\/edition.cnn.com\/2020\/03\/08\/asia\/coronavirus-covid-19-update-intl-hnk\/index.html<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 08 March 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Italy+announces+lockdown+as+global+coronavirus+cases+surpass+105%2C000&rft.atitle=CNN&rft.aulast=Regan%2C+H.&rft.au=Regan%2C+H.&rft.date=08+March+2020&rft_id=https%3A%2F%2Fedition.cnn.com%2F2020%2F03%2F08%2Fasia%2Fcoronavirus-covid-19-update-intl-hnk%2Findex.html&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-WuNow20-15\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-WuNow20_15-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Wu, J.T.; Leung, K.; Leung, G.M. (2020). \"Nowcasting and forecasting the potential domestic and international spread of the 2019-nCoV outbreak originating in Wuhan, China: A modelling study\". <i>Lancet<\/i> <b>395<\/b> (10225): 689-697. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2FS0140-6736%2820%2930260-9\" target=\"_blank\">10.1016\/S0140-6736(20)30260-9<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/32014114\" target=\"_blank\">32014114<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Nowcasting+and+forecasting+the+potential+domestic+and+international+spread+of+the+2019-nCoV+outbreak+originating+in+Wuhan%2C+China%3A+A+modelling+study&rft.jtitle=Lancet&rft.aulast=Wu%2C+J.T.%3B+Leung%2C+K.%3B+Leung%2C+G.M.&rft.au=Wu%2C+J.T.%3B+Leung%2C+K.%3B+Leung%2C+G.M.&rft.date=2020&rft.volume=395&rft.issue=10225&rft.pages=689-697&rft_id=info:doi\/10.1016%2FS0140-6736%2820%2930260-9&rft_id=info:pmid\/32014114&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-TangAnUpdated20-16\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-TangAnUpdated20_16-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Tang, B.; Bragazzi, N.L.; Li, Q. et al. (2020). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7029158\" target=\"_blank\">\"An updated estimation of the risk of transmission of the novel coronavirus (2019-nCov)\"<\/a>. <i>Infectious Disease Modelling<\/i> <b>5<\/b>: 248-255. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.idm.2020.02.001\" target=\"_blank\">10.1016\/j.idm.2020.02.001<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC7029158\/\" target=\"_blank\">PMC7029158<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/32099934\" target=\"_blank\">32099934<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7029158\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7029158<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=An+updated+estimation+of+the+risk+of+transmission+of+the+novel+coronavirus+%282019-nCov%29&rft.jtitle=Infectious+Disease+Modelling&rft.aulast=Tang%2C+B.%3B+Bragazzi%2C+N.L.%3B+Li%2C+Q.+et+al.&rft.au=Tang%2C+B.%3B+Bragazzi%2C+N.L.%3B+Li%2C+Q.+et+al.&rft.date=2020&rft.volume=5&rft.pages=248-255&rft_id=info:doi\/10.1016%2Fj.idm.2020.02.001&rft_id=info:pmc\/PMC7029158&rft_id=info:pmid\/32099934&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC7029158&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-GallagherCorona01-17\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-GallagherCorona01_17-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Gallagher, T.M.; Buchmeier, M.J. (2001). \"Coronavirus spike proteins in viral entry and pathogenesis\". <i>Virology<\/i> <b>279<\/b> (2): 371\u20134. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1006%2Fviro.2000.0757\" target=\"_blank\">10.1006\/viro.2000.0757<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/11162792\" target=\"_blank\">11162792<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Coronavirus+spike+proteins+in+viral+entry+and+pathogenesis&rft.jtitle=Virology&rft.aulast=Gallagher%2C+T.M.%3B+Buchmeier%2C+M.J.&rft.au=Gallagher%2C+T.M.%3B+Buchmeier%2C+M.J.&rft.date=2001&rft.volume=279&rft.issue=2&rft.pages=371%E2%80%934&rft_id=info:doi\/10.1006%2Fviro.2000.0757&rft_id=info:pmid\/11162792&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-SchoemanCorona19-18\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-SchoemanCorona19_18-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Schoeman, D.; Fielding, B.C. (2019). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6537279\" target=\"_blank\">\"Coronavirus envelope protein: Current knowledge\"<\/a>. <i>Virology Journal<\/i> <b>16<\/b> (1): 69. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1186%2Fs12985-019-1182-0\" target=\"_blank\">10.1186\/s12985-019-1182-0<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6537279\/\" target=\"_blank\">PMC6537279<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/31133031\" target=\"_blank\">31133031<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6537279\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6537279<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Coronavirus+envelope+protein%3A+Current+knowledge&rft.jtitle=Virology+Journal&rft.aulast=Schoeman%2C+D.%3B+Fielding%2C+B.C.&rft.au=Schoeman%2C+D.%3B+Fielding%2C+B.C.&rft.date=2019&rft.volume=16&rft.issue=1&rft.pages=69&rft_id=info:doi\/10.1186%2Fs12985-019-1182-0&rft_id=info:pmc\/PMC6537279&rft_id=info:pmid\/31133031&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC6537279&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-GralinskiReturn20-19\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-GralinskiReturn20_19-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Gralinski, L.E.; Menechary, V.D. (2020). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7077245\" target=\"_blank\">\"Return of the Coronavirus: 2019-nCoV\"<\/a>. <i>Viruses<\/i> <b>12<\/b> (2): E135. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.3390%2Fv12020135\" target=\"_blank\">10.3390\/v12020135<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC7077245\/\" target=\"_blank\">PMC7077245<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/31991541\" target=\"_blank\">31991541<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7077245\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7077245<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Return+of+the+Coronavirus%3A+2019-nCoV&rft.jtitle=Viruses&rft.aulast=Gralinski%2C+L.E.%3B+Menechary%2C+V.D.&rft.au=Gralinski%2C+L.E.%3B+Menechary%2C+V.D.&rft.date=2020&rft.volume=12&rft.issue=2&rft.pages=E135&rft_id=info:doi\/10.3390%2Fv12020135&rft_id=info:pmc\/PMC7077245&rft_id=info:pmid\/31991541&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC7077245&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-HuangClin20-20\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-HuangClin20_20-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Huang, C.; Wang, T.; Li, X. et al. (2020). \"Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China\". <i>Lancet<\/i> <b>395<\/b> (10223): 497\u2013506. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2FS0140-6736%2820%2930183-5\" target=\"_blank\">10.1016\/S0140-6736(20)30183-5<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/31986264\" target=\"_blank\">31986264<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Clinical+features+of+patients+infected+with+2019+novel+coronavirus+in+Wuhan%2C+China&rft.jtitle=Lancet&rft.aulast=Huang%2C+C.%3B+Wang%2C+T.%3B+Li%2C+X.+et+al.&rft.au=Huang%2C+C.%3B+Wang%2C+T.%3B+Li%2C+X.+et+al.&rft.date=2020&rft.volume=395&rft.issue=10223&rft.pages=497%E2%80%93506&rft_id=info:doi\/10.1016%2FS0140-6736%2820%2930183-5&rft_id=info:pmid\/31986264&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-NguyenFromLab18-21\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-NguyenFromLab18_21-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Nguyen, T.; Zo\u00ebga Andreasen, S.; Wolff, A. et al. (2018). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6187319\" target=\"_blank\">\"From Lab on a Chip to Point of Care Devices: The Role of Open Source Microcontrollers\"<\/a>. <i>Micromachines<\/i> <b>9<\/b> (8): E403. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.3390%2Fmi9080403\" target=\"_blank\">10.3390\/mi9080403<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6187319\/\" target=\"_blank\">PMC6187319<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/30424336\" target=\"_blank\">30424336<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6187319\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6187319<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=From+Lab+on+a+Chip+to+Point+of+Care+Devices%3A+The+Role+of+Open+Source+Microcontrollers&rft.jtitle=Micromachines&rft.aulast=Nguyen%2C+T.%3B+Zo%C3%ABga+Andreasen%2C+S.%3B+Wolff%2C+A.+et+al.&rft.au=Nguyen%2C+T.%3B+Zo%C3%ABga+Andreasen%2C+S.%3B+Wolff%2C+A.+et+al.&rft.date=2018&rft.volume=9&rft.issue=8&rft.pages=E403&rft_id=info:doi\/10.3390%2Fmi9080403&rft_id=info:pmc\/PMC6187319&rft_id=info:pmid\/30424336&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC6187319&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-KeOutbreak15-22\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-KeOutbreak15_22-0\">22.0<\/a><\/sup> <sup><a href=\"#cite_ref-KeOutbreak15_22-1\">22.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Ke, C.-M.; Tsai, H.-C.; Chen, Y.-S. et al. (2015). \"Outbreak investigation of pandemic influenza A H1N1 at the emergency department in a medical center in Southern Taiwan\". <i>Journal of Microbiology, Immunology and Infection<\/i> <b>48<\/b> (2, Suppl. 1): S36. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.jmii.2015.02.051\" target=\"_blank\">10.1016\/j.jmii.2015.02.051<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Outbreak+investigation+of+pandemic+influenza+A+H1N1+at+the+emergency+department+in+a+medical+center+in+Southern+Taiwan&rft.jtitle=Journal+of+Microbiology%2C+Immunology+and+Infection&rft.aulast=Ke%2C+C.-M.%3B+Tsai%2C+H.-C.%3B+Chen%2C+Y.-S.+et+al.&rft.au=Ke%2C+C.-M.%3B+Tsai%2C+H.-C.%3B+Chen%2C+Y.-S.+et+al.&rft.date=2015&rft.volume=48&rft.issue=2%2C+Suppl.+1&rft.pages=S36&rft_id=info:doi\/10.1016%2Fj.jmii.2015.02.051&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-IsereAnOver15-23\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-IsereAnOver15_23-0\">23.0<\/a><\/sup> <sup><a href=\"#cite_ref-IsereAnOver15_23-1\">23.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Isere, E.E.; Fatiregun, A.A.; Ajayi, I.O. (2015). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4518330\" target=\"_blank\">\"An overview of disease surveillance and notification system in Nigeria and the roles of clinicians in disease outbreak prevention and control\"<\/a>. <i>Nigerian Medical Journal<\/i> <b>56<\/b> (3): 161\u20138. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.4103%2F0300-1652.160347\" target=\"_blank\">10.4103\/0300-1652.160347<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC4518330\/\" target=\"_blank\">PMC4518330<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/26229222\" target=\"_blank\">26229222<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4518330\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4518330<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=An+overview+of+disease+surveillance+and+notification+system+in+Nigeria+and+the+roles+of+clinicians+in+disease+outbreak+prevention+and+control&rft.jtitle=Nigerian+Medical+Journal&rft.aulast=Isere%2C+E.E.%3B+Fatiregun%2C+A.A.%3B+Ajayi%2C+I.O.&rft.au=Isere%2C+E.E.%3B+Fatiregun%2C+A.A.%3B+Ajayi%2C+I.O.&rft.date=2015&rft.volume=56&rft.issue=3&rft.pages=161%E2%80%938&rft_id=info:doi\/10.4103%2F0300-1652.160347&rft_id=info:pmc\/PMC4518330&rft_id=info:pmid\/26229222&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC4518330&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-JonesTheFrench14-24\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-JonesTheFrench14_24-0\">24.0<\/a><\/sup> <sup><a href=\"#cite_ref-JonesTheFrench14_24-1\">24.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Jones, G.; Le Hello, S.; Jourdan-da Silva, N. et al. (2014). \"The French human Salmonella surveillance system: evaluation of timeliness of laboratory reporting and factors associated with delays, 2007 to 2011\". <i>Euro Surveillance<\/i> <b>19<\/b> (1): 20664. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.2807%2F1560-7917.es2014.19.1.20664\" target=\"_blank\">10.2807\/1560-7917.es2014.19.1.20664<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/24434174\" target=\"_blank\">24434174<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=The+French+human+Salmonella+surveillance+system%3A+evaluation+of+timeliness+of+laboratory+reporting+and+factors+associated+with+delays%2C+2007+to+2011&rft.jtitle=Euro+Surveillance&rft.aulast=Jones%2C+G.%3B+Le+Hello%2C+S.%3B+Jourdan-da+Silva%2C+N.+et+al.&rft.au=Jones%2C+G.%3B+Le+Hello%2C+S.%3B+Jourdan-da+Silva%2C+N.+et+al.&rft.date=2014&rft.volume=19&rft.issue=1&rft.pages=20664&rft_id=info:doi\/10.2807%2F1560-7917.es2014.19.1.20664&rft_id=info:pmid\/24434174&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-WHOCorona28_20-25\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-WHOCorona28_20_25-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">World Health Organization (17 February 2020). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.who.int\/docs\/default-source\/coronaviruse\/situation-reports\/20200217-sitrep-28-covid-19.pdf\" target=\"_blank\">\"Coronavirus disease 2019 (COVID-19): Situation Report - 28\"<\/a> (PDF). World Health Organization<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.who.int\/docs\/default-source\/coronaviruse\/situation-reports\/20200217-sitrep-28-covid-19.pdf\" target=\"_blank\">https:\/\/www.who.int\/docs\/default-source\/coronaviruse\/situation-reports\/20200217-sitrep-28-covid-19.pdf<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 13 March 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Coronavirus+disease+2019+%28COVID-19%29%3A+Situation+Report+-+28&rft.atitle=&rft.aulast=World+Health+Organization&rft.au=World+Health+Organization&rft.date=17+February+2020&rft.pub=World+Health+Organization&rft_id=https%3A%2F%2Fwww.who.int%2Fdocs%2Fdefault-source%2Fcoronaviruse%2Fsituation-reports%2F20200217-sitrep-28-covid-19.pdf&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-TJTCorona20-26\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-TJTCorona20_26-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">The Japan Times Staff (10 February 2020). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.japantimes.co.jp\/news\/2020\/02\/10\/national\/japan-test-all-passengers-diamond-princess-cruise-ship-coronavirus\/\" target=\"_blank\">\"Coronavirus infection tally on Diamond Princess hits 135 as tests for all passengers eyed\"<\/a>. <i>The Japan Times<\/i><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.japantimes.co.jp\/news\/2020\/02\/10\/national\/japan-test-all-passengers-diamond-princess-cruise-ship-coronavirus\/\" target=\"_blank\">https:\/\/www.japantimes.co.jp\/news\/2020\/02\/10\/national\/japan-test-all-passengers-diamond-princess-cruise-ship-coronavirus\/<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 10 February 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Coronavirus+infection+tally+on+Diamond+Princess+hits+135+as+tests+for+all+passengers+eyed&rft.atitle=The+Japan+Times&rft.aulast=The+Japan+Times+Staff&rft.au=The+Japan+Times+Staff&rft.date=10+February+2020&rft_id=https%3A%2F%2Fwww.japantimes.co.jp%2Fnews%2F2020%2F02%2F10%2Fnational%2Fjapan-test-all-passengers-diamond-princess-cruise-ship-coronavirus%2F&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-CormanDetect20-27\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-CormanDetect20_27-0\">27.0<\/a><\/sup> <sup><a href=\"#cite_ref-CormanDetect20_27-1\">27.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Corman, V.M.; Landt, O.; Kaiser, M. et al. (2020). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6988269\" target=\"_blank\">\"Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR\"<\/a>. <i>Euro Surveillance<\/i> <b>25<\/b> (3): 2000045. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.2807%2F1560-7917.ES.2020.25.3.2000045\" target=\"_blank\">10.2807\/1560-7917.ES.2020.25.3.2000045<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6988269\/\" target=\"_blank\">PMC6988269<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/31992387\" target=\"_blank\">31992387<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6988269\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6988269<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Detection+of+2019+novel+coronavirus+%282019-nCoV%29+by+real-time+RT-PCR&rft.jtitle=Euro+Surveillance&rft.aulast=Corman%2C+V.M.%3B+Landt%2C+O.%3B+Kaiser%2C+M.+et+al.&rft.au=Corman%2C+V.M.%3B+Landt%2C+O.%3B+Kaiser%2C+M.+et+al.&rft.date=2020&rft.volume=25&rft.issue=3&rft.pages=2000045&rft_id=info:doi\/10.2807%2F1560-7917.ES.2020.25.3.2000045&rft_id=info:pmc\/PMC6988269&rft_id=info:pmid\/31992387&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC6988269&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ChuMolec20-28\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-ChuMolec20_28-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Chu, D.K.W.; Pan, Y.; Cheng, S.M.S. et al. (2020). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7108203\" target=\"_blank\">\"Molecular Diagnosis of a Novel Coronavirus (2019-nCoV) Causing an Outbreak of Pneumonia\"<\/a>. <i>Clinical Chemistry<\/i> <b>66<\/b> (4): 549-555. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1093%2Fclinchem%2Fhvaa029\" target=\"_blank\">10.1093\/clinchem\/hvaa029<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC7108203\/\" target=\"_blank\">PMC7108203<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/32031583\" target=\"_blank\">32031583<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7108203\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7108203<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Molecular+Diagnosis+of+a+Novel+Coronavirus+%282019-nCoV%29+Causing+an+Outbreak+of+Pneumonia&rft.jtitle=Clinical+Chemistry&rft.aulast=Chu%2C+D.K.W.%3B+Pan%2C+Y.%3B+Cheng%2C+S.M.S.+et+al.&rft.au=Chu%2C+D.K.W.%3B+Pan%2C+Y.%3B+Cheng%2C+S.M.S.+et+al.&rft.date=2020&rft.volume=66&rft.issue=4&rft.pages=549-555&rft_id=info:doi\/10.1093%2Fclinchem%2Fhvaa029&rft_id=info:pmc\/PMC7108203&rft_id=info:pmid\/32031583&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC7108203&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-BruningRapid18-29\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-BruningRapid18_29-0\">29.0<\/a><\/sup> <sup><a href=\"#cite_ref-BruningRapid18_29-1\">29.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Bruning, A.H.L.; Aatola, H.; Toivola, H. et al. (2020). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5986163\" target=\"_blank\">\"Rapid detection and monitoring of human coronavirus infections\"<\/a>. <i>New Microbes and New Infections<\/i> <b>24<\/b>: 52\u201355. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.nmni.2018.04.007\" target=\"_blank\">10.1016\/j.nmni.2018.04.007<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC5986163\/\" target=\"_blank\">PMC5986163<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/29872531\" target=\"_blank\">29872531<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5986163\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5986163<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Rapid+detection+and+monitoring+of+human+coronavirus+infections&rft.jtitle=New+Microbes+and+New+Infections&rft.aulast=Bruning%2C+A.H.L.%3B+Aatola%2C+H.%3B+Toivola%2C+H.+et+al.&rft.au=Bruning%2C+A.H.L.%3B+Aatola%2C+H.%3B+Toivola%2C+H.+et+al.&rft.date=2020&rft.volume=24&rft.pages=52%E2%80%9355&rft_id=info:doi\/10.1016%2Fj.nmni.2018.04.007&rft_id=info:pmc\/PMC5986163&rft_id=info:pmid\/29872531&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC5986163&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-GauntEpidem10-30\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-GauntEpidem10_30-0\">30.0<\/a><\/sup> <sup><a href=\"#cite_ref-GauntEpidem10_30-1\">30.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Gaunt, E.R.; Hardie, A.; Claas, E.C. et al. (2020). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2916580\" target=\"_blank\">\"Epidemiology and clinical presentations of the four human coronaviruses 229E, HKU1, NL63, and OC43 detected over three years using a novel multiplex real-time PCR method\"<\/a>. <i>Journal of Clinical Microbiology<\/i> <b>48<\/b> (8): 2940-7. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1128%2FJCM.00636-10\" target=\"_blank\">10.1128\/JCM.00636-10<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC2916580\/\" target=\"_blank\">PMC2916580<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/20554810\" target=\"_blank\">20554810<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2916580\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2916580<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Epidemiology+and+clinical+presentations+of+the+four+human+coronaviruses+229E%2C+HKU1%2C+NL63%2C+and+OC43+detected+over+three+years+using+a+novel+multiplex+real-time+PCR+method&rft.jtitle=Journal+of+Clinical+Microbiology&rft.aulast=Gaunt%2C+E.R.%3B+Hardie%2C+A.%3B+Claas%2C+E.C.+et+al.&rft.au=Gaunt%2C+E.R.%3B+Hardie%2C+A.%3B+Claas%2C+E.C.+et+al.&rft.date=2020&rft.volume=48&rft.issue=8&rft.pages=2940-7&rft_id=info:doi\/10.1128%2FJCM.00636-10&rft_id=info:pmc\/PMC2916580&rft_id=info:pmid\/20554810&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC2916580&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ChoEval14-31\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-ChoEval14_31-0\">31.0<\/a><\/sup> <sup><a href=\"#cite_ref-ChoEval14_31-1\">31.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Cho, C.H.; Lee, C.K.; Nam, M.H. et al. (2014). \"Evaluation of the AdvanSure real-time RT-PCR compared with culture and Seeplex RV15 for simultaneous detection of respiratory viruses\". <i>Diagnostic Microbiology and Infectious Disease<\/i> <b>79<\/b> (1): 14\u201318. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.diagmicrobio.2014.01.016\" target=\"_blank\">10.1016\/j.diagmicrobio.2014.01.016<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/24582583\" target=\"_blank\">24582583<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Evaluation+of+the+AdvanSure+real-time+RT-PCR+compared+with+culture+and+Seeplex+RV15+for+simultaneous+detection+of+respiratory+viruses&rft.jtitle=Diagnostic+Microbiology+and+Infectious+Disease&rft.aulast=Cho%2C+C.H.%3B+Lee%2C+C.K.%3B+Nam%2C+M.H.+et+al.&rft.au=Cho%2C+C.H.%3B+Lee%2C+C.K.%3B+Nam%2C+M.H.+et+al.&rft.date=2014&rft.volume=79&rft.issue=1&rft.pages=14%E2%80%9318&rft_id=info:doi\/10.1016%2Fj.diagmicrobio.2014.01.016&rft_id=info:pmid\/24582583&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-BrueckThere20-32\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-BrueckThere20_32-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Brueck, H. (30 January 2020). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.businessinsider.com\/how-to-know-if-you-have-the-coronavirus-pcr-test-2020-1\" target=\"_blank\">\"There's only one way to know if you have the coronavirus, and it involves machines full of spit and mucus\"<\/a>. <i>Business Insider<\/i><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.businessinsider.com\/how-to-know-if-you-have-the-coronavirus-pcr-test-2020-1\" target=\"_blank\">https:\/\/www.businessinsider.com\/how-to-know-if-you-have-the-coronavirus-pcr-test-2020-1<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 13 March 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=There%27s+only+one+way+to+know+if+you+have+the+coronavirus%2C+and+it+involves+machines+full+of+spit+and+mucus&rft.atitle=Business+Insider&rft.aulast=Brueck%2C+H.&rft.au=Brueck%2C+H.&rft.date=30+January+2020&rft_id=https%3A%2F%2Fwww.businessinsider.com%2Fhow-to-know-if-you-have-the-coronavirus-pcr-test-2020-1&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-MolteniTheUS20-33\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-MolteniTheUS20_33-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Molteni, M. (04 February 2020). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.wired.com\/story\/the-us-fast-tracked-a-coronavirus-test\/\" target=\"_blank\">\"The US Fast-Tracked a Coronavirus Test to Speed Up Diagnoses\"<\/a>. <i>Wired<\/i><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.wired.com\/story\/the-us-fast-tracked-a-coronavirus-test\/\" target=\"_blank\">https:\/\/www.wired.com\/story\/the-us-fast-tracked-a-coronavirus-test\/<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 13 March 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=The+US+Fast-Tracked+a+Coronavirus+Test+to+Speed+Up+Diagnoses&rft.atitle=Wired&rft.aulast=Molteni%2C+M.&rft.au=Molteni%2C+M.&rft.date=04+February+2020&rft_id=https%3A%2F%2Fwww.wired.com%2Fstory%2Fthe-us-fast-tracked-a-coronavirus-test%2F&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-CCDCWuhan20-34\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-CCDCWuhan20_34-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Chinese Center for Disease Control and Prevention (04 February 2020). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.chinacdc.cn\/yw_9324\/202002\/t20200204_212214.html\" target=\"_blank\">\"\u9a70\u63f4\u6b66\u6c49,\u9ad8\u7b49\u7ea7\u79fb\u52a8\u751f\u7269\u5b89\u5168\u5b9e\u9a8c\u5ba4\u542f\u7a0b\"<\/a>. Chinese Center for Disease Control and Prevention<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.chinacdc.cn\/yw_9324\/202002\/t20200204_212214.html\" target=\"_blank\">http:\/\/www.chinacdc.cn\/yw_9324\/202002\/t20200204_212214.html<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 13 March 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=%E9%A9%B0%E6%8F%B4%E6%AD%A6%E6%B1%89%2C%E9%AB%98%E7%AD%89%E7%BA%A7%E7%A7%BB%E5%8A%A8%E7%94%9F%E7%89%A9%E5%AE%89%E5%85%A8%E5%AE%9E%E9%AA%8C%E5%AE%A4%E5%90%AF%E7%A8%8B&rft.atitle=&rft.aulast=Chinese+Center+for+Disease+Control+and+Prevention&rft.au=Chinese+Center+for+Disease+Control+and+Prevention&rft.date=04+February+2020&rft.pub=Chinese+Center+for+Disease+Control+and+Prevention&rft_id=http%3A%2F%2Fwww.chinacdc.cn%2Fyw_9324%2F202002%2Ft20200204_212214.html&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-BGINewEmerg20-35\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-BGINewEmerg20_35-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\"><a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.bgi.com\/global\/company\/news\/new-emergency-detection-laboratory-run-by-bgi-starts-trial-operation-in-wuhan-designed-to-test-10000-samples-daily\/\" target=\"_blank\">\"New Emergency Detection Laboratory Run by BGI Starts Trial Operation in Wuhan, Designed to Test 10,000 Samples Daily\"<\/a>. <i>BGI News<\/i>. BGI. 06 February 2020<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.bgi.com\/global\/company\/news\/new-emergency-detection-laboratory-run-by-bgi-starts-trial-operation-in-wuhan-designed-to-test-10000-samples-daily\/\" target=\"_blank\">https:\/\/www.bgi.com\/global\/company\/news\/new-emergency-detection-laboratory-run-by-bgi-starts-trial-operation-in-wuhan-designed-to-test-10000-samples-daily\/<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 13 March 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=New+Emergency+Detection+Laboratory+Run+by+BGI+Starts+Trial+Operation+in+Wuhan%2C+Designed+to+Test+10%2C000+Samples+Daily&rft.atitle=BGI+News&rft.date=06+February+2020&rft.pub=BGI&rft_id=https%3A%2F%2Fwww.bgi.com%2Fglobal%2Fcompany%2Fnews%2Fnew-emergency-detection-laboratory-run-by-bgi-starts-trial-operation-in-wuhan-designed-to-test-10000-samples-daily%2F&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-NagamineAccel02-36\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-NagamineAccel02_36-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Nagamine, K.; Hase, T.; Notomi, T. (2002). \"Accelerated reaction by loop-mediated isothermal amplification using loop primers\". <i>Molecular and Cellular Probes<\/i> <b>16<\/b> (3): 223-9. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1006%2Fmcpr.2002.0415\" target=\"_blank\">10.1006\/mcpr.2002.0415<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/12144774\" target=\"_blank\">12144774<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Accelerated+reaction+by+loop-mediated+isothermal+amplification+using+loop+primers&rft.jtitle=Molecular+and+Cellular+Probes&rft.aulast=Nagamine%2C+K.%3B+Hase%2C+T.%3B+Notomi%2C+T.&rft.au=Nagamine%2C+K.%3B+Hase%2C+T.%3B+Notomi%2C+T.&rft.date=2002&rft.volume=16&rft.issue=3&rft.pages=223-9&rft_id=info:doi\/10.1006%2Fmcpr.2002.0415&rft_id=info:pmid\/12144774&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-FrancoisRobust11-37\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-FrancoisRobust11_37-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Francois, P.; Tangomo, M.; Hibbs, J. et al. (2011). \"Robustness of a loop-mediated isothermal amplification reaction for diagnostic applications\". <i>FEMS Immunology and Medical Microbiology<\/i> <b>62<\/b> (1): 41\u20138. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1111%2Fj.1574-695X.2011.00785.x\" target=\"_blank\">10.1111\/j.1574-695X.2011.00785.x<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/21276085\" target=\"_blank\">21276085<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Robustness+of+a+loop-mediated+isothermal+amplification+reaction+for+diagnostic+applications&rft.jtitle=FEMS+Immunology+and+Medical+Microbiology&rft.aulast=Francois%2C+P.%3B+Tangomo%2C+M.%3B+Hibbs%2C+J.+et+al.&rft.au=Francois%2C+P.%3B+Tangomo%2C+M.%3B+Hibbs%2C+J.+et+al.&rft.date=2011&rft.volume=62&rft.issue=1&rft.pages=41%E2%80%938&rft_id=info:doi\/10.1111%2Fj.1574-695X.2011.00785.x&rft_id=info:pmid\/21276085&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-GalvezLoop20-38\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-GalvezLoop20_38-0\">38.0<\/a><\/sup> <sup><a href=\"#cite_ref-GalvezLoop20_38-1\">38.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Galvez, L.C.; Barbosa, C.F.C.; Koh, R.B.L. et al. (2020). \"Loop-mediated isothermal amplification (LAMP) assays for the detection of abaca bunchy top virus and banana bunchy top virus in abaca\". <i>Crop Protection<\/i> <b>131<\/b>: 105101. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.cropro.2020.105101\" target=\"_blank\">10.1016\/j.cropro.2020.105101<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Loop-mediated+isothermal+amplification+%28LAMP%29+assays+for+the+detection+of+abaca+bunchy+top+virus+and+banana+bunchy+top+virus+in+abaca&rft.jtitle=Crop+Protection&rft.aulast=Galvez%2C+L.C.%3B+Barbosa%2C+C.F.C.%3B+Koh%2C+R.B.L.+et+al.&rft.au=Galvez%2C+L.C.%3B+Barbosa%2C+C.F.C.%3B+Koh%2C+R.B.L.+et+al.&rft.date=2020&rft.volume=131&rft.pages=105101&rft_id=info:doi\/10.1016%2Fj.cropro.2020.105101&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-AhnRapid19-39\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-AhnRapid19_39-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Ahn, S.J.; Baek, Y.H.; Lloren, K.K.S. et al. (2019). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6669974\" target=\"_blank\">\"Rapid and simple colorimetric detection of multiple influenza viruses infecting humans using a reverse transcriptional loop-mediated isothermal amplification (RT-LAMP) diagnostic platform\"<\/a>. <i>BMC Infectious Diseases<\/i> <b>19<\/b> (1): 676. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1186%2Fs12879-019-4277-8\" target=\"_blank\">10.1186\/s12879-019-4277-8<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6669974\/\" target=\"_blank\">PMC6669974<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/31370782\" target=\"_blank\">31370782<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6669974\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6669974<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Rapid+and+simple+colorimetric+detection+of+multiple+influenza+viruses+infecting+humans+using+a+reverse+transcriptional+loop-mediated+isothermal+amplification+%28RT-LAMP%29+diagnostic+platform&rft.jtitle=BMC+Infectious+Diseases&rft.aulast=Ahn%2C+S.J.%3B+Baek%2C+Y.H.%3B+Lloren%2C+K.K.S.+et+al.&rft.au=Ahn%2C+S.J.%3B+Baek%2C+Y.H.%3B+Lloren%2C+K.K.S.+et+al.&rft.date=2019&rft.volume=19&rft.issue=1&rft.pages=676&rft_id=info:doi\/10.1186%2Fs12879-019-4277-8&rft_id=info:pmc\/PMC6669974&rft_id=info:pmid\/31370782&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC6669974&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-JeonDevelop17-40\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-JeonDevelop17_40-0\">40.0<\/a><\/sup> <sup><a href=\"#cite_ref-JeonDevelop17_40-1\">40.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Jeon, S.B.; Seo, D.J.; Oh, H. et al. (2017). \"Development of one-step reverse transcription loop-mediated isothermal amplification for norovirus detection in oysters\". <i>Food Control<\/i> <b>73<\/b> (Part B): 1002\u20139. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.foodcont.2016.10.005\" target=\"_blank\">10.1016\/j.foodcont.2016.10.005<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Development+of+one-step+reverse+transcription+loop-mediated+isothermal+amplification+for+norovirus+detection+in+oysters&rft.jtitle=Food+Control&rft.aulast=Jeon%2C+S.B.%3B+Seo%2C+D.J.%3B+Oh%2C+H.+et+al.&rft.au=Jeon%2C+S.B.%3B+Seo%2C+D.J.%3B+Oh%2C+H.+et+al.&rft.date=2017&rft.volume=73&rft.issue=Part+B&rft.pages=1002%E2%80%939&rft_id=info:doi\/10.1016%2Fj.foodcont.2016.10.005&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-WangComp14-41\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-WangComp14_41-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Wang, X.; Seo, D.J.; Lee, M.H. et al. (2014). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3911361\" target=\"_blank\">\"Comparison of conventional PCR, multiplex PCR, and loop-mediated isothermal amplification assays for rapid detection of Arcobacter species\"<\/a>. <i>Journal of Clinical Microbiology<\/i> <b>52<\/b> (2): 557\u201363. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1128%2FJCM.02883-13\" target=\"_blank\">10.1128\/JCM.02883-13<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC3911361\/\" target=\"_blank\">PMC3911361<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/24478488\" target=\"_blank\">24478488<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3911361\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3911361<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Comparison+of+conventional+PCR%2C+multiplex+PCR%2C+and+loop-mediated+isothermal+amplification+assays+for+rapid+detection+of+Arcobacter+species&rft.jtitle=Journal+of+Clinical+Microbiology&rft.aulast=Wang%2C+X.%3B+Seo%2C+D.J.%3B+Lee%2C+M.H.+et+al.&rft.au=Wang%2C+X.%3B+Seo%2C+D.J.%3B+Lee%2C+M.H.+et+al.&rft.date=2014&rft.volume=52&rft.issue=2&rft.pages=557%E2%80%9363&rft_id=info:doi\/10.1128%2FJCM.02883-13&rft_id=info:pmc\/PMC3911361&rft_id=info:pmid\/24478488&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC3911361&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-VIVALDI20-42\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-VIVALDI20_42-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\"><a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.vivaldi-ia.eu\/\" target=\"_blank\">\"VIVALDI\"<\/a>. DTU Bioengineering, Technical University of Denmark. 2020<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.vivaldi-ia.eu\/\" target=\"_blank\">https:\/\/www.vivaldi-ia.eu\/<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 13 March 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=VIVALDI&rft.atitle=&rft.date=2020&rft.pub=DTU+Bioengineering%2C+Technical+University+of+Denmark&rft_id=https%3A%2F%2Fwww.vivaldi-ia.eu%2F&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-VIVALDI_VETPOD20-43\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-VIVALDI_VETPOD20_43-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\"><a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.vivaldi-ia.eu\/Research\" target=\"_blank\">\"VIVALDI - Research\"<\/a>. DTU Bioengineering, Technical University of Denmark. 2020<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.vivaldi-ia.eu\/Research\" target=\"_blank\">https:\/\/www.vivaldi-ia.eu\/Research<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 13 March 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=VIVALDI+-+Research&rft.atitle=&rft.date=2020&rft.pub=DTU+Bioengineering%2C+Technical+University+of+Denmark&rft_id=https%3A%2F%2Fwww.vivaldi-ia.eu%2FResearch&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-BioMedomicsCOVID20-44\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-BioMedomicsCOVID20_44-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\"><a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.biomedomics.com\/products\/infectious-disease\/covid-19-rt\/\" target=\"_blank\">\"COVID-19 IgM\/IgG Rapid Test\"<\/a>. BioMedomics, Inc. 2020<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.biomedomics.com\/products\/infectious-disease\/covid-19-rt\/\" target=\"_blank\">https:\/\/www.biomedomics.com\/products\/infectious-disease\/covid-19-rt\/<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 13 March 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=COVID-19+IgM%2FIgG+Rapid+Test&rft.atitle=&rft.date=2020&rft.pub=BioMedomics%2C+Inc&rft_id=https%3A%2F%2Fwww.biomedomics.com%2Fproducts%2Finfectious-disease%2Fcovid-19-rt%2F&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-WHO_US675_20-45\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-WHO_US675_20_45-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">World Health Organization (05 February 2020). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.who.int\/news-room\/detail\/05-02-2020-us-675-million-needed-for-new-coronavirus-preparedness-and-response-global-plan\" target=\"_blank\">\"US$675 million needed for new coronavirus preparedness and response global plan\"<\/a>. World Health Organization<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.who.int\/news-room\/detail\/05-02-2020-us-675-million-needed-for-new-coronavirus-preparedness-and-response-global-plan\" target=\"_blank\">https:\/\/www.who.int\/news-room\/detail\/05-02-2020-us-675-million-needed-for-new-coronavirus-preparedness-and-response-global-plan<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 13 March 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=US%24675+million+needed+for+new+coronavirus+preparedness+and+response+global+plan&rft.atitle=&rft.aulast=World+Health+Organization&rft.au=World+Health+Organization&rft.date=05+February+2020&rft.pub=World+Health+Organization&rft_id=https%3A%2F%2Fwww.who.int%2Fnews-room%2Fdetail%2F05-02-2020-us-675-million-needed-for-new-coronavirus-preparedness-and-response-global-plan&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-RagaEcon20-46\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-RagaEcon20_46-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Raga, S. (05 February 2020). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.odi.org\/blogs\/16639-economic-vulnerabilities-coronavirus-top-countries-risk\" target=\"_blank\">\"Economic vulnerabilities to the coronavirus: Top countries at risk\"<\/a>. <i>ODI Blog<\/i>. ODI<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.odi.org\/blogs\/16639-economic-vulnerabilities-coronavirus-top-countries-risk\" target=\"_blank\">https:\/\/www.odi.org\/blogs\/16639-economic-vulnerabilities-coronavirus-top-countries-risk<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 13 March 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Economic+vulnerabilities+to+the+coronavirus%3A+Top+countries+at+risk&rft.atitle=ODI+Blog&rft.aulast=Raga%2C+S.&rft.au=Raga%2C+S.&rft.date=05+February+2020&rft.pub=ODI&rft_id=https%3A%2F%2Fwww.odi.org%2Fblogs%2F16639-economic-vulnerabilities-coronavirus-top-countries-risk&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-WangANovel20-47\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-WangANovel20_47-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Wang, C.; Horby, P.W.; Hayden, F.G. et al. (2020). \"A novel coronavirus outbreak of global health concern\". <i>Lancet<\/i> <b>395<\/b> (10223): 470-473. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2FS0140-6736%2820%2930185-9\" target=\"_blank\">10.1016\/S0140-6736(20)30185-9<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/31986257\" target=\"_blank\">31986257<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=A+novel+coronavirus+outbreak+of+global+health+concern&rft.jtitle=Lancet&rft.aulast=Wang%2C+C.%3B+Horby%2C+P.W.%3B+Hayden%2C+F.G.+et+al.&rft.au=Wang%2C+C.%3B+Horby%2C+P.W.%3B+Hayden%2C+F.G.+et+al.&rft.date=2020&rft.volume=395&rft.issue=10223&rft.pages=470-473&rft_id=info:doi\/10.1016%2FS0140-6736%2820%2930185-9&rft_id=info:pmid\/31986257&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ZhouAPneumonia20-48\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-ZhouAPneumonia20_48-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Zhou, P.; Yang, X.L.; Wang, X.G. et al. (2020). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7095418\" target=\"_blank\">\"A pneumonia outbreak associated with a new coronavirus of probable bat origin\"<\/a>. <i>Nature<\/i> <b>579<\/b> (7798): 270\u201373. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1038%2Fs41586-020-2012-7\" target=\"_blank\">10.1038\/s41586-020-2012-7<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC7095418\/\" target=\"_blank\">PMC7095418<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/32015507\" target=\"_blank\">32015507<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7095418\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7095418<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=A+pneumonia+outbreak+associated+with+a+new+coronavirus+of+probable+bat+origin&rft.jtitle=Nature&rft.aulast=Zhou%2C+P.%3B+Yang%2C+X.L.%3B+Wang%2C+X.G.+et+al.&rft.au=Zhou%2C+P.%3B+Yang%2C+X.L.%3B+Wang%2C+X.G.+et+al.&rft.date=2020&rft.volume=579&rft.issue=7798&rft.pages=270%E2%80%9373&rft_id=info:doi\/10.1038%2Fs41586-020-2012-7&rft_id=info:pmc\/PMC7095418&rft_id=info:pmid\/32015507&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC7095418&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ZhangPotential20-49\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-ZhangPotential20_49-0\">49.0<\/a><\/sup> <sup><a href=\"#cite_ref-ZhangPotential20_49-1\">49.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Zhang, L.; Liu, Y. (2020). \"Potential interventions for novel coronavirus in China: A systematic review\". <i>Journal of Medical Virology<\/i> <b>95<\/b> (2): 479-490. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1002%2Fjmv.25707\" target=\"_blank\">10.1002\/jmv.25707<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/32052466\" target=\"_blank\">32052466<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Potential+interventions+for+novel+coronavirus+in+China%3A+A+systematic+review&rft.jtitle=Journal+of+Medical+Virology&rft.aulast=Zhang%2C+L.%3B+Liu%2C+Y.&rft.au=Zhang%2C+L.%3B+Liu%2C+Y.&rft.date=2020&rft.volume=95&rft.issue=2&rft.pages=479-490&rft_id=info:doi\/10.1002%2Fjmv.25707&rft_id=info:pmid\/32052466&rfr_id=info:sid\/en.wikipedia.org:Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<\/ol><\/div>\n<h2><span class=\"mw-headline\" id=\"Notes\">Notes<\/span><\/h2>\n<p>This presentation is faithful to the original, with only a few minor changes to presentation. In some cases important information was missing from the references, and that information was added. The original article referenced a generic situation report page from the WHO for the Diamond Princess infection numbers; the specific report (#28) is referenced for this version. Similarly, a more specific citation was used in this version for the mentioned VETPOD system. In a few places, \"SARS-CoV-2\" replaced \"COVID-19\" when the authors intended to reference the virus but referenced the disease.\n<\/p>\n<!-- \nNewPP limit report\nCached time: 20200707205106\nCache expiry: 86400\nDynamic content: false\nCPU time usage: 0.938 seconds\nReal time usage: 1.955 seconds\nPreprocessor visited node count: 36929\/1000000\nPreprocessor generated node count: 37968\/1000000\nPost\u2010expand include size: 316887\/2097152 bytes\nTemplate argument size: 107789\/2097152 bytes\nHighest expansion depth: 18\/40\nExpensive parser function count: 0\/100\n-->\n\n<!-- \nTransclusion expansion time report (%,ms,calls,template)\n100.00% 734.865 1 - -total\n 89.19% 655.411 1 - Template:Reflist\n 75.67% 556.039 49 - Template:Citation\/core\n 53.03% 389.700 30 - Template:Cite_journal\n 25.96% 190.745 19 - Template:Cite_web\n 8.17% 60.074 70 - Template:Citation\/identifier\n 5.12% 37.612 1 - Template:Infobox_journal_article\n 4.88% 35.846 1 - Template:Infobox\n 4.50% 33.097 57 - Template:Citation\/make_link\n 3.27% 24.007 80 - Template:Infobox\/row\n-->\n\n<!-- Saved in parser cache with key limswiki:pcache:idhash:11873-0!*!0!!en!5!* and timestamp 20200707205104 and revision id 38922\n -->\n<\/div><div class=\"printfooter\">Source: <a rel=\"external_link\" class=\"external\" href=\"https:\/\/www.limswiki.org\/index.php\/Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics\">https:\/\/www.limswiki.org\/index.php\/Journal:2019_novel_coronavirus_disease_(COVID-19):_Paving_the_road_for_rapid_detection_and_point-of-care_diagnostics<\/a><\/div>\n\t\t\t\t\t\t\t\t\t\t<!-- end content -->\n\t\t\t\t\t\t\t\t\t\t<div class=\"visualClear\"><\/div>\n\t\t\t\t<\/div>\n\t\t\t<\/div>\n\t\t<\/div>\n\t\t<!-- end of the left (by default at least) column -->\n\t\t<div class=\"visualClear\"><\/div>\n\t\t\t\t\t\n\t\t<\/div>\n\t\t\n\n<\/body>","5a2f572706bf2e7b99579d5658274a83_images":["https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/7\/7a\/Fig1_Nguyen_Micromachines2020_11-3.png","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/b\/be\/Fig2_Nguyen_Micromachines2020_11-3.png"],"5a2f572706bf2e7b99579d5658274a83_timestamp":1594155064,"d97817f5ad624daefeddef56fcde6d94_type":"article","d97817f5ad624daefeddef56fcde6d94_title":"The regulatory landscape of precision oncology laboratory medicine in the United States: Perspective on the past five years and considerations for future regulation (Konnick 2020)","d97817f5ad624daefeddef56fcde6d94_url":"https:\/\/www.limswiki.org\/index.php\/Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation","d97817f5ad624daefeddef56fcde6d94_plaintext":"\n\n\t\t\n\t\t\t\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t\n\n\t\t\t\tJournal:The regulatory landscape of precision oncology laboratory medicine in the United States: Perspective on the past five years and considerations for future regulation\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t\tFrom LIMSWiki\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\tJump to: navigation, search\n\n\t\t\t\t\t\n\t\t\t\t\tFull article title\n \nThe regulatory landscape of precision oncology laboratory medicine in the United States:\r\nPerspective on the past five years and considerations for future regulationJournal\n \nPractical Laboratory MedicineAuthor(s)\n \nKonnick, Eric Q.Author affiliation(s)\n \nUniversity of WashingtonPrimary contact\n \nEmail: konnick at uw dot eduYear published\n \n2020Volume and issue\n \n21Article #\n \ne00172DOI\n \n10.1016\/j.plabm.2020.e00172ISSN\n \n2352-5517Distribution license\n \nCreative Commons Attribution-NonCommercial-NoDerivatives 4.0 InternationalWebsite\n \nhttps:\/\/www.sciencedirect.com\/science\/article\/pii\/S2352551719301040Download\n \nhttps:\/\/www.sciencedirect.com\/science\/article\/pii\/S2352551719301040\/pdfft (PDF)\n\nContents\n\n1 Abstract \n2 The current regulatory environment in the United States \n3 Emergence of new regulatory proposals \n\n3.1 2014 draft guidance and evolution to legislation \n3.2 VALID Act of 2020 and VITAL Act of 2020 \n\n\n4 Commentary on the scope of regulation \n\n4.1 Risks to patients and the changing nature of LDTs \n4.2 Accuracy and equivalency between laboratory tests \n4.3 Regulatory certainty and innovation \n\n\n5 Recommendations for policymakers, regulators, and stakeholders \n\n5.1 Assessment of risks to patient \n5.2 Addressing analytical concerns \n5.3 Innovation and application \n\n\n6 Conclusion \n7 Acknowledgements \n\n7.1 Competing interests \n\n\n8 References \n9 Notes \n\n\n\nAbstract \nThe regulatory landscape for precision oncology in the United States is complicated, with multiple governmental regulatory agencies with different scopes of jurisdiction. Several regulatory proposals have been introduced since the Food and Drug Administration released draft guidance to regulate laboratory developed tests in 2014. Key aspects of the most recent proposals and discussion of central arguments related to the regulation of precision oncology laboratory tests provides insight to stakeholders for future discussions related to regulation of laboratory tests.\nKeywords: oncology, regulation, testing, LDTs, FDA, CLIA, CMS\n\nThe current regulatory environment in the United States \nThe current state of laboratory test regulation in the United States (U.S.) is complex, and the prospect of changes in the current paradigm has been continually on the horizon since 2014. Briefly, clinical laboratories in the U.S. are regulated under the Clinical Laboratory Improvement Amendments of 1988 (CLIA \u203288)[1] of the Public Health Services Act, which are administered by the Centers for Medicare and Medicaid Services (CMS). These regulations were put in place to improve the quality of the processes in clinical laboratories, but the regulations allow for organizations that have received certification from CMS to inspect laboratories as a deemed entity. This status allows deemed entities to place additional requirements in place, so long as the underlying CLIA requirements are met. \nCLIA regulations have a flexible framework that allows individual medical directors and laboratories to have some leeway in how the specific requirements are met, which allows for accommodation of unique population-, laboratory-, and test-level factors that can improve the overall quality of testing, while also allowing for the development of tests by laboratory medicine practitioners within certain bounds. Testing kits that are manufactured and shipped across state lines are regulated by the U.S. Food and Drug Administration (FDA) via the Medical Device Amendments of 1976[2], which amended the Federal Food, Drug, and Cosmetic Act of 1938. The FDA has several review and approval pathways where the manufacturer submits documentation and data to the FDA for review, and if the data fulfill the FDA\u2019s requirements, the test recieves marketing authorization. Manufacturers can then sell their products to laboratories, who wish to perform that testing. \nTesting kits which are cleared or approved by the FDA are regulated under CLIA when they are performed in a certified laboratory. In addition, under the current structure, laboratories are expected to verify the performance of these products and, under CLIA, are allowed to modify them if deemed necessary by medical leadership. If a manufactured product is modified by the user's laboratory, the test is considered a \"laboratory developed test.\" Such modifications are frequently made to improve assay performance, use the assay in a way different from the use claimed by the manufacturer (e.g., diagnostic instead of screening applications), or allow acceptance of additional sample types that were not submitted to the FDA for approval. This regulatory flexibility allows clinical laboratories to offer tests that are accurate and medically relevant to their patients. Currently, many high-complexity clinical laboratories are accredited by the College of American Pathologists (CAP), which conducts unannounced biannual laboratory inspections and administers a multitude of proficiency testing programs to evaluate the accuracy and agreement between laboratories across the spectrum of laboratory tests. \nThe FDA has maintained that they have the statutory authority to regulate all laboratory tests, including tests that are developed and offered in a single lab, but have chosen to operate under a policy of enforcement discretion.\n\nEmergence of new regulatory proposals \n2014 draft guidance and evolution to legislation \nIn October of 2014, the U.S. FDA released draft guidance[3] that proposed to dramatically change the regulatory landscape of tests that were developed and offered in a single laboratory, formally referred to as \"laboratory developed tests\" or LDTs. There was a large amount of feedback from academic, community, commercial, and professional stakeholders, with several hundred comments submitted to the FDA docket.[4] After the 2016 presidential election, the FDA publicly stated that the agency will defer to the legislative branch of the U.S. government to update the regulatory landscape of LDTs and manufactured laboratory tests, also know as in vitro diagnostic devices.[5] Although the FDA has stated that it will not wholesale change the regulatory requirements for LDTs in the interim, the agency has continued to release guidance documents, in both draft and final forms, that touch on the regulation of laboratory diagnostics that are used in the care of oncology patients.\nDuring this same period of time, a variety of stakeholders, including the CAP[6] and the Association for Molecular Pathology (AMP)[7], proposed alternative regulatory approaches. In addition, a consortium of commercial laboratories, test manufacturers, and large reference laboratories with academic affiliations helped draft the basis for the proposed Diagnostic Accuracy and Innovation Act (DAIA)[8], which was made available for red-line comments by representatives in the U.S. House of Representatives in 2017. This proposal introduced the new term \"in vitro clinical tests\" (IVCTs) as a common term for both commercial manufactured tests and LDTs, and as a term to differentiate such tests from medical devices. As part of the feedback process, the legislative sponsors requested technical assistance (TA) and comments from the FDA.\n\nVALID Act of 2020 and VITAL Act of 2020 \nThe process of obtaining the FDA's TA document for the DAIA took over a year, and the TA document that was received by the sponsors was not a commentary on the draft legislation that was provided to them, but rather it was an entirely new legislative discussion draft that outlined an almost entirely different regulatory scheme from DAIA. The legislative sponsors quickly evaluated the TA document and released the Verifying Accurate, Leading-edge IVCT Development (VALID) Act. Over the following years, the VALID Act was the topic of many meetings among stakeholders, the FDA, and legislative staff, and a final version was introduced into the U.S. House of Representatives and U.S. Senate on March 5, 2020[9], during the early days of the SARS-CoV-2 pandemic in the United States. On March 17, 2020, an alternative regulatory bill, the Verified Innovative Testing in American Laboratories (VITAL) Act of 2020[10], was introduced into the Senate.\nThe approach outlined in the VALID Act of 2020 continues the FDA\u2019s long-standing assertion that the agency be the central arbiter of a laboratory developed test's analytical accuracy and validity. Key components of VALID include extensive grandfathering of existing LDTs, a new classification scheme for new tests, and a framework for a precertification scheme that is designed to allow laboratories to create, validate, and offer certain tests without FDA review in certain circumstances. While many previous approaches to regulation included three risk levels for tests (low, moderate, and high), the VALID Act of 2020 only has two categories: low- and high-risk. Tests in the low-risk categorization would be allowed to be developed and used for patient care through individual submission to the FDA or through use of the precertification pathway. Tests considered to be in the high-risk category would not be eligible for using the precertification pathway and would require the test to be submitted to the FDA via a pathway similar to the current premarket approval (PMA) pathway. Given that many current molecular oncology LDTs are used to select therapy regimens or could be used to decide prophylactic surgeries, most of these tests are expected to be classified in the high-risk category, requiring a time-consuming and expensive PMA should VALID become law. While there is the provision for high-risk tests to use \u201cmitigating measures\u201d that would allow a different regulatory pathway, it is unclear how this might work in practice, and none of the examples cited in the legislation reference professional practice or expertise. \nThe proposed precertification process is similar in concept to some existing programs, including the conditional approval process utilized by the New York State Department of Health (NYDOH)[11], but it uses a technology classification system to allow laboratories or manufacturers to develop within a certain scope of expertise. The technological categories have underlying scientific principles that are considered generally similar by the FDA. The technology categories are clot detection, colorimetric, enzymatic, fluorometry, immunoassay, mass spectrometry\/chromatography, microbial culture, nephlometric\/turbidimetric, next generation sequencing (NGS), non-NGS nucleic acid analysis, slide-based technology, and spectroscopy. The VALID Act of 2020 stipulates that a laboratory would become precertified for a specific technology by submitting an initial assay through the stand-alone pathway, and, if successful, the lab would obtain a multi-year permission to develop and modify tests within that technology class. At the end of a certification term, the lab could submit a new assay for review and could receive an extension of the precertification. While tests developed in the precertification window would not need to be submitted for review, documentation would have to be maintained for inspection by the FDA or third-party reviewers.\nA key provision of VALID is the extensive grandfathering provision that is included in the legislation, where tests that are available before the legislation enactment can continue to be offered after the law is in effect. This grandfathering was included to prevent the sudden loss of laboratory tests as the law is enacted. A key aspect of this grandfathering is that tests cannot be modified after VALID becomes law, and the FDA has the authority to order any test off the market if they choose.\nWhile the VALID Act of 2020 has numerous provisions\u2014weighing in at over 245 pages\u2014and ensconces many aspects of regulation of LDTs in statute, the VITAL Act of 2020 takes the opposite approach. The VITAL Act of 2020 is only seven pages in length and simply states that all development and performance of LDTs will be under the jurisdiction of the Public Health Services Act and cannot be regulated under the Medical Device Act. These two legislative bills are indicative of the extreme differences that people, companies, and institutions have taken on the issue of regulation of laboratory services and the methods that are used to provide data to inform patient care. The key regulatory proposals and legislation are presented in Table 1.\n\n\n\n\n\n\n\nTable 1. Timeline of key developments in the regulation of laboratory testing\n\n\nDate\n\nDocument\n\nRelevant statute\n\n\n1976\n\nMedical Device Regulation Act\n\nFood, Drug, and Cosmetic Act of 1938\n\n\n1998\n\nClinical Laboratory Improvement Amendments (42 USC 263a)\n\nPublic Health Services Act\n\n\n2014\n\nFramework for Regulatory Oversight of Laboratory Developed Tests (LDTs)\n\nFood, Drug, and Cosmetic Act of 1938\n\n\n2017\n\nDiagnostic Accuracy and Innovation Act (DAIA)\n\nFood, Drug, and Cosmetic Act of 1938\n\n\n2018\n\nVerifying Accurate Leading-edge IVCT Development Act of 2018 (FDA technical assessment of DAIA)\n\nFood, Drug, and Cosmetic Act of 1938\n\n\n2019\n\nVerifying Accurate Leading-edge IVCT Development Act of 2018 (FDA technical assessment of DAIA)\n\nFood, Drug, and Cosmetic Act of 1938\n\n\nMarch 2020\n\nVerifying Accurate Leading-edge IVCT Development Act of 2020\n\nFood, Drug, and Cosmetic Act of 1938\n\n\nMarch 2020\n\nVerified Innovative Testing in American Laboratories Act of 2020\n\nFood, Drug, and Cosmetic Act of 1938\n\n\n\nThe fates of the current legislation are uncertain, given the current state of the U.S. political climate, but evaluation of key underlying concepts related to the logic of regulation may benefit the stakeholders who are interested in this regulation.\n\nCommentary on the scope of regulation \nThere are numerous manufacturers who have developed targeted precision oncology tests and companion diagnostics that have achieved FDA approval. Despite the availably of these manufactured tests, many laboratories continue to develop and use LDTs for oncology testing, especially at academic institutions. There are several examples of specific comprehensive tests that were developed and used as LDTs that have sought both PMA (Foundation medicine) and 510(k) (MSK-IMPACT) approval.[12] While the existing FDA regulatory pathways are clearly available to all laboratories that develop LDTs, the observation that these pathways have not been used except by a handful of large and well-funded organizations suggests that the burdens of seeking such approvals are sufficiently large and complex[13][14] to dissuade laboratories from undertaking, despite any benefits. Laboratories that develop LDTs often state that the ability to modify tests without needing to seek regulatory approval allows for tests to be continuously improved and updated to meet patient needs. In the setting of precision oncology, laboratory tests are undergoing constant revision and updating as new discoveries in science and medicine are applied to routine patient care.\nIn many discussions and talking points related to the need for regulation of LDTs, several topics are consistently raised as key reasons for increased LDT regulation. These factors include the risk of patient harm, the changing nature of LDTs, accuracy and interchangeability of results, the need to encourage innovation, and the requirement for a single regulatory pathway.\n\nRisks to patients and the changing nature of LDTs \nA commonly cited reason for additional regulation of laboratory testing is to reduce the risk of patient harm due to tests that do not perform as expected.[15] Although many assertions of patient harm due solely to laboratory developed tests are often easily debunked[16], the possibility of patient harm is a serious possibility that should be considered. Manufactured products that are produced and shipped across state lines may require more extensive regulatory oversight because the manufacturer has no control over the specific skills or expertise of the laboratory staff and directors who are implementing the test. As such, having a test that can be understood and used by novices and experts alike may be a reasonable requirement, which is the current state of manufactured tests in the United States. \nLDTs are often developed and implemented in laboratories that have specific expertise and patient needs that require specialized testing. LDTs are also commonly used in areas of medicine where there is a rapid increase in knowledge (e.g., oncology), or where testing methods must be nimble due to changing analytes (e.g., infectious disease). The ability to rapidly adapt testing methods and implement new scientific and medical findings with LDTs stands in contrast to the extensive and costly process required for tests pased through the FDA processes, which have been estimated to result in multiple years delay in test availability compared to other Western countries, with potential costs of tens of millions of dollars per FDA sumission.[17] Given the costs associated with obtaining FDA approval for laboratory tests, there will be significant costs that laboratories will have to bear under the proposed VALID Act, both in terms of submitting tests for consideration of precertification and in maintaining that certification. In addition, tests that are in the high-risk classification will be less likely to be laboratory developed and will either need a commercial solution or require referral to an outside laboratory.\nA concern that has been repeatedly raised by the FDA and other groups is that the nature of LDTs has changed over past decades. Where LDTs were once mostly performed in hospital laboratories for local patients, in the present day, LDTs are often performed in central laboratories that are removed from the site of patient care. These labs can fall into several general categories: reference laboratories for hospital systems, regional reference laboratories, national reference laboratories, and commercial for-profit entities. While these laboratories are all likely to adhere to high standards and perform analytically sound tests, the change of LDTs from a primarily local to a regional or national scale has been suggested by the FDA to be a rationale for no longer applying enforcement discretion. Although not explicitly stated in the FDA\u2019s statements, the implication lies in the potential for decreased patient safety, not due to the type of test performed (LDT vs. FDA-approved), but due to decreased interaction of laboratory experts with the team caring for individual patients.\nWhen any tests are performed in centralized laboratories with limited access to clinical records, there is a higher risk of making pre-analytical, post-analytical, and cognitive errors that can impact patient care. In addition, incentives such as the payment structure of the laboratory can incentivize behaviors that are divergent from the best interest of patients and the health system. Many decentralized laboratories use a fee-for-service payment model, which has been suggested to increase overutilization[18][19] and can potentially lead to situations where analytical and clinical validity claims may overreach the available data.[20] Research has also suggested that laboratory testing done remotely from the patient may lead to increases in cost, turnaround time, duplicative orders, unnecessary studies, and errors.[21][22] Ironically, the addition of additional and costly regulations via the VALID Act may actually drive further consolidation of the centralization model of laboratory testing, which could lead to additional errors as previously described. As complex testing is removed from regional and academic centers and concentrated in centralized laboratories, the ability of laboratory medicine experts to interact with their patient-facing colleagues is likely to decrease, resulting in further degradation in care.\nIn contrast, integration of laboratory medicine experts in the clinical care team has been suggested to improve diagnostic yield, especially in the setting of complex and nuanced laboratory data. This type of integration has been proposed as a valuable and beneficial service, as pathologists, for example, can provide insight into and leadership for the activities of clinical care teams.[23] As precision oncology has become more reliant on numerous biomarkers and mutations to direct treatment, systematic studies have demonstrated that interpretations of results may benefit from expert consultation[24], which may not be available when the testing is performed remotely. While it is true that the type and complexity of tests that have been developed as LDTs has changed, the more critical aspect that has changed is the decentralization of care that has simultaneously occurred, and that is an aspect of medical practice that cannot be regulated by the FDA.\n\nAccuracy and equivalency between laboratory tests \nA commonly cited rationale for the need to regulate LDTs is the need to ensure that results are equivalent between assays, especially in the area of oncology tests that are used to direct oncologic decision-making and treatments. While the rhetoric is often that the accuracy of LDTs is not known, there are many studies and programs in place that laboratories use to evaluate the performance of their LDTs and manufactured kits, with proficiency testing and comparative studies being key tools. Many published scientific studies have demonstrated good equivalence between molecular oncology tests, both LDTs and FDA approved[25][26][27][28][29][30], including studies examining assessment of important recurrent oncologic mutations that are frequently assessed in proficiency testing. It is also critical to remember that even when the same test is used to assess identical samples, but in different labs, there will be slight differences in performance due to statistical factors.[31] There are publications citing disagreement between specific laboratory methods, but investigation of the methods and biology relevant to specific comparisons often reveal that the apparent differences may actually be due to biological phenomena[32][33], or specific disease biology[34][35][36], highlighting the importance of the expertise of medical practitioners in interpreting testing data and applying the results of these studies.\nProficiency testing is required under CLIA, and the CAP develops proficiency testing programs using content experts to devise appropriate challenges[37], in addition to developing accreditation checklists[38] and clinical guidelines.[39] Multiple studies examining CAP proficiency testing data using well-characterized reference materials have demonstrated that real-world challenges of total assay performance show excellent agreement among a variety of FDA-approved, FDA-cleared, and LDT precision-oncology assays across a broad range of technologies.[40][41][42][43][44]\nHowever, as the field of precision oncology diagnostics has evolved, new technologies and approaches such as next-generation sequencing (NGS) present additional problems, including the need for sometimes complex bioinformatics pipelines to analyze and interpret large volumes of data. To complicate the scenario, some laboratories use outside services for bioinformatics, which allows for decreased internal resources for this specialized field, but opens the possibility for errors that may be difficult to diagnose and detect. Studies have demonstrated the feasibility of using in silico manipulation of data to simulate variants in data generated in the laboratory under evaluation[45], indicating that innovative approaches to new problems using existing structure can quickly address new problems as they emerge. These common practices of comparisons of different laboratories using blinded, standardized materials demonstrates the analytical accuracy of the methods and provides a mechanism for identifying laboratories and tests that are not performing up to standard, while also offering a route to problem resolution. The participation in proficiency testing programs is another mitigating measure that allows for continuous quality improvement and should also be considered in any regulatory scheme.\n\nRegulatory certainty and innovation \nRegulatory certainty has been stated as a key component to encouraging innovation in the realm of laboratory testing. Regulatory certainty is often framed as providing a financial incentive for investing in innovation, which focuses on the financial and business aspects of laboratory testing, but neglecting the medical needs that often drive test development. Regulatory certainty has been present for manufactured kits for many years, but the long developmental timeline for many assays has led to assays being obsolete when they finally become available[29], which can be problematic if the state of scientific and medical understanding change in the intervening years. In order to effectively undertake long regulatory approval processes, entities must have not only the resources to undertake the process, but also the necessary return on investment in order to proceed. In contrast, many LDTs are developed to assess a specific medical or operational need that is not possible or practical to address by alterative means. Having a regulatory framework that allows for both scenarios will allow for patients to have the maximum access to important diagnostic tests. Many manufacturers and regulators have stated that a single regulatory pathway is the most appropriate and efficient approach, but that view focuses on the needs of those constituencies while neglecting other considerations. A chief concern is the reality that most laboratories are responsible for managing thousands of tests that are required for patient care, while manufacturers and specialty laboratories generally have a limited portfolio of tests that they maintain. Having a single regulatory path could result in much higher regulatory burden for professionals that are providing medical care to patients, potentially reducing the number of tests available for patient care and diverting monetary and personnel resources from patient care activities to administrative tasks. While both arguments have some merit, the convenience of the regulatory body and special interests need to be balanced against the need for flexibility to provide appropriate services to patients and providers.\n\nRecommendations for policymakers, regulators, and stakeholders \nAs of this writing, the political landscape in the United States is such that comprehensive reform of laboratory regulations does not seem likely to advance. In addition, the events surrounding the delayed rollout of laboratory diagnostics to address the initial encounter with the SARS-CoV-2 pandemic in the United States has brought new attention to the issue of regulation of laboratory tests.[46] Reflecting on the half-decade that has elapsed since the FDA\u2019s draft guidance to regulate LDTs, several key observations can be made with regard to the common themes in the public discussion and proposals for the regulation of laboratory tests:\n\n The level of risk to the patient should be taken into account.\n Most laboratories involved in testing of biomarkers related to precision oncology have comparable results.\n Precision oncology relies on the ability of laboratories to rapidly innovate to provide optimal patient care.\nAssessment of risks to patient \nManufactured tests, tests provided by for-profit laboratories, or labs that have a profit motive (startup laboratories, public companies, etc.) may require additional regulation to ensure that the primacy of analytical accuracy and clinical validity are appropriate for the claims of the laboratory. The observation that fee-for-service can result in increased utilization and errors suggest that additional scrutiny may be needed in these situations. Laboratories that are integrated with the patients they serve, including oncology patients, have the opportunity to embrace the role of diagnostic consultant, utilizing the professional services of expert medical directors to aid in the interpretation and dissemination of understanding of complex test results, and hence requiring less regulation.\n\nAddressing analytical concerns \nWhile data have demonstrated that precision oncology assays have excellent accuracy and concordance, the concern that disparate assays should be able to be accurately evaluated during development is valid. Rather than a rigid regulatory construct, this specific concern can be addressed through establishing professional practice guidelines and recommendations, and though developing standards that can be used for assay development and quality control[47][48] for established biomarkers. As scientific knowledge and medical understanding are constantly evolving, it is critical that professionals investigate and understand the technical, biological, and medical variables that impact laboratory tests, which will require deep involvement and expertise. Such resources are especially important in the setting of precision oncology as some highly-actionable alterations are also extremely rare and difficult to detect by many technologies.[49][50][51] When such standards are available and routinely used, the risk that an incorrect result will be generated in the analytical process decreases. Similarly, tests that use proprietary algorithms or artificial intelligence should have a higher level of scrutiny because comparing individual tests using a standard material may not be appropriate. Development of physical and performance standards by professional societies should be leveraged to allow for test development and comparison. Utilizing professional societies will allow for the integration of the most recent scientific and medical findings, which is potentially more nimble than a process embedded in a federal agency.\n\nInnovation and application \nPatients expect that the assay that is being used to guide care for them uses the most up-to-date method possible; as such, tests must be able to updated as necessary to maintain their performance and relevance. For manufacturers and commercial laboratories, a precertification pathway as delineated in the VALID Act may be a sensible approach for precision oncology applications, if such tests can be assigned an appropriate risk classification. With regards to laboratories that are closely associated with physicians providing patient care, a more flexible approach akin to that currently under CLIA provides an optimal balance between the ability of laboratory medicine physicians to practice medicine, protect patients, provide relevant laboratory results, and overcome regulatory burden.\n\nConclusion \nThe regulatory environment of precision oncology tests in the U.S. is complex, and multiple legislative proposals to update the regulatory environment have been introduced. As discussions around laboratory regulation proceed, careful consideration of the risks, benefits, and costs of various regulatory approaches must be considered. In order to deliver the most appropriate care to patients in difficult circumstances, broader evaluation of the implications of test regulation should be contemplated. Many assertions and assumptions have been made as to why additional regulation of laboratory tests is required, but the likely effects of that regulation on patient care have not been evaluated with regards to patients and the full spectrum of stakeholders. Identifying tools that can be leveraged to improve laboratory test quality may offer many benefits that do not necessarily require a burdensome regulatory framework.\n\nAcknowledgements \nCompeting interests \nI have no relevant conflicts related to this manuscript.\n\nReferences \n\n\n\u2191 \"Public Law 100-578 - Clinical Laboratory Improvement Amendments of 1988\" (PDF). U.S. Government Publishing Office. 31 October 1988. https:\/\/www.govinfo.gov\/content\/pkg\/STATUTE-102\/pdf\/STATUTE-102-Pg2903.pdf . Retrieved 30 August 2019 .   \n\n\u2191 \"Public Law 94\u2013295 - Medical Device Amendments of 1976\" (PDF). U.S. Government Publishing Office. 28 May 1976. https:\/\/www.govinfo.gov\/content\/pkg\/STATUTE-90\/pdf\/STATUTE-90-Pg539.pdf . Retrieved 31 August 2019 .   \n\n\u2191 Food and Drug Administration (03 October 2014). \"Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs) - Draft Guidance\". Food and Drug Administration. https:\/\/www.fda.gov\/media\/89841\/download . Retrieved 31 August 2019 .   \n\n\u2191 Food and Drug Administration (02 February 2015). \"Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs)\". Regulations.gov. https:\/\/www.regulations.gov\/docket?D=FDA-2011-D-0360 . Retrieved 31 August 2019 .   \n\n\u2191 Food and Drug Administration (13 January 2017). \"Discussion Paper on Laboratory Developed Tests (LDTs)\". Food and Drug Administration. https:\/\/www.fda.gov\/media\/102367\/download . Retrieved 31 August 2019 .   \n\n\u2191 Vance, G.H. (2011). \"College of American Pathologists Proposal for the Oversight of Laboratory-Developed Tests\". Archives of Pathology & Laboratory Medicine 135 (11): 1432\u20135. doi:10.5858\/arpa.2011-0304-SA. PMID 22032569.   \n\n\u2191 Ferreira-Gonzalez, A.; Emmadi, R.; Day, S.P. et al. (2014). \"Revisiting Oversight and Regulation of Molecular-Based Laboratory-Developed Tests: A Position Statement of the Association for Molecular Pathology\". Journal of Molecular Diagnostics 16 (1): 3\u20136. doi:10.1016\/j.jmoldx.2013.10.003. PMID 24331365.   \n\n\u2191 Food and Drug Administration (03 August 2018). \"FDA's views on the Diagnostic Accuracy and Innovation Act (DAIA)\" (PDF). Food and Drug Administration. http:\/\/www.fdalawblog.net\/wp-content\/uploads\/2018\/08\/FDA-LDT-Draft-Leg.pdf . Retrieved 31 August 2019 .   \n\n\u2191 Burr, R. (05 March 2020). \"S.3404 - VALID Act of 2020\". Congress.gov. Library of Congress. https:\/\/www.congress.gov\/bill\/116th-congress\/senate-bill\/3404\/text .   \n\n\u2191 Paul, R. (17 March 2020). \"S.3512 - VITAL Act of 2020\". Congress.gov. Library of Congress. https:\/\/www.congress.gov\/bill\/116th-congress\/senate-bill\/3512\/text .   \n\n\u2191 Wadsworth Center (August 2019). \"History: NYSDOH Wadsworth Center\u2019s Clinical Laboratory Evaluation Program (CLEP)\" (PDF). Wadsworth Center. https:\/\/www.wadsworth.org\/sites\/default\/files\/WebDoc\/Tiered_LDT_Review_Policy_June2019_REVISED_Aug%202019.pdf . Retrieved 31 August 2019 .   \n\n\u2191 Allegretti, M.; Fabi, A.; Buglioni, S. et al. (2018). \"Tearing Down the Walls: FDA Approves Next Generation Sequencing (NGS) Assays for Actionable Cancer Genomic Aberrations\". Journal of Experimental & Clinical Cancer Research 37 (1): 47. doi:10.1186\/s13046-018-0702-x. PMC PMC5838869. PMID 29506529. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5838869 .   \n\n\u2191 Goodsaid, F.M. (2019). \"The Labyrinth of Product Development and Regulatory Approvals in Liquid Biopsy Diagnostics\". Clinical and Translational Science 12 (5): 431-439. doi:10.1111\/cts.12657. PMC PMC6742934. PMID 31162800. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6742934 .   \n\n\u2191 Liotta, L.A.; Petricoin 3rd, E.F. (2012). \"Regulatory Approval Pathways for Molecular Diagnostic Technology\". Methods in Molecular Biology 823: 409\u201320. doi:10.1007\/978-1-60327-216-2_27. PMID 22081361.   \n\n\u2191 Food and Drug Administration (18 November 2015). \"The Public Health Evidence for FDA Oversight of Laboratory Developed Tests: 20 Case Studies\". Food and Drug Administration. Archived from the original on 14 November 2017. http:\/\/wayback.archive-it.org\/7993\/20171114205911\/https:\/\/www.fda.gov\/AboutFDA\/ReportsManualsForms\/Reports\/ucm472773.htm .   \n\n\u2191 Association for Molecular Pathology (13 December 2015). \"Facts FDA Ignored: An analysis of the FDA report, \u201cThe Public Health Evidence for FDA Oversight of Laboratory Developed Tests: 20 Case Studies\u201d\". Association for Molecular Pathology. https:\/\/www.amp.org\/AMP\/assets\/File\/position-statements\/2015\/AMPResponseFDACaseReportFinal.pdf?pass=58 . Retrieved 28 April 2020 .   \n\n\u2191 Makower, J.; Meer, a.; Denend, L. (November 2010). \"FDA Impact on U.S. Medical Technology Innovation\" (PDF). AdvaMed. https:\/\/www.advamed.org\/sites\/default\/files\/resource\/30_10_11_10_2010_Study_CAgenda_makowerreportfinal.pdf .   \n\n\u2191 Lynch, J.A.; Berse, B.; Dotson, W.D. et al. (2017). \"Utilization of Genetic Tests: Analysis of Gene-Specific Billing in Medicare Claims Data\". Genetics in Medicine 19 (8): 890\u201399. doi:10.1038\/gim.2016.209. PMID 28125086.   \n\n\u2191 Paton, C. (2008). \"Institute of Medicine, Rewarding provider performance (aligning incentives in medicare), Washington, D.C., National Academies Press, 2007, 248 pp., ISBN\u201013: 978\u20100\u2010309\u201010216\u20102; ISBN\u201010: 0\u2010309\u201010216\u20102\". The International Journal of Health Planning and Management 23 (1): 83\u201384. doi:10.1002\/hpm.923.   \n\n\u2191 Association for Molecular Pathology (14 August 2015). \"Proposal for Modernization of CLIA Regulations for Laboratory Developed Testing Procedures (LDPs)\" (PDF). Association for Molecular Pathology. https:\/\/www.amp.org\/AMP\/assets\/File\/advocacy\/AMPCLIAmodernizationproposalFINAL8_14_15.pdf?pass=50 . Retrieved 31 August 2019 .   \n\n\u2191 Chasin, B.S.; Elliott, S.P.; Klotz, S.A. (2007). \"Medical Errors Arising From Outsourcing Laboratory and Radiology Services\". American Journal of Medicine 120 (9): 819.e9-11. doi:10.1016\/j.amjmed.2006.07.024. PMID 17765055.   \n\n\u2191 Mrak, R.E.; Parslow, T.G.; Tomaszewski, J.E. (2018). \"Outsourcing of Academic Clinical Laboratories: Experiences and Lessons From the Association of Pathology Chairs Laboratory Outsourcing Survey\". Academic Pathology 5: 2374289518765435. doi:10.1177\/2374289518765435. PMC PMC5888821. PMID 29637086. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5888821 .   \n\n\u2191 Ducatman, B.S.; Ducatman, A.M.; Crawford, J.M. et al. (2020). \"The Value Proposition for Pathologists: A Population Health Approach\". Academic Pathology 7: 2374289519898857. doi:10.1177\/2374289519898857. PMC PMC6961144. PMID 31984223. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6961144 .   \n\n\u2191 Brusco, L.L.; Wathoo, C.; Mills Shaw, K.R. et al. (2018). \"Physician Interpretation of Genomic Test Results and Treatment Selection\". Cancer 124 (5): 966-972. doi:10.1002\/cncr.31112. PMC PMC5821595. PMID 29165790. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5821595 .   \n\n\u2191 Xu, X.; Yang, Y.; Li, H. et al. (2016). \"Assessment of the Clinical Application of Detecting EGFR, KRAS, PIK3CA and BRAF Mutations in Patients With Non-Small Cell Lung Cancer Using Next-Generation Sequencing\". Scandinavian Journal of Clinical and Laboratory Investigation 76 (5): 386\u201392. doi:10.1080\/00365513.2016.1183813. PMID 27215271.   \n\n\u2191 Gao, J.; Wu, H.; Wang, L. et al. (2016). \"Validation of Targeted Next-Generation Sequencing for RAS Mutation Detection in FFPE Colorectal Cancer Tissues: Comparison With Sanger Sequencing and ARMS-Scorpion Real-Time PCR\". BMJ Open 6 (1): e009532. doi:10.1136\/bmjopen-2015-009532. PMC PMC4716245. PMID 26747035. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4716245 .   \n\n\u2191 Simen, B.B.; Yin, L.; Goswami, C.P. et al. (2015). \"Validation of a Next-Generation-Sequencing Cancer Panel for Use in the Clinical Laboratory\". Archives of Pathology & Laboratory Medicine 139 (4): 508\u201317. doi:10.5858\/arpa.2013-0710-OA. PMID 25356985.   \n\n\u2191 Tuononen, K.; M\u00e4ki-Nevala, S.; Sarhadi, V.K. et al. (2013). \"Comparison of Targeted Next-Generation Sequencing (NGS) and Real-Time PCR in the Detection of EGFR, KRAS, and BRAF Mutations on Formalin-Fixed, Paraffin-Embedded Tumor Material of Non-Small Cell Lung Carcinoma-Superiority of NGS\". Genes, Chromosomes & Cancer 52 (5): 503\u201311. doi:10.1002\/gcc.22047. PMID 23362162.   \n\n\u2191 29.0 29.1 Lopez-Rios, F.; Angulo, B.; Gomez, B. et al. (2013). \"Comparison of Testing Methods for the Detection of BRAF V600E Mutations in Malignant Melanoma: Pre-Approval Validation Study of the Companion Diagnostic Test for Vemurafenib\". PLoS One 8 (1): e53733. doi:10.1371\/journal.pone.0053733. PMC PMC3542342. PMID 23326492. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3542342 .   \n\n\u2191 Kothari, N.; Schell, M.J.; Teer, J.K. et al. (2014). \"Comparison of KRAS mutation analysis of colorectal cancer samples by standard testing and next-generation sequencing\". Journal of Clinical Pathology 67 (9): 764\u20137. doi:10.1136\/jclinpath-2014-202405. PMC PMC4743643. PMID 25004944. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4743643 .   \n\n\u2191 Keppens, C.; Palma, J.F.; Das, P.M. et al. (2018). \"Detection of EGFR Variants in Plasma: A Multilaboratory Comparison of a Real-Time PCR EGFR Mutation Test in Europe\". Journal of Molecular Diagnostics 20 (4): 483\u201394. doi:10.1016\/j.jmoldx.2018.03.006. PMID 29704571.   \n\n\u2191 Torga, G.; Pienta, K.J. (2018). \"Patient-Paired Sample Congruence Between 2 Commercial Liquid Biopsy Tests\". JAMA Oncology 4 (6): 868-870. doi:10.1001\/jamaoncol.2017.4027. PMC PMC6145681. PMID 29242909. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6145681 .   \n\n\u2191 Schweizer, M.T.; Gulati, R.; Beightol, M. et al. (2019). \"Clinical Determinants for Successful Circulating Tumor DNA Analysis in Prostate Cancer\". Prostate 79 (7): 701-708. doi:10.1002\/pros.23778. PMC PMC6589085. PMID 30865311. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6589085 .   \n\n\u2191 Poirot, B.; Doucet, L.; Benhenda, S. et al. (2017). \"MET Exon 14 Alterations and New Resistance Mutations to Tyrosine Kinase Inhibitors: Risk of Inadequate Detection With Current Amplicon-Based NGS Panels\". Journal of Thoracic Oncology 12 (10): 1582\u201387. doi:10.1016\/j.jtho.2017.07.026. PMID 28779874.   \n\n\u2191 Rosenbaum, J.N.; Bloom, R.; Forys, J.T. et al. (2018). \"Genomic Heterogeneity of ALK Fusion Breakpoints in Non-Small-Cell Lung Cancer\". Modern Pathology 31 (5): 791\u2013808. doi:10.1016\/j.jtho.2018.12.020. PMID 29327716.   \n\n\u2191 Davies, K.D.; Lomboy, A.; Lawrence, C.A. et al. (2019). \"DNA-Based Versus RNA-Based Detection of MET Exon 14 Skipping Events in Lung Cancer\". Journal of Thoracic Oncology 14 (4): 737\u201341. doi:10.1038\/modpathol.2017.181. PMID 30639620.   \n\n\u2191 Hamlin, W. (1992). \"Proficiency Testing as a Regulatory Device: A CAP Perspective\". Clinical Chemistry 38 (7): 1234\u20136. PMID 1623587.   \n\n\u2191 Endrullat, C.; Gl\u00f6kler, J.; Franke, P. et al. (2016). \"Standardization and Quality Management in Next-Generation Sequencing\". Applied and Translational Genomics 10: 2\u20139. doi:10.1016\/j.atg.2016.06.001. PMC PMC5025460. PMID 27668169. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5025460 .   \n\n\u2191 Wolff, A.C.; Hammond, M.E.H.; Allison, K.H. et al. (2018). \"Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology\/College of American Pathologists Clinical Practice Guideline Focused Update\". Archives of Pathology & Laboratory Medicine 142 (11): 1364-1382. doi:10.5858\/arpa.2018-0902-SA. PMID 29846104.   \n\n\u2191 Kim, A.S.; Bartley, A.N.; Bridge, J.A. et al. (2018). \"Comparison of Laboratory-Developed Tests and FDA-Approved Assays for BRAF, EGFR, and KRAS Testing\". JAMA Oncology 4 (6): 838-841. doi:10.1001\/jamaoncol.2017.4021. PMC PMC6145687. PMID 29242895. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6145687 .   \n\n\u2191 Merker, J.D.; Devereaux, K.; Iafrate, A.J. et al. (2019). \"Proficiency Testing of Standardized Samples Shows Very High Interlaboratory Agreement for Clinical Next-Generation Sequencing-Based Oncology Assays\". Archives of Pathology & Laboratory Medicine 143 (4): 463-471. doi:10.5858\/arpa.2018-0336-CP. PMC PMC6910717. PMID 30376374. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6910717 .   \n\n\u2191 Surrey L.F.; Oakley, F.D.; Merker, J.D. et al. (2019). \"Next-Generation Sequencing (NGS) Methods Show Superior or Equivalent Performance to Non-NGS Methods on BRAF, EGFR, and KRAS Proficiency Testing Samples\". Archives of Pathology & Laboratory Medicine 143 (8): 980-984. doi:10.5858\/arpa.2018-0394-CP. PMID 30865489.   \n\n\u2191 Moncur, J.T.; Bartley, A.N.; Bridge, J.A. et al. (2019). \"Performance comparison of different analytic methods in proficiency testing for mutations in the BRAF, EGFR, and KRAS genes: A study of the College of American pathologists molecular oncology committee\". Archives of Pathology & Laboratory Medicine 143 (10): 1203\u201311. doi:10.5858\/arpa.2018-0396-CP. PMID 30969158.   \n\n\u2191 Keegan, A.; Bridge, J.A.; Lindeman, N.I. et al. (2020). \"Proficiency Testing of Standardized Samples Shows High Interlaboratory Agreement for Clinical Next Generation Sequencing-Based Hematologic Malignancy Assays With Survey Material-Specific Differences in Variant Frequencies\". Archives of Pathology & Laboratory Medicine. doi:10.5858\/arpa.2019-0352-CP. PMID 31986076.   \n\n\u2191 Duncavage, E.J.; Abel, H.J.; Merker, J.D. et al. (2016). \"A Model Study of In Silico Proficiency Testing for Clinical Next-Generation Sequencing\". Archives of Pathology & Laboratory Medicine. doi:10.5858\/arpa.2016-0194-CP. PMID 27388684.   \n\n\u2191 Sharfstein, J.M.; Becker, S.J.; Mello, M.M. (2020). \"Diagnostic Testing for the Novel Coronavirus\". JAMA 323 (15): 1437\u201338. doi:10.1001\/jama.2020.3864. PMID 32150622.   \n\n\u2191 Craig, D.W.; Nasser, S.; Corbett, R. et al. (2016). \"A Somatic Reference Standard for Cancer Genome Sequencing\". Scientific Reports. doi:10.1038\/srep24607. PMC PMC4837349. PMID 27094764. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4837349 .   \n\n\u2191 Zook, J.M.; Catoe, D.; McDaniel, J. et al. (2016). \"Extensive Sequencing of Seven Human Genomes to Characterize Benchmark Reference Materials\". Scientific Data 3: 160025. doi:10.1038\/sdata.2016.25. PMC PMC4896128. PMID 27271295. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4896128 .   \n\n\u2191 Marchi\u00f2, C.; Scaltriti, M.; Ladanyi, M. et al. (2019). \"ESMO Recommendations on the Standard Methods to Detect NTRK Fusions in Daily Practice and Clinical Research\". Annals of Oncology 30 (9): 1417\u20131427. doi:10.1093\/annonc\/mdz204. PMID 31268127.   \n\n\u2191 Penault-Llorca, F.; Rudzinkski, E.R.; Sepulveda, A.R. (2019). \"Testing Algorithm for Identification of Patients With TRK Fusion Cancer\". Journal of Clinical Pathology 72 (7): 460\u201367. doi:10.1136\/jclinpath-2018-205679. PMC PMC6589488. PMID 31072837. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6589488 .   \n\n\u2191 Solomon, J.P.; Linkov, I.; Rosado, A. et al. (2020). \"NTRK Fusion Detection Across Multiple Assays and 33,997 Cases: Diagnostic Implications and Pitfalls\". Modern Pathology 33 (1): 38\u201346. doi:10.1038\/s41379-019-0324-7. PMID 31375766.   \n\n\nNotes \nThis presentation is faithful to the original, with only a few minor changes to presentation. Some grammar and punctuation was cleaned up to improve readability. The original article appears to accidentally duplicate citation #8 for citation #7; what is believed to have been the intended citation has been substituted for citation #7 in this version. Several of the original article's citations are completely out of order or nonsensical. For example, the original citations #9 and #10 in no way verify the statement about the VALID Act and were removed for this version. In fact, original citation #10 should have been original citation #13 (used here), and it's not clear where original citation #13 was intended to go (omitted here). Otherwise, in accordance with the NoDerivatives portion of the original license, nothing else has been changed.\n\n\n\n\n\n\nSource: <a rel=\"external_link\" class=\"external\" href=\"https:\/\/www.limswiki.org\/index.php\/Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\">https:\/\/www.limswiki.org\/index.php\/Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation<\/a>\n\t\t\t\t\tCategories: LIMSwiki journal articles (added in 2020)LIMSwiki journal articles (all)LIMSwiki journal articles on laboratory medicineLIMSwiki journal articles on laws and regulations\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\n\t\t\t\t\n\t\t\t\n\t\t\n\t\t\n\t\t\tNavigation menu\n\t\t\t\t\t\n\t\t\tViews\n\n\t\t\t\n\t\t\t\t\n\t\t\t\tJournal\n\t\t\t\tDiscussion\n\t\t\t\tView source\n\t\t\t\tHistory\n\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\n\t\t\t\t\n\t\t\t\tPersonal tools\n\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\t\t\tLog in\n\t\t\t\t\t\t\t\t\t\t\t\t\tRequest account\n\t\t\t\t\t\t\t\t\t\t\t\n\t\t\t\t\n\t\t\t\n\t\t\t\n\t\t\t\t\n\t\t\t\n\t\t\t\t\n\t\tNavigation\n\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\tMain page\n\t\t\t\t\t\t\t\t\t\t\tRecent changes\n\t\t\t\t\t\t\t\t\t\t\tRandom page\n\t\t\t\t\t\t\t\t\t\t\tHelp\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\n\t\t\t\n\t\t\tSearch\n\n\t\t\t\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t \n\t\t\t\t\t\t\n\t\t\t\t\n\n\t\t\t\t\t\t\t\n\t\t\n\t\t\t\n\t\t\tTools\n\n\t\t\t\n\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\tWhat links here\n\t\t\t\t\t\t\t\t\t\t\tRelated changes\n\t\t\t\t\t\t\t\t\t\t\tSpecial pages\n\t\t\t\t\t\t\t\t\t\t\tPermanent link\n\t\t\t\t\t\t\t\t\t\t\tPage information\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\n\t\t\n\t\tPrint\/export\n\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\tCreate a book\n\t\t\t\t\t\t\t\t\t\t\tDownload as PDF\n\t\t\t\t\t\t\t\t\t\t\tDownload as Plain text\n\t\t\t\t\t\t\t\t\t\t\tPrintable version\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\n\t\t\n\t\tSponsors\n\t\t\n\t\t\t \r\n\n\t\r\n\n\t\r\n\n\t\n\t\r\n\n\t\r\n\n\t\n\t\r\n\n \n\t\r\n\n\t\n\t\r\n\n \n\t\n\t\r\n\n\t\n\t\n\t\r\n\n\t\r\n\n\t\r\n\n\t\n\t\r\n\n\t\r\n\t\t\n\t\t\n\t\t\t\n\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t This page was last modified on 16 June 2020, at 18:46.\n\t\t\t\t\t\t\t\t\tThis page has been accessed 153 times.\n\t\t\t\t\t\t\t\t\tContent is available under a Creative Commons Attribution-ShareAlike 4.0 International License unless otherwise noted.\n\t\t\t\t\t\t\t\t\tPrivacy policy\n\t\t\t\t\t\t\t\t\tAbout LIMSWiki\n\t\t\t\t\t\t\t\t\tDisclaimers\n\t\t\t\t\t\t\t\n\t\t\n\t\t\n\t\t\n\n","d97817f5ad624daefeddef56fcde6d94_html":"<body class=\"mediawiki ltr sitedir-ltr ns-206 ns-subject page-Journal_The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States_Perspective_on_the_past_five_years_and_considerations_for_future_regulation skin-monobook action-view\">\n<div id=\"rdp-ebb-globalWrapper\">\n\t\t<div id=\"rdp-ebb-column-content\">\n\t\t\t<div id=\"rdp-ebb-content\" class=\"mw-body\" role=\"main\">\n\t\t\t\t<a id=\"rdp-ebb-top\"><\/a>\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t<h1 id=\"rdp-ebb-firstHeading\" class=\"firstHeading\" lang=\"en\">Journal:The regulatory landscape of precision oncology laboratory medicine in the United States: Perspective on the past five years and considerations for future regulation<\/h1>\n\t\t\t\t\n\t\t\t\t<div id=\"rdp-ebb-bodyContent\" class=\"mw-body-content\">\n\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\n\n\t\t\t\t\t<!-- start content -->\n\t\t\t\t\t<div id=\"rdp-ebb-mw-content-text\" lang=\"en\" dir=\"ltr\" class=\"mw-content-ltr\">\n\n\n<h2><span class=\"mw-headline\" id=\"Abstract\">Abstract<\/span><\/h2>\n<p>The <a href=\"https:\/\/www.limswiki.org\/index.php\/Regulatory_compliance\" title=\"Regulatory compliance\" class=\"wiki-link\" data-key=\"7dbc9be278a8efda25a4b592ee6ef0ca\">regulatory<\/a> landscape for precision <a href=\"https:\/\/www.limswiki.org\/index.php\/Oncology\" title=\"Oncology\" class=\"wiki-link\" data-key=\"6c962c118dffc629e1bae0d5f95e68e2\">oncology<\/a> in the United States is complicated, with multiple governmental regulatory agencies with different scopes of jurisdiction. Several regulatory proposals have been introduced since the <a href=\"https:\/\/www.limswiki.org\/index.php\/Food_and_Drug_Administration\" title=\"Food and Drug Administration\" class=\"wiki-link\" data-key=\"e2be8927071ac419c0929f7aa1ede7fe\">Food and Drug Administration<\/a> released draft guidance to regulate <a href=\"https:\/\/www.limswiki.org\/index.php\/Laboratory_developed_test\" title=\"Laboratory developed test\" class=\"wiki-link\" data-key=\"c02aacbf30e9b175e3da72ba8c3aaf8e\">laboratory developed tests<\/a> in 2014. Key aspects of the most recent proposals and discussion of central arguments related to the regulation of precision oncology laboratory tests provides insight to stakeholders for future discussions related to regulation of <a href=\"https:\/\/www.limswiki.org\/index.php\/Laboratory\" title=\"Laboratory\" class=\"wiki-link\" data-key=\"c57fc5aac9e4abf31dccae81df664c33\">laboratory<\/a> <a href=\"https:\/\/www.limswiki.org\/index.php\/Medical_test\" title=\"Medical test\" class=\"wiki-link\" data-key=\"0e5a509a721423b5cae83265bbb80c85\">tests<\/a>.\n<\/p><p><b>Keywords<\/b>: oncology, regulation, testing, LDTs, FDA, CLIA, CMS\n<\/p>\n<h2><span class=\"mw-headline\" id=\"The_current_regulatory_environment_in_the_United_States\">The current regulatory environment in the United States<\/span><\/h2>\n<p>The current state of <a href=\"https:\/\/www.limswiki.org\/index.php\/Laboratory\" title=\"Laboratory\" class=\"wiki-link\" data-key=\"c57fc5aac9e4abf31dccae81df664c33\">laboratory<\/a> <a href=\"https:\/\/www.limswiki.org\/index.php\/Medical_test\" title=\"Medical test\" class=\"wiki-link\" data-key=\"0e5a509a721423b5cae83265bbb80c85\">test<\/a> regulation in the United States (U.S.) is complex, and the prospect of changes in the current paradigm has been continually on the horizon since 2014. Briefly, <a href=\"https:\/\/www.limswiki.org\/index.php\/Clinical_laboratory\" title=\"Clinical laboratory\" class=\"wiki-link\" data-key=\"307bcdf1bdbcd1bb167cee435b7a5463\">clinical laboratories<\/a> in the U.S. are <a href=\"https:\/\/www.limswiki.org\/index.php\/Regulatory_compliance\" title=\"Regulatory compliance\" class=\"wiki-link\" data-key=\"7dbc9be278a8efda25a4b592ee6ef0ca\">regulated<\/a> under the <a href=\"https:\/\/www.limswiki.org\/index.php\/Clinical_Laboratory_Improvement_Amendments\" title=\"Clinical Laboratory Improvement Amendments\" class=\"wiki-link\" data-key=\"64bdae1dc17c40c28e0c560396a6ae35\">Clinical Laboratory Improvement Amendments of 1988<\/a> (CLIA \u203288)<sup id=\"rdp-ebb-cite_ref-USGPO_PublicLaw100-578_1-0\" class=\"reference\"><a href=\"#cite_note-USGPO_PublicLaw100-578-1\">[1]<\/a><\/sup> of the Public Health Services Act, which are administered by the <a href=\"https:\/\/www.limswiki.org\/index.php\/Centers_for_Medicare_and_Medicaid_Services\" title=\"Centers for Medicare and Medicaid Services\" class=\"wiki-link\" data-key=\"654b4449e4816e190325b420c264df1a\">Centers for Medicare and Medicaid Services<\/a> (CMS). These regulations were put in place to improve the <a href=\"https:\/\/www.limswiki.org\/index.php\/Quality_control\" title=\"Quality control\" class=\"wiki-link\" data-key=\"1e0e0c2eb3e45aff02f5d61799821f0f\">quality<\/a> of the processes in clinical laboratories, but the regulations allow for organizations that have received certification from CMS to inspect laboratories as a deemed entity. This status allows deemed entities to place additional requirements in place, so long as the underlying CLIA requirements are met. \n<\/p><p>CLIA regulations have a flexible framework that allows individual medical directors and laboratories to have some leeway in how the specific requirements are met, which allows for accommodation of unique population-, laboratory-, and test-level factors that can improve the overall quality of testing, while also allowing for the development of tests by laboratory medicine practitioners within certain bounds. Testing kits that are manufactured and shipped across state lines are regulated by the U.S. <a href=\"https:\/\/www.limswiki.org\/index.php\/Food_and_Drug_Administration\" title=\"Food and Drug Administration\" class=\"wiki-link\" data-key=\"e2be8927071ac419c0929f7aa1ede7fe\">Food and Drug Administration<\/a> (FDA) via the <a href=\"https:\/\/www.limswiki.org\/index.php\/Medical_Device_Regulation_Act\" title=\"Medical Device Regulation Act\" class=\"wiki-link\" data-key=\"2fa613f847c38e74dbf92a27cdbdd178\">Medical Device Amendments of 1976<\/a><sup id=\"rdp-ebb-cite_ref-USGPO_PublicLaw94-295_2-0\" class=\"reference\"><a href=\"#cite_note-USGPO_PublicLaw94-295-2\">[2]<\/a><\/sup>, which amended the <a href=\"https:\/\/www.limswiki.org\/index.php\/Federal_Food,_Drug,_and_Cosmetic_Act\" title=\"Federal Food, Drug, and Cosmetic Act\" class=\"wiki-link\" data-key=\"0571bb1b10f7ea304585c7b95cd6317e\">Federal Food, Drug, and Cosmetic Act of 1938<\/a>. The FDA has several review and approval pathways where the manufacturer submits documentation and data to the FDA for review, and if the data fulfill the FDA\u2019s requirements, the test recieves marketing authorization. Manufacturers can then sell their products to laboratories, who wish to perform that testing. \n<\/p><p>Testing kits which are cleared or approved by the FDA are regulated under CLIA when they are performed in a certified laboratory. In addition, under the current structure, laboratories are expected to verify the performance of these products and, under CLIA, are allowed to modify them if deemed necessary by medical leadership. If a manufactured product is modified by the user's laboratory, the test is considered a \"<a href=\"https:\/\/www.limswiki.org\/index.php\/Laboratory_developed_test\" title=\"Laboratory developed test\" class=\"wiki-link\" data-key=\"c02aacbf30e9b175e3da72ba8c3aaf8e\">laboratory developed test<\/a>.\" Such modifications are frequently made to improve assay performance, use the assay in a way different from the use claimed by the manufacturer (e.g., diagnostic instead of screening applications), or allow acceptance of additional <a href=\"https:\/\/www.limswiki.org\/index.php\/Sample_(material)\" title=\"Sample (material)\" class=\"wiki-link\" data-key=\"7f8cd41a077a88d02370c02a3ba3d9d6\">sample<\/a> types that were not submitted to the FDA for approval. This regulatory flexibility allows clinical laboratories to offer tests that are accurate and medically relevant to their patients. Currently, many <a href=\"https:\/\/www.limswiki.org\/index.php\/Clinical_Laboratory_Improvement_Amendments#CLIA_program\" title=\"Clinical Laboratory Improvement Amendments\" class=\"wiki-link\" data-key=\"36e85f2f6fb0f13991095d04db6a1abb\">high-complexity<\/a> clinical laboratories are accredited by the College of American Pathologists (CAP), which conducts unannounced biannual laboratory inspections and administers a multitude of proficiency testing programs to evaluate the accuracy and agreement between laboratories across the spectrum of laboratory tests. \n<\/p><p>The FDA has maintained that they have the statutory authority to regulate all laboratory tests, including tests that are developed and offered in a single lab, but have chosen to operate under a policy of enforcement discretion.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Emergence_of_new_regulatory_proposals\">Emergence of new regulatory proposals<\/span><\/h2>\n<h3><span class=\"mw-headline\" id=\"2014_draft_guidance_and_evolution_to_legislation\">2014 draft guidance and evolution to legislation<\/span><\/h3>\n<p>In October of 2014, the U.S. FDA released draft guidance<sup id=\"rdp-ebb-cite_ref-FDAFramework14_3-0\" class=\"reference\"><a href=\"#cite_note-FDAFramework14-3\">[3]<\/a><\/sup> that proposed to dramatically change the regulatory landscape of tests that were developed and offered in a single laboratory, formally referred to as \"laboratory developed tests\" or LDTs. There was a large amount of feedback from academic, community, commercial, and professional stakeholders, with several hundred comments submitted to the FDA docket.<sup id=\"rdp-ebb-cite_ref-FDAFrameworkDocket15_4-0\" class=\"reference\"><a href=\"#cite_note-FDAFrameworkDocket15-4\">[4]<\/a><\/sup> After the 2016 presidential election, the FDA publicly stated that the agency will defer to the legislative branch of the U.S. government to update the regulatory landscape of LDTs and manufactured laboratory tests, also know as <i>in vitro<\/i> diagnostic devices.<sup id=\"rdp-ebb-cite_ref-FDADiscussion17_5-0\" class=\"reference\"><a href=\"#cite_note-FDADiscussion17-5\">[5]<\/a><\/sup> Although the FDA has stated that it will not wholesale change the regulatory requirements for LDTs in the interim, the agency has continued to release guidance documents, in both draft and final forms, that touch on the regulation of laboratory diagnostics that are used in the care of <a href=\"https:\/\/www.limswiki.org\/index.php\/Oncology\" title=\"Oncology\" class=\"wiki-link\" data-key=\"6c962c118dffc629e1bae0d5f95e68e2\">oncology<\/a> patients.\n<\/p><p>During this same period of time, a variety of stakeholders, including the CAP<sup id=\"rdp-ebb-cite_ref-VanceCollege11_6-0\" class=\"reference\"><a href=\"#cite_note-VanceCollege11-6\">[6]<\/a><\/sup> and the Association for Molecular Pathology (AMP)<sup id=\"rdp-ebb-cite_ref-Ferreira-GonzalezRevisit14_7-0\" class=\"reference\"><a href=\"#cite_note-Ferreira-GonzalezRevisit14-7\">[7]<\/a><\/sup>, proposed alternative regulatory approaches. In addition, a consortium of commercial laboratories, test manufacturers, and large reference laboratories with academic affiliations helped draft the basis for the proposed Diagnostic Accuracy and Innovation Act (DAIA)<sup id=\"rdp-ebb-cite_ref-FDAViews18_8-0\" class=\"reference\"><a href=\"#cite_note-FDAViews18-8\">[8]<\/a><\/sup>, which was made available for red-line comments by representatives in the U.S. House of Representatives in 2017. This proposal introduced the new term \"<i>in vitro<\/i> clinical tests\" (IVCTs) as a common term for both commercial manufactured tests and LDTs, and as a term to differentiate such tests from <a href=\"https:\/\/www.limswiki.org\/index.php\/Medical_device\" title=\"Medical device\" class=\"wiki-link\" data-key=\"8e821122daa731f0fa8782fae57831fa\">medical devices<\/a>. As part of the feedback process, the legislative sponsors requested technical assistance (TA) and comments from the FDA.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"VALID_Act_of_2020_and_VITAL_Act_of_2020\">VALID Act of 2020 and VITAL Act of 2020<\/span><\/h3>\n<p>The process of obtaining the FDA's TA document for the DAIA took over a year, and the TA document that was received by the sponsors was not a commentary on the draft legislation that was provided to them, but rather it was an entirely new legislative discussion draft that outlined an almost entirely different regulatory scheme from DAIA. The legislative sponsors quickly evaluated the TA document and released the Verifying Accurate, Leading-edge IVCT Development (VALID) Act. Over the following years, the VALID Act was the topic of many meetings among stakeholders, the FDA, and legislative staff, and a final version was introduced into the U.S. House of Representatives and U.S. Senate on March 5, 2020<sup id=\"rdp-ebb-cite_ref-CongressVALID20_9-0\" class=\"reference\"><a href=\"#cite_note-CongressVALID20-9\">[9]<\/a><\/sup>, during the early days of the <a href=\"https:\/\/www.limswiki.org\/index.php\/SARS-CoV-2\" title=\"SARS-CoV-2\" class=\"mw-redirect wiki-link\" data-key=\"6c6b78479de2c640028696ed32948526\">SARS-CoV-2<\/a> <a href=\"https:\/\/www.limswiki.org\/index.php\/Pandemic\" title=\"Pandemic\" class=\"wiki-link\" data-key=\"bd9a48e6c6e41b6d603ee703836b01f1\">pandemic<\/a> in the United States. On March 17, 2020, an alternative regulatory bill, the Verified Innovative Testing in American Laboratories (VITAL) Act of 2020<sup id=\"rdp-ebb-cite_ref-CongressVITAL20_10-0\" class=\"reference\"><a href=\"#cite_note-CongressVITAL20-10\">[10]<\/a><\/sup>, was introduced into the Senate.\n<\/p><p>The approach outlined in the VALID Act of 2020 continues the FDA\u2019s long-standing assertion that the agency be the central arbiter of a laboratory developed test's analytical accuracy and validity. Key components of VALID include extensive grandfathering of existing LDTs, a new classification scheme for new tests, and a framework for a precertification scheme that is designed to allow laboratories to create, validate, and offer certain tests without FDA review in certain circumstances. While many previous approaches to regulation included three risk levels for tests (low, moderate, and high), the VALID Act of 2020 only has two categories: low- and high-risk. Tests in the low-risk categorization would be allowed to be developed and used for patient care through individual submission to the FDA or through use of the precertification pathway. Tests considered to be in the high-risk category would not be eligible for using the precertification pathway and would require the test to be submitted to the FDA via a pathway similar to the current premarket approval (PMA) pathway. Given that many current <a href=\"https:\/\/www.limswiki.org\/index.php\/Molecular_diagnostics\" title=\"Molecular diagnostics\" class=\"wiki-link\" data-key=\"8fc14cae7a6fbac9a53fae1394fae7ee\">molecular<\/a> oncology LDTs are used to select therapy regimens or could be used to decide prophylactic surgeries, most of these tests are expected to be classified in the high-risk category, requiring a time-consuming and expensive PMA should VALID become law. While there is the provision for high-risk tests to use \u201cmitigating measures\u201d that would allow a different regulatory pathway, it is unclear how this might work in practice, and none of the examples cited in the legislation reference professional practice or expertise. \n<\/p><p>The proposed precertification process is similar in concept to some existing programs, including the conditional approval process utilized by the New York State Department of Health (NYDOH)<sup id=\"rdp-ebb-cite_ref-WadsworthLDT19_11-0\" class=\"reference\"><a href=\"#cite_note-WadsworthLDT19-11\">[11]<\/a><\/sup>, but it uses a technology classification system to allow laboratories or manufacturers to develop within a certain scope of expertise. The technological categories have underlying scientific principles that are considered generally similar by the FDA. The technology categories are clot detection, colorimetric, enzymatic, fluorometry, immunoassay, mass spectrometry\/chromatography, microbial culture, nephlometric\/turbidimetric, next generation sequencing (NGS), non-NGS nucleic acid analysis, slide-based technology, and spectroscopy. The VALID Act of 2020 stipulates that a laboratory would become precertified for a specific technology by submitting an initial assay through the stand-alone pathway, and, if successful, the lab would obtain a multi-year permission to develop and modify tests within that technology class. At the end of a certification term, the lab could submit a new assay for review and could receive an extension of the precertification. While tests developed in the precertification window would not need to be submitted for review, documentation would have to be maintained for inspection by the FDA or third-party reviewers.\n<\/p><p>A key provision of VALID is the extensive grandfathering provision that is included in the legislation, where tests that are available before the legislation enactment can continue to be offered after the law is in effect. This grandfathering was included to prevent the sudden loss of laboratory tests as the law is enacted. A key aspect of this grandfathering is that tests cannot be modified after VALID becomes law, and the FDA has the authority to order any test off the market if they choose.\n<\/p><p>While the VALID Act of 2020 has numerous provisions\u2014weighing in at over 245 pages\u2014and ensconces many aspects of regulation of LDTs in statute, the VITAL Act of 2020 takes the opposite approach. The VITAL Act of 2020 is only seven pages in length and simply states that all development and performance of LDTs will be under the jurisdiction of the Public Health Services Act and cannot be regulated under the Medical Device Act. These two legislative bills are indicative of the extreme differences that people, companies, and institutions have taken on the issue of regulation of laboratory services and the methods that are used to provide data to inform patient care. The key regulatory proposals and legislation are presented in Table 1.\n<\/p>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table class=\"wikitable\" border=\"1\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\" colspan=\"3\"><b>Table 1.<\/b> Timeline of key developments in the regulation of laboratory testing\n<\/td><\/tr>\n<tr>\n<th style=\"background-color:#dddddd; padding-left:10px; padding-right:10px;\">Date\n<\/th>\n<th style=\"background-color:#dddddd; padding-left:10px; padding-right:10px;\">Document\n<\/th>\n<th style=\"background-color:#dddddd; padding-left:10px; padding-right:10px;\">Relevant statute\n<\/th><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">1976\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Medical Device Regulation Act\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Food, Drug, and Cosmetic Act of 1938\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">1998\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Clinical Laboratory Improvement Amendments (42 USC 263a)\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Public Health Services Act\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">2014\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs)\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Food, Drug, and Cosmetic Act of 1938\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">2017\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Diagnostic Accuracy and Innovation Act (DAIA)\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Food, Drug, and Cosmetic Act of 1938\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">2018\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Verifying Accurate Leading-edge IVCT Development Act of 2018 (FDA technical assessment of DAIA)\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Food, Drug, and Cosmetic Act of 1938\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">2019\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Verifying Accurate Leading-edge IVCT Development Act of 2018 (FDA technical assessment of DAIA)\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Food, Drug, and Cosmetic Act of 1938\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">March 2020\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Verifying Accurate Leading-edge IVCT Development Act of 2020\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Food, Drug, and Cosmetic Act of 1938\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">March 2020\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Verified Innovative Testing in American Laboratories Act of 2020\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Food, Drug, and Cosmetic Act of 1938\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>The fates of the current legislation are uncertain, given the current state of the U.S. political climate, but evaluation of key underlying concepts related to the logic of regulation may benefit the stakeholders who are interested in this regulation.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Commentary_on_the_scope_of_regulation\">Commentary on the scope of regulation<\/span><\/h2>\n<p>There are numerous manufacturers who have developed targeted precision oncology tests and companion diagnostics that have achieved FDA approval. Despite the availably of these manufactured tests, many laboratories continue to develop and use LDTs for oncology testing, especially at academic institutions. There are several examples of specific comprehensive tests that were developed and used as LDTs that have sought both PMA (Foundation medicine) and 510(k) (MSK-IMPACT) approval.<sup id=\"rdp-ebb-cite_ref-AllegrettiTearing18_12-0\" class=\"reference\"><a href=\"#cite_note-AllegrettiTearing18-12\">[12]<\/a><\/sup> While the existing FDA regulatory pathways are clearly available to all laboratories that develop LDTs, the observation that these pathways have not been used except by a handful of large and well-funded organizations suggests that the burdens of seeking such approvals are sufficiently large and complex<sup id=\"rdp-ebb-cite_ref-GoodsaidTheLab19_13-0\" class=\"reference\"><a href=\"#cite_note-GoodsaidTheLab19-13\">[13]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-LiottaReg12_14-0\" class=\"reference\"><a href=\"#cite_note-LiottaReg12-14\">[14]<\/a><\/sup> to dissuade laboratories from undertaking, despite any benefits. Laboratories that develop LDTs often state that the ability to modify tests without needing to seek regulatory approval allows for tests to be continuously improved and updated to meet patient needs. In the setting of precision oncology, laboratory tests are undergoing constant revision and updating as new discoveries in science and medicine are applied to routine patient care.\n<\/p><p>In many discussions and talking points related to the need for regulation of LDTs, several topics are consistently raised as key reasons for increased LDT regulation. These factors include the risk of patient harm, the changing nature of LDTs, accuracy and interchangeability of results, the need to encourage innovation, and the requirement for a single regulatory pathway.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Risks_to_patients_and_the_changing_nature_of_LDTs\">Risks to patients and the changing nature of LDTs<\/span><\/h3>\n<p>A commonly cited reason for additional regulation of laboratory testing is to reduce the risk of patient harm due to tests that do not perform as expected.<sup id=\"rdp-ebb-cite_ref-FDAThePublic15_15-0\" class=\"reference\"><a href=\"#cite_note-FDAThePublic15-15\">[15]<\/a><\/sup> Although many assertions of patient harm due solely to laboratory developed tests are often easily debunked<sup id=\"rdp-ebb-cite_ref-AMPFacts15_16-0\" class=\"reference\"><a href=\"#cite_note-AMPFacts15-16\">[16]<\/a><\/sup>, the possibility of patient harm is a serious possibility that should be considered. Manufactured products that are produced and shipped across state lines may require more extensive regulatory oversight because the manufacturer has no control over the specific skills or expertise of the laboratory staff and directors who are implementing the test. As such, having a test that can be understood and used by novices and experts alike may be a reasonable requirement, which is the current state of manufactured tests in the United States. \n<\/p><p>LDTs are often developed and implemented in laboratories that have specific expertise and patient needs that require specialized testing. LDTs are also commonly used in areas of medicine where there is a rapid increase in knowledge (e.g., oncology), or where testing methods must be nimble due to changing analytes (e.g., infectious disease). The ability to rapidly adapt testing methods and implement new scientific and medical findings with LDTs stands in contrast to the extensive and costly process required for tests pased through the FDA processes, which have been estimated to result in multiple years delay in test availability compared to other Western countries, with potential costs of tens of millions of dollars per FDA sumission.<sup id=\"rdp-ebb-cite_ref-MakowerFDA10_17-0\" class=\"reference\"><a href=\"#cite_note-MakowerFDA10-17\">[17]<\/a><\/sup> Given the costs associated with obtaining FDA approval for laboratory tests, there will be significant costs that laboratories will have to bear under the proposed VALID Act, both in terms of submitting tests for consideration of precertification and in maintaining that certification. In addition, tests that are in the high-risk classification will be less likely to be laboratory developed and will either need a commercial solution or require referral to an outside laboratory.\n<\/p><p>A concern that has been repeatedly raised by the FDA and other groups is that the nature of LDTs has changed over past decades. Where LDTs were once mostly performed in <a href=\"https:\/\/www.limswiki.org\/index.php\/Hospital\" title=\"Hospital\" class=\"wiki-link\" data-key=\"b8f070c66d8123fe91063594befebdff\">hospital<\/a> laboratories for local patients, in the present day, LDTs are often performed in central laboratories that are removed from the site of patient care. These labs can fall into several general categories: <a href=\"https:\/\/www.limswiki.org\/index.php\/Reference_laboratory\" title=\"Reference laboratory\" class=\"wiki-link\" data-key=\"f719f408e1660f86b53857eef2f13f32\">reference laboratories<\/a> for hospital systems, regional reference laboratories, national reference laboratories, and commercial for-profit entities. While these laboratories are all likely to adhere to high standards and perform analytically sound tests, the change of LDTs from a primarily local to a regional or national scale has been suggested by the FDA to be a rationale for no longer applying enforcement discretion. Although not explicitly stated in the FDA\u2019s statements, the implication lies in the potential for decreased patient safety, not due to the type of test performed (LDT vs. FDA-approved), but due to decreased interaction of laboratory experts with the team caring for individual patients.\n<\/p><p>When any tests are performed in centralized laboratories with limited access to clinical records, there is a higher risk of making pre-analytical, post-analytical, and cognitive errors that can impact patient care. In addition, incentives such as the payment structure of the laboratory can incentivize behaviors that are divergent from the best interest of patients and the health system. Many decentralized laboratories use a fee-for-service payment model, which has been suggested to increase overutilization<sup id=\"rdp-ebb-cite_ref-LynchUtil17_18-0\" class=\"reference\"><a href=\"#cite_note-LynchUtil17-18\">[18]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-PatonInstitute08_19-0\" class=\"reference\"><a href=\"#cite_note-PatonInstitute08-19\">[19]<\/a><\/sup> and can potentially lead to situations where analytical and clinical validity claims may overreach the available data.<sup id=\"rdp-ebb-cite_ref-AMPProposal15_20-0\" class=\"reference\"><a href=\"#cite_note-AMPProposal15-20\">[20]<\/a><\/sup> Research has also suggested that laboratory testing done remotely from the patient may lead to increases in cost, turnaround time, duplicative orders, unnecessary studies, and errors.<sup id=\"rdp-ebb-cite_ref-ChasinMedical07_21-0\" class=\"reference\"><a href=\"#cite_note-ChasinMedical07-21\">[21]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-MrakOut18_22-0\" class=\"reference\"><a href=\"#cite_note-MrakOut18-22\">[22]<\/a><\/sup> Ironically, the addition of additional and costly regulations via the VALID Act may actually drive further consolidation of the centralization model of laboratory testing, which could lead to additional errors as previously described. As complex testing is removed from regional and academic centers and concentrated in centralized laboratories, the ability of laboratory medicine experts to interact with their patient-facing colleagues is likely to decrease, resulting in further degradation in care.\n<\/p><p>In contrast, integration of laboratory medicine experts in the clinical care team has been suggested to improve diagnostic yield, especially in the setting of complex and nuanced laboratory data. This type of integration has been proposed as a valuable and beneficial service, as pathologists, for example, can provide insight into and leadership for the activities of clinical care teams.<sup id=\"rdp-ebb-cite_ref-DucatmanTheValue20_23-0\" class=\"reference\"><a href=\"#cite_note-DucatmanTheValue20-23\">[23]<\/a><\/sup> As precision oncology has become more reliant on numerous biomarkers and mutations to direct treatment, systematic studies have demonstrated that interpretations of results may benefit from expert consultation<sup id=\"rdp-ebb-cite_ref-BruscoPhys18_24-0\" class=\"reference\"><a href=\"#cite_note-BruscoPhys18-24\">[24]<\/a><\/sup>, which may not be available when the testing is performed remotely. While it is true that the type and complexity of tests that have been developed as LDTs has changed, the more critical aspect that has changed is the decentralization of care that has simultaneously occurred, and that is an aspect of medical practice that cannot be regulated by the FDA.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Accuracy_and_equivalency_between_laboratory_tests\">Accuracy and equivalency between laboratory tests<\/span><\/h3>\n<p>A commonly cited rationale for the need to regulate LDTs is the need to ensure that results are equivalent between assays, especially in the area of oncology tests that are used to direct oncologic decision-making and treatments. While the rhetoric is often that the accuracy of LDTs is not known, there are many studies and programs in place that laboratories use to evaluate the performance of their LDTs and manufactured kits, with proficiency testing and comparative studies being key tools. Many published scientific studies have demonstrated good equivalence between molecular oncology tests, both LDTs and FDA approved<sup id=\"rdp-ebb-cite_ref-XuAss16_25-0\" class=\"reference\"><a href=\"#cite_note-XuAss16-25\">[25]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-GaoValid16_26-0\" class=\"reference\"><a href=\"#cite_note-GaoValid16-26\">[26]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-SimenValid15_27-0\" class=\"reference\"><a href=\"#cite_note-SimenValid15-27\">[27]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-TuononenComp13_28-0\" class=\"reference\"><a href=\"#cite_note-TuononenComp13-28\">[28]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-Lopez-RiosComp13_29-0\" class=\"reference\"><a href=\"#cite_note-Lopez-RiosComp13-29\">[29]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-KothariComp14_30-0\" class=\"reference\"><a href=\"#cite_note-KothariComp14-30\">[30]<\/a><\/sup>, including studies examining assessment of important recurrent oncologic mutations that are frequently assessed in proficiency testing. It is also critical to remember that even when the same test is used to assess identical samples, but in different labs, there will be slight differences in performance due to statistical factors.<sup id=\"rdp-ebb-cite_ref-KeppensDetect18_31-0\" class=\"reference\"><a href=\"#cite_note-KeppensDetect18-31\">[31]<\/a><\/sup> There are publications citing disagreement between specific laboratory methods, but investigation of the methods and biology relevant to specific comparisons often reveal that the apparent differences may actually be due to biological phenomena<sup id=\"rdp-ebb-cite_ref-TorgaPatient18_32-0\" class=\"reference\"><a href=\"#cite_note-TorgaPatient18-32\">[32]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-SchweizerClinical19_33-0\" class=\"reference\"><a href=\"#cite_note-SchweizerClinical19-33\">[33]<\/a><\/sup>, or specific disease biology<sup id=\"rdp-ebb-cite_ref-PoirotMET17_34-0\" class=\"reference\"><a href=\"#cite_note-PoirotMET17-34\">[34]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-RosenbaumGenomic18_35-0\" class=\"reference\"><a href=\"#cite_note-RosenbaumGenomic18-35\">[35]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-DaviesDNA19_36-0\" class=\"reference\"><a href=\"#cite_note-DaviesDNA19-36\">[36]<\/a><\/sup>, highlighting the importance of the expertise of medical practitioners in interpreting testing data and applying the results of these studies.\n<\/p><p>Proficiency testing is required under CLIA, and the CAP develops proficiency testing programs using content experts to devise appropriate challenges<sup id=\"rdp-ebb-cite_ref-HamlinProfic92_37-0\" class=\"reference\"><a href=\"#cite_note-HamlinProfic92-37\">[37]<\/a><\/sup>, in addition to developing accreditation checklists<sup id=\"rdp-ebb-cite_ref-EndrullatStand16_38-0\" class=\"reference\"><a href=\"#cite_note-EndrullatStand16-38\">[38]<\/a><\/sup> and clinical guidelines.<sup id=\"rdp-ebb-cite_ref-WolffHuman18_39-0\" class=\"reference\"><a href=\"#cite_note-WolffHuman18-39\">[39]<\/a><\/sup> Multiple studies examining CAP proficiency testing data using well-characterized reference materials have demonstrated that real-world challenges of total assay performance show excellent agreement among a variety of FDA-approved, FDA-cleared, and LDT precision-oncology assays across a broad range of technologies.<sup id=\"rdp-ebb-cite_ref-KimComp18_40-0\" class=\"reference\"><a href=\"#cite_note-KimComp18-40\">[40]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-MerkerProf19_41-0\" class=\"reference\"><a href=\"#cite_note-MerkerProf19-41\">[41]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-SurreyNext19_42-0\" class=\"reference\"><a href=\"#cite_note-SurreyNext19-42\">[42]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-MoncurPerform19_43-0\" class=\"reference\"><a href=\"#cite_note-MoncurPerform19-43\">[43]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-KeeganProf20_44-0\" class=\"reference\"><a href=\"#cite_note-KeeganProf20-44\">[44]<\/a><\/sup>\n<\/p><p>However, as the field of precision oncology diagnostics has evolved, new technologies and approaches such as <a href=\"https:\/\/www.limswiki.org\/index.php\/DNA_sequencing#High-throughput_sequencing_.28HTS.29_methods\" title=\"DNA sequencing\" class=\"wiki-link\" data-key=\"0bfff2c9a686c74f57fc9f7ca97140b9\">next-generation sequencing<\/a> (NGS) present additional problems, including the need for sometimes complex <a href=\"https:\/\/www.limswiki.org\/index.php\/Bioinformatics\" title=\"Bioinformatics\" class=\"wiki-link\" data-key=\"8f506695fdbb26e3f314da308f8c053b\">bioinformatics<\/a> pipelines to analyze and interpret large volumes of data. To complicate the scenario, some laboratories use outside services for bioinformatics, which allows for decreased internal resources for this specialized field, but opens the possibility for errors that may be difficult to diagnose and detect. Studies have demonstrated the feasibility of using <i>in silico<\/i> manipulation of data to simulate variants in data generated in the laboratory under evaluation<sup id=\"rdp-ebb-cite_ref-DuncavageAMod16_45-0\" class=\"reference\"><a href=\"#cite_note-DuncavageAMod16-45\">[45]<\/a><\/sup>, indicating that innovative approaches to new problems using existing structure can quickly address new problems as they emerge. These common practices of comparisons of different laboratories using blinded, standardized materials demonstrates the analytical accuracy of the methods and provides a mechanism for identifying laboratories and tests that are not performing up to standard, while also offering a route to problem resolution. The participation in proficiency testing programs is another mitigating measure that allows for <a href=\"https:\/\/www.limswiki.org\/index.php\/Continual_improvement_process\" title=\"Continual improvement process\" class=\"wiki-link\" data-key=\"fd7b54be3f6cdd0e8ed84d501486d668\">continuous quality improvement<\/a> and should also be considered in any regulatory scheme.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Regulatory_certainty_and_innovation\">Regulatory certainty and innovation<\/span><\/h3>\n<p>Regulatory certainty has been stated as a key component to encouraging innovation in the realm of laboratory testing. Regulatory certainty is often framed as providing a financial incentive for investing in innovation, which focuses on the financial and business aspects of laboratory testing, but neglecting the medical needs that often drive test development. Regulatory certainty has been present for manufactured kits for many years, but the long developmental timeline for many assays has led to assays being obsolete when they finally become available<sup id=\"rdp-ebb-cite_ref-Lopez-RiosComp13_29-1\" class=\"reference\"><a href=\"#cite_note-Lopez-RiosComp13-29\">[29]<\/a><\/sup>, which can be problematic if the state of scientific and medical understanding change in the intervening years. In order to effectively undertake long regulatory approval processes, entities must have not only the resources to undertake the process, but also the necessary return on investment in order to proceed. In contrast, many LDTs are developed to assess a specific medical or operational need that is not possible or practical to address by alterative means. Having a regulatory framework that allows for both scenarios will allow for patients to have the maximum access to important diagnostic tests. Many manufacturers and regulators have stated that a single regulatory pathway is the most appropriate and efficient approach, but that view focuses on the needs of those constituencies while neglecting other considerations. A chief concern is the reality that most laboratories are responsible for managing thousands of tests that are required for patient care, while manufacturers and specialty laboratories generally have a limited portfolio of tests that they maintain. Having a single regulatory path could result in much higher regulatory burden for professionals that are providing medical care to patients, potentially reducing the number of tests available for patient care and diverting monetary and personnel resources from patient care activities to administrative tasks. While both arguments have some merit, the convenience of the regulatory body and special interests need to be balanced against the need for flexibility to provide appropriate services to patients and providers.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Recommendations_for_policymakers.2C_regulators.2C_and_stakeholders\">Recommendations for policymakers, regulators, and stakeholders<\/span><\/h2>\n<p>As of this writing, the political landscape in the United States is such that comprehensive reform of laboratory regulations does not seem likely to advance. In addition, the events surrounding the delayed rollout of laboratory diagnostics to address the initial encounter with the SARS-CoV-2 pandemic in the United States has brought new attention to the issue of regulation of laboratory tests.<sup id=\"rdp-ebb-cite_ref-SharfsteinDiag20_46-0\" class=\"reference\"><a href=\"#cite_note-SharfsteinDiag20-46\">[46]<\/a><\/sup> Reflecting on the half-decade that has elapsed since the FDA\u2019s draft guidance to regulate LDTs, several key observations can be made with regard to the common themes in the public discussion and proposals for the regulation of laboratory tests:\n<\/p>\n<ul><li> The level of risk to the patient should be taken into account.<\/li>\n<li> Most laboratories involved in testing of biomarkers related to precision oncology have comparable results.<\/li>\n<li> Precision oncology relies on the ability of laboratories to rapidly innovate to provide optimal patient care.<\/li><\/ul>\n<h3><span class=\"mw-headline\" id=\"Assessment_of_risks_to_patient\">Assessment of risks to patient<\/span><\/h3>\n<p>Manufactured tests, tests provided by for-profit laboratories, or labs that have a profit motive (startup laboratories, public companies, etc.) may require additional regulation to ensure that the primacy of analytical accuracy and clinical validity are appropriate for the claims of the laboratory. The observation that fee-for-service can result in increased utilization and errors suggest that additional scrutiny may be needed in these situations. Laboratories that are integrated with the patients they serve, including oncology patients, have the opportunity to embrace the role of diagnostic consultant, utilizing the professional services of expert medical directors to aid in the interpretation and dissemination of understanding of complex test results, and hence requiring less regulation.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Addressing_analytical_concerns\">Addressing analytical concerns<\/span><\/h3>\n<p>While data have demonstrated that precision oncology assays have excellent accuracy and concordance, the concern that disparate assays should be able to be accurately evaluated during development is valid. Rather than a rigid regulatory construct, this specific concern can be addressed through establishing professional practice guidelines and recommendations, and though developing standards that can be used for assay development and quality control<sup id=\"rdp-ebb-cite_ref-CraigASomatic16_47-0\" class=\"reference\"><a href=\"#cite_note-CraigASomatic16-47\">[47]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ZookExtensive16_48-0\" class=\"reference\"><a href=\"#cite_note-ZookExtensive16-48\">[48]<\/a><\/sup> for established biomarkers. As scientific knowledge and medical understanding are constantly evolving, it is critical that professionals investigate and understand the technical, biological, and medical variables that impact laboratory tests, which will require deep involvement and expertise. Such resources are especially important in the setting of precision oncology as some highly-actionable alterations are also extremely rare and difficult to detect by many technologies.<sup id=\"rdp-ebb-cite_ref-Marchi.C3.B2ESMO19_49-0\" class=\"reference\"><a href=\"#cite_note-Marchi.C3.B2ESMO19-49\">[49]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-Penault-LlorcaTesting19_50-0\" class=\"reference\"><a href=\"#cite_note-Penault-LlorcaTesting19-50\">[50]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-SolomonNTRK20_51-0\" class=\"reference\"><a href=\"#cite_note-SolomonNTRK20-51\">[51]<\/a><\/sup> When such standards are available and routinely used, the risk that an incorrect result will be generated in the analytical process decreases. Similarly, tests that use proprietary algorithms or artificial intelligence should have a higher level of scrutiny because comparing individual tests using a standard material may not be appropriate. Development of physical and performance standards by professional societies should be leveraged to allow for test development and comparison. Utilizing professional societies will allow for the integration of the most recent scientific and medical findings, which is potentially more nimble than a process embedded in a federal agency.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Innovation_and_application\">Innovation and application<\/span><\/h3>\n<p>Patients expect that the assay that is being used to guide care for them uses the most up-to-date method possible; as such, tests must be able to updated as necessary to maintain their performance and relevance. For manufacturers and commercial laboratories, a precertification pathway as delineated in the VALID Act may be a sensible approach for precision oncology applications, if such tests can be assigned an appropriate risk classification. With regards to laboratories that are closely associated with physicians providing patient care, a more flexible approach akin to that currently under CLIA provides an optimal balance between the ability of laboratory medicine physicians to practice medicine, protect patients, provide relevant laboratory results, and overcome regulatory burden.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Conclusion\">Conclusion<\/span><\/h2>\n<p>The regulatory environment of precision oncology tests in the U.S. is complex, and multiple legislative proposals to update the regulatory environment have been introduced. As discussions around laboratory regulation proceed, careful consideration of the risks, benefits, and costs of various regulatory approaches must be considered. In order to deliver the most appropriate care to patients in difficult circumstances, broader evaluation of the implications of test regulation should be contemplated. Many assertions and assumptions have been made as to why additional regulation of laboratory tests is required, but the likely effects of that regulation on patient care have not been evaluated with regards to patients and the full spectrum of stakeholders. Identifying tools that can be leveraged to improve laboratory test quality may offer many benefits that do not necessarily require a burdensome regulatory framework.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Acknowledgements\">Acknowledgements<\/span><\/h2>\n<h3><span class=\"mw-headline\" id=\"Competing_interests\">Competing interests<\/span><\/h3>\n<p>I have no relevant conflicts related to this manuscript.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"References\">References<\/span><\/h2>\n<div class=\"reflist references-column-width\" style=\"-moz-column-width: 30em; -webkit-column-width: 30em; column-width: 30em; list-style-type: decimal;\">\n<ol class=\"references\">\n<li id=\"cite_note-USGPO_PublicLaw100-578-1\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-USGPO_PublicLaw100-578_1-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\"><a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.govinfo.gov\/content\/pkg\/STATUTE-102\/pdf\/STATUTE-102-Pg2903.pdf\" target=\"_blank\">\"Public Law 100-578 - Clinical Laboratory Improvement Amendments of 1988\"<\/a> (PDF). U.S. Government Publishing Office. 31 October 1988<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.govinfo.gov\/content\/pkg\/STATUTE-102\/pdf\/STATUTE-102-Pg2903.pdf\" target=\"_blank\">https:\/\/www.govinfo.gov\/content\/pkg\/STATUTE-102\/pdf\/STATUTE-102-Pg2903.pdf<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 30 August 2019<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Public+Law+100-578+-+Clinical+Laboratory+Improvement+Amendments+of+1988&rft.atitle=&rft.date=31+October+1988&rft.pub=U.S.+Government+Publishing+Office&rft_id=https%3A%2F%2Fwww.govinfo.gov%2Fcontent%2Fpkg%2FSTATUTE-102%2Fpdf%2FSTATUTE-102-Pg2903.pdf&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-USGPO_PublicLaw94-295-2\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-USGPO_PublicLaw94-295_2-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\"><a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.govinfo.gov\/content\/pkg\/STATUTE-90\/pdf\/STATUTE-90-Pg539.pdf\" target=\"_blank\">\"Public Law 94\u2013295 - Medical Device Amendments of 1976\"<\/a> (PDF). U.S. Government Publishing Office. 28 May 1976<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.govinfo.gov\/content\/pkg\/STATUTE-90\/pdf\/STATUTE-90-Pg539.pdf\" target=\"_blank\">https:\/\/www.govinfo.gov\/content\/pkg\/STATUTE-90\/pdf\/STATUTE-90-Pg539.pdf<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 31 August 2019<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Public+Law+94%E2%80%93295+-+Medical+Device+Amendments+of+1976&rft.atitle=&rft.date=28+May+1976&rft.pub=U.S.+Government+Publishing+Office&rft_id=https%3A%2F%2Fwww.govinfo.gov%2Fcontent%2Fpkg%2FSTATUTE-90%2Fpdf%2FSTATUTE-90-Pg539.pdf&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-FDAFramework14-3\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-FDAFramework14_3-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Food and Drug Administration (03 October 2014). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.fda.gov\/media\/89841\/download\" target=\"_blank\">\"Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs) - Draft Guidance\"<\/a>. Food and Drug Administration<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.fda.gov\/media\/89841\/download\" target=\"_blank\">https:\/\/www.fda.gov\/media\/89841\/download<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 31 August 2019<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Framework+for+Regulatory+Oversight+of+Laboratory+Developed+Tests+%28LDTs%29+-+Draft+Guidance&rft.atitle=&rft.aulast=Food+and+Drug+Administration&rft.au=Food+and+Drug+Administration&rft.date=03+October+2014&rft.pub=Food+and+Drug+Administration&rft_id=https%3A%2F%2Fwww.fda.gov%2Fmedia%2F89841%2Fdownload&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-FDAFrameworkDocket15-4\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-FDAFrameworkDocket15_4-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Food and Drug Administration (02 February 2015). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.regulations.gov\/docket?D=FDA-2011-D-0360\" target=\"_blank\">\"Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs)\"<\/a>. <i>Regulations.gov<\/i><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.regulations.gov\/docket?D=FDA-2011-D-0360\" target=\"_blank\">https:\/\/www.regulations.gov\/docket?D=FDA-2011-D-0360<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 31 August 2019<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Framework+for+Regulatory+Oversight+of+Laboratory+Developed+Tests+%28LDTs%29&rft.atitle=Regulations.gov&rft.aulast=Food+and+Drug+Administration&rft.au=Food+and+Drug+Administration&rft.date=02+February+2015&rft_id=https%3A%2F%2Fwww.regulations.gov%2Fdocket%3FD%3DFDA-2011-D-0360&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-FDADiscussion17-5\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-FDADiscussion17_5-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Food and Drug Administration (13 January 2017). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.fda.gov\/media\/102367\/download\" target=\"_blank\">\"Discussion Paper on Laboratory Developed Tests (LDTs)\"<\/a>. Food and Drug Administration<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.fda.gov\/media\/102367\/download\" target=\"_blank\">https:\/\/www.fda.gov\/media\/102367\/download<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 31 August 2019<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Discussion+Paper+on+Laboratory+Developed+Tests+%28LDTs%29&rft.atitle=&rft.aulast=Food+and+Drug+Administration&rft.au=Food+and+Drug+Administration&rft.date=13+January+2017&rft.pub=Food+and+Drug+Administration&rft_id=https%3A%2F%2Fwww.fda.gov%2Fmedia%2F102367%2Fdownload&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-VanceCollege11-6\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-VanceCollege11_6-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Vance, G.H. (2011). \"College of American Pathologists Proposal for the Oversight of Laboratory-Developed Tests\". <i>Archives of Pathology & Laboratory Medicine<\/i> <b>135<\/b> (11): 1432\u20135. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.5858%2Farpa.2011-0304-SA\" target=\"_blank\">10.5858\/arpa.2011-0304-SA<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/22032569\" target=\"_blank\">22032569<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=College+of+American+Pathologists+Proposal+for+the+Oversight+of+Laboratory-Developed+Tests&rft.jtitle=Archives+of+Pathology+%26+Laboratory+Medicine&rft.aulast=Vance%2C+G.H.&rft.au=Vance%2C+G.H.&rft.date=2011&rft.volume=135&rft.issue=11&rft.pages=1432%E2%80%935&rft_id=info:doi\/10.5858%2Farpa.2011-0304-SA&rft_id=info:pmid\/22032569&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-Ferreira-GonzalezRevisit14-7\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-Ferreira-GonzalezRevisit14_7-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Ferreira-Gonzalez, A.; Emmadi, R.; Day, S.P. et al. (2014). \"Revisiting Oversight and Regulation of Molecular-Based Laboratory-Developed Tests: A Position Statement of the Association for Molecular Pathology\". <i>Journal of Molecular Diagnostics<\/i> <b>16<\/b> (1): 3\u20136. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.jmoldx.2013.10.003\" target=\"_blank\">10.1016\/j.jmoldx.2013.10.003<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/24331365\" target=\"_blank\">24331365<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Revisiting+Oversight+and+Regulation+of+Molecular-Based+Laboratory-Developed+Tests%3A+A+Position+Statement+of+the+Association+for+Molecular+Pathology&rft.jtitle=Journal+of+Molecular+Diagnostics&rft.aulast=Ferreira-Gonzalez%2C+A.%3B+Emmadi%2C+R.%3B+Day%2C+S.P.+et+al.&rft.au=Ferreira-Gonzalez%2C+A.%3B+Emmadi%2C+R.%3B+Day%2C+S.P.+et+al.&rft.date=2014&rft.volume=16&rft.issue=1&rft.pages=3%E2%80%936&rft_id=info:doi\/10.1016%2Fj.jmoldx.2013.10.003&rft_id=info:pmid\/24331365&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-FDAViews18-8\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-FDAViews18_8-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Food and Drug Administration (03 August 2018). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.fdalawblog.net\/wp-content\/uploads\/2018\/08\/FDA-LDT-Draft-Leg.pdf\" target=\"_blank\">\"FDA's views on the Diagnostic Accuracy and Innovation Act (DAIA)\"<\/a> (PDF). Food and Drug Administration<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.fdalawblog.net\/wp-content\/uploads\/2018\/08\/FDA-LDT-Draft-Leg.pdf\" target=\"_blank\">http:\/\/www.fdalawblog.net\/wp-content\/uploads\/2018\/08\/FDA-LDT-Draft-Leg.pdf<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 31 August 2019<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=FDA%27s+views+on+the+Diagnostic+Accuracy+and+Innovation+Act+%28DAIA%29&rft.atitle=&rft.aulast=Food+and+Drug+Administration&rft.au=Food+and+Drug+Administration&rft.date=03+August+2018&rft.pub=Food+and+Drug+Administration&rft_id=http%3A%2F%2Fwww.fdalawblog.net%2Fwp-content%2Fuploads%2F2018%2F08%2FFDA-LDT-Draft-Leg.pdf&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-CongressVALID20-9\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-CongressVALID20_9-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Burr, R. (05 March 2020). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.congress.gov\/bill\/116th-congress\/senate-bill\/3404\/text\" target=\"_blank\">\"S.3404 - VALID Act of 2020\"<\/a>. <i>Congress.gov<\/i>. Library of Congress<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.congress.gov\/bill\/116th-congress\/senate-bill\/3404\/text\" target=\"_blank\">https:\/\/www.congress.gov\/bill\/116th-congress\/senate-bill\/3404\/text<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=S.3404+-+VALID+Act+of+2020&rft.atitle=Congress.gov&rft.aulast=Burr%2C+R.&rft.au=Burr%2C+R.&rft.date=05+March+2020&rft.pub=Library+of+Congress&rft_id=https%3A%2F%2Fwww.congress.gov%2Fbill%2F116th-congress%2Fsenate-bill%2F3404%2Ftext&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-CongressVITAL20-10\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-CongressVITAL20_10-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Paul, R. (17 March 2020). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.congress.gov\/bill\/116th-congress\/senate-bill\/3512\/text\" target=\"_blank\">\"S.3512 - VITAL Act of 2020\"<\/a>. <i>Congress.gov<\/i>. Library of Congress<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.congress.gov\/bill\/116th-congress\/senate-bill\/3512\/text\" target=\"_blank\">https:\/\/www.congress.gov\/bill\/116th-congress\/senate-bill\/3512\/text<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=S.3512+-+VITAL+Act+of+2020&rft.atitle=Congress.gov&rft.aulast=Paul%2C+R.&rft.au=Paul%2C+R.&rft.date=17+March+2020&rft.pub=Library+of+Congress&rft_id=https%3A%2F%2Fwww.congress.gov%2Fbill%2F116th-congress%2Fsenate-bill%2F3512%2Ftext&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-WadsworthLDT19-11\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-WadsworthLDT19_11-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Wadsworth Center (August 2019). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.wadsworth.org\/sites\/default\/files\/WebDoc\/Tiered_LDT_Review_Policy_June2019_REVISED_Aug%202019.pdf\" target=\"_blank\">\"History: NYSDOH Wadsworth Center\u2019s Clinical Laboratory Evaluation Program (CLEP)\"<\/a> (PDF). Wadsworth Center<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.wadsworth.org\/sites\/default\/files\/WebDoc\/Tiered_LDT_Review_Policy_June2019_REVISED_Aug%202019.pdf\" target=\"_blank\">https:\/\/www.wadsworth.org\/sites\/default\/files\/WebDoc\/Tiered_LDT_Review_Policy_June2019_REVISED_Aug%202019.pdf<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 31 August 2019<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=History%3A+NYSDOH+Wadsworth+Center%E2%80%99s+Clinical+Laboratory+Evaluation+Program+%28CLEP%29&rft.atitle=&rft.aulast=Wadsworth+Center&rft.au=Wadsworth+Center&rft.date=August+2019&rft.pub=Wadsworth+Center&rft_id=https%3A%2F%2Fwww.wadsworth.org%2Fsites%2Fdefault%2Ffiles%2FWebDoc%2FTiered_LDT_Review_Policy_June2019_REVISED_Aug%25202019.pdf&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-AllegrettiTearing18-12\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-AllegrettiTearing18_12-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Allegretti, M.; Fabi, A.; Buglioni, S. et al. (2018). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5838869\" target=\"_blank\">\"Tearing Down the Walls: FDA Approves Next Generation Sequencing (NGS) Assays for Actionable Cancer Genomic Aberrations\"<\/a>. <i>Journal of Experimental & Clinical Cancer Research<\/i> <b>37<\/b> (1): 47. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1186%2Fs13046-018-0702-x\" target=\"_blank\">10.1186\/s13046-018-0702-x<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC5838869\/\" target=\"_blank\">PMC5838869<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/29506529\" target=\"_blank\">29506529<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5838869\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5838869<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Tearing+Down+the+Walls%3A+FDA+Approves+Next+Generation+Sequencing+%28NGS%29+Assays+for+Actionable+Cancer+Genomic+Aberrations&rft.jtitle=Journal+of+Experimental+%26+Clinical+Cancer+Research&rft.aulast=Allegretti%2C+M.%3B+Fabi%2C+A.%3B+Buglioni%2C+S.+et+al.&rft.au=Allegretti%2C+M.%3B+Fabi%2C+A.%3B+Buglioni%2C+S.+et+al.&rft.date=2018&rft.volume=37&rft.issue=1&rft.pages=47&rft_id=info:doi\/10.1186%2Fs13046-018-0702-x&rft_id=info:pmc\/PMC5838869&rft_id=info:pmid\/29506529&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC5838869&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-GoodsaidTheLab19-13\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-GoodsaidTheLab19_13-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Goodsaid, F.M. (2019). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6742934\" target=\"_blank\">\"The Labyrinth of Product Development and Regulatory Approvals in Liquid Biopsy Diagnostics\"<\/a>. <i>Clinical and Translational Science<\/i> <b>12<\/b> (5): 431-439. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1111%2Fcts.12657\" target=\"_blank\">10.1111\/cts.12657<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6742934\/\" target=\"_blank\">PMC6742934<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/31162800\" target=\"_blank\">31162800<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6742934\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6742934<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=The+Labyrinth+of+Product+Development+and+Regulatory+Approvals+in+Liquid+Biopsy+Diagnostics&rft.jtitle=Clinical+and+Translational+Science&rft.aulast=Goodsaid%2C+F.M.&rft.au=Goodsaid%2C+F.M.&rft.date=2019&rft.volume=12&rft.issue=5&rft.pages=431-439&rft_id=info:doi\/10.1111%2Fcts.12657&rft_id=info:pmc\/PMC6742934&rft_id=info:pmid\/31162800&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC6742934&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-LiottaReg12-14\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-LiottaReg12_14-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Liotta, L.A.; Petricoin 3rd, E.F. (2012). \"Regulatory Approval Pathways for Molecular Diagnostic Technology\". <i>Methods in Molecular Biology<\/i> <b>823<\/b>: 409\u201320. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1007%2F978-1-60327-216-2_27\" target=\"_blank\">10.1007\/978-1-60327-216-2_27<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/22081361\" target=\"_blank\">22081361<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Regulatory+Approval+Pathways+for+Molecular+Diagnostic+Technology&rft.jtitle=Methods+in+Molecular+Biology&rft.aulast=Liotta%2C+L.A.%3B+Petricoin+3rd%2C+E.F.&rft.au=Liotta%2C+L.A.%3B+Petricoin+3rd%2C+E.F.&rft.date=2012&rft.volume=823&rft.pages=409%E2%80%9320&rft_id=info:doi\/10.1007%2F978-1-60327-216-2_27&rft_id=info:pmid\/22081361&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-FDAThePublic15-15\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-FDAThePublic15_15-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Food and Drug Administration (18 November 2015). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/wayback.archive-it.org\/7993\/20171114205911\/https:\/\/www.fda.gov\/AboutFDA\/ReportsManualsForms\/Reports\/ucm472773.htm\" target=\"_blank\">\"The Public Health Evidence for FDA Oversight of Laboratory Developed Tests: 20 Case Studies\"<\/a>. Food and Drug Administration. Archived from <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.fda.gov\/AboutFDA\/ReportsManualsForms\/Reports\/ucm472773.htm\" target=\"_blank\">the original<\/a> on 14 November 2017<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/wayback.archive-it.org\/7993\/20171114205911\/https:\/\/www.fda.gov\/AboutFDA\/ReportsManualsForms\/Reports\/ucm472773.htm\" target=\"_blank\">http:\/\/wayback.archive-it.org\/7993\/20171114205911\/https:\/\/www.fda.gov\/AboutFDA\/ReportsManualsForms\/Reports\/ucm472773.htm<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=The+Public+Health+Evidence+for+FDA+Oversight+of+Laboratory+Developed+Tests%3A+20+Case+Studies&rft.atitle=&rft.aulast=Food+and+Drug+Administration&rft.au=Food+and+Drug+Administration&rft.date=18+November+2015&rft.pub=Food+and+Drug+Administration&rft_id=http%3A%2F%2Fwayback.archive-it.org%2F7993%2F20171114205911%2Fhttps%3A%2F%2Fwww.fda.gov%2FAboutFDA%2FReportsManualsForms%2FReports%2Fucm472773.htm&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-AMPFacts15-16\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-AMPFacts15_16-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Association for Molecular Pathology (13 December 2015). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.amp.org\/AMP\/assets\/File\/position-statements\/2015\/AMPResponseFDACaseReportFinal.pdf?pass=58\" target=\"_blank\">\"Facts FDA Ignored: An analysis of the FDA report, \u201cThe Public Health Evidence for FDA Oversight of Laboratory Developed Tests: 20 Case Studies\u201d\"<\/a>. Association for Molecular Pathology<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.amp.org\/AMP\/assets\/File\/position-statements\/2015\/AMPResponseFDACaseReportFinal.pdf?pass=58\" target=\"_blank\">https:\/\/www.amp.org\/AMP\/assets\/File\/position-statements\/2015\/AMPResponseFDACaseReportFinal.pdf?pass=58<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 28 April 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Facts+FDA+Ignored%3A+An+analysis+of+the+FDA+report%2C+%E2%80%9CThe+Public+Health+Evidence+for+FDA+Oversight+of+Laboratory+Developed+Tests%3A+20+Case+Studies%E2%80%9D&rft.atitle=&rft.aulast=Association+for+Molecular+Pathology&rft.au=Association+for+Molecular+Pathology&rft.date=13+December+2015&rft.pub=Association+for+Molecular+Pathology&rft_id=https%3A%2F%2Fwww.amp.org%2FAMP%2Fassets%2FFile%2Fposition-statements%2F2015%2FAMPResponseFDACaseReportFinal.pdf%3Fpass%3D58&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-MakowerFDA10-17\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-MakowerFDA10_17-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Makower, J.; Meer, a.; Denend, L. (November 2010). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.advamed.org\/sites\/default\/files\/resource\/30_10_11_10_2010_Study_CAgenda_makowerreportfinal.pdf\" target=\"_blank\">\"FDA Impact on U.S. Medical Technology Innovation\"<\/a> (PDF). AdvaMed<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.advamed.org\/sites\/default\/files\/resource\/30_10_11_10_2010_Study_CAgenda_makowerreportfinal.pdf\" target=\"_blank\">https:\/\/www.advamed.org\/sites\/default\/files\/resource\/30_10_11_10_2010_Study_CAgenda_makowerreportfinal.pdf<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=FDA+Impact+on+U.S.+Medical+Technology+Innovation&rft.atitle=&rft.aulast=Makower%2C+J.%3B+Meer%2C+a.%3B+Denend%2C+L.&rft.au=Makower%2C+J.%3B+Meer%2C+a.%3B+Denend%2C+L.&rft.date=November+2010&rft.pub=AdvaMed&rft_id=https%3A%2F%2Fwww.advamed.org%2Fsites%2Fdefault%2Ffiles%2Fresource%2F30_10_11_10_2010_Study_CAgenda_makowerreportfinal.pdf&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-LynchUtil17-18\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-LynchUtil17_18-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Lynch, J.A.; Berse, B.; Dotson, W.D. et al. (2017). \"Utilization of Genetic Tests: Analysis of Gene-Specific Billing in Medicare Claims Data\". <i>Genetics in Medicine<\/i> <b>19<\/b> (8): 890\u201399. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1038%2Fgim.2016.209\" target=\"_blank\">10.1038\/gim.2016.209<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/28125086\" target=\"_blank\">28125086<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Utilization+of+Genetic+Tests%3A+Analysis+of+Gene-Specific+Billing+in+Medicare+Claims+Data&rft.jtitle=Genetics+in+Medicine&rft.aulast=Lynch%2C+J.A.%3B+Berse%2C+B.%3B+Dotson%2C+W.D.+et+al.&rft.au=Lynch%2C+J.A.%3B+Berse%2C+B.%3B+Dotson%2C+W.D.+et+al.&rft.date=2017&rft.volume=19&rft.issue=8&rft.pages=890%E2%80%9399&rft_id=info:doi\/10.1038%2Fgim.2016.209&rft_id=info:pmid\/28125086&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-PatonInstitute08-19\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-PatonInstitute08_19-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Paton, C. (2008). \"Institute of Medicine, Rewarding provider performance (aligning incentives in medicare), Washington, D.C., National Academies Press, 2007, 248 pp., ISBN\u201013: 978\u20100\u2010309\u201010216\u20102; ISBN\u201010: 0\u2010309\u201010216\u20102\". <i>The International Journal of Health Planning and Management<\/i> <b>23<\/b> (1): 83\u201384. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1002%2Fhpm.923\" target=\"_blank\">10.1002\/hpm.923<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Institute+of+Medicine%2C+Rewarding+provider+performance+%28aligning+incentives+in+medicare%29%2C+Washington%2C+D.C.%2C+National+Academies+Press%2C+2007%2C+248+pp.%2C+ISBN%E2%80%9013%3A+978%E2%80%900%E2%80%90309%E2%80%9010216%E2%80%902%3B+ISBN%E2%80%9010%3A+0%E2%80%90309%E2%80%9010216%E2%80%902&rft.jtitle=The+International+Journal+of+Health+Planning+and+Management&rft.aulast=Paton%2C+C.&rft.au=Paton%2C+C.&rft.date=2008&rft.volume=23&rft.issue=1&rft.pages=83%E2%80%9384&rft_id=info:doi\/10.1002%2Fhpm.923&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-AMPProposal15-20\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-AMPProposal15_20-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Association for Molecular Pathology (14 August 2015). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.amp.org\/AMP\/assets\/File\/advocacy\/AMPCLIAmodernizationproposalFINAL8_14_15.pdf?pass=50\" target=\"_blank\">\"Proposal for Modernization of CLIA Regulations for Laboratory Developed Testing Procedures (LDPs)\"<\/a> (PDF). Association for Molecular Pathology<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.amp.org\/AMP\/assets\/File\/advocacy\/AMPCLIAmodernizationproposalFINAL8_14_15.pdf?pass=50\" target=\"_blank\">https:\/\/www.amp.org\/AMP\/assets\/File\/advocacy\/AMPCLIAmodernizationproposalFINAL8_14_15.pdf?pass=50<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 31 August 2019<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Proposal+for+Modernization+of+CLIA+Regulations+for+Laboratory+Developed+Testing+Procedures+%28LDPs%29&rft.atitle=&rft.aulast=Association+for+Molecular+Pathology&rft.au=Association+for+Molecular+Pathology&rft.date=14+August+2015&rft.pub=Association+for+Molecular+Pathology&rft_id=https%3A%2F%2Fwww.amp.org%2FAMP%2Fassets%2FFile%2Fadvocacy%2FAMPCLIAmodernizationproposalFINAL8_14_15.pdf%3Fpass%3D50&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ChasinMedical07-21\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-ChasinMedical07_21-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Chasin, B.S.; Elliott, S.P.; Klotz, S.A. (2007). \"Medical Errors Arising From Outsourcing Laboratory and Radiology Services\". <i>American Journal of Medicine<\/i> <b>120<\/b> (9): 819.e9-11. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.amjmed.2006.07.024\" target=\"_blank\">10.1016\/j.amjmed.2006.07.024<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/17765055\" target=\"_blank\">17765055<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Medical+Errors+Arising+From+Outsourcing+Laboratory+and+Radiology+Services&rft.jtitle=American+Journal+of+Medicine&rft.aulast=Chasin%2C+B.S.%3B+Elliott%2C+S.P.%3B+Klotz%2C+S.A.&rft.au=Chasin%2C+B.S.%3B+Elliott%2C+S.P.%3B+Klotz%2C+S.A.&rft.date=2007&rft.volume=120&rft.issue=9&rft.pages=819.e9-11&rft_id=info:doi\/10.1016%2Fj.amjmed.2006.07.024&rft_id=info:pmid\/17765055&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-MrakOut18-22\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-MrakOut18_22-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Mrak, R.E.; Parslow, T.G.; Tomaszewski, J.E. (2018). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5888821\" target=\"_blank\">\"Outsourcing of Academic Clinical Laboratories: Experiences and Lessons From the Association of Pathology Chairs Laboratory Outsourcing Survey\"<\/a>. <i>Academic Pathology<\/i> <b>5<\/b>: 2374289518765435. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1177%2F2374289518765435\" target=\"_blank\">10.1177\/2374289518765435<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC5888821\/\" target=\"_blank\">PMC5888821<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/29637086\" target=\"_blank\">29637086<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5888821\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5888821<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Outsourcing+of+Academic+Clinical+Laboratories%3A+Experiences+and+Lessons+From+the+Association+of+Pathology+Chairs+Laboratory+Outsourcing+Survey&rft.jtitle=Academic+Pathology&rft.aulast=Mrak%2C+R.E.%3B+Parslow%2C+T.G.%3B+Tomaszewski%2C+J.E.&rft.au=Mrak%2C+R.E.%3B+Parslow%2C+T.G.%3B+Tomaszewski%2C+J.E.&rft.date=2018&rft.volume=5&rft.pages=2374289518765435&rft_id=info:doi\/10.1177%2F2374289518765435&rft_id=info:pmc\/PMC5888821&rft_id=info:pmid\/29637086&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC5888821&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-DucatmanTheValue20-23\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-DucatmanTheValue20_23-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Ducatman, B.S.; Ducatman, A.M.; Crawford, J.M. et al. (2020). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6961144\" target=\"_blank\">\"The Value Proposition for Pathologists: A Population Health Approach\"<\/a>. <i>Academic Pathology<\/i> <b>7<\/b>: 2374289519898857. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1177%2F2374289519898857\" target=\"_blank\">10.1177\/2374289519898857<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6961144\/\" target=\"_blank\">PMC6961144<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/31984223\" target=\"_blank\">31984223<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6961144\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6961144<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=The+Value+Proposition+for+Pathologists%3A+A+Population+Health+Approach&rft.jtitle=Academic+Pathology&rft.aulast=Ducatman%2C+B.S.%3B+Ducatman%2C+A.M.%3B+Crawford%2C+J.M.+et+al.&rft.au=Ducatman%2C+B.S.%3B+Ducatman%2C+A.M.%3B+Crawford%2C+J.M.+et+al.&rft.date=2020&rft.volume=7&rft.pages=2374289519898857&rft_id=info:doi\/10.1177%2F2374289519898857&rft_id=info:pmc\/PMC6961144&rft_id=info:pmid\/31984223&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC6961144&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-BruscoPhys18-24\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-BruscoPhys18_24-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Brusco, L.L.; Wathoo, C.; Mills Shaw, K.R. et al. (2018). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5821595\" target=\"_blank\">\"Physician Interpretation of Genomic Test Results and Treatment Selection\"<\/a>. <i>Cancer<\/i> <b>124<\/b> (5): 966-972. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1002%2Fcncr.31112\" target=\"_blank\">10.1002\/cncr.31112<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC5821595\/\" target=\"_blank\">PMC5821595<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/29165790\" target=\"_blank\">29165790<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5821595\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5821595<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Physician+Interpretation+of+Genomic+Test+Results+and+Treatment+Selection&rft.jtitle=Cancer&rft.aulast=Brusco%2C+L.L.%3B+Wathoo%2C+C.%3B+Mills+Shaw%2C+K.R.+et+al.&rft.au=Brusco%2C+L.L.%3B+Wathoo%2C+C.%3B+Mills+Shaw%2C+K.R.+et+al.&rft.date=2018&rft.volume=124&rft.issue=5&rft.pages=966-972&rft_id=info:doi\/10.1002%2Fcncr.31112&rft_id=info:pmc\/PMC5821595&rft_id=info:pmid\/29165790&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC5821595&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-XuAss16-25\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-XuAss16_25-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Xu, X.; Yang, Y.; Li, H. et al. (2016). \"Assessment of the Clinical Application of Detecting EGFR, KRAS, PIK3CA and BRAF Mutations in Patients With Non-Small Cell Lung Cancer Using Next-Generation Sequencing\". <i>Scandinavian Journal of Clinical and Laboratory Investigation<\/i> <b>76<\/b> (5): 386\u201392. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1080%2F00365513.2016.1183813\" target=\"_blank\">10.1080\/00365513.2016.1183813<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/27215271\" target=\"_blank\">27215271<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Assessment+of+the+Clinical+Application+of+Detecting+EGFR%2C+KRAS%2C+PIK3CA+and+BRAF+Mutations+in+Patients+With+Non-Small+Cell+Lung+Cancer+Using+Next-Generation+Sequencing&rft.jtitle=Scandinavian+Journal+of+Clinical+and+Laboratory+Investigation&rft.aulast=Xu%2C+X.%3B+Yang%2C+Y.%3B+Li%2C+H.+et+al.&rft.au=Xu%2C+X.%3B+Yang%2C+Y.%3B+Li%2C+H.+et+al.&rft.date=2016&rft.volume=76&rft.issue=5&rft.pages=386%E2%80%9392&rft_id=info:doi\/10.1080%2F00365513.2016.1183813&rft_id=info:pmid\/27215271&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-GaoValid16-26\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-GaoValid16_26-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Gao, J.; Wu, H.; Wang, L. et al. (2016). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4716245\" target=\"_blank\">\"Validation of Targeted Next-Generation Sequencing for RAS Mutation Detection in FFPE Colorectal Cancer Tissues: Comparison With Sanger Sequencing and ARMS-Scorpion Real-Time PCR\"<\/a>. <i>BMJ Open<\/i> <b>6<\/b> (1): e009532. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1136%2Fbmjopen-2015-009532\" target=\"_blank\">10.1136\/bmjopen-2015-009532<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC4716245\/\" target=\"_blank\">PMC4716245<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/26747035\" target=\"_blank\">26747035<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4716245\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4716245<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Validation+of+Targeted+Next-Generation+Sequencing+for+RAS+Mutation+Detection+in+FFPE+Colorectal+Cancer+Tissues%3A+Comparison+With+Sanger+Sequencing+and+ARMS-Scorpion+Real-Time+PCR&rft.jtitle=BMJ+Open&rft.aulast=Gao%2C+J.%3B+Wu%2C+H.%3B+Wang%2C+L.+et+al.&rft.au=Gao%2C+J.%3B+Wu%2C+H.%3B+Wang%2C+L.+et+al.&rft.date=2016&rft.volume=6&rft.issue=1&rft.pages=e009532&rft_id=info:doi\/10.1136%2Fbmjopen-2015-009532&rft_id=info:pmc\/PMC4716245&rft_id=info:pmid\/26747035&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC4716245&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-SimenValid15-27\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-SimenValid15_27-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Simen, B.B.; Yin, L.; Goswami, C.P. et al. (2015). \"Validation of a Next-Generation-Sequencing Cancer Panel for Use in the Clinical Laboratory\". <i>Archives of Pathology & Laboratory Medicine<\/i> <b>139<\/b> (4): 508\u201317. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.5858%2Farpa.2013-0710-OA\" target=\"_blank\">10.5858\/arpa.2013-0710-OA<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/25356985\" target=\"_blank\">25356985<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Validation+of+a+Next-Generation-Sequencing+Cancer+Panel+for+Use+in+the+Clinical+Laboratory&rft.jtitle=Archives+of+Pathology+%26+Laboratory+Medicine&rft.aulast=Simen%2C+B.B.%3B+Yin%2C+L.%3B+Goswami%2C+C.P.+et+al.&rft.au=Simen%2C+B.B.%3B+Yin%2C+L.%3B+Goswami%2C+C.P.+et+al.&rft.date=2015&rft.volume=139&rft.issue=4&rft.pages=508%E2%80%9317&rft_id=info:doi\/10.5858%2Farpa.2013-0710-OA&rft_id=info:pmid\/25356985&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-TuononenComp13-28\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-TuononenComp13_28-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Tuononen, K.; M\u00e4ki-Nevala, S.; Sarhadi, V.K. et al. (2013). \"Comparison of Targeted Next-Generation Sequencing (NGS) and Real-Time PCR in the Detection of EGFR, KRAS, and BRAF Mutations on Formalin-Fixed, Paraffin-Embedded Tumor Material of Non-Small Cell Lung Carcinoma-Superiority of NGS\". <i>Genes, Chromosomes & Cancer<\/i> <b>52<\/b> (5): 503\u201311. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1002%2Fgcc.22047\" target=\"_blank\">10.1002\/gcc.22047<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/23362162\" target=\"_blank\">23362162<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Comparison+of+Targeted+Next-Generation+Sequencing+%28NGS%29+and+Real-Time+PCR+in+the+Detection+of+EGFR%2C+KRAS%2C+and+BRAF+Mutations+on+Formalin-Fixed%2C+Paraffin-Embedded+Tumor+Material+of+Non-Small+Cell+Lung+Carcinoma-Superiority+of+NGS&rft.jtitle=Genes%2C+Chromosomes+%26+Cancer&rft.aulast=Tuononen%2C+K.%3B+M%C3%A4ki-Nevala%2C+S.%3B+Sarhadi%2C+V.K.+et+al.&rft.au=Tuononen%2C+K.%3B+M%C3%A4ki-Nevala%2C+S.%3B+Sarhadi%2C+V.K.+et+al.&rft.date=2013&rft.volume=52&rft.issue=5&rft.pages=503%E2%80%9311&rft_id=info:doi\/10.1002%2Fgcc.22047&rft_id=info:pmid\/23362162&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-Lopez-RiosComp13-29\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-Lopez-RiosComp13_29-0\">29.0<\/a><\/sup> <sup><a href=\"#cite_ref-Lopez-RiosComp13_29-1\">29.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Lopez-Rios, F.; Angulo, B.; Gomez, B. et al. (2013). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3542342\" target=\"_blank\">\"Comparison of Testing Methods for the Detection of BRAF V600E Mutations in Malignant Melanoma: Pre-Approval Validation Study of the Companion Diagnostic Test for Vemurafenib\"<\/a>. <i>PLoS One<\/i> <b>8<\/b> (1): e53733. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1371%2Fjournal.pone.0053733\" target=\"_blank\">10.1371\/journal.pone.0053733<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC3542342\/\" target=\"_blank\">PMC3542342<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/23326492\" target=\"_blank\">23326492<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3542342\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3542342<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Comparison+of+Testing+Methods+for+the+Detection+of+BRAF+V600E+Mutations+in+Malignant+Melanoma%3A+Pre-Approval+Validation+Study+of+the+Companion+Diagnostic+Test+for+Vemurafenib&rft.jtitle=PLoS+One&rft.aulast=Lopez-Rios%2C+F.%3B+Angulo%2C+B.%3B+Gomez%2C+B.+et+al.&rft.au=Lopez-Rios%2C+F.%3B+Angulo%2C+B.%3B+Gomez%2C+B.+et+al.&rft.date=2013&rft.volume=8&rft.issue=1&rft.pages=e53733&rft_id=info:doi\/10.1371%2Fjournal.pone.0053733&rft_id=info:pmc\/PMC3542342&rft_id=info:pmid\/23326492&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC3542342&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-KothariComp14-30\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-KothariComp14_30-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Kothari, N.; Schell, M.J.; Teer, J.K. et al. (2014). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4743643\" target=\"_blank\">\"Comparison of KRAS mutation analysis of colorectal cancer samples by standard testing and next-generation sequencing\"<\/a>. <i>Journal of Clinical Pathology<\/i> <b>67<\/b> (9): 764\u20137. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1136%2Fjclinpath-2014-202405\" target=\"_blank\">10.1136\/jclinpath-2014-202405<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC4743643\/\" target=\"_blank\">PMC4743643<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/25004944\" target=\"_blank\">25004944<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4743643\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4743643<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Comparison+of+KRAS+mutation+analysis+of+colorectal+cancer+samples+by+standard+testing+and+next-generation+sequencing&rft.jtitle=Journal+of+Clinical+Pathology&rft.aulast=Kothari%2C+N.%3B+Schell%2C+M.J.%3B+Teer%2C+J.K.+et+al.&rft.au=Kothari%2C+N.%3B+Schell%2C+M.J.%3B+Teer%2C+J.K.+et+al.&rft.date=2014&rft.volume=67&rft.issue=9&rft.pages=764%E2%80%937&rft_id=info:doi\/10.1136%2Fjclinpath-2014-202405&rft_id=info:pmc\/PMC4743643&rft_id=info:pmid\/25004944&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC4743643&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-KeppensDetect18-31\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-KeppensDetect18_31-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Keppens, C.; Palma, J.F.; Das, P.M. et al. (2018). \"Detection of EGFR Variants in Plasma: A Multilaboratory Comparison of a Real-Time PCR EGFR Mutation Test in Europe\". <i>Journal of Molecular Diagnostics<\/i> <b>20<\/b> (4): 483\u201394. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.jmoldx.2018.03.006\" target=\"_blank\">10.1016\/j.jmoldx.2018.03.006<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/29704571\" target=\"_blank\">29704571<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Detection+of+EGFR+Variants+in+Plasma%3A+A+Multilaboratory+Comparison+of+a+Real-Time+PCR+EGFR+Mutation+Test+in+Europe&rft.jtitle=Journal+of+Molecular+Diagnostics&rft.aulast=Keppens%2C+C.%3B+Palma%2C+J.F.%3B+Das%2C+P.M.+et+al.&rft.au=Keppens%2C+C.%3B+Palma%2C+J.F.%3B+Das%2C+P.M.+et+al.&rft.date=2018&rft.volume=20&rft.issue=4&rft.pages=483%E2%80%9394&rft_id=info:doi\/10.1016%2Fj.jmoldx.2018.03.006&rft_id=info:pmid\/29704571&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-TorgaPatient18-32\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-TorgaPatient18_32-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Torga, G.; Pienta, K.J. (2018). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6145681\" target=\"_blank\">\"Patient-Paired Sample Congruence Between 2 Commercial Liquid Biopsy Tests\"<\/a>. <i>JAMA Oncology<\/i> <b>4<\/b> (6): 868-870. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1001%2Fjamaoncol.2017.4027\" target=\"_blank\">10.1001\/jamaoncol.2017.4027<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6145681\/\" target=\"_blank\">PMC6145681<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/29242909\" target=\"_blank\">29242909<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6145681\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6145681<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Patient-Paired+Sample+Congruence+Between+2+Commercial+Liquid+Biopsy+Tests&rft.jtitle=JAMA+Oncology&rft.aulast=Torga%2C+G.%3B+Pienta%2C+K.J.&rft.au=Torga%2C+G.%3B+Pienta%2C+K.J.&rft.date=2018&rft.volume=4&rft.issue=6&rft.pages=868-870&rft_id=info:doi\/10.1001%2Fjamaoncol.2017.4027&rft_id=info:pmc\/PMC6145681&rft_id=info:pmid\/29242909&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC6145681&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-SchweizerClinical19-33\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-SchweizerClinical19_33-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Schweizer, M.T.; Gulati, R.; Beightol, M. et al. (2019). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6589085\" target=\"_blank\">\"Clinical Determinants for Successful Circulating Tumor DNA Analysis in Prostate Cancer\"<\/a>. <i>Prostate<\/i> <b>79<\/b> (7): 701-708. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1002%2Fpros.23778\" target=\"_blank\">10.1002\/pros.23778<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6589085\/\" target=\"_blank\">PMC6589085<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/30865311\" target=\"_blank\">30865311<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6589085\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6589085<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Clinical+Determinants+for+Successful+Circulating+Tumor+DNA+Analysis+in+Prostate+Cancer&rft.jtitle=Prostate&rft.aulast=Schweizer%2C+M.T.%3B+Gulati%2C+R.%3B+Beightol%2C+M.+et+al.&rft.au=Schweizer%2C+M.T.%3B+Gulati%2C+R.%3B+Beightol%2C+M.+et+al.&rft.date=2019&rft.volume=79&rft.issue=7&rft.pages=701-708&rft_id=info:doi\/10.1002%2Fpros.23778&rft_id=info:pmc\/PMC6589085&rft_id=info:pmid\/30865311&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC6589085&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-PoirotMET17-34\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-PoirotMET17_34-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Poirot, B.; Doucet, L.; Benhenda, S. et al. (2017). \"MET Exon 14 Alterations and New Resistance Mutations to Tyrosine Kinase Inhibitors: Risk of Inadequate Detection With Current Amplicon-Based NGS Panels\". <i>Journal of Thoracic Oncology<\/i> <b>12<\/b> (10): 1582\u201387. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.jtho.2017.07.026\" target=\"_blank\">10.1016\/j.jtho.2017.07.026<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/28779874\" target=\"_blank\">28779874<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=MET+Exon+14+Alterations+and+New+Resistance+Mutations+to+Tyrosine+Kinase+Inhibitors%3A+Risk+of+Inadequate+Detection+With+Current+Amplicon-Based+NGS+Panels&rft.jtitle=Journal+of+Thoracic+Oncology&rft.aulast=Poirot%2C+B.%3B+Doucet%2C+L.%3B+Benhenda%2C+S.+et+al.&rft.au=Poirot%2C+B.%3B+Doucet%2C+L.%3B+Benhenda%2C+S.+et+al.&rft.date=2017&rft.volume=12&rft.issue=10&rft.pages=1582%E2%80%9387&rft_id=info:doi\/10.1016%2Fj.jtho.2017.07.026&rft_id=info:pmid\/28779874&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-RosenbaumGenomic18-35\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-RosenbaumGenomic18_35-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Rosenbaum, J.N.; Bloom, R.; Forys, J.T. et al. (2018). \"Genomic Heterogeneity of ALK Fusion Breakpoints in Non-Small-Cell Lung Cancer\". <i>Modern Pathology<\/i> <b>31<\/b> (5): 791\u2013808. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.jtho.2018.12.020\" target=\"_blank\">10.1016\/j.jtho.2018.12.020<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/29327716\" target=\"_blank\">29327716<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Genomic+Heterogeneity+of+ALK+Fusion+Breakpoints+in+Non-Small-Cell+Lung+Cancer&rft.jtitle=Modern+Pathology&rft.aulast=Rosenbaum%2C+J.N.%3B+Bloom%2C+R.%3B+Forys%2C+J.T.+et+al.&rft.au=Rosenbaum%2C+J.N.%3B+Bloom%2C+R.%3B+Forys%2C+J.T.+et+al.&rft.date=2018&rft.volume=31&rft.issue=5&rft.pages=791%E2%80%93808&rft_id=info:doi\/10.1016%2Fj.jtho.2018.12.020&rft_id=info:pmid\/29327716&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-DaviesDNA19-36\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-DaviesDNA19_36-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Davies, K.D.; Lomboy, A.; Lawrence, C.A. et al. (2019). \"DNA-Based Versus RNA-Based Detection of MET Exon 14 Skipping Events in Lung Cancer\". <i>Journal of Thoracic Oncology<\/i> <b>14<\/b> (4): 737\u201341. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1038%2Fmodpathol.2017.181\" target=\"_blank\">10.1038\/modpathol.2017.181<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/30639620\" target=\"_blank\">30639620<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=DNA-Based+Versus+RNA-Based+Detection+of+MET+Exon+14+Skipping+Events+in+Lung+Cancer&rft.jtitle=Journal+of+Thoracic+Oncology&rft.aulast=Davies%2C+K.D.%3B+Lomboy%2C+A.%3B+Lawrence%2C+C.A.+et+al.&rft.au=Davies%2C+K.D.%3B+Lomboy%2C+A.%3B+Lawrence%2C+C.A.+et+al.&rft.date=2019&rft.volume=14&rft.issue=4&rft.pages=737%E2%80%9341&rft_id=info:doi\/10.1038%2Fmodpathol.2017.181&rft_id=info:pmid\/30639620&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-HamlinProfic92-37\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-HamlinProfic92_37-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Hamlin, W. (1992). \"Proficiency Testing as a Regulatory Device: A CAP Perspective\". <i>Clinical Chemistry<\/i> <b>38<\/b> (7): 1234\u20136. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/1623587\" target=\"_blank\">1623587<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Proficiency+Testing+as+a+Regulatory+Device%3A+A+CAP+Perspective&rft.jtitle=Clinical+Chemistry&rft.aulast=Hamlin%2C+W.&rft.au=Hamlin%2C+W.&rft.date=1992&rft.volume=38&rft.issue=7&rft.pages=1234%E2%80%936&rft_id=info:pmid\/1623587&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-EndrullatStand16-38\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-EndrullatStand16_38-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Endrullat, C.; Gl\u00f6kler, J.; Franke, P. et al. (2016). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5025460\" target=\"_blank\">\"Standardization and Quality Management in Next-Generation Sequencing\"<\/a>. <i>Applied and Translational Genomics<\/i> <b>10<\/b>: 2\u20139. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.atg.2016.06.001\" target=\"_blank\">10.1016\/j.atg.2016.06.001<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC5025460\/\" target=\"_blank\">PMC5025460<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/27668169\" target=\"_blank\">27668169<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5025460\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5025460<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Standardization+and+Quality+Management+in+Next-Generation+Sequencing&rft.jtitle=Applied+and+Translational+Genomics&rft.aulast=Endrullat%2C+C.%3B+Gl%C3%B6kler%2C+J.%3B+Franke%2C+P.+et+al.&rft.au=Endrullat%2C+C.%3B+Gl%C3%B6kler%2C+J.%3B+Franke%2C+P.+et+al.&rft.date=2016&rft.volume=10&rft.pages=2%E2%80%939&rft_id=info:doi\/10.1016%2Fj.atg.2016.06.001&rft_id=info:pmc\/PMC5025460&rft_id=info:pmid\/27668169&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC5025460&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-WolffHuman18-39\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-WolffHuman18_39-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Wolff, A.C.; Hammond, M.E.H.; Allison, K.H. et al. (2018). \"Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology\/College of American Pathologists Clinical Practice Guideline Focused Update\". <i>Archives of Pathology & Laboratory Medicine<\/i> <b>142<\/b> (11): 1364-1382. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.5858%2Farpa.2018-0902-SA\" target=\"_blank\">10.5858\/arpa.2018-0902-SA<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/29846104\" target=\"_blank\">29846104<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Human+Epidermal+Growth+Factor+Receptor+2+Testing+in+Breast+Cancer%3A+American+Society+of+Clinical+Oncology%2FCollege+of+American+Pathologists+Clinical+Practice+Guideline+Focused+Update&rft.jtitle=Archives+of+Pathology+%26+Laboratory+Medicine&rft.aulast=Wolff%2C+A.C.%3B+Hammond%2C+M.E.H.%3B+Allison%2C+K.H.+et+al.&rft.au=Wolff%2C+A.C.%3B+Hammond%2C+M.E.H.%3B+Allison%2C+K.H.+et+al.&rft.date=2018&rft.volume=142&rft.issue=11&rft.pages=1364-1382&rft_id=info:doi\/10.5858%2Farpa.2018-0902-SA&rft_id=info:pmid\/29846104&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-KimComp18-40\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-KimComp18_40-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Kim, A.S.; Bartley, A.N.; Bridge, J.A. et al. (2018). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6145687\" target=\"_blank\">\"Comparison of Laboratory-Developed Tests and FDA-Approved Assays for BRAF, EGFR, and KRAS Testing\"<\/a>. <i>JAMA Oncology<\/i> <b>4<\/b> (6): 838-841. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1001%2Fjamaoncol.2017.4021\" target=\"_blank\">10.1001\/jamaoncol.2017.4021<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6145687\/\" target=\"_blank\">PMC6145687<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/29242895\" target=\"_blank\">29242895<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6145687\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6145687<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Comparison+of+Laboratory-Developed+Tests+and+FDA-Approved+Assays+for+BRAF%2C+EGFR%2C+and+KRAS+Testing&rft.jtitle=JAMA+Oncology&rft.aulast=Kim%2C+A.S.%3B+Bartley%2C+A.N.%3B+Bridge%2C+J.A.+et+al.&rft.au=Kim%2C+A.S.%3B+Bartley%2C+A.N.%3B+Bridge%2C+J.A.+et+al.&rft.date=2018&rft.volume=4&rft.issue=6&rft.pages=838-841&rft_id=info:doi\/10.1001%2Fjamaoncol.2017.4021&rft_id=info:pmc\/PMC6145687&rft_id=info:pmid\/29242895&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC6145687&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-MerkerProf19-41\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-MerkerProf19_41-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Merker, J.D.; Devereaux, K.; Iafrate, A.J. et al. (2019). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6910717\" target=\"_blank\">\"Proficiency Testing of Standardized Samples Shows Very High Interlaboratory Agreement for Clinical Next-Generation Sequencing-Based Oncology Assays\"<\/a>. <i>Archives of Pathology & Laboratory Medicine<\/i> <b>143<\/b> (4): 463-471. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.5858%2Farpa.2018-0336-CP\" target=\"_blank\">10.5858\/arpa.2018-0336-CP<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6910717\/\" target=\"_blank\">PMC6910717<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/30376374\" target=\"_blank\">30376374<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6910717\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6910717<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Proficiency+Testing+of+Standardized+Samples+Shows+Very+High+Interlaboratory+Agreement+for+Clinical+Next-Generation+Sequencing-Based+Oncology+Assays&rft.jtitle=Archives+of+Pathology+%26+Laboratory+Medicine&rft.aulast=Merker%2C+J.D.%3B+Devereaux%2C+K.%3B+Iafrate%2C+A.J.+et+al.&rft.au=Merker%2C+J.D.%3B+Devereaux%2C+K.%3B+Iafrate%2C+A.J.+et+al.&rft.date=2019&rft.volume=143&rft.issue=4&rft.pages=463-471&rft_id=info:doi\/10.5858%2Farpa.2018-0336-CP&rft_id=info:pmc\/PMC6910717&rft_id=info:pmid\/30376374&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC6910717&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-SurreyNext19-42\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-SurreyNext19_42-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Surrey L.F.; Oakley, F.D.; Merker, J.D. et al. (2019). \"Next-Generation Sequencing (NGS) Methods Show Superior or Equivalent Performance to Non-NGS Methods on BRAF, EGFR, and KRAS Proficiency Testing Samples\". <i>Archives of Pathology & Laboratory Medicine<\/i> <b>143<\/b> (8): 980-984. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.5858%2Farpa.2018-0394-CP\" target=\"_blank\">10.5858\/arpa.2018-0394-CP<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/30865489\" target=\"_blank\">30865489<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Next-Generation+Sequencing+%28NGS%29+Methods+Show+Superior+or+Equivalent+Performance+to+Non-NGS+Methods+on+BRAF%2C+EGFR%2C+and+KRAS+Proficiency+Testing+Samples&rft.jtitle=Archives+of+Pathology+%26+Laboratory+Medicine&rft.aulast=Surrey+L.F.%3B+Oakley%2C+F.D.%3B+Merker%2C+J.D.+et+al.&rft.au=Surrey+L.F.%3B+Oakley%2C+F.D.%3B+Merker%2C+J.D.+et+al.&rft.date=2019&rft.volume=143&rft.issue=8&rft.pages=980-984&rft_id=info:doi\/10.5858%2Farpa.2018-0394-CP&rft_id=info:pmid\/30865489&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-MoncurPerform19-43\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-MoncurPerform19_43-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Moncur, J.T.; Bartley, A.N.; Bridge, J.A. et al. (2019). \"Performance comparison of different analytic methods in proficiency testing for mutations in the BRAF, EGFR, and KRAS genes: A study of the College of American pathologists molecular oncology committee\". <i>Archives of Pathology & Laboratory Medicine<\/i> <b>143<\/b> (10): 1203\u201311. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.5858%2Farpa.2018-0396-CP\" target=\"_blank\">10.5858\/arpa.2018-0396-CP<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/30969158\" target=\"_blank\">30969158<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Performance+comparison+of+different+analytic+methods+in+proficiency+testing+for+mutations+in+the+BRAF%2C+EGFR%2C+and+KRAS+genes%3A+A+study+of+the+College+of+American+pathologists+molecular+oncology+committee&rft.jtitle=Archives+of+Pathology+%26+Laboratory+Medicine&rft.aulast=Moncur%2C+J.T.%3B+Bartley%2C+A.N.%3B+Bridge%2C+J.A.+et+al.&rft.au=Moncur%2C+J.T.%3B+Bartley%2C+A.N.%3B+Bridge%2C+J.A.+et+al.&rft.date=2019&rft.volume=143&rft.issue=10&rft.pages=1203%E2%80%9311&rft_id=info:doi\/10.5858%2Farpa.2018-0396-CP&rft_id=info:pmid\/30969158&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-KeeganProf20-44\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-KeeganProf20_44-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Keegan, A.; Bridge, J.A.; Lindeman, N.I. et al. (2020). \"Proficiency Testing of Standardized Samples Shows High Interlaboratory Agreement for Clinical Next Generation Sequencing-Based Hematologic Malignancy Assays With Survey Material-Specific Differences in Variant Frequencies\". <i>Archives of Pathology & Laboratory Medicine<\/i>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.5858%2Farpa.2019-0352-CP\" target=\"_blank\">10.5858\/arpa.2019-0352-CP<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/31986076\" target=\"_blank\">31986076<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Proficiency+Testing+of+Standardized+Samples+Shows+High+Interlaboratory+Agreement+for+Clinical+Next+Generation+Sequencing-Based+Hematologic+Malignancy+Assays+With+Survey+Material-Specific+Differences+in+Variant+Frequencies&rft.jtitle=Archives+of+Pathology+%26+Laboratory+Medicine&rft.aulast=Keegan%2C+A.%3B+Bridge%2C+J.A.%3B+Lindeman%2C+N.I.+et+al.&rft.au=Keegan%2C+A.%3B+Bridge%2C+J.A.%3B+Lindeman%2C+N.I.+et+al.&rft.date=2020&rft_id=info:doi\/10.5858%2Farpa.2019-0352-CP&rft_id=info:pmid\/31986076&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-DuncavageAMod16-45\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-DuncavageAMod16_45-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Duncavage, E.J.; Abel, H.J.; Merker, J.D. et al. (2016). \"A Model Study of In Silico Proficiency Testing for Clinical Next-Generation Sequencing\". <i>Archives of Pathology & Laboratory Medicine<\/i>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.5858%2Farpa.2016-0194-CP\" target=\"_blank\">10.5858\/arpa.2016-0194-CP<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/27388684\" target=\"_blank\">27388684<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=A+Model+Study+of+In+Silico+Proficiency+Testing+for+Clinical+Next-Generation+Sequencing&rft.jtitle=Archives+of+Pathology+%26+Laboratory+Medicine&rft.aulast=Duncavage%2C+E.J.%3B+Abel%2C+H.J.%3B+Merker%2C+J.D.+et+al.&rft.au=Duncavage%2C+E.J.%3B+Abel%2C+H.J.%3B+Merker%2C+J.D.+et+al.&rft.date=2016&rft_id=info:doi\/10.5858%2Farpa.2016-0194-CP&rft_id=info:pmid\/27388684&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-SharfsteinDiag20-46\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-SharfsteinDiag20_46-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Sharfstein, J.M.; Becker, S.J.; Mello, M.M. (2020). \"Diagnostic Testing for the Novel Coronavirus\". <i>JAMA<\/i> <b>323<\/b> (15): 1437\u201338. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1001%2Fjama.2020.3864\" target=\"_blank\">10.1001\/jama.2020.3864<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/32150622\" target=\"_blank\">32150622<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Diagnostic+Testing+for+the+Novel+Coronavirus&rft.jtitle=JAMA&rft.aulast=Sharfstein%2C+J.M.%3B+Becker%2C+S.J.%3B+Mello%2C+M.M.&rft.au=Sharfstein%2C+J.M.%3B+Becker%2C+S.J.%3B+Mello%2C+M.M.&rft.date=2020&rft.volume=323&rft.issue=15&rft.pages=1437%E2%80%9338&rft_id=info:doi\/10.1001%2Fjama.2020.3864&rft_id=info:pmid\/32150622&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-CraigASomatic16-47\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-CraigASomatic16_47-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Craig, D.W.; Nasser, S.; Corbett, R. et al. (2016). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4837349\" target=\"_blank\">\"A Somatic Reference Standard for Cancer Genome Sequencing\"<\/a>. <i>Scientific Reports<\/i>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1038%2Fsrep24607\" target=\"_blank\">10.1038\/srep24607<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC4837349\/\" target=\"_blank\">PMC4837349<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/27094764\" target=\"_blank\">27094764<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4837349\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4837349<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=A+Somatic+Reference+Standard+for+Cancer+Genome+Sequencing&rft.jtitle=Scientific+Reports&rft.aulast=Craig%2C+D.W.%3B+Nasser%2C+S.%3B+Corbett%2C+R.+et+al.&rft.au=Craig%2C+D.W.%3B+Nasser%2C+S.%3B+Corbett%2C+R.+et+al.&rft.date=2016&rft_id=info:doi\/10.1038%2Fsrep24607&rft_id=info:pmc\/PMC4837349&rft_id=info:pmid\/27094764&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC4837349&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ZookExtensive16-48\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-ZookExtensive16_48-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Zook, J.M.; Catoe, D.; McDaniel, J. et al. (2016). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4896128\" target=\"_blank\">\"Extensive Sequencing of Seven Human Genomes to Characterize Benchmark Reference Materials\"<\/a>. <i>Scientific Data<\/i> <b>3<\/b>: 160025. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1038%2Fsdata.2016.25\" target=\"_blank\">10.1038\/sdata.2016.25<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC4896128\/\" target=\"_blank\">PMC4896128<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/27271295\" target=\"_blank\">27271295<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4896128\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4896128<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Extensive+Sequencing+of+Seven+Human+Genomes+to+Characterize+Benchmark+Reference+Materials&rft.jtitle=Scientific+Data&rft.aulast=Zook%2C+J.M.%3B+Catoe%2C+D.%3B+McDaniel%2C+J.+et+al.&rft.au=Zook%2C+J.M.%3B+Catoe%2C+D.%3B+McDaniel%2C+J.+et+al.&rft.date=2016&rft.volume=3&rft.pages=160025&rft_id=info:doi\/10.1038%2Fsdata.2016.25&rft_id=info:pmc\/PMC4896128&rft_id=info:pmid\/27271295&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC4896128&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-Marchi.C3.B2ESMO19-49\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-Marchi.C3.B2ESMO19_49-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Marchi\u00f2, C.; Scaltriti, M.; Ladanyi, M. et al. (2019). \"ESMO Recommendations on the Standard Methods to Detect NTRK Fusions in Daily Practice and Clinical Research\". <i>Annals of Oncology<\/i> <b>30<\/b> (9): 1417\u20131427. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1093%2Fannonc%2Fmdz204\" target=\"_blank\">10.1093\/annonc\/mdz204<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/31268127\" target=\"_blank\">31268127<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=ESMO+Recommendations+on+the+Standard+Methods+to+Detect+NTRK+Fusions+in+Daily+Practice+and+Clinical+Research&rft.jtitle=Annals+of+Oncology&rft.aulast=Marchi%C3%B2%2C+C.%3B+Scaltriti%2C+M.%3B+Ladanyi%2C+M.+et+al.&rft.au=Marchi%C3%B2%2C+C.%3B+Scaltriti%2C+M.%3B+Ladanyi%2C+M.+et+al.&rft.date=2019&rft.volume=30&rft.issue=9&rft.pages=1417%E2%80%931427&rft_id=info:doi\/10.1093%2Fannonc%2Fmdz204&rft_id=info:pmid\/31268127&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-Penault-LlorcaTesting19-50\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-Penault-LlorcaTesting19_50-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Penault-Llorca, F.; Rudzinkski, E.R.; Sepulveda, A.R. (2019). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6589488\" target=\"_blank\">\"Testing Algorithm for Identification of Patients With TRK Fusion Cancer\"<\/a>. <i>Journal of Clinical Pathology<\/i> <b>72<\/b> (7): 460\u201367. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1136%2Fjclinpath-2018-205679\" target=\"_blank\">10.1136\/jclinpath-2018-205679<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6589488\/\" target=\"_blank\">PMC6589488<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/31072837\" target=\"_blank\">31072837<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6589488\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6589488<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Testing+Algorithm+for+Identification+of+Patients+With+TRK+Fusion+Cancer&rft.jtitle=Journal+of+Clinical+Pathology&rft.aulast=Penault-Llorca%2C+F.%3B+Rudzinkski%2C+E.R.%3B+Sepulveda%2C+A.R.&rft.au=Penault-Llorca%2C+F.%3B+Rudzinkski%2C+E.R.%3B+Sepulveda%2C+A.R.&rft.date=2019&rft.volume=72&rft.issue=7&rft.pages=460%E2%80%9367&rft_id=info:doi\/10.1136%2Fjclinpath-2018-205679&rft_id=info:pmc\/PMC6589488&rft_id=info:pmid\/31072837&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC6589488&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-SolomonNTRK20-51\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-SolomonNTRK20_51-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Solomon, J.P.; Linkov, I.; Rosado, A. et al. (2020). \"NTRK Fusion Detection Across Multiple Assays and 33,997 Cases: Diagnostic Implications and Pitfalls\". <i>Modern Pathology<\/i> <b>33<\/b> (1): 38\u201346. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1038%2Fs41379-019-0324-7\" target=\"_blank\">10.1038\/s41379-019-0324-7<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/31375766\" target=\"_blank\">31375766<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=NTRK+Fusion+Detection+Across+Multiple+Assays+and+33%2C997+Cases%3A+Diagnostic+Implications+and+Pitfalls&rft.jtitle=Modern+Pathology&rft.aulast=Solomon%2C+J.P.%3B+Linkov%2C+I.%3B+Rosado%2C+A.+et+al.&rft.au=Solomon%2C+J.P.%3B+Linkov%2C+I.%3B+Rosado%2C+A.+et+al.&rft.date=2020&rft.volume=33&rft.issue=1&rft.pages=38%E2%80%9346&rft_id=info:doi\/10.1038%2Fs41379-019-0324-7&rft_id=info:pmid\/31375766&rfr_id=info:sid\/en.wikipedia.org:Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<\/ol><\/div>\n<h2><span class=\"mw-headline\" id=\"Notes\">Notes<\/span><\/h2>\n<p>This presentation is faithful to the original, with only a few minor changes to presentation. Some grammar and punctuation was cleaned up to improve readability. The original article appears to accidentally duplicate citation #8 for citation #7; what is believed to have been the intended citation has been substituted for citation #7 in this version. Several of the original article's citations are completely out of order or nonsensical. For example, the original citations #9 and #10 in no way verify the statement about the VALID Act and were removed for this version. In fact, original citation #10 should have been original citation #13 (used here), and it's not clear where original citation #13 was intended to go (omitted here). Otherwise, in accordance with the NoDerivatives portion of the original license, nothing else has been changed.\n<\/p>\n<!-- \nNewPP limit report\nCached time: 20200707205104\nCache expiry: 86400\nDynamic content: false\nCPU time usage: 0.812 seconds\nReal time usage: 0.833 seconds\nPreprocessor visited node count: 39347\/1000000\nPreprocessor generated node count: 37880\/1000000\nPost\u2010expand include size: 360880\/2097152 bytes\nTemplate argument size: 120880\/2097152 bytes\nHighest expansion depth: 18\/40\nExpensive parser function count: 0\/100\n-->\n\n<!-- \nTransclusion expansion time report (%,ms,calls,template)\n100.00% 791.373 1 - -total\n 90.65% 717.388 1 - Template:Reflist\n 77.35% 612.157 51 - Template:Citation\/core\n 63.59% 503.270 38 - Template:Cite_journal\n 17.01% 134.630 13 - Template:Cite_web\n 10.01% 79.181 90 - Template:Citation\/identifier\n 4.80% 37.993 1 - Template:Infobox_journal_article\n 4.58% 36.215 1 - Template:Infobox\n 4.17% 32.964 55 - Template:Citation\/make_link\n 3.63% 28.731 196 - Template:Hide_in_print\n-->\n\n<!-- Saved in parser cache with key limswiki:pcache:idhash:12001-0!*!0!!en!*!* and timestamp 20200707205103 and revision id 39668\n -->\n<\/div><div class=\"printfooter\">Source: <a rel=\"external_link\" class=\"external\" href=\"https:\/\/www.limswiki.org\/index.php\/Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation\">https:\/\/www.limswiki.org\/index.php\/Journal:The_regulatory_landscape_of_precision_oncology_laboratory_medicine_in_the_United_States:_Perspective_on_the_past_five_years_and_considerations_for_future_regulation<\/a><\/div>\n\t\t\t\t\t\t\t\t\t\t<!-- end content -->\n\t\t\t\t\t\t\t\t\t\t<div class=\"visualClear\"><\/div>\n\t\t\t\t<\/div>\n\t\t\t<\/div>\n\t\t<\/div>\n\t\t<!-- end of the left (by default at least) column -->\n\t\t<div class=\"visualClear\"><\/div>\n\t\t\t\t\t\n\t\t<\/div>\n\t\t\n\n<\/body>","d97817f5ad624daefeddef56fcde6d94_images":[],"d97817f5ad624daefeddef56fcde6d94_timestamp":1594155063,"bf4e9afee9a0f426bf85b45d063f9b47_type":"article","bf4e9afee9a0f426bf85b45d063f9b47_title":"Enzyme immunoassay for measuring aflatoxin B1 in legal cannabis (Di Nardo et al. 2020)","bf4e9afee9a0f426bf85b45d063f9b47_url":"https:\/\/www.limswiki.org\/index.php\/Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis","bf4e9afee9a0f426bf85b45d063f9b47_plaintext":"\n\n\t\t\n\t\t\t\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t\n\n\t\t\t\tJournal:Enzyme immunoassay for measuring aflatoxin B1 in legal cannabis\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t\tFrom LIMSWiki\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\tJump to: navigation, search\n\n\t\t\t\t\t\n\t\t\t\t\tFull article title\n \nEnzyme immunoassay for measuring aflatoxin B1 in legal cannabisJournal\n \nToxinsAuthor(s)\n \nDi Nardo, Fabio; Cavalera, Simone; Baggiani, Claudio; Ciarello, Matteo; Pazzi, Marco; Anfossi, LauraAuthor affiliation(s)\n \nUniversity of TurinPrimary contact\n \nEmail: laura dot anfossi at unito dot itYear published\n \n2020Volume and issue\n \n12(4)Article #\n \n265DOI\n \n10.3390\/toxins12040265ISSN\n \n2072-6651Distribution license\n \nCreative Commons Attribution 4.0 InternationalWebsite\n \nhttps:\/\/www.mdpi.com\/2072-6651\/12\/4\/265\/htmDownload\n \nhttps:\/\/www.mdpi.com\/2072-6651\/12\/4\/265\/pdf (PDF)\n\nContents\n\n1 Abstract \n2 Introduction \n3 Results \n\n3.1 Enzyme immunoassay adaptation to AFB1 detection in cannabis products \n3.2 Analytical figures of merits of the enzyme immunoassay \n3.3 Measuring AFB1 in cannabis products by the enzyme immunoassay \n3.4 Determination of AFB1 in cannabis products using high-performance liquid chromatography\u2013tandem mass spectrometry (HPLC\u2013MS\/MS) \n3.5 Method comparison: Enzyme immunoassay and HPLC-MS\/MS \n\n\n4 Discussion \n5 Materials and methods \n\n5.1 Reagents and apparatus \n5.2 Competitive direct ELISA \n5.3 Cross-reactivity study \n5.4 Samples and sample preparation \n5.5 Determination of AFB1 using HPLC\u2013MS\/MS \n\n\n6 Supplementary materials \n7 Acknowledgements \n\n7.1 Author contributions \n7.2 Funding \n7.3 Conflicts of interest \n\n\n8 References \n9 Notes \n\n\n\nAbstract \nThe diffusion of the legalization of cannabis for recreational, medicinal, and nutraceutical uses requires the development of adequate analytical methods to assure the safety and security of such products. In particular, aflatoxins are considered to pose a major risk for the health of cannabis consumers. Among analytical methods that allow for adequate monitoring of food safety, immunoassays play a major role thanks to their cost-effectiveness, high-throughput capacity, simplicity, and limited requirement for equipment and skilled operators. Therefore, a rapid and sensitive enzyme immunoassay has been adapted to measure the most hazardous aflatoxin B1 in cannabis products. The assay was acceptably accurate (recovery rate: 78\u2013136%), reproducible (intra- and inter-assay means coefficients of variation 11.8% and 13.8%, respectively), and sensitive (limit of detection and range of quantification: 0.35 ng mL\u22121 and 0.4\u20132 ng mL\u22121, respectively corresponding to 7 ng g\u22121 and 8\u201340 ng g\u22121 in the plant), while providing results which agreed with a high-performance liquid chromatography\u2013tandem mass spectrometry (HPLC-MS\/MS) method for the direct analysis of aflatoxin B1 in cannabis inflorescence and leaves. In addition, the carcinogenic aflatoxin B1 was detected in 50% of the cannabis products analyzed (14 samples collected from small retails) at levels exceeding those admitted by the European Union in commodities intended for direct human consumption, thus envisaging the need for effective surveillance of aflatoxin contamination in legal cannabis.\nKeywords: mycotoxins, food safety, medicinal herbs, competitive immunoassay\n\nIntroduction \nCannabis sativa is a plant of the Cannabaceae family and is well-known for its content of biologically active chemical compounds, among which are the major compounds \u03949-tetrahydrocannabinol (\u03949-THC) and cannabidiol (CBD). The flowering or fruiting tops of the Cannabis plant have been controlled in the United States under the Controlled Substances Act since 1970 under the drug class \u201cMarihuana.\u201d[1]\nCannabis products can be used for medicinal purposes (whether using the psychoactive constituent THC or the non-psychoactive constituent CBD, generally referred to as \"medical cannabis\"), in manufacturing (\"industrial hemp\"), and for non-medical intoxication (\"recreational or psychoactive cannabis\").[2] The number of active constituents found in cannabis and the variety of their effects have also suggested cannabis' potential use as a dietary supplement and nutraceutical.[1][3] According to the World Health Organization (WHO), recreational cannabis is the most widely used illicit drug and the most largely cultivated and trafficked worldwide.[4]\nThe therapeutic application of cannabis is increasing around the world.[5] For example, a medicine based on cannabis extract has been approved by the European Medicines Agency.[6] THC can be medically administered as capsules, mouth spray, or as flowers for making tea. And the U.S. Food and Drug Administration (FDA) has approved one cannabis-derived and three cannabis-related drug products.[7] \nThe cultivation and supply of cannabis for industrial use has been legal in the European Union since 2013, provided the cannabis' THC content does not exceed 0.2%.[8] In 2018, the U.S. legalized the production and marketing of hemp, provided that its THC content is below 0.3% on a dry weight basis.[1]\nAs cannabis increasingly becomes legalized for recreational purposes, dietary supplements, and various medical applications, growth of the global legal market of such products looks favorable in the coming years. However, the toxicity of common cannabis contaminants to humans is largely unknown. Due to the ambiguity between legal and illicit production and supply of cannabis products, there is a significant lacking in the literature regarding the prevalence of cannabis contaminants and of their harmfulness to humans. Contemporarily, the expanded use of cannabis products demands further research in this area, especially for therapeutic uses.[9]\nSeveral classes of contaminants can be present in cannabis, including heavy metals, which are able to bioaccumulate in Cannabis plants[10]; pesticides, (including illegal pesticides; given how long cannabis has been illegal, pesticide guidelines or maximal limits for pesticide residues have not been set for this substrate); microbiological contaminants; and toxins from microbial overloads, such as ochratoxins and aflatoxins.[11][12] \nMcKernan et al. showed that toxigenic fungi grow on cannabis (especially those producing ochratoxin and aflatoxin) and highlighted the need to investigate the presence of the corresponding mycotoxins in these kinds of samples.[13] Among mycotoxins that can affect cannabis, aflatoxins (AFs) are of utmost concern because of their toxicity and their widespread distribution. AFs are carcinogens, genotoxic, and immunosuppressive agents.[14] In particular, aflatoxin B1 (AFB1) is the most recurrent and carcinogenic of the aflatoxins, and it is well documented to be a causative agent of hepatocellular carcinoma as well as growth suppression, immune system modulation, and malnutrition.[15][16] AFB1 is produced by fungi of the Aspergillus genus, namely Aspergillus flavus and Aspergillus parasiticus.\nA. flavus is ubiquitously found in soil and contaminates a wide range of the world\u2019s crops. After establishing the plant as a host, the fungus produces aflatoxins, including AFB1. Fungal growth can occur on crops at any point in the pre- or post-harvest stage. Additionally, high temperatures and humidity favor fungal growth, so carelessness of storage conditions favors a large amount of AFB1 contamination occurring during storage.[17]\nThe lack of regulations and the prevailing illegal production, storage, and consumption of cannabis have meant a general unavailability of controls on its safety, including the absence of methods to monitor contamination. In this work, a rapid and sensitive enzyme immunoassay for measuring AFB1\u2014primarily developed to monitor the presence of the toxin in eggs[18]\u2014was adapted for detecting AFB1 in cannabis products. Although several accurate and sensitive immunoenzymatic kits for AFB1 detection are available on the market, the indiscriminate use of immunoassay kits originally developed and validated for application in specific matrices (to monitor AFB1 in very different materials) should be carefully evaluated. Therefore, samples of cannabis derivatives (inflorescence and leaves) legally sold under the requirement of THC content lower than 0.2% were collected in small retail outlets in Torino (Italy). The enzyme immunoassay was modified in order to comply with the effect of the herbaceous matrix and the modified assay was in-house validated. A chromatographic tandem mass spectrometry method was also developed to confirm accuracy of the enzyme immunoassay. Finally, the sensitive enzyme immunoassay was used to measure AFB1 contamination in 14 samples of cannabis products.\n\nResults \nEnzyme immunoassay adaptation to AFB1 detection in cannabis products \nExtraction of aflatoxin B1 from cannabis leaves and seeds was carried out by partitioning in 80% methanol, as previously reported by other researchers for AFB1 extraction from several kinds of medical plants.[19][20]\nThe enzyme immunoassay used in this work was initially developed for measuring aflatoxins in eggs[18] and consisted of a direct competitive immunoassay, in which a polyclonal antibody raised against aflatoxin M1 linked to bovine serum albumin (BSA) (antiM1-pAb) was adsorbed onto the polystyrene of microplate wells. The target compound (AFB1) and the enzyme probe (AFB1 linked to horse radish peroxidase, AFB1-HRP) competed for binding to the anchored antibody. After removing unbound fractions by washing the plate, the signal generated by the enzyme was developed and measured. The time required to complete the analysis was 30 minutes. In previous work, we also produced a second polyclonal antibody using AFB1 linked to BSA as the immunogen (antiB1-pAb). The antiB1-pAb showed higher selectivity towards AFB1 compared to the antiM1-pAb and was used in this work. Therefore, optimal AFB1-HRP and antiB1-pAb concentrations were defined ex-novo through the checkerboard titration approach. Other assay parameters were also re-evaluated. In particular, AFB1-HRP and antiB1-pAb concentrations and time of reactions were decided upon, providing a signal of the blank of approximately 1.5 UA and an IC50 of the calibration curve below 1 ng mL\u22121. Other parameters were defined based on minimizing matrix effect. Hence, extracts were fortified with known concentrations of AFB1 and the relative matrix effect (ME%) was calculated as follows:\n\nME% = (AFB1 measured in the fortified extract \u2212 AFB1 measured in the non-fortified extract) \/ AFB1 added \u00d7 100[21]\nAs the scope of the re-optimization of the enzyme immunoassay was intended for coping with new interference in AFB1 quantification due to the specific composition of the cannabis matrix, recovery was measured by fortifying the extract, which included potential interfering substances deriving from the sample.\nA modification of the pristine protocol was considered for statistically significant improvement of the obtained ME% rate.\nTwo samples (representative of leaves and inflorescence) collected in a small local retail outlet were extracted and, using the methanolic extracts fortified with AFB1, the following parameters were studied: (1) dilution of the methanolic extract with water; (2) volume of the diluted extract to be added to the reaction well; (3) time for the immuno- and enzymatic reactions; (4) nature of the buffer for AFB1-HRP dilution; and (5) composition of the washing solution.\nIn particular, we observed that a precipitate formed when the methanolic extracts were diluted with water; however, filtration and centrifugation to remove the particulate matter caused a dramatic loss of the toxin, measured by recovery values below 50%. Then, the raw suspension was diluted 1 + 1 and added directly to the wells. Higher dilution rate (1 + 3) decreased the sensitivity of the assay (because of sample dilution) without increasing recovery rates, while using the undiluted extract produced a strong matrix effect evidenced by a large overestimation of the AFB1. For avoiding excessive matrix interference, the sample volume was reduced to one half (further reducing sample volume was ineffective for increasing recovery and halved the sensitivity). The pH of the buffer used for the immunoreaction and of the washing solutions was also modified in order to obtain satisfying recovery rates. Specifically, lowering the pH of both solutions to 5.0 allowed us to suppress most of the matrix interference. On the contrary, modification of composition (salts and additives) of buffers did not allow us to significantly improve recovery rates (see Supplementary materials, Figure S1). Finally, the time of reactions was defined to limit the overall time required for completing the analysis while providing a signal of the blank that was measured with acceptable precision (>1 UA). The total time for the analysis was 40 minutes, which is quite low for microplate-based immunoassays and acceptable for the intended use as a first-level screening analysis. \nThe experimental conditions considered in the study and the protocol optimized for AFB1 detection in cannabis are shown in Table 1. Several parameters of the pristine protocol needed to be modified to achieve acceptable recovery rates in the detection of AFB1 in cannabis products instead of in egg yolk. This finding pointed out that the use of commercial kits originally intended for specific applications to different commodities without modifications can lead to inaccuracy and should be discouraged.\n\n\n\n\n\n\n\nTable 1. Protocol for the detection of aflatoxin B1 (AFB1) in cannabis leaves and flowers\r\n1 Conditions selected for the enzyme immunoassay are highlighted in bold.\n\n\nVariable\n\nPristine protocol, deduced from Anfossi et al.[18]\n\nConditions considered in this work1\n\n\nVolume of standard\/sample\n\n100 \u00b5L\n\n25, 50, 100 \u00b5L\n\n\nDilution factor of methanol extract\n\n1 + 1\n\n1 + 0, 1 + 1, 1 + 3\n\n\nBuffer for diluting AFB1-HRP\n\nPBST pH 7.4\n\nPBS\/T pH 5.0, 6.0, 7.4\r\nMES\/T pH 6.0\r\nphosphate\/citrate\/T pH 6.0\r\nTris\/T pH 7.4, 8.5\n\n\nWashing solution composition\n\n0.3 M NaCl + Tween 20\n\n05% Tween 20, 0.3 M NaCl\/T, PBS\/T pH 7.4, PBS\/T pH 5.0\n\n\nTime of reaction\n\n15\u2032 + 15\u2032\n\n15\u2032 + 15\u2032, 25\u2032 + 15\u2032, 15\u2032 + 25\u2032\n\n\n\nA typical calibration curve for measuring AFB1 obtained in the optimized conditions is shown in Figure 1.\n\r\n\n\n\n\n\n\n\n\n\n\n Fig. 1 The mean calibration curve obtained by averaging results from six individual curves carried out on six days. The limit of detection and the quantification interval calculated according to different methods are shown by grey areas: (a) signal-to-noise method[21][22], (b) IC10\/20-80 method[23][24][25][26], (c) error profile method[27], and (d) back calculation method.[28]\n\n\n\nAnalytical figures of merits of the enzyme immunoassay \nUsing six calibration curves, generated on different days, and by using six calibrators measured in duplicate on each day, we studied the reproducibility of the calibration (Table 2) and calculated the limit of detection (LOD) and the range of quantification (ROQ) of the assay (Table 3 and Figure 1, above). Signals recorded on each day were normalized by the signal of the calibrator containing no AFB1 (B0). The LOQ and ROQ were estimated according to four methods, variously applied to competitive immunoassays: the signal-to-noise method[21][22], the IC10\/20\u201380 method[23][24][25][26], the error profile method[27], and the back-calculation method.[28]\n\n\n\n\n\n\n\nTable 2. Parameters of the calibration curve fitting. Mean \u00b1 SD of the parameter were calculated from six curves obtained on different days. The fit was obtained from six calibrators, including the blank. Each calibrator was measured in duplicate on each day. The four-parameter logistic model was used for curve fitting.\n\n\nParameter\n\nMean \u00b1 SD\n\n\nBmax (UA)\n\n1.7 \u00b1 0.2\n\n\nBmin (UA)\n\n0.08 \u00b1 0.01\n\n\nIC50 (ng mL\u22121)\n\n0.8 \u00b1 0.1\n\n\nSlope\n\n\u22121.26 \u00b1 0.05\n\n\n\n\n\n\n\n\n\nTable 3. Analytical figures of merits of the enzyme immunoassay for measuring AFB1 estimated according to different definitions of limit of detection (LOD) and range of quantification (ROQ) reported in the literature.[21][22][23][24][25][26][27][28]\n\n\nMethod\n\nDefinition of LOD\n\nLOD (ng mL\u22121)\n\nDefinition of ROQ\n\nROQ (ng mL\u22121)\n\nReference\n\n\nSignal-to-noise ratio\n\nB0\u20133sd0\n\n0.2\n\nlinearity (y vs log x)\n\n0.2\u20132.5\n\n[21][22]\n\n\nBmax inhibition\n\nIC10\n\n0.12\n\nIC20\u2013IC80\n\n0.15\u20134\n\n[23][24][25][26]\n\n\nError profile\n\nRSD% = 50%\n\n0.2\n\nRSD% = 50%\n\n0.2\u201314\n\n[27]\n\n\nBack-calculation\n\nInaccuracy = 25%\n\n0.35\n\nInaccuracy = 20%\n\n0.4\u20132\n\n[28]\n\n\n\nThe calibration parameters were acceptably repeatable within different analytical sessions and days. The limit of detection varied depending on the method used for its estimation between 0.12 ng mL\u22121 (Bmax inhibition) and 0.35 ng mL\u22121 (back-calculation method). The quantification range also varied depending upon the method used to calculate it. Especially, the back-calculation method gave the narrower interval (0.4\u20132 ng mL\u22121) while according to the error profile method, the quantification range spanned from 0.2 to 14 ng mL\u22121 (Figure 1). The LOD varied among methods by a factor of three and the ROQ approximately by one order of magnitude. Whatever the method, the enzyme immunoassay showed high sensitivity.\nSelectivity towards other mycotoxins was measured by calculating the cross-reactivity (CR), defined as follows: CR% = IC<sub>50<\/sub> AFB1\/IC<sub>50<\/sub> mycotoxin \u00d7 100 (see Supplementary materials, Table S1). The selectivity trend was similar to the one observed previously for the same antibody.[15] In details, other compounds in the class of aflatoxins showed a certain degree of cross-reactivity, which ranged from 2.0% (AFM1) to 25.3% (AFG1). Other mycotoxins with unrelated structures (i.e., ochratoxin A, zearalenone, and fumonisins) did not interfere at all.\n\nMeasuring AFB1 in cannabis products by the enzyme immunoassay \nThe trueness of the assay was studied by recovery experiments. Two cannabis samples (#JA, made of leaves, and #DI comprising inflorescence) were analyzed directly and after fortification of the raw sample (10 and 20 ng\/g of AFB1). Apparently, sample #DI contained AFB1 (9.6 ng g\u22121), while sample #JA showed an apparent AFB1 content of 2.8 ng g\u22121(corresponding to 0.28 ng mL\u22121 in the extract). This value was below the LOD estimated by the back-calculation method, while exceeding those calculated by the other methods. Sample #JA was then diluted 1 + 1, 1 + 3, and 1 + 7 with the extraction solvent and analyzed again. We expected that sample dilution would produce a proportional signal increase. On the contrary, signals were randomly scattered. We conclude that AFB1 content of sample #JA was below the detection limit of the assay; therefore, we assumed the LOD calculated by the back-calculation method as the most reliable for determining AFB1 in cannabis samples. According to the assignment of sample #JA as containing undetectable amounts of AFB1, satisfactory recovery rates (83\u2013113%; see Supplementary materials, Table S2) were obtained for both samples.\nThe reproducibility of the enzyme assay was evaluated by measuring one sample in six replicates within the same day (intra-assay repeatability) and five samples in duplicates on two different days (inter-assay variability). The intra-assay relative standard deviation (RSD %) and the mean of inter-assay RSD% were 11.8% and 13.8%, respectively.\n\nDetermination of AFB1 in cannabis products using high-performance liquid chromatography\u2013tandem mass spectrometry (HPLC\u2013MS\/MS) \nTo validate the enzyme immunoassay, an HPLC-MS\/MS method for measuring AFB1 in cannabis products was developed in-house by adapting the method of Zheng et al., previously reported for the detection of major aflatoxins in medicinal herbs.[29] The method of Zheng et al. involved the analysis of the crude herbal extract without purification or pre-concentration and allowed the differentiation of various aflatoxins. The separation was obtained by a gradient elution in reverse phase liquid chromatography, and the detection was in the single reaction monitoring (SRM) mode. To comply with matrix interference, AFM1 was used as the internal standard, provided that AFM1 forms from the animal metabolism and then its presence in herbal extract could be excluded. The linearity of the calibration was confirmed between 5\u201340 ng mL\u22121 (y = 0.56x \u2212 0.67, r2 = 0.992; see Supplementary materials, Figure S2) and the LOD and LOQ were calculated as 1.8 and 5.8 ng mL\u22121 (corresponding to 18 and 58 ng g\u22121 in the sample), respectively. The limit of detection of the HPLC-MS\/MS method was five to ten times higher than the one calculated for the enzyme immunoassay (depending on the method used to calculate this last). The poor sensitivity compared to chromatography coupled to mass spectrometry[30] was due to the fact that we analyzed the crude extracts without applying any clean-up or pre-concentration and that we did not optimize the method. To evaluate matrix interference, four samples were analyzed by the HPLC-MS\/MS method. All samples contained AFB1 below the limit of detection of the method. The extracts from four samples (two extracts for each sample) were then fortified with 10 ng mL\u22121 of AFB1. Relative matrix effect values for fortified samples ranged from 81 to 123%, with a certain variability also among duplicate samples (Table 4).\n\n\n\n\n\n\n\nTable 4. AFB1 content in cannabis products from small local retails as measured by the enzyme immunoassay and by the HPLC-MS\/MS and matrix effect for sample extracts fortified with 10 ng mL\u22121 of AFB1.\r\n \r\na ME value was calculated as (AFB1 measured in the fortified sample\u2014AFB1 measured in the raw sample)\/AFB1 added*100. For the enzyme immunoassay, fortified extracts were diluted 1:10 before analysis. b The value obtained from the back calculation method (3.5 ng g\u22121) was considered. c LOD for the HPLC-MS\/MS method was 18 ng g\u22121. d Not determined.\n\n\nSample Id #\n\nEnzyme Immunoassay\n\nHPLC-MS\/MS\n\n\nAFB1 \u00b1 SD (ng g\u22121)\n\nME(%)a\n\nAFB1 \u00b1 SD (ng g\u22121)\n\nME(%)a\n\n\nNH-1\n\n12.1 \u00b1 0.9\n\n86\n\n<LOD c\n\n74\n\n\nNH-2\n\n14.8 \u00b1 2.6\n\n111\n\n<LOD c\n\n91\n\n\nGA-1\n\n<LOD b\n\n118\n\n<LOD c\n\n81\n\n\nGA-2\n\n8.7 \u00b1 0.1\n\n117\n\n<LOD c\n\n96\n\n\nWA-1\n\n<LOD b\n\n104\n\n<LOD c\n\n103\n\n\nWA-2\n\n<LOD b\n\n116\n\n<LOD c\n\n123\n\n\nEJ-1\n\n<LOD b\n\n102\n\n<LOD c\n\n123\n\n\nEJ-2\n\n<LOD b\n\n103\n\n<LOD c\n\n118\n\n\nVW\n\n13.8 \u00b1 0.2\n\n118\n\n<LOD c\n\n99\n\n\nAF\n\n<LOD\n\n78\n\n<LOD c\n\n119\n\n\nGS\n\n<LOD\n\n136\n\n<LOD c\n\n91\n\n\nDP\n\n13.4 \u00b1 1.8\n\n86\n\n<LOD c\n\n92\n\n\nBE\n\n11.5 \u00b1 1.1\n\n126\n\n<LOD c\n\n83\n\n\nLE\n\n<LOD\n\n98\n\n<LOD c\n\n85\n\n\nAH\n\n<LOD\n\n116\n\n<LOD c\n\n100\n\n\nJA\n\n17.7 \u00b1 0.2\n\n- d\n\n- d\n\n- d\n\n\nDI\n\n9.7 \u00b1 0.9\n\n- d\n\n- d\n\n- d\n\n\nSO\n\n8.6 \u00b1 0.4\n\n- d\n\n- d\n\n- d\n\n\n\nMethod comparison: Enzyme immunoassay and HPLC-MS\/MS \nTo further confirm that the enzyme immunoassay was not affected by the interference of the matrix and by its intrinsic variability (leaf, flowers, seeds and other parts of the cannabis plant were occasionally present in the samples collected in small retail outlets), four samples were divided into sub-samples (two sub-samples were generated for each sample) and extracted and analyzed on different days. As observed for the HPLC-MS\/MS validation, again certain variability between sub-samples was observed (Table 4, above).\nIn parallel, a further total of 10 samples was extracted and analyzed directly after fortifying the extracts with 10 ng mL-1 of AFB1 by the in-house-developed HPLC-MS\/MS method and by the enzyme immunoassay (fortified extracts were analyzed by the enzyme immunoassay after a 1:10 dilution in the extraction solvent to comply with the ROQ). The results showed all samples contained AFB1 below the limit of detection of the HPLC-MS\/MS method, while according to the enzyme immunoassay 50% of samples were contaminated above the LOD. The mean AFB1 content was measured to be 12.3 ng g-1 and the contamination level varied between 8.6 and 17.7 ng g-1 (Table 4, above).\nThe mean ME% calculated for fortified extracts were 108% (78\u2013136%) and 99% (74\u2013123%) for the enzyme immunoassay and the HPLC-MS\/MS method, respectively. Results which agreed were obtained in the two analytical methods, although the enzyme immunoassay showed a tendency to overestimate AFB1 contamination in comparison to the HPLC-MS\/MS method. (Figure 2 and Table 4, above).\n\r\n\n\n\n\n\n\n\n\n\n\n Fig. 2 Bland-Altman plot for comparing the enzyme immunoassay and HPLC-MS\/MS methods to measure AFB1 in cannabis products. Data are randomly scattered, with a positive bias of +16, representing the tendency of the enzyme immunoassay to overestimate AFB1 compared to the HPLC-MS\/MS method.\n\n\n\nDiscussion \nA rapid, accurate, and sensitive enzyme immunoassay was established for the measurements of AFB1 in cannabis products, based on previously developed bioreagents. The re-evaluation of assay parameters and particularly of the pH of the buffers and the washing solution allowed us to adapt the assay to the novel matrix and to mitigate the influence of the large variability in the composition of extracts from different part of the cannabis plant. To comply with possible variability of the matrix, a prudential limit of detection was decided, which was calculated from the inaccuracy of repeated calibration curves[28] and validated by dilution and recovery experiments on two cannabis samples. Actually, the limit of detection (LOD) and the range of quantification (ROQ) are variously defined for immunological-based assays, in particular for competitive immunoassays, where the signal is inversely (and not linearly) correlated to the concentration of the target. Sometimes, the signal-to-noise ratio method[21][22] is used to calculate the LOD, which is then assumed as the concentration of the analyte that corresponds to the signal of the standard 0 (B0) minus two or three standard deviation of the standard 0. However, this method has some limitations when applied to non-linear curve fitting. As an alternative, especially suitable for competitive immunoassays in which data are fitted by the four parameter logistic model (4-PL), a certain level of inhibition of the maximum binding (Bmax) is considered to estimate the LOD and ROQ.[23][24][25][26][31][32] The inhibition levels most frequently considered for the purpose are 90% for estimating the LOD, and 85%\u201315%[31][32] or 80\u201320%[23][24][25][26] for the ROQ, respectively. The rationale beyond this approach is represented by the fact that the typical standard curve of competitive immunoassays has a sigmoidal shape, and the upper and lower parts of the curve are strongly imprecise. However, the inhibition levels are, in some way, arbitrarily defined. \nA more robust identification of significant inhibition levels is based on the use of the error profile curve (also called precision profile). In this method, the relative standard deviation (RSD %) of repeated experiments is calculated for various concentrations of the analyte (typically for calibrators) and plotted towards the calibrators\u2019 concentrations. The ROQ and LOD are defined as the interval of concentrations that can be measured with a certain precision.[27][33] However, the level of acceptable imprecision is debated. Some authors have 30% and 10% for estimating the LOD and ROQ, respectively[29], while others considered 50% as the maximum acceptable imprecision.[31] In addition, modelling precision profile is complicated and discourages the application of this criterion. A concept similar to using the precision profile is the back-calculation method, in which the concentration of the calibrators is estimated by the fit of the curve and the interval of quantification is defined as the concentrations estimated with an acceptable accuracy (\u00b120%).[28][33] The limit of detection is calculated as the lower concentration that provides inaccuracy below 25%.[28]\nIn this work, we used repeated calibration curves to estimate LOD and ROQ according to the four approaches described above. The values obtained for the LOD varied approximately by a factor of three depending on the approach applied; the IC10\/20-80 method provided the lowest value (0.12 ng mL\u22121) while the highest value (0.35 ng mL\u22121) was calculated according to the back-calculation method. The quantification range varied also based upon the method used to calculate it and to a larger extent than the LOD. The back-calculation method provided the narrower interval (0.4\u20132 ng mL\u22121) and the error profile method the largest interval (0.2 to 14 ng mL\u22121). From a theoretical point of view, the error profile and the back-calculation approaches are the more robust; however, they require several experiments and complicated mathematical modeling. The signal-to-noise ratio allows the obtaining of a reasonable compromise, although it is based on the assumption of the linear dependency of the signal on the analyte concentration, which is not realistic for ligand-binding assays. The simplest method to calculate the LOD and ROQ is that based on defining levels of inhibition of Bmax. In this case, it is sufficient to fit the data and interpolate the values corresponding to IC10, IC20, and IC80. The simplicity of the calculation explains the success of the approach; however, the enzyme immunoassay reported here produced a significantly lower LOD compared to other approaches. Moreover, the IC10 limit was not robust when considering the capability of the assay for detecting AFB1 in real samples. The LOD calculated form other methods allowed us to reliably measure AFB1 in the extract from different cannabis products. The comparison suggests some precaution in comparing different competitive immunoassays where the analytical performance was calculated differently.\nThe estimated LOD for measuring AFB1 in cannabis leaves and flowers (3,5 ng g\u22121) was higher than that recently reported by Narv\u00e1ez et al.[30] However, the ultra-high sensitivity was reached by using ultra-high performance liquid chromatography coupled to high resolution tandem mass spectrometry and required a preliminary clean-up of the extracts. The enzyme immunoassay was applied to extracts without additional treatment and only required cost-efficient equipment and very limited training of personnel to be operated, thus allowing wide applications in low resource settings and for the affordable monitoring of the safety of cannabis products, including those used recreationally and as a food supplement. The limited number of samples analyzed in this work does not permit us to draw conclusions about the risk of AFB1 contamination in cannabis products legally sold in Italy; however the 50% of samples we analyzed, showing AFB1 contents above the detectable level and above the maximum limit admitted for commodities intended for direct human consumption[34], shed light on the need for increasing controls and, more generally, investigating the level of mycotoxin contamination of such products. These preliminary results also suggest implementing appropriate surveillance of aflatoxin contamination of cannabis products intended for medical use. In addition, specific analytical methods to measure other toxic metabolites in cannabis products should be developed in order to effectively protect consumers\u2019 health.\n\nMaterials and methods \nReagents and apparatus \nBovine serum albumin (BSA), 3,3\u20325,5\u2032-tetramethylbenzidine liquid substrate (TMB), and Aflatoxin B1, aflatoxin M1, aflatoxin B2, aflatoxin G1, aflatoxin G2, ochratoxin A (OTA), deoxynivalenol (DON), fumonisin B1 (FB1), and zearalenone (ZEA) standard solutions were purchased from Sigma Aldrich (Merck, Darmstadt, Germany). Methanol (HPLC grade), microplates, and all other chemicals were obtained from VWR International (Milan, Italy). Rabbit polyclonal antibodies directed towards aflatoxin B1 (anti-AFB1) and aflatoxin B1 conjugated to horse radish peroxidase (AFB1-HRP) were prepared in the laboratory as described in.[15] Optical density at 450 nm was measured by a Multiskan microplate reader (ThermoScientific, Waltham, MA, USA). Extract were centrifuged in a refrigerated centrifuge (BR, Juan, France).\n\nCompetitive direct ELISA \nThe assay was carried out as described previously, with minor modifications to assure optimal detectability. More specifics follow.\nThe immunoreactive wells were prepared by adsorbing overnight anti-AFB1 antibodies diluted in carbonate\/bicarbonate buffer (pH 9.6). After washing with 0.05% Tween 20, uncoated well surface was saturated with 0.5% BSA dissolved in phosphate buffer supplied with 0.15M NaCl and 0.05% Tween 20 (PBST_BSA) for one hour at room temperature, followed by three washings with 0.05% Tween 20.\nCalibration curves were generated by mixing 150 \u00b5L of AFB1-HRP (0.05 \u03bcg mL\u22121) in PBST_BSA and 50 \u00b5L of AFB1 standards diluted in aqueous methanol (40%) at concentrations ranging from 0 to 10 ng mL\u22121. After 15 minutes incubation in immunoreactive wells, unbound reagents were removed by five washings with PBST. Color due to TMB oxidation was stopped after 25 minutes incubation by adding sulphuric acid (2M) and measured at 450 nm. For cannabis samples, extracts prepared as described below were directly added to wells instead of AFB1 standards. All standards were measured in duplicate.\nUnknown sample concentrations were determined by interpolation on the calibration curve, where the signal was plotted against the analyte concentration. For each experiment, a calibration curve was determined by a nonlinear regression analysis of the data using the four-parameter logistic equation.\nReproducibility of the calibration was evaluated by comparing curves obtained across a period of six days. On each day, the normalized signal (S\/S0, %) was calculated as the signal produced by each calibrator (S) divided by the signal of the standard 0 (S0). Inter-day reproducibility was calculated as the coefficient of variation of the mean of normalized signals for each AFB1 level. In addition, percentage error of concentration was defined by back-calculating concentrations at each AFB1 level on each day and then considering the coefficient of variation of back-calculated concentrations.\nThe limit of detection and working interval of concentrations were estimated from the calibration curve obtained by averaging six individual curves according to different methods from the literature.[21][22][23][24][25][26][27][28]\nIn particular, for the signal-to-noise method, the mean value and the standard deviation of the calibrator \u201c0\u201d (blank) were calculated from 12 replicates (six days \u00d7 two replicates on each day). The signal-to-noise ratio was set at 3 and the LOD was calculated as the concentration corresponding to the blank minus three standard deviation of the blank. The ROQ was estimated from the curve as the interval that can be considered as approximatively linear, even if a competitive dose-response curve is intrinsically non-linear. The IC10\/20\u201380 method estimates the LOD as the 10% inhibition of the maximum binding (Bmax), while the ROQ is represented by values comprises between 20% and 80% of Bmax inhibition. In this case, Bmax is obtained from the 4-PL fit of data.\nThe error profile and the back-calculation methods encompass the measuring of the coefficient of variation and the inaccuracy at different levels of the target and plotting them towards the levels. LOQ and ROQ are defined accordingly with acceptable imprecision and inaccuracy. The error profile curve and the inaccuracy curve were also generated from repeated measurements of the calibrators (n = 12). The error profile curve was obtained by plotting the RSD% of calibrators towards their concentration, while the inaccuracy was obtained from the back-calculation of calibrator concentrations obtained by the 4 PL-fit compared to the true value for each calibrator.\n\nCross-reactivity study \nCalibration curves as described above were generated for other aflatoxins (AFG1, AFB2, AFG2, and AFM1) and unrelated mycotoxins (ochratoxin A, deoxynivalenol, fumonisins B1, and zearalenone). The same protocol was applied; however, a larger concentration range was investigated for unrelated mycotoxins (0\u2013100 ng mL\u22121).\nRelative cross-reactivity was calculated as follows: CR% = (IC<sub>50<\/sub> AFB1\/IC<sub>50<\/sub> mycotoxin) \u00d7 100, where IC50 is the mycotoxin concentration which causes 50% inhibition of the maximum observed signal.\n\nSamples and sample preparation \nFourteen samples of legal cannabis were purchased in small retail outlets in Torino (Italy) during the period January-March 2019. Samples were roughly minced, accurately weighted (0.2 g) and extracted with 2 mL of aqueous methanol (80%) by vortex mixing for two minutes and centrifuging at 5000\u00d7 g for 15 minutes (4 \u00b0C). Supernatants were diluted 1 + 1 with water and analyzed by the direct competitive ELISA. Depending on sample availability, 1-3 sub-samples were separately weighted and extracted. Extracts were analyzed in quadruplicate.\nTwo samples that did not show any detectable residues of aflatoxins were taken as the blank for recovery experiments. Fortified samples were prepared by adding 10, and 20 ng g\u22121 of AFB1, to the minced samples, leaving overnight under a hood for drying the solvent and homogenizing.\n\nDetermination of AFB1 using HPLC\u2013MS\/MS \nThe chromatographic separation was achieved by an Accela System (ThermoScientific, Waltham, MA, USA) and using a kinetic XB-C18 column (150 mm \u00d7 4.6 mm; 5 \u00b5m form Phenomenex, Torrance, CA, USA). Ammonium acetate (4 mmol L\u22121) and 0.1% formic acid (A) and methanol (B) were used as the mobile phase. Gradient elution was programmed as follows: five munutes of isocratic elution at 40% B, linear increase up to 80% in 15 minutes, then up to 100% in a further five minutes and finally, isocratic elution at 100% for a further five minutes. The total run time including re-conditioning was 30 minutes. Detection was obtained by the SRM method on a LCQ Fleet (ThermoScientific, Waltham, MA, USA), equipped with the electrospray source operating in positive mode. Transitions followed for AFB1 and AFM1 are detailed in the Supplementary materials, Table S3. For quantification, the calibration curve was built by plotting thee area of AFB1 peak divided by the area of AFM1 peak towards AFB1 concentrations (see Supplementary materials, Figure S1). The LOD and LOQ were calculated from several equations: LOD = (3 \u00d7 SD)\/m and LOQ = (10 \u00d7 SD)\/m.\n\nSupplementary materials \nThe following are enclosed in a downloadable .zip file:\n\n Figure S1: Optimization of the composition of AFB1-HRP diluent and of the washing solution\n Figure S2: Calibration curve for the HPLC-MS\/MS method to measure AFB1 in cannabis products\n Table S1: Cross-reactivity of the enzyme immunoassay towards mycotoxins\n Table S2: Recovery rates for two cannabis samples fortified with AFB1 and analyzed by the enzyme immunoassay\n Table S3: SMR transitions for AFB1 quantification in cannabis products\nAcknowledgements \nAuthor contributions \nF.D.N.: conceptualization and methodology, validation, writing\u2014original draft preparation; S.C., M.C. and M.P.: investigation and data curation; L.A.: conceptualization, supervision, project administration, writing\u2014review and editing; C.B.: supervision, funding acquisition. All authors have read and agreed to the published version of the manuscript.\n\nFunding \nThis research was funded by University of Torino, Ricerca Locale grant.\n\nConflicts of interest \nThe authors declare no conflict of interest.\n\nReferences \n\n\n\u2191 1.0 1.1 1.2 U.S. Food and Drug Administration. \"FDA Regulation of Cannabis and Cannabis-Derived Products, Including Cannabidiol (CBD)\". U.S. Food and Drug Administration. https:\/\/www.fda.gov\/news-events\/public-health-focus\/fda-regulation-cannabis-and-cannabis-derived-products-including-cannabidiol-cbd . Retrieved 10 July 2019 .   \n\n\u2191 Mead, A. (2019). \"Legal and Regulatory Issues Governing Cannabis and Cannabis-Derived Products in the United States\". Frontiers in Plant Science 10: 697. doi:10.3389\/fpls.2019.00697. PMC PMC6590107. PMID 31263468. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6590107 .   \n\n\u2191 Hartsel, J.A.; Eades, J.; Hickory, B.; Makriyannis, A. (2016). \"Chapter 53: Cannabis sativa and Hemp\". In Gupta, R.C.. Nutraceuticals: Efficacy, Safety and Toxicity. Academic Press. pp. 735\u2013754. ISBN 9780128021477.   \n\n\u2191 World Health Organization. \"Cannabis\". Management of substance abuse. World Health Organization. https:\/\/www.who.int\/substance_abuse\/facts\/cannabis\/en\/ . Retrieved 20 April 2020 .   \n\n\u2191 Bridgeman, M.B.; Abazia, D.T. (2017). \"Medicinal Cannabis: History, Pharmacology, And Implications for the Acute Care Setting\". P & T 42 (3): 180\u201388. PMC PMC5312634. PMID 28250701. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5312634 .   \n\n\u2191 European Monitoring Centre for Drugs and Drug Addiction (December 2018). \"Medical use of cannabis and cannabinoids: Questions and answers for policymaking\". EMCDDA. doi:0.2810\/979004. https:\/\/www.emcdda.europa.eu\/publications\/rapid-communications\/medical-use-of-cannabis-and-cannabinoids-questions-and-answers-for-policymaking_en . Retrieved 04 November 2019 .   \n\n\u2191 Corroon, J.; Kight, R. (2018). \"Regulatory Status of Cannabidiol in the United States: A Perspective\". Cannabis and Cannabinoid Research 3 (1): 190-194. doi:10.1089\/can.2018.0030. PMC PMC6154432. PMID 30283822. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6154432 .   \n\n\u2191 \"Regulation (EU) No 1307\/2013 of the European Parliament and of the Council\". Official Journal of the European Union. 20 December 2013. pp. 608\u201370. https:\/\/eur-lex.europa.eu\/LexUriServ\/LexUriServ.do?uri=OJ:L:2013:347:0608:0670:EN:PDF .   \n\n\u2191 Dryburgh, L.M.; Bolan, N.S.; Grof, C.P.L. et al. (2018). \"Cannabis Contaminants: Sources, Distribution, Human Toxicity and Pharmacologic Effects\". British Journal of Clinical Pharmacology 84 (11): 2468-2476. doi:10.1111\/bcp.13695. PMC PMC6177718. PMID 29953631. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6177718 .   \n\n\u2191 Zerihun, A. Chandravanshi, B.S.; Debebe, A. et al. (2015). \"Levels of Selected Metals in Leaves of Cannabis Sativa L. Cultivated in Ethiopia\". SpringerPlus 4: 359. doi:10.1186\/s40064-015-1145-x. PMC PMC4503701. PMID 26191486. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4503701 .   \n\n\u2191 Llewellyn, G.C.; O'Rear, C.E. (1977). \"Examination of Fungal Growth and Aflatoxin Production on Marihuana\". Mycopathologia 62 (2): 109\u201312. doi:10.1007\/BF01259400. PMID 414138.   \n\n\u2191 Wilcox, J.; Pazdanska, M.; Milligan, C. (2020). \"Analysis of Aflatoxins and Ochratoxin A in Cannabis and Cannabis Products by LC-Fluorescence Detection Using Cleanup With Either Multiantibody Immunoaffinity Columns or an Automated System With In-Line Reusable Immunoaffinity Cartridges\". Journal of AOAC International 103 (2): 494\u2013503. doi:10.5740\/jaoacint.19-0176. PMID 31558181.   \n\n\u2191 McKernan, K.; Spangler, J.; Zhang, L. et al. (2015). \"Cannabis Microbiome Sequencing Reveals Several Mycotoxic Fungi Native to Dispensary Grade Cannabis Flowers\". F1000Research 4: 1422. doi:10.12688\/f1000research.7507.2. PMC PMC4897766. PMID 27303623. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4897766 .   \n\n\u2191 European Food Safety Authority. \"Aflatoxins in food\". https:\/\/www.efsa.europa.eu\/en\/topics\/topic\/aflatoxins-food . Retrieved 10 July 2019 .   \n\n\u2191 15.0 15.1 15.2 Marchese, S.; Polo, A.; Ariano, A. et al. (2018). \"Aflatoxin B1 and M1: Biological Properties and Their Involvement in Cancer Development\". Toxins 10 (6): 214. doi:10.3390\/toxins10060214. PMC PMC6024316. PMID 29794965. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6024316 .   \n\n\u2191 International Agency for Research on Cancer (2002). Some Traditional Herbal Medicines, Some Mycotoxins, Naphthalene and Styrene. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. 82. pp. 171\u2013274. doi:10.3390\/toxins10060214. PMC PMC6024316. PMID 29794965.   \n\n\u2191 Rushing, B.R.; Selim, M.I. (2019). \"Aflatoxin B1: A Review on Metabolism, Toxicity, Occurrence in Food, Occupational Exposure, and Detoxification Methods\". Food and Chemical Toxicology 124: 81\u2013100. doi:10.1016\/j.fct.2018.11.047. PMID 30468841.   \n\n\u2191 18.0 18.1 18.2 Anfossi, L.; Di Nardo, F.; Giovannoli, C. et al. (2015). \"Enzyme immunoassay for monitoring aflatoxins in eggs\". Food Control 57: 115\u201321. doi:10.1016\/j.foodcont.2015.04.013.   \n\n\u2191 Ventura, M.; G\u00f3mez, A.; Anaya, I. et al. (2004). \"Determination of Aflatoxins B1, G1, B2 and G2 in Medicinal Herbs by Liquid Chromatography-Tandem Mass Spectrometry\". Journal of Chromatography A 1048 (1): 25\u20139. doi:10.1016\/j.chroma.2004.07.033. PMID 15453415.   \n\n\u2191 Arranz, I.; Sizoo, E.; van Egmond, H. et al. (2006). \"Determination of Aflatoxin B1 in Medical Herbs: Interlaboratory Study\". Journal of AOAC International 89 (3): 595-605. doi:10.1093\/jaoac\/89.3.595. PMID 16792057.   \n\n\u2191 21.0 21.1 21.2 21.3 21.4 21.5 21.6 Zhang, Z.; Dong, S.; Ge, D. et al. (2018). \"An Ultrasensitive Competitive Immunosensor Using Silica Nanoparticles as an Enzyme Carrier for Simultaneous Impedimetric Detection of Tetrabromobisphenol A bis(2-hydroxyethyl) Ether and Tetrabromobisphenol A Mono(hydroxyethyl) Ether\". Biosensors and Bioelectronics 105: 77\u201380. doi:10.1016\/j.bios.2018.01.029. PMID 29355782.   \n\n\u2191 22.0 22.1 22.2 22.3 22.4 22.5 Reimer, G.J.; Gee, S.J.; Hammock, B.D. (1998). \"Comparison of a Time-Resolved Fluorescence Immunoassay and an Enzyme-Linked Immunosorbent Assay for the Analysis of Atrazine in Water\". Journal of Agricultural and Food Chemistry 46 (8): 3353\u201358. doi:10.1021\/jf970965a.   \n\n\u2191 23.0 23.1 23.2 23.3 23.4 23.5 23.6 Sasaki, D.; Mitchell, R.A. (2001). \"How to Obtain Reproducible Quantitative ELISA Results\" (PDF). Oxford Biomedical Research, Inc. https:\/\/www.oxfordbiomed.com\/sites\/default\/files\/2017-02\/How%20to%20Obtain%20Reproducible%20Quantitative%20ELISA%20results.pdf .   \n\n\u2191 24.0 24.1 24.2 24.3 24.4 24.5 24.6 Saeed, A.F.U.H.; Ling, S.; Yuan, J. et al. (2017). \"The Preparation and Identification of a Monoclonal Antibody Against Domoic Acid and Establishment of Detection by Indirect Competitive ELISA\". Toxins 9 (8): 250. doi:10.3390\/toxins9080250. PMC PMC5577584. PMID 28817087. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5577584 .   \n\n\u2191 25.0 25.1 25.2 25.3 25.4 25.5 25.6 Zhang, X.; Yu, X.; Wen, K. et al. (2017). \"Multiplex Lateral Flow Immunoassays Based on Amorphous Carbon Nanoparticles for Detecting Three Fusarium Mycotoxins in Maize\". Journal of Agricultural and Food Chemistry 65 (36): 8063-8071. doi:10.1021\/acs.jafc.7b02827. PMID 28825819.   \n\n\u2191 26.0 26.1 26.2 26.3 26.4 26.5 26.6 Zhang, Z.; Zhu, N.; Zou, Y. et al. (2018). \"A Novel and Sensitive Chemiluminescence Immunoassay Based on AuNCs@pepsin@luminol for Simultaneous Detection of Tetrabromobisphenol A bis(2-hydroxyethyl) Ether and Tetrabromobisphenol A Mono(hydroxyethyl) Ether\". Analytica Chimica Acta 1035: 168-174. doi:10.1016\/j.aca.2018.06.039. PMID 30224136.   \n\n\u2191 27.0 27.1 27.2 27.3 27.4 27.5 Quinn, C.P.; Semenova, V.A.; Elie, C.M. et al. (2002). \"Specific, Sensitive, and Quantitative Enzyme-Linked Immunosorbent Assay for Human Immunoglobulin G Antibodies to Anthrax Toxin Protective Antigen\". Emerging Infectious Diseases 8 (10): 1103-10. doi:10.3201\/eid0810.020380. PMC PMC2730307. PMID 12396924. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2730307 .   \n\n\u2191 28.0 28.1 28.2 28.3 28.4 28.5 28.6 28.7 Dunn, J.; Wild, D. (2013). \"Calibration Curve Fitting\". In Wild, D.. The Immunoassay Handbook (3rd ed.). Elsevier Science. pp. 323\u2013336. ISBN 9780080445267.   \n\n\u2191 29.0 29.1 Zheng, R.; Xu, H.; Wang, W. et al. (2014). \"Simultaneous Determination of Aflatoxin B(1), B(2), G(1), G(2), Ochratoxin A, and Sterigmatocystin in Traditional Chinese Medicines by LC-MS-MS\". Analytical and Bioanalytical Chemistry 406 (13): 3031-9. doi:10.1007\/s00216-014-7750-7. PMID 24658469.   \n\n\u2191 30.0 30.1 Narv\u00e1ez, A.; Rodr\u00edguez-Carrasco, Y.; Castaldo, L. et al. (2020). \"Ultra-High-Performance Liquid Chromatography Coupled With Quadrupole Orbitrap High-Resolution Mass Spectrometry for Multi-Residue Analysis of Mycotoxins and Pesticides in Botanical Nutraceuticals\". Toxins 12 (2): 114. doi:10.3390\/toxins12020114. PMC PMC7076805. PMID 32059484. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7076805 .   \n\n\u2191 31.0 31.1 31.2 Peckham, G.D.; Hew, B.E.; Waller, D.F. et al. (2013). \"Amperometric Detection of Bacillus anthracis Spores: A Portable, Low-Cost Approach to the ELISA\". International Journal of Electrochemistry 2013: 803485. doi:10.1155\/2013\/803485.   \n\n\u2191 32.0 32.1 Zhang, C.; Zhang, Q.; Tang, X. et al. (2019). \"Development of an Anti-Idiotypic VHH Antibody and Toxin-Free Enzyme Immunoassay for Ochratoxin A in Cereals\". Toxins 11 (5): 280. doi:10.3390\/toxins11050280. PMC PMC6563187. PMID 31137467. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6563187 .   \n\n\u2191 33.0 33.1 Food and Drug Administration (June 2019). \"M10 Bioanalytical Method Validation\". FDA-2019-D-1469. Food and Drug Administration. https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/m10-bioanalytical-method-validation . Retrieved 01 November 2019 .   \n\n\u2191 \"Commission Regulation (EC) No 1881\/2006 of 19 December 2006\". Official Journal of the European Union. 20 December 2006. pp. 5\u201324. https:\/\/eur-lex.europa.eu\/legal-content\/EN\/TXT\/PDF\/?uri=CELEX:32006R1881&from=EN .   \n\n\nNotes \nThis presentation is faithful to the original, with only a few minor changes to presentation. Some grammar and punctuation was cleaned up to improve readability. In some cases important information was missing from the references, and that information was added. In the original article, citations 1 and 4 are duplicates; that duplication was removed for this version. The original's citation 34 is unclear, as they neither use the correct document name nor include a direct link to the document; an assumption is made that they intended to reference this FDA draft guidance.<\/sup>\n\n\n\n\n\n\nSource: <a rel=\"external_link\" class=\"external\" href=\"https:\/\/www.limswiki.org\/index.php\/Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\">https:\/\/www.limswiki.org\/index.php\/Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis<\/a>\n\t\t\t\t\tCategories: LIMSwiki journal articles (added in 2019)LIMSwiki journal articles (all)LIMSwiki journal articles on cannabis researchLIMSwiki journal articles on cannabis testing\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\n\t\t\t\t\n\t\t\t\n\t\t\n\t\t\n\t\t\tNavigation menu\n\t\t\t\t\t\n\t\t\tViews\n\n\t\t\t\n\t\t\t\t\n\t\t\t\tJournal\n\t\t\t\tDiscussion\n\t\t\t\tView source\n\t\t\t\tHistory\n\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\n\t\t\t\t\n\t\t\t\tPersonal tools\n\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\t\t\tLog in\n\t\t\t\t\t\t\t\t\t\t\t\t\tRequest account\n\t\t\t\t\t\t\t\t\t\t\t\n\t\t\t\t\n\t\t\t\n\t\t\t\n\t\t\t\t\n\t\t\t\n\t\t\t\t\n\t\tNavigation\n\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\tMain page\n\t\t\t\t\t\t\t\t\t\t\tRecent changes\n\t\t\t\t\t\t\t\t\t\t\tRandom page\n\t\t\t\t\t\t\t\t\t\t\tHelp\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\n\t\t\t\n\t\t\tSearch\n\n\t\t\t\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t \n\t\t\t\t\t\t\n\t\t\t\t\n\n\t\t\t\t\t\t\t\n\t\t\n\t\t\t\n\t\t\tTools\n\n\t\t\t\n\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\tWhat links here\n\t\t\t\t\t\t\t\t\t\t\tRelated changes\n\t\t\t\t\t\t\t\t\t\t\tSpecial pages\n\t\t\t\t\t\t\t\t\t\t\tPermanent link\n\t\t\t\t\t\t\t\t\t\t\tPage information\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\n\t\t\n\t\tPrint\/export\n\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\tCreate a book\n\t\t\t\t\t\t\t\t\t\t\tDownload as PDF\n\t\t\t\t\t\t\t\t\t\t\tDownload as Plain text\n\t\t\t\t\t\t\t\t\t\t\tPrintable version\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\n\t\t\n\t\tSponsors\n\t\t\n\t\t\t \r\n\n\t\r\n\n\t\r\n\n\t\n\t\r\n\n\t\r\n\n\t\n\t\r\n\n \n\t\r\n\n\t\n\t\r\n\n \n\t\n\t\r\n\n\t\n\t\n\t\r\n\n\t\r\n\n\t\r\n\n\t\n\t\r\n\n\t\r\n\t\t\n\t\t\n\t\t\t\n\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t This page was last modified on 23 June 2020, at 15:33.\n\t\t\t\t\t\t\t\t\tThis page has been accessed 333 times.\n\t\t\t\t\t\t\t\t\tContent is available under a Creative Commons Attribution-ShareAlike 4.0 International License unless otherwise noted.\n\t\t\t\t\t\t\t\t\tPrivacy policy\n\t\t\t\t\t\t\t\t\tAbout LIMSWiki\n\t\t\t\t\t\t\t\t\tDisclaimers\n\t\t\t\t\t\t\t\n\t\t\n\t\t\n\t\t\n\n","bf4e9afee9a0f426bf85b45d063f9b47_html":"<body class=\"mediawiki ltr sitedir-ltr ns-206 ns-subject page-Journal_Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis skin-monobook action-view\">\n<div id=\"rdp-ebb-globalWrapper\">\n\t\t<div id=\"rdp-ebb-column-content\">\n\t\t\t<div id=\"rdp-ebb-content\" class=\"mw-body\" role=\"main\">\n\t\t\t\t<a id=\"rdp-ebb-top\"><\/a>\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t<h1 id=\"rdp-ebb-firstHeading\" class=\"firstHeading\" lang=\"en\">Journal:Enzyme immunoassay for measuring aflatoxin B1 in legal cannabis<\/h1>\n\t\t\t\t\n\t\t\t\t<div id=\"rdp-ebb-bodyContent\" class=\"mw-body-content\">\n\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\n\n\t\t\t\t\t<!-- start content -->\n\t\t\t\t\t<div id=\"rdp-ebb-mw-content-text\" lang=\"en\" dir=\"ltr\" class=\"mw-content-ltr\">\n\n\n<h2><span class=\"mw-headline\" id=\"Abstract\">Abstract<\/span><\/h2>\n<p>The diffusion of the legalization of <a href=\"https:\/\/en.wikipedia.org\/wiki\/Cannabis\" class=\"extiw wiki-link\" title=\"wikipedia:Cannabis\" data-key=\"ae3a33525e4682427d4498e16c586f9e\">cannabis<\/a> for recreational, medicinal, and nutraceutical uses requires the development of adequate analytical methods to assure the safety and security of such products. In particular, <a href=\"https:\/\/en.wikipedia.org\/wiki\/Aflatoxin\" class=\"extiw wiki-link\" title=\"wikipedia:Aflatoxin\" data-key=\"356da02fd44d01b1bea93186e3b5721e\">aflatoxins<\/a> are considered to pose a major risk for the health of cannabis consumers. Among analytical methods that allow for adequate monitoring of food safety, <a href=\"https:\/\/www.limswiki.org\/index.php\/Immunoassay\" title=\"Immunoassay\" class=\"wiki-link\" data-key=\"ce415f577070e6fa6afa0a305f5f0247\">immunoassays<\/a> play a major role thanks to their cost-effectiveness, high-throughput capacity, simplicity, and limited requirement for equipment and skilled operators. Therefore, a rapid and sensitive <a href=\"https:\/\/www.limswiki.org\/index.php\/Enzyme_immunoassay\" title=\"Enzyme immunoassay\" class=\"mw-disambig wiki-link\" data-key=\"c38aa8ab3e6d66ab683a0f54c4159c02\">enzyme immunoassay<\/a> has been adapted to measure the most hazardous <a href=\"https:\/\/en.wikipedia.org\/wiki\/Aflatoxin_B1\" class=\"extiw wiki-link\" title=\"wikipedia:Aflatoxin B1\" data-key=\"5fcb83eb4e2b65260430e03837934826\">aflatoxin B<sub>1<\/sub><\/a> in cannabis products. The assay was acceptably accurate (recovery rate: 78\u2013136%), reproducible (intra- and inter-assay means coefficients of variation 11.8% and 13.8%, respectively), and sensitive (limit of detection and range of quantification: 0.35 ng mL<sup>\u22121<\/sup> and 0.4\u20132 ng mL<sup>\u22121<\/sup>, respectively corresponding to 7 ng g<sup>\u22121<\/sup> and 8\u201340 ng g<sup>\u22121<\/sup> in the plant), while providing results which agreed with a <a href=\"https:\/\/www.limswiki.org\/index.php\/High-performance_liquid_chromatography\" title=\"High-performance liquid chromatography\" class=\"wiki-link\" data-key=\"dc274e995eb18113903eebaef69c0cf9\">high-performance liquid chromatography<\/a>\u2013<a href=\"https:\/\/www.limswiki.org\/index.php\/Tandem_mass_spectrometry\" title=\"Tandem mass spectrometry\" class=\"wiki-link\" data-key=\"55f167a11d8b5037392ba845986bf6bf\">tandem mass spectrometry<\/a> (HPLC-MS\/MS) method for the direct analysis of aflatoxin B1 in cannabis <a href=\"https:\/\/en.wikipedia.org\/wiki\/Inflorescence\" class=\"extiw wiki-link\" title=\"wikipedia:Inflorescence\" data-key=\"1308d1a34e9f736776cdaadb382e8917\">inflorescence<\/a> and leaves. In addition, the carcinogenic aflatoxin B1 was detected in 50% of the cannabis products analyzed (14 samples collected from small retails) at levels exceeding those admitted by the European Union in commodities intended for direct human consumption, thus envisaging the need for effective surveillance of aflatoxin contamination in legal cannabis.\n<\/p><p><b>Keywords<\/b>: mycotoxins, food safety, medicinal herbs, competitive immunoassay\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Introduction\">Introduction<\/span><\/h2>\n<p><i><a href=\"https:\/\/en.wikipedia.org\/wiki\/Cannabis_sativa\" class=\"extiw wiki-link\" title=\"wikipedia:Cannabis sativa\" data-key=\"618f17d4f6938557aacc017ee0f52bbd\">Cannabis sativa<\/a><\/i> is a plant of the Cannabaceae family and is well-known for its content of biologically active chemical compounds, among which are the major compounds <a href=\"https:\/\/en.wikipedia.org\/wiki\/Tetrahydrocannabinol\" class=\"extiw wiki-link\" title=\"wikipedia:Tetrahydrocannabinol\" data-key=\"c63b7f849adf168f4b4ff293132f1e53\">\u03949-tetrahydrocannabinol<\/a> (\u03949-THC) and <a href=\"https:\/\/en.wikipedia.org\/wiki\/Cannabidiol\" class=\"extiw wiki-link\" title=\"wikipedia:Cannabidiol\" data-key=\"0c46162c3d7b370d7448646c25334265\">cannabidiol<\/a> (CBD). The flowering or fruiting tops of the <i>Cannabis<\/i> plant have been controlled in the United States under the <a href=\"https:\/\/en.wikipedia.org\/wiki\/Controlled_Substances_Act\" class=\"extiw wiki-link\" title=\"wikipedia:Controlled Substances Act\" data-key=\"dc9b3ee3a1db6f2642725d442821d995\">Controlled Substances Act<\/a> since 1970 under the drug class \u201cMarihuana.\u201d<sup id=\"rdp-ebb-cite_ref-FDAReguofCann19_1-0\" class=\"reference\"><a href=\"#cite_note-FDAReguofCann19-1\">[1]<\/a><\/sup>\n<\/p><p>Cannabis products can be used for <a href=\"https:\/\/en.wikipedia.org\/wiki\/Cannabis_(drug)\" class=\"extiw wiki-link\" title=\"wikipedia:Cannabis (drug)\" data-key=\"43fbd34351979f1e17186f202a2b1e49\">medicinal purposes<\/a> (whether using the psychoactive constituent THC or the non-psychoactive constituent CBD, generally referred to as \"medical cannabis\"), in manufacturing (\"<a href=\"https:\/\/en.wikipedia.org\/wiki\/Hemp\" class=\"extiw wiki-link\" title=\"wikipedia:Hemp\" data-key=\"2e896be8a228178ae105f8b468061a0f\">industrial hemp<\/a>\"), and for non-medical intoxication (\"recreational or psychoactive cannabis\").<sup id=\"rdp-ebb-cite_ref-MeadLegal19_2-0\" class=\"reference\"><a href=\"#cite_note-MeadLegal19-2\">[2]<\/a><\/sup> The number of active constituents found in cannabis and the variety of their effects have also suggested cannabis' potential use as a dietary supplement and nutraceutical.<sup id=\"rdp-ebb-cite_ref-FDAReguofCann19_1-1\" class=\"reference\"><a href=\"#cite_note-FDAReguofCann19-1\">[1]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-HartselCanna16_3-0\" class=\"reference\"><a href=\"#cite_note-HartselCanna16-3\">[3]<\/a><\/sup> According to the <a href=\"https:\/\/www.limswiki.org\/index.php\/World_Health_Organization\" title=\"World Health Organization\" class=\"wiki-link\" data-key=\"2a49f1470638d5f579e3f6419e239b03\">World Health Organization<\/a> (WHO), recreational cannabis is the most widely used illicit drug and the most largely <a href=\"https:\/\/en.wikipedia.org\/wiki\/Cannabis_cultivation\" class=\"extiw wiki-link\" title=\"wikipedia:Cannabis cultivation\" data-key=\"4dd8a55b106e9dead428ae3b92556976\">cultivated<\/a> and trafficked worldwide.<sup id=\"rdp-ebb-cite_ref-WHOManage_4-0\" class=\"reference\"><a href=\"#cite_note-WHOManage-4\">[4]<\/a><\/sup>\n<\/p><p>The therapeutic application of cannabis is increasing around the world.<sup id=\"rdp-ebb-cite_ref-BridgemanMedicinal17_5-0\" class=\"reference\"><a href=\"#cite_note-BridgemanMedicinal17-5\">[5]<\/a><\/sup> For example, a medicine based on cannabis extract has been approved by the European Medicines Agency.<sup id=\"rdp-ebb-cite_ref-EMCDDAMedical18_6-0\" class=\"reference\"><a href=\"#cite_note-EMCDDAMedical18-6\">[6]<\/a><\/sup> THC can be medically administered as capsules, mouth spray, or as flowers for making tea. And the U.S. <a href=\"https:\/\/www.limswiki.org\/index.php\/Food_and_Drug_Administration\" title=\"Food and Drug Administration\" class=\"wiki-link\" data-key=\"e2be8927071ac419c0929f7aa1ede7fe\">Food and Drug Administration<\/a> (FDA) has approved one cannabis-derived and three cannabis-related drug products.<sup id=\"rdp-ebb-cite_ref-CorroonReg18_7-0\" class=\"reference\"><a href=\"#cite_note-CorroonReg18-7\">[7]<\/a><\/sup> \n<\/p><p>The cultivation and supply of cannabis for industrial use has been legal in the European Union since 2013, provided the cannabis' THC content does not exceed 0.2%.<sup id=\"rdp-ebb-cite_ref-EU1307_13_8-0\" class=\"reference\"><a href=\"#cite_note-EU1307_13-8\">[8]<\/a><\/sup> In 2018, the U.S. legalized the production and marketing of hemp, provided that its THC content is below 0.3% on a dry weight basis.<sup id=\"rdp-ebb-cite_ref-FDAReguofCann19_1-2\" class=\"reference\"><a href=\"#cite_note-FDAReguofCann19-1\">[1]<\/a><\/sup>\n<\/p><p>As cannabis increasingly becomes legalized for recreational purposes, dietary supplements, and various medical applications, growth of the global legal market of such products looks favorable in the coming years. However, the toxicity of common cannabis <a href=\"https:\/\/en.wikipedia.org\/wiki\/Contamination\" class=\"extiw wiki-link\" title=\"wikipedia:Contamination\" data-key=\"9cbfd3981e731a2bcbbe30a9fc70826b\">contaminants<\/a> to humans is largely unknown. Due to the ambiguity between legal and illicit production and supply of cannabis products, there is a significant lacking in the literature regarding the prevalence of cannabis contaminants and of their harmfulness to humans. Contemporarily, the expanded use of cannabis products demands further research in this area, especially for therapeutic uses.<sup id=\"rdp-ebb-cite_ref-DryburghCanna18_9-0\" class=\"reference\"><a href=\"#cite_note-DryburghCanna18-9\">[9]<\/a><\/sup>\n<\/p><p>Several classes of contaminants can be present in cannabis, including <a href=\"https:\/\/en.wikipedia.org\/wiki\/Heavy_metals\" class=\"extiw wiki-link\" title=\"wikipedia:Heavy metals\" data-key=\"3ac86d769a2df3f6711d73649d10286b\">heavy metals<\/a>, which are able to <a href=\"https:\/\/en.wikipedia.org\/wiki\/Bioaccumulation\" class=\"extiw wiki-link\" title=\"wikipedia:Bioaccumulation\" data-key=\"cb77fbd7b9523306b127361251c7b15d\">bioaccumulate<\/a> in <i>Cannabis<\/i> plants<sup id=\"rdp-ebb-cite_ref-ZerihunLevels15_10-0\" class=\"reference\"><a href=\"#cite_note-ZerihunLevels15-10\">[10]<\/a><\/sup>; <a href=\"https:\/\/en.wikipedia.org\/wiki\/Pesticide\" class=\"extiw wiki-link\" title=\"wikipedia:Pesticide\" data-key=\"f8f48c48d08827872062ca688e326657\">pesticides<\/a>, (including illegal pesticides; given how long cannabis has been illegal, pesticide guidelines or maximal limits for pesticide residues have not been set for this substrate); microbiological contaminants; and toxins from microbial overloads, such as <a href=\"https:\/\/en.wikipedia.org\/wiki\/Ochratoxin\" class=\"extiw wiki-link\" title=\"wikipedia:Ochratoxin\" data-key=\"4b8b61caed9a9076f97523691c98e614\">ochratoxins<\/a> and <a href=\"https:\/\/en.wikipedia.org\/wiki\/Aflatoxin\" class=\"extiw wiki-link\" title=\"wikipedia:Aflatoxin\" data-key=\"356da02fd44d01b1bea93186e3b5721e\">aflatoxins<\/a>.<sup id=\"rdp-ebb-cite_ref-LlewellynExam77_11-0\" class=\"reference\"><a href=\"#cite_note-LlewellynExam77-11\">[11]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-WilcoxAnal19_12-0\" class=\"reference\"><a href=\"#cite_note-WilcoxAnal19-12\">[12]<\/a><\/sup> \n<\/p><p>McKernan <i>et al.<\/i> showed that toxigenic fungi grow on cannabis (especially those producing ochratoxin and aflatoxin) and highlighted the need to investigate the presence of the corresponding mycotoxins in these kinds of <a href=\"https:\/\/www.limswiki.org\/index.php\/Sample_(material)\" title=\"Sample (material)\" class=\"wiki-link\" data-key=\"7f8cd41a077a88d02370c02a3ba3d9d6\">samples<\/a>.<sup id=\"rdp-ebb-cite_ref-McKernanCanna15_13-0\" class=\"reference\"><a href=\"#cite_note-McKernanCanna15-13\">[13]<\/a><\/sup> Among mycotoxins that can affect cannabis, aflatoxins (AFs) are of utmost concern because of their toxicity and their widespread distribution. AFs are carcinogens, genotoxic, and immunosuppressive agents.<sup id=\"rdp-ebb-cite_ref-EFSAAflat_14-0\" class=\"reference\"><a href=\"#cite_note-EFSAAflat-14\">[14]<\/a><\/sup> In particular, <a href=\"https:\/\/en.wikipedia.org\/wiki\/Aflatoxin_B1\" class=\"extiw wiki-link\" title=\"wikipedia:Aflatoxin B1\" data-key=\"5fcb83eb4e2b65260430e03837934826\">aflatoxin B<sub>1<\/sub><\/a> (AFB1) is the most recurrent and carcinogenic of the aflatoxins, and it is well documented to be a causative agent of hepatocellular carcinoma as well as growth suppression, immune system modulation, and malnutrition.<sup id=\"rdp-ebb-cite_ref-MarcheseAflat18_15-0\" class=\"reference\"><a href=\"#cite_note-MarcheseAflat18-15\">[15]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-IARCSome02_16-0\" class=\"reference\"><a href=\"#cite_note-IARCSome02-16\">[16]<\/a><\/sup> AFB1 is produced by fungi of the <i><a href=\"https:\/\/en.wikipedia.org\/wiki\/Aspergillus\" class=\"extiw wiki-link\" title=\"wikipedia:Aspergillus\" data-key=\"8fa74c7e8a416c7d99056a355b2f0f3d\">Aspergillus<\/a><\/i> genus, namely <i>Aspergillus flavus<\/i> and <i>Aspergillus parasiticus<\/i>.\n<\/p><p><i>A. flavus<\/i> is ubiquitously found in soil and contaminates a wide range of the world\u2019s crops. After establishing the plant as a host, the fungus produces aflatoxins, including AFB1. Fungal growth can occur on crops at any point in the pre- or post-harvest stage. Additionally, high temperatures and humidity favor fungal growth, so carelessness of storage conditions favors a large amount of AFB1 contamination occurring during storage.<sup id=\"rdp-ebb-cite_ref-RushingAflat19_17-0\" class=\"reference\"><a href=\"#cite_note-RushingAflat19-17\">[17]<\/a><\/sup>\n<\/p><p>The lack of regulations and the prevailing illegal production, storage, and consumption of cannabis have meant a general unavailability of controls on its safety, including the absence of methods to monitor contamination. In this work, a rapid and sensitive <a href=\"https:\/\/www.limswiki.org\/index.php\/Enzyme_immunoassay\" title=\"Enzyme immunoassay\" class=\"mw-disambig wiki-link\" data-key=\"c38aa8ab3e6d66ab683a0f54c4159c02\">enzyme immunoassay<\/a> for measuring AFB1\u2014primarily developed to monitor the presence of the toxin in eggs<sup id=\"rdp-ebb-cite_ref-AnfossiEnzyme15_18-0\" class=\"reference\"><a href=\"#cite_note-AnfossiEnzyme15-18\">[18]<\/a><\/sup>\u2014was adapted for detecting AFB1 in cannabis products. Although several accurate and sensitive immunoenzymatic kits for AFB1 detection are available on the market, the indiscriminate use of immunoassay kits originally developed and validated for application in specific matrices (to monitor AFB1 in very different materials) should be carefully evaluated. Therefore, samples of cannabis derivatives (<a href=\"https:\/\/en.wikipedia.org\/wiki\/Inflorescence\" class=\"extiw wiki-link\" title=\"wikipedia:Inflorescence\" data-key=\"1308d1a34e9f736776cdaadb382e8917\">inflorescence<\/a> and leaves) legally sold under the requirement of THC content lower than 0.2% were collected in small retail outlets in Torino (Italy). The enzyme immunoassay was modified in order to comply with the effect of the herbaceous matrix and the modified assay was in-house validated. A <a href=\"https:\/\/www.limswiki.org\/index.php\/Chromatography\" title=\"Chromatography\" class=\"wiki-link\" data-key=\"2615535d1f14c6cffdfad7285999ad9d\">chromatographic<\/a> <a href=\"https:\/\/www.limswiki.org\/index.php\/Tandem_mass_spectrometry\" title=\"Tandem mass spectrometry\" class=\"wiki-link\" data-key=\"55f167a11d8b5037392ba845986bf6bf\">tandem mass spectrometry<\/a> method was also developed to confirm accuracy of the enzyme immunoassay. Finally, the sensitive enzyme immunoassay was used to measure AFB1 contamination in 14 samples of cannabis products.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Results\">Results<\/span><\/h2>\n<h3><span class=\"mw-headline\" id=\"Enzyme_immunoassay_adaptation_to_AFB1_detection_in_cannabis_products\">Enzyme immunoassay adaptation to AFB1 detection in cannabis products<\/span><\/h3>\n<p>Extraction of aflatoxin B1 from cannabis leaves and seeds was carried out by partitioning in 80% methanol, as previously reported by other researchers for AFB1 extraction from several kinds of medical plants.<sup id=\"rdp-ebb-cite_ref-VenturaDeterm04_19-0\" class=\"reference\"><a href=\"#cite_note-VenturaDeterm04-19\">[19]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ArranzDeterm06_20-0\" class=\"reference\"><a href=\"#cite_note-ArranzDeterm06-20\">[20]<\/a><\/sup>\n<\/p><p>The enzyme immunoassay used in this work was initially developed for measuring aflatoxins in eggs<sup id=\"rdp-ebb-cite_ref-AnfossiEnzyme15_18-1\" class=\"reference\"><a href=\"#cite_note-AnfossiEnzyme15-18\">[18]<\/a><\/sup> and consisted of a direct competitive immunoassay, in which a polyclonal antibody raised against aflatoxin M1 linked to bovine serum albumin (BSA) (antiM1-pAb) was adsorbed onto the polystyrene of microplate wells. The target compound (AFB1) and the enzyme probe (AFB1 linked to horse radish peroxidase, AFB1-HRP) competed for binding to the anchored antibody. After removing unbound fractions by washing the plate, the signal generated by the enzyme was developed and measured. The time required to complete the analysis was 30 minutes. In previous work, we also produced a second polyclonal antibody using AFB1 linked to BSA as the immunogen (antiB1-pAb). The antiB1-pAb showed higher selectivity towards AFB1 compared to the antiM1-pAb and was used in this work. Therefore, optimal AFB1-HRP and antiB1-pAb concentrations were defined ex-novo through the checkerboard titration approach. Other assay parameters were also re-evaluated. In particular, AFB1-HRP and antiB1-pAb concentrations and time of reactions were decided upon, providing a signal of the blank of approximately 1.5 UA and an IC50 of the calibration curve below 1 ng mL<sup>\u22121<\/sup>. Other parameters were defined based on minimizing matrix effect. Hence, extracts were fortified with known concentrations of AFB1 and the relative matrix effect (ME%) was calculated as follows:\n<\/p>\n<dl><dd><code>ME% = (AFB1 measured in the fortified extract \u2212 AFB1 measured in the non-fortified extract) \/ AFB1 added \u00d7 100<\/code><sup id=\"rdp-ebb-cite_ref-ZhangAnUlta18_21-0\" class=\"reference\"><a href=\"#cite_note-ZhangAnUlta18-21\">[21]<\/a><\/sup><\/dd><\/dl>\n<p>As the scope of the re-optimization of the enzyme immunoassay was intended for coping with new interference in AFB1 quantification due to the specific composition of the cannabis matrix, recovery was measured by fortifying the extract, which included potential interfering substances deriving from the sample.\n<\/p><p>A modification of the pristine protocol was considered for statistically significant improvement of the obtained ME% rate.\n<\/p><p>Two samples (representative of leaves and inflorescence) collected in a small local retail outlet were extracted and, using the methanolic extracts fortified with AFB1, the following parameters were studied: (1) dilution of the methanolic extract with water; (2) volume of the diluted extract to be added to the reaction well; (3) time for the immuno- and enzymatic reactions; (4) nature of the buffer for AFB1-HRP dilution; and (5) composition of the washing solution.\n<\/p><p>In particular, we observed that a precipitate formed when the methanolic extracts were diluted with water; however, filtration and centrifugation to remove the particulate matter caused a dramatic loss of the toxin, measured by recovery values below 50%. Then, the raw suspension was diluted 1 + 1 and added directly to the wells. Higher dilution rate (1 + 3) decreased the sensitivity of the assay (because of sample dilution) without increasing recovery rates, while using the undiluted extract produced a strong matrix effect evidenced by a large overestimation of the AFB1. For avoiding excessive matrix interference, the sample volume was reduced to one half (further reducing sample volume was ineffective for increasing recovery and halved the sensitivity). The of the buffer used for the immunoreaction and of the washing solutions was also modified in order to obtain satisfying recovery rates. Specifically, lowering the pH of both solutions to 5.0 allowed us to suppress most of the matrix interference. On the contrary, modification of composition (salts and additives) of buffers did not allow us to significantly improve recovery rates (see Supplementary materials, Figure S1). Finally, the time of reactions was defined to limit the overall time required for completing the analysis while providing a signal of the blank that was measured with acceptable precision (>1 UA). The total time for the analysis was 40 minutes, which is quite low for microplate-based immunoassays and acceptable for the intended use as a first-level screening analysis. \n<\/p><p>The experimental conditions considered in the study and the protocol optimized for AFB1 detection in cannabis are shown in Table 1. Several parameters of the pristine protocol needed to be modified to achieve acceptable recovery rates in the detection of AFB1 in cannabis products instead of in egg yolk. This finding pointed out that the use of commercial kits originally intended for specific applications to different commodities without modifications can lead to inaccuracy and should be discouraged.\n<\/p>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table class=\"wikitable\" border=\"1\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\" colspan=\"3\"><b>Table 1.<\/b> Protocol for the detection of aflatoxin B1 (AFB1) in cannabis leaves and flowers<br \/><sup>1<\/sup> Conditions selected for the enzyme immunoassay are highlighted in bold.\n<\/td><\/tr>\n<tr>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">Variable\n<\/th>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">Pristine protocol, deduced from Anfossi <i>et al.<\/i><sup id=\"rdp-ebb-cite_ref-AnfossiEnzyme15_18-2\" class=\"reference\"><a href=\"#cite_note-AnfossiEnzyme15-18\">[18]<\/a><\/sup>\n<\/th>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">Conditions considered in this work<sup>1\n<\/th><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Volume of standard\/sample\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">100 \u00b5L\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">25, <b>50<\/b>, 100 \u00b5L\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Dilution factor of methanol extract\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">1 + 1\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">1 + 0, <b>1 + 1<\/b>, 1 + 3\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Buffer for diluting AFB1-HRP\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">PBST pH 7.4\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><b>PBS\/T pH 5.0<\/b>, 6.0, 7.4<br \/>MES\/T pH 6.0<br \/>phosphate\/citrate\/T pH 6.0<br \/>Tris\/T pH 7.4, 8.5\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Washing solution composition\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">0.3 M NaCl + Tween 20\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">05% Tween 20, 0.3 M NaCl\/T, PBS\/T pH 7.4, <b>PBS\/T pH 5.0<\/b>\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Time of reaction\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">15\u2032 + 15\u2032\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">15\u2032 + 15\u2032, 25\u2032 + 15\u2032, <b>15\u2032 + 25\u2032<\/b>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>A typical calibration curve for measuring AFB1 obtained in the optimized conditions is shown in Figure 1.\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig1_DiNardo_Toxins2020_12-4.png\" class=\"image wiki-link\" data-key=\"1824dd8a599e0eece8483a73f5dd00d6\"><img alt=\"Fig1 DiNardo Toxins2020 12-4.png\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/7\/71\/Fig1_DiNardo_Toxins2020_12-4.png\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Fig. 1<\/b> The mean calibration curve obtained by averaging results from six individual curves carried out on six days. The limit of detection and the quantification interval calculated according to different methods are shown by grey areas: (<b>a<\/b>) signal-to-noise method<sup id=\"rdp-ebb-cite_ref-ZhangAnUlta18_21-1\" class=\"reference\"><a href=\"#cite_note-ZhangAnUlta18-21\">[21]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ReimerComp98_22-0\" class=\"reference\"><a href=\"#cite_note-ReimerComp98-22\">[22]<\/a><\/sup>, (<b>b<\/b>) IC10\/20-80 method<sup id=\"rdp-ebb-cite_ref-SasakiHowTo01_23-0\" class=\"reference\"><a href=\"#cite_note-SasakiHowTo01-23\">[23]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-SaeedThePrep17_24-0\" class=\"reference\"><a href=\"#cite_note-SaeedThePrep17-24\">[24]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ZhangMulti17_25-0\" class=\"reference\"><a href=\"#cite_note-ZhangMulti17-25\">[25]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ZhangANovel18_26-0\" class=\"reference\"><a href=\"#cite_note-ZhangANovel18-26\">[26]<\/a><\/sup>, (<b>c<\/b>) error profile method<sup id=\"rdp-ebb-cite_ref-QuinnSpec02_27-0\" class=\"reference\"><a href=\"#cite_note-QuinnSpec02-27\">[27]<\/a><\/sup>, and (<b>d<\/b>) back calculation method.<sup id=\"rdp-ebb-cite_ref-DunnCal13_28-0\" class=\"reference\"><a href=\"#cite_note-DunnCal13-28\">[28]<\/a><\/sup><\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<h3><span class=\"mw-headline\" id=\"Analytical_figures_of_merits_of_the_enzyme_immunoassay\">Analytical figures of merits of the enzyme immunoassay<\/span><\/h3>\n<p>Using six calibration curves, generated on different days, and by using six calibrators measured in duplicate on each day, we studied the reproducibility of the calibration (Table 2) and calculated the limit of detection (LOD) and the range of quantification (ROQ) of the assay (Table 3 and Figure 1, above). Signals recorded on each day were normalized by the signal of the calibrator containing no AFB1 (B0). The LOQ and ROQ were estimated according to four methods, variously applied to competitive immunoassays: the signal-to-noise method<sup id=\"rdp-ebb-cite_ref-ZhangAnUlta18_21-2\" class=\"reference\"><a href=\"#cite_note-ZhangAnUlta18-21\">[21]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ReimerComp98_22-1\" class=\"reference\"><a href=\"#cite_note-ReimerComp98-22\">[22]<\/a><\/sup>, the IC10\/20\u201380 method<sup id=\"rdp-ebb-cite_ref-SasakiHowTo01_23-1\" class=\"reference\"><a href=\"#cite_note-SasakiHowTo01-23\">[23]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-SaeedThePrep17_24-1\" class=\"reference\"><a href=\"#cite_note-SaeedThePrep17-24\">[24]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ZhangMulti17_25-1\" class=\"reference\"><a href=\"#cite_note-ZhangMulti17-25\">[25]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ZhangANovel18_26-1\" class=\"reference\"><a href=\"#cite_note-ZhangANovel18-26\">[26]<\/a><\/sup>, the error profile method<sup id=\"rdp-ebb-cite_ref-QuinnSpec02_27-1\" class=\"reference\"><a href=\"#cite_note-QuinnSpec02-27\">[27]<\/a><\/sup>, and the back-calculation method.<sup id=\"rdp-ebb-cite_ref-DunnCal13_28-1\" class=\"reference\"><a href=\"#cite_note-DunnCal13-28\">[28]<\/a><\/sup>\n<\/p>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table class=\"wikitable\" border=\"1\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\" colspan=\"2\"><b>Table 2.<\/b> Parameters of the calibration curve fitting. Mean \u00b1 SD of the parameter were calculated from six curves obtained on different days. The fit was obtained from six calibrators, including the blank. Each calibrator was measured in duplicate on each day. The four-parameter logistic model was used for curve fitting.\n<\/td><\/tr>\n<tr>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">Parameter\n<\/th>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">Mean \u00b1 SD\n<\/th><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">B<sub>max<\/sub> (UA)\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">1.7 \u00b1 0.2\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">B<sub>min<\/sub> (UA)\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">0.08 \u00b1 0.01\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">IC<sub>50<\/sub> (ng mL<sup>\u22121<\/sup>)\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">0.8 \u00b1 0.1\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Slope\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">\u22121.26 \u00b1 0.05\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table class=\"wikitable\" border=\"1\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\" colspan=\"6\"><b>Table 3.<\/b> Analytical figures of merits of the enzyme immunoassay for measuring AFB1 estimated according to different definitions of limit of detection (LOD) and range of quantification (ROQ) reported in the literature.<sup id=\"rdp-ebb-cite_ref-ZhangAnUlta18_21-3\" class=\"reference\"><a href=\"#cite_note-ZhangAnUlta18-21\">[21]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ReimerComp98_22-2\" class=\"reference\"><a href=\"#cite_note-ReimerComp98-22\">[22]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-SasakiHowTo01_23-2\" class=\"reference\"><a href=\"#cite_note-SasakiHowTo01-23\">[23]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-SaeedThePrep17_24-2\" class=\"reference\"><a href=\"#cite_note-SaeedThePrep17-24\">[24]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ZhangMulti17_25-2\" class=\"reference\"><a href=\"#cite_note-ZhangMulti17-25\">[25]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ZhangANovel18_26-2\" class=\"reference\"><a href=\"#cite_note-ZhangANovel18-26\">[26]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-QuinnSpec02_27-2\" class=\"reference\"><a href=\"#cite_note-QuinnSpec02-27\">[27]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-DunnCal13_28-2\" class=\"reference\"><a href=\"#cite_note-DunnCal13-28\">[28]<\/a><\/sup>\n<\/td><\/tr>\n<tr>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">Method\n<\/th>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">Definition of LOD\n<\/th>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">LOD (ng mL<sup>\u22121<\/sup>)\n<\/th>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">Definition of ROQ\n<\/th>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">ROQ (ng mL<sup>\u22121<\/sup>)\n<\/th>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">Reference\n<\/th><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Signal-to-noise ratio\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">B0\u20133sd0\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">0.2\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">linearity (y vs log x)\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">0.2\u20132.5\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><sup id=\"rdp-ebb-cite_ref-ZhangAnUlta18_21-4\" class=\"reference\"><a href=\"#cite_note-ZhangAnUlta18-21\">[21]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ReimerComp98_22-3\" class=\"reference\"><a href=\"#cite_note-ReimerComp98-22\">[22]<\/a><\/sup>\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">B<sub>max<\/sub> inhibition\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">IC<sub>10<\/sub>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">0.12\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">IC<sub>20<\/sub>\u2013IC<sub>80<\/sub>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">0.15\u20134\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><sup id=\"rdp-ebb-cite_ref-SasakiHowTo01_23-3\" class=\"reference\"><a href=\"#cite_note-SasakiHowTo01-23\">[23]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-SaeedThePrep17_24-3\" class=\"reference\"><a href=\"#cite_note-SaeedThePrep17-24\">[24]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ZhangMulti17_25-3\" class=\"reference\"><a href=\"#cite_note-ZhangMulti17-25\">[25]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ZhangANovel18_26-3\" class=\"reference\"><a href=\"#cite_note-ZhangANovel18-26\">[26]<\/a><\/sup>\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Error profile\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">RSD% = 50%\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">0.2\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">RSD% = 50%\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">0.2\u201314\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><sup id=\"rdp-ebb-cite_ref-QuinnSpec02_27-3\" class=\"reference\"><a href=\"#cite_note-QuinnSpec02-27\">[27]<\/a><\/sup>\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Back-calculation\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Inaccuracy = 25%\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">0.35\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Inaccuracy = 20%\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">0.4\u20132\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><sup id=\"rdp-ebb-cite_ref-DunnCal13_28-3\" class=\"reference\"><a href=\"#cite_note-DunnCal13-28\">[28]<\/a><\/sup>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>The calibration parameters were acceptably repeatable within different analytical sessions and days. The limit of detection varied depending on the method used for its estimation between 0.12 ng mL<sup>\u22121<\/sup> (B<sub>max<\/sub> inhibition) and 0.35 ng mL<sup>\u22121<\/sup> (back-calculation method). The quantification range also varied depending upon the method used to calculate it. Especially, the back-calculation method gave the narrower interval (0.4\u20132 ng mL<sup>\u22121<\/sup>) while according to the error profile method, the quantification range spanned from 0.2 to 14 ng mL<sup>\u22121<\/sup> (Figure 1). The LOD varied among methods by a factor of three and the ROQ approximately by one order of magnitude. Whatever the method, the enzyme immunoassay showed high sensitivity.\n<\/p><p>Selectivity towards other mycotoxins was measured by calculating the cross-reactivity (CR), defined as follows: <code>CR% = IC<sub>50<\/sub> AFB1\/IC<sub>50<\/sub> mycotoxin \u00d7 100<\/code> (see Supplementary materials, Table S1). The selectivity trend was similar to the one observed previously for the same antibody.<sup id=\"rdp-ebb-cite_ref-MarcheseAflat18_15-1\" class=\"reference\"><a href=\"#cite_note-MarcheseAflat18-15\">[15]<\/a><\/sup> In details, other compounds in the class of aflatoxins showed a certain degree of cross-reactivity, which ranged from 2.0% (AFM1) to 25.3% (AFG1). Other mycotoxins with unrelated structures (i.e., ochratoxin A, zearalenone, and fumonisins) did not interfere at all.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Measuring_AFB1_in_cannabis_products_by_the_enzyme_immunoassay\">Measuring AFB1 in cannabis products by the enzyme immunoassay<\/span><\/h3>\n<p>The trueness of the assay was studied by recovery experiments. Two cannabis samples (#JA, made of leaves, and #DI comprising inflorescence) were analyzed directly and after fortification of the raw sample (10 and 20 ng\/g of AFB1). Apparently, sample #DI contained AFB1 (9.6 ng g<sup>\u22121<\/sup>), while sample #JA showed an apparent AFB1 content of 2.8 ng g<sup>\u22121<\/sup>(corresponding to 0.28 ng mL<sup>\u22121<\/sup> in the extract). This value was below the LOD estimated by the back-calculation method, while exceeding those calculated by the other methods. Sample #JA was then diluted 1 + 1, 1 + 3, and 1 + 7 with the extraction solvent and analyzed again. We expected that sample dilution would produce a proportional signal increase. On the contrary, signals were randomly scattered. We conclude that AFB1 content of sample #JA was below the detection limit of the assay; therefore, we assumed the LOD calculated by the back-calculation method as the most reliable for determining AFB1 in cannabis samples. According to the assignment of sample #JA as containing undetectable amounts of AFB1, satisfactory recovery rates (83\u2013113%; see Supplementary materials, Table S2) were obtained for both samples.\n<\/p><p>The reproducibility of the enzyme assay was evaluated by measuring one sample in six replicates within the same day (intra-assay repeatability) and five samples in duplicates on two different days (inter-assay variability). The intra-assay relative standard deviation (RSD %) and the mean of inter-assay RSD% were 11.8% and 13.8%, respectively.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Determination_of_AFB1_in_cannabis_products_using_high-performance_liquid_chromatography.E2.80.93tandem_mass_spectrometry_.28HPLC.E2.80.93MS.2FMS.29\">Determination of AFB1 in cannabis products using high-performance liquid chromatography\u2013tandem mass spectrometry (HPLC\u2013MS\/MS)<\/span><\/h3>\n<p>To validate the enzyme immunoassay, an HPLC-MS\/MS method for measuring AFB1 in cannabis products was developed in-house by adapting the method of Zheng <i>et al.<\/i>, previously reported for the detection of major aflatoxins in medicinal herbs.<sup id=\"rdp-ebb-cite_ref-ZhengSimul14_29-0\" class=\"reference\"><a href=\"#cite_note-ZhengSimul14-29\">[29]<\/a><\/sup> The method of Zheng <i>et al.<\/i> involved the analysis of the crude herbal extract without purification or pre-concentration and allowed the differentiation of various aflatoxins. The separation was obtained by a gradient elution in reverse phase liquid chromatography, and the detection was in the single reaction monitoring (SRM) mode. To comply with matrix interference, AFM1 was used as the internal standard, provided that AFM1 forms from the animal metabolism and then its presence in herbal extract could be excluded. The linearity of the calibration was confirmed between 5\u201340 ng mL<sup>\u22121<\/sup> (y = 0.56x \u2212 0.67, r2 = 0.992; see Supplementary materials, Figure S2) and the LOD and LOQ were calculated as 1.8 and 5.8 ng mL<sup>\u22121<\/sup> (corresponding to 18 and 58 ng g<sup>\u22121<\/sup> in the sample), respectively. The limit of detection of the HPLC-MS\/MS method was five to ten times higher than the one calculated for the enzyme immunoassay (depending on the method used to calculate this last). The poor sensitivity compared to chromatography coupled to mass spectrometry<sup id=\"rdp-ebb-cite_ref-Narv.C3.A1ezUltra20_30-0\" class=\"reference\"><a href=\"#cite_note-Narv.C3.A1ezUltra20-30\">[30]<\/a><\/sup> was due to the fact that we analyzed the crude extracts without applying any clean-up or pre-concentration and that we did not optimize the method. To evaluate matrix interference, four samples were analyzed by the HPLC-MS\/MS method. All samples contained AFB1 below the limit of detection of the method. The extracts from four samples (two extracts for each sample) were then fortified with 10 ng mL<sup>\u22121<\/sup> of AFB1. Relative matrix effect values for fortified samples ranged from 81 to 123%, with a certain variability also among duplicate samples (Table 4).\n<\/p>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table class=\"wikitable\" border=\"1\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\" colspan=\"5\"><b>Table 4.<\/b> AFB1 content in cannabis products from small local retails as measured by the enzyme immunoassay and by the HPLC-MS\/MS and matrix effect for sample extracts fortified with 10 ng mL<sup>\u22121<\/sup> of AFB1.<br \/> <br \/><sup>a<\/sup> ME value was calculated as (AFB1 measured in the fortified sample\u2014AFB1 measured in the raw sample)\/AFB1 added*100. For the enzyme immunoassay, fortified extracts were diluted 1:10 before analysis. <sup>b<\/sup> The value obtained from the back calculation method (3.5 ng g<sup>\u22121<\/sup>) was considered. <sup>c<\/sup> LOD for the HPLC-MS\/MS method was 18 ng g<sup>\u22121<\/sup>. <sup>d<\/sup> Not determined.\n<\/td><\/tr>\n<tr>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\" rowspan=\"2\">Sample Id #\n<\/th>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\" colspan=\"2\">Enzyme Immunoassay\n<\/th>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\" colspan=\"2\">HPLC-MS\/MS\n<\/th><\/tr>\n<tr>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">AFB1 \u00b1 SD (ng g<sup>\u22121<\/sup>)\n<\/th>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">ME(%)<sup>a<\/sup>\n<\/th>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">AFB1 \u00b1 SD (ng g<sup>\u22121<\/sup>)\n<\/th>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">ME(%)<sup>a<\/sup>\n<\/th><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">NH-1\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">12.1 \u00b1 0.9\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">86\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><LOD <sup>c<\/sup>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">74\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">NH-2\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">14.8 \u00b1 2.6\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">111\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><LOD <sup>c<\/sup>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">91\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">GA-1\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><LOD <sup>b<\/sup>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">118\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><LOD <sup>c<\/sup>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">81\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">GA-2\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">8.7 \u00b1 0.1\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">117\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><LOD <sup>c<\/sup>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">96\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">WA-1\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><LOD <sup>b<\/sup>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">104\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><LOD <sup>c<\/sup>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">103\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">WA-2\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><LOD <sup>b<\/sup>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">116\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><LOD <sup>c<\/sup>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">123\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">EJ-1\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><LOD <sup>b<\/sup>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">102\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><LOD <sup>c<\/sup>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">123\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">EJ-2\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><LOD <sup>b<\/sup>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">103\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><LOD <sup>c<\/sup>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">118\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">VW\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">13.8 \u00b1 0.2\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">118\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><LOD <sup>c<\/sup>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">99\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">AF\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><LOD\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">78\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><LOD <sup>c<\/sup>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">119\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">GS\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><LOD\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">136\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><LOD <sup>c<\/sup>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">91\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">DP\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">13.4 \u00b1 1.8\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">86\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><LOD <sup>c<\/sup>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">92\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">BE\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">11.5 \u00b1 1.1\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">126\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><LOD <sup>c<\/sup>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">83\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">LE\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><LOD\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">98\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><LOD <sup>c<\/sup>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">85\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">AH\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><LOD\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">116\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><LOD <sup>c<\/sup>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">100\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">JA\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">17.7 \u00b1 0.2\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">- <sup>d<\/sup>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">- <sup>d<\/sup>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">- <sup>d<\/sup>\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">DI\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">9.7 \u00b1 0.9\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">- <sup>d<\/sup>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">- <sup>d<\/sup>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">- <sup>d<\/sup>\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">SO\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">8.6 \u00b1 0.4\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">- <sup>d<\/sup>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">- <sup>d<\/sup>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">- <sup>d<\/sup>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<h3><span class=\"mw-headline\" id=\"Method_comparison:_Enzyme_immunoassay_and_HPLC-MS.2FMS\">Method comparison: Enzyme immunoassay and HPLC-MS\/MS<\/span><\/h3>\n<p>To further confirm that the enzyme immunoassay was not affected by the interference of the matrix and by its intrinsic variability (leaf, flowers, seeds and other parts of the cannabis plant were occasionally present in the samples collected in small retail outlets), four samples were divided into sub-samples (two sub-samples were generated for each sample) and extracted and analyzed on different days. As observed for the HPLC-MS\/MS validation, again certain variability between sub-samples was observed (Table 4, above).\n<\/p><p>In parallel, a further total of 10 samples was extracted and analyzed directly after fortifying the extracts with 10 ng mL<sup>-1<\/sup> of AFB1 by the in-house-developed HPLC-MS\/MS method and by the enzyme immunoassay (fortified extracts were analyzed by the enzyme immunoassay after a 1:10 dilution in the extraction solvent to comply with the ROQ). The results showed all samples contained AFB1 below the limit of detection of the HPLC-MS\/MS method, while according to the enzyme immunoassay 50% of samples were contaminated above the LOD. The mean AFB1 content was measured to be 12.3 ng g<sup>-1<\/sup> and the contamination level varied between 8.6 and 17.7 ng g<sup>-1<\/sup> (Table 4, above).\n<\/p><p>The mean ME% calculated for fortified extracts were 108% (78\u2013136%) and 99% (74\u2013123%) for the enzyme immunoassay and the HPLC-MS\/MS method, respectively. Results which agreed were obtained in the two analytical methods, although the enzyme immunoassay showed a tendency to overestimate AFB1 contamination in comparison to the HPLC-MS\/MS method. (Figure 2 and Table 4, above).\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig2_DiNardo_Toxins2020_12-4.png\" class=\"image wiki-link\" data-key=\"56b42fba883362a88dc131bde6152f78\"><img alt=\"Fig2 DiNardo Toxins2020 12-4.png\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/8\/86\/Fig2_DiNardo_Toxins2020_12-4.png\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Fig. 2<\/b> Bland-Altman plot for comparing the enzyme immunoassay and HPLC-MS\/MS methods to measure AFB1 in cannabis products. Data are randomly scattered, with a positive bias of +16, representing the tendency of the enzyme immunoassay to overestimate AFB1 compared to the HPLC-MS\/MS method.<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<h2><span class=\"mw-headline\" id=\"Discussion\">Discussion<\/span><\/h2>\n<p>A rapid, accurate, and sensitive enzyme immunoassay was established for the measurements of AFB1 in cannabis products, based on previously developed bioreagents. The re-evaluation of assay parameters and particularly of the pH of the buffers and the washing solution allowed us to adapt the assay to the novel matrix and to mitigate the influence of the large variability in the composition of extracts from different part of the cannabis plant. To comply with possible variability of the matrix, a prudential limit of detection was decided, which was calculated from the inaccuracy of repeated calibration curves<sup id=\"rdp-ebb-cite_ref-DunnCal13_28-4\" class=\"reference\"><a href=\"#cite_note-DunnCal13-28\">[28]<\/a><\/sup> and validated by dilution and recovery experiments on two cannabis samples. Actually, the limit of detection (LOD) and the range of quantification (ROQ) are variously defined for immunological-based assays, in particular for competitive immunoassays, where the signal is inversely (and not linearly) correlated to the concentration of the target. Sometimes, the signal-to-noise ratio method<sup id=\"rdp-ebb-cite_ref-ZhangAnUlta18_21-5\" class=\"reference\"><a href=\"#cite_note-ZhangAnUlta18-21\">[21]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ReimerComp98_22-4\" class=\"reference\"><a href=\"#cite_note-ReimerComp98-22\">[22]<\/a><\/sup> is used to calculate the LOD, which is then assumed as the concentration of the analyte that corresponds to the signal of the standard 0 (B<sub>0<\/sub>) minus two or three standard deviation of the standard 0. However, this method has some limitations when applied to non-linear curve fitting. As an alternative, especially suitable for competitive immunoassays in which data are fitted by the four parameter logistic model (4-PL), a certain level of inhibition of the maximum binding (B<sub>max<\/sub>) is considered to estimate the LOD and ROQ.<sup id=\"rdp-ebb-cite_ref-SasakiHowTo01_23-4\" class=\"reference\"><a href=\"#cite_note-SasakiHowTo01-23\">[23]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-SaeedThePrep17_24-4\" class=\"reference\"><a href=\"#cite_note-SaeedThePrep17-24\">[24]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ZhangMulti17_25-4\" class=\"reference\"><a href=\"#cite_note-ZhangMulti17-25\">[25]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ZhangANovel18_26-4\" class=\"reference\"><a href=\"#cite_note-ZhangANovel18-26\">[26]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-PeckhamAmper13_31-0\" class=\"reference\"><a href=\"#cite_note-PeckhamAmper13-31\">[31]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ZhangDevelop19_32-0\" class=\"reference\"><a href=\"#cite_note-ZhangDevelop19-32\">[32]<\/a><\/sup> The inhibition levels most frequently considered for the purpose are 90% for estimating the LOD, and 85%\u201315%<sup id=\"rdp-ebb-cite_ref-PeckhamAmper13_31-1\" class=\"reference\"><a href=\"#cite_note-PeckhamAmper13-31\">[31]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ZhangDevelop19_32-1\" class=\"reference\"><a href=\"#cite_note-ZhangDevelop19-32\">[32]<\/a><\/sup> or 80\u201320%<sup id=\"rdp-ebb-cite_ref-SasakiHowTo01_23-5\" class=\"reference\"><a href=\"#cite_note-SasakiHowTo01-23\">[23]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-SaeedThePrep17_24-5\" class=\"reference\"><a href=\"#cite_note-SaeedThePrep17-24\">[24]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ZhangMulti17_25-5\" class=\"reference\"><a href=\"#cite_note-ZhangMulti17-25\">[25]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ZhangANovel18_26-5\" class=\"reference\"><a href=\"#cite_note-ZhangANovel18-26\">[26]<\/a><\/sup> for the ROQ, respectively. The rationale beyond this approach is represented by the fact that the typical standard curve of competitive immunoassays has a sigmoidal shape, and the upper and lower parts of the curve are strongly imprecise. However, the inhibition levels are, in some way, arbitrarily defined. \n<\/p><p>A more robust identification of significant inhibition levels is based on the use of the error profile curve (also called precision profile). In this method, the relative standard deviation (RSD %) of repeated experiments is calculated for various concentrations of the analyte (typically for calibrators) and plotted towards the calibrators\u2019 concentrations. The ROQ and LOD are defined as the interval of concentrations that can be measured with a certain precision.<sup id=\"rdp-ebb-cite_ref-QuinnSpec02_27-4\" class=\"reference\"><a href=\"#cite_note-QuinnSpec02-27\">[27]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-FDA_M1019_33-0\" class=\"reference\"><a href=\"#cite_note-FDA_M1019-33\">[33]<\/a><\/sup> However, the level of acceptable imprecision is debated. Some authors have 30% and 10% for estimating the LOD and ROQ, respectively<sup id=\"rdp-ebb-cite_ref-ZhengSimul14_29-1\" class=\"reference\"><a href=\"#cite_note-ZhengSimul14-29\">[29]<\/a><\/sup>, while others considered 50% as the maximum acceptable imprecision.<sup id=\"rdp-ebb-cite_ref-PeckhamAmper13_31-2\" class=\"reference\"><a href=\"#cite_note-PeckhamAmper13-31\">[31]<\/a><\/sup> In addition, modelling precision profile is complicated and discourages the application of this criterion. A concept similar to using the precision profile is the back-calculation method, in which the concentration of the calibrators is estimated by the fit of the curve and the interval of quantification is defined as the concentrations estimated with an acceptable accuracy (\u00b120%).<sup id=\"rdp-ebb-cite_ref-DunnCal13_28-5\" class=\"reference\"><a href=\"#cite_note-DunnCal13-28\">[28]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-FDA_M1019_33-1\" class=\"reference\"><a href=\"#cite_note-FDA_M1019-33\">[33]<\/a><\/sup> The limit of detection is calculated as the lower concentration that provides inaccuracy below 25%.<sup id=\"rdp-ebb-cite_ref-DunnCal13_28-6\" class=\"reference\"><a href=\"#cite_note-DunnCal13-28\">[28]<\/a><\/sup>\n<\/p><p>In this work, we used repeated calibration curves to estimate LOD and ROQ according to the four approaches described above. The values obtained for the LOD varied approximately by a factor of three depending on the approach applied; the IC<sub>10\/20-80<\/sub> method provided the lowest value (0.12 ng mL<sup>\u22121<\/sup>) while the highest value (0.35 ng mL<sup>\u22121<\/sup>) was calculated according to the back-calculation method. The quantification range varied also based upon the method used to calculate it and to a larger extent than the LOD. The back-calculation method provided the narrower interval (0.4\u20132 ng mL<sup>\u22121<\/sup>) and the error profile method the largest interval (0.2 to 14 ng mL<sup>\u22121<\/sup>). From a theoretical point of view, the error profile and the back-calculation approaches are the more robust; however, they require several experiments and complicated mathematical modeling. The signal-to-noise ratio allows the obtaining of a reasonable compromise, although it is based on the assumption of the linear dependency of the signal on the analyte concentration, which is not realistic for ligand-binding assays. The simplest method to calculate the LOD and ROQ is that based on defining levels of inhibition of B<sub>max<\/sub>. In this case, it is sufficient to fit the data and interpolate the values corresponding to IC<sub>10<\/sub>, IC<sub>20<\/sub>, and IC<sub>80<\/sub>. The simplicity of the calculation explains the success of the approach; however, the enzyme immunoassay reported here produced a significantly lower LOD compared to other approaches. Moreover, the IC<sub>10<\/sub> limit was not robust when considering the capability of the assay for detecting AFB1 in real samples. The LOD calculated form other methods allowed us to reliably measure AFB1 in the extract from different cannabis products. The comparison suggests some precaution in comparing different competitive immunoassays where the analytical performance was calculated differently.\n<\/p><p>The estimated LOD for measuring AFB1 in cannabis leaves and flowers (3,5 ng g<sup>\u22121<\/sup>) was higher than that recently reported by Narv\u00e1ez <i>et al.<\/i><sup id=\"rdp-ebb-cite_ref-Narv.C3.A1ezUltra20_30-1\" class=\"reference\"><a href=\"#cite_note-Narv.C3.A1ezUltra20-30\">[30]<\/a><\/sup> However, the ultra-high sensitivity was reached by using ultra-high performance liquid chromatography coupled to high resolution tandem mass spectrometry and required a preliminary clean-up of the extracts. The enzyme immunoassay was applied to extracts without additional treatment and only required cost-efficient equipment and very limited training of personnel to be operated, thus allowing wide applications in low resource settings and for the affordable monitoring of the safety of cannabis products, including those used recreationally and as a food supplement. The limited number of samples analyzed in this work does not permit us to draw conclusions about the risk of AFB1 contamination in cannabis products legally sold in Italy; however the 50% of samples we analyzed, showing AFB1 contents above the detectable level and above the maximum limit admitted for commodities intended for direct human consumption<sup id=\"rdp-ebb-cite_ref-EU1881_06_34-0\" class=\"reference\"><a href=\"#cite_note-EU1881_06-34\">[34]<\/a><\/sup>, shed light on the need for increasing controls and, more generally, investigating the level of mycotoxin contamination of such products. These preliminary results also suggest implementing appropriate surveillance of aflatoxin contamination of cannabis products intended for medical use. In addition, specific analytical methods to measure other toxic metabolites in cannabis products should be developed in order to effectively protect consumers\u2019 health.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Materials_and_methods\">Materials and methods<\/span><\/h2>\n<h3><span class=\"mw-headline\" id=\"Reagents_and_apparatus\">Reagents and apparatus<\/span><\/h3>\n<p>Bovine serum albumin (BSA), 3,3\u20325,5\u2032-tetramethylbenzidine liquid substrate (TMB), and Aflatoxin B1, aflatoxin M1, aflatoxin B2, aflatoxin G1, aflatoxin G2, ochratoxin A (OTA), deoxynivalenol (DON), fumonisin B1 (FB1), and zearalenone (ZEA) standard solutions were purchased from Sigma Aldrich (Merck, Darmstadt, Germany). Methanol (HPLC grade), microplates, and all other chemicals were obtained from VWR International (Milan, Italy). Rabbit polyclonal antibodies directed towards aflatoxin B1 (anti-AFB1) and aflatoxin B1 conjugated to horse radish peroxidase (AFB1-HRP) were prepared in the laboratory as described in.<sup id=\"rdp-ebb-cite_ref-MarcheseAflat18_15-2\" class=\"reference\"><a href=\"#cite_note-MarcheseAflat18-15\">[15]<\/a><\/sup> Optical density at 450 nm was measured by a Multiskan microplate reader (ThermoScientific, Waltham, MA, USA). Extract were centrifuged in a refrigerated centrifuge (BR, Juan, France).\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Competitive_direct_ELISA\">Competitive direct ELISA<\/span><\/h3>\n<p>The assay was carried out as described previously, with minor modifications to assure optimal detectability. More specifics follow.\n<\/p><p>The immunoreactive wells were prepared by adsorbing overnight anti-AFB1 antibodies diluted in carbonate\/bicarbonate buffer (pH 9.6). After washing with 0.05% Tween 20, uncoated well surface was saturated with 0.5% BSA dissolved in phosphate buffer supplied with 0.15M NaCl and 0.05% Tween 20 (PBST_BSA) for one hour at room temperature, followed by three washings with 0.05% Tween 20.\n<\/p><p>Calibration curves were generated by mixing 150 \u00b5L of AFB1-HRP (0.05 \u03bcg mL<sup>\u22121<\/sup>) in PBST_BSA and 50 \u00b5L of AFB1 standards diluted in aqueous methanol (40%) at concentrations ranging from 0 to 10 ng mL<sup>\u22121<\/sup>. After 15 minutes incubation in immunoreactive wells, unbound reagents were removed by five washings with PBST. Color due to TMB oxidation was stopped after 25 minutes incubation by adding sulphuric acid (2M) and measured at 450 nm. For cannabis samples, extracts prepared as described below were directly added to wells instead of AFB1 standards. All standards were measured in duplicate.\n<\/p><p>Unknown sample concentrations were determined by interpolation on the calibration curve, where the signal was plotted against the analyte concentration. For each experiment, a calibration curve was determined by a nonlinear regression analysis of the data using the four-parameter logistic equation.\n<\/p><p>Reproducibility of the calibration was evaluated by comparing curves obtained across a period of six days. On each day, the normalized signal (S\/S0, %) was calculated as the signal produced by each calibrator (S) divided by the signal of the standard 0 (S0). Inter-day reproducibility was calculated as the coefficient of variation of the mean of normalized signals for each AFB1 level. In addition, percentage error of concentration was defined by back-calculating concentrations at each AFB1 level on each day and then considering the coefficient of variation of back-calculated concentrations.\n<\/p><p>The limit of detection and working interval of concentrations were estimated from the calibration curve obtained by averaging six individual curves according to different methods from the literature.<sup id=\"rdp-ebb-cite_ref-ZhangAnUlta18_21-6\" class=\"reference\"><a href=\"#cite_note-ZhangAnUlta18-21\">[21]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ReimerComp98_22-5\" class=\"reference\"><a href=\"#cite_note-ReimerComp98-22\">[22]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-SasakiHowTo01_23-6\" class=\"reference\"><a href=\"#cite_note-SasakiHowTo01-23\">[23]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-SaeedThePrep17_24-6\" class=\"reference\"><a href=\"#cite_note-SaeedThePrep17-24\">[24]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ZhangMulti17_25-6\" class=\"reference\"><a href=\"#cite_note-ZhangMulti17-25\">[25]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ZhangANovel18_26-6\" class=\"reference\"><a href=\"#cite_note-ZhangANovel18-26\">[26]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-QuinnSpec02_27-5\" class=\"reference\"><a href=\"#cite_note-QuinnSpec02-27\">[27]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-DunnCal13_28-7\" class=\"reference\"><a href=\"#cite_note-DunnCal13-28\">[28]<\/a><\/sup>\n<\/p><p>In particular, for the signal-to-noise method, the mean value and the standard deviation of the calibrator \u201c0\u201d (blank) were calculated from 12 replicates (six days \u00d7 two replicates on each day). The signal-to-noise ratio was set at 3 and the LOD was calculated as the concentration corresponding to the blank minus three standard deviation of the blank. The ROQ was estimated from the curve as the interval that can be considered as approximatively linear, even if a competitive dose-response curve is intrinsically non-linear. The IC<sub>10\/20\u201380<\/sub> method estimates the LOD as the 10% inhibition of the maximum binding (B<sub>max<\/sub>), while the ROQ is represented by values comprises between 20% and 80% of B<sub>max<\/sub> inhibition. In this case, B<sub>max<\/sub> is obtained from the 4-PL fit of data.\n<\/p><p>The error profile and the back-calculation methods encompass the measuring of the coefficient of variation and the inaccuracy at different levels of the target and plotting them towards the levels. LOQ and ROQ are defined accordingly with acceptable imprecision and inaccuracy. The error profile curve and the inaccuracy curve were also generated from repeated measurements of the calibrators (<i>n<\/i> = 12). The error profile curve was obtained by plotting the RSD% of calibrators towards their concentration, while the inaccuracy was obtained from the back-calculation of calibrator concentrations obtained by the 4 PL-fit compared to the true value for each calibrator.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Cross-reactivity_study\">Cross-reactivity study<\/span><\/h3>\n<p>Calibration curves as described above were generated for other aflatoxins (AFG1, AFB2, AFG2, and AFM1) and unrelated mycotoxins (ochratoxin A, deoxynivalenol, fumonisins B1, and zearalenone). The same protocol was applied; however, a larger concentration range was investigated for unrelated mycotoxins (0\u2013100 ng mL<sup>\u22121<\/sup>).\n<\/p><p>Relative cross-reactivity was calculated as follows: <code>CR% = (IC<sub>50<\/sub> AFB1\/IC<sub>50<\/sub> mycotoxin) \u00d7 100<\/code>, where IC<sub>50<\/sub> is the mycotoxin concentration which causes 50% inhibition of the maximum observed signal.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Samples_and_sample_preparation\">Samples and sample preparation<\/span><\/h3>\n<p>Fourteen samples of legal cannabis were purchased in small retail outlets in Torino (Italy) during the period January-March 2019. Samples were roughly minced, accurately weighted (0.2 g) and extracted with 2 mL of aqueous methanol (80%) by vortex mixing for two minutes and centrifuging at 5000\u00d7 <i>g<\/i> for 15 minutes (4 \u00b0C). Supernatants were diluted 1 + 1 with water and analyzed by the direct competitive ELISA. Depending on sample availability, 1-3 sub-samples were separately weighted and extracted. Extracts were analyzed in quadruplicate.\n<\/p><p>Two samples that did not show any detectable residues of aflatoxins were taken as the blank for recovery experiments. Fortified samples were prepared by adding 10, and 20 ng g<sup>\u22121<\/sup> of AFB1, to the minced samples, leaving overnight under a hood for drying the solvent and homogenizing.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Determination_of_AFB1_using_HPLC.E2.80.93MS.2FMS\">Determination of AFB1 using HPLC\u2013MS\/MS<\/span><\/h3>\n<p>The chromatographic separation was achieved by an Accela System (ThermoScientific, Waltham, MA, USA) and using a kinetic XB-C18 column (150 mm \u00d7 4.6 mm; 5 \u00b5m form Phenomenex, Torrance, CA, USA). Ammonium acetate (4 mmol L<sup>\u22121<\/sup>) and 0.1% formic acid (A) and methanol (B) were used as the mobile phase. Gradient elution was programmed as follows: five munutes of isocratic elution at 40% B, linear increase up to 80% in 15 minutes, then up to 100% in a further five minutes and finally, isocratic elution at 100% for a further five minutes. The total run time including re-conditioning was 30 minutes. Detection was obtained by the SRM method on a LCQ Fleet (ThermoScientific, Waltham, MA, USA), equipped with the electrospray source operating in positive mode. Transitions followed for AFB1 and AFM1 are detailed in the Supplementary materials, Table S3. For quantification, the calibration curve was built by plotting thee area of AFB1 peak divided by the area of AFM1 peak towards AFB1 concentrations (see Supplementary materials, Figure S1). The LOD and LOQ were calculated from several equations: <code>LOD = (3 \u00d7 SD)\/m<\/code> and <code>LOQ = (10 \u00d7 SD)\/m<\/code>.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Supplementary_materials\">Supplementary materials<\/span><\/h2>\n<p>The following are enclosed in a <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.mdpi.com\/2072-6651\/12\/4\/265\/s1\" target=\"_blank\">downloadable .zip file<\/a>:\n<\/p>\n<ul><li> Figure S1: Optimization of the composition of AFB1-HRP diluent and of the washing solution<\/li>\n<li> Figure S2: Calibration curve for the HPLC-MS\/MS method to measure AFB1 in cannabis products<\/li>\n<li> Table S1: Cross-reactivity of the enzyme immunoassay towards mycotoxins<\/li>\n<li> Table S2: Recovery rates for two cannabis samples fortified with AFB1 and analyzed by the enzyme immunoassay<\/li>\n<li> Table S3: SMR transitions for AFB1 quantification in cannabis products<\/li><\/ul>\n<h2><span class=\"mw-headline\" id=\"Acknowledgements\">Acknowledgements<\/span><\/h2>\n<h3><span class=\"mw-headline\" id=\"Author_contributions\">Author contributions<\/span><\/h3>\n<p>F.D.N.: conceptualization and methodology, validation, writing\u2014original draft preparation; S.C., M.C. and M.P.: investigation and data curation; L.A.: conceptualization, supervision, project administration, writing\u2014review and editing; C.B.: supervision, funding acquisition. All authors have read and agreed to the published version of the manuscript.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Funding\">Funding<\/span><\/h3>\n<p>This research was funded by University of Torino, Ricerca Locale grant.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Conflicts_of_interest\">Conflicts of interest<\/span><\/h3>\n<p>The authors declare no conflict of interest.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"References\">References<\/span><\/h2>\n<div class=\"reflist references-column-width\" style=\"-moz-column-width: 30em; -webkit-column-width: 30em; column-width: 30em; list-style-type: decimal;\">\n<ol class=\"references\">\n<li id=\"cite_note-FDAReguofCann19-1\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-FDAReguofCann19_1-0\">1.0<\/a><\/sup> <sup><a href=\"#cite_ref-FDAReguofCann19_1-1\">1.1<\/a><\/sup> <sup><a href=\"#cite_ref-FDAReguofCann19_1-2\">1.2<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation web\">U.S. Food and Drug Administration. <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.fda.gov\/news-events\/public-health-focus\/fda-regulation-cannabis-and-cannabis-derived-products-including-cannabidiol-cbd\" target=\"_blank\">\"FDA Regulation of Cannabis and Cannabis-Derived Products, Including Cannabidiol (CBD)\"<\/a>. U.S. Food and Drug Administration<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.fda.gov\/news-events\/public-health-focus\/fda-regulation-cannabis-and-cannabis-derived-products-including-cannabidiol-cbd\" target=\"_blank\">https:\/\/www.fda.gov\/news-events\/public-health-focus\/fda-regulation-cannabis-and-cannabis-derived-products-including-cannabidiol-cbd<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 10 July 2019<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=FDA+Regulation+of+Cannabis+and+Cannabis-Derived+Products%2C+Including+Cannabidiol+%28CBD%29&rft.atitle=&rft.aulast=U.S.+Food+and+Drug+Administration&rft.au=U.S.+Food+and+Drug+Administration&rft.pub=U.S.+Food+and+Drug+Administration&rft_id=https%3A%2F%2Fwww.fda.gov%2Fnews-events%2Fpublic-health-focus%2Ffda-regulation-cannabis-and-cannabis-derived-products-including-cannabidiol-cbd&rfr_id=info:sid\/en.wikipedia.org:Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-MeadLegal19-2\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-MeadLegal19_2-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Mead, A. (2019). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6590107\" target=\"_blank\">\"Legal and Regulatory Issues Governing Cannabis and Cannabis-Derived Products in the United States\"<\/a>. <i>Frontiers in Plant Science<\/i> <b>10<\/b>: 697. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.3389%2Ffpls.2019.00697\" target=\"_blank\">10.3389\/fpls.2019.00697<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6590107\/\" target=\"_blank\">PMC6590107<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/31263468\" target=\"_blank\">31263468<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6590107\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6590107<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Legal+and+Regulatory+Issues+Governing+Cannabis+and+Cannabis-Derived+Products+in+the+United+States&rft.jtitle=Frontiers+in+Plant+Science&rft.aulast=Mead%2C+A.&rft.au=Mead%2C+A.&rft.date=2019&rft.volume=10&rft.pages=697&rft_id=info:doi\/10.3389%2Ffpls.2019.00697&rft_id=info:pmc\/PMC6590107&rft_id=info:pmid\/31263468&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC6590107&rfr_id=info:sid\/en.wikipedia.org:Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-HartselCanna16-3\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-HartselCanna16_3-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation book\">Hartsel, J.A.; Eades, J.; Hickory, B.; Makriyannis, A. (2016). \"Chapter 53: <i>Cannabis sativa<\/i> and Hemp\". In Gupta, R.C.. <i>Nutraceuticals: Efficacy, Safety and Toxicity<\/i>. Academic Press. pp. 735\u2013754. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/International_Standard_Book_Number\" data-key=\"f64947ba21e884434bd70e8d9e60bae6\">ISBN<\/a> 9780128021477.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Chapter+53%3A+%27%27Cannabis+sativa%27%27+and+Hemp&rft.atitle=Nutraceuticals%3A+Efficacy%2C+Safety+and+Toxicity&rft.aulast=Hartsel%2C+J.A.%3B+Eades%2C+J.%3B+Hickory%2C+B.%3B+Makriyannis%2C+A.&rft.au=Hartsel%2C+J.A.%3B+Eades%2C+J.%3B+Hickory%2C+B.%3B+Makriyannis%2C+A.&rft.date=2016&rft.pages=pp.%26nbsp%3B735%E2%80%93754&rft.pub=Academic+Press&rft.isbn=9780128021477&rfr_id=info:sid\/en.wikipedia.org:Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-WHOManage-4\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-WHOManage_4-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">World Health Organization. <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.who.int\/substance_abuse\/facts\/cannabis\/en\/\" target=\"_blank\">\"Cannabis\"<\/a>. <i>Management of substance abuse<\/i>. World Health Organization<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.who.int\/substance_abuse\/facts\/cannabis\/en\/\" target=\"_blank\">https:\/\/www.who.int\/substance_abuse\/facts\/cannabis\/en\/<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 20 April 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Cannabis&rft.atitle=Management+of+substance+abuse&rft.aulast=World+Health+Organization&rft.au=World+Health+Organization&rft.pub=World+Health+Organization&rft_id=https%3A%2F%2Fwww.who.int%2Fsubstance_abuse%2Ffacts%2Fcannabis%2Fen%2F&rfr_id=info:sid\/en.wikipedia.org:Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-BridgemanMedicinal17-5\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-BridgemanMedicinal17_5-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Bridgeman, M.B.; Abazia, D.T. (2017). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5312634\" target=\"_blank\">\"Medicinal Cannabis: History, Pharmacology, And Implications for the Acute Care Setting\"<\/a>. <i>P & T<\/i> <b>42<\/b> (3): 180\u201388. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC5312634\/\" target=\"_blank\">PMC5312634<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/28250701\" target=\"_blank\">28250701<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5312634\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5312634<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Medicinal+Cannabis%3A+History%2C+Pharmacology%2C+And+Implications+for+the+Acute+Care+Setting&rft.jtitle=P+%26+T&rft.aulast=Bridgeman%2C+M.B.%3B+Abazia%2C+D.T.&rft.au=Bridgeman%2C+M.B.%3B+Abazia%2C+D.T.&rft.date=2017&rft.volume=42&rft.issue=3&rft.pages=180%E2%80%9388&rft_id=info:pmc\/PMC5312634&rft_id=info:pmid\/28250701&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC5312634&rfr_id=info:sid\/en.wikipedia.org:Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-EMCDDAMedical18-6\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-EMCDDAMedical18_6-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">European Monitoring Centre for Drugs and Drug Addiction (December 2018). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.emcdda.europa.eu\/publications\/rapid-communications\/medical-use-of-cannabis-and-cannabinoids-questions-and-answers-for-policymaking_en\" target=\"_blank\">\"Medical use of cannabis and cannabinoids: Questions and answers for policymaking\"<\/a>. EMCDDA. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/0.2810%2F979004\" target=\"_blank\">0.2810\/979004<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.emcdda.europa.eu\/publications\/rapid-communications\/medical-use-of-cannabis-and-cannabinoids-questions-and-answers-for-policymaking_en\" target=\"_blank\">https:\/\/www.emcdda.europa.eu\/publications\/rapid-communications\/medical-use-of-cannabis-and-cannabinoids-questions-and-answers-for-policymaking_en<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 04 November 2019<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Medical+use+of+cannabis+and+cannabinoids%3A+Questions+and+answers+for+policymaking&rft.atitle=&rft.aulast=European+Monitoring+Centre+for+Drugs+and+Drug+Addiction&rft.au=European+Monitoring+Centre+for+Drugs+and+Drug+Addiction&rft.date=December+2018&rft.pub=EMCDDA&rft_id=info:doi\/0.2810%2F979004&rft_id=https%3A%2F%2Fwww.emcdda.europa.eu%2Fpublications%2Frapid-communications%2Fmedical-use-of-cannabis-and-cannabinoids-questions-and-answers-for-policymaking_en&rfr_id=info:sid\/en.wikipedia.org:Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-CorroonReg18-7\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-CorroonReg18_7-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Corroon, J.; Kight, R. (2018). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6154432\" target=\"_blank\">\"Regulatory Status of Cannabidiol in the United States: A Perspective\"<\/a>. <i>Cannabis and Cannabinoid Research<\/i> <b>3<\/b> (1): 190-194. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1089%2Fcan.2018.0030\" target=\"_blank\">10.1089\/can.2018.0030<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6154432\/\" target=\"_blank\">PMC6154432<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/30283822\" target=\"_blank\">30283822<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6154432\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6154432<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Regulatory+Status+of+Cannabidiol+in+the+United+States%3A+A+Perspective&rft.jtitle=Cannabis+and+Cannabinoid+Research&rft.aulast=Corroon%2C+J.%3B+Kight%2C+R.&rft.au=Corroon%2C+J.%3B+Kight%2C+R.&rft.date=2018&rft.volume=3&rft.issue=1&rft.pages=190-194&rft_id=info:doi\/10.1089%2Fcan.2018.0030&rft_id=info:pmc\/PMC6154432&rft_id=info:pmid\/30283822&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC6154432&rfr_id=info:sid\/en.wikipedia.org:Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-EU1307_13-8\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-EU1307_13_8-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\"><a rel=\"external_link\" class=\"external text\" href=\"https:\/\/eur-lex.europa.eu\/LexUriServ\/LexUriServ.do?uri=OJ:L:2013:347:0608:0670:EN:PDF\" target=\"_blank\">\"Regulation (EU) No 1307\/2013 of the European Parliament and of the Council\"<\/a>. <i>Official Journal of the European Union<\/i>. 20 December 2013. pp. 608\u201370<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/eur-lex.europa.eu\/LexUriServ\/LexUriServ.do?uri=OJ:L:2013:347:0608:0670:EN:PDF\" target=\"_blank\">https:\/\/eur-lex.europa.eu\/LexUriServ\/LexUriServ.do?uri=OJ:L:2013:347:0608:0670:EN:PDF<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Regulation+%28EU%29+No+1307%2F2013+of+the+European+Parliament+and+of+the+Council&rft.atitle=Official+Journal+of+the+European+Union&rft.date=20+December+2013&rft.pages=pp.+608%E2%80%9370&rft_id=https%3A%2F%2Feur-lex.europa.eu%2FLexUriServ%2FLexUriServ.do%3Furi%3DOJ%3AL%3A2013%3A347%3A0608%3A0670%3AEN%3APDF&rfr_id=info:sid\/en.wikipedia.org:Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-DryburghCanna18-9\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-DryburghCanna18_9-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Dryburgh, L.M.; Bolan, N.S.; Grof, C.P.L. et al. (2018). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6177718\" target=\"_blank\">\"Cannabis Contaminants: Sources, Distribution, Human Toxicity and Pharmacologic Effects\"<\/a>. <i>British Journal of Clinical Pharmacology<\/i> <b>84<\/b> (11): 2468-2476. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1111%2Fbcp.13695\" target=\"_blank\">10.1111\/bcp.13695<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6177718\/\" target=\"_blank\">PMC6177718<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/29953631\" target=\"_blank\">29953631<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6177718\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6177718<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Cannabis+Contaminants%3A+Sources%2C+Distribution%2C+Human+Toxicity+and+Pharmacologic+Effects&rft.jtitle=British+Journal+of+Clinical+Pharmacology&rft.aulast=Dryburgh%2C+L.M.%3B+Bolan%2C+N.S.%3B+Grof%2C+C.P.L.+et+al.&rft.au=Dryburgh%2C+L.M.%3B+Bolan%2C+N.S.%3B+Grof%2C+C.P.L.+et+al.&rft.date=2018&rft.volume=84&rft.issue=11&rft.pages=2468-2476&rft_id=info:doi\/10.1111%2Fbcp.13695&rft_id=info:pmc\/PMC6177718&rft_id=info:pmid\/29953631&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC6177718&rfr_id=info:sid\/en.wikipedia.org:Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ZerihunLevels15-10\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-ZerihunLevels15_10-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Zerihun, A. Chandravanshi, B.S.; Debebe, A. et al. (2015). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4503701\" target=\"_blank\">\"Levels of Selected Metals in Leaves of Cannabis Sativa L. Cultivated in Ethiopia\"<\/a>. <i>SpringerPlus<\/i> <b>4<\/b>: 359. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1186%2Fs40064-015-1145-x\" target=\"_blank\">10.1186\/s40064-015-1145-x<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC4503701\/\" target=\"_blank\">PMC4503701<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/26191486\" target=\"_blank\">26191486<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4503701\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4503701<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Levels+of+Selected+Metals+in+Leaves+of+Cannabis+Sativa+L.+Cultivated+in+Ethiopia&rft.jtitle=SpringerPlus&rft.aulast=Zerihun%2C+A.+Chandravanshi%2C+B.S.%3B+Debebe%2C+A.+et+al.&rft.au=Zerihun%2C+A.+Chandravanshi%2C+B.S.%3B+Debebe%2C+A.+et+al.&rft.date=2015&rft.volume=4&rft.pages=359&rft_id=info:doi\/10.1186%2Fs40064-015-1145-x&rft_id=info:pmc\/PMC4503701&rft_id=info:pmid\/26191486&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC4503701&rfr_id=info:sid\/en.wikipedia.org:Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-LlewellynExam77-11\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-LlewellynExam77_11-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Llewellyn, G.C.; O'Rear, C.E. (1977). \"Examination of Fungal Growth and Aflatoxin Production on Marihuana\". <i>Mycopathologia<\/i> <b>62<\/b> (2): 109\u201312. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1007%2FBF01259400\" target=\"_blank\">10.1007\/BF01259400<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/414138\" target=\"_blank\">414138<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Examination+of+Fungal+Growth+and+Aflatoxin+Production+on+Marihuana&rft.jtitle=Mycopathologia&rft.aulast=Llewellyn%2C+G.C.%3B+O%27Rear%2C+C.E.&rft.au=Llewellyn%2C+G.C.%3B+O%27Rear%2C+C.E.&rft.date=1977&rft.volume=62&rft.issue=2&rft.pages=109%E2%80%9312&rft_id=info:doi\/10.1007%2FBF01259400&rft_id=info:pmid\/414138&rfr_id=info:sid\/en.wikipedia.org:Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-WilcoxAnal19-12\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-WilcoxAnal19_12-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Wilcox, J.; Pazdanska, M.; Milligan, C. (2020). \"Analysis of Aflatoxins and Ochratoxin A in Cannabis and Cannabis Products by LC-Fluorescence Detection Using Cleanup With Either Multiantibody Immunoaffinity Columns or an Automated System With In-Line Reusable Immunoaffinity Cartridges\". <i>Journal of AOAC International<\/i> <b>103<\/b> (2): 494\u2013503. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.5740%2Fjaoacint.19-0176\" target=\"_blank\">10.5740\/jaoacint.19-0176<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/31558181\" target=\"_blank\">31558181<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Analysis+of+Aflatoxins+and+Ochratoxin+A+in+Cannabis+and+Cannabis+Products+by+LC-Fluorescence+Detection+Using+Cleanup+With+Either+Multiantibody+Immunoaffinity+Columns+or+an+Automated+System+With+In-Line+Reusable+Immunoaffinity+Cartridges&rft.jtitle=Journal+of+AOAC+International&rft.aulast=Wilcox%2C+J.%3B+Pazdanska%2C+M.%3B+Milligan%2C+C.&rft.au=Wilcox%2C+J.%3B+Pazdanska%2C+M.%3B+Milligan%2C+C.&rft.date=2020&rft.volume=103&rft.issue=2&rft.pages=494%E2%80%93503&rft_id=info:doi\/10.5740%2Fjaoacint.19-0176&rft_id=info:pmid\/31558181&rfr_id=info:sid\/en.wikipedia.org:Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-McKernanCanna15-13\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-McKernanCanna15_13-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">McKernan, K.; Spangler, J.; Zhang, L. et al. (2015). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4897766\" target=\"_blank\">\"Cannabis Microbiome Sequencing Reveals Several Mycotoxic Fungi Native to Dispensary Grade Cannabis Flowers\"<\/a>. <i>F1000Research<\/i> <b>4<\/b>: 1422. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.12688%2Ff1000research.7507.2\" target=\"_blank\">10.12688\/f1000research.7507.2<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC4897766\/\" target=\"_blank\">PMC4897766<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/27303623\" target=\"_blank\">27303623<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4897766\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4897766<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Cannabis+Microbiome+Sequencing+Reveals+Several+Mycotoxic+Fungi+Native+to+Dispensary+Grade+Cannabis+Flowers&rft.jtitle=F1000Research&rft.aulast=McKernan%2C+K.%3B+Spangler%2C+J.%3B+Zhang%2C+L.+et+al.&rft.au=McKernan%2C+K.%3B+Spangler%2C+J.%3B+Zhang%2C+L.+et+al.&rft.date=2015&rft.volume=4&rft.pages=1422&rft_id=info:doi\/10.12688%2Ff1000research.7507.2&rft_id=info:pmc\/PMC4897766&rft_id=info:pmid\/27303623&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC4897766&rfr_id=info:sid\/en.wikipedia.org:Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-EFSAAflat-14\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-EFSAAflat_14-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">European Food Safety Authority. <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.efsa.europa.eu\/en\/topics\/topic\/aflatoxins-food\" target=\"_blank\">\"Aflatoxins in food\"<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.efsa.europa.eu\/en\/topics\/topic\/aflatoxins-food\" target=\"_blank\">https:\/\/www.efsa.europa.eu\/en\/topics\/topic\/aflatoxins-food<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 10 July 2019<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Aflatoxins+in+food&rft.atitle=&rft.aulast=European+Food+Safety+Authority&rft.au=European+Food+Safety+Authority&rft_id=https%3A%2F%2Fwww.efsa.europa.eu%2Fen%2Ftopics%2Ftopic%2Faflatoxins-food&rfr_id=info:sid\/en.wikipedia.org:Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-MarcheseAflat18-15\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-MarcheseAflat18_15-0\">15.0<\/a><\/sup> <sup><a href=\"#cite_ref-MarcheseAflat18_15-1\">15.1<\/a><\/sup> <sup><a href=\"#cite_ref-MarcheseAflat18_15-2\">15.2<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Marchese, S.; Polo, A.; Ariano, A. et al. (2018). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6024316\" target=\"_blank\">\"Aflatoxin B1 and M1: Biological Properties and Their Involvement in Cancer Development\"<\/a>. <i>Toxins<\/i> <b>10<\/b> (6): 214. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.3390%2Ftoxins10060214\" target=\"_blank\">10.3390\/toxins10060214<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6024316\/\" target=\"_blank\">PMC6024316<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/29794965\" target=\"_blank\">29794965<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6024316\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6024316<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Aflatoxin+B1+and+M1%3A+Biological+Properties+and+Their+Involvement+in+Cancer+Development&rft.jtitle=Toxins&rft.aulast=Marchese%2C+S.%3B+Polo%2C+A.%3B+Ariano%2C+A.+et+al.&rft.au=Marchese%2C+S.%3B+Polo%2C+A.%3B+Ariano%2C+A.+et+al.&rft.date=2018&rft.volume=10&rft.issue=6&rft.pages=214&rft_id=info:doi\/10.3390%2Ftoxins10060214&rft_id=info:pmc\/PMC6024316&rft_id=info:pmid\/29794965&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC6024316&rfr_id=info:sid\/en.wikipedia.org:Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-IARCSome02-16\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-IARCSome02_16-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation book\">International Agency for Research on Cancer (2002). <i>Some Traditional Herbal Medicines, Some Mycotoxins, Naphthalene and Styrene<\/i>. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. <b>82<\/b>. pp. 171\u2013274. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.3390%2Ftoxins10060214\" target=\"_blank\">10.3390\/toxins10060214<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6024316\/\" target=\"_blank\">PMC6024316<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/29794965\" target=\"_blank\">29794965<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=book&rft.btitle=Some+Traditional+Herbal+Medicines%2C+Some+Mycotoxins%2C+Naphthalene+and+Styrene&rft.aulast=International+Agency+for+Research+on+Cancer&rft.au=International+Agency+for+Research+on+Cancer&rft.date=2002&rft.series=IARC+Monographs+on+the+Evaluation+of+Carcinogenic+Risks+to+Humans&rft.volume=82&rft.pages=pp.%26nbsp%3B171%E2%80%93274&rft_id=info:doi\/10.3390%2Ftoxins10060214&rft_id=info:pmc\/PMC6024316&rft_id=info:pmid\/29794965&rfr_id=info:sid\/en.wikipedia.org:Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-RushingAflat19-17\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-RushingAflat19_17-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Rushing, B.R.; Selim, M.I. (2019). \"Aflatoxin B1: A Review on Metabolism, Toxicity, Occurrence in Food, Occupational Exposure, and Detoxification Methods\". <i>Food and Chemical Toxicology<\/i> <b>124<\/b>: 81\u2013100. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.fct.2018.11.047\" target=\"_blank\">10.1016\/j.fct.2018.11.047<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/30468841\" target=\"_blank\">30468841<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Aflatoxin+B1%3A+A+Review+on+Metabolism%2C+Toxicity%2C+Occurrence+in+Food%2C+Occupational+Exposure%2C+and+Detoxification+Methods&rft.jtitle=Food+and+Chemical+Toxicology&rft.aulast=Rushing%2C+B.R.%3B+Selim%2C+M.I.&rft.au=Rushing%2C+B.R.%3B+Selim%2C+M.I.&rft.date=2019&rft.volume=124&rft.pages=81%E2%80%93100&rft_id=info:doi\/10.1016%2Fj.fct.2018.11.047&rft_id=info:pmid\/30468841&rfr_id=info:sid\/en.wikipedia.org:Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-AnfossiEnzyme15-18\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-AnfossiEnzyme15_18-0\">18.0<\/a><\/sup> <sup><a href=\"#cite_ref-AnfossiEnzyme15_18-1\">18.1<\/a><\/sup> <sup><a href=\"#cite_ref-AnfossiEnzyme15_18-2\">18.2<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Anfossi, L.; Di Nardo, F.; Giovannoli, C. et al. (2015). \"Enzyme immunoassay for monitoring aflatoxins in eggs\". <i>Food Control<\/i> <b>57<\/b>: 115\u201321. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.foodcont.2015.04.013\" target=\"_blank\">10.1016\/j.foodcont.2015.04.013<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Enzyme+immunoassay+for+monitoring+aflatoxins+in+eggs&rft.jtitle=Food+Control&rft.aulast=Anfossi%2C+L.%3B+Di+Nardo%2C+F.%3B+Giovannoli%2C+C.+et+al.&rft.au=Anfossi%2C+L.%3B+Di+Nardo%2C+F.%3B+Giovannoli%2C+C.+et+al.&rft.date=2015&rft.volume=57&rft.pages=115%E2%80%9321&rft_id=info:doi\/10.1016%2Fj.foodcont.2015.04.013&rfr_id=info:sid\/en.wikipedia.org:Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-VenturaDeterm04-19\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-VenturaDeterm04_19-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Ventura, M.; G\u00f3mez, A.; Anaya, I. et al. (2004). \"Determination of Aflatoxins B1, G1, B2 and G2 in Medicinal Herbs by Liquid Chromatography-Tandem Mass Spectrometry\". <i>Journal of Chromatography A<\/i> <b>1048<\/b> (1): 25\u20139. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.chroma.2004.07.033\" target=\"_blank\">10.1016\/j.chroma.2004.07.033<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/15453415\" target=\"_blank\">15453415<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Determination+of+Aflatoxins+B1%2C+G1%2C+B2+and+G2+in+Medicinal+Herbs+by+Liquid+Chromatography-Tandem+Mass+Spectrometry&rft.jtitle=Journal+of+Chromatography+A&rft.aulast=Ventura%2C+M.%3B+G%C3%B3mez%2C+A.%3B+Anaya%2C+I.+et+al.&rft.au=Ventura%2C+M.%3B+G%C3%B3mez%2C+A.%3B+Anaya%2C+I.+et+al.&rft.date=2004&rft.volume=1048&rft.issue=1&rft.pages=25%E2%80%939&rft_id=info:doi\/10.1016%2Fj.chroma.2004.07.033&rft_id=info:pmid\/15453415&rfr_id=info:sid\/en.wikipedia.org:Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ArranzDeterm06-20\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-ArranzDeterm06_20-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Arranz, I.; Sizoo, E.; van Egmond, H. et al. (2006). \"Determination of Aflatoxin B1 in Medical Herbs: Interlaboratory Study\". <i>Journal of AOAC International<\/i> <b>89<\/b> (3): 595-605. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1093%2Fjaoac%2F89.3.595\" target=\"_blank\">10.1093\/jaoac\/89.3.595<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/16792057\" target=\"_blank\">16792057<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Determination+of+Aflatoxin+B1+in+Medical+Herbs%3A+Interlaboratory+Study&rft.jtitle=Journal+of+AOAC+International&rft.aulast=Arranz%2C+I.%3B+Sizoo%2C+E.%3B+van+Egmond%2C+H.+et+al.&rft.au=Arranz%2C+I.%3B+Sizoo%2C+E.%3B+van+Egmond%2C+H.+et+al.&rft.date=2006&rft.volume=89&rft.issue=3&rft.pages=595-605&rft_id=info:doi\/10.1093%2Fjaoac%2F89.3.595&rft_id=info:pmid\/16792057&rfr_id=info:sid\/en.wikipedia.org:Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ZhangAnUlta18-21\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-ZhangAnUlta18_21-0\">21.0<\/a><\/sup> <sup><a href=\"#cite_ref-ZhangAnUlta18_21-1\">21.1<\/a><\/sup> <sup><a href=\"#cite_ref-ZhangAnUlta18_21-2\">21.2<\/a><\/sup> <sup><a href=\"#cite_ref-ZhangAnUlta18_21-3\">21.3<\/a><\/sup> <sup><a href=\"#cite_ref-ZhangAnUlta18_21-4\">21.4<\/a><\/sup> <sup><a href=\"#cite_ref-ZhangAnUlta18_21-5\">21.5<\/a><\/sup> <sup><a href=\"#cite_ref-ZhangAnUlta18_21-6\">21.6<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Zhang, Z.; Dong, S.; Ge, D. et al. (2018). \"An Ultrasensitive Competitive Immunosensor Using Silica Nanoparticles as an Enzyme Carrier for Simultaneous Impedimetric Detection of Tetrabromobisphenol A bis(2-hydroxyethyl) Ether and Tetrabromobisphenol A Mono(hydroxyethyl) Ether\". <i>Biosensors and Bioelectronics<\/i> <b>105<\/b>: 77\u201380. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.bios.2018.01.029\" target=\"_blank\">10.1016\/j.bios.2018.01.029<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/29355782\" target=\"_blank\">29355782<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=An+Ultrasensitive+Competitive+Immunosensor+Using+Silica+Nanoparticles+as+an+Enzyme+Carrier+for+Simultaneous+Impedimetric+Detection+of+Tetrabromobisphenol+A+bis%282-hydroxyethyl%29+Ether+and+Tetrabromobisphenol+A+Mono%28hydroxyethyl%29+Ether&rft.jtitle=Biosensors+and+Bioelectronics&rft.aulast=Zhang%2C+Z.%3B+Dong%2C+S.%3B+Ge%2C+D.+et+al.&rft.au=Zhang%2C+Z.%3B+Dong%2C+S.%3B+Ge%2C+D.+et+al.&rft.date=2018&rft.volume=105&rft.pages=77%E2%80%9380&rft_id=info:doi\/10.1016%2Fj.bios.2018.01.029&rft_id=info:pmid\/29355782&rfr_id=info:sid\/en.wikipedia.org:Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ReimerComp98-22\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-ReimerComp98_22-0\">22.0<\/a><\/sup> <sup><a href=\"#cite_ref-ReimerComp98_22-1\">22.1<\/a><\/sup> <sup><a href=\"#cite_ref-ReimerComp98_22-2\">22.2<\/a><\/sup> <sup><a href=\"#cite_ref-ReimerComp98_22-3\">22.3<\/a><\/sup> <sup><a href=\"#cite_ref-ReimerComp98_22-4\">22.4<\/a><\/sup> <sup><a href=\"#cite_ref-ReimerComp98_22-5\">22.5<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Reimer, G.J.; Gee, S.J.; Hammock, B.D. (1998). \"Comparison of a Time-Resolved Fluorescence Immunoassay and an Enzyme-Linked Immunosorbent Assay for the Analysis of Atrazine in Water\". <i>Journal of Agricultural and Food Chemistry<\/i> <b>46<\/b> (8): 3353\u201358. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1021%2Fjf970965a\" target=\"_blank\">10.1021\/jf970965a<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Comparison+of+a+Time-Resolved+Fluorescence+Immunoassay+and+an+Enzyme-Linked+Immunosorbent+Assay+for+the+Analysis+of+Atrazine+in+Water&rft.jtitle=Journal+of+Agricultural+and+Food+Chemistry&rft.aulast=Reimer%2C+G.J.%3B+Gee%2C+S.J.%3B+Hammock%2C+B.D.&rft.au=Reimer%2C+G.J.%3B+Gee%2C+S.J.%3B+Hammock%2C+B.D.&rft.date=1998&rft.volume=46&rft.issue=8&rft.pages=3353%E2%80%9358&rft_id=info:doi\/10.1021%2Fjf970965a&rfr_id=info:sid\/en.wikipedia.org:Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-SasakiHowTo01-23\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-SasakiHowTo01_23-0\">23.0<\/a><\/sup> <sup><a href=\"#cite_ref-SasakiHowTo01_23-1\">23.1<\/a><\/sup> <sup><a href=\"#cite_ref-SasakiHowTo01_23-2\">23.2<\/a><\/sup> <sup><a href=\"#cite_ref-SasakiHowTo01_23-3\">23.3<\/a><\/sup> <sup><a href=\"#cite_ref-SasakiHowTo01_23-4\">23.4<\/a><\/sup> <sup><a href=\"#cite_ref-SasakiHowTo01_23-5\">23.5<\/a><\/sup> <sup><a href=\"#cite_ref-SasakiHowTo01_23-6\">23.6<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation web\">Sasaki, D.; Mitchell, R.A. (2001). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.oxfordbiomed.com\/sites\/default\/files\/2017-02\/How%20to%20Obtain%20Reproducible%20Quantitative%20ELISA%20results.pdf\" target=\"_blank\">\"How to Obtain Reproducible Quantitative ELISA Results\"<\/a> (PDF). Oxford Biomedical Research, Inc<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.oxfordbiomed.com\/sites\/default\/files\/2017-02\/How%20to%20Obtain%20Reproducible%20Quantitative%20ELISA%20results.pdf\" target=\"_blank\">https:\/\/www.oxfordbiomed.com\/sites\/default\/files\/2017-02\/How%20to%20Obtain%20Reproducible%20Quantitative%20ELISA%20results.pdf<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=How+to+Obtain+Reproducible+Quantitative+ELISA+Results&rft.atitle=&rft.aulast=Sasaki%2C+D.%3B+Mitchell%2C+R.A.&rft.au=Sasaki%2C+D.%3B+Mitchell%2C+R.A.&rft.date=2001&rft.pub=Oxford+Biomedical+Research%2C+Inc&rft_id=https%3A%2F%2Fwww.oxfordbiomed.com%2Fsites%2Fdefault%2Ffiles%2F2017-02%2FHow%2520to%2520Obtain%2520Reproducible%2520Quantitative%2520ELISA%2520results.pdf&rfr_id=info:sid\/en.wikipedia.org:Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-SaeedThePrep17-24\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-SaeedThePrep17_24-0\">24.0<\/a><\/sup> <sup><a href=\"#cite_ref-SaeedThePrep17_24-1\">24.1<\/a><\/sup> <sup><a href=\"#cite_ref-SaeedThePrep17_24-2\">24.2<\/a><\/sup> <sup><a href=\"#cite_ref-SaeedThePrep17_24-3\">24.3<\/a><\/sup> <sup><a href=\"#cite_ref-SaeedThePrep17_24-4\">24.4<\/a><\/sup> <sup><a href=\"#cite_ref-SaeedThePrep17_24-5\">24.5<\/a><\/sup> <sup><a href=\"#cite_ref-SaeedThePrep17_24-6\">24.6<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Saeed, A.F.U.H.; Ling, S.; Yuan, J. et al. (2017). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5577584\" target=\"_blank\">\"The Preparation and Identification of a Monoclonal Antibody Against Domoic Acid and Establishment of Detection by Indirect Competitive ELISA\"<\/a>. <i>Toxins<\/i> <b>9<\/b> (8): 250. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.3390%2Ftoxins9080250\" target=\"_blank\">10.3390\/toxins9080250<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC5577584\/\" target=\"_blank\">PMC5577584<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/28817087\" target=\"_blank\">28817087<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5577584\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5577584<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=The+Preparation+and+Identification+of+a+Monoclonal+Antibody+Against+Domoic+Acid+and+Establishment+of+Detection+by+Indirect+Competitive+ELISA&rft.jtitle=Toxins&rft.aulast=Saeed%2C+A.F.U.H.%3B+Ling%2C+S.%3B+Yuan%2C+J.+et+al.&rft.au=Saeed%2C+A.F.U.H.%3B+Ling%2C+S.%3B+Yuan%2C+J.+et+al.&rft.date=2017&rft.volume=9&rft.issue=8&rft.pages=250&rft_id=info:doi\/10.3390%2Ftoxins9080250&rft_id=info:pmc\/PMC5577584&rft_id=info:pmid\/28817087&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC5577584&rfr_id=info:sid\/en.wikipedia.org:Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ZhangMulti17-25\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-ZhangMulti17_25-0\">25.0<\/a><\/sup> <sup><a href=\"#cite_ref-ZhangMulti17_25-1\">25.1<\/a><\/sup> <sup><a href=\"#cite_ref-ZhangMulti17_25-2\">25.2<\/a><\/sup> <sup><a href=\"#cite_ref-ZhangMulti17_25-3\">25.3<\/a><\/sup> <sup><a href=\"#cite_ref-ZhangMulti17_25-4\">25.4<\/a><\/sup> <sup><a href=\"#cite_ref-ZhangMulti17_25-5\">25.5<\/a><\/sup> <sup><a href=\"#cite_ref-ZhangMulti17_25-6\">25.6<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Zhang, X.; Yu, X.; Wen, K. et al. (2017). \"Multiplex Lateral Flow Immunoassays Based on Amorphous Carbon Nanoparticles for Detecting Three Fusarium Mycotoxins in Maize\". <i>Journal of Agricultural and Food Chemistry<\/i> <b>65<\/b> (36): 8063-8071. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1021%2Facs.jafc.7b02827\" target=\"_blank\">10.1021\/acs.jafc.7b02827<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/28825819\" target=\"_blank\">28825819<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Multiplex+Lateral+Flow+Immunoassays+Based+on+Amorphous+Carbon+Nanoparticles+for+Detecting+Three+Fusarium+Mycotoxins+in+Maize&rft.jtitle=Journal+of+Agricultural+and+Food+Chemistry&rft.aulast=Zhang%2C+X.%3B+Yu%2C+X.%3B+Wen%2C+K.+et+al.&rft.au=Zhang%2C+X.%3B+Yu%2C+X.%3B+Wen%2C+K.+et+al.&rft.date=2017&rft.volume=65&rft.issue=36&rft.pages=8063-8071&rft_id=info:doi\/10.1021%2Facs.jafc.7b02827&rft_id=info:pmid\/28825819&rfr_id=info:sid\/en.wikipedia.org:Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ZhangANovel18-26\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-ZhangANovel18_26-0\">26.0<\/a><\/sup> <sup><a href=\"#cite_ref-ZhangANovel18_26-1\">26.1<\/a><\/sup> <sup><a href=\"#cite_ref-ZhangANovel18_26-2\">26.2<\/a><\/sup> <sup><a href=\"#cite_ref-ZhangANovel18_26-3\">26.3<\/a><\/sup> <sup><a href=\"#cite_ref-ZhangANovel18_26-4\">26.4<\/a><\/sup> <sup><a href=\"#cite_ref-ZhangANovel18_26-5\">26.5<\/a><\/sup> <sup><a href=\"#cite_ref-ZhangANovel18_26-6\">26.6<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Zhang, Z.; Zhu, N.; Zou, Y. et al. (2018). \"A Novel and Sensitive Chemiluminescence Immunoassay Based on AuNCs@pepsin@luminol for Simultaneous Detection of Tetrabromobisphenol A bis(2-hydroxyethyl) Ether and Tetrabromobisphenol A Mono(hydroxyethyl) Ether\". <i>Analytica Chimica Acta<\/i> <b>1035<\/b>: 168-174. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.aca.2018.06.039\" target=\"_blank\">10.1016\/j.aca.2018.06.039<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/30224136\" target=\"_blank\">30224136<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=A+Novel+and+Sensitive+Chemiluminescence+Immunoassay+Based+on+AuNCs%40pepsin%40luminol+for+Simultaneous+Detection+of+Tetrabromobisphenol+A+bis%282-hydroxyethyl%29+Ether+and+Tetrabromobisphenol+A+Mono%28hydroxyethyl%29+Ether&rft.jtitle=Analytica+Chimica+Acta&rft.aulast=Zhang%2C+Z.%3B+Zhu%2C+N.%3B+Zou%2C+Y.+et+al.&rft.au=Zhang%2C+Z.%3B+Zhu%2C+N.%3B+Zou%2C+Y.+et+al.&rft.date=2018&rft.volume=1035&rft.pages=168-174&rft_id=info:doi\/10.1016%2Fj.aca.2018.06.039&rft_id=info:pmid\/30224136&rfr_id=info:sid\/en.wikipedia.org:Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-QuinnSpec02-27\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-QuinnSpec02_27-0\">27.0<\/a><\/sup> <sup><a href=\"#cite_ref-QuinnSpec02_27-1\">27.1<\/a><\/sup> <sup><a href=\"#cite_ref-QuinnSpec02_27-2\">27.2<\/a><\/sup> <sup><a href=\"#cite_ref-QuinnSpec02_27-3\">27.3<\/a><\/sup> <sup><a href=\"#cite_ref-QuinnSpec02_27-4\">27.4<\/a><\/sup> <sup><a href=\"#cite_ref-QuinnSpec02_27-5\">27.5<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Quinn, C.P.; Semenova, V.A.; Elie, C.M. et al. (2002). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2730307\" target=\"_blank\">\"Specific, Sensitive, and Quantitative Enzyme-Linked Immunosorbent Assay for Human Immunoglobulin G Antibodies to Anthrax Toxin Protective Antigen\"<\/a>. <i>Emerging Infectious Diseases<\/i> <b>8<\/b> (10): 1103-10. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.3201%2Feid0810.020380\" target=\"_blank\">10.3201\/eid0810.020380<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC2730307\/\" target=\"_blank\">PMC2730307<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/12396924\" target=\"_blank\">12396924<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2730307\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2730307<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Specific%2C+Sensitive%2C+and+Quantitative+Enzyme-Linked+Immunosorbent+Assay+for+Human+Immunoglobulin+G+Antibodies+to+Anthrax+Toxin+Protective+Antigen&rft.jtitle=Emerging+Infectious+Diseases&rft.aulast=Quinn%2C+C.P.%3B+Semenova%2C+V.A.%3B+Elie%2C+C.M.+et+al.&rft.au=Quinn%2C+C.P.%3B+Semenova%2C+V.A.%3B+Elie%2C+C.M.+et+al.&rft.date=2002&rft.volume=8&rft.issue=10&rft.pages=1103-10&rft_id=info:doi\/10.3201%2Feid0810.020380&rft_id=info:pmc\/PMC2730307&rft_id=info:pmid\/12396924&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC2730307&rfr_id=info:sid\/en.wikipedia.org:Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-DunnCal13-28\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-DunnCal13_28-0\">28.0<\/a><\/sup> <sup><a href=\"#cite_ref-DunnCal13_28-1\">28.1<\/a><\/sup> <sup><a href=\"#cite_ref-DunnCal13_28-2\">28.2<\/a><\/sup> <sup><a href=\"#cite_ref-DunnCal13_28-3\">28.3<\/a><\/sup> <sup><a href=\"#cite_ref-DunnCal13_28-4\">28.4<\/a><\/sup> <sup><a href=\"#cite_ref-DunnCal13_28-5\">28.5<\/a><\/sup> <sup><a href=\"#cite_ref-DunnCal13_28-6\">28.6<\/a><\/sup> <sup><a href=\"#cite_ref-DunnCal13_28-7\">28.7<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation book\">Dunn, J.; Wild, D. (2013). \"Calibration Curve Fitting\". In Wild, D.. <i>The Immunoassay Handbook<\/i> (3rd ed.). Elsevier Science. pp. 323\u2013336. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/International_Standard_Book_Number\" data-key=\"f64947ba21e884434bd70e8d9e60bae6\">ISBN<\/a> 9780080445267.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Calibration+Curve+Fitting&rft.atitle=The+Immunoassay+Handbook&rft.aulast=Dunn%2C+J.%3B+Wild%2C+D.&rft.au=Dunn%2C+J.%3B+Wild%2C+D.&rft.date=2013&rft.pages=pp.%26nbsp%3B323%E2%80%93336&rft.edition=3rd&rft.pub=Elsevier+Science&rft.isbn=9780080445267&rfr_id=info:sid\/en.wikipedia.org:Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ZhengSimul14-29\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-ZhengSimul14_29-0\">29.0<\/a><\/sup> <sup><a href=\"#cite_ref-ZhengSimul14_29-1\">29.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Zheng, R.; Xu, H.; Wang, W. et al. (2014). \"Simultaneous Determination of Aflatoxin B(1), B(2), G(1), G(2), Ochratoxin A, and Sterigmatocystin in Traditional Chinese Medicines by LC-MS-MS\". <i>Analytical and Bioanalytical Chemistry<\/i> <b>406<\/b> (13): 3031-9. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1007%2Fs00216-014-7750-7\" target=\"_blank\">10.1007\/s00216-014-7750-7<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/24658469\" target=\"_blank\">24658469<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Simultaneous+Determination+of+Aflatoxin+B%281%29%2C+B%282%29%2C+G%281%29%2C+G%282%29%2C+Ochratoxin+A%2C+and+Sterigmatocystin+in+Traditional+Chinese+Medicines+by+LC-MS-MS&rft.jtitle=Analytical+and+Bioanalytical+Chemistry&rft.aulast=Zheng%2C+R.%3B+Xu%2C+H.%3B+Wang%2C+W.+et+al.&rft.au=Zheng%2C+R.%3B+Xu%2C+H.%3B+Wang%2C+W.+et+al.&rft.date=2014&rft.volume=406&rft.issue=13&rft.pages=3031-9&rft_id=info:doi\/10.1007%2Fs00216-014-7750-7&rft_id=info:pmid\/24658469&rfr_id=info:sid\/en.wikipedia.org:Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-Narv.C3.A1ezUltra20-30\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-Narv.C3.A1ezUltra20_30-0\">30.0<\/a><\/sup> <sup><a href=\"#cite_ref-Narv.C3.A1ezUltra20_30-1\">30.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Narv\u00e1ez, A.; Rodr\u00edguez-Carrasco, Y.; Castaldo, L. et al. (2020). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7076805\" target=\"_blank\">\"Ultra-High-Performance Liquid Chromatography Coupled With Quadrupole Orbitrap High-Resolution Mass Spectrometry for Multi-Residue Analysis of Mycotoxins and Pesticides in Botanical Nutraceuticals\"<\/a>. <i>Toxins<\/i> <b>12<\/b> (2): 114. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.3390%2Ftoxins12020114\" target=\"_blank\">10.3390\/toxins12020114<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC7076805\/\" target=\"_blank\">PMC7076805<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/32059484\" target=\"_blank\">32059484<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7076805\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7076805<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Ultra-High-Performance+Liquid+Chromatography+Coupled+With+Quadrupole+Orbitrap+High-Resolution+Mass+Spectrometry+for+Multi-Residue+Analysis+of+Mycotoxins+and+Pesticides+in+Botanical+Nutraceuticals&rft.jtitle=Toxins&rft.aulast=Narv%C3%A1ez%2C+A.%3B+Rodr%C3%ADguez-Carrasco%2C+Y.%3B+Castaldo%2C+L.+et+al.&rft.au=Narv%C3%A1ez%2C+A.%3B+Rodr%C3%ADguez-Carrasco%2C+Y.%3B+Castaldo%2C+L.+et+al.&rft.date=2020&rft.volume=12&rft.issue=2&rft.pages=114&rft_id=info:doi\/10.3390%2Ftoxins12020114&rft_id=info:pmc\/PMC7076805&rft_id=info:pmid\/32059484&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC7076805&rfr_id=info:sid\/en.wikipedia.org:Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-PeckhamAmper13-31\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-PeckhamAmper13_31-0\">31.0<\/a><\/sup> <sup><a href=\"#cite_ref-PeckhamAmper13_31-1\">31.1<\/a><\/sup> <sup><a href=\"#cite_ref-PeckhamAmper13_31-2\">31.2<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Peckham, G.D.; Hew, B.E.; Waller, D.F. et al. (2013). \"Amperometric Detection of Bacillus anthracis Spores: A Portable, Low-Cost Approach to the ELISA\". <i>International Journal of Electrochemistry<\/i> <b>2013<\/b>: 803485. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1155%2F2013%2F803485\" target=\"_blank\">10.1155\/2013\/803485<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Amperometric+Detection+of+Bacillus+anthracis+Spores%3A+A+Portable%2C+Low-Cost+Approach+to+the+ELISA&rft.jtitle=International+Journal+of+Electrochemistry&rft.aulast=Peckham%2C+G.D.%3B+Hew%2C+B.E.%3B+Waller%2C+D.F.+et+al.&rft.au=Peckham%2C+G.D.%3B+Hew%2C+B.E.%3B+Waller%2C+D.F.+et+al.&rft.date=2013&rft.volume=2013&rft.pages=803485&rft_id=info:doi\/10.1155%2F2013%2F803485&rfr_id=info:sid\/en.wikipedia.org:Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ZhangDevelop19-32\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-ZhangDevelop19_32-0\">32.0<\/a><\/sup> <sup><a href=\"#cite_ref-ZhangDevelop19_32-1\">32.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Zhang, C.; Zhang, Q.; Tang, X. et al. (2019). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6563187\" target=\"_blank\">\"Development of an Anti-Idiotypic VHH Antibody and Toxin-Free Enzyme Immunoassay for Ochratoxin A in Cereals\"<\/a>. <i>Toxins<\/i> <b>11<\/b> (5): 280. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.3390%2Ftoxins11050280\" target=\"_blank\">10.3390\/toxins11050280<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6563187\/\" target=\"_blank\">PMC6563187<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/31137467\" target=\"_blank\">31137467<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6563187\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6563187<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Development+of+an+Anti-Idiotypic+VHH+Antibody+and+Toxin-Free+Enzyme+Immunoassay+for+Ochratoxin+A+in+Cereals&rft.jtitle=Toxins&rft.aulast=Zhang%2C+C.%3B+Zhang%2C+Q.%3B+Tang%2C+X.+et+al.&rft.au=Zhang%2C+C.%3B+Zhang%2C+Q.%3B+Tang%2C+X.+et+al.&rft.date=2019&rft.volume=11&rft.issue=5&rft.pages=280&rft_id=info:doi\/10.3390%2Ftoxins11050280&rft_id=info:pmc\/PMC6563187&rft_id=info:pmid\/31137467&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC6563187&rfr_id=info:sid\/en.wikipedia.org:Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-FDA_M1019-33\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-FDA_M1019_33-0\">33.0<\/a><\/sup> <sup><a href=\"#cite_ref-FDA_M1019_33-1\">33.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation web\">Food and Drug Administration (June 2019). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/m10-bioanalytical-method-validation\" target=\"_blank\">\"M10 Bioanalytical Method Validation\"<\/a>. <i>FDA-2019-D-1469<\/i>. Food and Drug Administration<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/m10-bioanalytical-method-validation\" target=\"_blank\">https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/m10-bioanalytical-method-validation<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 01 November 2019<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=M10+Bioanalytical+Method+Validation&rft.atitle=FDA-2019-D-1469&rft.aulast=Food+and+Drug+Administration&rft.au=Food+and+Drug+Administration&rft.date=June+2019&rft.pub=Food+and+Drug+Administration&rft_id=https%3A%2F%2Fwww.fda.gov%2Fregulatory-information%2Fsearch-fda-guidance-documents%2Fm10-bioanalytical-method-validation&rfr_id=info:sid\/en.wikipedia.org:Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-EU1881_06-34\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-EU1881_06_34-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\"><a rel=\"external_link\" class=\"external text\" href=\"https:\/\/eur-lex.europa.eu\/legal-content\/EN\/TXT\/PDF\/?uri=CELEX:32006R1881&from=EN\" target=\"_blank\">\"Commission Regulation (EC) No 1881\/2006 of 19 December 2006\"<\/a>. <i>Official Journal of the European Union<\/i>. 20 December 2006. pp. 5\u201324<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/eur-lex.europa.eu\/legal-content\/EN\/TXT\/PDF\/?uri=CELEX:32006R1881&from=EN\" target=\"_blank\">https:\/\/eur-lex.europa.eu\/legal-content\/EN\/TXT\/PDF\/?uri=CELEX:32006R1881&from=EN<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Commission+Regulation+%28EC%29+No+1881%2F2006+of+19+December+2006&rft.atitle=Official+Journal+of+the+European+Union&rft.date=20+December+2006&rft.pages=pp.+5%E2%80%9324&rft_id=https%3A%2F%2Feur-lex.europa.eu%2Flegal-content%2FEN%2FTXT%2FPDF%2F%3Furi%3DCELEX%3A32006R1881%26from%3DEN&rfr_id=info:sid\/en.wikipedia.org:Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<\/ol><\/div>\n<h2><span class=\"mw-headline\" id=\"Notes\">Notes<\/span><\/h2>\n<p>This presentation is faithful to the original, with only a few minor changes to presentation. Some grammar and punctuation was cleaned up to improve readability. In some cases important information was missing from the references, and that information was added. In the original article, citations 1 and 4 are duplicates; that duplication was removed for this version. The original's citation 34 is unclear, as they neither use the correct document name nor include a direct link to the document; an assumption is made that they intended to reference <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/m10-bioanalytical-method-validation\" target=\"_blank\">this<\/a> FDA draft guidance.<\/sup>\n<\/p>\n<!-- \nNewPP limit report\nCached time: 20200707205102\nCache expiry: 86400\nDynamic content: false\nCPU time usage: 0.831 seconds\nReal time usage: 2.152 seconds\nPreprocessor visited node count: 27861\/1000000\nPreprocessor generated node count: 40903\/1000000\nPost\u2010expand include size: 232589\/2097152 bytes\nTemplate argument size: 79253\/2097152 bytes\nHighest expansion depth: 18\/40\nExpensive parser function count: 0\/100\n-->\n\n<!-- \nTransclusion expansion time report (%,ms,calls,template)\n100.00% 589.963 1 - -total\n 83.34% 491.694 1 - Template:Reflist\n 69.70% 411.218 34 - Template:Citation\/core\n 51.94% 306.426 23 - Template:Cite_journal\n 14.59% 86.088 8 - Template:Cite_web\n 8.90% 52.495 59 - Template:Citation\/identifier\n 6.67% 39.340 3 - Template:Cite_book\n 6.43% 37.935 1 - Template:Infobox_journal_article\n 6.11% 36.065 1 - Template:Infobox\n 4.42% 26.063 40 - Template:Citation\/make_link\n-->\n\n<!-- Saved in parser cache with key limswiki:pcache:idhash:12005-0!*!0!!en!5!* and timestamp 20200707205100 and revision id 39692\n -->\n<\/div><div class=\"printfooter\">Source: <a rel=\"external_link\" class=\"external\" href=\"https:\/\/www.limswiki.org\/index.php\/Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis\">https:\/\/www.limswiki.org\/index.php\/Journal:Enzyme_immunoassay_for_measuring_aflatoxin_B1_in_legal_cannabis<\/a><\/div>\n\t\t\t\t\t\t\t\t\t\t<!-- end content -->\n\t\t\t\t\t\t\t\t\t\t<div class=\"visualClear\"><\/div>\n\t\t\t\t<\/div>\n\t\t\t<\/div>\n\t\t<\/div>\n\t\t<!-- end of the left (by default at least) column -->\n\t\t<div class=\"visualClear\"><\/div>\n\t\t\t\t\t\n\t\t<\/div>\n\t\t\n\n<\/body>","bf4e9afee9a0f426bf85b45d063f9b47_images":["https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/7\/71\/Fig1_DiNardo_Toxins2020_12-4.png","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/8\/86\/Fig2_DiNardo_Toxins2020_12-4.png"],"bf4e9afee9a0f426bf85b45d063f9b47_timestamp":1594155060,"14fe555f4f0cddcccf179363f98c5b79_type":"article","14fe555f4f0cddcccf179363f98c5b79_title":"Laboratory testing methods for novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (D'Cruz et al. 2020)","14fe555f4f0cddcccf179363f98c5b79_url":"https:\/\/www.limswiki.org\/index.php\/Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)","14fe555f4f0cddcccf179363f98c5b79_plaintext":"\n\n\t\t\n\t\t\t\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t\n\n\t\t\t\tJournal:Laboratory testing methods for novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t\tFrom LIMSWiki\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\tJump to: navigation, search\n\n\t\t\t\t\t\n\t\t\t\t\tFull article title\n \nLaboratory testing methods for novel Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2)Journal\n \nFrontiers in Cell and Developmental BiologyAuthor(s)\n \nD'Cruz, Roshan J.; Currier, Arthur W.; Sampson, Valerie B.Author affiliation(s)\n \nNemours\/Alfred I. duPont Hospital for ChildrenPrimary contact\n \nEmail: valerie dot sampson at nemours dot orgEditors\n \nLaBarge, Mark A.Year published\n \n2020Volume and issue\n \n8Article #\n \n468DOI\n \n10.3389\/fcell.2020.00468ISSN\n \n2296-634XDistribution license\n \nCreative Commons Attribution 4.0 InternationalWebsite\n \nhttps:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2020.00468\/fullDownload\n \nhttps:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2020.00468\/pdf (PDF)\n\nContents\n\n1 Abstract \n2 Introduction \n3 Detection of SARS-CoV-2 by real-time reverse transcription polymerase chain reaction (qRT-PCR) \n\n3.1 Specifics \n\n3.1.1 Sample collection \n3.1.2 RNA isolation \n3.1.3 qRT-PCR \n\n\n3.2 Advantages \n3.3 Disadvantages \n3.4 Key logistics \n\n\n4 Detection of antibodies against SARS-CoV-2 proteins by enzyme-linked immunosorbent assay (ELISA) \n\n4.1 Specifics \n\n4.1.1 Sample collection \n4.1.2 ELISA \n\n\n4.2 Advantages \n4.3 Disadvantages \n4.4 Key logistics \n\n\n5 Rapid detection of SARS-CoV-2 by lateral flow immunoassays (LFI) \n\n5.1 Specifics \n\n5.1.1 LFI \n\n\n5.2 Advantage \n5.3 Disadvantage \n5.4 Key logistics \n\n\n6 Serum virus neutralization assay (SVN) \n\n6.1 Specifics \n\n6.1.1 Sample collection \n6.1.2 SVN \n\n\n6.2 Advantages \n6.3 Disadvantages \n6.4 Key logistics \n\n\n7 Emerging methods for diagnosis of SARS-CoV-2 \n\n7.1 Isothermal nucleic acid amplification \n\n7.1.1 RT-LAMP \n7.1.2 RPA \n\n\n7.2 CRISPR (clustered regularly interspaced short palindromic repeats) \n\n7.2.1 Cas13a assay \n\n\n7.3 Next-generation sequencing \n\n7.3.1 Biosafety \n\n\n\n\n8 Conclusions \n9 Acknowledgements \n\n9.1 Author contributions \n9.2 Funding \n9.3 Conflict of interest \n\n\n10 References \n11 Notes \n\n\n\nAbstract \nFollowing the first reports of coronavirus disease 2019 (COVID-19) by China to the World Health Organization (WHO) on December 31, 2019, more than 4,302,774 cases of infection by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus have been reported by authorities in 212 countries and territories as of May 12, 2020. The outbreak and spread of COVID-19 worldwide highlights the critical need for developing rapid and accurate diagnostic testing methods for emerging human coronavirus (CoV) infections. Testing is crucial to tracking the spread of disease during a pandemic, and to swiftly permitting public health interventions, including isolation, quarantine, and appropriate clinical management of afflicted individuals. The key components of viral diagnostic tests are (1) collection of the appropriate sample (blood, nasal swab, and throat swab); (2) availability of the genetic and proteomic sequences of the novel virus for analysis; and (3) rapid and accurate laboratory testing methods. The current gold standard for the molecular diagnosis of SARS-CoV-2 infection is the real-time reverse transcription polymerase chain reaction (qRT-PCR) for the qualitative and quantitative detection of viral nucleic acids. Other relevant laboratory methods include enzyme-linked immunosorbent assays (ELISA) for viral antibody and antigen detection, and serum virus neutralization (SVN) assays for antibody neutralization determination. The challenges faced in developing a diagnostic test for a novel pathogen are the ability to measure low viral loads for early detection, to provide low or no cross-reactivity with other viral strains, and to deliver results rapidly. Several point-of-care molecular devices are currently being integrated for fast and accurate diagnosis of SARS-CoV-2 infections. This review discusses the current laboratory methods available to test for coronaviruses by focusing on the present COVID-19 outbreak.\nKeywords: coronavirus, RT-PCR, ELISA, lateral flow diagnostics, convalescent plasma\n\nIntroduction \nCoronavirus disease 2019 (COVID-19) is caused by a novel coronavirus (CoV) that was originally reported in Wuhan, Hubei province, China in December 2019.[1] The International Committee on Taxonomy of Viruses named the virus \"severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Infection by SARS-CoV-2 causes a respiratory illness that varies in severity from mild upper respiratory symptoms akin to the seasonal flu, to severe progressive respiratory failure that requires intensive care and can lead to death. Asymptomatic carriers of the virus have also been reported and pose a significant public health threat due to their ability to unknowingly spread the virus.[2] SARS-CoV-2 represents the third coronavirus in this millennium to cross species from animals to humans and cause a severe respiratory disease, after Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012[3] and severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003.[4][5] SARS-CoV-2 has now been identified as the seventh coronavirus that is transmissible between humans (a group which also includes HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1).[6] On January 30, 2020, the World Health Organization (WHO) declared the SARS-CoV-2 epidemic a public health emergency of international concern, and the public health emergency was upgraded to a pandemic on March 11. At least 4,302,774 confirmed cases and 289,561 deaths worldwide were reported as of May 12.[7] Diagnostic testing is critical during a pandemic as the ability to track the spread of SARS-CoV-2 is essential for effective disease management and control.\nSARS-CoV-2 is a positive-sense, single-stranded RNA (ssRNA), group IV virus. The genome was sequenced from the bronchoalveolar lavage fluid of a patient (Genbank: MN908947) and shared through the Global Initiative on Sharing All Influenza Data (GISAID) platform on January 12, 2020.[8] The ~30 k base pair genome is highly similar to the human SARS-CoV and bat CoV-SARS-like genomes, with 14 open reading frames (ORFs) that encode structural, replication, and non-structural accessory proteins, as depicted in Figure 1. Molecular modeling studies demonstrate that like SARS-CoV, SARS-CoV-2 is surrounded by a lipid bilayer membrane, containing structural membrane (M) and envelope (E) proteins that interact to form the viral envelope.[9] This layer also contains spike glycoproteins (S) that give the characteristic \u201ccorona\u201d appearance of this family of viruses. The spike proteins bind specific host cell receptors to facilitate host cell attachment and entry.[10] The nucleic acid-associated protein binds the RNA genome and forms the nucleocapsid (N). Other proteins include replication and non-structural accessory proteins, listed in Table 1. Reports of different strains of SARS-CoV-2 suggest an early split from the SARS-CoV-2 lineage and\/or that the virus is mutating. Ongoing research provides insight into the unique and conserved features of the genome and proteome of SARS-CoV-2 for tracking mutations and generates evidence about the evolution of the virus.[11][12] This is important as these changes may affect key structural and non-structural components of SARS-CoV-2 that can render some diagnostic tests ineffective or less sensitive and can also impact the selection of epitopes for the development of new tests.\n\r\n\n\n\n\n\n\n\n\n\n\n Figure 1. Schematic representation of SARS-CoV-2 genome. SARS-CoV-2 contains a positive-sense, positive-stranded mRNA genome with a 5\u2032 capped mRNA sequence (C) and a 3\u2032 poly-A tail. The coding genes are: ORF1a, ORF1b, Spike (S), ORF3a, ORF3b, Envelope (E), Membrane (M), ORF6, ORF7a, ORF7b, ORF8, ORF9b, ORF14, Nucleocapsid (N), and ORF10.\n\n\n\n\n\n\n\n\n\n\n\n\n Table 1. Proteins associated with the 14 ORFs of SARS-CoV.\n\n\n\nThe spread of SARS-CoV-2 is primarily by respiratory droplets that arise from individuals that harbor the virus. Symptomatic individuals with the disease are one source of virus, but a major public health concern is transmission by mildly ill or asymptomatic individuals during the incubation period. Rapid viral diagnostic testing for SARS-CoV-2 is critical to identify these individuals and facilitate the implementation of protective measures such as social distancing, quarantine, and isolation that help to mitigate the spread of the virus in the community. The development of rapid and accurate tests that detect antibodies post-infection provide information about an individual's exposure to the virus and can be used to monitor the possibility of immunity, relapse, or reinfection. This supports interventions to protect high-risk populations from developing more severe illness and can be used to investigate the efficacy of passive antibody therapies for COVID-19 infection. This review describes the available testing methods for SARS-CoV-2 and brings to light the importance of laboratory testing to control this disease and prepare for possible future disease threats.\n\nDetection of SARS-CoV-2 by real-time reverse transcription polymerase chain reaction (qRT-PCR) \nThe qRT-PCR method detects the genetic material of SARS-CoV-2 in order to identify the virus and\/or quantify viral load. Comparisons of the ssRNA genetic sequences of this virus have shown similarities to SARS-CoV and several bat coronaviruses.[13] This detailed knowledge has allowed the rapid development of qRT-PCR assays for SARS-CoV-2 using SARS-CoV and other known coronaviruses as references.\n\nSpecifics \nSample collection \nUpper and lower respiratory samples are collected. Nasopharyngeal swabs are high-priority specimens for SARS-CoV-2, and low-priority specimens include oropharyngeal swabs, bronchoalveolar lavage, tracheal aspirates, and sputum.[14]\n\nRNA isolation \nRNA is extracted from clinical specimens using approved viral isolation kits.[15]\n\nqRT-PCR \nRNA is reverse transcribed to cDNA and subsequently amplified using a real-time quantitative PCR instrument. WHO announced various primer and probe sets for SARS-CoV-2 previously developed in China, Germany, Hong Kong, Japan, Thailand, and the United States (Table 2).[16] Primers target different sections of the virus' genetic sequence, including the envelope E gene, the RNA-dependent RNA polymerase (RdRp) gene, and the N gene.[15][16][17] Targeting the E gene is reported for highest sensitivity, followed by the RdRp gene for confirmation.[15] Some laboratories have multiplexed PCR tests consisting of multiple primer and probe sets located at different regions in the SARS-CoV-2 genome. These assays can be designed to contain primer sets targeting multiple genes simultaneously (RdRp\/hel, S, N)[18], or to detect different regions in a single target such as the N gene (Table 2).[19] The use of multiplex assays is potentially beneficial as this can improve sensitivity in cases of loss or degradation of viral RNA during specimen collection and nucleic acid extraction, or in the event of mutation of the virus genome. These assays use in vitro synthesized RNA derived from transcripts (e.g., BetaCoV_Wuhan_WIV04_2019, GISAID Access number: EPI_ISL_402124) as positive controls and to generate standard curves. An internal control using RNAse P (RP) verifies the presence and quality of nucleic acid in samples, and molecular grade nuclease-free water is used as a negative amplification control. A negative patient sample serves both as a negative extraction control to monitor cross contamination across samples and to validate test reagents.\n\r\n\n\n\n\n\n\n\n\n\n\n Table 2. Table of primer and probe sequences for detecting SARS-CoV-2 genes.\n\n\n\nAdvantages \nqRT-PCR is the frontline diagnostic test for COVID-19, capable of analyzing thousands of specimens in a single day while showing a testing sensitivity of 95%.[15] The anticipated limit of detection of the SARS-CoV-2 qRT-PCR test is <10 copies\/reaction[17], which allows early detection of low viral titers. Gene amplification indicates a positive result for the presence of SARS-CoV-2 RNA and should correlate with clinical observations, patient history, and epidemiological information.\n\nDisadvantages \nFalse positive results could be generated by cross-reactivity of primers with nucleic acids arising from co-infection with other viruses or bacteria. In these cases, the agent detected may not be the definite cause of disease. Matching of the SARS-CoV-2 qRT-PCR primers and probes using reliable libraries (e.g., BLAST) is necessary to ensure there is no homology with other coronaviruses like SARS-CoV from 2003 or other organisms such as Staphylococcus aureus and Candida albicans. False positives can also occur if reagents in a laboratory become contaminated, which is a major concern, particularly with the high volume of testing encountered during a pandemic. A negative patient sample is useful to identify this error in testing.\nFalse negative results could potentially arise from mutations occurring in the primer and probe target regions in the SARS-CoV-2 genome. Negative results do not preclude SARS-CoV-2 infection, and results should be validated with different primer sets against the same gene target and combined with patient history and other clinical data to accurately determine patient infection status.\n\nKey logistics \nProvisions for testing laboratories, the use of approved tests, and validation of results with governing authorities to develop master protocols for use by multiple investigators must be in place to achieve rapid testing capacity. The output for number of tests per day and number of individuals tested per day relies on the availability of laboratory capacity, trained staff, reagents, supplies, and equipment. Large quantities of specific high-grade reagents are needed to perform tests, and supplies can be quickly depleted in a pandemic. This impacts the turnaround time for qRT-PCR diagnostic testing that ranges between two and five days. Strategies to rapidly scale up testing for novel human cornaviruses must be considered for future diagnostic testing.\n\nDetection of antibodies against SARS-CoV-2 proteins by enzyme-linked immunosorbent assay (ELISA) \nAn ELISA is a diagnostic method used to identify antibodies in patient blood sample or nasopharyngeal swabs. An ELISA employed for antibody detection against SARS-CoV-2 measures the host humoral response, including IgM, IgG, and IgA to define previous exposure to the virus.[20][21] IgM is the first immunoglobulin that is produced in response to an antigen and is primarily detected during the early onset of disease (the first three to seven days). IgG is the most abundant immunoglobulin that is produced in response to an antigen (seven to 25 days) and is maintained in the body after initial exposure. It may also have a protective role for acquired immunity. The IgA immunoglobulin plays a crucial role in the immune function of mucous membranes.\nThe SARS-CoV-2 S glycoprotein that mediates attachment and entry into cells is surface-exposed and is a key target for the production of host-neutralizing antibodies.[22] This feature has made the S protein the focal target of antibody and vaccine development. The N protein in human coronaviruses' functions as an antagonist of interferon[23][24] and viral encoded repressor (VSR) of RNA interference (RNAi) that facilitates viral replication, and is also a key target for antibody design.[25] Recombinant antigens derived from the receptor binding domain of S protein (rS) as well as recombinant N protein (rN) are being developed as suitable diagnostic targets to detect IgM, IgG, and IgA antibodies. Dual detection of IgM\/IgG and IgG\/IgA immunoglobulins is under development for use in conjunction with nucleic acid detection for detecting active infection and to define previous exposure to SARS-CoV-2.\n\nSpecifics \nSample collection \nSystemic blood samples are collected from individuals for extraction of serum.\n\nELISA \nPurified rS or rN are immobilized to the surface of a multi-well plate as capture antigens. Controls and inactivated SARS-CoV-2 serum samples are incubated with the antigen for SARS-CoV-2 antibody-antigen binding. A labeled secondary antibody-conjugate (e.g., horseradish peroxidase) is bound to the SARS-CoV antibodies for signal detection by substrate addition, and quantification.\n\nAdvantages \nAntibody tests provide the advantage of a simple method of detection of SARS-CoV-2 antibodies and are convenient to compare multiple samples from a single patient. Positive rates of detection for SARS-CoV-2 IgG in patients by ELISA measurements are 85.4% and 75.6\u201393.1% for IgM.[20] Jin et al.[26] reported sensitivities of serum IgM and IgG antibodies for detection were 48.1 and 88.9%, and specificities were 100 and 90.9%, with the highest sensitivity for antibody tests recorded two weeks after the first symptoms of disease. The lower IgM sensitivity may be because the IgM response occurs early then decreases and does not offer a strong detectable signal, while IgG signals may be more readily detected and present beyond 20 days. The incorporation of unique immunoglobulin labels may increase the sensitivity of rapid antibody tests for respiratory viruses.[27] Results from antibody testing could inform infection status and define previous exposure to SARS-CoV-2. Antibody detection is also used to identify recovered patients as human donors for the generation of convalescent patient serum or plasma as an investigational treatment for critically ill patients.[28]\n\nDisadvantages \nThe results of SARS-CoV-2 antibody tests may vary by apparent disease periods and by time after symptom onset, as well as on the reliability of diagnostic assays. It is not yet known when IgM or IgG antibodies specific to the SARS-CoV-2 virus will become detectable during an infection, how long antibodies persist following infection, and what extent of protection neutralizing antibodies offer against subsequent infection with the virus.\nThe overall sensitivity and specificity indicate the possibility of false negatives and false positives in this testing method. Since the risk for recurrent infection with SARS-CoV-2 is not known for COVID-19, detection of one or two antibodies (IgM and\/or IgG) does not necessarily guarantee immunity against reinfection. Negative results do not rule out SARS-CoV-2 infection\u2014particularly in those who have been in contact with the virus\u2014and positive results may be due to past or present infection with SARS-CoV[20] and possibly non-SARS-CoV strains.[29] It will be critical to conduct stringent evaluation of antibody diagnostic assays to determine the accuracy and reliability of results.\n\nKey logistics \nRecombinant systems are routinely used to express recombinant proteins to develop antibody assays. However, protein-expression systems can result in significant discrepancies between recombinant and native viral proteins. For example, the use of E. coli competent cells produces proteins that lack critical post-translational modifications in human cells (e.g., glycosylation) that can alter epitopes and protein conformation.[30] Consequently, this can compromise sensitivity and specificity of antigens for diagnostic assays. The use of mammalian expression systems to express recombinant proteins will produce antigens with post-translation modifications that more closely resemble human native proteins[31], leading to higher sensitivity and specificity of assays.\nSerological assays are currently under accelerated development for diagnosis of human coronavirus infections. Commercial reagents need to be validated by clinical trials using samples from patients with confirmed infections of SARS-CoV-2, and approved by the regulatory review process. Nonetheless, a rapid and sensitive platform for identification of antibody titers will also support screening to identify and minimize the risk of viral spread to others, as well as for epidemiological studies and vaccine evaluation studies. The U.S. Food and Drug Administration (FDA) allows the use of rapid antibody tests for SARS-CoV-2 under emergency use authorization (EUA). This expedites the assessment and optimization of these diagnostic tests, with the expectation that any test is sufficiently experimentally validated before it is made available to patients. If these tests do not provide accurate results, this can impair prevention efforts and delay appropriate treatment during the global pandemic response.\n\nRapid detection of SARS-CoV-2 by lateral flow immunoassays (LFI) \nTest developers have used the principles behind ELISA and applied them to develop lateral flow immunoassays (LFI) for the rapid qualitative detection of a substance. Some researchers are beginning to apply LFI to SARS-CoV-2 in the form of a simple, portable diagnostic strip to measure either SARS-CoV-2 antibodies or antigens. As viral titers are often low in nasal swabs and serum or plasma, detection of antigens may be more challenging in comparison to detection of antibodies. Serological antigen assays can target S1 and S2 domains of the S protein that binds angiotensin-converting enzyme-2 (ACE-2), an integral transmembrane protein in the lung alveolar epithelium that serves as the initial attachment site for SARS-CoV-2, or N proteins.\n\nSpecifics \nLFI \nThe design of the lateral flow test is that of a strip\/dipstick containing immobilized test reagents, enclosed in a cassette. Drops of a patient's blood are deposited on the strip, which contains a coating of purified monoclonal antibody (mAb) or recombinant antigen that is localized at specific regions on a nitrocellulose membrane. The mAb targets a viral antigen; the recombinant antigen is recognized by antibodies that are present in infected patients. The strip also contains labeled detector antibodies that bind the same antigen. A positive antibody result indicates binding between the coating antigen and patient antibodies and binding by the detector antibody. This generates a colored signal. A positive antigen result indicates binding between the coating antibody and patient antigen.\n\nAdvantage \nTwo drops of blood are sufficient for detection of SARS-CoV-2 and antibodies by this method. This technique delivers results in approximately 15 minutes and uses visual detection by the naked eye, in comparison to qRT-PCR (two to five days). Detection of antibodies shows previous viral exposure while detection of antigens indicates active carriers of SARS-CoV-2 virus. The specificity and sensitivity of LFIs are comparable with antibody and antigen assays.\n\nDisadvantage \nTests to detect SARS-CoV-2 in patients by identifying viral antigens are more challenging to develop than tests to detect the neutralizing antibodies against SARS-CoV-2 (see below), as purified monoclonal antibodies must be generated against target antigens. Further, these assays need to be assessed and optimized using blood from infected patients.\n\nKey logistics \nThe rapid development of some antigens for assays are led by the use of \u201cprototype\u201d pathogens and in silico models of antibody\u2013antigen interactions that are used to generate artificial antibody libraries.[32] Antibody phage display technology can be applied to discover antibodies against antigens.[33] These can be rapidly generated to produce prototypes of diagnostic tests for validation studies that expedite assessment and optimization, before the final commercial diagnostic kits are available. Integrating fast, portable tests with epidemiological surveillance will also provide quick and reliable information to public health authorities monitoring the spread of SARS-CoV-2.\n\nSerum virus neutralization assay (SVN) \nThe SVN assay is a serological test that measures the ability of a patient's antibodies to neutralize infectivity of SARS-CoV-2 and attenuate infection. This assay is considered the most reliable for the assessment of protective antibody and can inform the use of convalescent plasma as a passive antibody therapy for COVID-19 infection, particularly in severely ill patients. Although there is limited clinical data, early studies suggest that transfusion of convalescent plasma can suppress SARS-CoV-2 viral replication and protect an individual from infection.[20][28] The SVN assay is not used for routine diagnosis but is frontline for this special indication.\n\nSpecifics \nSample collection \nPlasma is prepared from systemic blood samples collected from COVID-19 convalescent donors. Written informed consent is required from both the donor and recipient.\n\nSVN \nSeveral cell lines are suitable for SARS-CoV-2 transduction, including Vero (monkey kidney cell line), Huh7 (human hepatoma cell line), and 293T (human kidney cell line).[34] Serial dilutions of patient convalescent serum are added to known strains of virus (BetaCoV\/Shenzhen\/SZTH-003\/2020 strain virus, GISAID access number: EPI_ISL_406594).[28] The mixture is inoculated into a susceptible cell monolayer and incubated for virus adsorption. The cytopathic effect can be measured by microscopic examination[28] after a five-day incubation, fluorescence[34], or plaque formation, following 24 hours of incubation. The neutralizing antibody titer is the highest dilution of serum that reduces activity of SARS-CoV-2.\n\nAdvantages \nThe SVN assay is a highly robust and reproducible test that may be applied to detect SARS-CoV-2 neutralizing antibodies in convalescent plasma samples to identify the best candidates for treatment. Neutralizing activities, along with viral load and antibody titers, can be simultaneously monitored in paired plasma samples in patients receiving convalescence plasma in order to establish algorithms for determining patient and donor factors that predict clinical efficacy.\n\nDisadvantages \nThe accessibility of the live SARS-CoV-2 strain is regulated, which limits the development of laboratory testing by SVN. While inexpensive, it is a manual assay and requires careful in-house standardization and quality control.\n\nKey logistics \nA preliminary case report of positive responses of five severely ill patients with COVID-19 who were treated in the Shenzhen Third People's Hospital, China using plasma from recovered individuals was recently published.[28] The convalescent plasma contained functional IgG and IgM anti\u2013SARS-CoV-2 neutralizing antibodies that inhibited viral growth in cell cultures. Notably, the SVN assay reliably measured the increases in the patients' neutralizing antibody titers between one and 12 days after plasma transfusion. This study was not evaluated in a randomized clinical trial, and there are limitations to the data interpretation. Nonetheless, these findings demonstrate the utility of the SVN assay for evaluating anti\u2013SARS-CoV-2 neutralizing antibodies for future convalescent plasma assessment in more rigorous clinical investigations involving a larger cohort of patients with severe COVID-19 illness.\n\nEmerging methods for diagnosis of SARS-CoV-2 \nMethods for the rapid detection of nucleic acids are being used to develop applications in clinical diagnostics of SAR-CoV-2.\n\nIsothermal nucleic acid amplification \nThis method amplifies DNA or RNA target sequence in a streamlined and exponential manner for detection, and in contrast to PCR, does not require thermal cycling. A wide variety of nucleic acid detection assays have been developed, including loop-mediated isothermal amplification (LAMP), a single-tube technique for the amplification of DNA; reverse transcription-LAMP, which combines reverse transcriptase and LAMP to detect RNA (RT-LAMP)[35]; recombinase polymerase amplification (RPA)[36]; helicase-dependent amplification (HDA)[37]; strand displacement amplification (SDA)[38]; and nucleic acid sequence-based amplification (NASBA).[39] These assays incorporate isothermal methods to enable primer binding followed by amplification using a polymerase with strand-displacement activity that separates the strand that is annealed to the target sequence for detection. Amplified gene products can be detected by photometry. Isothermal nucleic acid amplification is utilized in several commercial molecular diagnostic platforms and is considered the fastest available molecular laboratory and point-of-care test for the detection of novel SARS-CoV-2.\n\nRT-LAMP \nThe RT-LAMP method has been shown to effectively detect SARS-CoV-2 in clinical samples from individuals with COVID-19.[40] Multiple loop primers targeting the ORF1ab gene and the S gene were used for DNA strand displacement activity and target amplification that achieved detection of 20 copies\/reaction and 200 copies\/reaction, respectively. These results were comparable to qRT-PCR amplification. The reported 100% sensitivity and 100% specificity, as well as the mean time for detection being under 30 minutes, demonstrate this is a definitive testing method.\n\nRPA \nThis method detected total viral RNA derived from cell culture supernatant and 19 nasopharyngeal swab samples (eight positive and 11 negative) for SARS-CoV-2.[41] This approach integrates isothermal methods for reverse transcription followed by recombinase activity that mediates primer (targeting the N gene) binding to the homologous sequence in dsDNA. Subsequent amplification by polymerase mediated primer extension achieved 100% diagnostic sensitivity and specificity. This method offers potential advantages over qRT-PCR for speed, scale, and portability, allowing evidence-based clinical decisions to be made during a patient visit.\n\nCRISPR (clustered regularly interspaced short palindromic repeats) \nThe CRISPR assay functionality is being applied for detection of DNA or RNA using nucleic acid pre-amplification combined with CRISPR-Cas enzymology for specific recognition of sequences.\nThe CRISPR\/Cas13a system is a recently discovered CRISPR-RNA (crRNA) guided detection method that is specific for RNA and is being applied for SARS-CoV-2 detection. A key feature of this approach is the Cas13a (formerly named C2c2) enzyme that recognizes and binds targeted RNA in a sequence-specific manner, followed by non-specific trans-endonuclease cleavage of non-targeted RNA (\u201ccollateral\u201d cleavage) for signal amplification and nucleic acid detection. The Cas13a assay can be paired with target nucleic acid amplification for more sensitive results using an isothermal exponential amplification technique, most commonly RPA. This coupled technique is termed SHERLOCK (Specific High-Sensitivity Enzymatic Reporter unLOCKing) and allows fluorescence, colorimetric, lateral flow, and other readout approaches to enable the rapid detection of a variety of targets.[42]\n\nCas13a assay \nUnlike in vivo CRISPR tools, the Cas13a protein must be recombinantly expressed and purified. The endonuclease activity of purified Cas13a uses crRNA targeting sequences in the S gene and ORF1ab in SARS-CoV-2 RNA. Target site-recognition activates trans-cleavage of reporter probes resulting in increases in fluorescence output signals and confirming the presence of viral RNA. Using synthetic SARS-CoV-2 the reported performance of this method for detection of target sequences is 20\u2013200 aM.[42] The Cas13a\/crRNA platform has been adapted for lateral-flow assays and could have wide applications as a SARS-CoV2 detector in both research and in the clinic. Assays can be designed as a paper dipstick test that delivers signals within 30 to 60 minutes. This is a very promising technology and these positive advances in science offer immense hope for future disease control.\n\nNext-generation sequencing \nNext-generation sequencing (NGS) enables complete sequencing of the ~30,000 nucleotides of the SARS-CoV-2 genome. NGS provides a method for identification of SARS-CoV-2, for environmental monitoring and surveillance testing, while also providing insight into strain origin and viral evolution. Each sequence is deposited into the GISAID EpiCoVTM Database, and to date there are over 17,000 SARS-CoV-2 sequences from global NGS efforts.\nSample is prepared by extracting RNA from clinical specimens, similar to qRT-PCR, and the sample is further purified to remove human cytoplasmic and ribosomal rRNA. \nLibrary preparation involves fragmenting RNA, followed by cDNA synthesis. Through the use of a set of highly specific, universal coronavirus primers, all genomic segments are amplified and the DNA amplicons are sequenced to deliver highly accurate SARS-CoV-2 typing in less than 24 hours. Virus titer, efficiency of human rRNA depletion, and the number of reads per sample impact the number of virus-specific reads obtained and accurate coverage of the viral genome.\nCollectively, global NGS data suggest the SARS-CoV-2 genome is relatively stable, although mutations are being identified in symptomatic individuals that are not present in the original strain in Wuhan, China. Two recent NGS studies report a large base pair deletion consisting of 81 nucleotides in SARS-CoV-2 ORF7a in a virus sample from a U.S. patient[43], and point mutations that may suggest a more infectious strain of the virus than the original strain.[44] The ORF7a gene encodes an accessory protein that is involved in viral infection and host cell death.[45] These findings require investigation in other patient samples and to determine whether such mutations are selected in asymptomatic or symptomatic individuals. Although NGS is one of the most comprehensive approaches for identifying SARS-CoV-2, this method is relatively expensive, with multiple sample preparation steps. As such, it tends to not be used for large-scale testing.\n\nBiosafety \nRegulating authorities provide interim guidance on the handling of specimens associated with SARS-CoV-2.[46] Samples for testing can be performed in a Biosafety Level 2 (BSL-2) laboratory with unidirectional airflow and BSL-3 precautions, and respiratory protection and a designated area for personal protective equipment changes are recommended. Isolation of SARS-CoV-2 in cell culture and initial characterization of viral agents recovered in cultures of patient samples should be conducted at Biosafety Level 3 (BSL-3), with regulatory approval and guidance.\n\nConclusions \nFigure 2 and Table 3 summarize the main laboratory tests for detection of components of SARS-CoV-2 and the humoral response to the virus, and they depict key features of these approaches. Given the public health emergency that the expanding COVID-19 outbreak presents, more widespread testing is needed to investigate the disease (e.g., prevalence in the population, severity in age groups) and to identify individuals who are infected but have few or no symptoms. Detailed epidemiological data sets will better establish the rates of severe infection and death among infected populations.\n\r\n\n\n\n\n\n\n\n\n\n\n Figure 2. Molecular structure of SARS-CoV-2 and summary of the available laboratory tests and their target molecules. SARS-CoV-2 has a lipid bilayer membrane that contains Envelope (E) and Membrane (M) proteins that make up the envelope. Spike (S) glycoproteins project from the surface of the virion. Nucleocapsid protein (N) is composed of the protein that is associated with the viral genetic material. RT-PCR, reverse transcriptase polymerase chain reaction; ELISA, enzyme-linked immunosorbent assay; LFI, lateral flow immunoassay; SVN, serum virus neutralization assay; INAA, isothermal nucleic acid amplification; CRISPR, clustered regularly interspaced short palindromic repeats; NGS, next-generation sequencing; RT-LAMP, reverse transcriptase loop-mediated isothermal amplification; RPA, recombinase polymerase amplification.\n\n\n\n\r\n\n\n\n\n\n\n\n\n\n\n Table 3. Summary of main testing methods for COVID-19 highlighting the patient sample required for testing, material being tested, and key features.\n\n\n\nOngoing research is critical to optimize existing antibody tests to determine whether immunity prevents recurrent infection and to investigate the efficacy of passive antibody therapies for COVID-19 infection. The identification of novel disease biomarkers may be valuable for understanding what makes people susceptible to COVID-19 infection and in predicting the severity and progression of disease. Researchers could request approval to analyze stored samples of human blood or in animals that might be a natural reservoir of the virus. Specifically, guidance would be needed to direct blood and plasma collection centers to allow access of samples from COVID-19 patients.\nThe COVID-19 pandemic showcases how quickly information needs to be shared as responders address rapidly evolving situations. Establishing communication across laboratories worldwide helps to develop master protocols and establish reference panels for use by multiple investigators. This aids in coordinating the collection and use of data within the constraints of the regulatory infrastructure. Having a range of tests also puts less pressure on one manufacturer or supply chain, as different suppliers may use different materials. This could help alleviate difficult decisions to limit testing to the most vulnerable patients, which can have great public health consequences.\n\nAcknowledgements \nThe authors thank Robert E. Akins, Ph.D. (Nemours\/A. I. duPont Hospital for Children) for reading and editing this manuscript.\n\nAuthor contributions \nRD'C and VS contributed to concept and writing of manuscript. AC contributed to writing, and prepared tables and figure for this manuscript.\n\nFunding \nThis work was provided in part by Nemours\/The Fund.\n\nConflict of interest \nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nReferences \n\n\n\u2191 World Health Organization (2020). \"Naming the coronavirus disease (COVID-19) and the virus that causes it\". World Health Organization. https:\/\/www.who.int\/emergencies\/diseases\/novel-coronavirus-2019\/technical-guidance\/naming-the-coronavirus-disease-(covid-2019)-and-the-virus-that-causes-it . Retrieved May 2020 .   \n\n\u2191 Chan, J.F.-W.; Yuan, S.; Kok, K.-H. et al. (2020). \"A Familial Cluster of Pneumonia Associated With the 2019 Novel Coronavirus Indicating Person-To-Person Transmission: A Study of a Family Cluster\". Lancet 395 (10223): 514\u201323. doi:10.1016\/S0140-6736(20)30154-9. PMC PMC7159286. PMID 31986261. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7159286 .   \n\n\u2191 Zaki, A.M.; van Boheemen, S.; Besterbroer, T.M. et al. (2012). \"Isolation of a Novel Coronavirus From a Man With Pneumonia in Saudi Arabia\". New England Journal of Medicine 367 (19): 1814\u201320. doi:10.1056\/NEJMoa1211721. PMID 23075143.   \n\n\u2191 Drosten, C.; G\u00fcnther, S.; Preiser, W. et al. (2003). \"Identification of a Novel Coronavirus in Patients With Severe Acute Respiratory Syndrome\". New England Journal of Medicine 348 (20): 1967-76. doi:10.1056\/NEJMoa030747. PMID 12690091.   \n\n\u2191 Ksiazek, T.G.; Erdman, D.; Goldsmith, C.S. et al. (2003). \"A Novel Coronavirus Associated With Severe Acute Respiratory Syndrome\". New England Journal of Medicine 348 (20): 1953\u201366. doi:10.1056\/NEJMoa030781. PMID 12690092.   \n\n\u2191 Salata, C.; Calistri, A.; Parolin, C. et al. (2019). \"Coronaviruses: A Paradigm of New Emerging Zoonotic Diseases\". Pathogens and Disease 77 (9): ftaa006. doi:10.1093\/femspd\/ftaa006. PMC PMC7108526. PMID 32065221. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7108526 .   \n\n\u2191 \"COVID-19 Coronavirus Pandemic\". Worldometer. https:\/\/www.worldometers.info\/coronavirus\/ . Retrieved 12 May 2020 .   > \n\n\u2191 Wu, F.; Zhao, S.; Yu, B. et al. (2020). \"A New Coronavirus Associated With Human Respiratory Disease in China\". Nature 579 (7798): 265-269. doi:10.1038\/s41586-020-2008-3. PMC PMC7094943. PMID 32015508. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7094943 .   \n\n\u2191 Durrant, J.D.; Kochanek, S.E.; Casalino, L. et al. (2020). \"Mesoscale All-Atom Influenza Virus Simulations Suggest New Substrate Binding Mechanism\". ACS Central Science 6 (2): 189\u201396. doi:10.1021\/acscentsci.9b01071. PMC PMC7048371. PMID 32123736. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7048371 .   \n\n\u2191 Graham, R.L.; Baric, R.S. (2010). \"Recombination, Reservoirs, and the Modular Spike: Mechanisms of Coronavirus Cross-Species Transmission\". Journal of Virology 84 (7): 3134\u201346. doi:10.1128\/JVI.01394-09. PMC PMC2838128. PMID 19906932. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2838128 .   \n\n\u2191 Phan, T. (2020). \"Genetic Diversity and Evolution of SARS-CoV-2\". Infection, genetics and evolution 81: 104260. doi:10.1016\/j.meegid.2020.104260. PMC PMC7106203. PMID 32092483. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7106203 .   \n\n\u2191 Wang, C.; Liu, Z.; Chen, Z. et al. (2020). \"The Establishment of Reference Sequence for SARS-CoV-2 and Variation Analysis\". Journal of Medical Virology 92 (6): 667-674. doi:10.1002\/jmv.25762. PMC PMC7228400. PMID 32167180. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7228400 .   \n\n\u2191 Lu, R.; Zhao, X.; Li, J. et al. (2020). \"Genomic Characterisation and Epidemiology of 2019 Novel Coronavirus: Implications for Virus Origins and Receptor Binding\". Lancet 395 (10224): 565\u201374. doi:10.1016\/S0140-6736(20)30251-8. PMC PMC7159086. PMID 32007145. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7159086 .   \n\n\u2191 Centers for Disease Control and Prevention (22 May 2020). \"Interim Guidelines for Collecting, Handling, and Testing Clinical Specimens for COVID-19\". Centers for Disease Control and Prevention. https:\/\/www.cdc.gov\/coronavirus\/2019-nCoV\/lab\/guidelines-clinical-specimens.html . Retrieved May 2020 .   \n\n\u2191 15.0 15.1 15.2 15.3 Corman, V.M.; Landt, O.; Kaiser, M. et al. (2020). \"Detection of 2019 Novel Coronavirus (2019-nCoV) by Real-Time RT-PCR\". Euro Surveillance 25 (3): 2000045. doi:10.2807\/1560-7917.ES.2020.25.3.2000045. PMC PMC6988269. PMID 31992387. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6988269 .   \n\n\u2191 16.0 16.1 World Health Organization (2020). \"Coronavirus disease (COVID-19) technical guidance: Laboratory testing for 2019-nCoV in humans\". World Health Organization. https:\/\/www.who.int\/emergencies\/diseases\/novel-coronavirus-2019\/technical-guidance\/laboratory-guidance . Retrieved May 2020 .   \n\n\u2191 17.0 17.1 Chu, D.K.W.; Pan, Y.; Cheng, S.M.S. et al. (2020). \"Molecular Diagnosis of a Novel Coronavirus (2019-nCoV) Causing an Outbreak of Pneumonia\". Clinical Chemistry 66 (4): 549-555. doi:10.1093\/clinchem\/hvaa029. PMC PMC7108203. PMID 32031583. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7108203 .   \n\n\u2191 Chan, J.F.-K.; Yip, C.C.-Y.; To, K.K.-W. et al. (2020). \"Improved Molecular Diagnosis of COVID-19 by the Novel, Highly Sensitive and Specific COVID-19-RdRp\/Hel Real-Time Reverse Transcription-PCR Assay Validated In Vitro and With Clinical Specimens\". Journal of Clinical Microbiology 58 (5): e00310-20. doi:10.1128\/JCM.00310-20. PMC PMC7180250. PMID 32132196. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7180250 .   \n\n\u2191 U.S. Food and Drug Administration (2020). \"Orig3n 2019 Novel Coronavirus (COVID-19) Test EUA Summary\". U.S. Food and Drug Administration. https:\/\/www.fda.gov\/media\/136873\/download . Retrieved May 2020 .   \n\n\u2191 20.0 20.1 20.2 20.3 Guo, L.; Ren, L.; Yang, S. et al. (2020). \"Profiling Early Humoral Response to Diagnose Novel Coronavirus Disease (COVID-19)\". Clinical Infectious Diseases: ciaa310. doi:10.1093\/cid\/ciaa310. PMC PMC7184472. PMID 32198501. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7184472 .   \n\n\u2191 Okba, N.M.A.; M\u00fcller, M.A.; Li, W. et al. (2020). \"Severe Acute Respiratory Syndrome Coronavirus 2-Specific Antibody Responses in Coronavirus Disease 2019 Patients\". Emerging Infectious Diseases 26 (7). doi:10.3201\/eid2607.200841. PMID 32267220.   \n\n\u2191 Walls, A.C.; Tortorici, M.A.; Frenz, B. et al. (2016). \"Glycan Shield and Epitope Masking of a Coronavirus Spike Protein Observed by Cryo-Electron Microscopy\". Nature Structural and Molecular Biology 23 (10): 899-905. doi:10.1038\/nsmb.3293. PMC PMC5515730. PMID 27617430. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5515730 .   \n\n\u2191 Kopecky-Bromberg, S.A.; Mart\u00ednez-Sobrido, L.; Frieman, M. et al. (2007). \"Severe Acute Respiratory Syndrome Coronavirus Open Reading Frame (ORF) 3b, ORF 6, and Nucleocapsid Proteins Function as Interferon Antagonists\". Journal of Virology 81 (2): 548-57. doi:10.1128\/JVI.01782-06. PMC PMC1797484. PMID 17108024. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC1797484 .   \n\n\u2191 McBride, R.; van Zyl, M.; Fielding, B.C. et al. (2014). \"The Coronavirus Nucleocapsid Is a Multifunctional Protein\". Viruses 6 (8): 2991-3018. doi:10.3390\/v6082991. PMC PMC4147684. PMID 25105276. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4147684 .   \n\n\u2191 Leung, D.T.M.; Tam, F.C.H.; Ma, C.H. et al. (2004). \"Antibody Response of Patients With Severe Acute Respiratory Syndrome (SARS) Targets the Viral Nucleocapsid\". Journal of Infectious Diseases 190 (2): 379-86. doi:10.1086\/422040. PMC PMC7110057. PMID 15216476. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7110057 .   \n\n\u2191 Jin, Y.; Wang, M.; Zuo, Z. et al. (2020). \"Diagnostic Value and Dynamic Variance of Serum Antibody in Coronavirus Disease 2019\". International Journal of Infectious Diseases 94: 49\u201352. doi:10.1016\/j.ijid.2020.03.065. PMC PMC7194885. PMID 32251798. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7194885 .   \n\n\u2191 Li, R.; Tian, X.; Yu, Y. et al. (2018). \"Development of a Rapid Immunochromatographic Assay for Detection of Antibodies Against Porcine Epidemic Diarrhea Virus\". Polish Journal of Veterinary Sciences 21 (1): 139-147. doi:10.24425\/119032. PMID 29624018.   \n\n\u2191 28.0 28.1 28.2 28.3 28.4 Shen, C.; Wang, Z.; Zhao, F. et al. (2020). \"Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma\". JAMA 323 (16): 1582-1589. doi:10.1001\/jama.2020.4783. PMC PMC7101507. PMID 32219428. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7101507 .   \n\n\u2191 Gaunt, E.R.; Hardie, A.; Claas, E.C.J. et al. (2010). \"Epidemiology and Clinical Presentations of the Four Human Coronaviruses 229E, HKU1, NL63, and OC43 Detected Over 3 Years Using a Novel Multiplex Real-Time PCR Method\". Journal of Clinical Microbiology 48 (8): 2940-7. doi:10.1128\/JCM.00636-10. PMC PMC2916580. PMID 20554810. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2916580 .   \n\n\u2191 Gupta, S.J.; Shukla, P. (2018). \"Glycosylation Control Technologies for Recombinant Therapeutic Proteins\". Applied Microbiology and Biotechnology 102 (24): 10457-10468. doi:10.1007\/s00253-018-9430-6. PMID 30334089.   \n\n\u2191 Bandaranayak, A.D.; Almo, S.C. (2014). \"Recent Advances in Mammalian Protein Production\". FEBS Letters 588 (2): 253-60. doi:10.1016\/j.febslet.2013.11.035. PMID PMC3924552.   \n\n\u2191 Shao, Y.-M.; Yang, W.-B.; Peng, H.-P. et al. (2007). \"Structure-based Design and Synthesis of Highly Potent SARS-CoV 3CL Protease Inhibitors\". Chembiochem 8 (14): 1654-7. doi:10.1002\/cbic.200700254. PMID PMC7162026.   \n\n\u2191 Ledsgarrd, L.; Kilstrup, M.; Karatt-Vellatt, A. et al. (2018). \"Basics of Antibody Phage Display Technology\". Toxins 10 (6): 236. doi:10.3390\/toxins10060236. PMID PMC6024766.   \n\n\u2191 34.0 34.1 Nie, J.; Li, Q.; Wu, J. et al. (2020). \"Establishment and Validation of a Pseudovirus Neutralization Assay for SARS-CoV-2\". Emerging Microbes & Infections 9 (1): 680\u201386. doi:10.1080\/22221751.2020.1743767. PMID PMC7144318.   \n\n\u2191 Notomi, T.; Okayama, H.; Masubuchi, H. et al. (2020). \"Loop-mediated Isothermal Amplification of DNA\". Nucleic Acids Research 28 (12): E63. doi:10.1093\/nar\/28.12.e63. PMID PMC102748.   \n\n\u2191 Li, J.; Macdonald, J.; von Stetten, F. (2018). \"Review: A Comprehensive Summary of a Decade Development of the Recombinase Polymerase Amplification\". The Analyst 144 (1): 31\u201367. doi:10.1039\/c8an01621f. PMID 30426974.   \n\n\u2191 Vincent, M.; Xu, Y.; Kong, H. (2004). \"Helicase-dependent Isothermal DNA Amplification\". EMBO Reports 5 (8): 795\u2013800. doi:10.1038\/sj.embor.7400200. PMC PMC1249482. PMID 15247927. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC1249482 .   \n\n\u2191 Walker, G.T.; Fraiser, M.S.; Schram, J.L. et al. (1992). \"Strand Displacement Amplification--An Isothermal, in Vitro DNA Amplification Technique\". Nucleic Acids Research 20 (7): 1691-6. doi:10.1093\/nar\/20.7.1691. PMC PMC312258. PMID 1579461. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC312258 .   \n\n\u2191 Compton, J. (1991). \"Nucleic Acid Sequence-Based Amplification\". Nature 350 (6313): 91-2. doi:10.1038\/350091a0. PMID 1706072.   \n\n\u2191 Yan, C.; Cui, J.; Huang, L. et al. (2020). \"Rapid and Visual Detection of 2019 Novel Coronavirus (SARS-CoV-2) by a Reverse Transcription Loop-Mediated Isothermal Amplification Assay\". Clinical Microbiology and Infection 26 (6): 773\u201379. doi:10.1016\/j.cmi.2020.04.001. PMC PMC7144850. PMID 32276116. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7144850 .   \n\n\u2191 Behrmann, O.; Bchmann, I.; Spiegel, M. et al. (2020). \"Rapid Detection of SARS-CoV-2 by Low Volume Real-Time Single Tube Reverse Transcription Recombinase Polymerase Amplification Using an Exo Probe With an Internally Linked Quencher (exo-IQ)\". Clinical Chemistry: hvaa116. doi:10.1093\/clinchem\/hvaa116. PMC PMC7239256. PMID 32384153. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7239256 .   \n\n\u2191 42.0 42.1 Kellner, M.J.; Koob, J.G.; Gootenberg, J.S. et al. (2019). \"SHERLOCK: Nucleic Acid Detection With CRISPR Nucleases\". Nature Protocols 14 (10): 2986\u20133012. doi:10.1038\/s41596-019-0210-2. PMC PMC6956564. PMID 31548639. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6956564 .   \n\n\u2191 Holland, L.A.; Kaelin, E.A.; Maqsood, R. et al. (2020). \"An 81 Nucleotide Deletion in SARS-CoV-2 ORF7a Identified From Sentinel Surveillance in Arizona (Jan-Mar 2020)\". Journal of Virology: JVI.00711-20. doi:10.1128\/JVI.00711-20. PMID 32357959.   \n\n\u2191 Korber, B.; Fischer, W.M.; Gnanakaran, S. et al. (2020). \"Spike mutation pipeline reveals the emergence of a more transmissible form of SARS-CoV-2\". bioRxiv. doi:10.1101\/2020.04.29.069054.   \n\n\u2191 Schaecher, S.R.; Touchette, E.; Schriewer, J. et al. (2007). \"Severe Acute Respiratory Syndrome Coronavirus Gene 7 Products Contribute to Virus-Induced Apoptosis\". Journal of Virology 81 (20): 11054-68. doi:10.1128\/JVI.01266-07. PMC PMC2045523. PMID 17686858. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2045523 .   \n\n\u2191 Centers for Disease Control and Prevention (May 2020). \"Interim Laboratory Biosafety Guidelines for Handling and Processing Specimens Associated with Coronavirus Disease 2019 (COVID-19)\". Centers for Disease Control and Prevention. https:\/\/www.cdc.gov\/coronavirus\/2019-ncov\/lab\/lab-biosafety-guidelines.html . Retrieved May 2020 .   \n\n\nNotes \nThis presentation is faithful to the original, with only a few minor changes to presentation. In some cases important information was missing from the references, and that information was added. References in this version are listed in order of appearance\u2014by design\u2014rather than alphabetical order as the original was.\n\n\n\n\n\n\nSource: <a rel=\"external_link\" class=\"external\" href=\"https:\/\/www.limswiki.org\/index.php\/Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\">https:\/\/www.limswiki.org\/index.php\/Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)<\/a>\n\t\t\t\t\tCategories: LIMSwiki journal articles (added in 2020)LIMSwiki journal articles (all)LIMSwiki journal articles on clinical researchLIMSwiki journal articles on epidemiologyHidden category: Pages using duplicate arguments in template calls\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\n\t\t\t\t\n\t\t\t\n\t\t\n\t\t\n\t\t\tNavigation menu\n\t\t\t\t\t\n\t\t\tViews\n\n\t\t\t\n\t\t\t\t\n\t\t\t\tJournal\n\t\t\t\tDiscussion\n\t\t\t\tView source\n\t\t\t\tHistory\n\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\n\t\t\t\t\n\t\t\t\tPersonal tools\n\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\t\t\tLog in\n\t\t\t\t\t\t\t\t\t\t\t\t\tRequest account\n\t\t\t\t\t\t\t\t\t\t\t\n\t\t\t\t\n\t\t\t\n\t\t\t\n\t\t\t\t\n\t\t\t\n\t\t\t\t\n\t\tNavigation\n\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\tMain page\n\t\t\t\t\t\t\t\t\t\t\tRecent changes\n\t\t\t\t\t\t\t\t\t\t\tRandom page\n\t\t\t\t\t\t\t\t\t\t\tHelp\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\n\t\t\t\n\t\t\tSearch\n\n\t\t\t\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t \n\t\t\t\t\t\t\n\t\t\t\t\n\n\t\t\t\t\t\t\t\n\t\t\n\t\t\t\n\t\t\tTools\n\n\t\t\t\n\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\tWhat links here\n\t\t\t\t\t\t\t\t\t\t\tRelated changes\n\t\t\t\t\t\t\t\t\t\t\tSpecial pages\n\t\t\t\t\t\t\t\t\t\t\tPermanent link\n\t\t\t\t\t\t\t\t\t\t\tPage information\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\n\t\t\n\t\tPrint\/export\n\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\tCreate a book\n\t\t\t\t\t\t\t\t\t\t\tDownload as PDF\n\t\t\t\t\t\t\t\t\t\t\tDownload as Plain text\n\t\t\t\t\t\t\t\t\t\t\tPrintable version\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\n\t\t\n\t\tSponsors\n\t\t\n\t\t\t \r\n\n\t\r\n\n\t\r\n\n\t\n\t\r\n\n\t\r\n\n\t\n\t\r\n\n \n\t\r\n\n\t\n\t\r\n\n \n\t\n\t\r\n\n\t\n\t\n\t\r\n\n\t\r\n\n\t\r\n\n\t\n\t\r\n\n\t\r\n\t\t\n\t\t\n\t\t\t\n\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t This page was last modified on 9 June 2020, at 18:22.\n\t\t\t\t\t\t\t\t\tThis page has been accessed 392 times.\n\t\t\t\t\t\t\t\t\tContent is available under a Creative Commons Attribution-ShareAlike 4.0 International License unless otherwise noted.\n\t\t\t\t\t\t\t\t\tPrivacy policy\n\t\t\t\t\t\t\t\t\tAbout LIMSWiki\n\t\t\t\t\t\t\t\t\tDisclaimers\n\t\t\t\t\t\t\t\n\t\t\n\t\t\n\t\t\n\n","14fe555f4f0cddcccf179363f98c5b79_html":"<body class=\"mediawiki ltr sitedir-ltr ns-206 ns-subject page-Journal_Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_SARS-CoV-2 skin-monobook action-view\">\n<div id=\"rdp-ebb-globalWrapper\">\n\t\t<div id=\"rdp-ebb-column-content\">\n\t\t\t<div id=\"rdp-ebb-content\" class=\"mw-body\" role=\"main\">\n\t\t\t\t<a id=\"rdp-ebb-top\"><\/a>\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t<h1 id=\"rdp-ebb-firstHeading\" class=\"firstHeading\" lang=\"en\">Journal:Laboratory testing methods for novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)<\/h1>\n\t\t\t\t\n\t\t\t\t<div id=\"rdp-ebb-bodyContent\" class=\"mw-body-content\">\n\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\n\n\t\t\t\t\t<!-- start content -->\n\t\t\t\t\t<div id=\"rdp-ebb-mw-content-text\" lang=\"en\" dir=\"ltr\" class=\"mw-content-ltr\">\n\n\n<h2><span class=\"mw-headline\" id=\"Abstract\">Abstract<\/span><\/h2>\n<p>Following the first reports of <a href=\"https:\/\/www.limswiki.org\/index.php\/Coronavirus_disease_2019\" title=\"Coronavirus disease 2019\" class=\"wiki-link\" data-key=\"68331dff29df205bcb39c3ad9599c30c\">coronavirus disease 2019<\/a> (COVID-19) by China to the <a href=\"https:\/\/www.limswiki.org\/index.php\/World_Health_Organization\" title=\"World Health Organization\" class=\"wiki-link\" data-key=\"2a49f1470638d5f579e3f6419e239b03\">World Health Organization<\/a> (WHO) on December 31, 2019, more than 4,302,774 cases of infection by the novel <a href=\"https:\/\/www.limswiki.org\/index.php\/Severe_acute_respiratory_syndrome_coronavirus_2\" title=\"Severe acute respiratory syndrome coronavirus 2\" class=\"wiki-link\" data-key=\"beddd8bfa6022d0f538d26cdefb7df5c\">severe acute respiratory syndrome coronavirus 2<\/a> (SARS-CoV-2) virus have been reported by authorities in 212 countries and territories as of May 12, 2020. The outbreak and spread of COVID-19 worldwide highlights the critical need for developing rapid and accurate diagnostic testing methods for emerging human <a href=\"https:\/\/www.limswiki.org\/index.php\/Coronavirus\" title=\"Coronavirus\" class=\"wiki-link\" data-key=\"86c887aaa85c1b2b96fd478c10703204\">coronavirus<\/a> (CoV) infections. Testing is crucial to tracking the spread of disease during a <a href=\"https:\/\/www.limswiki.org\/index.php\/Pandemic\" title=\"Pandemic\" class=\"wiki-link\" data-key=\"bd9a48e6c6e41b6d603ee703836b01f1\">pandemic<\/a>, and to swiftly permitting <a href=\"https:\/\/www.limswiki.org\/index.php\/Public_health\" title=\"Public health\" class=\"wiki-link\" data-key=\"81092e25c0bd359cedd1b9f9dc350c86\">public health<\/a> interventions, including isolation, quarantine, and appropriate clinical management of afflicted individuals. The key components of viral diagnostic tests are (1) collection of the appropriate (blood, <a href=\"https:\/\/www.limswiki.org\/index.php\/Nasopharyngeal_swab\" title=\"Nasopharyngeal swab\" class=\"wiki-link\" data-key=\"18d5d4e09d1fc5ddb05a22b36ace9daf\">nasal swab<\/a>, and throat swab); (2) availability of the genetic and proteomic <a href=\"https:\/\/www.limswiki.org\/index.php\/DNA_sequencing\" title=\"DNA sequencing\" class=\"wiki-link\" data-key=\"7ff86b38049c37e30858efd13bd00925\">sequences<\/a> of the novel virus for analysis; and (3) rapid and accurate <a href=\"https:\/\/www.limswiki.org\/index.php\/Laboratory\" title=\"Laboratory\" class=\"wiki-link\" data-key=\"c57fc5aac9e4abf31dccae81df664c33\">laboratory<\/a> testing methods. The current gold standard for the <a href=\"https:\/\/www.limswiki.org\/index.php\/Molecular_diagnostics\" title=\"Molecular diagnostics\" class=\"wiki-link\" data-key=\"8fc14cae7a6fbac9a53fae1394fae7ee\">molecular diagnosis<\/a> of SARS-CoV-2 infection is the <a href=\"https:\/\/www.limswiki.org\/index.php\/Reverse_transcription_polymerase_chain_reaction\" title=\"Reverse transcription polymerase chain reaction\" class=\"wiki-link\" data-key=\"bb69657b45c41e6345baf4c8067c7aa3\">real-time reverse transcription polymerase chain reaction<\/a> (qRT-PCR) for the qualitative and quantitative detection of viral . Other relevant laboratory methods include <a href=\"https:\/\/www.limswiki.org\/index.php\/ELISA\" title=\"ELISA\" class=\"wiki-link\" data-key=\"f48f479ea5841a7362147598ac925bd6\">enzyme-linked immunosorbent assays<\/a> (ELISA) for viral antibody and antigen detection, and serum virus neutralization (SVN) assays for <a href=\"https:\/\/www.limswiki.org\/index.php\/Neutralizing_antibody\" title=\"Neutralizing antibody\" class=\"wiki-link\" data-key=\"c4003c575bab724e3425fcb689688797\">antibody neutralization<\/a> determination. The challenges faced in developing a diagnostic test for a novel pathogen are the ability to measure low viral loads for early detection, to provide low or no cross-reactivity with other viral strains, and to deliver results rapidly. Several point-of-care molecular devices are currently being integrated for fast and accurate diagnosis of SARS-CoV-2 infections. This review discusses the current laboratory methods available to test for coronaviruses by focusing on the present COVID-19 outbreak.\n<\/p><p><b>Keywords<\/b>: coronavirus, RT-PCR, ELISA, lateral flow diagnostics, convalescent plasma\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Introduction\">Introduction<\/span><\/h2>\n<p><a href=\"https:\/\/www.limswiki.org\/index.php\/Coronavirus_disease_2019\" title=\"Coronavirus disease 2019\" class=\"wiki-link\" data-key=\"68331dff29df205bcb39c3ad9599c30c\">Coronavirus disease 2019<\/a> (COVID-19) is caused by a novel <a href=\"https:\/\/www.limswiki.org\/index.php\/Coronavirus\" title=\"Coronavirus\" class=\"wiki-link\" data-key=\"86c887aaa85c1b2b96fd478c10703204\">coronavirus<\/a> (CoV) that was originally reported in Wuhan, Hubei province, China in December 2019.<sup id=\"rdp-ebb-cite_ref-WHONaming20_1-0\" class=\"reference\"><a href=\"#cite_note-WHONaming20-1\">[1]<\/a><\/sup> The International Committee on Taxonomy of Viruses named the virus \"<a href=\"https:\/\/www.limswiki.org\/index.php\/Severe_acute_respiratory_syndrome_coronavirus_2\" title=\"Severe acute respiratory syndrome coronavirus 2\" class=\"wiki-link\" data-key=\"beddd8bfa6022d0f538d26cdefb7df5c\">severe acute respiratory syndrome coronavirus 2<\/a> (SARS-CoV-2). Infection by SARS-CoV-2 causes a respiratory illness that varies in severity from mild upper respiratory symptoms akin to the seasonal flu, to severe progressive respiratory failure that requires intensive care and can lead to death. Asymptomatic carriers of the virus have also been reported and pose a significant <a href=\"https:\/\/www.limswiki.org\/index.php\/Public_health\" title=\"Public health\" class=\"wiki-link\" data-key=\"81092e25c0bd359cedd1b9f9dc350c86\">public health<\/a> threat due to their ability to unknowingly spread the virus.<sup id=\"rdp-ebb-cite_ref-ChanAFami20_2-0\" class=\"reference\"><a href=\"#cite_note-ChanAFami20-2\">[2]<\/a><\/sup> SARS-CoV-2 represents the third coronavirus in this millennium to cross species from animals to humans and cause a severe respiratory disease, after <a href=\"https:\/\/www.limswiki.org\/index.php\/Middle_East_respiratory_syndrome\" title=\"Middle East respiratory syndrome\" class=\"wiki-link\" data-key=\"6a290adf3ac17e4b8a75ef1ce0b28afd\">Middle East respiratory syndrome<\/a> coronavirus (MERS-CoV) in 2012<sup id=\"rdp-ebb-cite_ref-ZakiIso12_3-0\" class=\"reference\"><a href=\"#cite_note-ZakiIso12-3\">[3]<\/a><\/sup> and <a href=\"https:\/\/www.limswiki.org\/index.php\/Severe_acute_respiratory_syndrome\" title=\"Severe acute respiratory syndrome\" class=\"wiki-link\" data-key=\"11abe2043ece64ad43ee0052402c5cec\">severe acute respiratory syndrome<\/a> coronavirus (SARS-CoV) in 2003.<sup id=\"rdp-ebb-cite_ref-DrostenIdent03_4-0\" class=\"reference\"><a href=\"#cite_note-DrostenIdent03-4\">[4]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-KsiazekANovel03_5-0\" class=\"reference\"><a href=\"#cite_note-KsiazekANovel03-5\">[5]<\/a><\/sup> SARS-CoV-2 has now been identified as the seventh coronavirus that is transmissible between humans (a group which also includes HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1).<sup id=\"rdp-ebb-cite_ref-SalataCorona19_6-0\" class=\"reference\"><a href=\"#cite_note-SalataCorona19-6\">[6]<\/a><\/sup> On January 30, 2020, the <a href=\"https:\/\/www.limswiki.org\/index.php\/World_Health_Organization\" title=\"World Health Organization\" class=\"wiki-link\" data-key=\"2a49f1470638d5f579e3f6419e239b03\">World Health Organization<\/a> (WHO) declared the SARS-CoV-2 epidemic a public health emergency of international concern, and the public health emergency was upgraded to a <a href=\"https:\/\/www.limswiki.org\/index.php\/Pandemic\" title=\"Pandemic\" class=\"wiki-link\" data-key=\"bd9a48e6c6e41b6d603ee703836b01f1\">pandemic<\/a> on March 11. At least 4,302,774 confirmed cases and 289,561 deaths worldwide were reported as of May 12.<sup id=\"rdp-ebb-cite_ref-WorldCOVID_7-0\" class=\"reference\"><a href=\"#cite_note-WorldCOVID-7\">[7]<\/a><\/sup> Diagnostic testing is critical during a pandemic as the ability to track the spread of SARS-CoV-2 is essential for effective disease management and control.\n<\/p><p>SARS-CoV-2 is a positive-sense, single-stranded RNA (ssRNA), group IV virus. The genome was sequenced from the <a href=\"https:\/\/www.limswiki.org\/index.php\/Bronchoalveolar_lavage\" title=\"Bronchoalveolar lavage\" class=\"wiki-link\" data-key=\"500aa79d30c49b81ed6c58bc319231dc\">bronchoalveolar lavage<\/a> fluid of a patient (Genbank: MN908947) and shared through the Global Initiative on Sharing All Influenza Data (GISAID) platform on January 12, 2020.<sup id=\"rdp-ebb-cite_ref-WuANew20_8-0\" class=\"reference\"><a href=\"#cite_note-WuANew20-8\">[8]<\/a><\/sup> The ~30 k base pair genome is highly similar to the human SARS-CoV and bat CoV-SARS-like genomes, with 14 open reading frames (ORFs) that encode structural, replication, and non-structural accessory proteins, as depicted in Figure 1. Molecular modeling studies demonstrate that like SARS-CoV, SARS-CoV-2 is surrounded by a lipid bilayer membrane, containing structural membrane (M) and envelope (E) proteins that interact to form the viral envelope.<sup id=\"rdp-ebb-cite_ref-DurrantMeso20_9-0\" class=\"reference\"><a href=\"#cite_note-DurrantMeso20-9\">[9]<\/a><\/sup> This layer also contains spike glycoproteins (S) that give the characteristic \u201ccorona\u201d appearance of this family of viruses. The spike proteins bind specific host cell receptors to facilitate host cell attachment and entry.<sup id=\"rdp-ebb-cite_ref-GrahamRecomb10_10-0\" class=\"reference\"><a href=\"#cite_note-GrahamRecomb10-10\">[10]<\/a><\/sup> The nucleic acid-associated protein binds the RNA genome and forms the nucleocapsid (N). Other proteins include replication and non-structural accessory proteins, listed in Table 1. Reports of different strains of SARS-CoV-2 suggest an early split from the SARS-CoV-2 lineage and\/or that the virus is mutating. Ongoing research provides insight into the unique and conserved features of the genome and proteome of SARS-CoV-2 for tracking mutations and generates evidence about the evolution of the virus.<sup id=\"rdp-ebb-cite_ref-PhanGenetic20_11-0\" class=\"reference\"><a href=\"#cite_note-PhanGenetic20-11\">[11]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-WangTheEstab20_12-0\" class=\"reference\"><a href=\"#cite_note-WangTheEstab20-12\">[12]<\/a><\/sup> This is important as these changes may affect key structural and non-structural components of SARS-CoV-2 that can render some diagnostic tests ineffective or less sensitive and can also impact the selection of epitopes for the development of new tests.\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig1_D%27Cruz_FrontCellDevBio2020_8.jpg\" class=\"image wiki-link\" data-key=\"e3b3c70b007f95d0e38d6d722ade8b4a\"><img alt=\"Fig1 D'Cruz FrontCellDevBio2020 8.jpg\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/e\/e0\/Fig1_D%27Cruz_FrontCellDevBio2020_8.jpg\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Figure 1.<\/b> Schematic representation of SARS-CoV-2 genome. SARS-CoV-2 contains a positive-sense, positive-stranded mRNA genome with a 5\u2032 capped mRNA sequence (C) and a 3\u2032 poly-A tail. The coding genes are: ORF1a, ORF1b, Spike (S), ORF3a, ORF3b, Envelope (E), Membrane (M), ORF6, ORF7a, ORF7b, ORF8, ORF9b, ORF14, Nucleocapsid (N), and ORF10.<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p><a href=\"https:\/\/www.limswiki.org\/index.php\/File:Tab1_D%27Cruz_FrontCellDevBio2020_8.jpg\" class=\"image wiki-link\" data-key=\"18dd3ca5007fd7ca561e32a004491613\"><img alt=\"Tab1 D'Cruz FrontCellDevBio2020 8.jpg\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/d\/d6\/Tab1_D%27Cruz_FrontCellDevBio2020_8.jpg\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Table 1.<\/b> Proteins associated with the 14 ORFs of SARS-CoV.<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>The spread of SARS-CoV-2 is primarily by respiratory droplets that arise from individuals that harbor the virus. Symptomatic individuals with the disease are one source of virus, but a major public health concern is transmission by mildly ill or asymptomatic individuals during the incubation period. Rapid viral diagnostic testing for SARS-CoV-2 is critical to identify these individuals and facilitate the implementation of protective measures such as social distancing, quarantine, and isolation that help to mitigate the spread of the virus in the community. The development of rapid and accurate tests that detect antibodies post-infection provide information about an individual's exposure to the virus and can be used to monitor the possibility of immunity, relapse, or reinfection. This supports interventions to protect high-risk populations from developing more severe illness and can be used to investigate the efficacy of passive antibody therapies for COVID-19 infection. This review describes the available testing methods for SARS-CoV-2 and brings to light the importance of <a href=\"https:\/\/www.limswiki.org\/index.php\/Laboratory\" title=\"Laboratory\" class=\"wiki-link\" data-key=\"c57fc5aac9e4abf31dccae81df664c33\">laboratory<\/a> testing to control this disease and prepare for possible future disease threats.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Detection_of_SARS-CoV-2_by_real-time_reverse_transcription_polymerase_chain_reaction_.28qRT-PCR.29\">Detection of SARS-CoV-2 by real-time reverse transcription polymerase chain reaction (qRT-PCR)<\/span><\/h2>\n<p>The qRT-PCR method detects the genetic material of SARS-CoV-2 in order to identify the virus and\/or quantify viral load. Comparisons of the ssRNA genetic sequences of this virus have shown similarities to SARS-CoV and several bat coronaviruses.<sup id=\"rdp-ebb-cite_ref-LuGenomic20_13-0\" class=\"reference\"><a href=\"#cite_note-LuGenomic20-13\">[13]<\/a><\/sup> This detailed knowledge has allowed the rapid development of qRT-PCR assays for SARS-CoV-2 using SARS-CoV and other known coronaviruses as references.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Specifics\">Specifics<\/span><\/h3>\n<h4><span class=\"mw-headline\" id=\"Sample_collection\">Sample collection<\/span><\/h4>\n<p>Upper and lower respiratory samples are collected. <a href=\"https:\/\/www.limswiki.org\/index.php\/Nasopharyngeal_swab\" title=\"Nasopharyngeal swab\" class=\"wiki-link\" data-key=\"18d5d4e09d1fc5ddb05a22b36ace9daf\">Nasopharyngeal swabs<\/a> are high-priority specimens for SARS-CoV-2, and low-priority specimens include oropharyngeal swabs, <a href=\"https:\/\/www.limswiki.org\/index.php\/Bronchoalveolar_lavage\" title=\"Bronchoalveolar lavage\" class=\"wiki-link\" data-key=\"500aa79d30c49b81ed6c58bc319231dc\">bronchoalveolar lavage<\/a>, tracheal aspirates, and sputum.<sup id=\"rdp-ebb-cite_ref-CDCInterim20_14-0\" class=\"reference\"><a href=\"#cite_note-CDCInterim20-14\">[14]<\/a><\/sup>\n<\/p>\n<h4><span class=\"mw-headline\" id=\"RNA_isolation\">RNA isolation<\/span><\/h4>\n<p>RNA is extracted from clinical specimens using approved viral isolation kits.<sup id=\"rdp-ebb-cite_ref-CormanDetect20_15-0\" class=\"reference\"><a href=\"#cite_note-CormanDetect20-15\">[15]<\/a><\/sup>\n<\/p>\n<h4><span class=\"mw-headline\" id=\"qRT-PCR\">qRT-PCR<\/span><\/h4>\n<p>RNA is reverse transcribed to cDNA and subsequently amplified using a real-time quantitative PCR instrument. WHO announced various primer and probe sets for SARS-CoV-2 previously developed in China, Germany, Hong Kong, Japan, Thailand, and the United States (Table 2).<sup id=\"rdp-ebb-cite_ref-WHOCorona20_16-0\" class=\"reference\"><a href=\"#cite_note-WHOCorona20-16\">[16]<\/a><\/sup> Primers target different sections of the virus' genetic sequence, including the envelope E gene, the RNA-dependent RNA polymerase (RdRp) gene, and the N gene.<sup id=\"rdp-ebb-cite_ref-CormanDetect20_15-1\" class=\"reference\"><a href=\"#cite_note-CormanDetect20-15\">[15]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-WHOCorona20_16-1\" class=\"reference\"><a href=\"#cite_note-WHOCorona20-16\">[16]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ChuMolec20_17-0\" class=\"reference\"><a href=\"#cite_note-ChuMolec20-17\">[17]<\/a><\/sup> Targeting the E gene is reported for highest sensitivity, followed by the RdRp gene for confirmation.<sup id=\"rdp-ebb-cite_ref-CormanDetect20_15-2\" class=\"reference\"><a href=\"#cite_note-CormanDetect20-15\">[15]<\/a><\/sup> Some laboratories have multiplexed PCR tests consisting of multiple primer and probe sets located at different regions in the SARS-CoV-2 genome. These assays can be designed to contain primer sets targeting multiple genes simultaneously (RdRp\/hel, S, N)<sup id=\"rdp-ebb-cite_ref-ChanImproved20_18-0\" class=\"reference\"><a href=\"#cite_note-ChanImproved20-18\">[18]<\/a><\/sup>, or to detect different regions in a single target such as the N gene (Table 2).<sup id=\"rdp-ebb-cite_ref-FDAOrig3n20_19-0\" class=\"reference\"><a href=\"#cite_note-FDAOrig3n20-19\">[19]<\/a><\/sup> The use of multiplex assays is potentially beneficial as this can improve sensitivity in cases of loss or degradation of viral RNA during specimen collection and nucleic acid extraction, or in the event of mutation of the virus genome. These assays use <i>in vitro<\/i> synthesized RNA derived from transcripts (e.g., BetaCoV_Wuhan_WIV04_2019, GISAID Access number: EPI_ISL_402124) as positive controls and to generate standard curves. An internal control using RNAse P (RP) verifies the presence and quality of nucleic acid in samples, and molecular grade nuclease-free water is used as a negative amplification control. A negative patient sample serves both as a negative extraction control to monitor cross contamination across samples and to validate test reagents.\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Tab2_D%27Cruz_FrontCellDevBio2020_8.jpg\" class=\"image wiki-link\" data-key=\"c264fd3195dad7cac0fc33b4b6c7cd60\"><img alt=\"Tab2 D'Cruz FrontCellDevBio2020 8.jpg\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/4\/46\/Tab2_D%27Cruz_FrontCellDevBio2020_8.jpg\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Table 2.<\/b> Table of primer and probe sequences for detecting SARS-CoV-2 genes.<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<h3><span class=\"mw-headline\" id=\"Advantages\">Advantages<\/span><\/h3>\n<p>qRT-PCR is the frontline diagnostic test for COVID-19, capable of analyzing thousands of specimens in a single day while showing a testing sensitivity of 95%.<sup id=\"rdp-ebb-cite_ref-CormanDetect20_15-3\" class=\"reference\"><a href=\"#cite_note-CormanDetect20-15\">[15]<\/a><\/sup> The anticipated limit of detection of the SARS-CoV-2 qRT-PCR test is <10 copies\/reaction<sup id=\"rdp-ebb-cite_ref-ChuMolec20_17-1\" class=\"reference\"><a href=\"#cite_note-ChuMolec20-17\">[17]<\/a><\/sup>, which allows early detection of low viral titers. Gene amplification indicates a positive result for the presence of SARS-CoV-2 RNA and should correlate with clinical observations, patient history, and <a href=\"https:\/\/www.limswiki.org\/index.php\/Epidemiology\" title=\"Epidemiology\" class=\"wiki-link\" data-key=\"123badb8bf0b37a513182dbcfc3875bc\">epidemiological<\/a> information.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Disadvantages\">Disadvantages<\/span><\/h3>\n<p>False positive results could be generated by cross-reactivity of primers with nucleic acids arising from co-infection with other viruses or bacteria. In these cases, the agent detected may not be the definite cause of disease. Matching of the SARS-CoV-2 qRT-PCR primers and probes using reliable libraries (e.g., BLAST) is necessary to ensure there is no homology with other coronaviruses like SARS-CoV from 2003 or other organisms such as <i>Staphylococcus aureus<\/i> and <i>Candida albicans<\/i>. False positives can also occur if reagents in a laboratory become contaminated, which is a major concern, particularly with the high volume of testing encountered during a pandemic. A negative patient sample is useful to identify this error in testing.\n<\/p><p>False negative results could potentially arise from mutations occurring in the primer and probe target regions in the SARS-CoV-2 genome. Negative results do not preclude SARS-CoV-2 infection, and results should be validated with different primer sets against the same gene target and combined with patient history and other clinical data to accurately determine patient infection status.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Key_logistics\">Key logistics<\/span><\/h3>\n<p>Provisions for testing laboratories, the use of approved tests, and validation of results with governing authorities to develop master protocols for use by multiple investigators must be in place to achieve rapid testing capacity. The output for number of tests per day and number of individuals tested per day relies on the availability of laboratory capacity, trained staff, reagents, supplies, and equipment. Large quantities of specific high-grade reagents are needed to perform tests, and supplies can be quickly depleted in a pandemic. This impacts the turnaround time for qRT-PCR diagnostic testing that ranges between two and five days. Strategies to rapidly scale up testing for novel human cornaviruses must be considered for future diagnostic testing.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Detection_of_antibodies_against_SARS-CoV-2_proteins_by_enzyme-linked_immunosorbent_assay_.28ELISA.29\">Detection of antibodies against SARS-CoV-2 proteins by enzyme-linked immunosorbent assay (ELISA)<\/span><\/h2>\n<p>An ELISA is a diagnostic method used to identify antibodies in patient blood sample or nasopharyngeal swabs. An ELISA employed for antibody detection against SARS-CoV-2 measures the host humoral response, including IgM, IgG, and IgA to define previous exposure to the virus.<sup id=\"rdp-ebb-cite_ref-GuoProfiling20_20-0\" class=\"reference\"><a href=\"#cite_note-GuoProfiling20-20\">[20]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-OkbaSevere20_21-0\" class=\"reference\"><a href=\"#cite_note-OkbaSevere20-21\">[21]<\/a><\/sup> IgM is the first immunoglobulin that is produced in response to an antigen and is primarily detected during the early onset of disease (the first three to seven days). IgG is the most abundant immunoglobulin that is produced in response to an antigen (seven to 25 days) and is maintained in the body after initial exposure. It may also have a protective role for acquired immunity. The IgA immunoglobulin plays a crucial role in the immune function of mucous membranes.\n<\/p><p>The SARS-CoV-2 S glycoprotein that mediates attachment and entry into cells is surface-exposed and is a key target for the production of host-neutralizing antibodies.<sup id=\"rdp-ebb-cite_ref-WallsGlycan16_22-0\" class=\"reference\"><a href=\"#cite_note-WallsGlycan16-22\">[22]<\/a><\/sup> This feature has made the S protein the focal target of antibody and vaccine development. The N protein in human coronaviruses' functions as an antagonist of interferon<sup id=\"rdp-ebb-cite_ref-Kopecky-BrombergSevere07_23-0\" class=\"reference\"><a href=\"#cite_note-Kopecky-BrombergSevere07-23\">[23]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-McBrideTheCorona14_24-0\" class=\"reference\"><a href=\"#cite_note-McBrideTheCorona14-24\">[24]<\/a><\/sup> and viral encoded repressor (VSR) of RNA interference (RNAi) that facilitates viral replication, and is also a key target for antibody design.<sup id=\"rdp-ebb-cite_ref-LeungAntibody04_25-0\" class=\"reference\"><a href=\"#cite_note-LeungAntibody04-25\">[25]<\/a><\/sup> Recombinant antigens derived from the receptor binding domain of S protein (rS) as well as recombinant N protein (rN) are being developed as suitable diagnostic targets to detect IgM, IgG, and IgA antibodies. Dual detection of IgM\/IgG and IgG\/IgA immunoglobulins is under development for use in conjunction with nucleic acid detection for detecting active infection and to define previous exposure to SARS-CoV-2.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Specifics_2\">Specifics<\/span><\/h3>\n<h4><span class=\"mw-headline\" id=\"Sample_collection_2\">Sample collection<\/span><\/h4>\n<p>Systemic blood samples are collected from individuals for extraction of serum.\n<\/p>\n<h4><span class=\"mw-headline\" id=\"ELISA\">ELISA<\/span><\/h4>\n<p>Purified rS or rN are immobilized to the surface of a multi-well plate as capture antigens. Controls and inactivated SARS-CoV-2 serum samples are incubated with the antigen for SARS-CoV-2 antibody-antigen binding. A labeled secondary antibody-conjugate (e.g., horseradish peroxidase) is bound to the SARS-CoV antibodies for signal detection by substrate addition, and quantification.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Advantages_2\">Advantages<\/span><\/h3>\n<p>Antibody tests provide the advantage of a simple method of detection of SARS-CoV-2 antibodies and are convenient to compare multiple samples from a single patient. Positive rates of detection for SARS-CoV-2 IgG in patients by ELISA measurements are 85.4% and 75.6\u201393.1% for IgM.<sup id=\"rdp-ebb-cite_ref-GuoProfiling20_20-1\" class=\"reference\"><a href=\"#cite_note-GuoProfiling20-20\">[20]<\/a><\/sup> Jin <i>et al.<\/i><sup id=\"rdp-ebb-cite_ref-JinDiagnostic20_26-0\" class=\"reference\"><a href=\"#cite_note-JinDiagnostic20-26\">[26]<\/a><\/sup> reported sensitivities of serum IgM and IgG antibodies for detection were 48.1 and 88.9%, and specificities were 100 and 90.9%, with the highest sensitivity for antibody tests recorded two weeks after the first symptoms of disease. The lower IgM sensitivity may be because the IgM response occurs early then decreases and does not offer a strong detectable signal, while IgG signals may be more readily detected and present beyond 20 days. The incorporation of unique immunoglobulin labels may increase the sensitivity of rapid antibody tests for respiratory viruses.<sup id=\"rdp-ebb-cite_ref-LiDevelop18_27-0\" class=\"reference\"><a href=\"#cite_note-LiDevelop18-27\">[27]<\/a><\/sup> Results from antibody testing could inform infection status and define previous exposure to SARS-CoV-2. Antibody detection is also used to identify recovered patients as human donors for the generation of convalescent patient serum or plasma as an investigational treatment for critically ill patients.<sup id=\"rdp-ebb-cite_ref-ShenTreatment20_28-0\" class=\"reference\"><a href=\"#cite_note-ShenTreatment20-28\">[28]<\/a><\/sup>\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Disadvantages_2\">Disadvantages<\/span><\/h3>\n<p>The results of SARS-CoV-2 antibody tests may vary by apparent disease periods and by time after symptom onset, as well as on the reliability of diagnostic assays. It is not yet known when IgM or IgG antibodies specific to the SARS-CoV-2 virus will become detectable during an infection, how long antibodies persist following infection, and what extent of protection neutralizing antibodies offer against subsequent infection with the virus.\n<\/p><p>The overall sensitivity and specificity indicate the possibility of false negatives and false positives in this testing method. Since the risk for recurrent infection with SARS-CoV-2 is not known for COVID-19, detection of one or two antibodies (IgM and\/or IgG) does not necessarily guarantee immunity against reinfection. Negative results do not rule out SARS-CoV-2 infection\u2014particularly in those who have been in contact with the virus\u2014and positive results may be due to past or present infection with SARS-CoV<sup id=\"rdp-ebb-cite_ref-GuoProfiling20_20-2\" class=\"reference\"><a href=\"#cite_note-GuoProfiling20-20\">[20]<\/a><\/sup> and possibly non-SARS-CoV strains.<sup id=\"rdp-ebb-cite_ref-GauntEpidem10_29-0\" class=\"reference\"><a href=\"#cite_note-GauntEpidem10-29\">[29]<\/a><\/sup> It will be critical to conduct stringent evaluation of antibody diagnostic assays to determine the accuracy and reliability of results.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Key_logistics_2\">Key logistics<\/span><\/h3>\n<p>Recombinant systems are routinely used to express recombinant proteins to develop antibody assays. However, protein-expression systems can result in significant discrepancies between recombinant and native viral proteins. For example, the use of <i>E. coli<\/i> competent cells produces proteins that lack critical post-translational modifications in human cells (e.g., glycosylation) that can alter epitopes and protein conformation.<sup id=\"rdp-ebb-cite_ref-GuptaGlyco18_30-0\" class=\"reference\"><a href=\"#cite_note-GuptaGlyco18-30\">[30]<\/a><\/sup> Consequently, this can compromise sensitivity and specificity of antigens for diagnostic assays. The use of mammalian expression systems to express recombinant proteins will produce antigens with post-translation modifications that more closely resemble human native proteins<sup id=\"rdp-ebb-cite_ref-BandaranayakRecent14_31-0\" class=\"reference\"><a href=\"#cite_note-BandaranayakRecent14-31\">[31]<\/a><\/sup>, leading to higher sensitivity and specificity of assays.\n<\/p><p>Serological assays are currently under accelerated development for diagnosis of human coronavirus infections. Commercial reagents need to be validated by clinical trials using samples from patients with confirmed infections of SARS-CoV-2, and approved by the regulatory review process. Nonetheless, a rapid and sensitive platform for identification of antibody titers will also support screening to identify and minimize the risk of viral spread to others, as well as for epidemiological studies and vaccine evaluation studies. The U.S. Food and Drug Administration (FDA) allows the use of rapid antibody tests for SARS-CoV-2 under emergency use authorization (EUA). This expedites the assessment and optimization of these diagnostic tests, with the expectation that any test is sufficiently experimentally validated before it is made available to patients. If these tests do not provide accurate results, this can impair prevention efforts and delay appropriate treatment during the global pandemic response.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Rapid_detection_of_SARS-CoV-2_by_lateral_flow_immunoassays_.28LFI.29\">Rapid detection of SARS-CoV-2 by lateral flow immunoassays (LFI)<\/span><\/h2>\n<p>Test developers have used the principles behind ELISA and applied them to develop lateral flow immunoassays (LFI) for the rapid qualitative detection of a substance. Some researchers are beginning to apply LFI to SARS-CoV-2 in the form of a simple, portable diagnostic strip to measure either SARS-CoV-2 antibodies or antigens. As viral titers are often low in nasal swabs and serum or plasma, detection of antigens may be more challenging in comparison to detection of antibodies. Serological antigen assays can target S1 and S2 domains of the S protein that binds angiotensin-converting enzyme-2 (ACE-2), an integral transmembrane protein in the lung alveolar epithelium that serves as the initial attachment site for SARS-CoV-2, or N proteins.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Specifics_3\">Specifics<\/span><\/h3>\n<h4><span class=\"mw-headline\" id=\"LFI\">LFI<\/span><\/h4>\n<p>The design of the lateral flow test is that of a strip\/dipstick containing immobilized test reagents, enclosed in a cassette. Drops of a patient's blood are deposited on the strip, which contains a coating of purified monoclonal antibody (mAb) or recombinant antigen that is localized at specific regions on a nitrocellulose membrane. The mAb targets a viral antigen; the recombinant antigen is recognized by antibodies that are present in infected patients. The strip also contains labeled detector antibodies that bind the same antigen. A positive antibody result indicates binding between the coating antigen and patient antibodies and binding by the detector antibody. This generates a colored signal. A positive antigen result indicates binding between the coating antibody and patient antigen.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Advantage\">Advantage<\/span><\/h3>\n<p>Two drops of blood are sufficient for detection of SARS-CoV-2 and antibodies by this method. This technique delivers results in approximately 15 minutes and uses visual detection by the naked eye, in comparison to qRT-PCR (two to five days). Detection of antibodies shows previous viral exposure while detection of antigens indicates active carriers of SARS-CoV-2 virus. The specificity and sensitivity of LFIs are comparable with antibody and antigen assays.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Disadvantage\">Disadvantage<\/span><\/h3>\n<p>Tests to detect SARS-CoV-2 in patients by identifying viral antigens are more challenging to develop than tests to detect the neutralizing antibodies against SARS-CoV-2 (see below), as purified monoclonal antibodies must be generated against target antigens. Further, these assays need to be assessed and optimized using blood from infected patients.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Key_logistics_3\">Key logistics<\/span><\/h3>\n<p>The rapid development of some antigens for assays are led by the use of \u201cprototype\u201d pathogens and <i>in silico<\/i> models of antibody\u2013antigen interactions that are used to generate artificial antibody libraries.<sup id=\"rdp-ebb-cite_ref-ShaoStructure07_32-0\" class=\"reference\"><a href=\"#cite_note-ShaoStructure07-32\">[32]<\/a><\/sup> Antibody phage display technology can be applied to discover antibodies against antigens.<sup id=\"rdp-ebb-cite_ref-LedsgaardBasics18_33-0\" class=\"reference\"><a href=\"#cite_note-LedsgaardBasics18-33\">[33]<\/a><\/sup> These can be rapidly generated to produce prototypes of diagnostic tests for validation studies that expedite assessment and optimization, before the final commercial diagnostic kits are available. Integrating fast, portable tests with epidemiological surveillance will also provide quick and reliable information to public health authorities monitoring the spread of SARS-CoV-2.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Serum_virus_neutralization_assay_.28SVN.29\">Serum virus neutralization assay (SVN)<\/span><\/h2>\n<p>The SVN assay is a serological test that measures the ability of a patient's antibodies to neutralize infectivity of SARS-CoV-2 and attenuate infection. This assay is considered the most reliable for the assessment of protective antibody and can inform the use of convalescent plasma as a passive antibody therapy for COVID-19 infection, particularly in severely ill patients. Although there is limited clinical data, early studies suggest that transfusion of convalescent plasma can suppress SARS-CoV-2 viral replication and protect an individual from infection.<sup id=\"rdp-ebb-cite_ref-GuoProfiling20_20-3\" class=\"reference\"><a href=\"#cite_note-GuoProfiling20-20\">[20]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ShenTreatment20_28-1\" class=\"reference\"><a href=\"#cite_note-ShenTreatment20-28\">[28]<\/a><\/sup> The SVN assay is not used for routine diagnosis but is frontline for this special indication.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Specifics_4\">Specifics<\/span><\/h3>\n<h4><span class=\"mw-headline\" id=\"Sample_collection_3\">Sample collection<\/span><\/h4>\n<p>Plasma is prepared from systemic blood samples collected from COVID-19 convalescent donors. Written informed consent is required from both the donor and recipient.\n<\/p>\n<h4><span class=\"mw-headline\" id=\"SVN\">SVN<\/span><\/h4>\n<p>Several cell lines are suitable for SARS-CoV-2 transduction, including Vero (monkey kidney cell line), Huh7 (human hepatoma cell line), and 293T (human kidney cell line).<sup id=\"rdp-ebb-cite_ref-NieEstab20_34-0\" class=\"reference\"><a href=\"#cite_note-NieEstab20-34\">[34]<\/a><\/sup> Serial dilutions of patient convalescent serum are added to known strains of virus (BetaCoV\/Shenzhen\/SZTH-003\/2020 strain virus, GISAID access number: EPI_ISL_406594).<sup id=\"rdp-ebb-cite_ref-ShenTreatment20_28-2\" class=\"reference\"><a href=\"#cite_note-ShenTreatment20-28\">[28]<\/a><\/sup> The mixture is inoculated into a susceptible cell monolayer and incubated for virus adsorption. The cytopathic effect can be measured by microscopic examination<sup id=\"rdp-ebb-cite_ref-ShenTreatment20_28-3\" class=\"reference\"><a href=\"#cite_note-ShenTreatment20-28\">[28]<\/a><\/sup> after a five-day incubation, fluorescence<sup id=\"rdp-ebb-cite_ref-NieEstab20_34-1\" class=\"reference\"><a href=\"#cite_note-NieEstab20-34\">[34]<\/a><\/sup>, or plaque formation, following 24 hours of incubation. The neutralizing antibody titer is the highest dilution of serum that reduces activity of SARS-CoV-2.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Advantages_3\">Advantages<\/span><\/h3>\n<p>The SVN assay is a highly robust and reproducible test that may be applied to detect SARS-CoV-2 neutralizing antibodies in convalescent plasma samples to identify the best candidates for treatment. Neutralizing activities, along with viral load and antibody titers, can be simultaneously monitored in paired plasma samples in patients receiving convalescence plasma in order to establish algorithms for determining patient and donor factors that predict clinical efficacy.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Disadvantages_3\">Disadvantages<\/span><\/h3>\n<p>The accessibility of the live SARS-CoV-2 strain is regulated, which limits the development of laboratory testing by SVN. While inexpensive, it is a manual assay and requires careful in-house standardization and quality control.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Key_logistics_4\">Key logistics<\/span><\/h3>\n<p>A preliminary case report of positive responses of five severely ill patients with COVID-19 who were treated in the Shenzhen Third People's Hospital, China using plasma from recovered individuals was recently published.<sup id=\"rdp-ebb-cite_ref-ShenTreatment20_28-4\" class=\"reference\"><a href=\"#cite_note-ShenTreatment20-28\">[28]<\/a><\/sup> The convalescent plasma contained functional IgG and IgM anti\u2013SARS-CoV-2 neutralizing antibodies that inhibited viral growth in cell cultures. Notably, the SVN assay reliably measured the increases in the patients' neutralizing antibody titers between one and 12 days after plasma transfusion. This study was not evaluated in a randomized clinical trial, and there are limitations to the data interpretation. Nonetheless, these findings demonstrate the utility of the SVN assay for evaluating anti\u2013SARS-CoV-2 neutralizing antibodies for future convalescent plasma assessment in more rigorous clinical investigations involving a larger cohort of patients with severe COVID-19 illness.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Emerging_methods_for_diagnosis_of_SARS-CoV-2\">Emerging methods for diagnosis of SARS-CoV-2<\/span><\/h2>\n<p>Methods for the rapid detection of nucleic acids are being used to develop applications in clinical diagnostics of SAR-CoV-2.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Isothermal_nucleic_acid_amplification\">Isothermal nucleic acid amplification<\/span><\/h3>\n<p>This method amplifies DNA or RNA target sequence in a streamlined and exponential manner for detection, and in contrast to PCR, does not require thermal cycling. A wide variety of nucleic acid detection assays have been developed, including loop-mediated isothermal amplification (LAMP), a single-tube technique for the amplification of DNA; reverse transcription-LAMP, which combines reverse transcriptase and LAMP to detect RNA (RT-LAMP)<sup id=\"rdp-ebb-cite_ref-NotomiLoop00_35-0\" class=\"reference\"><a href=\"#cite_note-NotomiLoop00-35\">[35]<\/a><\/sup>; recombinase polymerase amplification (RPA)<sup id=\"rdp-ebb-cite_ref-LiReview18_36-0\" class=\"reference\"><a href=\"#cite_note-LiReview18-36\">[36]<\/a><\/sup>; helicase-dependent amplification (HDA)<sup id=\"rdp-ebb-cite_ref-VincentHelicase04_37-0\" class=\"reference\"><a href=\"#cite_note-VincentHelicase04-37\">[37]<\/a><\/sup>; strand displacement amplification (SDA)<sup id=\"rdp-ebb-cite_ref-WalkerStrand92_38-0\" class=\"reference\"><a href=\"#cite_note-WalkerStrand92-38\">[38]<\/a><\/sup>; and nucleic acid sequence-based amplification (NASBA).<sup id=\"rdp-ebb-cite_ref-ComptonNucleic91_39-0\" class=\"reference\"><a href=\"#cite_note-ComptonNucleic91-39\">[39]<\/a><\/sup> These assays incorporate isothermal methods to enable primer binding followed by amplification using a polymerase with strand-displacement activity that separates the strand that is annealed to the target sequence for detection. Amplified gene products can be detected by photometry. Isothermal nucleic acid amplification is utilized in several commercial molecular diagnostic platforms and is considered the fastest available molecular laboratory and point-of-care test for the detection of novel SARS-CoV-2.\n<\/p>\n<h4><span class=\"mw-headline\" id=\"RT-LAMP\">RT-LAMP<\/span><\/h4>\n<p>The RT-LAMP method has been shown to effectively detect SARS-CoV-2 in clinical samples from individuals with COVID-19.<sup id=\"rdp-ebb-cite_ref-YanRapid20_40-0\" class=\"reference\"><a href=\"#cite_note-YanRapid20-40\">[40]<\/a><\/sup> Multiple loop primers targeting the ORF1ab gene and the S gene were used for DNA strand displacement activity and target amplification that achieved detection of 20 copies\/reaction and 200 copies\/reaction, respectively. These results were comparable to qRT-PCR amplification. The reported 100% sensitivity and 100% specificity, as well as the mean time for detection being under 30 minutes, demonstrate this is a definitive testing method.\n<\/p>\n<h4><span class=\"mw-headline\" id=\"RPA\">RPA<\/span><\/h4>\n<p>This method detected total viral RNA derived from cell culture supernatant and 19 nasopharyngeal swab samples (eight positive and 11 negative) for SARS-CoV-2.<sup id=\"rdp-ebb-cite_ref-BehrmannRapid20_41-0\" class=\"reference\"><a href=\"#cite_note-BehrmannRapid20-41\">[41]<\/a><\/sup> This approach integrates isothermal methods for reverse transcription followed by recombinase activity that mediates primer (targeting the N gene) binding to the homologous sequence in dsDNA. Subsequent amplification by polymerase mediated primer extension achieved 100% diagnostic sensitivity and specificity. This method offers potential advantages over qRT-PCR for speed, scale, and portability, allowing evidence-based clinical decisions to be made during a patient visit.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"CRISPR_.28clustered_regularly_interspaced_short_palindromic_repeats.29\">CRISPR (clustered regularly interspaced short palindromic repeats)<\/span><\/h3>\n<p>The CRISPR assay functionality is being applied for detection of DNA or RNA using nucleic acid pre-amplification combined with CRISPR-Cas enzymology for specific recognition of sequences.\n<\/p><p>The CRISPR\/Cas13a system is a recently discovered CRISPR-RNA (crRNA) guided detection method that is specific for RNA and is being applied for SARS-CoV-2 detection. A key feature of this approach is the Cas13a (formerly named C2c2) enzyme that recognizes and binds targeted RNA in a sequence-specific manner, followed by non-specific trans-endonuclease cleavage of non-targeted RNA (\u201ccollateral\u201d cleavage) for signal amplification and nucleic acid detection. The Cas13a assay can be paired with target nucleic acid amplification for more sensitive results using an isothermal exponential amplification technique, most commonly RPA. This coupled technique is termed SHERLOCK (Specific High-Sensitivity Enzymatic Reporter unLOCKing) and allows fluorescence, colorimetric, lateral flow, and other readout approaches to enable the rapid detection of a variety of targets.<sup id=\"rdp-ebb-cite_ref-KellnerSHER19_42-0\" class=\"reference\"><a href=\"#cite_note-KellnerSHER19-42\">[42]<\/a><\/sup>\n<\/p>\n<h4><span class=\"mw-headline\" id=\"Cas13a_assay\">Cas13a assay<\/span><\/h4>\n<p>Unlike <i>in vivo<\/i> CRISPR tools, the Cas13a protein must be recombinantly expressed and purified. The endonuclease activity of purified Cas13a uses crRNA targeting sequences in the S gene and ORF1ab in SARS-CoV-2 RNA. Target site-recognition activates trans-cleavage of reporter probes resulting in increases in fluorescence output signals and confirming the presence of viral RNA. Using synthetic SARS-CoV-2 the reported performance of this method for detection of target sequences is 20\u2013200 aM.<sup id=\"rdp-ebb-cite_ref-KellnerSHER19_42-1\" class=\"reference\"><a href=\"#cite_note-KellnerSHER19-42\">[42]<\/a><\/sup> The Cas13a\/crRNA platform has been adapted for lateral-flow assays and could have wide applications as a SARS-CoV2 detector in both research and in the clinic. Assays can be designed as a paper dipstick test that delivers signals within 30 to 60 minutes. This is a very promising technology and these positive advances in science offer immense hope for future disease control.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Next-generation_sequencing\">Next-generation sequencing<\/span><\/h3>\n<p><a href=\"https:\/\/www.limswiki.org\/index.php\/DNA_sequencing#High-throughput_methods\" title=\"DNA sequencing\" class=\"wiki-link\" data-key=\"090351f8c03a4d52a4aa39a94f5b52ba\">Next-generation sequencing<\/a> (NGS) enables complete sequencing of the ~30,000 nucleotides of the SARS-CoV-2 genome. NGS provides a method for identification of SARS-CoV-2, for environmental monitoring and surveillance testing, while also providing insight into strain origin and viral evolution. Each sequence is deposited into the GISAID EpiCoVTM Database, and to date there are over 17,000 SARS-CoV-2 sequences from global NGS efforts.\n<\/p><p>Sample is prepared by extracting RNA from clinical specimens, similar to qRT-PCR, and the sample is further purified to remove human cytoplasmic and ribosomal rRNA. \n<\/p><p>Library preparation involves fragmenting RNA, followed by cDNA synthesis. Through the use of a set of highly specific, universal coronavirus primers, all genomic segments are amplified and the DNA amplicons are sequenced to deliver highly accurate SARS-CoV-2 typing in less than 24 hours. Virus titer, efficiency of human rRNA depletion, and the number of reads per sample impact the number of virus-specific reads obtained and accurate coverage of the viral genome.\n<\/p><p>Collectively, global NGS data suggest the SARS-CoV-2 genome is relatively stable, although mutations are being identified in symptomatic individuals that are not present in the original strain in Wuhan, China. Two recent NGS studies report a large base pair deletion consisting of 81 nucleotides in SARS-CoV-2 ORF7a in a virus sample from a U.S. patient<sup id=\"rdp-ebb-cite_ref-HollandAn81_20_43-0\" class=\"reference\"><a href=\"#cite_note-HollandAn81_20-43\">[43]<\/a><\/sup>, and point mutations that may suggest a more infectious strain of the virus than the original strain.<sup id=\"rdp-ebb-cite_ref-KorberSpike20_44-0\" class=\"reference\"><a href=\"#cite_note-KorberSpike20-44\">[44]<\/a><\/sup> The ORF7a gene encodes an accessory protein that is involved in viral infection and host cell death.<sup id=\"rdp-ebb-cite_ref-SchaecherSevere07_45-0\" class=\"reference\"><a href=\"#cite_note-SchaecherSevere07-45\">[45]<\/a><\/sup> These findings require investigation in other patient samples and to determine whether such mutations are selected in asymptomatic or symptomatic individuals. Although NGS is one of the most comprehensive approaches for identifying SARS-CoV-2, this method is relatively expensive, with multiple sample preparation steps. As such, it tends to not be used for large-scale testing.\n<\/p>\n<h4><span class=\"mw-headline\" id=\"Biosafety\">Biosafety<\/span><\/h4>\n<p>Regulating authorities provide interim guidance on the handling of specimens associated with SARS-CoV-2.<sup id=\"rdp-ebb-cite_ref-CDCInterimBio20_46-0\" class=\"reference\"><a href=\"#cite_note-CDCInterimBio20-46\">[46]<\/a><\/sup> Samples for testing can be performed in a <a href=\"https:\/\/www.limswiki.org\/index.php\/Biosafety_level\" title=\"Biosafety level\" class=\"wiki-link\" data-key=\"df3da482bc6a095d4f125bcf7fccfc76\">Biosafety Level 2<\/a> (BSL-2) laboratory with unidirectional airflow and BSL-3 precautions, and respiratory protection and a designated area for personal protective equipment changes are recommended. Isolation of SARS-CoV-2 in cell culture and initial characterization of viral agents recovered in cultures of patient samples should be conducted at Biosafety Level 3 (BSL-3), with regulatory approval and guidance.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Conclusions\">Conclusions<\/span><\/h2>\n<p>Figure 2 and Table 3 summarize the main laboratory tests for detection of components of SARS-CoV-2 and the humoral response to the virus, and they depict key features of these approaches. Given the public health emergency that the expanding COVID-19 outbreak presents, more widespread testing is needed to investigate the disease (e.g., prevalence in the population, severity in age groups) and to identify individuals who are infected but have few or no symptoms. Detailed epidemiological data sets will better establish the rates of severe infection and death among infected populations.\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig2_D%27Cruz_FrontCellDevBio2020_8.jpg\" class=\"image wiki-link\" data-key=\"8b97966a7c1bc9ddac8064c5933a60a5\"><img alt=\"Fig2 D'Cruz FrontCellDevBio2020 8.jpg\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/4\/48\/Fig2_D%27Cruz_FrontCellDevBio2020_8.jpg\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Figure 2.<\/b> Molecular structure of SARS-CoV-2 and summary of the available laboratory tests and their target molecules. SARS-CoV-2 has a lipid bilayer membrane that contains Envelope (E) and Membrane (M) proteins that make up the envelope. Spike (S) glycoproteins project from the surface of the virion. Nucleocapsid protein (N) is composed of the protein that is associated with the viral genetic material. RT-PCR, reverse transcriptase polymerase chain reaction; ELISA, enzyme-linked immunosorbent assay; LFI, lateral flow immunoassay; SVN, serum virus neutralization assay; INAA, isothermal nucleic acid amplification; CRISPR, clustered regularly interspaced short palindromic repeats; NGS, next-generation sequencing; RT-LAMP, reverse transcriptase loop-mediated isothermal amplification; RPA, recombinase polymerase amplification.<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Tab3_D%27Cruz_FrontCellDevBio2020_8.jpg\" class=\"image wiki-link\" data-key=\"3680586a54d56cdf7dd636b2ffa25a27\"><img alt=\"Tab3 D'Cruz FrontCellDevBio2020 8.jpg\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/d\/dc\/Tab3_D%27Cruz_FrontCellDevBio2020_8.jpg\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Table 3.<\/b> Summary of main testing methods for COVID-19 highlighting the patient sample required for testing, material being tested, and key features.<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>Ongoing research is critical to optimize existing antibody tests to determine whether immunity prevents recurrent infection and to investigate the efficacy of passive antibody therapies for COVID-19 infection. The identification of novel disease biomarkers may be valuable for understanding what makes people susceptible to COVID-19 infection and in predicting the severity and progression of disease. Researchers could request approval to analyze stored samples of human blood or in animals that might be a natural reservoir of the virus. Specifically, guidance would be needed to direct blood and plasma collection centers to allow access of samples from COVID-19 patients.\n<\/p><p>The COVID-19 pandemic showcases how quickly information needs to be shared as responders address rapidly evolving situations. Establishing communication across laboratories worldwide helps to develop master protocols and establish reference panels for use by multiple investigators. This aids in coordinating the collection and use of data within the constraints of the regulatory infrastructure. Having a range of tests also puts less pressure on one manufacturer or supply chain, as different suppliers may use different materials. This could help alleviate difficult decisions to limit testing to the most vulnerable patients, which can have great public health consequences.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Acknowledgements\">Acknowledgements<\/span><\/h2>\n<p>The authors thank Robert E. Akins, Ph.D. (Nemours\/A. I. duPont Hospital for Children) for reading and editing this manuscript.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Author_contributions\">Author contributions<\/span><\/h3>\n<p>RD'C and VS contributed to concept and writing of manuscript. AC contributed to writing, and prepared tables and figure for this manuscript.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Funding\">Funding<\/span><\/h3>\n<p>This work was provided in part by Nemours\/The Fund.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Conflict_of_interest\">Conflict of interest<\/span><\/h3>\n<p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"References\">References<\/span><\/h2>\n<div class=\"reflist references-column-width\" style=\"-moz-column-width: 30em; -webkit-column-width: 30em; column-width: 30em; list-style-type: decimal;\">\n<ol class=\"references\">\n<li id=\"cite_note-WHONaming20-1\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-WHONaming20_1-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">World Health Organization (2020). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.who.int\/emergencies\/diseases\/novel-coronavirus-2019\/technical-guidance\/naming-the-coronavirus-disease-(covid-2019)-and-the-virus-that-causes-it\" target=\"_blank\">\"Naming the coronavirus disease (COVID-19) and the virus that causes it\"<\/a>. World Health Organization<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.who.int\/emergencies\/diseases\/novel-coronavirus-2019\/technical-guidance\/naming-the-coronavirus-disease-(covid-2019)-and-the-virus-that-causes-it\" target=\"_blank\">https:\/\/www.who.int\/emergencies\/diseases\/novel-coronavirus-2019\/technical-guidance\/naming-the-coronavirus-disease-(covid-2019)-and-the-virus-that-causes-it<\/a><\/span><span class=\"reference-accessdate\">. Retrieved May 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Naming+the+coronavirus+disease+%28COVID-19%29+and+the+virus+that+causes+it&rft.atitle=&rft.aulast=World+Health+Organization&rft.au=World+Health+Organization&rft.date=2020&rft.pub=World+Health+Organization&rft_id=https%3A%2F%2Fwww.who.int%2Femergencies%2Fdiseases%2Fnovel-coronavirus-2019%2Ftechnical-guidance%2Fnaming-the-coronavirus-disease-%28covid-2019%29-and-the-virus-that-causes-it&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ChanAFami20-2\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-ChanAFami20_2-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Chan, J.F.-W.; Yuan, S.; Kok, K.-H. et al. (2020). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7159286\" target=\"_blank\">\"A Familial Cluster of Pneumonia Associated With the 2019 Novel Coronavirus Indicating Person-To-Person Transmission: A Study of a Family Cluster\"<\/a>. <i>Lancet<\/i> <b>395<\/b> (10223): 514\u201323. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2FS0140-6736%2820%2930154-9\" target=\"_blank\">10.1016\/S0140-6736(20)30154-9<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC7159286\/\" target=\"_blank\">PMC7159286<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/31986261\" target=\"_blank\">31986261<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7159286\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7159286<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=A+Familial+Cluster+of+Pneumonia+Associated+With+the+2019+Novel+Coronavirus+Indicating+Person-To-Person+Transmission%3A+A+Study+of+a+Family+Cluster&rft.jtitle=Lancet&rft.aulast=Chan%2C+J.F.-W.%3B+Yuan%2C+S.%3B+Kok%2C+K.-H.+et+al.&rft.au=Chan%2C+J.F.-W.%3B+Yuan%2C+S.%3B+Kok%2C+K.-H.+et+al.&rft.date=2020&rft.volume=395&rft.issue=10223&rft.pages=514%E2%80%9323&rft_id=info:doi\/10.1016%2FS0140-6736%2820%2930154-9&rft_id=info:pmc\/PMC7159286&rft_id=info:pmid\/31986261&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC7159286&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ZakiIso12-3\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-ZakiIso12_3-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Zaki, A.M.; van Boheemen, S.; Besterbroer, T.M. et al. (2012). \"Isolation of a Novel Coronavirus From a Man With Pneumonia in Saudi Arabia\". <i>New England Journal of Medicine<\/i> <b>367<\/b> (19): 1814\u201320. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1056%2FNEJMoa1211721\" target=\"_blank\">10.1056\/NEJMoa1211721<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/23075143\" target=\"_blank\">23075143<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Isolation+of+a+Novel+Coronavirus+From+a+Man+With+Pneumonia+in+Saudi+Arabia&rft.jtitle=New+England+Journal+of+Medicine&rft.aulast=Zaki%2C+A.M.%3B+van+Boheemen%2C+S.%3B+Besterbroer%2C+T.M.+et+al.&rft.au=Zaki%2C+A.M.%3B+van+Boheemen%2C+S.%3B+Besterbroer%2C+T.M.+et+al.&rft.date=2012&rft.volume=367&rft.issue=19&rft.pages=1814%E2%80%9320&rft_id=info:doi\/10.1056%2FNEJMoa1211721&rft_id=info:pmid\/23075143&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-DrostenIdent03-4\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-DrostenIdent03_4-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Drosten, C.; G\u00fcnther, S.; Preiser, W. et al. (2003). \"Identification of a Novel Coronavirus in Patients With Severe Acute Respiratory Syndrome\". <i>New England Journal of Medicine<\/i> <b>348<\/b> (20): 1967-76. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1056%2FNEJMoa030747\" target=\"_blank\">10.1056\/NEJMoa030747<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/12690091\" target=\"_blank\">12690091<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Identification+of+a+Novel+Coronavirus+in+Patients+With+Severe+Acute+Respiratory+Syndrome&rft.jtitle=New+England+Journal+of+Medicine&rft.aulast=Drosten%2C+C.%3B+G%C3%BCnther%2C+S.%3B+Preiser%2C+W.+et+al.&rft.au=Drosten%2C+C.%3B+G%C3%BCnther%2C+S.%3B+Preiser%2C+W.+et+al.&rft.date=2003&rft.volume=348&rft.issue=20&rft.pages=1967-76&rft_id=info:doi\/10.1056%2FNEJMoa030747&rft_id=info:pmid\/12690091&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-KsiazekANovel03-5\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-KsiazekANovel03_5-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Ksiazek, T.G.; Erdman, D.; Goldsmith, C.S. et al. (2003). \"A Novel Coronavirus Associated With Severe Acute Respiratory Syndrome\". <i>New England Journal of Medicine<\/i> <b>348<\/b> (20): 1953\u201366. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1056%2FNEJMoa030781\" target=\"_blank\">10.1056\/NEJMoa030781<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/12690092\" target=\"_blank\">12690092<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=A+Novel+Coronavirus+Associated+With+Severe+Acute+Respiratory+Syndrome&rft.jtitle=New+England+Journal+of+Medicine&rft.aulast=Ksiazek%2C+T.G.%3B+Erdman%2C+D.%3B+Goldsmith%2C+C.S.+et+al.&rft.au=Ksiazek%2C+T.G.%3B+Erdman%2C+D.%3B+Goldsmith%2C+C.S.+et+al.&rft.date=2003&rft.volume=348&rft.issue=20&rft.pages=1953%E2%80%9366&rft_id=info:doi\/10.1056%2FNEJMoa030781&rft_id=info:pmid\/12690092&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-SalataCorona19-6\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-SalataCorona19_6-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Salata, C.; Calistri, A.; Parolin, C. et al. (2019). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7108526\" target=\"_blank\">\"Coronaviruses: A Paradigm of New Emerging Zoonotic Diseases\"<\/a>. <i>Pathogens and Disease<\/i> <b>77<\/b> (9): ftaa006. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1093%2Ffemspd%2Fftaa006\" target=\"_blank\">10.1093\/femspd\/ftaa006<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC7108526\/\" target=\"_blank\">PMC7108526<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/32065221\" target=\"_blank\">32065221<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7108526\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7108526<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Coronaviruses%3A+A+Paradigm+of+New+Emerging+Zoonotic+Diseases&rft.jtitle=Pathogens+and+Disease&rft.aulast=Salata%2C+C.%3B+Calistri%2C+A.%3B+Parolin%2C+C.+et+al.&rft.au=Salata%2C+C.%3B+Calistri%2C+A.%3B+Parolin%2C+C.+et+al.&rft.date=2019&rft.volume=77&rft.issue=9&rft.pages=ftaa006&rft_id=info:doi\/10.1093%2Ffemspd%2Fftaa006&rft_id=info:pmc\/PMC7108526&rft_id=info:pmid\/32065221&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC7108526&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-WorldCOVID-7\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-WorldCOVID_7-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\"><a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.worldometers.info\/coronavirus\/\" target=\"_blank\">\"COVID-19 Coronavirus Pandemic\"<\/a>. <i>Worldometer<\/i><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.worldometers.info\/coronavirus\/\" target=\"_blank\">https:\/\/www.worldometers.info\/coronavirus\/<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 12 May 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=COVID-19+Coronavirus+Pandemic&rft.atitle=Worldometer&rft_id=https%3A%2F%2Fwww.worldometers.info%2Fcoronavirus%2F&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span>><\/span>\n<\/li>\n<li id=\"cite_note-WuANew20-8\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-WuANew20_8-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Wu, F.; Zhao, S.; Yu, B. et al. (2020). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7094943\" target=\"_blank\">\"A New Coronavirus Associated With Human Respiratory Disease in China\"<\/a>. <i>Nature<\/i> <b>579<\/b> (7798): 265-269. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1038%2Fs41586-020-2008-3\" target=\"_blank\">10.1038\/s41586-020-2008-3<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC7094943\/\" target=\"_blank\">PMC7094943<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/32015508\" target=\"_blank\">32015508<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7094943\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7094943<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=A+New+Coronavirus+Associated+With+Human+Respiratory+Disease+in+China&rft.jtitle=Nature&rft.aulast=Wu%2C+F.%3B+Zhao%2C+S.%3B+Yu%2C+B.+et+al.&rft.au=Wu%2C+F.%3B+Zhao%2C+S.%3B+Yu%2C+B.+et+al.&rft.date=2020&rft.volume=579&rft.issue=7798&rft.pages=265-269&rft_id=info:doi\/10.1038%2Fs41586-020-2008-3&rft_id=info:pmc\/PMC7094943&rft_id=info:pmid\/32015508&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC7094943&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-DurrantMeso20-9\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-DurrantMeso20_9-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Durrant, J.D.; Kochanek, S.E.; Casalino, L. et al. (2020). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7048371\" target=\"_blank\">\"Mesoscale All-Atom Influenza Virus Simulations Suggest New Substrate Binding Mechanism\"<\/a>. <i>ACS Central Science<\/i> <b>6<\/b> (2): 189\u201396. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1021%2Facscentsci.9b01071\" target=\"_blank\">10.1021\/acscentsci.9b01071<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC7048371\/\" target=\"_blank\">PMC7048371<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/32123736\" target=\"_blank\">32123736<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7048371\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7048371<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Mesoscale+All-Atom+Influenza+Virus+Simulations+Suggest+New+Substrate+Binding+Mechanism&rft.jtitle=ACS+Central+Science&rft.aulast=Durrant%2C+J.D.%3B+Kochanek%2C+S.E.%3B+Casalino%2C+L.+et+al.&rft.au=Durrant%2C+J.D.%3B+Kochanek%2C+S.E.%3B+Casalino%2C+L.+et+al.&rft.date=2020&rft.volume=6&rft.issue=2&rft.pages=189%E2%80%9396&rft_id=info:doi\/10.1021%2Facscentsci.9b01071&rft_id=info:pmc\/PMC7048371&rft_id=info:pmid\/32123736&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC7048371&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-GrahamRecomb10-10\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-GrahamRecomb10_10-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Graham, R.L.; Baric, R.S. (2010). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2838128\" target=\"_blank\">\"Recombination, Reservoirs, and the Modular Spike: Mechanisms of Coronavirus Cross-Species Transmission\"<\/a>. <i>Journal of Virology<\/i> <b>84<\/b> (7): 3134\u201346. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1128%2FJVI.01394-09\" target=\"_blank\">10.1128\/JVI.01394-09<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC2838128\/\" target=\"_blank\">PMC2838128<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/19906932\" target=\"_blank\">19906932<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2838128\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2838128<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Recombination%2C+Reservoirs%2C+and+the+Modular+Spike%3A+Mechanisms+of+Coronavirus+Cross-Species+Transmission&rft.jtitle=Journal+of+Virology&rft.aulast=Graham%2C+R.L.%3B+Baric%2C+R.S.&rft.au=Graham%2C+R.L.%3B+Baric%2C+R.S.&rft.date=2010&rft.volume=84&rft.issue=7&rft.pages=3134%E2%80%9346&rft_id=info:doi\/10.1128%2FJVI.01394-09&rft_id=info:pmc\/PMC2838128&rft_id=info:pmid\/19906932&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC2838128&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-PhanGenetic20-11\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-PhanGenetic20_11-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Phan, T. (2020). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7106203\" target=\"_blank\">\"Genetic Diversity and Evolution of SARS-CoV-2\"<\/a>. <i>Infection, genetics and evolution<\/i> <b>81<\/b>: 104260. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.meegid.2020.104260\" target=\"_blank\">10.1016\/j.meegid.2020.104260<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC7106203\/\" target=\"_blank\">PMC7106203<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/32092483\" target=\"_blank\">32092483<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7106203\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7106203<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Genetic+Diversity+and+Evolution+of+SARS-CoV-2&rft.jtitle=Infection%2C+genetics+and+evolution&rft.aulast=Phan%2C+T.&rft.au=Phan%2C+T.&rft.date=2020&rft.volume=81&rft.pages=104260&rft_id=info:doi\/10.1016%2Fj.meegid.2020.104260&rft_id=info:pmc\/PMC7106203&rft_id=info:pmid\/32092483&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC7106203&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-WangTheEstab20-12\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-WangTheEstab20_12-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Wang, C.; Liu, Z.; Chen, Z. et al. (2020). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7228400\" target=\"_blank\">\"The Establishment of Reference Sequence for SARS-CoV-2 and Variation Analysis\"<\/a>. <i>Journal of Medical Virology<\/i> <b>92<\/b> (6): 667-674. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1002%2Fjmv.25762\" target=\"_blank\">10.1002\/jmv.25762<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC7228400\/\" target=\"_blank\">PMC7228400<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/32167180\" target=\"_blank\">32167180<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7228400\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7228400<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=The+Establishment+of+Reference+Sequence+for+SARS-CoV-2+and+Variation+Analysis&rft.jtitle=Journal+of+Medical+Virology&rft.aulast=Wang%2C+C.%3B+Liu%2C+Z.%3B+Chen%2C+Z.+et+al.&rft.au=Wang%2C+C.%3B+Liu%2C+Z.%3B+Chen%2C+Z.+et+al.&rft.date=2020&rft.volume=92&rft.issue=6&rft.pages=667-674&rft_id=info:doi\/10.1002%2Fjmv.25762&rft_id=info:pmc\/PMC7228400&rft_id=info:pmid\/32167180&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC7228400&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-LuGenomic20-13\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-LuGenomic20_13-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Lu, R.; Zhao, X.; Li, J. et al. (2020). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7159086\" target=\"_blank\">\"Genomic Characterisation and Epidemiology of 2019 Novel Coronavirus: Implications for Virus Origins and Receptor Binding\"<\/a>. <i>Lancet<\/i> <b>395<\/b> (10224): 565\u201374. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2FS0140-6736%2820%2930251-8\" target=\"_blank\">10.1016\/S0140-6736(20)30251-8<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC7159086\/\" target=\"_blank\">PMC7159086<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/32007145\" target=\"_blank\">32007145<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7159086\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7159086<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Genomic+Characterisation+and+Epidemiology+of+2019+Novel+Coronavirus%3A+Implications+for+Virus+Origins+and+Receptor+Binding&rft.jtitle=Lancet&rft.aulast=Lu%2C+R.%3B+Zhao%2C+X.%3B+Li%2C+J.+et+al.&rft.au=Lu%2C+R.%3B+Zhao%2C+X.%3B+Li%2C+J.+et+al.&rft.date=2020&rft.volume=395&rft.issue=10224&rft.pages=565%E2%80%9374&rft_id=info:doi\/10.1016%2FS0140-6736%2820%2930251-8&rft_id=info:pmc\/PMC7159086&rft_id=info:pmid\/32007145&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC7159086&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-CDCInterim20-14\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-CDCInterim20_14-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Centers for Disease Control and Prevention (22 May 2020). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.cdc.gov\/coronavirus\/2019-nCoV\/lab\/guidelines-clinical-specimens.html\" target=\"_blank\">\"Interim Guidelines for Collecting, Handling, and Testing Clinical Specimens for COVID-19\"<\/a>. Centers for Disease Control and Prevention<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.cdc.gov\/coronavirus\/2019-nCoV\/lab\/guidelines-clinical-specimens.html\" target=\"_blank\">https:\/\/www.cdc.gov\/coronavirus\/2019-nCoV\/lab\/guidelines-clinical-specimens.html<\/a><\/span><span class=\"reference-accessdate\">. Retrieved May 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Interim+Guidelines+for+Collecting%2C+Handling%2C+and+Testing+Clinical+Specimens+for+COVID-19&rft.atitle=&rft.aulast=Centers+for+Disease+Control+and+Prevention&rft.au=Centers+for+Disease+Control+and+Prevention&rft.date=22+May+2020&rft.pub=Centers+for+Disease+Control+and+Prevention&rft_id=https%3A%2F%2Fwww.cdc.gov%2Fcoronavirus%2F2019-nCoV%2Flab%2Fguidelines-clinical-specimens.html&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-CormanDetect20-15\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-CormanDetect20_15-0\">15.0<\/a><\/sup> <sup><a href=\"#cite_ref-CormanDetect20_15-1\">15.1<\/a><\/sup> <sup><a href=\"#cite_ref-CormanDetect20_15-2\">15.2<\/a><\/sup> <sup><a href=\"#cite_ref-CormanDetect20_15-3\">15.3<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Corman, V.M.; Landt, O.; Kaiser, M. et al. (2020). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6988269\" target=\"_blank\">\"Detection of 2019 Novel Coronavirus (2019-nCoV) by Real-Time RT-PCR\"<\/a>. <i>Euro Surveillance<\/i> <b>25<\/b> (3): 2000045. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.2807%2F1560-7917.ES.2020.25.3.2000045\" target=\"_blank\">10.2807\/1560-7917.ES.2020.25.3.2000045<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6988269\/\" target=\"_blank\">PMC6988269<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/31992387\" target=\"_blank\">31992387<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6988269\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6988269<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Detection+of+2019+Novel+Coronavirus+%282019-nCoV%29+by+Real-Time+RT-PCR&rft.jtitle=Euro+Surveillance&rft.aulast=Corman%2C+V.M.%3B+Landt%2C+O.%3B+Kaiser%2C+M.+et+al.&rft.au=Corman%2C+V.M.%3B+Landt%2C+O.%3B+Kaiser%2C+M.+et+al.&rft.date=2020&rft.volume=25&rft.issue=3&rft.pages=2000045&rft_id=info:doi\/10.2807%2F1560-7917.ES.2020.25.3.2000045&rft_id=info:pmc\/PMC6988269&rft_id=info:pmid\/31992387&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC6988269&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-WHOCorona20-16\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-WHOCorona20_16-0\">16.0<\/a><\/sup> <sup><a href=\"#cite_ref-WHOCorona20_16-1\">16.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation web\">World Health Organization (2020). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.who.int\/emergencies\/diseases\/novel-coronavirus-2019\/technical-guidance\/laboratory-guidance\" target=\"_blank\">\"Coronavirus disease (COVID-19) technical guidance: Laboratory testing for 2019-nCoV in humans\"<\/a>. World Health Organization<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.who.int\/emergencies\/diseases\/novel-coronavirus-2019\/technical-guidance\/laboratory-guidance\" target=\"_blank\">https:\/\/www.who.int\/emergencies\/diseases\/novel-coronavirus-2019\/technical-guidance\/laboratory-guidance<\/a><\/span><span class=\"reference-accessdate\">. Retrieved May 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Coronavirus+disease+%28COVID-19%29+technical+guidance%3A+Laboratory+testing+for+2019-nCoV+in+humans&rft.atitle=&rft.aulast=World+Health+Organization&rft.au=World+Health+Organization&rft.date=2020&rft.pub=World+Health+Organization&rft_id=https%3A%2F%2Fwww.who.int%2Femergencies%2Fdiseases%2Fnovel-coronavirus-2019%2Ftechnical-guidance%2Flaboratory-guidance&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ChuMolec20-17\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-ChuMolec20_17-0\">17.0<\/a><\/sup> <sup><a href=\"#cite_ref-ChuMolec20_17-1\">17.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Chu, D.K.W.; Pan, Y.; Cheng, S.M.S. et al. (2020). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7108203\" target=\"_blank\">\"Molecular Diagnosis of a Novel Coronavirus (2019-nCoV) Causing an Outbreak of Pneumonia\"<\/a>. <i>Clinical Chemistry<\/i> <b>66<\/b> (4): 549-555. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1093%2Fclinchem%2Fhvaa029\" target=\"_blank\">10.1093\/clinchem\/hvaa029<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC7108203\/\" target=\"_blank\">PMC7108203<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/32031583\" target=\"_blank\">32031583<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7108203\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7108203<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Molecular+Diagnosis+of+a+Novel+Coronavirus+%282019-nCoV%29+Causing+an+Outbreak+of+Pneumonia&rft.jtitle=Clinical+Chemistry&rft.aulast=Chu%2C+D.K.W.%3B+Pan%2C+Y.%3B+Cheng%2C+S.M.S.+et+al.&rft.au=Chu%2C+D.K.W.%3B+Pan%2C+Y.%3B+Cheng%2C+S.M.S.+et+al.&rft.date=2020&rft.volume=66&rft.issue=4&rft.pages=549-555&rft_id=info:doi\/10.1093%2Fclinchem%2Fhvaa029&rft_id=info:pmc\/PMC7108203&rft_id=info:pmid\/32031583&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC7108203&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ChanImproved20-18\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-ChanImproved20_18-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Chan, J.F.-K.; Yip, C.C.-Y.; To, K.K.-W. et al. (2020). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7180250\" target=\"_blank\">\"Improved Molecular Diagnosis of COVID-19 by the Novel, Highly Sensitive and Specific COVID-19-RdRp\/Hel Real-Time Reverse Transcription-PCR Assay Validated In Vitro and With Clinical Specimens\"<\/a>. <i>Journal of Clinical Microbiology<\/i> <b>58<\/b> (5): e00310-20. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1128%2FJCM.00310-20\" target=\"_blank\">10.1128\/JCM.00310-20<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC7180250\/\" target=\"_blank\">PMC7180250<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/32132196\" target=\"_blank\">32132196<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7180250\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7180250<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Improved+Molecular+Diagnosis+of+COVID-19+by+the+Novel%2C+Highly+Sensitive+and+Specific+COVID-19-RdRp%2FHel+Real-Time+Reverse+Transcription-PCR+Assay+Validated+In+Vitro+and+With+Clinical+Specimens&rft.jtitle=Journal+of+Clinical+Microbiology&rft.aulast=Chan%2C+J.F.-K.%3B+Yip%2C+C.C.-Y.%3B+To%2C+K.K.-W.+et+al.&rft.au=Chan%2C+J.F.-K.%3B+Yip%2C+C.C.-Y.%3B+To%2C+K.K.-W.+et+al.&rft.date=2020&rft.volume=58&rft.issue=5&rft.pages=e00310-20&rft_id=info:doi\/10.1128%2FJCM.00310-20&rft_id=info:pmc\/PMC7180250&rft_id=info:pmid\/32132196&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC7180250&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-FDAOrig3n20-19\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-FDAOrig3n20_19-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">U.S. Food and Drug Administration (2020). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.fda.gov\/media\/136873\/download\" target=\"_blank\">\"Orig3n 2019 Novel Coronavirus (COVID-19) Test EUA Summary\"<\/a>. U.S. Food and Drug Administration<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.fda.gov\/media\/136873\/download\" target=\"_blank\">https:\/\/www.fda.gov\/media\/136873\/download<\/a><\/span><span class=\"reference-accessdate\">. Retrieved May 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Orig3n+2019+Novel+Coronavirus+%28COVID-19%29+Test+EUA+Summary&rft.atitle=&rft.aulast=U.S.+Food+and+Drug+Administration&rft.au=U.S.+Food+and+Drug+Administration&rft.date=2020&rft.pub=U.S.+Food+and+Drug+Administration&rft_id=https%3A%2F%2Fwww.fda.gov%2Fmedia%2F136873%2Fdownload&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-GuoProfiling20-20\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-GuoProfiling20_20-0\">20.0<\/a><\/sup> <sup><a href=\"#cite_ref-GuoProfiling20_20-1\">20.1<\/a><\/sup> <sup><a href=\"#cite_ref-GuoProfiling20_20-2\">20.2<\/a><\/sup> <sup><a href=\"#cite_ref-GuoProfiling20_20-3\">20.3<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Guo, L.; Ren, L.; Yang, S. et al. (2020). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7184472\" target=\"_blank\">\"Profiling Early Humoral Response to Diagnose Novel Coronavirus Disease (COVID-19)\"<\/a>. <i>Clinical Infectious Diseases<\/i>: ciaa310. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1093%2Fcid%2Fciaa310\" target=\"_blank\">10.1093\/cid\/ciaa310<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC7184472\/\" target=\"_blank\">PMC7184472<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/32198501\" target=\"_blank\">32198501<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7184472\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7184472<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Profiling+Early+Humoral+Response+to+Diagnose+Novel+Coronavirus+Disease+%28COVID-19%29&rft.jtitle=Clinical+Infectious+Diseases&rft.aulast=Guo%2C+L.%3B+Ren%2C+L.%3B+Yang%2C+S.+et+al.&rft.au=Guo%2C+L.%3B+Ren%2C+L.%3B+Yang%2C+S.+et+al.&rft.date=2020&rft.pages=ciaa310&rft_id=info:doi\/10.1093%2Fcid%2Fciaa310&rft_id=info:pmc\/PMC7184472&rft_id=info:pmid\/32198501&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC7184472&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-OkbaSevere20-21\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-OkbaSevere20_21-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Okba, N.M.A.; M\u00fcller, M.A.; Li, W. et al. (2020). \"Severe Acute Respiratory Syndrome Coronavirus 2-Specific Antibody Responses in Coronavirus Disease 2019 Patients\". <i>Emerging Infectious Diseases<\/i> <b>26<\/b> (7). <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.3201%2Feid2607.200841\" target=\"_blank\">10.3201\/eid2607.200841<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/32267220\" target=\"_blank\">32267220<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Severe+Acute+Respiratory+Syndrome+Coronavirus+2-Specific+Antibody+Responses+in+Coronavirus+Disease+2019+Patients&rft.jtitle=Emerging+Infectious+Diseases&rft.aulast=Okba%2C+N.M.A.%3B+M%C3%BCller%2C+M.A.%3B+Li%2C+W.+et+al.&rft.au=Okba%2C+N.M.A.%3B+M%C3%BCller%2C+M.A.%3B+Li%2C+W.+et+al.&rft.date=2020&rft.volume=26&rft.issue=7&rft_id=info:doi\/10.3201%2Feid2607.200841&rft_id=info:pmid\/32267220&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-WallsGlycan16-22\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-WallsGlycan16_22-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Walls, A.C.; Tortorici, M.A.; Frenz, B. et al. (2016). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5515730\" target=\"_blank\">\"Glycan Shield and Epitope Masking of a Coronavirus Spike Protein Observed by Cryo-Electron Microscopy\"<\/a>. <i>Nature Structural and Molecular Biology<\/i> <b>23<\/b> (10): 899-905. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1038%2Fnsmb.3293\" target=\"_blank\">10.1038\/nsmb.3293<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC5515730\/\" target=\"_blank\">PMC5515730<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/27617430\" target=\"_blank\">27617430<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5515730\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5515730<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Glycan+Shield+and+Epitope+Masking+of+a+Coronavirus+Spike+Protein+Observed+by+Cryo-Electron+Microscopy&rft.jtitle=Nature+Structural+and+Molecular+Biology&rft.aulast=Walls%2C+A.C.%3B+Tortorici%2C+M.A.%3B+Frenz%2C+B.+et+al.&rft.au=Walls%2C+A.C.%3B+Tortorici%2C+M.A.%3B+Frenz%2C+B.+et+al.&rft.date=2016&rft.volume=23&rft.issue=10&rft.pages=899-905&rft_id=info:doi\/10.1038%2Fnsmb.3293&rft_id=info:pmc\/PMC5515730&rft_id=info:pmid\/27617430&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC5515730&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-Kopecky-BrombergSevere07-23\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-Kopecky-BrombergSevere07_23-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Kopecky-Bromberg, S.A.; Mart\u00ednez-Sobrido, L.; Frieman, M. et al. (2007). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC1797484\" target=\"_blank\">\"Severe Acute Respiratory Syndrome Coronavirus Open Reading Frame (ORF) 3b, ORF 6, and Nucleocapsid Proteins Function as Interferon Antagonists\"<\/a>. <i>Journal of Virology<\/i> <b>81<\/b> (2): 548-57. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1128%2FJVI.01782-06\" target=\"_blank\">10.1128\/JVI.01782-06<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC1797484\/\" target=\"_blank\">PMC1797484<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/17108024\" target=\"_blank\">17108024<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC1797484\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC1797484<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Severe+Acute+Respiratory+Syndrome+Coronavirus+Open+Reading+Frame+%28ORF%29+3b%2C+ORF+6%2C+and+Nucleocapsid+Proteins+Function+as+Interferon+Antagonists&rft.jtitle=Journal+of+Virology&rft.aulast=Kopecky-Bromberg%2C+S.A.%3B+Mart%C3%ADnez-Sobrido%2C+L.%3B+Frieman%2C+M.+et+al.&rft.au=Kopecky-Bromberg%2C+S.A.%3B+Mart%C3%ADnez-Sobrido%2C+L.%3B+Frieman%2C+M.+et+al.&rft.date=2007&rft.volume=81&rft.issue=2&rft.pages=548-57&rft_id=info:doi\/10.1128%2FJVI.01782-06&rft_id=info:pmc\/PMC1797484&rft_id=info:pmid\/17108024&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC1797484&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-McBrideTheCorona14-24\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-McBrideTheCorona14_24-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">McBride, R.; van Zyl, M.; Fielding, B.C. et al. (2014). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4147684\" target=\"_blank\">\"The Coronavirus Nucleocapsid Is a Multifunctional Protein\"<\/a>. <i>Viruses<\/i> <b>6<\/b> (8): 2991-3018. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.3390%2Fv6082991\" target=\"_blank\">10.3390\/v6082991<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC4147684\/\" target=\"_blank\">PMC4147684<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/25105276\" target=\"_blank\">25105276<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4147684\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4147684<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=The+Coronavirus+Nucleocapsid+Is+a+Multifunctional+Protein&rft.jtitle=Viruses&rft.aulast=McBride%2C+R.%3B+van+Zyl%2C+M.%3B+Fielding%2C+B.C.+et+al.&rft.au=McBride%2C+R.%3B+van+Zyl%2C+M.%3B+Fielding%2C+B.C.+et+al.&rft.date=2014&rft.volume=6&rft.issue=8&rft.pages=2991-3018&rft_id=info:doi\/10.3390%2Fv6082991&rft_id=info:pmc\/PMC4147684&rft_id=info:pmid\/25105276&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC4147684&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-LeungAntibody04-25\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-LeungAntibody04_25-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Leung, D.T.M.; Tam, F.C.H.; Ma, C.H. et al. (2004). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7110057\" target=\"_blank\">\"Antibody Response of Patients With Severe Acute Respiratory Syndrome (SARS) Targets the Viral Nucleocapsid\"<\/a>. <i>Journal of Infectious Diseases<\/i> <b>190<\/b> (2): 379-86. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1086%2F422040\" target=\"_blank\">10.1086\/422040<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC7110057\/\" target=\"_blank\">PMC7110057<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/15216476\" target=\"_blank\">15216476<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7110057\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7110057<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Antibody+Response+of+Patients+With+Severe+Acute+Respiratory+Syndrome+%28SARS%29+Targets+the+Viral+Nucleocapsid&rft.jtitle=Journal+of+Infectious+Diseases&rft.aulast=Leung%2C+D.T.M.%3B+Tam%2C+F.C.H.%3B+Ma%2C+C.H.+et+al.&rft.au=Leung%2C+D.T.M.%3B+Tam%2C+F.C.H.%3B+Ma%2C+C.H.+et+al.&rft.date=2004&rft.volume=190&rft.issue=2&rft.pages=379-86&rft_id=info:doi\/10.1086%2F422040&rft_id=info:pmc\/PMC7110057&rft_id=info:pmid\/15216476&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC7110057&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-JinDiagnostic20-26\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-JinDiagnostic20_26-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Jin, Y.; Wang, M.; Zuo, Z. et al. (2020). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7194885\" target=\"_blank\">\"Diagnostic Value and Dynamic Variance of Serum Antibody in Coronavirus Disease 2019\"<\/a>. <i>International Journal of Infectious Diseases<\/i> <b>94<\/b>: 49\u201352. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.ijid.2020.03.065\" target=\"_blank\">10.1016\/j.ijid.2020.03.065<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC7194885\/\" target=\"_blank\">PMC7194885<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/32251798\" target=\"_blank\">32251798<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7194885\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7194885<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Diagnostic+Value+and+Dynamic+Variance+of+Serum+Antibody+in+Coronavirus+Disease+2019&rft.jtitle=International+Journal+of+Infectious+Diseases&rft.aulast=Jin%2C+Y.%3B+Wang%2C+M.%3B+Zuo%2C+Z.+et+al.&rft.au=Jin%2C+Y.%3B+Wang%2C+M.%3B+Zuo%2C+Z.+et+al.&rft.date=2020&rft.volume=94&rft.pages=49%E2%80%9352&rft_id=info:doi\/10.1016%2Fj.ijid.2020.03.065&rft_id=info:pmc\/PMC7194885&rft_id=info:pmid\/32251798&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC7194885&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-LiDevelop18-27\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-LiDevelop18_27-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Li, R.; Tian, X.; Yu, Y. et al. (2018). \"Development of a Rapid Immunochromatographic Assay for Detection of Antibodies Against Porcine Epidemic Diarrhea Virus\". <i>Polish Journal of Veterinary Sciences<\/i> <b>21<\/b> (1): 139-147. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.24425%2F119032\" target=\"_blank\">10.24425\/119032<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/29624018\" target=\"_blank\">29624018<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Development+of+a+Rapid+Immunochromatographic+Assay+for+Detection+of+Antibodies+Against+Porcine+Epidemic+Diarrhea+Virus&rft.jtitle=Polish+Journal+of+Veterinary+Sciences&rft.aulast=Li%2C+R.%3B+Tian%2C+X.%3B+Yu%2C+Y.+et+al.&rft.au=Li%2C+R.%3B+Tian%2C+X.%3B+Yu%2C+Y.+et+al.&rft.date=2018&rft.volume=21&rft.issue=1&rft.pages=139-147&rft_id=info:doi\/10.24425%2F119032&rft_id=info:pmid\/29624018&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ShenTreatment20-28\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-ShenTreatment20_28-0\">28.0<\/a><\/sup> <sup><a href=\"#cite_ref-ShenTreatment20_28-1\">28.1<\/a><\/sup> <sup><a href=\"#cite_ref-ShenTreatment20_28-2\">28.2<\/a><\/sup> <sup><a href=\"#cite_ref-ShenTreatment20_28-3\">28.3<\/a><\/sup> <sup><a href=\"#cite_ref-ShenTreatment20_28-4\">28.4<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Shen, C.; Wang, Z.; Zhao, F. et al. (2020). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7101507\" target=\"_blank\">\"Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma\"<\/a>. <i>JAMA<\/i> <b>323<\/b> (16): 1582-1589. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1001%2Fjama.2020.4783\" target=\"_blank\">10.1001\/jama.2020.4783<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC7101507\/\" target=\"_blank\">PMC7101507<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/32219428\" target=\"_blank\">32219428<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7101507\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7101507<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Treatment+of+5+Critically+Ill+Patients+With+COVID-19+With+Convalescent+Plasma&rft.jtitle=JAMA&rft.aulast=Shen%2C+C.%3B+Wang%2C+Z.%3B+Zhao%2C+F.+et+al.&rft.au=Shen%2C+C.%3B+Wang%2C+Z.%3B+Zhao%2C+F.+et+al.&rft.date=2020&rft.volume=323&rft.issue=16&rft.pages=1582-1589&rft_id=info:doi\/10.1001%2Fjama.2020.4783&rft_id=info:pmc\/PMC7101507&rft_id=info:pmid\/32219428&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC7101507&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-GauntEpidem10-29\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-GauntEpidem10_29-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Gaunt, E.R.; Hardie, A.; Claas, E.C.J. et al. (2010). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2916580\" target=\"_blank\">\"Epidemiology and Clinical Presentations of the Four Human Coronaviruses 229E, HKU1, NL63, and OC43 Detected Over 3 Years Using a Novel Multiplex Real-Time PCR Method\"<\/a>. <i>Journal of Clinical Microbiology<\/i> <b>48<\/b> (8): 2940-7. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1128%2FJCM.00636-10\" target=\"_blank\">10.1128\/JCM.00636-10<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC2916580\/\" target=\"_blank\">PMC2916580<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/20554810\" target=\"_blank\">20554810<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2916580\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2916580<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Epidemiology+and+Clinical+Presentations+of+the+Four+Human+Coronaviruses+229E%2C+HKU1%2C+NL63%2C+and+OC43+Detected+Over+3+Years+Using+a+Novel+Multiplex+Real-Time+PCR+Method&rft.jtitle=Journal+of+Clinical+Microbiology&rft.aulast=Gaunt%2C+E.R.%3B+Hardie%2C+A.%3B+Claas%2C+E.C.J.+et+al.&rft.au=Gaunt%2C+E.R.%3B+Hardie%2C+A.%3B+Claas%2C+E.C.J.+et+al.&rft.date=2010&rft.volume=48&rft.issue=8&rft.pages=2940-7&rft_id=info:doi\/10.1128%2FJCM.00636-10&rft_id=info:pmc\/PMC2916580&rft_id=info:pmid\/20554810&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC2916580&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-GuptaGlyco18-30\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-GuptaGlyco18_30-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Gupta, S.J.; Shukla, P. (2018). \"Glycosylation Control Technologies for Recombinant Therapeutic Proteins\". <i>Applied Microbiology and Biotechnology<\/i> <b>102<\/b> (24): 10457-10468. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1007%2Fs00253-018-9430-6\" target=\"_blank\">10.1007\/s00253-018-9430-6<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/30334089\" target=\"_blank\">30334089<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Glycosylation+Control+Technologies+for+Recombinant+Therapeutic+Proteins&rft.jtitle=Applied+Microbiology+and+Biotechnology&rft.aulast=Gupta%2C+S.J.%3B+Shukla%2C+P.&rft.au=Gupta%2C+S.J.%3B+Shukla%2C+P.&rft.date=2018&rft.volume=102&rft.issue=24&rft.pages=10457-10468&rft_id=info:doi\/10.1007%2Fs00253-018-9430-6&rft_id=info:pmid\/30334089&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-BandaranayakRecent14-31\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-BandaranayakRecent14_31-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Bandaranayak, A.D.; Almo, S.C. (2014). \"Recent Advances in Mammalian Protein Production\". <i>FEBS Letters<\/i> <b>588<\/b> (2): 253-60. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.febslet.2013.11.035\" target=\"_blank\">10.1016\/j.febslet.2013.11.035<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/PMC3924552\" target=\"_blank\">PMC3924552<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Recent+Advances+in+Mammalian+Protein+Production&rft.jtitle=FEBS+Letters&rft.aulast=Bandaranayak%2C+A.D.%3B+Almo%2C+S.C.&rft.au=Bandaranayak%2C+A.D.%3B+Almo%2C+S.C.&rft.date=2014&rft.volume=588&rft.issue=2&rft.pages=253-60&rft_id=info:doi\/10.1016%2Fj.febslet.2013.11.035&rft_id=info:pmid\/PMC3924552&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ShaoStructure07-32\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-ShaoStructure07_32-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Shao, Y.-M.; Yang, W.-B.; Peng, H.-P. et al. (2007). \"Structure-based Design and Synthesis of Highly Potent SARS-CoV 3CL Protease Inhibitors\". <i>Chembiochem<\/i> <b>8<\/b> (14): 1654-7. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1002%2Fcbic.200700254\" target=\"_blank\">10.1002\/cbic.200700254<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/PMC7162026\" target=\"_blank\">PMC7162026<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Structure-based+Design+and+Synthesis+of+Highly+Potent+SARS-CoV+3CL+Protease+Inhibitors&rft.jtitle=Chembiochem&rft.aulast=Shao%2C+Y.-M.%3B+Yang%2C+W.-B.%3B+Peng%2C+H.-P.+et+al.&rft.au=Shao%2C+Y.-M.%3B+Yang%2C+W.-B.%3B+Peng%2C+H.-P.+et+al.&rft.date=2007&rft.volume=8&rft.issue=14&rft.pages=1654-7&rft_id=info:doi\/10.1002%2Fcbic.200700254&rft_id=info:pmid\/PMC7162026&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-LedsgaardBasics18-33\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-LedsgaardBasics18_33-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Ledsgarrd, L.; Kilstrup, M.; Karatt-Vellatt, A. et al. (2018). \"Basics of Antibody Phage Display Technology\". <i>Toxins<\/i> <b>10<\/b> (6): 236. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.3390%2Ftoxins10060236\" target=\"_blank\">10.3390\/toxins10060236<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/PMC6024766\" target=\"_blank\">PMC6024766<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Basics+of+Antibody+Phage+Display+Technology&rft.jtitle=Toxins&rft.aulast=Ledsgarrd%2C+L.%3B+Kilstrup%2C+M.%3B+Karatt-Vellatt%2C+A.+et+al.&rft.au=Ledsgarrd%2C+L.%3B+Kilstrup%2C+M.%3B+Karatt-Vellatt%2C+A.+et+al.&rft.date=2018&rft.volume=10&rft.issue=6&rft.pages=236&rft_id=info:doi\/10.3390%2Ftoxins10060236&rft_id=info:pmid\/PMC6024766&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-NieEstab20-34\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-NieEstab20_34-0\">34.0<\/a><\/sup> <sup><a href=\"#cite_ref-NieEstab20_34-1\">34.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Nie, J.; Li, Q.; Wu, J. et al. (2020). \"Establishment and Validation of a Pseudovirus Neutralization Assay for SARS-CoV-2\". <i>Emerging Microbes & Infections<\/i> <b>9<\/b> (1): 680\u201386. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1080%2F22221751.2020.1743767\" target=\"_blank\">10.1080\/22221751.2020.1743767<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/PMC7144318\" target=\"_blank\">PMC7144318<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Establishment+and+Validation+of+a+Pseudovirus+Neutralization+Assay+for+SARS-CoV-2&rft.jtitle=Emerging+Microbes+%26+Infections&rft.aulast=Nie%2C+J.%3B+Li%2C+Q.%3B+Wu%2C+J.+et+al.&rft.au=Nie%2C+J.%3B+Li%2C+Q.%3B+Wu%2C+J.+et+al.&rft.date=2020&rft.volume=9&rft.issue=1&rft.pages=680%E2%80%9386&rft_id=info:doi\/10.1080%2F22221751.2020.1743767&rft_id=info:pmid\/PMC7144318&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-NotomiLoop00-35\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-NotomiLoop00_35-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Notomi, T.; Okayama, H.; Masubuchi, H. et al. (2020). \"Loop-mediated Isothermal Amplification of DNA\". <i>Nucleic Acids Research<\/i> <b>28<\/b> (12): E63. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1093%2Fnar%2F28.12.e63\" target=\"_blank\">10.1093\/nar\/28.12.e63<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/PMC102748\" target=\"_blank\">PMC102748<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Loop-mediated+Isothermal+Amplification+of+DNA&rft.jtitle=Nucleic+Acids+Research&rft.aulast=Notomi%2C+T.%3B+Okayama%2C+H.%3B+Masubuchi%2C+H.+et+al.&rft.au=Notomi%2C+T.%3B+Okayama%2C+H.%3B+Masubuchi%2C+H.+et+al.&rft.date=2020&rft.volume=28&rft.issue=12&rft.pages=E63&rft_id=info:doi\/10.1093%2Fnar%2F28.12.e63&rft_id=info:pmid\/PMC102748&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-LiReview18-36\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-LiReview18_36-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Li, J.; Macdonald, J.; von Stetten, F. (2018). \"Review: A Comprehensive Summary of a Decade Development of the Recombinase Polymerase Amplification\". <i>The Analyst<\/i> <b>144<\/b> (1): 31\u201367. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1039%2Fc8an01621f\" target=\"_blank\">10.1039\/c8an01621f<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/30426974\" target=\"_blank\">30426974<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Review%3A+A+Comprehensive+Summary+of+a+Decade+Development+of+the+Recombinase+Polymerase+Amplification&rft.jtitle=The+Analyst&rft.aulast=Li%2C+J.%3B+Macdonald%2C+J.%3B+von+Stetten%2C+F.&rft.au=Li%2C+J.%3B+Macdonald%2C+J.%3B+von+Stetten%2C+F.&rft.date=2018&rft.volume=144&rft.issue=1&rft.pages=31%E2%80%9367&rft_id=info:doi\/10.1039%2Fc8an01621f&rft_id=info:pmid\/30426974&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-VincentHelicase04-37\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-VincentHelicase04_37-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Vincent, M.; Xu, Y.; Kong, H. (2004). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC1249482\" target=\"_blank\">\"Helicase-dependent Isothermal DNA Amplification\"<\/a>. <i>EMBO Reports<\/i> <b>5<\/b> (8): 795\u2013800. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1038%2Fsj.embor.7400200\" target=\"_blank\">10.1038\/sj.embor.7400200<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC1249482\/\" target=\"_blank\">PMC1249482<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/15247927\" target=\"_blank\">15247927<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC1249482\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC1249482<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Helicase-dependent+Isothermal+DNA+Amplification&rft.jtitle=EMBO+Reports&rft.aulast=Vincent%2C+M.%3B+Xu%2C+Y.%3B+Kong%2C+H.&rft.au=Vincent%2C+M.%3B+Xu%2C+Y.%3B+Kong%2C+H.&rft.date=2004&rft.volume=5&rft.issue=8&rft.pages=795%E2%80%93800&rft_id=info:doi\/10.1038%2Fsj.embor.7400200&rft_id=info:pmc\/PMC1249482&rft_id=info:pmid\/15247927&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC1249482&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-WalkerStrand92-38\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-WalkerStrand92_38-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Walker, G.T.; Fraiser, M.S.; Schram, J.L. et al. (1992). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC312258\" target=\"_blank\">\"Strand Displacement Amplification--An Isothermal, in Vitro DNA Amplification Technique\"<\/a>. <i>Nucleic Acids Research<\/i> <b>20<\/b> (7): 1691-6. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1093%2Fnar%2F20.7.1691\" target=\"_blank\">10.1093\/nar\/20.7.1691<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC312258\/\" target=\"_blank\">PMC312258<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/1579461\" target=\"_blank\">1579461<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC312258\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC312258<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Strand+Displacement+Amplification--An+Isothermal%2C+in+Vitro+DNA+Amplification+Technique&rft.jtitle=Nucleic+Acids+Research&rft.aulast=Walker%2C+G.T.%3B+Fraiser%2C+M.S.%3B+Schram%2C+J.L.+et+al.&rft.au=Walker%2C+G.T.%3B+Fraiser%2C+M.S.%3B+Schram%2C+J.L.+et+al.&rft.date=1992&rft.volume=20&rft.issue=7&rft.pages=1691-6&rft_id=info:doi\/10.1093%2Fnar%2F20.7.1691&rft_id=info:pmc\/PMC312258&rft_id=info:pmid\/1579461&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC312258&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ComptonNucleic91-39\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-ComptonNucleic91_39-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Compton, J. (1991). \"Nucleic Acid Sequence-Based Amplification\". <i>Nature<\/i> <b>350<\/b> (6313): 91-2. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1038%2F350091a0\" target=\"_blank\">10.1038\/350091a0<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/1706072\" target=\"_blank\">1706072<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Nucleic+Acid+Sequence-Based+Amplification&rft.jtitle=Nature&rft.aulast=Compton%2C+J.&rft.au=Compton%2C+J.&rft.date=1991&rft.volume=350&rft.issue=6313&rft.pages=91-2&rft_id=info:doi\/10.1038%2F350091a0&rft_id=info:pmid\/1706072&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-YanRapid20-40\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-YanRapid20_40-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Yan, C.; Cui, J.; Huang, L. et al. (2020). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7144850\" target=\"_blank\">\"Rapid and Visual Detection of 2019 Novel Coronavirus (SARS-CoV-2) by a Reverse Transcription Loop-Mediated Isothermal Amplification Assay\"<\/a>. <i>Clinical Microbiology and Infection<\/i> <b>26<\/b> (6): 773\u201379. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.cmi.2020.04.001\" target=\"_blank\">10.1016\/j.cmi.2020.04.001<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC7144850\/\" target=\"_blank\">PMC7144850<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/32276116\" target=\"_blank\">32276116<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7144850\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7144850<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Rapid+and+Visual+Detection+of+2019+Novel+Coronavirus+%28SARS-CoV-2%29+by+a+Reverse+Transcription+Loop-Mediated+Isothermal+Amplification+Assay&rft.jtitle=Clinical+Microbiology+and+Infection&rft.aulast=Yan%2C+C.%3B+Cui%2C+J.%3B+Huang%2C+L.+et+al.&rft.au=Yan%2C+C.%3B+Cui%2C+J.%3B+Huang%2C+L.+et+al.&rft.date=2020&rft.volume=26&rft.issue=6&rft.pages=773%E2%80%9379&rft_id=info:doi\/10.1016%2Fj.cmi.2020.04.001&rft_id=info:pmc\/PMC7144850&rft_id=info:pmid\/32276116&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC7144850&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-BehrmannRapid20-41\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-BehrmannRapid20_41-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Behrmann, O.; Bchmann, I.; Spiegel, M. et al. (2020). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7239256\" target=\"_blank\">\"Rapid Detection of SARS-CoV-2 by Low Volume Real-Time Single Tube Reverse Transcription Recombinase Polymerase Amplification Using an Exo Probe With an Internally Linked Quencher (exo-IQ)\"<\/a>. <i>Clinical Chemistry<\/i>: hvaa116. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1093%2Fclinchem%2Fhvaa116\" target=\"_blank\">10.1093\/clinchem\/hvaa116<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC7239256\/\" target=\"_blank\">PMC7239256<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/32384153\" target=\"_blank\">32384153<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7239256\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7239256<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Rapid+Detection+of+SARS-CoV-2+by+Low+Volume+Real-Time+Single+Tube+Reverse+Transcription+Recombinase+Polymerase+Amplification+Using+an+Exo+Probe+With+an+Internally+Linked+Quencher+%28exo-IQ%29&rft.jtitle=Clinical+Chemistry&rft.aulast=Behrmann%2C+O.%3B+Bchmann%2C+I.%3B+Spiegel%2C+M.+et+al.&rft.au=Behrmann%2C+O.%3B+Bchmann%2C+I.%3B+Spiegel%2C+M.+et+al.&rft.date=2020&rft.pages=hvaa116&rft_id=info:doi\/10.1093%2Fclinchem%2Fhvaa116&rft_id=info:pmc\/PMC7239256&rft_id=info:pmid\/32384153&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC7239256&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-KellnerSHER19-42\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-KellnerSHER19_42-0\">42.0<\/a><\/sup> <sup><a href=\"#cite_ref-KellnerSHER19_42-1\">42.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Kellner, M.J.; Koob, J.G.; Gootenberg, J.S. et al. (2019). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6956564\" target=\"_blank\">\"SHERLOCK: Nucleic Acid Detection With CRISPR Nucleases\"<\/a>. <i>Nature Protocols<\/i> <b>14<\/b> (10): 2986\u20133012. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1038%2Fs41596-019-0210-2\" target=\"_blank\">10.1038\/s41596-019-0210-2<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6956564\/\" target=\"_blank\">PMC6956564<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/31548639\" target=\"_blank\">31548639<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6956564\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6956564<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=SHERLOCK%3A+Nucleic+Acid+Detection+With+CRISPR+Nucleases&rft.jtitle=Nature+Protocols&rft.aulast=Kellner%2C+M.J.%3B+Koob%2C+J.G.%3B+Gootenberg%2C+J.S.+et+al.&rft.au=Kellner%2C+M.J.%3B+Koob%2C+J.G.%3B+Gootenberg%2C+J.S.+et+al.&rft.date=2019&rft.volume=14&rft.issue=10&rft.pages=2986%E2%80%933012&rft_id=info:doi\/10.1038%2Fs41596-019-0210-2&rft_id=info:pmc\/PMC6956564&rft_id=info:pmid\/31548639&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC6956564&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-HollandAn81_20-43\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-HollandAn81_20_43-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Holland, L.A.; Kaelin, E.A.; Maqsood, R. et al. (2020). \"An 81 Nucleotide Deletion in SARS-CoV-2 ORF7a Identified From Sentinel Surveillance in Arizona (Jan-Mar 2020)\". <i>Journal of Virology<\/i>: JVI.00711-20. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1128%2FJVI.00711-20\" target=\"_blank\">10.1128\/JVI.00711-20<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/32357959\" target=\"_blank\">32357959<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=An+81+Nucleotide+Deletion+in+SARS-CoV-2+ORF7a+Identified+From+Sentinel+Surveillance+in+Arizona+%28Jan-Mar+2020%29&rft.jtitle=Journal+of+Virology&rft.aulast=Holland%2C+L.A.%3B+Kaelin%2C+E.A.%3B+Maqsood%2C+R.+et+al.&rft.au=Holland%2C+L.A.%3B+Kaelin%2C+E.A.%3B+Maqsood%2C+R.+et+al.&rft.date=2020&rft.pages=JVI.00711-20&rft_id=info:doi\/10.1128%2FJVI.00711-20&rft_id=info:pmid\/32357959&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-KorberSpike20-44\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-KorberSpike20_44-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Korber, B.; Fischer, W.M.; Gnanakaran, S. et al. (2020). \"Spike mutation pipeline reveals the emergence of a more transmissible form of SARS-CoV-2\". <i>bioRxiv<\/i>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1101%2F2020.04.29.069054\" target=\"_blank\">10.1101\/2020.04.29.069054<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Spike+mutation+pipeline+reveals+the+emergence+of+a+more+transmissible+form+of+SARS-CoV-2&rft.jtitle=bioRxiv&rft.aulast=Korber%2C+B.%3B+Fischer%2C+W.M.%3B+Gnanakaran%2C+S.+et+al.&rft.au=Korber%2C+B.%3B+Fischer%2C+W.M.%3B+Gnanakaran%2C+S.+et+al.&rft.date=2020&rft_id=info:doi\/10.1101%2F2020.04.29.069054&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-SchaecherSevere07-45\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-SchaecherSevere07_45-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Schaecher, S.R.; Touchette, E.; Schriewer, J. et al. (2007). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2045523\" target=\"_blank\">\"Severe Acute Respiratory Syndrome Coronavirus Gene 7 Products Contribute to Virus-Induced Apoptosis\"<\/a>. <i>Journal of Virology<\/i> <b>81<\/b> (20): 11054-68. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1128%2FJVI.01266-07\" target=\"_blank\">10.1128\/JVI.01266-07<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC2045523\/\" target=\"_blank\">PMC2045523<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/17686858\" target=\"_blank\">17686858<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2045523\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2045523<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Severe+Acute+Respiratory+Syndrome+Coronavirus+Gene+7+Products+Contribute+to+Virus-Induced+Apoptosis&rft.jtitle=Journal+of+Virology&rft.aulast=Schaecher%2C+S.R.%3B+Touchette%2C+E.%3B+Schriewer%2C+J.+et+al.&rft.au=Schaecher%2C+S.R.%3B+Touchette%2C+E.%3B+Schriewer%2C+J.+et+al.&rft.date=2007&rft.volume=81&rft.issue=20&rft.pages=11054-68&rft_id=info:doi\/10.1128%2FJVI.01266-07&rft_id=info:pmc\/PMC2045523&rft_id=info:pmid\/17686858&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC2045523&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-CDCInterimBio20-46\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-CDCInterimBio20_46-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Centers for Disease Control and Prevention (May 2020). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.cdc.gov\/coronavirus\/2019-ncov\/lab\/lab-biosafety-guidelines.html\" target=\"_blank\">\"Interim Laboratory Biosafety Guidelines for Handling and Processing Specimens Associated with Coronavirus Disease 2019 (COVID-19)\"<\/a>. Centers for Disease Control and Prevention<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.cdc.gov\/coronavirus\/2019-ncov\/lab\/lab-biosafety-guidelines.html\" target=\"_blank\">https:\/\/www.cdc.gov\/coronavirus\/2019-ncov\/lab\/lab-biosafety-guidelines.html<\/a><\/span><span class=\"reference-accessdate\">. Retrieved May 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Interim+Laboratory+Biosafety+Guidelines+for+Handling+and+Processing+Specimens+Associated+with+Coronavirus+Disease+2019+%28COVID-19%29&rft.atitle=&rft.aulast=Centers+for+Disease+Control+and+Prevention&rft.au=Centers+for+Disease+Control+and+Prevention&rft.date=May+2020&rft.pub=Centers+for+Disease+Control+and+Prevention&rft_id=https%3A%2F%2Fwww.cdc.gov%2Fcoronavirus%2F2019-ncov%2Flab%2Flab-biosafety-guidelines.html&rfr_id=info:sid\/en.wikipedia.org:Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<\/ol><\/div>\n<h2><span class=\"mw-headline\" id=\"Notes\">Notes<\/span><\/h2>\n<p>This presentation is faithful to the original, with only a few minor changes to presentation. In some cases important information was missing from the references, and that information was added. References in this version are listed in order of appearance\u2014by design\u2014rather than alphabetical order as the original was.\n<\/p>\n<!-- \nNewPP limit report\nCached time: 20200707205100\nCache expiry: 86400\nDynamic content: false\nCPU time usage: 1.086 seconds\nReal time usage: 2.560 seconds\nPreprocessor visited node count: 37730\/1000000\nPreprocessor generated node count: 38212\/1000000\nPost\u2010expand include size: 347205\/2097152 bytes\nTemplate argument size: 111244\/2097152 bytes\nHighest expansion depth: 18\/40\nExpensive parser function count: 0\/100\n-->\n\n<!-- \nTransclusion expansion time report (%,ms,calls,template)\n100.00% 853.467 1 - -total\n 87.97% 750.811 1 - Template:Reflist\n 71.86% 613.338 46 - Template:Citation\/core\n 66.87% 570.676 40 - Template:Cite_journal\n 10.68% 91.191 104 - Template:Citation\/identifier\n 8.76% 74.792 6 - Template:Cite_web\n 7.14% 60.931 1 - Template:Infobox_journal_article\n 6.83% 58.318 1 - Template:Infobox\n 4.46% 38.107 80 - Template:Infobox\/row\n 4.06% 34.655 47 - Template:Citation\/make_link\n-->\n\n<!-- Saved in parser cache with key limswiki:pcache:idhash:11991-0!*!0!!en!5!* and timestamp 20200707205057 and revision id 39624\n -->\n<\/div><div class=\"printfooter\">Source: <a rel=\"external_link\" class=\"external\" href=\"https:\/\/www.limswiki.org\/index.php\/Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)\">https:\/\/www.limswiki.org\/index.php\/Journal:Laboratory_testing_methods_for_novel_severe_acute_respiratory_syndrome_coronavirus_2_(SARS-CoV-2)<\/a><\/div>\n\t\t\t\t\t\t\t\t\t\t<!-- end content -->\n\t\t\t\t\t\t\t\t\t\t<div class=\"visualClear\"><\/div>\n\t\t\t\t<\/div>\n\t\t\t<\/div>\n\t\t<\/div>\n\t\t<!-- end of the left (by default at least) column -->\n\t\t<div class=\"visualClear\"><\/div>\n\t\t\t\t\t\n\t\t<\/div>\n\t\t\n\n<\/body>","14fe555f4f0cddcccf179363f98c5b79_images":["https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/e\/e0\/Fig1_D%27Cruz_FrontCellDevBio2020_8.jpg","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/d\/d6\/Tab1_D%27Cruz_FrontCellDevBio2020_8.jpg","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/4\/46\/Tab2_D%27Cruz_FrontCellDevBio2020_8.jpg","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/4\/48\/Fig2_D%27Cruz_FrontCellDevBio2020_8.jpg","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/d\/dc\/Tab3_D%27Cruz_FrontCellDevBio2020_8.jpg"],"14fe555f4f0cddcccf179363f98c5b79_timestamp":1594155057,"35e1a79a2c5ed34c82e174e1cfc01af1_type":"article","35e1a79a2c5ed34c82e174e1cfc01af1_title":"Bridging the collaboration gap: Real-time identification of clinical specimens for biomedical research (Durant et al. 2020)","35e1a79a2c5ed34c82e174e1cfc01af1_url":"https:\/\/www.limswiki.org\/index.php\/Journal:Bridging_the_collaboration_gap:_Real-time_identification_of_clinical_specimens_for_biomedical_research","35e1a79a2c5ed34c82e174e1cfc01af1_plaintext":"\n\n\t\t\n\t\t\t\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t\n\n\t\t\t\tJournal:Bridging the collaboration gap: Real-time identification of clinical specimens for biomedical research\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t\tFrom LIMSWiki\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\tJump to: navigation, search\n\n\t\t\t\t\t\n\t\t\t\t\tFull article title\n \nBridging the collaboration gap: Real-time identification of clinical specimens for biomedical researchJournal\n \nJournal of Pathology InformaticsAuthor(s)\n \nDurant, Thomas J.S.; Gong, Guannan; Price, Nathan; Schilz, Wade L.Author affiliation(s)\n \nYale New Haven Hospital, Yale New Haven HealthPrimary contact\n \nEmail: Log in requiredYear published\n \n2020Volume and issue\n \n11Article #\n \n14DOI\n \n10.4103\/jpi.jpi_15_20ISSN\n \n2153-3539Distribution license\n \nCreative Commons Attribution-NonCommercial-ShareAlike 4.0 International LicenseWebsite\n \nhttp:\/\/www.jpathinformatics.org\/article.aspDownload\n \nhttp:\/\/www.jpathinformatics.org\/temp\/JPatholInform11114-7412119_203521.pdf\n\nContents\n\n1 Abstract \n2 Introduction \n3 Methods \n\n3.1 Prism platform architecture \n3.2 Throughput assessment \n\n\n4 Results \n\n4.1 Babesia specimen identification \n4.2 Diabetic biomarker specimen identification \n4.3 Throughput assessment \n\n\n5 Discussion \n6 Acknowledgements \n\n6.1 Disclosure \n6.2 Financial support and sponsorship \n6.3 Conflicts of interest \n\n\n7 References \n8 Notes \n\n\n\nAbstract \nIntroduction: Biomedical and translational research often relies on the evaluation of patients or specimens that meet specific clinical or laboratory criteria. The typical approach used to identify biospecimens is a manual, retrospective process that exists outside the clinical workflow. This often makes biospecimen collection cost prohibitive and prevents the collection of analytes with short stability times. Emerging data architectures offer novel approaches to enhance specimen-identification practices. To this end, we present a new tool that can be deployed in a real-time environment to automate the identification and notification of available biospecimens for biomedical research. \nMethods: Real-time clinical and laboratory data from Cloverleaf (Infor, NY, NY) were acquired within our computational health platform, which is built on open-source applications. Study-specific filters were developed in NiFi (Apache Software Foundation, Wakefield, MA, USA) to identify the study-appropriate specimens in real time. Specimen metadata were stored in Elasticsearch (Elastic N. V., Mountain View, CA, USA) for visualization and automated alerting. \nResults: Between June 2018 and December 2018, we identified 2,992 unique specimens belonging to 2,815 unique patients, split between two different use cases. Based on laboratory policy for specimen retention and study-specific stability requirements, secure e-mail notifications were sent to investigators to automatically notify them of availability. The assessment of throughput on commodity hardware demonstrates the ability to scale to approximately 2,000 results per second.\nConclusion: This work demonstrates that real-world clinical data can be analyzed in real-time to increase the efficiency of biospecimen identification with minimal overhead for the clinical laboratory. Future work will integrate additional data types, including the analysis of unstructured data, to enable more complex cases and biospecimen identification.\nKeywords: biobanking, biomedical research, biospecimen science, clinical specimens, real-time identification, translational research\n\nIntroduction \nIn the era of precision medicine, human biospecimens are an important resource for basic, translational, and clinical research and are increasingly needed to advance our understanding of human physiology, disease, treatment response, and outcomes. The field of biobanking has undergone significant optimization efforts by national and international communities to improve and harmonize biospecimen curation to support this need.[1][2] However, the operationalization and maintenance of biobanks is resource-intensive and often cost prohibitive for many institutions. In addition, long-term biobanking may be suboptimal for some types of testing, such as for studies that rely on labile analytes.[3][4] As a result, comprehensive access to human biospecimens remains limited, and there is a persistent need for efficient solutions that can provide access to high-quality and recently acquired human biospecimens.[5]\nHuman biospecimens can always be found in clinical laboratories, but access for the research is complicated by a series of technical, logistic, regulatory, and ethical challenges. Beyond the demands of delivering clinical results, laboratories lack efficient processes for biospecimen identification, human resources for specimen acquisition, and procedural infrastructure for biospecimen collection under the provisions of human interventional ethics committees. Despite these challenges, the clinical laboratory is a promising resource for the acquisition of biospecimens, and researchers are beginning to investigate curation methods that can integrate with existing clinical workflows and leverage electronic health record (EHR) metadata for biospecimen identification and annotation.[6][7]\nOne of the first automated biospecimen identification systems was Crimson, an application used to identify the discarded blood samples accessioned into the clinical laboratory by querying the laboratory information system (LIS). Specimens, which met predetermined inclusion criteria, were electronically reaccessioned into a deidentified research database that could be accessed by researchers with institutional review board (IRB) approval.[8] While biobanks routinely link health information between specimen and participant postenrollment, such solutions demonstrate how EHR integration and associated metadata can be used for targeted and automated biospecimen selection. However, examples of this framework remain limited, both in the literature and in practice, which typically focus on retrospective specimen identification for long-term biobanking. With the increased digitization of healthcare and modern data architectures that allow for real-time analysis of clinical data, biospecimens can be identified as samples that are processed through the clinical laboratory. This approach offers the benefit of increasing access to specimens of interest, including those with labile analytes, while not disrupting routine clinical workflows.[4]\nIn this report, we present Prism, a new tool built on open-source technology that can efficiently identify and notify the investigators of biospecimen availability in near real time. We describe the pipeline architecture and our experience with two IRB-approved pilot projects within our department (IRB Protocol IDs: Babesia \u2013 2000023123; Diabetic biomarkers \u2013 2000022266).\n\nMethods \nPrism platform architecture \nWe implemented a real-time pipeline, called Prism, that consists of three key components: real-time data acquisition, stream processing, and end-user alerting, to support case and specimen identification (Fig. 1). Parameterized processors for Apache's open-source dataflow (stream processing) system NiFi were used to filter and identify the clinical specimens based on study-specific inclusion criteria extracted from corresponding laboratory result metadata. Specimens that met inclusion criteria were indexed within Elastic search (Elastic NV; Mountain View, CA, United States). Alerting was done through Watcher (Elastic NV; Mountain View, CA, United States) and secure e-mail, with a reporting dashboard built in Kibana (Elastic NV; Mountain View, CA, United States).\n\r\n\n\n\n\n\n\n\n\n\n\n Figure 1. Dataflow diagram for laboratory results using NiFi and Elasticsearch. (A) Existing laboratory result dataflow. (B) Prism specimen identification dataflow. BI: Business Intelligence, HDFS: Hadoop-Distributed File System, HL7: Health Level 7, JSON: Java Script Object Notation\n\n\n\nThis framework was deployed within our organization's computational health care platform, Baikal, which has been previously described (see Supplemental Figure 1 in Additional file 1).[9] The Baikal platform is built on open-source technology and provides a mechanism to manage and analyze high-volume and high-frequency clinical data in real time, including laboratory results.\n\nThroughput assessment \nScalability and computing resource needs for Prism were estimated through the deployment in a standalone workstation environment with a single CPU with six cores (Intel Core i7-6850K CPU @ 3.60GHz) and 256 GiB of memory. Apache NiFi was deployed within a Docker (version 19.03.2, build 6a30dfc; Docker, Inc., San Francisco, CA, United States) container under the Ubuntu (Version: 16.04.6 LTS (Xenial); Canonical Ltd; London, UK) operating system. We ran a modified version of the Prism dataflow using file-based record I\/O instead of streaming data from a network interface. Data for the assessment were obtained by randomly selecting data from our production Health Level 7 (HL7) feed, and the data were assembled into three datasets of increasing size. These datasets contained 1 \u00d7 105, 1 \u00d7 106, and 1 \u00d7 107 JavaScript Object Notation-transformed HL7 ORU messages, resulting in 0.75 GB, 7.27 GB, and 72.8 GB of data, respectively. Two series of five trials were performed with the 1 \u00d7 106 record data set. In the first series, all five trials were run consecutively. In the second series, Docker was restarted between each trial to assess for any possible performance impacts in long-running containers. Throughput was measured using built-in NiFi monitoring tools to assess record count and throughput.\n\nResults \nBabesia specimen identification \nBabesia is a tick-borne hemoprotozoan, which infects human erythrocytes and can be life-threatening for patients who are asplenic, immunocompromised, or elderly. The gold standard for the laboratory diagnosis is microscopic analysis of a peripheral blood smear. For research into the automation of digital microscopic analysis using the computer vision, the researcher needed peripheral blood smears, which were identified as containing Babesia. Incoming HL7 messages corresponding to a Babesia result record with a \u201cPositive\u201d result value were flagged and sent to the Prism index in Elasticsearch (Fig. 2). Researchers were securely notified of all \u201cPositive\u201d Babesia specimens identified every four hours.\n\r\n\n\n\n\n\n\n\n\n\n\n Figure 2. Laboratory result monitoring for positive Babesia specimens. Incoming HL7 observations are transformed to denormalized JSON documents and stored to HDFS. Prism dataflow ingests streaming JSON result records and filters \u201cPositive\u201d Babesia results to the \u201cPrism\u201d Specimen Surveillance Index from which secure notifications of positive Babesia results are generated. HDFS: Hadoop-Distributed File System, HL7: Health-Level 7, JSON: Java Script Object Notation\n\n\n\nSpecimen identification for positive Babesia specimens went live in May 2018. In a collection period of 16 months (June 2018\u2013September 2019), Prism identified 131 unique lavender-top tubes, belonging to 44 unique patients, which were identified as positive for Babesia by manual light microscopy. The collection period for this project was extended beyond the anticipated time requirement as Babesia exhibits a strong seasonal prevalence, and positive specimen rates dropped over the colder months (Fig. 3).\n\r\n\n\n\n\n\n\n\n\n\n\n Figure 3. Total number of unique patients and specimens identified for Babesia and A1C-LGT specific use cases within the specified date range. Columns represent count of unique specimens per week. Right Y-axis: HbA1c-LGT, Left Y-axis: Babesia. HbA1c: Hemoglobin A1c, LGT: Light-green top\n\n\n\nDiabetic biomarker specimen identification \nThe development of type 2 diabetes can be prevented or delayed in prediabetic individuals with lifestyle modifications such as dietary changes or increased physical activity. Accordingly, there is a need to identify the biomarkers to guide preventative interventions.[10][11] To identify possible biomarkers, a researcher at our institution was interested in obtaining blood specimens from patients with and without diabetes, with borderline cases excluded, as a prelude to a larger prospective biomarker study. The deidentified samples would undergo metabolomic analysis by liquid chromatography\u2013mass spectrometry to identify the metabolites that were significantly changed between the two groups as candidate biomarkers.\nHemoglobin A1C values < 5.7 and > 6.5 were used to delineate between diabetic and nondiabetic patients, with additional inclusion criteria of outpatient specimen collection and patient age range 18\u201370 years. Of note, the preferred collection container for Hgb A1c at our institution is a lavender-top tube, which does not contain gel-separation barriers. In an effort to optimize biomarker recovery, plasma from light-green-top (LGT) tubes was requested for this study. Accordingly, LGT tubes were flagged when a paired sample with an Hgb A1c within the appropriate range was found within seven days (Fig. 4). Researchers were securely notified every morning by e-mail of all matching LGT specimens present in the Prism index reported within 24 hours prior.\n\r\n\n\n\n\n\n\n\n\n\n\n Figure 4. Laboratory result processing diagram for diabetic biomarker monitoring. Incoming HL7 observations are transformed to denormalized JavaScript Object Notation documents and stored to HDFS. The Prism dataflow ingests streaming JavaScript Object Notation result records and filters hemoglobin A1C results in the \u201cNormal\u201d (<5.7) and \u201cDiabetic\u201d (>6.5) cohorts to the Prism Specimen Surveillance Index in Elastic. Results from CMP\/BMP panels (light-green top specimens) are sent to the Prism index. Secure notifications are sent for A1C specimen IDs with related light-green specimen info. BMP: Basic Metabolic Panel, CMP: Comprehensive Metabolic Panel, HbA1c: Hemoglobin A1c; HDFS: Hadoop-Distributed File System, HL7: Health-Level 7, JSON: Java Script Object Notation\n\n\n\nSpecimen identification for diabetic biomarker discovery went live in December 2018. In a collection period of four months (December 2018\u2013March 2019), Prism identified 2,861 unique LGT specimens from 2,771 unique patients (Fig. 3).\n\nThroughput assessment \nWe assessed the processing throughput to ensure the pipeline could scale to large environments and consistently manage high-volume data. Our institution's computational health platform processes approximately 350,000 discrete HL7 ORU messages per day. Accordingly, we evaluated processing time across five trials and observed an average execution time of approximately eight minutes for one million records, which represents slightly less than three days of laboratory result volume. Processing time was observed to be linear over two orders of magnitude in dataset size (Fig. 5a), and the average total execution time to process one million messages differed by 2% between runs with (494 seconds) and without (483 seconds) Docker container restart (Fig. 5b).\n\r\n\n\n\n\n\n\n\n\n\n\n Figure 5. Laboratory result processing diagram for diabetic biomarker monitoring. Incoming HL7 observations are transformed to denormalized JavaScript Object Notation documents and stored to HDFS. The Prism dataflow ingests streaming JavaScript Object Notation result records and filters hemoglobin A1C results in the \u201cNormal\u201d (<5.7) and \u201cDiabetic\u201d (>6.5) cohorts to the Prism Specimen Surveillance Index in Elastic. Results from CMP\/BMP panels (light-green top specimens) are sent to the Prism index. Secure notifications are sent for A1C specimen IDs with related light-green specimen info. BMP: Basic Metabolic Panel, CMP: Comprehensive Metabolic Panel, HbA1c: Hemoglobin A1c; HDFS: Hadoop-Distributed File System, HL7: Health-Level 7, JSON: Java Script Object Notation\n\n\n\nDiscussion \nIn this report, we describe a novel data analysis pipeline called Prism that can be used to improve the efficiency of biospecimen collection. This workflow has been deployed to identify the biospecimens in near real-time for two biomedical research use cases. We demonstrated that this solution is highly scalable to meet the needs of even large academic centers and reference laboratories. We also found, consistent with our prior work, that virtualization of this workflow within a microservices environment does not introduce a performance penalty.[12]\nIn 2000, it was estimated that 300 million human biospecimens were preserved in the United States, with a projected 7% annual growth rate.[13] However, researchers continue to report difficulty in obtaining specimens for biomedical research and express underlying concerns in the validity of their results when using specimens subjected to long-term storage conditions.[5] In addition, while many biospecimens are being stored, a large proportion is expected to remain unused, and there is increasing concern that untargeted collection of biospecimens consumes resources that could be better allocated.[14][15][16] Accordingly, as institutions seek to expand biomedical research efforts, particularly in the era of personalized medicine, novel approaches for improving access to high-quality human biospecimens should be evaluated.\nThe quality of biomedical research is dependent on the integrity of biospecimens and as with clinical testing, analyte recovery is subject to a significant number of preanalytical considerations.[4] While biobanking procedures have seen significant optimization in recent years, poor reproducibility of studies that use biospecimens has been thought to be caused, in part, by the variable quality and inadequate documentation of biospecimen metadata.[5] To this end, biobanks are beginning to emulate testing procedures found in the clinical laboratory to optimize analyte recovery and test reproducibility.[17][18] Tools that can identify the samples accessioned to the clinical laboratory, such as Prism, would align with these efforts by identifying the specimens that have been collected and processed under clinical conditions.\nDespite ongoing adoption of clinical procedures in biospecimen science, the collection and processing of labile analytes remain challenging, and some components may require unique processing protocols.[17][19] Proteomic and molecular analytes are particularly sensitive to specimen transport delays, matrix effects, and optimal-storage environments.[20] Accordingly, some components of interest may require sample processing techniques that exist outside routine clinical workflows. In this setting, real-time streaming analytics could also be envisioned to identify patients which match study-specific inclusion criteria to guide targeted subject enrollment and subsequent collection.\nIn addition to specimen identification and collection, annotation with patient metadata remains an important and challenging facet of contemporary biobanking. Large scale biobanks such as the U.K. Biobank rely on a combination of data sources for curating specimen metadata, including participant enrollment surveys, physical measures (e.g., blood pressure and spirometry), and linkage to digital health information.[21][22] Indeed, while the majority of national biobanking resources capture data from both inpatient and outpatient medical records, there is also interest in capturing data that is not stored in the EHR.[21][23][24] As digital health information continues to expand, health care systems are increasingly working to develop clinically integrated data management tools for the centralization of disparate data resources.[9] Deployment of automated specimen identification tools in these frameworks may facilitate correlation with these data and would align with national efforts to do so.\nIt should be noted that the use cases described in this report were selected based on the immediate needs among researchers in our department. However, similar open-source tools could be similarly envisioned to integrate with anatomic pathology data and the EHR, to automatically phenotype tissue specimens as they are processed in the laboratory. While the majority of data elements in the clinical laboratory are discrete, identifying tissue specimens in the anatomic pathology laboratory may require technologies such as natural language processing (NLP) to process semistructured and unstructured data, such as those commonly found in pathology reports.[25] While not used for this implementation, custom NiFi processors would allow the users to develop more complex filters and integrate NLP or machine learning-based technology for free text or nested data structures commonly found in anatomic pathology. Similarly, the platform can also be used to identify the patients who may be eligible to consent and enroll in studies, rather than simply for biospecimen collection.\nIn the era of digital and personalized medicine, novel approaches to increase the efficiency of biospecimen identification will be crucial to accelerate discovery. Modern data architectures as described here can be used to address the fundamental challenges in the procurement of biospecimens in support of biomedical research. Future work will seek to integrate additional data types, including the analysis of unstructured data, to enable more complex case and biospecimen identification.\n\nAcknowledgements \nDisclosure \nWade Schulz was an investigator for a research agreement, through Yale University, from the Shenzhen Center for Health Information for work to advance intelligent disease prevention and health promotion. Schulz also collaborates with the National Center for Cardiovascular Diseases in Beijing; is a technical consultant to HugoHealth, a personal health information platform, and co-founder of Refactor Health, an AI-augmented data management platform for healthcare; and is a consultant for Interpace Diagnostics Group, a molecular diagnostics company.\n\nFinancial support and sponsorship \nNil.\n\nConflicts of interest \nThere are no conflicts of interest.\n\nReferences \n\n\n\u2191 van Ommen, G.-J.B.; T\u00f6rnwall, O.; Br\u00e9chot, C. et al. (2015). \"BBMRI-ERIC as a Resource for Pharmaceutical and Life Science Industries: The Development of Biobank-Based Expert Centres\". European Journal of Human Genetics 23 (7): 893-900. doi:10.1038\/ejhg.2014.235. PMC PMC4463510. PMID 25407005. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4463510 .   \n\n\u2191 Langhof, H.; Kahrass, H.; Illig, T. et al. (2018). \"Current Practices for Access, Compensation, and Prioritization in Biobanks. Results From an Interview Study\". European Journal of Human Genetics 26 (11): 1572\u20131581. doi:10.1038\/s41431-018-0228-x. PMC PMC6189200. PMID 30089824. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6189200 .   \n\n\u2191 Shabihkhani, M.; Lucey, G.M.; Wei, B. et al. (2014). \"The Procurement, Storage, and Quality Assurance of Frozen Blood and Tissue Biospecimens in Pathology, Biorepository, and Biobank Settings\". Clinical Biochemistry 47 (4\u20135): 258-66. doi:10.1016\/j.clinbiochem.2014.01.002. PMC PMC3982909. PMID 24424103. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3982909 .   \n\n\u2191 4.0 4.1 4.2 Ellervik, C.; Vaught, J. (2015). \"Preanalytical Variables Affecting the Integrity of Human Biospecimens in Biobanking\". Clinical Chemistry 61 (7): 914-34. doi:10.1373\/clinchem.2014.228783. PMID 25979952.   \n\n\u2191 5.0 5.1 5.2 Massett, H.A.; Atkinson, N.L.; Weber, D. et al. (2011). \"Assessing the Need for a Standardized Cancer HUman Biobank (caHUB): Findings From a National Survey With Cancer Researchers\". Journal of the National Cancer Institute Monographs 2011 (42): 8\u201315. doi:10.1093\/jncimonographs\/lgr007. PMID 21672890.   \n\n\u2191 Moore, H,M.; Jelly, A.; McShane, L.M. et al. (2013). \"Biospecimen Reporting for Improved Study Quality (BRISQ)\". Transfusion 53 (7): e1. doi:10.1111\/trf.12281. PMID 23844646.   \n\n\u2191 Simeon-Dubach, D.; Burt, A.D.; Hall, P.A. (2012). \"Quality Really Matters: The Need to Improve Specimen Quality in Biomedical Research\". Journal of Pathology 228 (4): 431\u20133. doi:10.1002\/path.4117. PMID 23023660.   \n\n\u2191 Murphy, S.; Churchill, S.; Bry, L. et al. (2009). \"Instrumenting the Health Care Enterprise for Discovery Research in the Genomic Era\". Genome Research 19 (9): 1675\u201381. doi:10.1101\/gr.094615.109. PMC PMC2752136. PMID 19602638. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2752136 .   \n\n\u2191 9.0 9.1 McPadden, J.; Durant, T.J.S.; Bunch, D.R. et al. (2019). \"Health Care and Precision Medicine Research: Analysis of a Scalable Data Science Platform\". Journal of Medical Internet Research 21 (4): e13043. doi:10.2196\/13043. PMC PMC6477571. PMID 30964441. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6477571 .   \n\n\u2191 Wang-Sattler, R.; Yu, Z.; Herder, C. et al. (2012). \"Novel Biomarkers for Pre-Diabetes Identified by Metabolomics\". Molecular Systems Biology 8: 615. doi:10.1038\/msb.2012.43. PMC PMC3472689. PMID 23010998. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3472689 .   \n\n\u2191 Guasch-Ferr\u00e9, M.; Hruby, A.; Toledo, E. et al. (2016). \"Metabolomics in Prediabetes and Diabetes: A Systematic Review and Meta-analysis\". Diabetes Care 39 (5): 833-46. doi:10.2337\/dc15-2251. PMC PMC4839172. PMID 27208380. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4839172 .   \n\n\u2191 Schulz, W.L.; Durant, T.J. S.; Siddon, A.J. et al. (2016). \"Use of Application Containers and Workflows for Genomic Data Analysis\". Journal of Pathology Informatics 7: 53. doi:10.4103\/2153-3539.197197. PMC PMC5248400. PMID 28163975. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5248400 .   \n\n\u2191 Eiseman, E.; Haga, S.B. (1999). Handbook of Human Tissue Sources: A National Resource of Human Tissue Samples. RAND Corporation. ISBN 0833027662.   \n\n\u2191 Gee, S.; Georghiou, L.; Oliver, R. et al. (June 2013). \"Financing UK biobanks: Rationale for a National Biobanking Research Infrastructure\". Manchester Business School, Faculty of Humanities. https:\/\/www.escholar.manchester.ac.uk\/uk-ac-man-scw:199203 .   \n\n\u2191 Simeon-Dubach, D.; Watson, P. (2014). \"Biobanking 3.0: Evidence Based and Customer Focused Biobanking\". Clinical Biochemistry 47 (4\u20135): 300-8. doi:10.1016\/j.clinbiochem.2013.12.018. PMID 24406300.   \n\n\u2191 Simeon-Dubach, D.; Henderson, M.K. (2014). \"Sustainability in Biobanking\". Biopreservation and Biobanking 12 (5): 287\u201391. doi:10.1089\/bio.2014.1251. PMID 25314050.   \n\n\u2191 17.0 17.1 Vaught, J. (2016). \"Biobanking Comes of Age: The Transition to Biospecimen Science\". Annual Review of Pharmacology and Toxicology 56: 211\u201328. doi:10.1146\/annurev-pharmtox-010715-103246. PMID 26514206.   \n\n\u2191 Betsou, F.; Barnes, R.; Burke, T. et al. (2009). \"Human Biospecimen Research: Experimental Protocol and Quality Control Tools\". Cancer Epidemiology, Biomarkers & Prevention 18 (4): 1017-25. doi:10.1158\/1055-9965.EPI-08-1231. PMID 19336543.   \n\n\u2191 Vaught, J.; Rogers, J.; Myers, K. et al. (2011). \"An NCI Perspective on Creating Sustainable Biospecimen Resources\". Journal of the National Cancer Institute Monographs 2011 (42): 1\u20137. doi:10.1093\/jncimonographs\/lgr006. PMID 21672889.   \n\n\u2191 El Messaoudi, S.; Rolet, F.; Mouliere, F. et al. (2013). \"Circulating Cell Free DNA: Preanalytical Considerations\". Clinica Chimica Acta 424: 222\u201330. doi:10.1016\/j.cca.2013.05.022. PMID 23727028.   \n\n\u2191 21.0 21.1 All of Us Research Program Investigators; Denny, J.C.; Rutter, J.L. et al. (2019). \"The \"All of Us\" Research Program\". New England Journal of Medicine 381 (7): 668-676. doi:10.1056\/NEJMsr1809937. PMID 31412182.   \n\n\u2191 Bycroft, C.; Freeman, C.; Petkova, D. et al. (2018). \"The UK Biobank Resource With Deep Phenotyping and Genomic Data\". Nature 562 (7726): 203\u20139. doi:10.1038\/s41586-018-0579-z. PMC PMC6786975. PMID 30305743. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6786975 .   \n\n\u2191 Chen, Z.; Chen, J.; Collins, R. et al. (2011). \"China Kadoorie Biobank of 0.5 Million People: Survey Methods, Baseline Characteristics and Long-Term Follow-Up\". International Journal of Epidemiology 40 (6): 1652-66. doi:10.1093\/ije\/dyr120. PMC PMC3235021. PMID 22158673. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3235021 .   \n\n\u2191 Gaziano, J.M.; Concato, J.; Brophy, M. et al. (2016). \"Million Veteran Program: A Mega-Biobank to Study Genetic Influences on Health and Disease\". Journal of Clinical Epidemiology 70: 214\u201323. doi:10.1016\/j.jclinepi.2015.09.016. PMID 26441289.   \n\n\u2191 Buckley, J.M.; Coopey, S.B.; Sharko, J. et al. (2012). \"The Feasibility of Using Natural Language Processing to Extract Clinical Information From Breast Pathology Reports\". Journal of Pathology Informatics 3: 23. doi:10.4103\/2153-3539.97788. PMC PMC3424662. PMID 22934236. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3424662 .   \n\n\nNotes \nThis presentation is faithful to the original, with only a few minor changes to presentation. Grammar was cleaned up for smoother reading. In some cases important information was missing from the references, and that information was added. As the time of loading this article, the link to Additional file 1 was broken on the original site. 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The typical approach used to identify biospecimens is a manual, retrospective process that exists outside the clinical <a href=\"https:\/\/www.limswiki.org\/index.php\/Workflow\" title=\"Workflow\" class=\"wiki-link\" data-key=\"92bd8748272e20d891008dcb8243e8a8\">workflow<\/a>. This often makes biospecimen collection cost prohibitive and prevents the collection of analytes with short stability times. Emerging data architectures offer novel approaches to enhance specimen-identification practices. To this end, we present a new tool that can be deployed in a real-time environment to automate the identification and notification of available biospecimens for biomedical research. \n<\/p><p><b>Methods<\/b>: Real-time clinical and laboratory data from Cloverleaf (Infor, NY, NY) were acquired within our computational health platform, which is built on open-source applications. Study-specific filters were developed in NiFi (Apache Software Foundation, Wakefield, MA, USA) to identify the study-appropriate specimens in real time. Specimen metadata were stored in Elasticsearch (Elastic N. V., Mountain View, CA, USA) for <a href=\"https:\/\/www.limswiki.org\/index.php\/Data_visualization\" title=\"Data visualization\" class=\"wiki-link\" data-key=\"4a3b86cba74bc7bb7471aa3fc2fcccc3\">visualization<\/a> and automated alerting. \n<\/p><p><b>Results<\/b>: Between June 2018 and December 2018, we identified 2,992 unique specimens belonging to 2,815 unique patients, split between two different use cases. Based on laboratory policy for specimen retention and study-specific stability requirements, secure e-mail notifications were sent to investigators to automatically notify them of availability. The assessment of throughput on commodity hardware demonstrates the ability to scale to approximately 2,000 results per second.\n<\/p><p><b>Conclusion<\/b>: This work demonstrates that real-world clinical data can be analyzed in real-time to increase the efficiency of biospecimen identification with minimal overhead for the <a href=\"https:\/\/www.limswiki.org\/index.php\/Clinical_laboratory\" title=\"Clinical laboratory\" class=\"wiki-link\" data-key=\"307bcdf1bdbcd1bb167cee435b7a5463\">clinical laboratory<\/a>. Future work will integrate additional data types, including the analysis of unstructured data, to enable more complex cases and biospecimen identification.\n<\/p><p><b>Keywords<\/b>: biobanking, biomedical research, biospecimen science, clinical specimens, real-time identification, translational research\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Introduction\">Introduction<\/span><\/h2>\n<p>In the era of precision medicine, human biospecimens are an important resource for basic, <a href=\"https:\/\/www.limswiki.org\/index.php\/Translational_research\" title=\"Translational research\" class=\"wiki-link\" data-key=\"b5462c2278492de7f21a60e40299b634\">translational<\/a>, and clinical research and are increasingly needed to advance our understanding of human physiology, disease, treatment response, and outcomes. The field of <a href=\"https:\/\/www.limswiki.org\/index.php\/Biobank\" title=\"Biobank\" class=\"wiki-link\" data-key=\"4e5f94a2b2036266701220c1fd724bd2\">biobanking<\/a> has undergone significant optimization efforts by national and international communities to improve and harmonize biospecimen curation to support this need.<sup id=\"rdp-ebb-cite_ref-vanOmmenBBMRI15_1-0\" class=\"reference\"><a href=\"#cite_note-vanOmmenBBMRI15-1\">[1]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-LanghofCurrent18_2-0\" class=\"reference\"><a href=\"#cite_note-LanghofCurrent18-2\">[2]<\/a><\/sup> However, the operationalization and maintenance of biobanks is resource-intensive and often cost prohibitive for many institutions. In addition, long-term biobanking may be suboptimal for some types of testing, such as for studies that rely on <a href=\"https:\/\/www.limswiki.org\/index.php\/Lability\" title=\"Lability\" class=\"wiki-link\" data-key=\"992014245f90562c37aaaa5f3941462e\">labile<\/a> analytes.<sup id=\"rdp-ebb-cite_ref-ShabhikhaniTheProc14_3-0\" class=\"reference\"><a href=\"#cite_note-ShabhikhaniTheProc14-3\">[3]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-EllervikPreanal15_4-0\" class=\"reference\"><a href=\"#cite_note-EllervikPreanal15-4\">[4]<\/a><\/sup> As a result, comprehensive access to human biospecimens remains limited, and there is a persistent need for efficient solutions that can provide access to high-quality and recently acquired human biospecimens.<sup id=\"rdp-ebb-cite_ref-MassettAss11_5-0\" class=\"reference\"><a href=\"#cite_note-MassettAss11-5\">[5]<\/a><\/sup>\n<\/p><p>Human biospecimens can always be found in <a href=\"https:\/\/www.limswiki.org\/index.php\/Clinical_laboratory\" title=\"Clinical laboratory\" class=\"wiki-link\" data-key=\"307bcdf1bdbcd1bb167cee435b7a5463\">clinical laboratories<\/a>, but access for the research is complicated by a series of technical, logistic, regulatory, and ethical challenges. Beyond the demands of delivering clinical results, laboratories lack efficient processes for biospecimen identification, human resources for <a href=\"https:\/\/www.limswiki.org\/index.php\/Sample_(material)\" title=\"Sample (material)\" class=\"wiki-link\" data-key=\"7f8cd41a077a88d02370c02a3ba3d9d6\">specimen<\/a> acquisition, and procedural infrastructure for biospecimen collection under the provisions of human interventional ethics committees. Despite these challenges, the clinical laboratory is a promising resource for the acquisition of biospecimens, and researchers are beginning to investigate curation methods that can integrate with existing clinical workflows and leverage <a href=\"https:\/\/www.limswiki.org\/index.php\/Electronic_health_record\" title=\"Electronic health record\" class=\"wiki-link\" data-key=\"f2e31a73217185bb01389404c1fd5255\">electronic health record<\/a> (EHR) <a href=\"https:\/\/www.limswiki.org\/index.php\/Metadata\" title=\"Metadata\" class=\"wiki-link\" data-key=\"f872d4d6272811392bafe802f3edf2d8\">metadata<\/a> for biospecimen identification and annotation.<sup id=\"rdp-ebb-cite_ref-MooreBio13_6-0\" class=\"reference\"><a href=\"#cite_note-MooreBio13-6\">[6]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-Simeon-DubachQual12_7-0\" class=\"reference\"><a href=\"#cite_note-Simeon-DubachQual12-7\">[7]<\/a><\/sup>\n<\/p><p>One of the first automated biospecimen identification systems was Crimson, an application used to identify the discarded blood samples accessioned into the clinical laboratory by querying the <a href=\"https:\/\/www.limswiki.org\/index.php\/Laboratory_information_system\" title=\"Laboratory information system\" class=\"wiki-link\" data-key=\"37add65b4d1c678b382a7d4817a9cf64\">laboratory information system<\/a> (LIS). Specimens, which met predetermined inclusion criteria, were electronically reaccessioned into a deidentified research database that could be accessed by researchers with institutional review board (IRB) approval.<sup id=\"rdp-ebb-cite_ref-MurphyInstrum09_8-0\" class=\"reference\"><a href=\"#cite_note-MurphyInstrum09-8\">[8]<\/a><\/sup> While biobanks routinely link health information between specimen and participant postenrollment, such solutions demonstrate how EHR integration and associated metadata can be used for targeted and automated biospecimen selection. However, examples of this framework remain limited, both in the literature and in practice, which typically focus on retrospective specimen identification for long-term biobanking. With the increased digitization of healthcare and modern data architectures that allow for real-time analysis of clinical data, biospecimens can be identified as samples that are processed through the clinical laboratory. This approach offers the benefit of increasing access to specimens of interest, including those with labile analytes, while not disrupting routine clinical <a href=\"https:\/\/www.limswiki.org\/index.php\/Workflow\" title=\"Workflow\" class=\"wiki-link\" data-key=\"92bd8748272e20d891008dcb8243e8a8\">workflows<\/a>.<sup id=\"rdp-ebb-cite_ref-EllervikPreanal15_4-1\" class=\"reference\"><a href=\"#cite_note-EllervikPreanal15-4\">[4]<\/a><\/sup>\n<\/p><p>In this report, we present Prism, a new tool built on open-source technology that can efficiently identify and notify the investigators of biospecimen availability in near real time. We describe the pipeline architecture and our experience with two IRB-approved pilot projects within our department (IRB Protocol IDs: Babesia \u2013 2000023123; Diabetic biomarkers \u2013 2000022266).\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Methods\">Methods<\/span><\/h2>\n<h3><span class=\"mw-headline\" id=\"Prism_platform_architecture\">Prism platform architecture<\/span><\/h3>\n<p>We implemented a real-time pipeline, called Prism, that consists of three key components: real-time data acquisition, stream processing, and end-user alerting, to support case and specimen identification (Fig. 1). Parameterized processors for Apache's open-source dataflow (stream processing) system NiFi were used to filter and identify the clinical specimens based on study-specific inclusion criteria extracted from corresponding laboratory result metadata. Specimens that met inclusion criteria were indexed within Elastic search (Elastic NV; Mountain View, CA, United States). Alerting was done through Watcher (Elastic NV; Mountain View, CA, United States) and secure e-mail, with a reporting dashboard built in Kibana (Elastic NV; Mountain View, CA, United States).\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig1_Durant_JofPathInfo2020_11.jpg\" class=\"image wiki-link\" data-key=\"613afcd04aa5aae58c73e7841368d98c\"><img alt=\"Fig1 Durant JofPathInfo2020 11.jpg\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/0\/0e\/Fig1_Durant_JofPathInfo2020_11.jpg\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Figure 1.<\/b> Dataflow diagram for laboratory results using NiFi and Elasticsearch. (<b>A<\/b>) Existing laboratory result dataflow. (<b>B<\/b>) Prism specimen identification dataflow. BI: Business Intelligence, HDFS: Hadoop-Distributed File System, HL7: Health Level 7, JSON: Java Script Object Notation<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>This framework was deployed within our organization's computational health care platform, Baikal, which has been previously described (see Supplemental Figure 1 in Additional file 1).<sup id=\"rdp-ebb-cite_ref-McPaddenHealth19_9-0\" class=\"reference\"><a href=\"#cite_note-McPaddenHealth19-9\">[9]<\/a><\/sup> The Baikal platform is built on open-source technology and provides a mechanism to manage and analyze high-volume and high-frequency clinical data in real time, including laboratory results.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Throughput_assessment\">Throughput assessment<\/span><\/h3>\n<p>Scalability and computing resource needs for Prism were estimated through the deployment in a standalone workstation environment with a single CPU with six cores (Intel Core i7-6850K CPU @ 3.60GHz) and 256 GiB of memory. Apache NiFi was deployed within a Docker (version 19.03.2, build 6a30dfc; Docker, Inc., San Francisco, CA, United States) container under the Ubuntu (Version: 16.04.6 LTS (Xenial); Canonical Ltd; London, UK) operating system. We ran a modified version of the Prism dataflow using file-based record I\/O instead of streaming data from a network interface. Data for the assessment were obtained by randomly selecting data from our production <a href=\"https:\/\/www.limswiki.org\/index.php\/Health_Level_7\" title=\"Health Level 7\" class=\"wiki-link\" data-key=\"e0bf845fb58d2bae05a846b47629e86f\">Health Level 7<\/a> (HL7) feed, and the data were assembled into three datasets of increasing size. These datasets contained 1 \u00d7 105, 1 \u00d7 106, and 1 \u00d7 107 JavaScript Object Notation-transformed HL7 ORU messages, resulting in 0.75 GB, 7.27 GB, and 72.8 GB of data, respectively. Two series of five trials were performed with the 1 \u00d7 106 record data set. In the first series, all five trials were run consecutively. In the second series, Docker was restarted between each trial to assess for any possible performance impacts in long-running containers. Throughput was measured using built-in NiFi monitoring tools to assess record count and throughput.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Results\">Results<\/span><\/h2>\n<h3><span class=\"mw-headline\" id=\"Babesia_specimen_identification\">Babesia specimen identification<\/span><\/h3>\n<p>Babesia is a tick-borne hemoprotozoan, which infects human erythrocytes and can be life-threatening for patients who are asplenic, immunocompromised, or elderly. The gold standard for the laboratory diagnosis is microscopic analysis of a peripheral blood smear. For research into the automation of digital microscopic analysis using the computer vision, the researcher needed peripheral blood smears, which were identified as containing Babesia. Incoming HL7 messages corresponding to a Babesia result record with a \u201cPositive\u201d result value were flagged and sent to the Prism index in Elasticsearch (Fig. 2). Researchers were securely notified of all \u201cPositive\u201d Babesia specimens identified every four hours.\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig2_Durant_JofPathInfo2020_11.jpg\" class=\"image wiki-link\" data-key=\"0b9bf3035694e6f60738b4b1ad14c424\"><img alt=\"Fig2 Durant JofPathInfo2020 11.jpg\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/a\/a9\/Fig2_Durant_JofPathInfo2020_11.jpg\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Figure 2.<\/b> Laboratory result monitoring for positive Babesia specimens. Incoming HL7 observations are transformed to denormalized JSON documents and stored to HDFS. Prism dataflow ingests streaming JSON result records and filters \u201cPositive\u201d Babesia results to the \u201cPrism\u201d Specimen Surveillance Index from which secure notifications of positive Babesia results are generated. HDFS: Hadoop-Distributed File System, HL7: Health-Level 7, JSON: Java Script Object Notation<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>Specimen identification for positive Babesia specimens went live in May 2018. In a collection period of 16 months (June 2018\u2013September 2019), Prism identified 131 unique lavender-top tubes, belonging to 44 unique patients, which were identified as positive for Babesia by manual light microscopy. The collection period for this project was extended beyond the anticipated time requirement as Babesia exhibits a strong seasonal prevalence, and positive specimen rates dropped over the colder months (Fig. 3).\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig3_Durant_JofPathInfo2020_11.jpg\" class=\"image wiki-link\" data-key=\"f36e0735c8ec4762bf8ee73caef050c5\"><img alt=\"Fig3 Durant JofPathInfo2020 11.jpg\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/3\/39\/Fig3_Durant_JofPathInfo2020_11.jpg\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Figure 3.<\/b> Total number of unique patients and specimens identified for Babesia and A1C-LGT specific use cases within the specified date range. Columns represent count of unique specimens per week. Right Y-axis: HbA1c-LGT, Left Y-axis: Babesia. HbA1c: Hemoglobin A1c, LGT: Light-green top<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<h3><span class=\"mw-headline\" id=\"Diabetic_biomarker_specimen_identification\">Diabetic biomarker specimen identification<\/span><\/h3>\n<p>The development of type 2 diabetes can be prevented or delayed in prediabetic individuals with lifestyle modifications such as dietary changes or increased physical activity. Accordingly, there is a need to identify the biomarkers to guide preventative interventions.<sup id=\"rdp-ebb-cite_ref-Wang-SattlerNovel12_10-0\" class=\"reference\"><a href=\"#cite_note-Wang-SattlerNovel12-10\">[10]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-Guasch-Ferr.C3.A9Metab16_11-0\" class=\"reference\"><a href=\"#cite_note-Guasch-Ferr.C3.A9Metab16-11\">[11]<\/a><\/sup> To identify possible biomarkers, a researcher at our institution was interested in obtaining blood specimens from patients with and without diabetes, with borderline cases excluded, as a prelude to a larger prospective biomarker study. The deidentified samples would undergo metabolomic analysis by <a href=\"https:\/\/www.limswiki.org\/index.php\/Liquid_chromatography%E2%80%93mass_spectrometry\" title=\"Liquid chromatography\u2013mass spectrometry\" class=\"wiki-link\" data-key=\"d171745b38c8d2ed7d274d2cc13fa1f3\">liquid chromatography\u2013mass spectrometry<\/a> to identify the metabolites that were significantly changed between the two groups as candidate biomarkers.\n<\/p><p>Hemoglobin A1C values < 5.7 and > 6.5 were used to delineate between diabetic and nondiabetic patients, with additional inclusion criteria of outpatient specimen collection and patient age range 18\u201370 years. Of note, the preferred collection container for Hgb A1c at our institution is a lavender-top tube, which does not contain gel-separation barriers. In an effort to optimize biomarker recovery, plasma from light-green-top (LGT) tubes was requested for this study. Accordingly, LGT tubes were flagged when a paired sample with an Hgb A1c within the appropriate range was found within seven days (Fig. 4). Researchers were securely notified every morning by e-mail of all matching LGT specimens present in the Prism index reported within 24 hours prior.\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig4_Durant_JofPathInfo2020_11.jpg\" class=\"image wiki-link\" data-key=\"c2132c111e258573172a944c67d02434\"><img alt=\"Fig4 Durant JofPathInfo2020 11.jpg\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/3\/3a\/Fig4_Durant_JofPathInfo2020_11.jpg\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Figure 4.<\/b> Laboratory result processing diagram for diabetic biomarker monitoring. Incoming HL7 observations are transformed to denormalized JavaScript Object Notation documents and stored to HDFS. The Prism dataflow ingests streaming JavaScript Object Notation result records and filters hemoglobin A1C results in the \u201cNormal\u201d (<5.7) and \u201cDiabetic\u201d (>6.5) cohorts to the Prism Specimen Surveillance Index in Elastic. Results from CMP\/BMP panels (light-green top specimens) are sent to the Prism index. Secure notifications are sent for A1C specimen IDs with related light-green specimen info. BMP: Basic Metabolic Panel, CMP: Comprehensive Metabolic Panel, HbA1c: Hemoglobin A1c; HDFS: Hadoop-Distributed File System, HL7: Health-Level 7, JSON: Java Script Object Notation<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>Specimen identification for diabetic biomarker discovery went live in December 2018. In a collection period of four months (December 2018\u2013March 2019), Prism identified 2,861 unique LGT specimens from 2,771 unique patients (Fig. 3).\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Throughput_assessment_2\">Throughput assessment<\/span><\/h3>\n<p>We assessed the processing throughput to ensure the pipeline could scale to large environments and consistently manage high-volume data. Our institution's computational health platform processes approximately 350,000 discrete HL7 ORU messages per day. Accordingly, we evaluated processing time across five trials and observed an average execution time of approximately eight minutes for one million records, which represents slightly less than three days of laboratory result volume. Processing time was observed to be linear over two orders of magnitude in dataset size (Fig. 5a), and the average total execution time to process one million messages differed by 2% between runs with (494 seconds) and without (483 seconds) Docker container restart (Fig. 5b).\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig5_Durant_JofPathInfo2020_11.jpg\" class=\"image wiki-link\" data-key=\"0bbfc045890d3062d692dd745676c93c\"><img alt=\"Fig5 Durant JofPathInfo2020 11.jpg\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/3\/35\/Fig5_Durant_JofPathInfo2020_11.jpg\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Figure 5.<\/b> Laboratory result processing diagram for diabetic biomarker monitoring. Incoming HL7 observations are transformed to denormalized JavaScript Object Notation documents and stored to HDFS. The Prism dataflow ingests streaming JavaScript Object Notation result records and filters hemoglobin A1C results in the \u201cNormal\u201d (<5.7) and \u201cDiabetic\u201d (>6.5) cohorts to the Prism Specimen Surveillance Index in Elastic. Results from CMP\/BMP panels (light-green top specimens) are sent to the Prism index. Secure notifications are sent for A1C specimen IDs with related light-green specimen info. BMP: Basic Metabolic Panel, CMP: Comprehensive Metabolic Panel, HbA1c: Hemoglobin A1c; HDFS: Hadoop-Distributed File System, HL7: Health-Level 7, JSON: Java Script Object Notation<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<h2><span class=\"mw-headline\" id=\"Discussion\">Discussion<\/span><\/h2>\n<p>In this report, we describe a novel data analysis pipeline called Prism that can be used to improve the efficiency of biospecimen collection. This workflow has been deployed to identify the biospecimens in near real-time for two biomedical research use cases. We demonstrated that this solution is highly scalable to meet the needs of even large academic centers and <a href=\"https:\/\/www.limswiki.org\/index.php\/Reference_laboratory\" title=\"Reference laboratory\" class=\"wiki-link\" data-key=\"f719f408e1660f86b53857eef2f13f32\">reference laboratories<\/a>. We also found, consistent with our prior work, that virtualization of this workflow within a microservices environment does not introduce a performance penalty.<sup id=\"rdp-ebb-cite_ref-SchulzUseOf16_12-0\" class=\"reference\"><a href=\"#cite_note-SchulzUseOf16-12\">[12]<\/a><\/sup>\n<\/p><p>In 2000, it was estimated that 300 million human biospecimens were preserved in the United States, with a projected 7% annual growth rate.<sup id=\"rdp-ebb-cite_ref-EisemanHandbook99_13-0\" class=\"reference\"><a href=\"#cite_note-EisemanHandbook99-13\">[13]<\/a><\/sup> However, researchers continue to report difficulty in obtaining specimens for biomedical research and express underlying concerns in the validity of their results when using specimens subjected to long-term storage conditions.<sup id=\"rdp-ebb-cite_ref-MassettAss11_5-1\" class=\"reference\"><a href=\"#cite_note-MassettAss11-5\">[5]<\/a><\/sup> In addition, while many biospecimens are being stored, a large proportion is expected to remain unused, and there is increasing concern that untargeted collection of biospecimens consumes resources that could be better allocated.<sup id=\"rdp-ebb-cite_ref-GeeFinancing13_14-0\" class=\"reference\"><a href=\"#cite_note-GeeFinancing13-14\">[14]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-Simeon-DubachBiobank14_15-0\" class=\"reference\"><a href=\"#cite_note-Simeon-DubachBiobank14-15\">[15]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-Simeon-DubachSustain14_16-0\" class=\"reference\"><a href=\"#cite_note-Simeon-DubachSustain14-16\">[16]<\/a><\/sup> Accordingly, as institutions seek to expand biomedical research efforts, particularly in the era of personalized medicine, novel approaches for improving access to high-quality human biospecimens should be evaluated.\n<\/p><p>The quality of biomedical research is dependent on the integrity of biospecimens and as with clinical testing, analyte recovery is subject to a significant number of preanalytical considerations.<sup id=\"rdp-ebb-cite_ref-EllervikPreanal15_4-2\" class=\"reference\"><a href=\"#cite_note-EllervikPreanal15-4\">[4]<\/a><\/sup> While biobanking procedures have seen significant optimization in recent years, poor reproducibility of studies that use biospecimens has been thought to be caused, in part, by the variable quality and inadequate documentation of biospecimen metadata.<sup id=\"rdp-ebb-cite_ref-MassettAss11_5-2\" class=\"reference\"><a href=\"#cite_note-MassettAss11-5\">[5]<\/a><\/sup> To this end, biobanks are beginning to emulate testing procedures found in the clinical laboratory to optimize analyte recovery and test reproducibility.<sup id=\"rdp-ebb-cite_ref-VaughtBiobank16_17-0\" class=\"reference\"><a href=\"#cite_note-VaughtBiobank16-17\">[17]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-BetsouHuman09_18-0\" class=\"reference\"><a href=\"#cite_note-BetsouHuman09-18\">[18]<\/a><\/sup> Tools that can identify the samples accessioned to the clinical laboratory, such as Prism, would align with these efforts by identifying the specimens that have been collected and processed under clinical conditions.\n<\/p><p>Despite ongoing adoption of clinical procedures in biospecimen science, the collection and processing of labile analytes remain challenging, and some components may require unique processing protocols.<sup id=\"rdp-ebb-cite_ref-VaughtBiobank16_17-1\" class=\"reference\"><a href=\"#cite_note-VaughtBiobank16-17\">[17]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-VaughtAnNCI11_19-0\" class=\"reference\"><a href=\"#cite_note-VaughtAnNCI11-19\">[19]<\/a><\/sup> Proteomic and molecular analytes are particularly sensitive to specimen transport delays, matrix effects, and optimal-storage environments.<sup id=\"rdp-ebb-cite_ref-ElMessaoudiCirc13_20-0\" class=\"reference\"><a href=\"#cite_note-ElMessaoudiCirc13-20\">[20]<\/a><\/sup> Accordingly, some components of interest may require sample processing techniques that exist outside routine clinical workflows. In this setting, real-time streaming analytics could also be envisioned to identify patients which match study-specific inclusion criteria to guide targeted subject enrollment and subsequent collection.\n<\/p><p>In addition to specimen identification and collection, annotation with patient metadata remains an important and challenging facet of contemporary biobanking. Large scale biobanks such as the U.K. Biobank rely on a combination of data sources for curating specimen metadata, including participant enrollment surveys, physical measures (e.g., blood pressure and spirometry), and linkage to digital health information.<sup id=\"rdp-ebb-cite_ref-InvestigatorsTheAll19_21-0\" class=\"reference\"><a href=\"#cite_note-InvestigatorsTheAll19-21\">[21]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-BycroftTheUK18_22-0\" class=\"reference\"><a href=\"#cite_note-BycroftTheUK18-22\">[22]<\/a><\/sup> Indeed, while the majority of national biobanking resources capture data from both inpatient and outpatient medical records, there is also interest in capturing data that is not stored in the EHR.<sup id=\"rdp-ebb-cite_ref-InvestigatorsTheAll19_21-1\" class=\"reference\"><a href=\"#cite_note-InvestigatorsTheAll19-21\">[21]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ChenChina11_23-0\" class=\"reference\"><a href=\"#cite_note-ChenChina11-23\">[23]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-GazianoMillion16_24-0\" class=\"reference\"><a href=\"#cite_note-GazianoMillion16-24\">[24]<\/a><\/sup> As digital health information continues to expand, health care systems are increasingly working to develop clinically integrated <a href=\"https:\/\/www.limswiki.org\/index.php\/Information_management\" title=\"Information management\" class=\"wiki-link\" data-key=\"f8672d270c0750a858ed940158ca0a73\">data management<\/a> tools for the centralization of disparate data resources.<sup id=\"rdp-ebb-cite_ref-McPaddenHealth19_9-1\" class=\"reference\"><a href=\"#cite_note-McPaddenHealth19-9\">[9]<\/a><\/sup> Deployment of automated specimen identification tools in these frameworks may facilitate correlation with these data and would align with national efforts to do so.\n<\/p><p>It should be noted that the use cases described in this report were selected based on the immediate needs among researchers in our department. However, similar open-source tools could be similarly envisioned to integrate with <a href=\"https:\/\/www.limswiki.org\/index.php\/Anatomical_pathology\" title=\"Anatomical pathology\" class=\"wiki-link\" data-key=\"5668db6faf37e8c1432a1d7953f30cb7\">anatomic pathology<\/a> data and the EHR, to automatically phenotype tissue specimens as they are processed in the laboratory. While the majority of data elements in the clinical laboratory are discrete, identifying tissue specimens in the anatomic pathology laboratory may require technologies such as natural language processing (NLP) to process semistructured and unstructured data, such as those commonly found in pathology reports.<sup id=\"rdp-ebb-cite_ref-BuckleyTheFeas12_25-0\" class=\"reference\"><a href=\"#cite_note-BuckleyTheFeas12-25\">[25]<\/a><\/sup> While not used for this implementation, custom NiFi processors would allow the users to develop more complex filters and integrate NLP or machine learning-based technology for free text or nested data structures commonly found in anatomic pathology. Similarly, the platform can also be used to identify the patients who may be eligible to consent and enroll in studies, rather than simply for biospecimen collection.\n<\/p><p>In the era of digital and personalized medicine, novel approaches to increase the efficiency of biospecimen identification will be crucial to accelerate discovery. Modern data architectures as described here can be used to address the fundamental challenges in the procurement of biospecimens in support of biomedical research. Future work will seek to integrate additional data types, including the analysis of unstructured data, to enable more complex case and biospecimen identification.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Acknowledgements\">Acknowledgements<\/span><\/h2>\n<h3><span class=\"mw-headline\" id=\"Disclosure\">Disclosure<\/span><\/h3>\n<p>Wade Schulz was an investigator for a research agreement, through Yale University, from the Shenzhen Center for Health Information for work to advance intelligent disease prevention and health promotion. Schulz also collaborates with the National Center for Cardiovascular Diseases in Beijing; is a technical consultant to HugoHealth, a personal health information platform, and co-founder of Refactor Health, an AI-augmented data management platform for healthcare; and is a consultant for Interpace Diagnostics Group, a molecular diagnostics company.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Financial_support_and_sponsorship\">Financial support and sponsorship<\/span><\/h3>\n<p>Nil.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Conflicts_of_interest\">Conflicts of interest<\/span><\/h3>\n<p>There are no conflicts of interest.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"References\">References<\/span><\/h2>\n<div class=\"reflist references-column-width\" style=\"-moz-column-width: 30em; -webkit-column-width: 30em; column-width: 30em; list-style-type: decimal;\">\n<ol class=\"references\">\n<li id=\"cite_note-vanOmmenBBMRI15-1\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-vanOmmenBBMRI15_1-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">van Ommen, G.-J.B.; T\u00f6rnwall, O.; Br\u00e9chot, C. et al. (2015). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4463510\" target=\"_blank\">\"BBMRI-ERIC as a Resource for Pharmaceutical and Life Science Industries: The Development of Biobank-Based Expert Centres\"<\/a>. <i>European Journal of Human Genetics<\/i> <b>23<\/b> (7): 893-900. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1038%2Fejhg.2014.235\" target=\"_blank\">10.1038\/ejhg.2014.235<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC4463510\/\" target=\"_blank\">PMC4463510<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/25407005\" target=\"_blank\">25407005<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4463510\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4463510<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=BBMRI-ERIC+as+a+Resource+for+Pharmaceutical+and+Life+Science+Industries%3A+The+Development+of+Biobank-Based+Expert+Centres&rft.jtitle=European+Journal+of+Human+Genetics&rft.aulast=van+Ommen%2C+G.-J.B.%3B+T%C3%B6rnwall%2C+O.%3B+Br%C3%A9chot%2C+C.+et+al.&rft.au=van+Ommen%2C+G.-J.B.%3B+T%C3%B6rnwall%2C+O.%3B+Br%C3%A9chot%2C+C.+et+al.&rft.date=2015&rft.volume=23&rft.issue=7&rft.pages=893-900&rft_id=info:doi\/10.1038%2Fejhg.2014.235&rft_id=info:pmc\/PMC4463510&rft_id=info:pmid\/25407005&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC4463510&rfr_id=info:sid\/en.wikipedia.org:Journal:Bridging_the_collaboration_gap:_Real-time_identification_of_clinical_specimens_for_biomedical_research\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-LanghofCurrent18-2\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-LanghofCurrent18_2-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Langhof, H.; Kahrass, H.; Illig, T. et al. (2018). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6189200\" target=\"_blank\">\"Current Practices for Access, Compensation, and Prioritization in Biobanks. Results From an Interview Study\"<\/a>. <i>European Journal of Human Genetics<\/i> <b>26<\/b> (11): 1572\u20131581. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1038%2Fs41431-018-0228-x\" target=\"_blank\">10.1038\/s41431-018-0228-x<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6189200\/\" target=\"_blank\">PMC6189200<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/30089824\" target=\"_blank\">30089824<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6189200\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6189200<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Current+Practices+for+Access%2C+Compensation%2C+and+Prioritization+in+Biobanks.+Results+From+an+Interview+Study&rft.jtitle=European+Journal+of+Human+Genetics&rft.aulast=Langhof%2C+H.%3B+Kahrass%2C+H.%3B+Illig%2C+T.+et+al.&rft.au=Langhof%2C+H.%3B+Kahrass%2C+H.%3B+Illig%2C+T.+et+al.&rft.date=2018&rft.volume=26&rft.issue=11&rft.pages=1572%E2%80%931581&rft_id=info:doi\/10.1038%2Fs41431-018-0228-x&rft_id=info:pmc\/PMC6189200&rft_id=info:pmid\/30089824&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC6189200&rfr_id=info:sid\/en.wikipedia.org:Journal:Bridging_the_collaboration_gap:_Real-time_identification_of_clinical_specimens_for_biomedical_research\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ShabhikhaniTheProc14-3\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-ShabhikhaniTheProc14_3-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Shabihkhani, M.; Lucey, G.M.; Wei, B. et al. (2014). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3982909\" target=\"_blank\">\"The Procurement, Storage, and Quality Assurance of Frozen Blood and Tissue Biospecimens in Pathology, Biorepository, and Biobank Settings\"<\/a>. <i>Clinical Biochemistry<\/i> <b>47<\/b> (4\u20135): 258-66. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.clinbiochem.2014.01.002\" target=\"_blank\">10.1016\/j.clinbiochem.2014.01.002<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC3982909\/\" target=\"_blank\">PMC3982909<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/24424103\" target=\"_blank\">24424103<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3982909\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3982909<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=The+Procurement%2C+Storage%2C+and+Quality+Assurance+of+Frozen+Blood+and+Tissue+Biospecimens+in+Pathology%2C+Biorepository%2C+and+Biobank+Settings&rft.jtitle=Clinical+Biochemistry&rft.aulast=Shabihkhani%2C+M.%3B+Lucey%2C+G.M.%3B+Wei%2C+B.+et+al.&rft.au=Shabihkhani%2C+M.%3B+Lucey%2C+G.M.%3B+Wei%2C+B.+et+al.&rft.date=2014&rft.volume=47&rft.issue=4%E2%80%935&rft.pages=258-66&rft_id=info:doi\/10.1016%2Fj.clinbiochem.2014.01.002&rft_id=info:pmc\/PMC3982909&rft_id=info:pmid\/24424103&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC3982909&rfr_id=info:sid\/en.wikipedia.org:Journal:Bridging_the_collaboration_gap:_Real-time_identification_of_clinical_specimens_for_biomedical_research\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-EllervikPreanal15-4\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-EllervikPreanal15_4-0\">4.0<\/a><\/sup> <sup><a href=\"#cite_ref-EllervikPreanal15_4-1\">4.1<\/a><\/sup> <sup><a href=\"#cite_ref-EllervikPreanal15_4-2\">4.2<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Ellervik, C.; Vaught, J. (2015). \"Preanalytical Variables Affecting the Integrity of Human Biospecimens in Biobanking\". <i>Clinical Chemistry<\/i> <b>61<\/b> (7): 914-34. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1373%2Fclinchem.2014.228783\" target=\"_blank\">10.1373\/clinchem.2014.228783<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/25979952\" target=\"_blank\">25979952<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Preanalytical+Variables+Affecting+the+Integrity+of+Human+Biospecimens+in+Biobanking&rft.jtitle=Clinical+Chemistry&rft.aulast=Ellervik%2C+C.%3B+Vaught%2C+J.&rft.au=Ellervik%2C+C.%3B+Vaught%2C+J.&rft.date=2015&rft.volume=61&rft.issue=7&rft.pages=914-34&rft_id=info:doi\/10.1373%2Fclinchem.2014.228783&rft_id=info:pmid\/25979952&rfr_id=info:sid\/en.wikipedia.org:Journal:Bridging_the_collaboration_gap:_Real-time_identification_of_clinical_specimens_for_biomedical_research\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-MassettAss11-5\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-MassettAss11_5-0\">5.0<\/a><\/sup> <sup><a href=\"#cite_ref-MassettAss11_5-1\">5.1<\/a><\/sup> <sup><a href=\"#cite_ref-MassettAss11_5-2\">5.2<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Massett, H.A.; Atkinson, N.L.; Weber, D. et al. (2011). \"Assessing the Need for a Standardized Cancer HUman Biobank (caHUB): Findings From a National Survey With Cancer Researchers\". <i>Journal of the National Cancer Institute Monographs<\/i> <b>2011<\/b> (42): 8\u201315. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1093%2Fjncimonographs%2Flgr007\" target=\"_blank\">10.1093\/jncimonographs\/lgr007<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/21672890\" target=\"_blank\">21672890<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Assessing+the+Need+for+a+Standardized+Cancer+HUman+Biobank+%28caHUB%29%3A+Findings+From+a+National+Survey+With+Cancer+Researchers&rft.jtitle=Journal+of+the+National+Cancer+Institute+Monographs&rft.aulast=Massett%2C+H.A.%3B+Atkinson%2C+N.L.%3B+Weber%2C+D.+et+al.&rft.au=Massett%2C+H.A.%3B+Atkinson%2C+N.L.%3B+Weber%2C+D.+et+al.&rft.date=2011&rft.volume=2011&rft.issue=42&rft.pages=8%E2%80%9315&rft_id=info:doi\/10.1093%2Fjncimonographs%2Flgr007&rft_id=info:pmid\/21672890&rfr_id=info:sid\/en.wikipedia.org:Journal:Bridging_the_collaboration_gap:_Real-time_identification_of_clinical_specimens_for_biomedical_research\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-MooreBio13-6\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-MooreBio13_6-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Moore, H,M.; Jelly, A.; McShane, L.M. et al. (2013). \"Biospecimen Reporting for Improved Study Quality (BRISQ)\". <i>Transfusion<\/i> <b>53<\/b> (7): e1. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1111%2Ftrf.12281\" target=\"_blank\">10.1111\/trf.12281<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/23844646\" target=\"_blank\">23844646<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Biospecimen+Reporting+for+Improved+Study+Quality+%28BRISQ%29&rft.jtitle=Transfusion&rft.aulast=Moore%2C+H%2CM.%3B+Jelly%2C+A.%3B+McShane%2C+L.M.+et+al.&rft.au=Moore%2C+H%2CM.%3B+Jelly%2C+A.%3B+McShane%2C+L.M.+et+al.&rft.date=2013&rft.volume=53&rft.issue=7&rft.pages=e1&rft_id=info:doi\/10.1111%2Ftrf.12281&rft_id=info:pmid\/23844646&rfr_id=info:sid\/en.wikipedia.org:Journal:Bridging_the_collaboration_gap:_Real-time_identification_of_clinical_specimens_for_biomedical_research\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-Simeon-DubachQual12-7\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-Simeon-DubachQual12_7-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Simeon-Dubach, D.; Burt, A.D.; Hall, P.A. (2012). \"Quality Really Matters: The Need to Improve Specimen Quality in Biomedical Research\". <i>Journal of Pathology<\/i> <b>228<\/b> (4): 431\u20133. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1002%2Fpath.4117\" target=\"_blank\">10.1002\/path.4117<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/23023660\" target=\"_blank\">23023660<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Quality+Really+Matters%3A+The+Need+to+Improve+Specimen+Quality+in+Biomedical+Research&rft.jtitle=Journal+of+Pathology&rft.aulast=Simeon-Dubach%2C+D.%3B+Burt%2C+A.D.%3B+Hall%2C+P.A.&rft.au=Simeon-Dubach%2C+D.%3B+Burt%2C+A.D.%3B+Hall%2C+P.A.&rft.date=2012&rft.volume=228&rft.issue=4&rft.pages=431%E2%80%933&rft_id=info:doi\/10.1002%2Fpath.4117&rft_id=info:pmid\/23023660&rfr_id=info:sid\/en.wikipedia.org:Journal:Bridging_the_collaboration_gap:_Real-time_identification_of_clinical_specimens_for_biomedical_research\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-MurphyInstrum09-8\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-MurphyInstrum09_8-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Murphy, S.; Churchill, S.; Bry, L. et al. (2009). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2752136\" target=\"_blank\">\"Instrumenting the Health Care Enterprise for Discovery Research in the Genomic Era\"<\/a>. <i>Genome Research<\/i> <b>19<\/b> (9): 1675\u201381. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1101%2Fgr.094615.109\" target=\"_blank\">10.1101\/gr.094615.109<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC2752136\/\" target=\"_blank\">PMC2752136<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/19602638\" target=\"_blank\">19602638<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2752136\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2752136<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Instrumenting+the+Health+Care+Enterprise+for+Discovery+Research+in+the+Genomic+Era&rft.jtitle=Genome+Research&rft.aulast=Murphy%2C+S.%3B+Churchill%2C+S.%3B+Bry%2C+L.+et+al.&rft.au=Murphy%2C+S.%3B+Churchill%2C+S.%3B+Bry%2C+L.+et+al.&rft.date=2009&rft.volume=19&rft.issue=9&rft.pages=1675%E2%80%9381&rft_id=info:doi\/10.1101%2Fgr.094615.109&rft_id=info:pmc\/PMC2752136&rft_id=info:pmid\/19602638&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC2752136&rfr_id=info:sid\/en.wikipedia.org:Journal:Bridging_the_collaboration_gap:_Real-time_identification_of_clinical_specimens_for_biomedical_research\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-McPaddenHealth19-9\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-McPaddenHealth19_9-0\">9.0<\/a><\/sup> <sup><a href=\"#cite_ref-McPaddenHealth19_9-1\">9.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">McPadden, J.; Durant, T.J.S.; Bunch, D.R. et al. (2019). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6477571\" target=\"_blank\">\"Health Care and Precision Medicine Research: Analysis of a Scalable Data Science Platform\"<\/a>. <i>Journal of Medical Internet Research<\/i> <b>21<\/b> (4): e13043. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.2196%2F13043\" target=\"_blank\">10.2196\/13043<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6477571\/\" target=\"_blank\">PMC6477571<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/30964441\" target=\"_blank\">30964441<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6477571\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6477571<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Health+Care+and+Precision+Medicine+Research%3A+Analysis+of+a+Scalable+Data+Science+Platform&rft.jtitle=Journal+of+Medical+Internet+Research&rft.aulast=McPadden%2C+J.%3B+Durant%2C+T.J.S.%3B+Bunch%2C+D.R.+et+al.&rft.au=McPadden%2C+J.%3B+Durant%2C+T.J.S.%3B+Bunch%2C+D.R.+et+al.&rft.date=2019&rft.volume=21&rft.issue=4&rft.pages=e13043&rft_id=info:doi\/10.2196%2F13043&rft_id=info:pmc\/PMC6477571&rft_id=info:pmid\/30964441&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC6477571&rfr_id=info:sid\/en.wikipedia.org:Journal:Bridging_the_collaboration_gap:_Real-time_identification_of_clinical_specimens_for_biomedical_research\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-Wang-SattlerNovel12-10\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-Wang-SattlerNovel12_10-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Wang-Sattler, R.; Yu, Z.; Herder, C. et al. (2012). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3472689\" target=\"_blank\">\"Novel Biomarkers for Pre-Diabetes Identified by Metabolomics\"<\/a>. <i>Molecular Systems Biology<\/i> <b>8<\/b>: 615. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1038%2Fmsb.2012.43\" target=\"_blank\">10.1038\/msb.2012.43<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC3472689\/\" target=\"_blank\">PMC3472689<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/23010998\" target=\"_blank\">23010998<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3472689\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3472689<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Novel+Biomarkers+for+Pre-Diabetes+Identified+by+Metabolomics&rft.jtitle=Molecular+Systems+Biology&rft.aulast=Wang-Sattler%2C+R.%3B+Yu%2C+Z.%3B+Herder%2C+C.+et+al.&rft.au=Wang-Sattler%2C+R.%3B+Yu%2C+Z.%3B+Herder%2C+C.+et+al.&rft.date=2012&rft.volume=8&rft.pages=615&rft_id=info:doi\/10.1038%2Fmsb.2012.43&rft_id=info:pmc\/PMC3472689&rft_id=info:pmid\/23010998&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC3472689&rfr_id=info:sid\/en.wikipedia.org:Journal:Bridging_the_collaboration_gap:_Real-time_identification_of_clinical_specimens_for_biomedical_research\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-Guasch-Ferr.C3.A9Metab16-11\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-Guasch-Ferr.C3.A9Metab16_11-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Guasch-Ferr\u00e9, M.; Hruby, A.; Toledo, E. et al. (2016). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4839172\" target=\"_blank\">\"Metabolomics in Prediabetes and Diabetes: A Systematic Review and Meta-analysis\"<\/a>. <i>Diabetes Care<\/i> <b>39<\/b> (5): 833-46. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.2337%2Fdc15-2251\" target=\"_blank\">10.2337\/dc15-2251<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC4839172\/\" target=\"_blank\">PMC4839172<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/27208380\" target=\"_blank\">27208380<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4839172\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4839172<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Metabolomics+in+Prediabetes+and+Diabetes%3A+A+Systematic+Review+and+Meta-analysis&rft.jtitle=Diabetes+Care&rft.aulast=Guasch-Ferr%C3%A9%2C+M.%3B+Hruby%2C+A.%3B+Toledo%2C+E.+et+al.&rft.au=Guasch-Ferr%C3%A9%2C+M.%3B+Hruby%2C+A.%3B+Toledo%2C+E.+et+al.&rft.date=2016&rft.volume=39&rft.issue=5&rft.pages=833-46&rft_id=info:doi\/10.2337%2Fdc15-2251&rft_id=info:pmc\/PMC4839172&rft_id=info:pmid\/27208380&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC4839172&rfr_id=info:sid\/en.wikipedia.org:Journal:Bridging_the_collaboration_gap:_Real-time_identification_of_clinical_specimens_for_biomedical_research\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-SchulzUseOf16-12\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-SchulzUseOf16_12-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Schulz, W.L.; Durant, T.J. S.; Siddon, A.J. et al. (2016). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5248400\" target=\"_blank\">\"Use of Application Containers and Workflows for Genomic Data Analysis\"<\/a>. <i>Journal of Pathology Informatics<\/i> <b>7<\/b>: 53. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.4103%2F2153-3539.197197\" target=\"_blank\">10.4103\/2153-3539.197197<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC5248400\/\" target=\"_blank\">PMC5248400<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/28163975\" target=\"_blank\">28163975<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5248400\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5248400<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Use+of+Application+Containers+and+Workflows+for+Genomic+Data+Analysis&rft.jtitle=Journal+of+Pathology+Informatics&rft.aulast=Schulz%2C+W.L.%3B+Durant%2C+T.J.+S.%3B+Siddon%2C+A.J.+et+al.&rft.au=Schulz%2C+W.L.%3B+Durant%2C+T.J.+S.%3B+Siddon%2C+A.J.+et+al.&rft.date=2016&rft.volume=7&rft.pages=53&rft_id=info:doi\/10.4103%2F2153-3539.197197&rft_id=info:pmc\/PMC5248400&rft_id=info:pmid\/28163975&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC5248400&rfr_id=info:sid\/en.wikipedia.org:Journal:Bridging_the_collaboration_gap:_Real-time_identification_of_clinical_specimens_for_biomedical_research\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-EisemanHandbook99-13\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-EisemanHandbook99_13-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation book\">Eiseman, E.; Haga, S.B. (1999). <i>Handbook of Human Tissue Sources: A National Resource of Human Tissue Samples<\/i>. RAND Corporation. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/International_Standard_Book_Number\" data-key=\"f64947ba21e884434bd70e8d9e60bae6\">ISBN<\/a> 0833027662.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=book&rft.btitle=Handbook+of+Human+Tissue+Sources%3A+A+National+Resource+of+Human+Tissue+Samples&rft.aulast=Eiseman%2C+E.%3B+Haga%2C+S.B.&rft.au=Eiseman%2C+E.%3B+Haga%2C+S.B.&rft.date=1999&rft.pub=RAND+Corporation&rft.isbn=0833027662&rfr_id=info:sid\/en.wikipedia.org:Journal:Bridging_the_collaboration_gap:_Real-time_identification_of_clinical_specimens_for_biomedical_research\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-GeeFinancing13-14\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-GeeFinancing13_14-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Gee, S.; Georghiou, L.; Oliver, R. et al. (June 2013). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.escholar.manchester.ac.uk\/uk-ac-man-scw:199203\" target=\"_blank\">\"Financing UK biobanks: Rationale for a National Biobanking Research Infrastructure\"<\/a>. Manchester Business School, Faculty of Humanities<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.escholar.manchester.ac.uk\/uk-ac-man-scw:199203\" target=\"_blank\">https:\/\/www.escholar.manchester.ac.uk\/uk-ac-man-scw:199203<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Financing+UK+biobanks%3A+Rationale+for+a+National+Biobanking+Research+Infrastructure&rft.atitle=&rft.aulast=Gee%2C+S.%3B+Georghiou%2C+L.%3B+Oliver%2C+R.+et+al.&rft.au=Gee%2C+S.%3B+Georghiou%2C+L.%3B+Oliver%2C+R.+et+al.&rft.date=June+2013&rft.pub=Manchester+Business+School%2C+Faculty+of+Humanities&rft_id=https%3A%2F%2Fwww.escholar.manchester.ac.uk%2Fuk-ac-man-scw%3A199203&rfr_id=info:sid\/en.wikipedia.org:Journal:Bridging_the_collaboration_gap:_Real-time_identification_of_clinical_specimens_for_biomedical_research\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-Simeon-DubachBiobank14-15\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-Simeon-DubachBiobank14_15-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Simeon-Dubach, D.; Watson, P. (2014). \"Biobanking 3.0: Evidence Based and Customer Focused Biobanking\". <i>Clinical Biochemistry<\/i> <b>47<\/b> (4\u20135): 300-8. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.clinbiochem.2013.12.018\" target=\"_blank\">10.1016\/j.clinbiochem.2013.12.018<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/24406300\" target=\"_blank\">24406300<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Biobanking+3.0%3A+Evidence+Based+and+Customer+Focused+Biobanking&rft.jtitle=Clinical+Biochemistry&rft.aulast=Simeon-Dubach%2C+D.%3B+Watson%2C+P.&rft.au=Simeon-Dubach%2C+D.%3B+Watson%2C+P.&rft.date=2014&rft.volume=47&rft.issue=4%E2%80%935&rft.pages=300-8&rft_id=info:doi\/10.1016%2Fj.clinbiochem.2013.12.018&rft_id=info:pmid\/24406300&rfr_id=info:sid\/en.wikipedia.org:Journal:Bridging_the_collaboration_gap:_Real-time_identification_of_clinical_specimens_for_biomedical_research\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-Simeon-DubachSustain14-16\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-Simeon-DubachSustain14_16-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Simeon-Dubach, D.; Henderson, M.K. (2014). \"Sustainability in Biobanking\". <i>Biopreservation and Biobanking<\/i> <b>12<\/b> (5): 287\u201391. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1089%2Fbio.2014.1251\" target=\"_blank\">10.1089\/bio.2014.1251<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/25314050\" target=\"_blank\">25314050<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Sustainability+in+Biobanking&rft.jtitle=Biopreservation+and+Biobanking&rft.aulast=Simeon-Dubach%2C+D.%3B+Henderson%2C+M.K.&rft.au=Simeon-Dubach%2C+D.%3B+Henderson%2C+M.K.&rft.date=2014&rft.volume=12&rft.issue=5&rft.pages=287%E2%80%9391&rft_id=info:doi\/10.1089%2Fbio.2014.1251&rft_id=info:pmid\/25314050&rfr_id=info:sid\/en.wikipedia.org:Journal:Bridging_the_collaboration_gap:_Real-time_identification_of_clinical_specimens_for_biomedical_research\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-VaughtBiobank16-17\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-VaughtBiobank16_17-0\">17.0<\/a><\/sup> <sup><a href=\"#cite_ref-VaughtBiobank16_17-1\">17.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Vaught, J. (2016). \"Biobanking Comes of Age: The Transition to Biospecimen Science\". <i>Annual Review of Pharmacology and Toxicology<\/i> <b>56<\/b>: 211\u201328. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1146%2Fannurev-pharmtox-010715-103246\" target=\"_blank\">10.1146\/annurev-pharmtox-010715-103246<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/26514206\" target=\"_blank\">26514206<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Biobanking+Comes+of+Age%3A+The+Transition+to+Biospecimen+Science&rft.jtitle=Annual+Review+of+Pharmacology+and+Toxicology&rft.aulast=Vaught%2C+J.&rft.au=Vaught%2C+J.&rft.date=2016&rft.volume=56&rft.pages=211%E2%80%9328&rft_id=info:doi\/10.1146%2Fannurev-pharmtox-010715-103246&rft_id=info:pmid\/26514206&rfr_id=info:sid\/en.wikipedia.org:Journal:Bridging_the_collaboration_gap:_Real-time_identification_of_clinical_specimens_for_biomedical_research\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-BetsouHuman09-18\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-BetsouHuman09_18-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Betsou, F.; Barnes, R.; Burke, T. et al. (2009). \"Human Biospecimen Research: Experimental Protocol and Quality Control Tools\". <i>Cancer Epidemiology, Biomarkers & Prevention<\/i> <b>18<\/b> (4): 1017-25. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1158%2F1055-9965.EPI-08-1231\" target=\"_blank\">10.1158\/1055-9965.EPI-08-1231<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/19336543\" target=\"_blank\">19336543<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Human+Biospecimen+Research%3A+Experimental+Protocol+and+Quality+Control+Tools&rft.jtitle=Cancer+Epidemiology%2C+Biomarkers+%26+Prevention&rft.aulast=Betsou%2C+F.%3B+Barnes%2C+R.%3B+Burke%2C+T.+et+al.&rft.au=Betsou%2C+F.%3B+Barnes%2C+R.%3B+Burke%2C+T.+et+al.&rft.date=2009&rft.volume=18&rft.issue=4&rft.pages=1017-25&rft_id=info:doi\/10.1158%2F1055-9965.EPI-08-1231&rft_id=info:pmid\/19336543&rfr_id=info:sid\/en.wikipedia.org:Journal:Bridging_the_collaboration_gap:_Real-time_identification_of_clinical_specimens_for_biomedical_research\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-VaughtAnNCI11-19\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-VaughtAnNCI11_19-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Vaught, J.; Rogers, J.; Myers, K. et al. (2011). \"An NCI Perspective on Creating Sustainable Biospecimen Resources\". <i>Journal of the National Cancer Institute Monographs<\/i> <b>2011<\/b> (42): 1\u20137. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1093%2Fjncimonographs%2Flgr006\" target=\"_blank\">10.1093\/jncimonographs\/lgr006<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/21672889\" target=\"_blank\">21672889<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=An+NCI+Perspective+on+Creating+Sustainable+Biospecimen+Resources&rft.jtitle=Journal+of+the+National+Cancer+Institute+Monographs&rft.aulast=Vaught%2C+J.%3B+Rogers%2C+J.%3B+Myers%2C+K.+et+al.&rft.au=Vaught%2C+J.%3B+Rogers%2C+J.%3B+Myers%2C+K.+et+al.&rft.date=2011&rft.volume=2011&rft.issue=42&rft.pages=1%E2%80%937&rft_id=info:doi\/10.1093%2Fjncimonographs%2Flgr006&rft_id=info:pmid\/21672889&rfr_id=info:sid\/en.wikipedia.org:Journal:Bridging_the_collaboration_gap:_Real-time_identification_of_clinical_specimens_for_biomedical_research\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ElMessaoudiCirc13-20\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-ElMessaoudiCirc13_20-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">El Messaoudi, S.; Rolet, F.; Mouliere, F. et al. (2013). \"Circulating Cell Free DNA: Preanalytical Considerations\". <i>Clinica Chimica Acta<\/i> <b>424<\/b>: 222\u201330. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.cca.2013.05.022\" target=\"_blank\">10.1016\/j.cca.2013.05.022<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/23727028\" target=\"_blank\">23727028<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Circulating+Cell+Free+DNA%3A+Preanalytical+Considerations&rft.jtitle=Clinica+Chimica+Acta&rft.aulast=El+Messaoudi%2C+S.%3B+Rolet%2C+F.%3B+Mouliere%2C+F.+et+al.&rft.au=El+Messaoudi%2C+S.%3B+Rolet%2C+F.%3B+Mouliere%2C+F.+et+al.&rft.date=2013&rft.volume=424&rft.pages=222%E2%80%9330&rft_id=info:doi\/10.1016%2Fj.cca.2013.05.022&rft_id=info:pmid\/23727028&rfr_id=info:sid\/en.wikipedia.org:Journal:Bridging_the_collaboration_gap:_Real-time_identification_of_clinical_specimens_for_biomedical_research\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-InvestigatorsTheAll19-21\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-InvestigatorsTheAll19_21-0\">21.0<\/a><\/sup> <sup><a href=\"#cite_ref-InvestigatorsTheAll19_21-1\">21.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">All of Us Research Program Investigators; Denny, J.C.; Rutter, J.L. et al. (2019). \"The \"All of Us\" Research Program\". <i>New England Journal of Medicine<\/i> <b>381<\/b> (7): 668-676. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1056%2FNEJMsr1809937\" target=\"_blank\">10.1056\/NEJMsr1809937<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/31412182\" target=\"_blank\">31412182<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=The+%22All+of+Us%22+Research+Program&rft.jtitle=New+England+Journal+of+Medicine&rft.aulast=All+of+Us+Research+Program+Investigators%3B+Denny%2C+J.C.%3B+Rutter%2C+J.L.+et+al.&rft.au=All+of+Us+Research+Program+Investigators%3B+Denny%2C+J.C.%3B+Rutter%2C+J.L.+et+al.&rft.date=2019&rft.volume=381&rft.issue=7&rft.pages=668-676&rft_id=info:doi\/10.1056%2FNEJMsr1809937&rft_id=info:pmid\/31412182&rfr_id=info:sid\/en.wikipedia.org:Journal:Bridging_the_collaboration_gap:_Real-time_identification_of_clinical_specimens_for_biomedical_research\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-BycroftTheUK18-22\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-BycroftTheUK18_22-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Bycroft, C.; Freeman, C.; Petkova, D. et al. (2018). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6786975\" target=\"_blank\">\"The UK Biobank Resource With Deep Phenotyping and Genomic Data\"<\/a>. <i>Nature<\/i> <b>562<\/b> (7726): 203\u20139. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1038%2Fs41586-018-0579-z\" target=\"_blank\">10.1038\/s41586-018-0579-z<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6786975\/\" target=\"_blank\">PMC6786975<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/30305743\" target=\"_blank\">30305743<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6786975\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6786975<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=The+UK+Biobank+Resource+With+Deep+Phenotyping+and+Genomic+Data&rft.jtitle=Nature&rft.aulast=Bycroft%2C+C.%3B+Freeman%2C+C.%3B+Petkova%2C+D.+et+al.&rft.au=Bycroft%2C+C.%3B+Freeman%2C+C.%3B+Petkova%2C+D.+et+al.&rft.date=2018&rft.volume=562&rft.issue=7726&rft.pages=203%E2%80%939&rft_id=info:doi\/10.1038%2Fs41586-018-0579-z&rft_id=info:pmc\/PMC6786975&rft_id=info:pmid\/30305743&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC6786975&rfr_id=info:sid\/en.wikipedia.org:Journal:Bridging_the_collaboration_gap:_Real-time_identification_of_clinical_specimens_for_biomedical_research\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ChenChina11-23\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-ChenChina11_23-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Chen, Z.; Chen, J.; Collins, R. et al. (2011). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3235021\" target=\"_blank\">\"China Kadoorie Biobank of 0.5 Million People: Survey Methods, Baseline Characteristics and Long-Term Follow-Up\"<\/a>. <i>International Journal of Epidemiology<\/i> <b>40<\/b> (6): 1652-66. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1093%2Fije%2Fdyr120\" target=\"_blank\">10.1093\/ije\/dyr120<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC3235021\/\" target=\"_blank\">PMC3235021<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/22158673\" target=\"_blank\">22158673<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3235021\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3235021<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=China+Kadoorie+Biobank+of+0.5+Million+People%3A+Survey+Methods%2C+Baseline+Characteristics+and+Long-Term+Follow-Up&rft.jtitle=International+Journal+of+Epidemiology&rft.aulast=Chen%2C+Z.%3B+Chen%2C+J.%3B+Collins%2C+R.+et+al.&rft.au=Chen%2C+Z.%3B+Chen%2C+J.%3B+Collins%2C+R.+et+al.&rft.date=2011&rft.volume=40&rft.issue=6&rft.pages=1652-66&rft_id=info:doi\/10.1093%2Fije%2Fdyr120&rft_id=info:pmc\/PMC3235021&rft_id=info:pmid\/22158673&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC3235021&rfr_id=info:sid\/en.wikipedia.org:Journal:Bridging_the_collaboration_gap:_Real-time_identification_of_clinical_specimens_for_biomedical_research\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-GazianoMillion16-24\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-GazianoMillion16_24-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Gaziano, J.M.; Concato, J.; Brophy, M. et al. (2016). \"Million Veteran Program: A Mega-Biobank to Study Genetic Influences on Health and Disease\". <i>Journal of Clinical Epidemiology<\/i> <b>70<\/b>: 214\u201323. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.jclinepi.2015.09.016\" target=\"_blank\">10.1016\/j.jclinepi.2015.09.016<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/26441289\" target=\"_blank\">26441289<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Million+Veteran+Program%3A+A+Mega-Biobank+to+Study+Genetic+Influences+on+Health+and+Disease&rft.jtitle=Journal+of+Clinical+Epidemiology&rft.aulast=Gaziano%2C+J.M.%3B+Concato%2C+J.%3B+Brophy%2C+M.+et+al.&rft.au=Gaziano%2C+J.M.%3B+Concato%2C+J.%3B+Brophy%2C+M.+et+al.&rft.date=2016&rft.volume=70&rft.pages=214%E2%80%9323&rft_id=info:doi\/10.1016%2Fj.jclinepi.2015.09.016&rft_id=info:pmid\/26441289&rfr_id=info:sid\/en.wikipedia.org:Journal:Bridging_the_collaboration_gap:_Real-time_identification_of_clinical_specimens_for_biomedical_research\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-BuckleyTheFeas12-25\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-BuckleyTheFeas12_25-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Buckley, J.M.; Coopey, S.B.; Sharko, J. et al. (2012). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3424662\" target=\"_blank\">\"The Feasibility of Using Natural Language Processing to Extract Clinical Information From Breast Pathology Reports\"<\/a>. <i>Journal of Pathology Informatics<\/i> <b>3<\/b>: 23. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.4103%2F2153-3539.97788\" target=\"_blank\">10.4103\/2153-3539.97788<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC3424662\/\" target=\"_blank\">PMC3424662<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/22934236\" target=\"_blank\">22934236<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3424662\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3424662<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=The+Feasibility+of+Using+Natural+Language+Processing+to+Extract+Clinical+Information+From+Breast+Pathology+Reports&rft.jtitle=Journal+of+Pathology+Informatics&rft.aulast=Buckley%2C+J.M.%3B+Coopey%2C+S.B.%3B+Sharko%2C+J.+et+al.&rft.au=Buckley%2C+J.M.%3B+Coopey%2C+S.B.%3B+Sharko%2C+J.+et+al.&rft.date=2012&rft.volume=3&rft.pages=23&rft_id=info:doi\/10.4103%2F2153-3539.97788&rft_id=info:pmc\/PMC3424662&rft_id=info:pmid\/22934236&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC3424662&rfr_id=info:sid\/en.wikipedia.org:Journal:Bridging_the_collaboration_gap:_Real-time_identification_of_clinical_specimens_for_biomedical_research\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<\/ol><\/div>\n<h2><span class=\"mw-headline\" id=\"Notes\">Notes<\/span><\/h2>\n<p>This presentation is faithful to the original, with only a few minor changes to presentation. Grammar was cleaned up for smoother reading. In some cases important information was missing from the references, and that information was added. As the time of loading this article, the link to Additional file 1 was broken on the original site. Unfortunately, it can not be included here.\n<\/p>\n<!-- \nNewPP limit report\nCached time: 20200707205057\nCache expiry: 86400\nDynamic content: false\nCPU time usage: 0.707 seconds\nReal time usage: 3.433 seconds\nPreprocessor visited node count: 21499\/1000000\nPreprocessor generated node count: 36399\/1000000\nPost\u2010expand include size: 188752\/2097152 bytes\nTemplate argument size: 60165\/2097152 bytes\nHighest expansion depth: 18\/40\nExpensive parser function count: 0\/100\n-->\n\n<!-- \nTransclusion expansion time report (%,ms,calls,template)\n100.00% 458.412 1 - -total\n 86.46% 396.324 1 - Template:Reflist\n 73.07% 334.972 25 - Template:Citation\/core\n 71.12% 326.012 23 - Template:Cite_journal\n 11.59% 53.133 58 - Template:Citation\/identifier\n 8.29% 37.989 1 - Template:Infobox_journal_article\n 7.94% 36.414 1 - Template:Infobox\n 5.32% 24.380 80 - Template:Infobox\/row\n 4.41% 20.231 25 - Template:Citation\/make_link\n 4.23% 19.405 127 - Template:Hide_in_print\n-->\n\n<!-- Saved in parser cache with key limswiki:pcache:idhash:11982-0!*!0!!en!5!* and timestamp 20200707205053 and revision id 39599\n -->\n<\/div><div class=\"printfooter\">Source: <a rel=\"external_link\" class=\"external\" href=\"https:\/\/www.limswiki.org\/index.php\/Journal:Bridging_the_collaboration_gap:_Real-time_identification_of_clinical_specimens_for_biomedical_research\">https:\/\/www.limswiki.org\/index.php\/Journal:Bridging_the_collaboration_gap:_Real-time_identification_of_clinical_specimens_for_biomedical_research<\/a><\/div>\n\t\t\t\t\t\t\t\t\t\t<!-- end content -->\n\t\t\t\t\t\t\t\t\t\t<div class=\"visualClear\"><\/div>\n\t\t\t\t<\/div>\n\t\t\t<\/div>\n\t\t<\/div>\n\t\t<!-- end of the left (by default at least) column -->\n\t\t<div class=\"visualClear\"><\/div>\n\t\t\t\t\t\n\t\t<\/div>\n\t\t\n\n<\/body>","35e1a79a2c5ed34c82e174e1cfc01af1_images":["https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/0\/0e\/Fig1_Durant_JofPathInfo2020_11.jpg","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/a\/a9\/Fig2_Durant_JofPathInfo2020_11.jpg","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/3\/39\/Fig3_Durant_JofPathInfo2020_11.jpg","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/3\/3a\/Fig4_Durant_JofPathInfo2020_11.jpg","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/3\/35\/Fig5_Durant_JofPathInfo2020_11.jpg"],"35e1a79a2c5ed34c82e174e1cfc01af1_timestamp":1594155053,"3d21e2245fe30f0192b9b2b65131c7c2_type":"article","3d21e2245fe30f0192b9b2b65131c7c2_title":"Institutional ELN-LIMS deployment: Highly customizable ELN-LIMS platform as a cornerstone of digital transformation for life sciences research institutes (Argento 2020)","3d21e2245fe30f0192b9b2b65131c7c2_url":"https:\/\/www.limswiki.org\/index.php\/Journal:Institutional_ELN-LIMS_deployment:_Highly_customizable_ELN-LIMS_platform_as_a_cornerstone_of_digital_transformation_for_life_sciences_research_institutes","3d21e2245fe30f0192b9b2b65131c7c2_plaintext":"\n\n\t\t\n\t\t\t\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t\n\n\t\t\t\tJournal:Institutional ELN-LIMS deployment: Highly customizable ELN-LIMS platform as a cornerstone of digital transformation for life sciences research institutes\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t\tFrom LIMSWiki\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\tJump to: navigation, search\n\n\t\t\t\t\t\n\t\t\t\t\tFull article title\n \nInstitutional ELN-LIMS deployment: Highly customizable ELN-LIMS platform as a\r\ncornerstone of digital transformation for life sciences research institutesJournal\n \nEMBO ReportsAuthor(s)\n \nArgento, NicolasAuthor affiliation(s)\n \n\u00c9cole Polytechnique F\u00e9d\u00e9rale de LausanneYear published\n \n2020Volume and issue\n \n21(3)Article #\n \ne49862DOI\n \n10.15252\/embr.201949862ISSN\n \n1469-3178Distribution license\n \nCreative Commons Attribution 4.0 InternationalWebsite\n \nhttps:\/\/www.embopress.org\/doi\/full\/10.15252\/embr.201949862Download\n \nhttps:\/\/www.embopress.org\/doi\/epdf\/10.15252\/embr.201949862\n\nContents\n\n1 Abstract \n2 Introduction \n3 The project \n\n3.1 Initiating the project \n3.2 Identification of a suitable ELN-LIMS platform \n3.3 Pilot and full deployment \n\n3.3.1 The stakeholders and their roles in the deployment \n\n\n3.4 Configuration and go-live \n\n\n4 The laboratory data manager \n5 Conclusions \n6 Acknowledgements \n\n6.1 Funding \n\n\n7 References \n8 Notes \n\n\n\nAbstract \nThe systematic recording and management of experimental data in academic life science research remains an open problem. \u00c9cole Polytechnique F\u00e9d\u00e9rale de Lausanne (EPFL) engaged in a program of deploying both an electronic laboratory notebook (ELN) and a laboratory information management system (LIMS) six years ago, encountering a host of fundamental questions at the institutional level and within each laboratory. Here, based on our experience, we aim to share with research institute managers, principal investigators (PIs), and any scientists involved in a combined ELN-LIMS deployment helpful tips and tools, with a focus on surrounding yourself with the right people and the right software at the right time. In this article we describe the resources used, the challenges encountered, key success factors, and the results obtained at each phase of our project. Finally, we discuss the current and next challenges we face, as well as how our experience leads us to support the creation of a new position in the research group: the laboratory data manager.\nKeywords: electronic laboratory notebook, laboratory information management system, life sciences, research, laboratory data management\n\nIntroduction \nResearch tools in the life sciences are continuously evolving and improving, and scientists have always been eager to use the latest equipment. Ironically though, their main method of recording and managing experimental data has remained largely the same for centuries, with the paper-based laboratory notebook still the main method of record\u2010keeping. (Fig. 1) The adoption of electronic laboratory notebooks (ELNs) in academic laboratories has been slow, if laboratories have actually shown any interest at all. Their implementation necessitates institutional support[1], and despite much discussion of ELNs in the literature[2][3], success stories and recipes for their deployment remain scarce.[4][5][6] Moreover, although ELNs can improve efficiency in data capturing and reuse, they lack the features to rigorously document data critical for experimental reproducibility, such as sample traceability data and standard operating procedures (SOP). These features are, however, part of another tool for data management called the laboratory information management system (LIMS). (See Table 1 for a comparison of the two.)\n\r\n\n\n\n\n\n\n\n\n\n\n Figure 1. Challenges of traditional record\u2010keeping in modern science. (A) Comparison of research instruments and laboratory records from the 1700s and 2000s. While the development of research instruments has driven progress, laboratory record\u2010keeping is almost unchanged. (B) Data are distributed across multiple locations and media, including notebooks, printed material, physical samples, disks, hard drives, servers and cloud storage. (C) Locating specific data is difficult as the location may be unknown, and the media may be difficult to search.\n\n\n\n\n\n\n\n\n\nTable 1. ELN and LIMS main benefits in research institutions\n\n\nELN benefits\n\nLIMS benefits\n\n\n\n Provides research work traceability\r\n\n Enhances knowledge transmission\r\n\n Protects intellectual property and patents\n\n\n Supports sample management (plasmids, virus, antibodies, chemicals databases)\r\n\n Provides stock management\r\n\n Improves workflows, typically with templates\r\n\n Improves management of SOPs\r\n\n Tracks laboratory equipment usage and inventory\r\n\n Offers equipment integration for direct data acquisition\n\n\n\nIn order to encourage adoption of ELNs at the institutional level, \u00c9cole Polytechnique F\u00e9d\u00e9rale de Lausanne (EPFL) started a dedicated program for ELN-LIMS deployment six years ago that involved research institute managers, principal investigators (PIs), and scientists at all levels. Here, we share the challenges, key success factors, and the results obtained at each phase of our project. Afterwards, we discuss the current and upcoming challenges and how our experience led us to support the creation of a new position in research groups: the laboratory data manager.\n\nThe project \nOur efforts towards ELN-LIMS deployment began in March 2012 and has run through five distinct phases, as shown in Fig. 2.\n\r\n\n\n\n\n\n\n\n\n\n\n Figure 2. Institutional ELN-LIMS project macro\u2010planning. Project phases are indicated in blue underneath a timeline from March 2012, and associated human resources in FTE (full\u2010time equivalent) for each period are indicated in green (see text for details).\n\n\n\nIn the following sections, we present the step\u2010by\u2010step approach to deploy the platform in a laboratory. From our experience, each step contributed to successful and sustained ELN-LIMS adoption and use.\n\nInitiating the project \nBy definition, an institutional ELN and LIMS project involves management, PIs, scientists at all levels, and the institute's IT department. As such, the steering committee for our project therefore included the Vice President of Research, who is responsible for scientific information, and the Vice President of Information Systems, who is responsible for IT governance and IT core services on campus. Representing the main users, the Life Sciences Faculty's Dean chaired the committee. This executive body defined the overall goals: to rationalize laboratories\u2019 efforts, reduce waste of time and money, reduce loss and enable reuse of data, improve the reproducibility of experiments, and facilitate data sharing for collaborative projects.\nThe steering committee hired a project manager to coordinate the interests and requirements of the multiple stakeholders from distant fields, which made this project as complex as it was fascinating. To ensure the introduction of an ELN-LIMS service was suitable for those affected, we involved a panel of scientists. The project manager also played the role of a \u201cbusiness analyst\u201d by meeting and surveying 25 laboratories whose needs and demands were synthesized in a weighted wish list that, along with legal requirements, helped to choose the ELN-LIMS solution. For instance, our institutional rules and laws about privacy and the use of human data prevented us from using a cloud\u2010based solution.\n\nIdentification of a suitable ELN-LIMS platform \nThe initiation phase revealed that the project required more than just picking a commercial off\u2010the\u2010shelf (COTS) ELN. Our key users were active in bioengineering, immunology, neurology, and oncology, with correspondingly diverse approaches and demands, though developers of technology platforms also showed a strong interest (Fig. 3). Those stakeholders' routine workflows required additional functionality and administrative support. An analysis of those needs highlighted difficulties in managing data related to laboratory SOPs and samples, which are crucial for data reusability and experimental reproducibility in biomedical research.[7] Samples and experiments with human data require more sophisticated privacy management, a requirement that is increasing with the rise of personalized medicine. Feedback from laboratory staff also indicated that integration with third\u2010party information systems would be of added value for everyday work. For example, importing data from an animal facility was relevant to the experimental laboratories, while integration with work request forms and integration with the billing system were key features for technology platforms. The issue of authentication was also raised by laboratories and IT staff, for ease of use for the first group and security for the second group. \n\r\n\n\n\n\n\n\n\n\n\n\n Figure 3. Laboratory participation by institute. Number of laboratories participating in the ELN\/LIMS project at EPFL from each Institute in the School of Life Sciences listed since the project's inception in 2019. Others refers to laboratories at EPFL, but outside life sciences. Note the largest increase in laboratory participation in 2018 (see text for details).\n\n\n\nInvolving the IT department from the beginning prevented us from taking obvious wrong directions in terms of technical choice. A striking example of their input was highlighting the heterogeneity of the scientists\u2019 personal computers in the research institute, which made the choice of a web\u2010based solution almost mandatory, rather than installing software on each computer. However, the most interesting technical question was how to manage the diversity of needs. And the most important question for scientists was how to preserve creativity and freedom of research without introducing new technological burdens and hassles.\nIt was important that individual laboratories using our services remain architects of their own information system so as to preserve and maintain freedom and creativity. An ELN typically has highly standardized features, but new software technologies allow the creation of highly customizable databases and graphical user interfaces. The software we chose uses visual, declarative techniques instead of programming to enable fast, iterative, collaborative, and tailored implementation. Applications can be rapidly modified and maintained centrally.\nMastering such a powerful toolbox required the appointment of skilled people and best practices of implementation. This investment was counterbalanced by the possibility of the inclusion of a wide range of data, development of home-made features (e.g., financial management, work request forms), and integration with other information systems. It also opened the possibility for compliance with ISO 9001 or 21 CFR Part 11 standards that are required by some technology platforms. Those standards' quality assurance and data privacy concerns affect many industries and can also help to foster reproducibility in the life sciences.[8][9]\n\nPilot and full deployment \nTo accurately assess the personnel and skills needed to install and configure the platform, and then train the staff, a dedicated budget to run a pilot phase was required. This budget covered a six\u2010month license fee for the ELN-LIMS platform and a system administrator along with training and support. Through this pilot, five volunteer laboratories began to configure and use the ELN-LIMS platform. At the end, all stakeholders validated the choice of the solution over the short and long term, and the steering committee approved deployment at a larger scale. \nThe same staff then organized the full deployment. A dedicated ELN-LIMS platform engineer was hired to help laboratories to get the most from the customizable platform (Fig 2). Such an ELN-LIMS expert needed to have strong IT competencies, project management skills, and good general knowledge in research to efficiently communicate with the scientific staff. More specifically, the engineer developed and optimized the work methodology to ensure sustainable growth from a technical and scientific point of view. The announcement of the Swiss National Science Foundation (SNSF) to make a data management plan mandatory for all grant applications from October 2017[10] created a peak of demand for our services in 2018, when 10 laboratories voluntarily started ELN-LIMS deployment (Fig. 3). Nonetheless, laboratories were not forced to use the ELN-LIMS, and it still remains a PI's decision to use the platform. Fig. 4 shows examples of the current typical usage of the ELN-LIMS platform.\n\r\n\n\n\n\n\n\n\n\n\n\n Figure 4. Typical usage of the ELN \/LIMS platform. (A) ELN with scientist's notes, samples linked to the laboratory inventories, files, and procedures showing how we solved the initial issue illustrated in Fig 1C. (B) Laboratory sample inventories viewed with associated physical storage locations and links to ELN entries. (C) Example of a biopsy biobank and list of all derived crypts, organoids, and cryovial samples from one single biopsy.\n\n\n\nEach ELN-LIMS platform deployment is managed as a separate sub\u2010project, since the information systems are tailor\u2010made for each laboratory. The deployment phase starts with informal discussions between the ELN-LIMS application expert and the laboratory's management to demonstrate the offered services. This introduction aims to confirm that the tool could support the laboratory's objectives. If so, the list of objectives is formalized and validated by the project sponsor, the PI in this case. Objectives are prioritized (Box 1) and have an appointed reference person. Roles and responsibilities must be clarified.\n\n\n\n\n\n\n\nBox 1. Example of research laboratory requirements, sorted by decreasing priority\n\n\n\n Configure and adopt ELN\/LIMS for all laboratory members\r\n\n Create a standard operating procedure (SOP) and simple operating procedure library accessible for everyone\r\n\n Centralize antibody database\r\n\n Centralize plasmid database\r\n\n Centralize chemical database\r\n\n Manage the laboratory storage location (freezer, cabinet, etc.)\r\n\n Define uniform identification of locations and sample thanks to label printers\n\n\n\nThe stakeholders and their roles in the deployment \nThe PI is the sponsor, who initiates the project and assumes overall responsibility. He or she usually delegates the work to appropriate staff members. Along the deployment, the PI can be asked to make decisions on proposals.\nLaboratory referents take the lead and responsibility to fulfill the aims delegated by the PI. Initially, this task was given to newly arrived PhD students, but we soon realized that a thorough knowledge of the laboratory operation is required for efficient implementation. This role should therefore be given to experienced scientists or technicians; the latter often have associated laboratory planning tasks and are less likely to leave than scientific staff. Those considerations make them more prone to act as a catalyst in adopting the ELN-LIMS platform. This view is supported by raw record creation quantity as a function of staff position (Fig. 5).\n\r\n\n\n\n\n\n\n\n\n\n\n Figure 5. Record creation by institutional role. This pie chart describes the proportion of records (file, sample, or experiment) created as a function of the institutional role of the person creating the record at EPFL. Note that records where the institutional role was not available are not shown, amounting to < 0.4% of the total. The records created by PIs are not visible at this scale (see text for details).\n\n\n\nThe ELN-LIMS application expert is responsible for configuring the system according to the laboratory referents\u2019 requests and to advise about best practices; they translate the identified needs into configuration and code. A strong know\u2010how in ELN-LIMS customization, best practices, and general knowledge about the scientific field are tremendously important. By working in several laboratories, our ELN-LIMS expert team developed strong skills in laboratory data management and project management that the typical laboratory does not have. Consequently, they currently work as a deployment project manager, whereas ideally, their role should be restricted to supporting the workflows of the adopting laboratory, not imposing (well\u2010intentioned) ideas from the outside.\nELN-LIMS end users are the laboratory staff and PIs, and their active participation in the deployment and their remarks and comments are crucial for setting up a tool that fits their needs and habits. While sample and SOP management are usually easily adopted, the use of the ELN is trickier as it offers a large range of possibilities to organize projects and experiments, compared to paper notebooks. This can make adaptation frustrating and can take weeks; indeed, some laboratories decided not to use the ELN or only a part of the staff adopted it. We have also seen a few laboratories abandon the ELN. Close support during the first week of usage and regular communication are necessary to reduce the impact of initial difficulty of use. Here, the normal turnover of scientific staff in research laboratories can be used as an opportunity. It is problematic to ask a post\u2010doctoral researcher or a PhD student to change their data management tools and habits in the middle of their project, whereas new recruits can start fresh with the ELN-LIMS system.\n\nConfiguration and go-live \nIn this phase, the ELN-LIMS expert needs to work as closely as possible with researchers to translate laboratory context, culture, and workflow into the configuration. According to our experience, the conception must be an incremental process. This process is common practice in the software industry's \u201cagile\u201d methodology, one based on continuous small deliveries and short daily meetings.[11] While preparing for deployment of the system (or additional components), we organize regular meetings to discuss the ELN-LIMS platform configuration and design and, depending on the test performed by the referent, further adapt the configuration for the next meeting (Fig. 6). The cycle is repeated until the result is sufficiently convincing to validate the deployment of this feature and corresponding training.\n\r\n\n\n\n\n\n\n\n\n\n\n Figure 6. Agile cycle adapted to ELN-LIMS deployment in a life sciences research laboratory. Flow chart of process and decisions in ELN-LIMS deployment used at EPFL. Note the agile cycle shown in purple for rapid adaptation of the platform to the needs of each laboratory.\n\n\n\nFor almost five years, we have been serving the original laboratories involved with the project as well as new volunteer laboratories. The raw record creation (files and samples) in the platform accelerated in mid\u20102014 when technology platforms joined the system (Fig. 7). The number of created experiments in the ELN (green) has grown more rapidly since 2016, reflecting improvement in training, communication between stakeholders, and continuous upgrades.\n\r\n\n\n\n\n\n\n\n\n\n\n Figure 7. Evolution of raw record creation in research laboratories. Increase in the number of file, sample, and experiment records is plotted, normalized to the total number for each class at the time of writing, over the period of the ELN-LIMS project at EPFL. Note the inflection points in file and sample creation in mid\u20102014, and in experiments at the beginning of 2016 (see text for details).\n\n\n\nAlthough the service is hosted at the School of Life Sciences IT department, the platform has been requested and used by biologists from other faculties on the campus (Fig 3). As of early 2020, three full\u2010time ELN-LIMS application expert staff serve 52 laboratories. This team is composed of people with heterogenous competencies from bioengineering and chemistry to computer sciences and IT management. In addition, a full-time system administrator operates the servers and data storage, while a part-time assistant ensures the service management. The whole service requires four full-time employees and one part-time employee (Fig 2) to guarantee the system's sustainability and evolution. They ensure day\u2010to\u2010day assistance with user deployments and training sessions while coordinating and performing the regular maintenance of the infrastructure. A frequently overlooked, yet important and time\u2010consuming task they manage is to ensure platform upgrades, which has a key impact on user experiences and data integrity.\nOne of our ELN-LIMS configurations is used by an \u201cindustrial\u201d technology platform that sterilizes glass, decontaminates waste, and prepares standard solutions. They are ISO 9001-certified, and their data management is audited every year. As we operate the major part of their information systems, we are audited too, and thus we have also put a quality system in place for maintenance and data backup. Generally, technology platforms are natural customers of such services. They run more standardized experiments with higher requirements for traceability. (Figure 5 reminds us that they are the main record producer in the ELN-LIMS platform.)\n\nThe laboratory data manager \nWe experienced that ELN-LIMS application experts were regularly asked by laboratory referents to organize their data management. However, data management should be driven by science and not vice versa, which is one of the reasons we propose a \u201claboratory data manager\u201d for managing sensitive or crucial data. \nObviously, the particular skills required for a data manager in cutting\u2010edge research is a challenge. As a trial, we placed a properly skilled data manager into one of our research groups for a couple of months. As shown in Fig. 8, it had an immediate impact on the amount of data collected in the ELN and enabled the laboratory to review their data management practices. We do not have information about the quality of the data produced, but we expect improvement at this level, and we anticipate that the publishing process could also be accelerated, owing to better reusability of data inside the laboratory. \nIn all, a laboratory data manager would apply general institutional or research\u2010specific policies and good practices, and convert general infrastructure into daily practical solutions that fit the localized needs of the laboratory. Being integrated with the laboratory is necessary to legitimize changing practices while maintaining the flexibility and freedom required by science. Note that a data manager would not necessarily be a full\u2010time job, depending on the laboratory's activity.\n\r\n\n\n\n\n\n\n\n\n\n\n Figure 8. Increased experiment record creation with the introduction of a laboratory data manager. The number of experiment records created in the ELN per month in 2018\u20132019 from a single laboratory at EPFL, displayed as a bar graph on a timeline, and annotated with the introduction and departure of a trained data manager in the laboratory.\n\n\n\nConclusions \nIn summary, we believe our institutional project showed that the ELN-LIMS platform helps to capture and record data, and helps to make the data to become findable, accessible, interoperable, and reusable (FAIR). The reusability criterion implies quality improvements that are more dependent on data management practice than on the available electronic tools.\nSeveral challenges for the success of data management yet remain. One challenge is the slow adoption of the ELN by research staff, partly because the ELN is still a work in progress, partly because old working habits are slow to change. Furthermore, managing huge files\u2014e.g., genomic data or microscopy images\u2014remains a major challenge, as is archiving the data collected by the ELN-LIMS systems. Finally, integration with other elements of the institutional information system is technically possible, but requires governance of business applications, interface development, and resources for maintenance. Amidst all of these challenges, we strongly believe funding the position of data managers remains a priority. In the end, it is the daily practice of the scientists that will drive and sustain the digital transformation of the life sciences.\n\nAcknowledgements \nI acknowledge Ga\u00ebl Anex and all the School of Life Sciences and EPFL directors for creating this favorable environment, improving laboratory data management; Pr. Andy Oates and Pierig Le Pottier for their strong support and help in writing the article; my colleagues from the IT department, in particular Paul Schalbetter, for the scripting of the figures, as well as Philippe Borel, Peter Hliva, and Christopher Tremblay who ensure the continuity of ELN-LIMS deployments; and finally all the scientific staff who actively fostered and participated in the ELN and LIMS deployments in their laboratory.\n\nFunding \nThe EPFL, School of Life Sciences provided funding for this research.\n\nReferences \n\n\n\u2191 Ash, J.S.; Anderson, N.R.; Tarczy-Hornoch, P. (2008). \"People and Organizational Issues in Research Systems Implementation\". JAMIA 15 (3): 283\u20139. doi:10.1197\/jamia.M2582. PMC PMC2410012. PMID 18308986. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2410012 .   \n\n\u2191 Kwok, R. (2028). \"How to Pick an Electronic Laboratory Notebook\". Nature 560 (7717): 269-270. doi:10.1038\/d41586-018-05895-3. PMID 30082695.   \n\n\u2191 Menzel, J.; Weil, P.; Bittihn, P. et al. (2013). \"Requirement analysis for an electronic laboratory notebook for sustainable data management in biomedical research\". Studies in Health Technologies and Informatics 192: 1108. doi:10.3233\/978-1-61499-289-9-1108. PMID 23920882.   \n\n\u2191 Guerrero, S.; Dujardin, G.; Cabrera-Andrade, A. et al. (2016). \"Analysis and Implementation of an Electronic Laboratory Notebook in a Biomedical Research Institute\". PLoS One 11 (8): e0160428. doi:10.1371\/journal.pone.0160428. PMC PMC4968837. PMID 27479083. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4968837 .   \n\n\u2191 Dirnagl, U.; Przesdzing, I. (2016). \"A pocket guide to electronic laboratory notebooks in the academic life sciences\". F1000Research 5: 2. doi:10.12688\/f1000research.7628.1. PMC PMC4722687. PMID 26835004. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4722687 .   \n\n\u2191 Riley, E.M.; Hattaway, H.Z.; Felse, P.A. (2017). \"Implementation and use of cloud-based electronic lab notebook in a bioprocess engineering teaching laboratory\". Journal of Biological Engineering 11: 40. doi:10.1186\/s13036-017-0083-2. PMC PMC5701295. PMID 29201138. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5701295 .   \n\n\u2191 Freedman, L.P.; Cockburn, I.M.; Simcoe, T.S. (2015). \"The Economics of Reproducibility in Preclinical Research\". PLoS Biology 13 (6): e1002165. doi:10.1371\/journal.pbio.1002165. PMC PMC4461318. PMID 26057340. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4461318 .   \n\n\u2191 Dirngal, U.; Kurreck, C.; Casta\u00f1os-V\u00e9lez, E. et al. (2018). \"Quality Management for Academic Laboratories: Burden or Boon? Professional Quality Management Could Be Very Beneficial for Academic Research but Needs to Overcome Specific Caveats\". EMBO Reports 19 (11): e47143. doi:10.15252\/embr.201847143. PMC PMC6216282. PMID 30341068. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6216282 .   \n\n\u2191 Riedl, D.H.; Dunn, M.K. (2013). \"Quality Assurance Mechanisms for the Unregulated Research Environment\". Trends in Biotechnology 31 (10): 552-4. doi:10.1016\/j.tibtech.2013.06.007. PMID 24054820.   \n\n\u2191 Swiss National Science Foundation (06 March 2017). \"Open Research Data: Data management plans will be introduced in project funding\". http:\/\/www.snf.ch\/en\/researchinFocus\/newsroom\/Pages\/news-170306-towards-open-research-data.aspx .   \n\n\u2191 Conforto, E.C.; Salum, F.; Amaral, D.C. et al. (2014). \"Can Agile Project Management Be Adopted by Industries Other than Software Development?\". Project Management Journal 45 (3): 21\u201334. doi:10.1002\/pmj.21410.   \n\n\nNotes \nThis presentation is faithful to the original, with only a few minor changes to presentation. Grammar was cleaned up for smoother reading. In some cases important information was missing from the references, and that information was added. The inline link to the SNSF article was turned into a formal citation for this version. Additional section headers were made to make the material flow better.\n\n\n\n\n\n\nSource: <a rel=\"external_link\" class=\"external\" href=\"https:\/\/www.limswiki.org\/index.php\/Journal:Institutional_ELN-LIMS_deployment:_Highly_customizable_ELN-LIMS_platform_as_a_cornerstone_of_digital_transformation_for_life_sciences_research_institutes\">https:\/\/www.limswiki.org\/index.php\/Journal:Institutional_ELN-LIMS_deployment:_Highly_customizable_ELN-LIMS_platform_as_a_cornerstone_of_digital_transformation_for_life_sciences_research_institutes<\/a>\n\t\t\t\t\tCategories: LIMSwiki journal articles (added in 2020)LIMSwiki journal articles (all)LIMSwiki journal articles on laboratory informaticsLIMSwiki journal articles on information technology\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\n\t\t\t\t\n\t\t\t\n\t\t\n\t\t\n\t\t\tNavigation menu\n\t\t\t\t\t\n\t\t\tViews\n\n\t\t\t\n\t\t\t\t\n\t\t\t\tJournal\n\t\t\t\tDiscussion\n\t\t\t\tView source\n\t\t\t\tHistory\n\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\n\t\t\t\t\n\t\t\t\tPersonal tools\n\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\t\t\tLog in\n\t\t\t\t\t\t\t\t\t\t\t\t\tRequest account\n\t\t\t\t\t\t\t\t\t\t\t\n\t\t\t\t\n\t\t\t\n\t\t\t\n\t\t\t\t\n\t\t\t\n\t\t\t\t\n\t\tNavigation\n\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\tMain page\n\t\t\t\t\t\t\t\t\t\t\tRecent changes\n\t\t\t\t\t\t\t\t\t\t\tRandom page\n\t\t\t\t\t\t\t\t\t\t\tHelp\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\n\t\t\t\n\t\t\tSearch\n\n\t\t\t\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t \n\t\t\t\t\t\t\n\t\t\t\t\n\n\t\t\t\t\t\t\t\n\t\t\n\t\t\t\n\t\t\tTools\n\n\t\t\t\n\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\tWhat links here\n\t\t\t\t\t\t\t\t\t\t\tRelated changes\n\t\t\t\t\t\t\t\t\t\t\tSpecial pages\n\t\t\t\t\t\t\t\t\t\t\tPermanent link\n\t\t\t\t\t\t\t\t\t\t\tPage information\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\n\t\t\n\t\tPrint\/export\n\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\tCreate a book\n\t\t\t\t\t\t\t\t\t\t\tDownload as PDF\n\t\t\t\t\t\t\t\t\t\t\tDownload as Plain text\n\t\t\t\t\t\t\t\t\t\t\tPrintable version\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\n\t\t\n\t\tSponsors\n\t\t\n\t\t\t \r\n\n\t\r\n\n\t\r\n\n\t\n\t\r\n\n\t\r\n\n\t\n\t\r\n\n \n\t\r\n\n\t\n\t\r\n\n \n\t\n\t\r\n\n\t\n\t\n\t\r\n\n\t\r\n\n\t\r\n\n\t\n\t\r\n\n\t\r\n\t\t\n\t\t\n\t\t\t\n\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t This page was last modified on 26 May 2020, at 23:16.\n\t\t\t\t\t\t\t\t\tThis page has been accessed 354 times.\n\t\t\t\t\t\t\t\t\tContent is available under a Creative Commons Attribution-ShareAlike 4.0 International License unless otherwise noted.\n\t\t\t\t\t\t\t\t\tPrivacy policy\n\t\t\t\t\t\t\t\t\tAbout LIMSWiki\n\t\t\t\t\t\t\t\t\tDisclaimers\n\t\t\t\t\t\t\t\n\t\t\n\t\t\n\t\t\n\n","3d21e2245fe30f0192b9b2b65131c7c2_html":"<body class=\"mediawiki ltr sitedir-ltr ns-206 ns-subject page-Journal_Institutional_ELN-LIMS_deployment_Highly_customizable_ELN-LIMS_platform_as_a_cornerstone_of_digital_transformation_for_life_sciences_research_institutes skin-monobook action-view\">\n<div id=\"rdp-ebb-globalWrapper\">\n\t\t<div id=\"rdp-ebb-column-content\">\n\t\t\t<div id=\"rdp-ebb-content\" class=\"mw-body\" role=\"main\">\n\t\t\t\t<a id=\"rdp-ebb-top\"><\/a>\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t<h1 id=\"rdp-ebb-firstHeading\" class=\"firstHeading\" lang=\"en\">Journal:Institutional ELN-LIMS deployment: Highly customizable ELN-LIMS platform as a cornerstone of digital transformation for life sciences research institutes<\/h1>\n\t\t\t\t\n\t\t\t\t<div id=\"rdp-ebb-bodyContent\" class=\"mw-body-content\">\n\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\n\n\t\t\t\t\t<!-- start content -->\n\t\t\t\t\t<div id=\"rdp-ebb-mw-content-text\" lang=\"en\" dir=\"ltr\" class=\"mw-content-ltr\">\n\n\n<h2><span class=\"mw-headline\" id=\"Abstract\">Abstract<\/span><\/h2>\n<p>The systematic recording and management of experimental data in academic life science research remains an open problem. \u00c9cole Polytechnique F\u00e9d\u00e9rale de Lausanne (EPFL) engaged in a program of deploying both an <a href=\"https:\/\/www.limswiki.org\/index.php\/Electronic_laboratory_notebook\" title=\"Electronic laboratory notebook\" class=\"wiki-link\" data-key=\"a9fbbd5e0807980106763fab31f1e72f\">electronic laboratory notebook<\/a> (ELN) and a <a href=\"https:\/\/www.limswiki.org\/index.php\/Laboratory_information_management_system\" title=\"Laboratory information management system\" class=\"wiki-link\" data-key=\"8ff56a51d34c9b1806fcebdcde634d00\">laboratory information management system<\/a> (LIMS) six years ago, encountering a host of fundamental questions at the institutional level and within each <a href=\"https:\/\/www.limswiki.org\/index.php\/Laboratory\" title=\"Laboratory\" class=\"wiki-link\" data-key=\"c57fc5aac9e4abf31dccae81df664c33\">laboratory<\/a>. Here, based on our experience, we aim to share with research institute managers, principal investigators (PIs), and any scientists involved in a combined ELN-LIMS deployment helpful tips and tools, with a focus on surrounding yourself with the right people and the right software at the right time. In this article we describe the resources used, the challenges encountered, key success factors, and the results obtained at each phase of our project. Finally, we discuss the current and next challenges we face, as well as how our experience leads us to support the creation of a new position in the research group: the laboratory data manager.\n<\/p><p><b>Keywords<\/b>: electronic laboratory notebook, laboratory information management system, life sciences, research, laboratory data management\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Introduction\">Introduction<\/span><\/h2>\n<p>Research tools in the life sciences are continuously evolving and improving, and scientists have always been eager to use the latest equipment. Ironically though, their main method of recording and managing experimental data has remained largely the same for centuries, with the paper-based <a href=\"https:\/\/www.limswiki.org\/index.php\/Laboratory_notebook\" title=\"Laboratory notebook\" class=\"wiki-link\" data-key=\"be60c7be96aba8e9a84537fd8835fa54\">laboratory notebook<\/a> still the main method of record\u2010keeping. (Fig. 1) The adoption of <a href=\"https:\/\/www.limswiki.org\/index.php\/Electronic_laboratory_notebook\" title=\"Electronic laboratory notebook\" class=\"wiki-link\" data-key=\"a9fbbd5e0807980106763fab31f1e72f\">electronic laboratory notebooks<\/a> (ELNs) in academic laboratories has been slow, if laboratories have actually shown any interest at all. Their implementation necessitates institutional support<sup id=\"rdp-ebb-cite_ref-AshPeople08_1-0\" class=\"reference\"><a href=\"#cite_note-AshPeople08-1\">[1]<\/a><\/sup>, and despite much discussion of ELNs in the literature<sup id=\"rdp-ebb-cite_ref-KwokHow18_2-0\" class=\"reference\"><a href=\"#cite_note-KwokHow18-2\">[2]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ManzelRequire13_3-0\" class=\"reference\"><a href=\"#cite_note-ManzelRequire13-3\">[3]<\/a><\/sup>, success stories and recipes for their deployment remain scarce.<sup id=\"rdp-ebb-cite_ref-GuerreroAnalysis16_4-0\" class=\"reference\"><a href=\"#cite_note-GuerreroAnalysis16-4\">[4]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-DirnaglAPocket16_5-0\" class=\"reference\"><a href=\"#cite_note-DirnaglAPocket16-5\">[5]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-RileyImplement17_6-0\" class=\"reference\"><a href=\"#cite_note-RileyImplement17-6\">[6]<\/a><\/sup> Moreover, although ELNs can improve efficiency in data capturing and reuse, they lack the features to rigorously document data critical for experimental reproducibility, such as sample traceability data and standard operating procedures (SOP). These features are, however, part of another tool for data management called the <a href=\"https:\/\/www.limswiki.org\/index.php\/Laboratory_information_management_system\" title=\"Laboratory information management system\" class=\"wiki-link\" data-key=\"8ff56a51d34c9b1806fcebdcde634d00\">laboratory information management system<\/a> (LIMS). (See Table 1 for a comparison of the two.)\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig1_Argento_EMBOReports2020_21-3.jpg\" class=\"image wiki-link\" data-key=\"a046f4d1f4d1028e828f34b9348784c2\"><img alt=\"Fig1 Argento EMBOReports2020 21-3.jpg\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/1\/16\/Fig1_Argento_EMBOReports2020_21-3.jpg\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Figure 1.<\/b> Challenges of traditional record\u2010keeping in modern science. (<b>A<\/b>) Comparison of research instruments and laboratory records from the 1700s and 2000s. While the development of research instruments has driven progress, laboratory record\u2010keeping is almost unchanged. (<b>B<\/b>) Data are distributed across multiple locations and media, including notebooks, printed material, physical samples, disks, hard drives, servers and cloud storage. (<b>C<\/b>) Locating specific data is difficult as the location may be unknown, and the media may be difficult to search.<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table class=\"wikitable\" border=\"1\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\" colspan=\"4\"><b>Table 1.<\/b> ELN and LIMS main benefits in research institutions\n<\/td><\/tr>\n<tr>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">ELN benefits\n<\/th>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">LIMS benefits\n<\/th><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">\n<ul><li> Provides research work traceability<br \/><\/li>\n<li> Enhances knowledge transmission<br \/><\/li>\n<li> Protects intellectual property and patents<\/li><\/ul>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">\n<ul><li> Supports sample management (plasmids, virus, antibodies, chemicals databases)<br \/><\/li>\n<li> Provides stock management<br \/><\/li>\n<li> Improves workflows, typically with templates<br \/><\/li>\n<li> Improves management of SOPs<br \/><\/li>\n<li> Tracks laboratory equipment usage and inventory<br \/><\/li>\n<li> Offers equipment integration for direct data acquisition<\/li><\/ul>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>In order to encourage adoption of ELNs at the institutional level, \u00c9cole Polytechnique F\u00e9d\u00e9rale de Lausanne (EPFL) started a dedicated program for ELN-LIMS deployment six years ago that involved research institute managers, principal investigators (PIs), and scientists at all levels. Here, we share the challenges, key success factors, and the results obtained at each phase of our project. Afterwards, we discuss the current and upcoming challenges and how our experience led us to support the creation of a new position in research groups: the laboratory data manager.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"The_project\">The project<\/span><\/h2>\n<p>Our efforts towards ELN-LIMS deployment began in March 2012 and has run through five distinct phases, as shown in Fig. 2.\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig2_Argento_EMBOReports2020_21-3.jpg\" class=\"image wiki-link\" data-key=\"c441eb53c3081608f9272e9f21ec24ed\"><img alt=\"Fig2 Argento EMBOReports2020 21-3.jpg\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/c\/cd\/Fig2_Argento_EMBOReports2020_21-3.jpg\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Figure 2.<\/b> Institutional ELN-LIMS project macro\u2010planning. Project phases are indicated in blue underneath a timeline from March 2012, and associated human resources in FTE (full\u2010time equivalent) for each period are indicated in green (see text for details).<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>In the following sections, we present the step\u2010by\u2010step approach to deploy the platform in a laboratory. From our experience, each step contributed to successful and sustained ELN-LIMS adoption and use.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Initiating_the_project\">Initiating the project<\/span><\/h3>\n<p>By definition, an institutional ELN and LIMS project involves management, PIs, scientists at all levels, and the institute's IT department. As such, the steering committee for our project therefore included the Vice President of Research, who is responsible for scientific information, and the Vice President of Information Systems, who is responsible for IT governance and IT core services on campus. Representing the main users, the Life Sciences Faculty's Dean chaired the committee. This executive body defined the overall goals: to rationalize laboratories\u2019 efforts, reduce waste of time and money, reduce loss and enable reuse of data, improve the reproducibility of experiments, and facilitate data sharing for collaborative projects.\n<\/p><p>The steering committee hired a project manager to coordinate the interests and requirements of the multiple stakeholders from distant fields, which made this project as complex as it was fascinating. To ensure the introduction of an ELN-LIMS service was suitable for those affected, we involved a panel of scientists. The project manager also played the role of a \u201cbusiness analyst\u201d by meeting and surveying 25 laboratories whose needs and demands were synthesized in a weighted wish list that, along with legal requirements, helped to choose the ELN-LIMS solution. For instance, our institutional rules and laws about privacy and the use of human data prevented us from using a <a href=\"https:\/\/www.limswiki.org\/index.php\/Cloud_computing\" title=\"Cloud computing\" class=\"wiki-link\" data-key=\"fcfe5882eaa018d920cedb88398b604f\">cloud\u2010based<\/a> solution.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Identification_of_a_suitable_ELN-LIMS_platform\">Identification of a suitable ELN-LIMS platform<\/span><\/h3>\n<p>The initiation phase revealed that the project required more than just picking a commercial off\u2010the\u2010shelf (COTS) ELN. Our key users were active in bioengineering, immunology, neurology, and oncology, with correspondingly diverse approaches and demands, though developers of technology platforms also showed a strong interest (Fig. 3). Those stakeholders' routine workflows required additional functionality and administrative support. An analysis of those needs highlighted difficulties in managing data related to laboratory SOPs and samples, which are crucial for data reusability and experimental reproducibility in biomedical research.<sup id=\"rdp-ebb-cite_ref-FreedmanTheEcon15_7-0\" class=\"reference\"><a href=\"#cite_note-FreedmanTheEcon15-7\">[7]<\/a><\/sup> Samples and experiments with human data require more sophisticated privacy management, a requirement that is increasing with the rise of personalized medicine. Feedback from laboratory staff also indicated that integration with third\u2010party information systems would be of added value for everyday work. For example, importing data from an animal facility was relevant to the experimental laboratories, while integration with work request forms and integration with the billing system were key features for technology platforms. The issue of authentication was also raised by laboratories and IT staff, for ease of use for the first group and security for the second group. \n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig3_Argento_EMBOReports2020_21-3.jpg\" class=\"image wiki-link\" data-key=\"ad0b5f501ab32aadce8c1dbc5e2427ff\"><img alt=\"Fig3 Argento EMBOReports2020 21-3.jpg\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/7\/73\/Fig3_Argento_EMBOReports2020_21-3.jpg\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Figure 3.<\/b> Laboratory participation by institute. Number of laboratories participating in the ELN\/LIMS project at EPFL from each Institute in the School of Life Sciences listed since the project's inception in 2019. Others refers to laboratories at EPFL, but outside life sciences. Note the largest increase in laboratory participation in 2018 (see text for details).<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>Involving the IT department from the beginning prevented us from taking obvious wrong directions in terms of technical choice. A striking example of their input was highlighting the heterogeneity of the scientists\u2019 personal computers in the research institute, which made the choice of a web\u2010based solution almost mandatory, rather than installing software on each computer. However, the most interesting technical question was how to manage the diversity of needs. And the most important question for scientists was how to preserve creativity and freedom of research without introducing new technological burdens and hassles.\n<\/p><p>It was important that individual laboratories using our services remain architects of their own information system so as to preserve and maintain freedom and creativity. An ELN typically has highly standardized features, but new software technologies allow the creation of highly customizable databases and graphical user interfaces. The software we chose uses visual, declarative techniques instead of programming to enable fast, iterative, collaborative, and tailored implementation. Applications can be rapidly modified and maintained centrally.\n<\/p><p>Mastering such a powerful toolbox required the appointment of skilled people and best practices of implementation. This investment was counterbalanced by the possibility of the inclusion of a wide range of data, development of home-made features (e.g., financial management, work request forms), and integration with other information systems. It also opened the possibility for compliance with <a href=\"https:\/\/www.limswiki.org\/index.php\/ISO_9000\" title=\"ISO 9000\" class=\"wiki-link\" data-key=\"53ace2d12e80a7d890ce881bc6fe244a\">ISO 9001<\/a> or <a href=\"https:\/\/www.limswiki.org\/index.php\/21_CFR_Part_11\" title=\"21 CFR Part 11\" class=\"wiki-link\" data-key=\"0ec495c20a8f17894bd0c1388eda8e7a\">21 CFR Part 11<\/a> standards that are required by some technology platforms. Those standards' quality assurance and data privacy concerns affect many industries and can also help to foster reproducibility in the life sciences.<sup id=\"rdp-ebb-cite_ref-DirnaglQuality18_8-0\" class=\"reference\"><a href=\"#cite_note-DirnaglQuality18-8\">[8]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-RiedlQuality13_9-0\" class=\"reference\"><a href=\"#cite_note-RiedlQuality13-9\">[9]<\/a><\/sup>\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Pilot_and_full_deployment\">Pilot and full deployment<\/span><\/h3>\n<p>To accurately assess the personnel and skills needed to install and configure the platform, and then train the staff, a dedicated budget to run a pilot phase was required. This budget covered a six\u2010month license fee for the ELN-LIMS platform and a system administrator along with training and support. Through this pilot, five volunteer laboratories began to configure and use the ELN-LIMS platform. At the end, all stakeholders validated the choice of the solution over the short and long term, and the steering committee approved deployment at a larger scale. \n<\/p><p>The same staff then organized the full deployment. A dedicated ELN-LIMS platform engineer was hired to help laboratories to get the most from the customizable platform (Fig 2). Such an ELN-LIMS expert needed to have strong IT competencies, project management skills, and good general knowledge in research to efficiently communicate with the scientific staff. More specifically, the engineer developed and optimized the work methodology to ensure sustainable growth from a technical and scientific point of view. The announcement of the Swiss National Science Foundation (SNSF) to make a data management plan mandatory for all grant applications from October 2017<sup id=\"rdp-ebb-cite_ref-SNSFOpen17_10-0\" class=\"reference\"><a href=\"#cite_note-SNSFOpen17-10\">[10]<\/a><\/sup> created a peak of demand for our services in 2018, when 10 laboratories voluntarily started ELN-LIMS deployment (Fig. 3). Nonetheless, laboratories were not forced to use the ELN-LIMS, and it still remains a PI's decision to use the platform. Fig. 4 shows examples of the current typical usage of the ELN-LIMS platform.\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig4_Argento_EMBOReports2020_21-3.jpg\" class=\"image wiki-link\" data-key=\"f1d2e6e4d659a6ea3e91dcdb4b0aa5b0\"><img alt=\"Fig4 Argento EMBOReports2020 21-3.jpg\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/8\/89\/Fig4_Argento_EMBOReports2020_21-3.jpg\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Figure 4.<\/b> Typical usage of the ELN \/LIMS platform. (<b>A<\/b>) ELN with scientist's notes, samples linked to the laboratory inventories, files, and procedures showing how we solved the initial issue illustrated in Fig 1C. (<b>B<\/b>) Laboratory sample inventories viewed with associated physical storage locations and links to ELN entries. (<b>C<\/b>) Example of a biopsy biobank and list of all derived crypts, organoids, and cryovial samples from one single biopsy.<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>Each ELN-LIMS platform deployment is managed as a separate sub\u2010project, since the information systems are tailor\u2010made for each laboratory. The deployment phase starts with informal discussions between the ELN-LIMS application expert and the laboratory's management to demonstrate the offered services. This introduction aims to confirm that the tool could support the laboratory's objectives. If so, the list of objectives is formalized and validated by the project sponsor, the PI in this case. Objectives are prioritized (Box 1) and have an appointed reference person. Roles and responsibilities must be clarified.\n<\/p>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table class=\"wikitable\" border=\"1\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\" colspan=\"1\"><b>Box 1.<\/b> Example of research laboratory requirements, sorted by decreasing priority\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">\n<ul><li> Configure and adopt ELN\/LIMS for all laboratory members<br \/><\/li>\n<li> Create a standard operating procedure (SOP) and simple operating procedure library accessible for everyone<br \/><\/li>\n<li> Centralize antibody database<br \/><\/li>\n<li> Centralize plasmid database<br \/><\/li>\n<li> Centralize chemical database<br \/><\/li>\n<li> Manage the laboratory storage location (freezer, cabinet, etc.)<br \/><\/li>\n<li> Define uniform identification of locations and sample thanks to label printers<\/li><\/ul>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<h4><span class=\"mw-headline\" id=\"The_stakeholders_and_their_roles_in_the_deployment\">The stakeholders and their roles in the deployment<\/span><\/h4>\n<p>The PI is the sponsor, who initiates the project and assumes overall responsibility. He or she usually delegates the work to appropriate staff members. Along the deployment, the PI can be asked to make decisions on proposals.\n<\/p><p>Laboratory referents take the lead and responsibility to fulfill the aims delegated by the PI. Initially, this task was given to newly arrived PhD students, but we soon realized that a thorough knowledge of the laboratory operation is required for efficient implementation. This role should therefore be given to experienced scientists or technicians; the latter often have associated laboratory planning tasks and are less likely to leave than scientific staff. Those considerations make them more prone to act as a catalyst in adopting the ELN-LIMS platform. This view is supported by raw record creation quantity as a function of staff position (Fig. 5).\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig5_Argento_EMBOReports2020_21-3.jpg\" class=\"image wiki-link\" data-key=\"6cf26461283d9e87307a541242bcb2e1\"><img alt=\"Fig5 Argento EMBOReports2020 21-3.jpg\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/8\/8a\/Fig5_Argento_EMBOReports2020_21-3.jpg\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Figure 5.<\/b> Record creation by institutional role. This pie chart describes the proportion of records (file, sample, or experiment) created as a function of the institutional role of the person creating the record at EPFL. Note that records where the institutional role was not available are not shown, amounting to < 0.4% of the total. The records created by PIs are not visible at this scale (see text for details).<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>The ELN-LIMS application expert is responsible for configuring the system according to the laboratory referents\u2019 requests and to advise about best practices; they translate the identified needs into configuration and code. A strong know\u2010how in ELN-LIMS customization, best practices, and general knowledge about the scientific field are tremendously important. By working in several laboratories, our ELN-LIMS expert team developed strong skills in laboratory data management and project management that the typical laboratory does not have. Consequently, they currently work as a deployment project manager, whereas ideally, their role should be restricted to supporting the workflows of the adopting laboratory, not imposing (well\u2010intentioned) ideas from the outside.\n<\/p><p>ELN-LIMS end users are the laboratory staff and PIs, and their active participation in the deployment and their remarks and comments are crucial for setting up a tool that fits their needs and habits. While sample and SOP management are usually easily adopted, the use of the ELN is trickier as it offers a large range of possibilities to organize projects and experiments, compared to paper notebooks. This can make adaptation frustrating and can take weeks; indeed, some laboratories decided not to use the ELN or only a part of the staff adopted it. We have also seen a few laboratories abandon the ELN. Close support during the first week of usage and regular communication are necessary to reduce the impact of initial difficulty of use. Here, the normal turnover of scientific staff in research laboratories can be used as an opportunity. It is problematic to ask a post\u2010doctoral researcher or a PhD student to change their data management tools and habits in the middle of their project, whereas new recruits can start fresh with the ELN-LIMS system.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Configuration_and_go-live\">Configuration and go-live<\/span><\/h3>\n<p>In this phase, the ELN-LIMS expert needs to work as closely as possible with researchers to translate laboratory context, culture, and workflow into the configuration. According to our experience, the conception must be an incremental process. This process is common practice in the software industry's \u201cagile\u201d methodology, one based on continuous small deliveries and short daily meetings.<sup id=\"rdp-ebb-cite_ref-ConfortoCanAgile14_11-0\" class=\"reference\"><a href=\"#cite_note-ConfortoCanAgile14-11\">[11]<\/a><\/sup> While preparing for deployment of the system (or additional components), we organize regular meetings to discuss the ELN-LIMS platform configuration and design and, depending on the test performed by the referent, further adapt the configuration for the next meeting (Fig. 6). The cycle is repeated until the result is sufficiently convincing to validate the deployment of this feature and corresponding training.\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig6_Argento_EMBOReports2020_21-3.jpg\" class=\"image wiki-link\" data-key=\"f7bbc11cd70cd300a26ae8b6e7065501\"><img alt=\"Fig6 Argento EMBOReports2020 21-3.jpg\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/c\/ca\/Fig6_Argento_EMBOReports2020_21-3.jpg\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Figure 6.<\/b> Agile cycle adapted to ELN-LIMS deployment in a life sciences research laboratory. Flow chart of process and decisions in ELN-LIMS deployment used at EPFL. Note the agile cycle shown in purple for rapid adaptation of the platform to the needs of each laboratory.<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>For almost five years, we have been serving the original laboratories involved with the project as well as new volunteer laboratories. The raw record creation (files and samples) in the platform accelerated in mid\u20102014 when technology platforms joined the system (Fig. 7). The number of created experiments in the ELN (green) has grown more rapidly since 2016, reflecting improvement in training, communication between stakeholders, and continuous upgrades.\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig7_Argento_EMBOReports2020_21-3.jpg\" class=\"image wiki-link\" data-key=\"a495956d012ef7bbaebba8a86938bf84\"><img alt=\"Fig7 Argento EMBOReports2020 21-3.jpg\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/e\/ec\/Fig7_Argento_EMBOReports2020_21-3.jpg\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Figure 7.<\/b> Evolution of raw record creation in research laboratories. Increase in the number of file, sample, and experiment records is plotted, normalized to the total number for each class at the time of writing, over the period of the ELN-LIMS project at EPFL. Note the inflection points in file and sample creation in mid\u20102014, and in experiments at the beginning of 2016 (see text for details).<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>Although the service is hosted at the School of Life Sciences IT department, the platform has been requested and used by biologists from other faculties on the campus (Fig 3). As of early 2020, three full\u2010time ELN-LIMS application expert staff serve 52 laboratories. This team is composed of people with heterogenous competencies from bioengineering and chemistry to computer sciences and IT management. In addition, a full-time system administrator operates the servers and data storage, while a part-time assistant ensures the service management. The whole service requires four full-time employees and one part-time employee (Fig 2) to guarantee the system's sustainability and evolution. They ensure day\u2010to\u2010day assistance with user deployments and training sessions while coordinating and performing the regular maintenance of the infrastructure. A frequently overlooked, yet important and time\u2010consuming task they manage is to ensure platform upgrades, which has a key impact on user experiences and data integrity.\n<\/p><p>One of our ELN-LIMS configurations is used by an \u201cindustrial\u201d technology platform that sterilizes glass, decontaminates waste, and prepares standard solutions. They are ISO 9001-certified, and their data management is audited every year. As we operate the major part of their information systems, we are audited too, and thus we have also put a quality system in place for maintenance and data backup. Generally, technology platforms are natural customers of such services. They run more standardized experiments with higher requirements for traceability. (Figure 5 reminds us that they are the main record producer in the ELN-LIMS platform.)\n<\/p>\n<h2><span class=\"mw-headline\" id=\"The_laboratory_data_manager\">The laboratory data manager<\/span><\/h2>\n<p>We experienced that ELN-LIMS application experts were regularly asked by laboratory referents to organize their data management. However, data management should be driven by science and not vice versa, which is one of the reasons we propose a \u201claboratory data manager\u201d for managing sensitive or crucial data. \n<\/p><p>Obviously, the particular skills required for a data manager in cutting\u2010edge research is a challenge. As a trial, we placed a properly skilled data manager into one of our research groups for a couple of months. As shown in Fig. 8, it had an immediate impact on the amount of data collected in the ELN and enabled the laboratory to review their data management practices. We do not have information about the quality of the data produced, but we expect improvement at this level, and we anticipate that the publishing process could also be accelerated, owing to better reusability of data inside the laboratory. \n<\/p><p>In all, a laboratory data manager would apply general institutional or research\u2010specific policies and good practices, and convert general infrastructure into daily practical solutions that fit the localized needs of the laboratory. Being integrated with the laboratory is necessary to legitimize changing practices while maintaining the flexibility and freedom required by science. Note that a data manager would not necessarily be a full\u2010time job, depending on the laboratory's activity.\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig8_Argento_EMBOReports2020_21-3.jpg\" class=\"image wiki-link\" data-key=\"b224bcb9bee3c0fcd95deea2baa103e9\"><img alt=\"Fig8 Argento EMBOReports2020 21-3.jpg\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/1\/19\/Fig8_Argento_EMBOReports2020_21-3.jpg\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Figure 8.<\/b> Increased experiment record creation with the introduction of a laboratory data manager. The number of experiment records created in the ELN per month in 2018\u20132019 from a single laboratory at EPFL, displayed as a bar graph on a timeline, and annotated with the introduction and departure of a trained data manager in the laboratory.<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<h2><span class=\"mw-headline\" id=\"Conclusions\">Conclusions<\/span><\/h2>\n<p>In summary, we believe our institutional project showed that the ELN-LIMS platform helps to capture and record data, and helps to make the data to become findable, accessible, interoperable, and reusable (FAIR). The reusability criterion implies quality improvements that are more dependent on data management practice than on the available electronic tools.\n<\/p><p>Several challenges for the success of data management yet remain. One challenge is the slow adoption of the ELN by research staff, partly because the ELN is still a work in progress, partly because old working habits are slow to change. Furthermore, managing huge files\u2014e.g., genomic data or microscopy images\u2014remains a major challenge, as is archiving the data collected by the ELN-LIMS systems. Finally, integration with other elements of the institutional information system is technically possible, but requires governance of business applications, interface development, and resources for maintenance. Amidst all of these challenges, we strongly believe funding the position of data managers remains a priority. In the end, it is the daily practice of the scientists that will drive and sustain the digital transformation of the life sciences.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Acknowledgements\">Acknowledgements<\/span><\/h2>\n<p>I acknowledge Ga\u00ebl Anex and all the School of Life Sciences and EPFL directors for creating this favorable environment, improving laboratory data management; Pr. Andy Oates and Pierig Le Pottier for their strong support and help in writing the article; my colleagues from the IT department, in particular Paul Schalbetter, for the scripting of the figures, as well as Philippe Borel, Peter Hliva, and Christopher Tremblay who ensure the continuity of ELN-LIMS deployments; and finally all the scientific staff who actively fostered and participated in the ELN and LIMS deployments in their laboratory.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Funding\">Funding<\/span><\/h3>\n<p>The EPFL, School of Life Sciences provided funding for this research.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"References\">References<\/span><\/h2>\n<div class=\"reflist references-column-width\" style=\"-moz-column-width: 30em; -webkit-column-width: 30em; column-width: 30em; list-style-type: decimal;\">\n<ol class=\"references\">\n<li id=\"cite_note-AshPeople08-1\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-AshPeople08_1-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Ash, J.S.; Anderson, N.R.; Tarczy-Hornoch, P. (2008). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2410012\" target=\"_blank\">\"People and Organizational Issues in Research Systems Implementation\"<\/a>. <i>JAMIA<\/i> <b>15<\/b> (3): 283\u20139. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1197%2Fjamia.M2582\" target=\"_blank\">10.1197\/jamia.M2582<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC2410012\/\" target=\"_blank\">PMC2410012<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/18308986\" target=\"_blank\">18308986<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2410012\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2410012<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=People+and+Organizational+Issues+in+Research+Systems+Implementation&rft.jtitle=JAMIA&rft.aulast=Ash%2C+J.S.%3B+Anderson%2C+N.R.%3B+Tarczy-Hornoch%2C+P.&rft.au=Ash%2C+J.S.%3B+Anderson%2C+N.R.%3B+Tarczy-Hornoch%2C+P.&rft.date=2008&rft.volume=15&rft.issue=3&rft.pages=283%E2%80%939&rft_id=info:doi\/10.1197%2Fjamia.M2582&rft_id=info:pmc\/PMC2410012&rft_id=info:pmid\/18308986&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC2410012&rfr_id=info:sid\/en.wikipedia.org:Journal:Institutional_ELN-LIMS_deployment:_Highly_customizable_ELN-LIMS_platform_as_a_cornerstone_of_digital_transformation_for_life_sciences_research_institutes\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-KwokHow18-2\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-KwokHow18_2-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Kwok, R. (2028). \"How to Pick an Electronic Laboratory Notebook\". <i>Nature<\/i> <b>560<\/b> (7717): 269-270. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1038%2Fd41586-018-05895-3\" target=\"_blank\">10.1038\/d41586-018-05895-3<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/30082695\" target=\"_blank\">30082695<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=How+to+Pick+an+Electronic+Laboratory+Notebook&rft.jtitle=Nature&rft.aulast=Kwok%2C+R.&rft.au=Kwok%2C+R.&rft.date=2028&rft.volume=560&rft.issue=7717&rft.pages=269-270&rft_id=info:doi\/10.1038%2Fd41586-018-05895-3&rft_id=info:pmid\/30082695&rfr_id=info:sid\/en.wikipedia.org:Journal:Institutional_ELN-LIMS_deployment:_Highly_customizable_ELN-LIMS_platform_as_a_cornerstone_of_digital_transformation_for_life_sciences_research_institutes\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ManzelRequire13-3\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-ManzelRequire13_3-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Menzel, J.; Weil, P.; Bittihn, P. et al. (2013). \"Requirement analysis for an electronic laboratory notebook for sustainable data management in biomedical research\". <i>Studies in Health Technologies and Informatics<\/i> <b>192<\/b>: 1108. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.3233%2F978-1-61499-289-9-1108\" target=\"_blank\">10.3233\/978-1-61499-289-9-1108<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/23920882\" target=\"_blank\">23920882<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Requirement+analysis+for+an+electronic+laboratory+notebook+for+sustainable+data+management+in+biomedical+research&rft.jtitle=Studies+in+Health+Technologies+and+Informatics&rft.aulast=Menzel%2C+J.%3B+Weil%2C+P.%3B+Bittihn%2C+P.+et+al.&rft.au=Menzel%2C+J.%3B+Weil%2C+P.%3B+Bittihn%2C+P.+et+al.&rft.date=2013&rft.volume=192&rft.pages=1108&rft_id=info:doi\/10.3233%2F978-1-61499-289-9-1108&rft_id=info:pmid\/23920882&rfr_id=info:sid\/en.wikipedia.org:Journal:Institutional_ELN-LIMS_deployment:_Highly_customizable_ELN-LIMS_platform_as_a_cornerstone_of_digital_transformation_for_life_sciences_research_institutes\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-GuerreroAnalysis16-4\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-GuerreroAnalysis16_4-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Guerrero, S.; Dujardin, G.; Cabrera-Andrade, A. et al. (2016). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4968837\" target=\"_blank\">\"Analysis and Implementation of an Electronic Laboratory Notebook in a Biomedical Research Institute\"<\/a>. <i>PLoS One<\/i> <b>11<\/b> (8): e0160428. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1371%2Fjournal.pone.0160428\" target=\"_blank\">10.1371\/journal.pone.0160428<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC4968837\/\" target=\"_blank\">PMC4968837<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/27479083\" target=\"_blank\">27479083<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4968837\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4968837<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Analysis+and+Implementation+of+an+Electronic+Laboratory+Notebook+in+a+Biomedical+Research+Institute&rft.jtitle=PLoS+One&rft.aulast=Guerrero%2C+S.%3B+Dujardin%2C+G.%3B+Cabrera-Andrade%2C+A.+et+al.&rft.au=Guerrero%2C+S.%3B+Dujardin%2C+G.%3B+Cabrera-Andrade%2C+A.+et+al.&rft.date=2016&rft.volume=11&rft.issue=8&rft.pages=e0160428&rft_id=info:doi\/10.1371%2Fjournal.pone.0160428&rft_id=info:pmc\/PMC4968837&rft_id=info:pmid\/27479083&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC4968837&rfr_id=info:sid\/en.wikipedia.org:Journal:Institutional_ELN-LIMS_deployment:_Highly_customizable_ELN-LIMS_platform_as_a_cornerstone_of_digital_transformation_for_life_sciences_research_institutes\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-DirnaglAPocket16-5\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-DirnaglAPocket16_5-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Dirnagl, U.; Przesdzing, I. (2016). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4722687\" target=\"_blank\">\"A pocket guide to electronic laboratory notebooks in the academic life sciences\"<\/a>. <i>F1000Research<\/i> <b>5<\/b>: 2. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.12688%2Ff1000research.7628.1\" target=\"_blank\">10.12688\/f1000research.7628.1<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC4722687\/\" target=\"_blank\">PMC4722687<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/26835004\" target=\"_blank\">26835004<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4722687\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4722687<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=A+pocket+guide+to+electronic+laboratory+notebooks+in+the+academic+life+sciences&rft.jtitle=F1000Research&rft.aulast=Dirnagl%2C+U.%3B+Przesdzing%2C+I.&rft.au=Dirnagl%2C+U.%3B+Przesdzing%2C+I.&rft.date=2016&rft.volume=5&rft.pages=2&rft_id=info:doi\/10.12688%2Ff1000research.7628.1&rft_id=info:pmc\/PMC4722687&rft_id=info:pmid\/26835004&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC4722687&rfr_id=info:sid\/en.wikipedia.org:Journal:Institutional_ELN-LIMS_deployment:_Highly_customizable_ELN-LIMS_platform_as_a_cornerstone_of_digital_transformation_for_life_sciences_research_institutes\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-RileyImplement17-6\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-RileyImplement17_6-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Riley, E.M.; Hattaway, H.Z.; Felse, P.A. (2017). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5701295\" target=\"_blank\">\"Implementation and use of cloud-based electronic lab notebook in a bioprocess engineering teaching laboratory\"<\/a>. <i>Journal of Biological Engineering<\/i> <b>11<\/b>: 40. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1186%2Fs13036-017-0083-2\" target=\"_blank\">10.1186\/s13036-017-0083-2<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC5701295\/\" target=\"_blank\">PMC5701295<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/29201138\" target=\"_blank\">29201138<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5701295\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5701295<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Implementation+and+use+of+cloud-based+electronic+lab+notebook+in+a+bioprocess+engineering+teaching+laboratory&rft.jtitle=Journal+of+Biological+Engineering&rft.aulast=Riley%2C+E.M.%3B+Hattaway%2C+H.Z.%3B+Felse%2C+P.A.&rft.au=Riley%2C+E.M.%3B+Hattaway%2C+H.Z.%3B+Felse%2C+P.A.&rft.date=2017&rft.volume=11&rft.pages=40&rft_id=info:doi\/10.1186%2Fs13036-017-0083-2&rft_id=info:pmc\/PMC5701295&rft_id=info:pmid\/29201138&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC5701295&rfr_id=info:sid\/en.wikipedia.org:Journal:Institutional_ELN-LIMS_deployment:_Highly_customizable_ELN-LIMS_platform_as_a_cornerstone_of_digital_transformation_for_life_sciences_research_institutes\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-FreedmanTheEcon15-7\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-FreedmanTheEcon15_7-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Freedman, L.P.; Cockburn, I.M.; Simcoe, T.S. (2015). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4461318\" target=\"_blank\">\"The Economics of Reproducibility in Preclinical Research\"<\/a>. <i>PLoS Biology<\/i> <b>13<\/b> (6): e1002165. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1371%2Fjournal.pbio.1002165\" target=\"_blank\">10.1371\/journal.pbio.1002165<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC4461318\/\" target=\"_blank\">PMC4461318<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/26057340\" target=\"_blank\">26057340<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4461318\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4461318<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=The+Economics+of+Reproducibility+in+Preclinical+Research&rft.jtitle=PLoS+Biology&rft.aulast=Freedman%2C+L.P.%3B+Cockburn%2C+I.M.%3B+Simcoe%2C+T.S.&rft.au=Freedman%2C+L.P.%3B+Cockburn%2C+I.M.%3B+Simcoe%2C+T.S.&rft.date=2015&rft.volume=13&rft.issue=6&rft.pages=e1002165&rft_id=info:doi\/10.1371%2Fjournal.pbio.1002165&rft_id=info:pmc\/PMC4461318&rft_id=info:pmid\/26057340&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC4461318&rfr_id=info:sid\/en.wikipedia.org:Journal:Institutional_ELN-LIMS_deployment:_Highly_customizable_ELN-LIMS_platform_as_a_cornerstone_of_digital_transformation_for_life_sciences_research_institutes\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-DirnaglQuality18-8\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-DirnaglQuality18_8-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Dirngal, U.; Kurreck, C.; Casta\u00f1os-V\u00e9lez, E. et al. (2018). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6216282\" target=\"_blank\">\"Quality Management for Academic Laboratories: Burden or Boon? Professional Quality Management Could Be Very Beneficial for Academic Research but Needs to Overcome Specific Caveats\"<\/a>. <i>EMBO Reports<\/i> <b>19<\/b> (11): e47143. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.15252%2Fembr.201847143\" target=\"_blank\">10.15252\/embr.201847143<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6216282\/\" target=\"_blank\">PMC6216282<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/30341068\" target=\"_blank\">30341068<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6216282\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6216282<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Quality+Management+for+Academic+Laboratories%3A+Burden+or+Boon%3F+Professional+Quality+Management+Could+Be+Very+Beneficial+for+Academic+Research+but+Needs+to+Overcome+Specific+Caveats&rft.jtitle=EMBO+Reports&rft.aulast=Dirngal%2C+U.%3B+Kurreck%2C+C.%3B+Casta%C3%B1os-V%C3%A9lez%2C+E.+et+al.&rft.au=Dirngal%2C+U.%3B+Kurreck%2C+C.%3B+Casta%C3%B1os-V%C3%A9lez%2C+E.+et+al.&rft.date=2018&rft.volume=19&rft.issue=11&rft.pages=e47143&rft_id=info:doi\/10.15252%2Fembr.201847143&rft_id=info:pmc\/PMC6216282&rft_id=info:pmid\/30341068&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC6216282&rfr_id=info:sid\/en.wikipedia.org:Journal:Institutional_ELN-LIMS_deployment:_Highly_customizable_ELN-LIMS_platform_as_a_cornerstone_of_digital_transformation_for_life_sciences_research_institutes\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-RiedlQuality13-9\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-RiedlQuality13_9-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Riedl, D.H.; Dunn, M.K. (2013). \"Quality Assurance Mechanisms for the Unregulated Research Environment\". <i>Trends in Biotechnology<\/i> <b>31<\/b> (10): 552-4. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.tibtech.2013.06.007\" target=\"_blank\">10.1016\/j.tibtech.2013.06.007<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/24054820\" target=\"_blank\">24054820<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Quality+Assurance+Mechanisms+for+the+Unregulated+Research+Environment&rft.jtitle=Trends+in+Biotechnology&rft.aulast=Riedl%2C+D.H.%3B+Dunn%2C+M.K.&rft.au=Riedl%2C+D.H.%3B+Dunn%2C+M.K.&rft.date=2013&rft.volume=31&rft.issue=10&rft.pages=552-4&rft_id=info:doi\/10.1016%2Fj.tibtech.2013.06.007&rft_id=info:pmid\/24054820&rfr_id=info:sid\/en.wikipedia.org:Journal:Institutional_ELN-LIMS_deployment:_Highly_customizable_ELN-LIMS_platform_as_a_cornerstone_of_digital_transformation_for_life_sciences_research_institutes\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-SNSFOpen17-10\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-SNSFOpen17_10-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Swiss National Science Foundation (06 March 2017). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.snf.ch\/en\/researchinFocus\/newsroom\/Pages\/news-170306-towards-open-research-data.aspx\" target=\"_blank\">\"Open Research Data: Data management plans will be introduced in project funding\"<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.snf.ch\/en\/researchinFocus\/newsroom\/Pages\/news-170306-towards-open-research-data.aspx\" target=\"_blank\">http:\/\/www.snf.ch\/en\/researchinFocus\/newsroom\/Pages\/news-170306-towards-open-research-data.aspx<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Open+Research+Data%3A+Data+management+plans+will+be+introduced+in+project+funding&rft.atitle=&rft.aulast=Swiss+National+Science+Foundation&rft.au=Swiss+National+Science+Foundation&rft.date=06+March+2017&rft_id=http%3A%2F%2Fwww.snf.ch%2Fen%2FresearchinFocus%2Fnewsroom%2FPages%2Fnews-170306-towards-open-research-data.aspx&rfr_id=info:sid\/en.wikipedia.org:Journal:Institutional_ELN-LIMS_deployment:_Highly_customizable_ELN-LIMS_platform_as_a_cornerstone_of_digital_transformation_for_life_sciences_research_institutes\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ConfortoCanAgile14-11\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-ConfortoCanAgile14_11-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Conforto, E.C.; Salum, F.; Amaral, D.C. et al. (2014). \"Can Agile Project Management Be Adopted by Industries Other than Software Development?\". <i>Project Management Journal<\/i> <b>45<\/b> (3): 21\u201334. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1002%2Fpmj.21410\" target=\"_blank\">10.1002\/pmj.21410<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Can+Agile+Project+Management+Be+Adopted+by+Industries+Other+than+Software+Development%3F&rft.jtitle=Project+Management+Journal&rft.aulast=Conforto%2C+E.C.%3B+Salum%2C+F.%3B+Amaral%2C+D.C.+et+al.&rft.au=Conforto%2C+E.C.%3B+Salum%2C+F.%3B+Amaral%2C+D.C.+et+al.&rft.date=2014&rft.volume=45&rft.issue=3&rft.pages=21%E2%80%9334&rft_id=info:doi\/10.1002%2Fpmj.21410&rfr_id=info:sid\/en.wikipedia.org:Journal:Institutional_ELN-LIMS_deployment:_Highly_customizable_ELN-LIMS_platform_as_a_cornerstone_of_digital_transformation_for_life_sciences_research_institutes\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<\/ol><\/div>\n<h2><span class=\"mw-headline\" id=\"Notes\">Notes<\/span><\/h2>\n<p>This presentation is faithful to the original, with only a few minor changes to presentation. Grammar was cleaned up for smoother reading. In some cases important information was missing from the references, and that information was added. The inline link to the SNSF article was turned into a formal citation for this version. Additional section headers were made to make the material flow better.\n<\/p>\n<!-- \nNewPP limit report\nCached time: 20200707205053\nCache expiry: 86400\nDynamic content: false\nCPU time usage: 0.597 seconds\nReal time usage: 3.538 seconds\nPreprocessor visited node count: 10618\/1000000\nPreprocessor generated node count: 30472\/1000000\nPost\u2010expand include size: 92842\/2097152 bytes\nTemplate argument size: 28745\/2097152 bytes\nHighest expansion depth: 18\/40\nExpensive parser function count: 0\/100\n-->\n\n<!-- \nTransclusion expansion time report (%,ms,calls,template)\n100.00% 234.191 1 - -total\n 78.10% 182.894 1 - Template:Reflist\n 65.57% 153.565 11 - Template:Citation\/core\n 64.19% 150.321 10 - Template:Cite_journal\n 16.58% 38.832 1 - Template:Infobox_journal_article\n 15.93% 37.310 1 - Template:Infobox\n 10.65% 24.946 80 - Template:Infobox\/row\n 10.12% 23.689 25 - Template:Citation\/identifier\n 5.05% 11.817 1 - Template:Cite_web\n 4.31% 10.096 11 - Template:Citation\/make_link\n-->\n\n<!-- Saved in parser cache with key limswiki:pcache:idhash:11973-0!*!0!!en!5!* and timestamp 20200707205049 and revision id 39566\n -->\n<\/div><div class=\"printfooter\">Source: <a rel=\"external_link\" class=\"external\" href=\"https:\/\/www.limswiki.org\/index.php\/Journal:Institutional_ELN-LIMS_deployment:_Highly_customizable_ELN-LIMS_platform_as_a_cornerstone_of_digital_transformation_for_life_sciences_research_institutes\">https:\/\/www.limswiki.org\/index.php\/Journal:Institutional_ELN-LIMS_deployment:_Highly_customizable_ELN-LIMS_platform_as_a_cornerstone_of_digital_transformation_for_life_sciences_research_institutes<\/a><\/div>\n\t\t\t\t\t\t\t\t\t\t<!-- end content -->\n\t\t\t\t\t\t\t\t\t\t<div class=\"visualClear\"><\/div>\n\t\t\t\t<\/div>\n\t\t\t<\/div>\n\t\t<\/div>\n\t\t<!-- end of the left (by default at least) column -->\n\t\t<div class=\"visualClear\"><\/div>\n\t\t\t\t\t\n\t\t<\/div>\n\t\t\n\n<\/body>","3d21e2245fe30f0192b9b2b65131c7c2_images":["https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/1\/16\/Fig1_Argento_EMBOReports2020_21-3.jpg","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/c\/cd\/Fig2_Argento_EMBOReports2020_21-3.jpg","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/7\/73\/Fig3_Argento_EMBOReports2020_21-3.jpg","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/8\/89\/Fig4_Argento_EMBOReports2020_21-3.jpg","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/8\/8a\/Fig5_Argento_EMBOReports2020_21-3.jpg","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/c\/ca\/Fig6_Argento_EMBOReports2020_21-3.jpg","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/e\/ec\/Fig7_Argento_EMBOReports2020_21-3.jpg","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/1\/19\/Fig8_Argento_EMBOReports2020_21-3.jpg"],"3d21e2245fe30f0192b9b2b65131c7c2_timestamp":1594155049,"02fce1e6c14e5effed2c3ceedc4e9443_type":"article","02fce1e6c14e5effed2c3ceedc4e9443_title":"Blockchain and artificial intelligence technology for novel coronavirus disease 2019 self-testing (Mashamba-Thompson and Crayton 2020)","02fce1e6c14e5effed2c3ceedc4e9443_url":"https:\/\/www.limswiki.org\/index.php\/Journal:Blockchain_and_artificial_intelligence_technology_for_novel_coronavirus_disease_2019_self-testing","02fce1e6c14e5effed2c3ceedc4e9443_plaintext":"\n\n\t\t\n\t\t\t\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t\n\n\t\t\t\tJournal:Blockchain and artificial intelligence technology for novel coronavirus disease 2019 self-testing\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t\tFrom LIMSWiki\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\tJump to: navigation, search\n\n\t\t\t\t\t\n\t\t\t\t\tFull article title\n \nBlockchain and artificial intelligence technology for novel coronavirus disease 2019 self-testingJournal\n \nDiagnosticsAuthor(s)\n \nMashamba-Thompson, Tivani P.; Crayton, Ellen D.Author affiliation(s)\n \nUniversity of Limpopo, Genesis Technology and Management GroupPrimary contact\n \nEmail: tivani dot mashamba at ul dot ac dot zaYear published\n \n2020Volume and issue\n \n10(4)Article #\n \n198DOI\n \n10.3390\/diagnostics10040198ISSN\n \n2075-4418Distribution license\n \nCreative Commons Attribution 4.0 InternationalWebsite\n \nhttps:\/\/www.mdpi.com\/2075-4418\/10\/4\/198\/htmDownload\n \nhttps:\/\/www.mdpi.com\/2075-4418\/10\/4\/198\/pdf (PDF)\n\nContents\n\n1 Abstract \n2 Editorial \n3 Acknowledgements \n\n3.1 Funding \n3.2 Conflicts of interest \n\n\n4 References \n5 Notes \n\n\n\nAbstract \nThe novel coronavirus disease 2019 (COVID-19) is rapidly spreading, with a rising death toll and transmission rate reported in high-income countries rather than in low-income countries. However, the overburdened healthcare systems and poor disease surveillance systems in resource-limited settings may struggle to cope with this COVID-19 outbreak, which calls for a tailored strategic response within these settings. Here, we recommend a low-cost blockchain and artificial intelligence-coupled self-testing and tracking system for COVID-19 and other emerging infectious diseases. Prompt deployment and appropriate implementation of the proposed system have the potential to curb the transmission of COVID-19 and its related mortalities, particularly in settings with poor access to laboratory infrastructure.\nKeywords: self-testing, novel coronavirus disease-19, blockchain, artificial intelligence\n\nEditorial \nThe novel coronavirus disease 2019 (COVID-19) has now reached sub-Saharan Africa (SSA), with cases reported in more than 40 SSA countries. SSA health systems are already battling with poor health outcomes and high mortality rates linked to the unique quadruple (HIV, tuberculosis (TB), and non-communicable diseases) burden of disease.[1] In addition, SSA\u2019s dense communities, informal settlements, and rural and resource-limited settings are at particular risk for being vulnerable to the COVID-19 outbreak. These populations are underserved in terms of health services and have the potential to become to new COVID-19 epicenters. The global COVID-19 statistics surprisingly show low transmission rates and fewer deaths in resource-limited countries, particularly countries in Sub-Saharan Africa (SSA). However, while SSA\u2019s young population and warm climate may put SSA at an advantage for coping with the COVID-19 outbreak[2], there is growing concern about the impact of COVID-19 co-infections among the people living with other immune-system-weakening conditions such as HIV, TB, and diabetes, particularly given a struggling health care system in resource-limited settings such as SSA countries.[3][4]\nThere is a growing concern about a failure to find and report cases, especially given weak health systems, inadequate surveillance, insufficient laboratory capacity, and limited public health infrastructure in African countries.[5] Access to accurate diagnosis, monitoring, and reporting of health outbreaks requires a well-resourced healthcare system.[6] Evidence shows that most resource-limited countries lack an effective, rapid surveillance system.[7] These settings also have a limited availability of health technologies for the electronic surveillance of infectious diseases to facilitate the prevention and containment of emerging infectious diseases such as COVID-19.[7] Universal health coverage, as well as access to high-quality and timely pathology and laboratory medicine (PALM) services, is crucially needed to support healthcare systems that are tasked with achieving sustainable developmental goals.[8] This calls for the rapid development and deployment of health innovations for accurate diagnosis and electronic surveillance of COVID-19 in underserved populations.\nRecent evidence shows that prompt development and deployment of point-of-care (POC) diagnostics for screening in response to the COVID-19 outbreak can help to curb the spread of the disease and to alleviate the burden on the healthcare system.[9][10] The impact of rapid testing on the COVID-19 death rate has been shown in Germany.[11] Emerging health innovations such as blockchain and artificial intelligence (AI) technology can be coupled with POC diagnostics to enable self-testing of patients in isolation as a result of exposure to COVID-19. Blockchain is a digital, public ledger that records online transactions. It involves the digital distribution of ledger and consensus algorithms and eliminates all the threats of intermediaries.[12][13] One of the commonly-known applications of blockchain is the cryptocurrency Bitcoin[14], which has been successfully used as a financial alternative in emerging economies including countries in SSA.[15] Blockchain technology has shown adaptability in recent years, leading to its incorporation in a wide range of applications, including biomedical and healthcare systems.[16][17][18] The use of blockchain and AI in healthcare has been demonstrated in the management of electronic medical records, drug and pharmaceutical supply chains, biomedical research, education, remote patient monitoring, and healthcare data analytics.[17]\nMobile connected point-of-care diagnostics and self-testing has been successfully implemented in resource-limited settings.[19][20][21] However, there is limited evidence on the use of blockchain and AI technology for disease diagnosis. Bearing in mind the era of COVID-19 and the evidence on the overburdened healthcare systems and poor disease surveillance systems in resource-limited settings, and taking advantage of the available mobile Health (mHealth) systems, we recommend a rapid development and deployment of low-cost blockchain and AI-coupled mHealth connected self-testing and tracking systems as one of the strategic response strategies for COVID-19 and other emerging infectious diseases (Figure 1).\n\r\n\n\n\n\n\n\n\n\n\n\n Figure 1. Proposed community-based blockchain and artificial intelligence-coupled mobile-linked self-testing and tracking system for emerging infectious diseases.\n\n\n\nThe initial step for this system is through a mobile phone or tablet application (app) which could be adapted from existing self-testing apps.[22][23] The app requests a user\u2019s personal identifier before opening pre-testing instructions. Following testing, the user then uploads results into the app. The blockchain and AI system enables the transfer of the test result to alert the outbreak surveillance authorities of all tests performed, as well as the number of positive and negative test results. This helps ensure that all positive cases are referred to a quarantine site for treatment and monitoring. The built-in geographic information system (GIS) in mobile devices enables the tracking of those who tested positive. This system could also be connected to local, national, and international databases to ensure appropriate surveillance and control of an outbreak.\nThe AI component of this technology enables powerful data collection (patient information, geographic location of the patient, and test results), security, analysis, and curation of disparate and clinical data sets from federated blockchain platforms to derive triangulated data at very high degrees of confidence and speed. With this well-architected integrative technology platform, public health researchers could ensure secure and immutable data sets that enable the collection of high-quality data and allow for deep insights to be made. Local development of these diagnostic tools can help overcome supply chain challenges[24] and related costs, which can limit accessibility of POC diagnostics in resource-limited settings. Additionally, this technology can be adapted for use in community-based case finding of other infectious diseases such as HIV, TB, and Malaria, which may be exacerbated by the current COVID-19 outbreak. However, relevant stakeholders\u2019 involvement is crucial to ensure the efficient development and sustainable implementation of the proposed technology, particularly in underserved populations.\n\nAcknowledgements \nFunding \nThis research received no external funding.\n\nConflicts of interest \nThe authors declare no conflict of interest.\n\nReferences \n\n\n\u2191 Institute for Health Metrics and Evaluation (2018). \"Findings from the Global Burden of Disease Study 2017\" (PDF). Institute for Health Metrics and Evaluation. https:\/\/www.healthdata.org\/sites\/default\/files\/files\/policy_report\/2019\/GBD_2017_Booklet.pdf . Retrieved 25 March 2020 .   \n\n\u2191 Chopera, D. (24 March 2020). \"Can Africa Withstand COVID-19?\". Project Syndicate. https:\/\/www.project-syndicate.org\/commentary\/africa-covid19-advantages-disadvantages-by-denis-chopera-2020-03-2020-03 . Retrieved 25 March 2020 .   \n\n\u2191 Wong, E. (24 March 2020). \"TB, HIV and COVID-19: Urgent questions as three epidemics collide\". The Conversation. https:\/\/theconversation.com\/tb-hiv-and-covid-19-urgent-questions-as-three-epidemics-collide-134554 . Retrieved 25 March 2020 .   \n\n\u2191 Powell, A. (27 March 2020). \"On-again, off-again looks to be best social-distancing option\". The Harvard Gazette. https:\/\/news.harvard.edu\/gazette\/story\/2020\/03\/how-to-prevent-overwhelming-hospitals-and-build-immunity\/ . Retrieved 28 March 2020 .   \n\n\u2191 Whiteside, A. (25 March 2020). \"Covid-19 Watch: The World Wakes Up\". alan-whiteside.com. https:\/\/alan-whiteside.com\/2020\/03\/25\/covid-19-watch-the-crisis-deepens-2\/ . Retrieved 25 March 2020 .   \n\n\u2191 Herida, M.; Dervaux, B.; Desenclos, J.C. (2016). \"Economic Evaluations of Public Health Surveillance Systems: A Systematic Review\". European Journal of Public Health 26 (4): 674\u201380. doi:10.1093\/eurpub\/ckv250. PMC PMC7108512. PMID 26850905. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7108512 .   \n\n\u2191 7.0 7.1 Rattanaumpawan, P.; Boonyasiri, A.; Vong, S. et al. (2018). \"Systematic review of electronic surveillance of infectious diseases with emphasis on antimicrobial resistance surveillance in resource-limited settings\". American Journal of Infection Control 46 (2): 139\u201346. doi:10.1016\/j.ajic.2017.08.006. PMID 29029814.   \n\n\u2191 United Nations (2019). \"The Sustainable Development Goals Report 2019\" (PDF). United Nations. ISBN 978-92-1-047887-8. https:\/\/unstats.un.org\/sdgs\/report\/2019\/The-Sustainable-Development-Goals-Report-2019.pdf . Retrieved 19 March 2020 .   \n\n\u2191 Pang, J.; Wang, M.X.; Ang, I.Y.H. et al. (2020). \"Potential Rapid Diagnostics, Vaccine and Therapeutics for 2019 Novel Coronavirus (2019-nCoV): A Systematic Review\". Journal of Clinical Medicine 9 (3): E623. doi:10.3390\/jcm9030623. PMC PMC7141113. PMID 32110875. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7141113 .   \n\n\u2191 Wang, C.; Horby, P.W.; Hayden, F.G. et al. (2020). \"A novel coronavirus outbreak of global health concern\". Lancet 395 (10223): 470\u201373. doi:10.1016\/S0140-6736(20)30185-9. PMC PMC7135038. PMID 31986257. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7135038 .   \n\n\u2191 Jordans, F. (09 March 2020). \"Experts: Rapid Testing Helps Explain Few German Virus Deaths\". U.S. News & World Report. https:\/\/www.usnews.com\/news\/health-news\/articles\/2020-03-09\/experts-rapid-testing-helps-explain-few-german-virus-deaths . Retrieved 19 March 2020 .   \n\n\u2191 Yaqoob, S.; Khan, M.M.; Talib, R. et al. (2019). \"Use of Blockchain in Healthcare: A Systematic Literature Review\". International Journal of Advanced Computer Science and Applications 10 (5). doi:10.14569\/IJACSA.2019.0100581.   \n\n\u2191 Gomez, M.; Bustamante, P.; Weiss, M.B.H. et al. (2019). \"Is Blockchain the Next Step in the Evolution Chain of [Market] Intermediaries?\". SSRN: 20. doi:10.2139\/ssrn.3427506.   \n\n\u2191 Nakamoto, S.. \"Bitcoin: A Peer-to-Peer Electronic Cash System\" (PDF). https:\/\/bitcoin.org\/bitcoin.pdf . Retrieved 25 March 2020 .   \n\n\u2191 Vincent, O. (2019). \"Can cryptocurrency, mobile phones, and internet herald sustainable financial sector development in emerging markets?\". Journal of Transnational Management 24 (3): 259\u201379. doi:10.1080\/15475778.2019.1633170.   \n\n\u2191 Mettler, M. (2016). \"Blockchain technology in healthcare: The revolution starts here\". Proceedings from the 2016 IEEE 18th International Conference on e-Health Networking, Applications and Services: 1\u20133. doi:10.1109\/HealthCom.2016.7749510.   \n\n\u2191 17.0 17.1 Agbo, C.C.; Mahmoud, Q.H.; Eklund, J.M. (2019). \"Blockchain Technology in Healthcare: A Systematic Review\". Healthcare 7 (2): E56. doi:10.3390\/healthcare7020056. PMC PMC6627742. PMID 30987333. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6627742 .   \n\n\u2191 Zhang, P.; Schmidt, D.C.; White, J.; Lenz, G. (2018). \"Blockchain Technology Use Cases in Healthcare\". Advanced in Computers 111: 1\u201341. doi:10.1016\/bs.adcom.2018.03.006.   \n\n\u2191 Makhudu, S.; Kuupiel, D.; Gwala, N. et al. (2019). \"The Use of Patient Self-Testing in Low- and Middle-Income Countries: A Systematic Scoping Review\". Point of Care 18 (1): 9\u201316. doi:10.1097\/POC.0000000000000179.   \n\n\u2191 Bervell, B.; Al-Samarraie, H. (2019). \"A comparative review of mobile health and electronic health utilization in sub-Saharan African countries\". Social Science & Medicine 232: 1\u201316. doi:10.1016\/j.socscimed.2019.04.024. PMID 31035241.   \n\n\u2191 Adeagbo, O.; Kim, H.Y.; Tanser, F. et al. (2020). \"Acceptability of a tablet-based application to support early HIV testing among men in rural KwaZulu-Natal, South Africa: a mixed method study\". AIDS Care: 1\u20138. doi:10.1080\/09540121.2020.1742867. PMID 32172596.   \n\n\u2191 Pant Pai, N.; Behlim, T.; Abrahams, L. et al. (2013). \"Will an unsupervised self-testing strategy for HIV work in health care workers of South Africa? A cross sectional pilot feasibility study\". PLoS One 8 (11): e79772. doi:10.1371\/journal.pone.0079772. PMC PMC3842310. PMID 24312185. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3842310 .   \n\n\u2191 Tay, I.; Garland, S.; Gorelik, A. et al. (2017). \"Development and Testing of a Mobile Phone App for Self-Monitoring of Calcium Intake in Young Women\". JMIR mHealth and uHealth 5 (3): e27. doi:10.2196\/mhealth.5717. PMC PMC5360908. PMID 28270379. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5360908 .   \n\n\u2191 Kuupiel, D.; Bawontuo, V.; Mashamba-Thompson, T.P. (2017). \"Improving the Accessibility and Efficiency of Point-of-Care Diagnostics Services in Low- and Middle-Income Countries: Lean and Agile Supply Chain Management\". Diagnostics 7 (4): e58. doi:10.3390\/diagnostics7040058. PMC PMC5745394. PMID 29186013. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5745394 .   \n\n\nNotes \nThis presentation is faithful to the original, with only a few minor changes to presentation. In some cases important information was missing from the references, and that information was added.\n\n\n\n\n\n\nSource: <a rel=\"external_link\" class=\"external\" href=\"https:\/\/www.limswiki.org\/index.php\/Journal:Blockchain_and_artificial_intelligence_technology_for_novel_coronavirus_disease_2019_self-testing\">https:\/\/www.limswiki.org\/index.php\/Journal:Blockchain_and_artificial_intelligence_technology_for_novel_coronavirus_disease_2019_self-testing<\/a>\n\t\t\t\t\tCategories: LIMSwiki journal articles (added in 2020)LIMSwiki journal articles (all)LIMSwiki journal articles on artificial intelligenceLIMSwiki journal articles on epidemiology\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\n\t\t\t\t\n\t\t\t\n\t\t\n\t\t\n\t\t\tNavigation menu\n\t\t\t\t\t\n\t\t\tViews\n\n\t\t\t\n\t\t\t\t\n\t\t\t\tJournal\n\t\t\t\tDiscussion\n\t\t\t\tView source\n\t\t\t\tHistory\n\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\n\t\t\t\t\n\t\t\t\tPersonal tools\n\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\t\t\tLog in\n\t\t\t\t\t\t\t\t\t\t\t\t\tRequest account\n\t\t\t\t\t\t\t\t\t\t\t\n\t\t\t\t\n\t\t\t\n\t\t\t\n\t\t\t\t\n\t\t\t\n\t\t\t\t\n\t\tNavigation\n\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\tMain page\n\t\t\t\t\t\t\t\t\t\t\tRecent changes\n\t\t\t\t\t\t\t\t\t\t\tRandom page\n\t\t\t\t\t\t\t\t\t\t\tHelp\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\n\t\t\t\n\t\t\tSearch\n\n\t\t\t\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t \n\t\t\t\t\t\t\n\t\t\t\t\n\n\t\t\t\t\t\t\t\n\t\t\n\t\t\t\n\t\t\tTools\n\n\t\t\t\n\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\tWhat links here\n\t\t\t\t\t\t\t\t\t\t\tRelated changes\n\t\t\t\t\t\t\t\t\t\t\tSpecial pages\n\t\t\t\t\t\t\t\t\t\t\tPermanent link\n\t\t\t\t\t\t\t\t\t\t\tPage information\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\n\t\t\n\t\tPrint\/export\n\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\tCreate a book\n\t\t\t\t\t\t\t\t\t\t\tDownload as PDF\n\t\t\t\t\t\t\t\t\t\t\tDownload as Plain text\n\t\t\t\t\t\t\t\t\t\t\tPrintable version\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\n\t\t\n\t\tSponsors\n\t\t\n\t\t\t \r\n\n\t\r\n\n\t\r\n\n\t\n\t\r\n\n\t\r\n\n\t\n\t\r\n\n \n\t\r\n\n\t\n\t\r\n\n \n\t\n\t\r\n\n\t\n\t\n\t\r\n\n\t\r\n\n\t\r\n\n\t\n\t\r\n\n\t\r\n\t\t\n\t\t\n\t\t\t\n\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t This page was last modified on 20 April 2020, at 21:59.\n\t\t\t\t\t\t\t\t\tThis page has been accessed 435 times.\n\t\t\t\t\t\t\t\t\tContent is available under a Creative Commons Attribution-ShareAlike 4.0 International License unless otherwise noted.\n\t\t\t\t\t\t\t\t\tPrivacy policy\n\t\t\t\t\t\t\t\t\tAbout LIMSWiki\n\t\t\t\t\t\t\t\t\tDisclaimers\n\t\t\t\t\t\t\t\n\t\t\n\t\t\n\t\t\n\n","02fce1e6c14e5effed2c3ceedc4e9443_html":"<body class=\"mediawiki ltr sitedir-ltr ns-206 ns-subject page-Journal_Blockchain_and_artificial_intelligence_technology_for_novel_coronavirus_disease_2019_self-testing skin-monobook action-view\">\n<div id=\"rdp-ebb-globalWrapper\">\n\t\t<div id=\"rdp-ebb-column-content\">\n\t\t\t<div id=\"rdp-ebb-content\" class=\"mw-body\" role=\"main\">\n\t\t\t\t<a id=\"rdp-ebb-top\"><\/a>\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t<h1 id=\"rdp-ebb-firstHeading\" class=\"firstHeading\" lang=\"en\">Journal:Blockchain and artificial intelligence technology for novel coronavirus disease 2019 self-testing<\/h1>\n\t\t\t\t\n\t\t\t\t<div id=\"rdp-ebb-bodyContent\" class=\"mw-body-content\">\n\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\n\n\t\t\t\t\t<!-- start content -->\n\t\t\t\t\t<div id=\"rdp-ebb-mw-content-text\" lang=\"en\" dir=\"ltr\" class=\"mw-content-ltr\">\n\n\n<h2><span class=\"mw-headline\" id=\"Abstract\">Abstract<\/span><\/h2>\n<p>The novel <a href=\"https:\/\/www.limswiki.org\/index.php\/Coronavirus_disease_2019\" title=\"Coronavirus disease 2019\" class=\"wiki-link\" data-key=\"68331dff29df205bcb39c3ad9599c30c\">coronavirus disease 2019<\/a> (COVID-19) is rapidly spreading, with a rising death toll and transmission rate reported in high-income countries rather than in low-income countries. However, the overburdened healthcare systems and poor disease surveillance systems in resource-limited settings may struggle to cope with this COVID-19 outbreak, which calls for a tailored strategic response within these settings. Here, we recommend a low-cost <a href=\"https:\/\/www.limswiki.org\/index.php\/Blockchain\" title=\"Blockchain\" class=\"wiki-link\" data-key=\"ae8b186c311716aca561aaee91944f8e\">blockchain<\/a> and <a href=\"https:\/\/www.limswiki.org\/index.php\/Artificial_intelligence\" title=\"Artificial intelligence\" class=\"wiki-link\" data-key=\"0c45a597361ca47e1cd8112af676276e\">artificial intelligence<\/a>-coupled self-testing and tracking system for COVID-19 and other emerging infectious diseases. Prompt deployment and appropriate implementation of the proposed system have the potential to curb the transmission of COVID-19 and its related mortalities, particularly in settings with poor access to <a href=\"https:\/\/www.limswiki.org\/index.php\/Laboratory\" title=\"Laboratory\" class=\"wiki-link\" data-key=\"c57fc5aac9e4abf31dccae81df664c33\">laboratory<\/a> infrastructure.\n<\/p><p><b>Keywords<\/b>: self-testing, novel coronavirus disease-19, blockchain, artificial intelligence\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Editorial\">Editorial<\/span><\/h2>\n<p>The novel <a href=\"https:\/\/www.limswiki.org\/index.php\/Coronavirus_disease_2019\" title=\"Coronavirus disease 2019\" class=\"wiki-link\" data-key=\"68331dff29df205bcb39c3ad9599c30c\">coronavirus disease 2019<\/a> (COVID-19) has now reached sub-Saharan Africa (SSA), with cases reported in more than 40 SSA countries. SSA health systems are already battling with poor health outcomes and high mortality rates linked to the unique quadruple (HIV, tuberculosis (TB), and non-communicable diseases) burden of disease.<sup id=\"rdp-ebb-cite_ref-IHMEFindings18_1-0\" class=\"reference\"><a href=\"#cite_note-IHMEFindings18-1\">[1]<\/a><\/sup> In addition, SSA\u2019s dense communities, informal settlements, and rural and resource-limited settings are at particular risk for being vulnerable to the COVID-19 outbreak. These populations are underserved in terms of health services and have the potential to become to new COVID-19 epicenters. The global COVID-19 statistics surprisingly show low transmission rates and fewer deaths in resource-limited countries, particularly countries in Sub-Saharan Africa (SSA). However, while SSA\u2019s young population and warm climate may put SSA at an advantage for coping with the COVID-19 outbreak<sup id=\"rdp-ebb-cite_ref-ChoperaCanAfrica20_2-0\" class=\"reference\"><a href=\"#cite_note-ChoperaCanAfrica20-2\">[2]<\/a><\/sup>, there is growing concern about the impact of COVID-19 co-infections among the people living with other immune-system-weakening conditions such as HIV, TB, and diabetes, particularly given a struggling health care system in resource-limited settings such as SSA countries.<sup id=\"rdp-ebb-cite_ref-WongTB20_3-0\" class=\"reference\"><a href=\"#cite_note-WongTB20-3\">[3]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-LovenOnAgain20_4-0\" class=\"reference\"><a href=\"#cite_note-LovenOnAgain20-4\">[4]<\/a><\/sup>\n<\/p><p>There is a growing concern about a failure to find and report cases, especially given weak health systems, inadequate surveillance, insufficient <a href=\"https:\/\/www.limswiki.org\/index.php\/Laboratory\" title=\"Laboratory\" class=\"wiki-link\" data-key=\"c57fc5aac9e4abf31dccae81df664c33\">laboratory<\/a> capacity, and limited public health infrastructure in African countries.<sup id=\"rdp-ebb-cite_ref-WhitesideCOVID20_5-0\" class=\"reference\"><a href=\"#cite_note-WhitesideCOVID20-5\">[5]<\/a><\/sup> Access to accurate diagnosis, monitoring, and reporting of health outbreaks requires a well-resourced healthcare system.<sup id=\"rdp-ebb-cite_ref-HeridaEcon16_6-0\" class=\"reference\"><a href=\"#cite_note-HeridaEcon16-6\">[6]<\/a><\/sup> Evidence shows that most resource-limited countries lack an effective, rapid surveillance system.<sup id=\"rdp-ebb-cite_ref-RattanaumpawanSyst18_7-0\" class=\"reference\"><a href=\"#cite_note-RattanaumpawanSyst18-7\">[7]<\/a><\/sup> These settings also have a limited availability of health technologies for the electronic surveillance of infectious diseases to facilitate the prevention and containment of emerging infectious diseases such as COVID-19.<sup id=\"rdp-ebb-cite_ref-RattanaumpawanSyst18_7-1\" class=\"reference\"><a href=\"#cite_note-RattanaumpawanSyst18-7\">[7]<\/a><\/sup> Universal health coverage, as well as access to high-quality and timely pathology and laboratory medicine (PALM) services, is crucially needed to support healthcare systems that are tasked with achieving sustainable developmental goals.<sup id=\"rdp-ebb-cite_ref-UNTheSust19_8-0\" class=\"reference\"><a href=\"#cite_note-UNTheSust19-8\">[8]<\/a><\/sup> This calls for the rapid development and deployment of health innovations for accurate diagnosis and electronic surveillance of COVID-19 in underserved populations.\n<\/p><p>Recent evidence shows that prompt development and deployment of point-of-care (POC) diagnostics for screening in response to the COVID-19 outbreak can help to curb the spread of the disease and to alleviate the burden on the healthcare system.<sup id=\"rdp-ebb-cite_ref-PangPotent20_9-0\" class=\"reference\"><a href=\"#cite_note-PangPotent20-9\">[9]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-WangANovel20_10-0\" class=\"reference\"><a href=\"#cite_note-WangANovel20-10\">[10]<\/a><\/sup> The impact of rapid testing on the COVID-19 death rate has been shown in Germany.<sup id=\"rdp-ebb-cite_ref-JordansExperts20_11-0\" class=\"reference\"><a href=\"#cite_note-JordansExperts20-11\">[11]<\/a><\/sup> Emerging health innovations such as <a href=\"https:\/\/www.limswiki.org\/index.php\/Blockchain\" title=\"Blockchain\" class=\"wiki-link\" data-key=\"ae8b186c311716aca561aaee91944f8e\">blockchain<\/a> and <a href=\"https:\/\/www.limswiki.org\/index.php\/Artificial_intelligence\" title=\"Artificial intelligence\" class=\"wiki-link\" data-key=\"0c45a597361ca47e1cd8112af676276e\">artificial intelligence<\/a> (AI) technology can be coupled with POC diagnostics to enable self-testing of patients in isolation as a result of exposure to COVID-19. Blockchain is a digital, public ledger that records online transactions. It involves the digital distribution of ledger and consensus algorithms and eliminates all the threats of intermediaries.<sup id=\"rdp-ebb-cite_ref-YaqoobUseOf19_12-0\" class=\"reference\"><a href=\"#cite_note-YaqoobUseOf19-12\">[12]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-GomezIsBlock19_13-0\" class=\"reference\"><a href=\"#cite_note-GomezIsBlock19-13\">[13]<\/a><\/sup> One of the commonly-known applications of blockchain is the cryptocurrency Bitcoin<sup id=\"rdp-ebb-cite_ref-NakamotoBit_14-0\" class=\"reference\"><a href=\"#cite_note-NakamotoBit-14\">[14]<\/a><\/sup>, which has been successfully used as a financial alternative in emerging economies including countries in SSA.<sup id=\"rdp-ebb-cite_ref-VincentCanCrypto19_15-0\" class=\"reference\"><a href=\"#cite_note-VincentCanCrypto19-15\">[15]<\/a><\/sup> Blockchain technology has shown adaptability in recent years, leading to its incorporation in a wide range of applications, including biomedical and healthcare systems.<sup id=\"rdp-ebb-cite_ref-MettlerBlock16_16-0\" class=\"reference\"><a href=\"#cite_note-MettlerBlock16-16\">[16]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-AgboBlock19_17-0\" class=\"reference\"><a href=\"#cite_note-AgboBlock19-17\">[17]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ZhangBlock18_18-0\" class=\"reference\"><a href=\"#cite_note-ZhangBlock18-18\">[18]<\/a><\/sup> The use of blockchain and AI in healthcare has been demonstrated in the management of electronic medical records, drug and pharmaceutical supply chains, biomedical research, education, remote patient monitoring, and healthcare data analytics.<sup id=\"rdp-ebb-cite_ref-AgboBlock19_17-1\" class=\"reference\"><a href=\"#cite_note-AgboBlock19-17\">[17]<\/a><\/sup>\n<\/p><p>Mobile connected point-of-care diagnostics and self-testing has been successfully implemented in resource-limited settings.<sup id=\"rdp-ebb-cite_ref-MakhuduTheUse19_19-0\" class=\"reference\"><a href=\"#cite_note-MakhuduTheUse19-19\">[19]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-BervellAComp19_20-0\" class=\"reference\"><a href=\"#cite_note-BervellAComp19-20\">[20]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-AdeagboAccept20_21-0\" class=\"reference\"><a href=\"#cite_note-AdeagboAccept20-21\">[21]<\/a><\/sup> However, there is limited evidence on the use of blockchain and AI technology for disease diagnosis. Bearing in mind the era of COVID-19 and the evidence on the overburdened healthcare systems and poor disease surveillance systems in resource-limited settings, and taking advantage of the available mobile Health (mHealth) systems, we recommend a rapid development and deployment of low-cost blockchain and AI-coupled mHealth connected self-testing and tracking systems as one of the strategic response strategies for COVID-19 and other emerging infectious diseases (Figure 1).\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig1_Mashamba-Thompson_Diagnostics2020_10-4.png\" class=\"image wiki-link\" data-key=\"f07e4b78add5483e917227da69c91ef7\"><img alt=\"Fig1 Mashamba-Thompson Diagnostics2020 10-4.png\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/a\/a2\/Fig1_Mashamba-Thompson_Diagnostics2020_10-4.png\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Figure 1.<\/b> Proposed community-based blockchain and artificial intelligence-coupled mobile-linked self-testing and tracking system for emerging infectious diseases.<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>The initial step for this system is through a mobile phone or tablet application (app) which could be adapted from existing self-testing apps.<sup id=\"rdp-ebb-cite_ref-PantPaiWill13_22-0\" class=\"reference\"><a href=\"#cite_note-PantPaiWill13-22\">[22]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-TayDevelop17_23-0\" class=\"reference\"><a href=\"#cite_note-TayDevelop17-23\">[23]<\/a><\/sup> The app requests a user\u2019s personal identifier before opening pre-testing instructions. Following testing, the user then uploads results into the app. The blockchain and AI system enables the transfer of the test result to alert the outbreak surveillance authorities of all tests performed, as well as the number of positive and negative test results. This helps ensure that all positive cases are referred to a quarantine site for treatment and monitoring. The built-in <a href=\"https:\/\/www.limswiki.org\/index.php\/Geographic_information_system\" title=\"Geographic information system\" class=\"wiki-link\" data-key=\"8981ab93f8ebf0730c3b38949b39ad99\">geographic information system<\/a> (GIS) in mobile devices enables the tracking of those who tested positive. This system could also be connected to local, national, and international databases to ensure appropriate surveillance and control of an outbreak.\n<\/p><p>The AI component of this technology enables powerful data collection (patient information, geographic location of the patient, and test results), security, analysis, and curation of disparate and clinical data sets from federated blockchain platforms to derive triangulated data at very high degrees of confidence and speed. With this well-architected integrative technology platform, public health researchers could ensure secure and immutable data sets that enable the collection of high-quality data and allow for deep insights to be made. Local development of these diagnostic tools can help overcome supply chain challenges<sup id=\"rdp-ebb-cite_ref-KuupielImproving_24-0\" class=\"reference\"><a href=\"#cite_note-KuupielImproving-24\">[24]<\/a><\/sup> and related costs, which can limit accessibility of POC diagnostics in resource-limited settings. Additionally, this technology can be adapted for use in community-based case finding of other infectious diseases such as HIV, TB, and Malaria, which may be exacerbated by the current COVID-19 outbreak. However, relevant stakeholders\u2019 involvement is crucial to ensure the efficient development and sustainable implementation of the proposed technology, particularly in underserved populations.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Acknowledgements\">Acknowledgements<\/span><\/h2>\n<h3><span class=\"mw-headline\" id=\"Funding\">Funding<\/span><\/h3>\n<p>This research received no external funding.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Conflicts_of_interest\">Conflicts of interest<\/span><\/h3>\n<p>The authors declare no conflict of interest.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"References\">References<\/span><\/h2>\n<div class=\"reflist references-column-width\" style=\"-moz-column-width: 30em; -webkit-column-width: 30em; column-width: 30em; list-style-type: decimal;\">\n<ol class=\"references\">\n<li id=\"cite_note-IHMEFindings18-1\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-IHMEFindings18_1-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Institute for Health Metrics and Evaluation (2018). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.healthdata.org\/sites\/default\/files\/files\/policy_report\/2019\/GBD_2017_Booklet.pdf\" target=\"_blank\">\"Findings from the Global Burden of Disease Study 2017\"<\/a> (PDF). Institute for Health Metrics and Evaluation<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.healthdata.org\/sites\/default\/files\/files\/policy_report\/2019\/GBD_2017_Booklet.pdf\" target=\"_blank\">https:\/\/www.healthdata.org\/sites\/default\/files\/files\/policy_report\/2019\/GBD_2017_Booklet.pdf<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 25 March 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Findings+from+the+Global+Burden+of+Disease+Study+2017&rft.atitle=&rft.aulast=Institute+for+Health+Metrics+and+Evaluation&rft.au=Institute+for+Health+Metrics+and+Evaluation&rft.date=2018&rft.pub=Institute+for+Health+Metrics+and+Evaluation&rft_id=https%3A%2F%2Fwww.healthdata.org%2Fsites%2Fdefault%2Ffiles%2Ffiles%2Fpolicy_report%2F2019%2FGBD_2017_Booklet.pdf&rfr_id=info:sid\/en.wikipedia.org:Journal:Blockchain_and_artificial_intelligence_technology_for_novel_coronavirus_disease_2019_self-testing\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ChoperaCanAfrica20-2\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-ChoperaCanAfrica20_2-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Chopera, D. (24 March 2020). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.project-syndicate.org\/commentary\/africa-covid19-advantages-disadvantages-by-denis-chopera-2020-03-2020-03\" target=\"_blank\">\"Can Africa Withstand COVID-19?\"<\/a>. <i>Project Syndicate<\/i><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.project-syndicate.org\/commentary\/africa-covid19-advantages-disadvantages-by-denis-chopera-2020-03-2020-03\" target=\"_blank\">https:\/\/www.project-syndicate.org\/commentary\/africa-covid19-advantages-disadvantages-by-denis-chopera-2020-03-2020-03<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 25 March 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Can+Africa+Withstand+COVID-19%3F&rft.atitle=Project+Syndicate&rft.aulast=Chopera%2C+D.&rft.au=Chopera%2C+D.&rft.date=24+March+2020&rft_id=https%3A%2F%2Fwww.project-syndicate.org%2Fcommentary%2Fafrica-covid19-advantages-disadvantages-by-denis-chopera-2020-03-2020-03&rfr_id=info:sid\/en.wikipedia.org:Journal:Blockchain_and_artificial_intelligence_technology_for_novel_coronavirus_disease_2019_self-testing\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-WongTB20-3\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-WongTB20_3-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Wong, E. (24 March 2020). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/theconversation.com\/tb-hiv-and-covid-19-urgent-questions-as-three-epidemics-collide-134554\" target=\"_blank\">\"TB, HIV and COVID-19: Urgent questions as three epidemics collide\"<\/a>. <i>The Conversation<\/i><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/theconversation.com\/tb-hiv-and-covid-19-urgent-questions-as-three-epidemics-collide-134554\" target=\"_blank\">https:\/\/theconversation.com\/tb-hiv-and-covid-19-urgent-questions-as-three-epidemics-collide-134554<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 25 March 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=TB%2C+HIV+and+COVID-19%3A+Urgent+questions+as+three+epidemics+collide&rft.atitle=The+Conversation&rft.aulast=Wong%2C+E.&rft.au=Wong%2C+E.&rft.date=24+March+2020&rft_id=https%3A%2F%2Ftheconversation.com%2Ftb-hiv-and-covid-19-urgent-questions-as-three-epidemics-collide-134554&rfr_id=info:sid\/en.wikipedia.org:Journal:Blockchain_and_artificial_intelligence_technology_for_novel_coronavirus_disease_2019_self-testing\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-LovenOnAgain20-4\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-LovenOnAgain20_4-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Powell, A. (27 March 2020). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/news.harvard.edu\/gazette\/story\/2020\/03\/how-to-prevent-overwhelming-hospitals-and-build-immunity\/\" target=\"_blank\">\"On-again, off-again looks to be best social-distancing option\"<\/a>. <i>The Harvard Gazette<\/i><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/news.harvard.edu\/gazette\/story\/2020\/03\/how-to-prevent-overwhelming-hospitals-and-build-immunity\/\" target=\"_blank\">https:\/\/news.harvard.edu\/gazette\/story\/2020\/03\/how-to-prevent-overwhelming-hospitals-and-build-immunity\/<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 28 March 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=On-again%2C+off-again+looks+to+be+best+social-distancing+option&rft.atitle=The+Harvard+Gazette&rft.aulast=Powell%2C+A.&rft.au=Powell%2C+A.&rft.date=27+March+2020&rft_id=https%3A%2F%2Fnews.harvard.edu%2Fgazette%2Fstory%2F2020%2F03%2Fhow-to-prevent-overwhelming-hospitals-and-build-immunity%2F&rfr_id=info:sid\/en.wikipedia.org:Journal:Blockchain_and_artificial_intelligence_technology_for_novel_coronavirus_disease_2019_self-testing\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-WhitesideCOVID20-5\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-WhitesideCOVID20_5-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Whiteside, A. (25 March 2020). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/alan-whiteside.com\/2020\/03\/25\/covid-19-watch-the-crisis-deepens-2\/\" target=\"_blank\">\"Covid-19 Watch: The World Wakes Up\"<\/a>. <i>alan-whiteside.com<\/i><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/alan-whiteside.com\/2020\/03\/25\/covid-19-watch-the-crisis-deepens-2\/\" target=\"_blank\">https:\/\/alan-whiteside.com\/2020\/03\/25\/covid-19-watch-the-crisis-deepens-2\/<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 25 March 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Covid-19+Watch%3A+The+World+Wakes+Up&rft.atitle=alan-whiteside.com&rft.aulast=Whiteside%2C+A.&rft.au=Whiteside%2C+A.&rft.date=25+March+2020&rft_id=https%3A%2F%2Falan-whiteside.com%2F2020%2F03%2F25%2Fcovid-19-watch-the-crisis-deepens-2%2F&rfr_id=info:sid\/en.wikipedia.org:Journal:Blockchain_and_artificial_intelligence_technology_for_novel_coronavirus_disease_2019_self-testing\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-HeridaEcon16-6\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-HeridaEcon16_6-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Herida, M.; Dervaux, B.; Desenclos, J.C. (2016). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7108512\" target=\"_blank\">\"Economic Evaluations of Public Health Surveillance Systems: A Systematic Review\"<\/a>. <i>European Journal of Public Health<\/i> <b>26<\/b> (4): 674\u201380. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1093%2Feurpub%2Fckv250\" target=\"_blank\">10.1093\/eurpub\/ckv250<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC7108512\/\" target=\"_blank\">PMC7108512<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/26850905\" target=\"_blank\">26850905<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7108512\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7108512<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Economic+Evaluations+of+Public+Health+Surveillance+Systems%3A+A+Systematic+Review&rft.jtitle=European+Journal+of+Public+Health&rft.aulast=Herida%2C+M.%3B+Dervaux%2C+B.%3B+Desenclos%2C+J.C.&rft.au=Herida%2C+M.%3B+Dervaux%2C+B.%3B+Desenclos%2C+J.C.&rft.date=2016&rft.volume=26&rft.issue=4&rft.pages=674%E2%80%9380&rft_id=info:doi\/10.1093%2Feurpub%2Fckv250&rft_id=info:pmc\/PMC7108512&rft_id=info:pmid\/26850905&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC7108512&rfr_id=info:sid\/en.wikipedia.org:Journal:Blockchain_and_artificial_intelligence_technology_for_novel_coronavirus_disease_2019_self-testing\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-RattanaumpawanSyst18-7\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-RattanaumpawanSyst18_7-0\">7.0<\/a><\/sup> <sup><a href=\"#cite_ref-RattanaumpawanSyst18_7-1\">7.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Rattanaumpawan, P.; Boonyasiri, A.; Vong, S. et al. (2018). \"Systematic review of electronic surveillance of infectious diseases with emphasis on antimicrobial resistance surveillance in resource-limited settings\". <i>American Journal of Infection Control<\/i> <b>46<\/b> (2): 139\u201346. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.ajic.2017.08.006\" target=\"_blank\">10.1016\/j.ajic.2017.08.006<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/29029814\" target=\"_blank\">29029814<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Systematic+review+of+electronic+surveillance+of+infectious+diseases+with+emphasis+on+antimicrobial+resistance+surveillance+in+resource-limited+settings&rft.jtitle=American+Journal+of+Infection+Control&rft.aulast=Rattanaumpawan%2C+P.%3B+Boonyasiri%2C+A.%3B+Vong%2C+S.+et+al.&rft.au=Rattanaumpawan%2C+P.%3B+Boonyasiri%2C+A.%3B+Vong%2C+S.+et+al.&rft.date=2018&rft.volume=46&rft.issue=2&rft.pages=139%E2%80%9346&rft_id=info:doi\/10.1016%2Fj.ajic.2017.08.006&rft_id=info:pmid\/29029814&rfr_id=info:sid\/en.wikipedia.org:Journal:Blockchain_and_artificial_intelligence_technology_for_novel_coronavirus_disease_2019_self-testing\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-UNTheSust19-8\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-UNTheSust19_8-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">United Nations (2019). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/unstats.un.org\/sdgs\/report\/2019\/The-Sustainable-Development-Goals-Report-2019.pdf\" target=\"_blank\">\"The Sustainable Development Goals Report 2019\"<\/a> (PDF). United Nations. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/International_Standard_Book_Number\" data-key=\"f64947ba21e884434bd70e8d9e60bae6\">ISBN<\/a> 978-92-1-047887-8<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/unstats.un.org\/sdgs\/report\/2019\/The-Sustainable-Development-Goals-Report-2019.pdf\" target=\"_blank\">https:\/\/unstats.un.org\/sdgs\/report\/2019\/The-Sustainable-Development-Goals-Report-2019.pdf<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 19 March 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=The+Sustainable+Development+Goals+Report+2019&rft.atitle=&rft.aulast=United+Nations&rft.au=United+Nations&rft.date=2019&rft.pub=United+Nations&rft.isbn=978-92-1-047887-8&rft_id=https%3A%2F%2Funstats.un.org%2Fsdgs%2Freport%2F2019%2FThe-Sustainable-Development-Goals-Report-2019.pdf&rfr_id=info:sid\/en.wikipedia.org:Journal:Blockchain_and_artificial_intelligence_technology_for_novel_coronavirus_disease_2019_self-testing\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-PangPotent20-9\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-PangPotent20_9-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Pang, J.; Wang, M.X.; Ang, I.Y.H. et al. (2020). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7141113\" target=\"_blank\">\"Potential Rapid Diagnostics, Vaccine and Therapeutics for 2019 Novel Coronavirus (2019-nCoV): A Systematic Review\"<\/a>. <i>Journal of Clinical Medicine<\/i> <b>9<\/b> (3): E623. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.3390%2Fjcm9030623\" target=\"_blank\">10.3390\/jcm9030623<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC7141113\/\" target=\"_blank\">PMC7141113<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/32110875\" target=\"_blank\">32110875<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7141113\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7141113<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Potential+Rapid+Diagnostics%2C+Vaccine+and+Therapeutics+for+2019+Novel+Coronavirus+%282019-nCoV%29%3A+A+Systematic+Review&rft.jtitle=Journal+of+Clinical+Medicine&rft.aulast=Pang%2C+J.%3B+Wang%2C+M.X.%3B+Ang%2C+I.Y.H.+et+al.&rft.au=Pang%2C+J.%3B+Wang%2C+M.X.%3B+Ang%2C+I.Y.H.+et+al.&rft.date=2020&rft.volume=9&rft.issue=3&rft.pages=E623&rft_id=info:doi\/10.3390%2Fjcm9030623&rft_id=info:pmc\/PMC7141113&rft_id=info:pmid\/32110875&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC7141113&rfr_id=info:sid\/en.wikipedia.org:Journal:Blockchain_and_artificial_intelligence_technology_for_novel_coronavirus_disease_2019_self-testing\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-WangANovel20-10\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-WangANovel20_10-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Wang, C.; Horby, P.W.; Hayden, F.G. et al. (2020). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7135038\" target=\"_blank\">\"A novel coronavirus outbreak of global health concern\"<\/a>. <i>Lancet<\/i> <b>395<\/b> (10223): 470\u201373. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2FS0140-6736%2820%2930185-9\" target=\"_blank\">10.1016\/S0140-6736(20)30185-9<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC7135038\/\" target=\"_blank\">PMC7135038<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/31986257\" target=\"_blank\">31986257<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7135038\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7135038<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=A+novel+coronavirus+outbreak+of+global+health+concern&rft.jtitle=Lancet&rft.aulast=Wang%2C+C.%3B+Horby%2C+P.W.%3B+Hayden%2C+F.G.+et+al.&rft.au=Wang%2C+C.%3B+Horby%2C+P.W.%3B+Hayden%2C+F.G.+et+al.&rft.date=2020&rft.volume=395&rft.issue=10223&rft.pages=470%E2%80%9373&rft_id=info:doi\/10.1016%2FS0140-6736%2820%2930185-9&rft_id=info:pmc\/PMC7135038&rft_id=info:pmid\/31986257&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC7135038&rfr_id=info:sid\/en.wikipedia.org:Journal:Blockchain_and_artificial_intelligence_technology_for_novel_coronavirus_disease_2019_self-testing\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-JordansExperts20-11\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-JordansExperts20_11-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Jordans, F. (09 March 2020). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.usnews.com\/news\/health-news\/articles\/2020-03-09\/experts-rapid-testing-helps-explain-few-german-virus-deaths\" target=\"_blank\">\"Experts: Rapid Testing Helps Explain Few German Virus Deaths\"<\/a>. <i>U.S. News & World Report<\/i><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.usnews.com\/news\/health-news\/articles\/2020-03-09\/experts-rapid-testing-helps-explain-few-german-virus-deaths\" target=\"_blank\">https:\/\/www.usnews.com\/news\/health-news\/articles\/2020-03-09\/experts-rapid-testing-helps-explain-few-german-virus-deaths<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 19 March 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Experts%3A+Rapid+Testing+Helps+Explain+Few+German+Virus+Deaths&rft.atitle=U.S.+News+%26+World+Report&rft.aulast=Jordans%2C+F.&rft.au=Jordans%2C+F.&rft.date=09+March+2020&rft_id=https%3A%2F%2Fwww.usnews.com%2Fnews%2Fhealth-news%2Farticles%2F2020-03-09%2Fexperts-rapid-testing-helps-explain-few-german-virus-deaths&rfr_id=info:sid\/en.wikipedia.org:Journal:Blockchain_and_artificial_intelligence_technology_for_novel_coronavirus_disease_2019_self-testing\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-YaqoobUseOf19-12\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-YaqoobUseOf19_12-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Yaqoob, S.; Khan, M.M.; Talib, R. et al. (2019). \"Use of Blockchain in Healthcare: A Systematic Literature Review\". <i>International Journal of Advanced Computer Science and Applications<\/i> <b>10<\/b> (5). <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.14569%2FIJACSA.2019.0100581\" target=\"_blank\">10.14569\/IJACSA.2019.0100581<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Use+of+Blockchain+in+Healthcare%3A+A+Systematic+Literature+Review&rft.jtitle=International+Journal+of+Advanced+Computer+Science+and+Applications&rft.aulast=Yaqoob%2C+S.%3B+Khan%2C+M.M.%3B+Talib%2C+R.+et+al.&rft.au=Yaqoob%2C+S.%3B+Khan%2C+M.M.%3B+Talib%2C+R.+et+al.&rft.date=2019&rft.volume=10&rft.issue=5&rft_id=info:doi\/10.14569%2FIJACSA.2019.0100581&rfr_id=info:sid\/en.wikipedia.org:Journal:Blockchain_and_artificial_intelligence_technology_for_novel_coronavirus_disease_2019_self-testing\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-GomezIsBlock19-13\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-GomezIsBlock19_13-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Gomez, M.; Bustamante, P.; Weiss, M.B.H. et al. (2019). \"Is Blockchain the Next Step in the Evolution Chain of [Market] Intermediaries?\". <i>SSRN<\/i>: 20. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.2139%2Fssrn.3427506\" target=\"_blank\">10.2139\/ssrn.3427506<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Is+Blockchain+the+Next+Step+in+the+Evolution+Chain+of+%5BMarket%5D+Intermediaries%3F&rft.jtitle=SSRN&rft.aulast=Gomez%2C+M.%3B+Bustamante%2C+P.%3B+Weiss%2C+M.B.H.+et+al.&rft.au=Gomez%2C+M.%3B+Bustamante%2C+P.%3B+Weiss%2C+M.B.H.+et+al.&rft.date=2019&rft.pages=20&rft_id=info:doi\/10.2139%2Fssrn.3427506&rfr_id=info:sid\/en.wikipedia.org:Journal:Blockchain_and_artificial_intelligence_technology_for_novel_coronavirus_disease_2019_self-testing\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-NakamotoBit-14\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-NakamotoBit_14-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Nakamoto, S.. <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/bitcoin.org\/bitcoin.pdf\" target=\"_blank\">\"Bitcoin: A Peer-to-Peer Electronic Cash System\"<\/a> (PDF)<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/bitcoin.org\/bitcoin.pdf\" target=\"_blank\">https:\/\/bitcoin.org\/bitcoin.pdf<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 25 March 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Bitcoin%3A+A+Peer-to-Peer+Electronic+Cash+System&rft.atitle=&rft.aulast=Nakamoto%2C+S.&rft.au=Nakamoto%2C+S.&rft_id=https%3A%2F%2Fbitcoin.org%2Fbitcoin.pdf&rfr_id=info:sid\/en.wikipedia.org:Journal:Blockchain_and_artificial_intelligence_technology_for_novel_coronavirus_disease_2019_self-testing\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-VincentCanCrypto19-15\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-VincentCanCrypto19_15-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Vincent, O. (2019). \"Can cryptocurrency, mobile phones, and internet herald sustainable financial sector development in emerging markets?\". <i>Journal of Transnational Management<\/i> <b>24<\/b> (3): 259\u201379. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1080%2F15475778.2019.1633170\" target=\"_blank\">10.1080\/15475778.2019.1633170<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Can+cryptocurrency%2C+mobile+phones%2C+and+internet+herald+sustainable+financial+sector+development+in+emerging+markets%3F&rft.jtitle=Journal+of+Transnational+Management&rft.aulast=Vincent%2C+O.&rft.au=Vincent%2C+O.&rft.date=2019&rft.volume=24&rft.issue=3&rft.pages=259%E2%80%9379&rft_id=info:doi\/10.1080%2F15475778.2019.1633170&rfr_id=info:sid\/en.wikipedia.org:Journal:Blockchain_and_artificial_intelligence_technology_for_novel_coronavirus_disease_2019_self-testing\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-MettlerBlock16-16\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-MettlerBlock16_16-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Mettler, M. (2016). \"Blockchain technology in healthcare: The revolution starts here\". <i>Proceedings from the 2016 IEEE 18th International Conference on e-Health Networking, Applications and Services<\/i>: 1\u20133. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1109%2FHealthCom.2016.7749510\" target=\"_blank\">10.1109\/HealthCom.2016.7749510<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Blockchain+technology+in+healthcare%3A+The+revolution+starts+here&rft.jtitle=Proceedings+from+the+2016+IEEE+18th+International+Conference+on+e-Health+Networking%2C+Applications+and+Services&rft.aulast=Mettler%2C+M.&rft.au=Mettler%2C+M.&rft.date=2016&rft.pages=1%E2%80%933&rft_id=info:doi\/10.1109%2FHealthCom.2016.7749510&rfr_id=info:sid\/en.wikipedia.org:Journal:Blockchain_and_artificial_intelligence_technology_for_novel_coronavirus_disease_2019_self-testing\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-AgboBlock19-17\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-AgboBlock19_17-0\">17.0<\/a><\/sup> <sup><a href=\"#cite_ref-AgboBlock19_17-1\">17.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Agbo, C.C.; Mahmoud, Q.H.; Eklund, J.M. (2019). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6627742\" target=\"_blank\">\"Blockchain Technology in Healthcare: A Systematic Review\"<\/a>. <i>Healthcare<\/i> <b>7<\/b> (2): E56. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.3390%2Fhealthcare7020056\" target=\"_blank\">10.3390\/healthcare7020056<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6627742\/\" target=\"_blank\">PMC6627742<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/30987333\" target=\"_blank\">30987333<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6627742\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6627742<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Blockchain+Technology+in+Healthcare%3A+A+Systematic+Review&rft.jtitle=Healthcare&rft.aulast=Agbo%2C+C.C.%3B+Mahmoud%2C+Q.H.%3B+Eklund%2C+J.M.&rft.au=Agbo%2C+C.C.%3B+Mahmoud%2C+Q.H.%3B+Eklund%2C+J.M.&rft.date=2019&rft.volume=7&rft.issue=2&rft.pages=E56&rft_id=info:doi\/10.3390%2Fhealthcare7020056&rft_id=info:pmc\/PMC6627742&rft_id=info:pmid\/30987333&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC6627742&rfr_id=info:sid\/en.wikipedia.org:Journal:Blockchain_and_artificial_intelligence_technology_for_novel_coronavirus_disease_2019_self-testing\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ZhangBlock18-18\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-ZhangBlock18_18-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Zhang, P.; Schmidt, D.C.; White, J.; Lenz, G. (2018). \"Blockchain Technology Use Cases in Healthcare\". <i>Advanced in Computers<\/i> <b>111<\/b>: 1\u201341. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fbs.adcom.2018.03.006\" target=\"_blank\">10.1016\/bs.adcom.2018.03.006<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Blockchain+Technology+Use+Cases+in+Healthcare&rft.jtitle=Advanced+in+Computers&rft.aulast=Zhang%2C+P.%3B+Schmidt%2C+D.C.%3B+White%2C+J.%3B+Lenz%2C+G.&rft.au=Zhang%2C+P.%3B+Schmidt%2C+D.C.%3B+White%2C+J.%3B+Lenz%2C+G.&rft.date=2018&rft.volume=111&rft.pages=1%E2%80%9341&rft_id=info:doi\/10.1016%2Fbs.adcom.2018.03.006&rfr_id=info:sid\/en.wikipedia.org:Journal:Blockchain_and_artificial_intelligence_technology_for_novel_coronavirus_disease_2019_self-testing\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-MakhuduTheUse19-19\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-MakhuduTheUse19_19-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Makhudu, S.; Kuupiel, D.; Gwala, N. et al. (2019). \"The Use of Patient Self-Testing in Low- and Middle-Income Countries: A Systematic Scoping Review\". <i>Point of Care<\/i> <b>18<\/b> (1): 9\u201316. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1097%2FPOC.0000000000000179\" target=\"_blank\">10.1097\/POC.0000000000000179<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=The+Use+of+Patient+Self-Testing+in+Low-+and+Middle-Income+Countries%3A+A+Systematic+Scoping+Review&rft.jtitle=Point+of+Care&rft.aulast=Makhudu%2C+S.%3B+Kuupiel%2C+D.%3B+Gwala%2C+N.+et+al.&rft.au=Makhudu%2C+S.%3B+Kuupiel%2C+D.%3B+Gwala%2C+N.+et+al.&rft.date=2019&rft.volume=18&rft.issue=1&rft.pages=9%E2%80%9316&rft_id=info:doi\/10.1097%2FPOC.0000000000000179&rfr_id=info:sid\/en.wikipedia.org:Journal:Blockchain_and_artificial_intelligence_technology_for_novel_coronavirus_disease_2019_self-testing\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-BervellAComp19-20\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-BervellAComp19_20-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Bervell, B.; Al-Samarraie, H. (2019). \"A comparative review of mobile health and electronic health utilization in sub-Saharan African countries\". <i>Social Science & Medicine<\/i> <b>232<\/b>: 1\u201316. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.socscimed.2019.04.024\" target=\"_blank\">10.1016\/j.socscimed.2019.04.024<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/31035241\" target=\"_blank\">31035241<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=A+comparative+review+of+mobile+health+and+electronic+health+utilization+in+sub-Saharan+African+countries&rft.jtitle=Social+Science+%26+Medicine&rft.aulast=Bervell%2C+B.%3B+Al-Samarraie%2C+H.&rft.au=Bervell%2C+B.%3B+Al-Samarraie%2C+H.&rft.date=2019&rft.volume=232&rft.pages=1%E2%80%9316&rft_id=info:doi\/10.1016%2Fj.socscimed.2019.04.024&rft_id=info:pmid\/31035241&rfr_id=info:sid\/en.wikipedia.org:Journal:Blockchain_and_artificial_intelligence_technology_for_novel_coronavirus_disease_2019_self-testing\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-AdeagboAccept20-21\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-AdeagboAccept20_21-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Adeagbo, O.; Kim, H.Y.; Tanser, F. et al. (2020). \"Acceptability of a tablet-based application to support early HIV testing among men in rural KwaZulu-Natal, South Africa: a mixed method study\". <i>AIDS Care<\/i>: 1\u20138. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1080%2F09540121.2020.1742867\" target=\"_blank\">10.1080\/09540121.2020.1742867<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/32172596\" target=\"_blank\">32172596<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Acceptability+of+a+tablet-based+application+to+support+early+HIV+testing+among+men+in+rural+KwaZulu-Natal%2C+South+Africa%3A+a+mixed+method+study&rft.jtitle=AIDS+Care&rft.aulast=Adeagbo%2C+O.%3B+Kim%2C+H.Y.%3B+Tanser%2C+F.+et+al.&rft.au=Adeagbo%2C+O.%3B+Kim%2C+H.Y.%3B+Tanser%2C+F.+et+al.&rft.date=2020&rft.pages=1%E2%80%938&rft_id=info:doi\/10.1080%2F09540121.2020.1742867&rft_id=info:pmid\/32172596&rfr_id=info:sid\/en.wikipedia.org:Journal:Blockchain_and_artificial_intelligence_technology_for_novel_coronavirus_disease_2019_self-testing\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-PantPaiWill13-22\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-PantPaiWill13_22-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Pant Pai, N.; Behlim, T.; Abrahams, L. et al. (2013). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3842310\" target=\"_blank\">\"Will an unsupervised self-testing strategy for HIV work in health care workers of South Africa? A cross sectional pilot feasibility study\"<\/a>. <i>PLoS One<\/i> <b>8<\/b> (11): e79772. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1371%2Fjournal.pone.0079772\" target=\"_blank\">10.1371\/journal.pone.0079772<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC3842310\/\" target=\"_blank\">PMC3842310<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/24312185\" target=\"_blank\">24312185<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3842310\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3842310<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Will+an+unsupervised+self-testing+strategy+for+HIV+work+in+health+care+workers+of+South+Africa%3F+A+cross+sectional+pilot+feasibility+study&rft.jtitle=PLoS+One&rft.aulast=Pant+Pai%2C+N.%3B+Behlim%2C+T.%3B+Abrahams%2C+L.+et+al.&rft.au=Pant+Pai%2C+N.%3B+Behlim%2C+T.%3B+Abrahams%2C+L.+et+al.&rft.date=2013&rft.volume=8&rft.issue=11&rft.pages=e79772&rft_id=info:doi\/10.1371%2Fjournal.pone.0079772&rft_id=info:pmc\/PMC3842310&rft_id=info:pmid\/24312185&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC3842310&rfr_id=info:sid\/en.wikipedia.org:Journal:Blockchain_and_artificial_intelligence_technology_for_novel_coronavirus_disease_2019_self-testing\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-TayDevelop17-23\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-TayDevelop17_23-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Tay, I.; Garland, S.; Gorelik, A. et al. (2017). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5360908\" target=\"_blank\">\"Development and Testing of a Mobile Phone App for Self-Monitoring of Calcium Intake in Young Women\"<\/a>. <i>JMIR mHealth and uHealth<\/i> <b>5<\/b> (3): e27. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.2196%2Fmhealth.5717\" target=\"_blank\">10.2196\/mhealth.5717<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC5360908\/\" target=\"_blank\">PMC5360908<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/28270379\" target=\"_blank\">28270379<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5360908\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5360908<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Development+and+Testing+of+a+Mobile+Phone+App+for+Self-Monitoring+of+Calcium+Intake+in+Young+Women&rft.jtitle=JMIR+mHealth+and+uHealth&rft.aulast=Tay%2C+I.%3B+Garland%2C+S.%3B+Gorelik%2C+A.+et+al.&rft.au=Tay%2C+I.%3B+Garland%2C+S.%3B+Gorelik%2C+A.+et+al.&rft.date=2017&rft.volume=5&rft.issue=3&rft.pages=e27&rft_id=info:doi\/10.2196%2Fmhealth.5717&rft_id=info:pmc\/PMC5360908&rft_id=info:pmid\/28270379&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC5360908&rfr_id=info:sid\/en.wikipedia.org:Journal:Blockchain_and_artificial_intelligence_technology_for_novel_coronavirus_disease_2019_self-testing\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-KuupielImproving-24\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-KuupielImproving_24-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Kuupiel, D.; Bawontuo, V.; Mashamba-Thompson, T.P. (2017). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5745394\" target=\"_blank\">\"Improving the Accessibility and Efficiency of Point-of-Care Diagnostics Services in Low- and Middle-Income Countries: Lean and Agile Supply Chain Management\"<\/a>. <i>Diagnostics<\/i> <b>7<\/b> (4): e58. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.3390%2Fdiagnostics7040058\" target=\"_blank\">10.3390\/diagnostics7040058<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC5745394\/\" target=\"_blank\">PMC5745394<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/29186013\" target=\"_blank\">29186013<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5745394\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5745394<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Improving+the+Accessibility+and+Efficiency+of+Point-of-Care+Diagnostics+Services+in+Low-+and+Middle-Income+Countries%3A+Lean+and+Agile+Supply+Chain+Management&rft.jtitle=Diagnostics&rft.aulast=Kuupiel%2C+D.%3B+Bawontuo%2C+V.%3B+Mashamba-Thompson%2C+T.P.&rft.au=Kuupiel%2C+D.%3B+Bawontuo%2C+V.%3B+Mashamba-Thompson%2C+T.P.&rft.date=2017&rft.volume=7&rft.issue=4&rft.pages=e58&rft_id=info:doi\/10.3390%2Fdiagnostics7040058&rft_id=info:pmc\/PMC5745394&rft_id=info:pmid\/29186013&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC5745394&rfr_id=info:sid\/en.wikipedia.org:Journal:Blockchain_and_artificial_intelligence_technology_for_novel_coronavirus_disease_2019_self-testing\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<\/ol><\/div>\n<h2><span class=\"mw-headline\" id=\"Notes\">Notes<\/span><\/h2>\n<p>This presentation is faithful to the original, with only a few minor changes to presentation. In some cases important information was missing from the references, and that information was added.\n<\/p>\n<!-- \nNewPP limit report\nCached time: 20200707205049\nCache expiry: 86400\nDynamic content: false\nCPU time usage: 0.432 seconds\nReal time usage: 0.791 seconds\nPreprocessor visited node count: 19199\/1000000\nPreprocessor generated node count: 32698\/1000000\nPost\u2010expand include size: 157686\/2097152 bytes\nTemplate argument size: 53805\/2097152 bytes\nHighest expansion depth: 18\/40\nExpensive parser function count: 0\/100\n-->\n\n<!-- \nTransclusion expansion time report (%,ms,calls,template)\n100.00% 400.030 1 - -total\n 84.93% 339.730 1 - Template:Reflist\n 71.31% 285.247 24 - Template:Citation\/core\n 52.82% 211.277 16 - Template:Cite_journal\n 22.05% 88.189 8 - Template:Cite_web\n 9.49% 37.970 1 - Template:Infobox_journal_article\n 9.03% 36.113 1 - Template:Infobox\n 7.78% 31.125 34 - Template:Citation\/identifier\n 6.13% 24.518 80 - Template:Infobox\/row\n 4.80% 19.189 29 - Template:Citation\/make_link\n-->\n\n<!-- Saved in parser cache with key limswiki:pcache:idhash:11889-0!*!0!!en!5!* and timestamp 20200707205048 and revision id 39077\n -->\n<\/div><div class=\"printfooter\">Source: <a rel=\"external_link\" class=\"external\" href=\"https:\/\/www.limswiki.org\/index.php\/Journal:Blockchain_and_artificial_intelligence_technology_for_novel_coronavirus_disease_2019_self-testing\">https:\/\/www.limswiki.org\/index.php\/Journal:Blockchain_and_artificial_intelligence_technology_for_novel_coronavirus_disease_2019_self-testing<\/a><\/div>\n\t\t\t\t\t\t\t\t\t\t<!-- end content -->\n\t\t\t\t\t\t\t\t\t\t<div class=\"visualClear\"><\/div>\n\t\t\t\t<\/div>\n\t\t\t<\/div>\n\t\t<\/div>\n\t\t<!-- end of the left (by default at least) column -->\n\t\t<div class=\"visualClear\"><\/div>\n\t\t\t\t\t\n\t\t<\/div>\n\t\t\n\n<\/body>","02fce1e6c14e5effed2c3ceedc4e9443_images":["https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/a\/a2\/Fig1_Mashamba-Thompson_Diagnostics2020_10-4.png"],"02fce1e6c14e5effed2c3ceedc4e9443_timestamp":1594155048,"a4527a9687a2e4995aa12c37d0db8fb1_type":"article","a4527a9687a2e4995aa12c37d0db8fb1_title":"Health care and cybersecurity: Bibliometric analysis of the literature (Jalali et al. 2019)","a4527a9687a2e4995aa12c37d0db8fb1_url":"https:\/\/www.limswiki.org\/index.php\/Journal:Health_care_and_cybersecurity:_Bibliometric_analysis_of_the_literature","a4527a9687a2e4995aa12c37d0db8fb1_plaintext":"\n\n\t\t\n\t\t\t\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t\n\n\t\t\t\tJournal:Health care and cybersecurity: Bibliometric analysis of the literature\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t\tFrom LIMSWiki\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\tJump to: navigation, search\n\n\t\t\t\t\t\n\t\t\t\t\tFull article title\n \nHealth care and cybersecurity: Bibliometric analysis of the literatureJournal\n \nJournal of Medical Internet ResearchAuthor(s)\n \nJalali, Mohammad S.; Razak, Sabina; Gordon, William; Perakslis, Eric; Madnick, StuartAuthor affiliation(s)\n \nHarvard Medical School, Massachusetts Institute of Technology, Brigham & Women\u2019s Hospital, Partners Healthcare,Primary contact\n \nEmail: msjalali at mgh dot harvard dot eduEditors\n \nEysenbach, G.Year published\n \n2019Volume and issue\n \n21(2)Article #\n \ne12644DOI\n \n10.2196\/12644ISSN\n \n1438-8871Distribution license\n \nCreative Commons Attribution 4.0 InternationalWebsite\n \nhttps:\/\/www.jmir.org\/2019\/2\/e12644\/Download\n \nhttps:\/\/www.jmir.org\/2019\/2\/e12644\/pdf (PDF)\n\nContents\n\n1 Abstract \n2 Introduction \n3 Methods \n\n3.1 Study eligibility criteria \n3.2 Screening selection \n3.3 Chronological clustering and trend analysis \n3.4 Text analysis \n\n\n4 Results \n\n4.1 Search results \n4.2 Chronological clustering and trend analysis \n4.3 Journal characteristics \n4.4 Characteristics of the most cited articles \n4.5 Test analysis \n\n\n5 Discussion \n\n5.1 Overview \n5.2 Limitations and suggestions for future research \n\n\n6 Abbreviations \n7 Multimedia Appendix 1 \n8 Acknowledgements \n\n8.1 Conflicts of interest \n\n\n9 References \n10 Notes \n\n\n\nAbstract \nBackground: Over the past decade, clinical care has become globally dependent on information technology. The cybersecurity of health care information systems is now an essential component of safe, reliable, and effective health care delivery.\nObjective: The objective of this study was to provide an overview of the literature at the intersection of cybersecurity and health care delivery.\nMethods: A comprehensive search was conducted using PubMed and Web of Science for English-language peer-reviewed articles. We carried out chronological analysis, domain clustering analysis, and text analysis of the included articles to generate a high-level concept map composed of specific words and the connections between them.\nResults: Our final sample included 472 English-language journal articles. Our review results revealed that a majority of the articles were focused on technology. Technology\u2013focused articles made up more than half of all the clusters, whereas managerial articles accounted for only 32 percent of all clusters. This finding suggests that nontechnological variables (human\u2013based and organizational aspects, strategy, and management) may be understudied. In addition, software development security, business continuity, and disaster recovery planning each accounted for three percent of the studied articles. Our results also showed that publications on physical security account for only one percent of the literature, and research in this area is lacking. Cyber vulnerabilities are not all digital; many physical threats contribute to breaches and potentially affect the physical safety of patients.\nConclusions: Our results revealed an overall increase in research on cybersecurity and identified major gaps and opportunities for future work.\nKeywords: bibliometric review, cybersecurity, health care, literature analysis, text mining \n\nIntroduction \nCybersecurity is an increasingly critical aspect of health care information technology infrastructure. The rapid digitization of health care delivery, from electronic health records (EHR) and telehealth to mobile health (mHealth) and network-enabled medical devices, introduces risks related to cybersecurity vulnerabilities.[1] These vulnerabilities are particularly worrisome because cyberattacks in a health care setting can result in the exposure of highly sensitive personal information or cause disruptions in clinical care.[2][3][4][5] Cyberattacks may also affect the safety of patients, for example, by compromising the integrity of data or impairing medical device functionality. The WannaCry and NotPetya ransomware attacks and vulnerabilities in Medtronic Implantable Cardiac Device Programmers are recent examples that have resulted in impaired health care delivery capabilities.[6]\nHealth care organizations are particularly vulnerable to cyber threats. Verizon\u2019s 2018 Data Breach Investigations Report found that the health care field, in general, was most affected by data breaches, which accounted for 24 percent of all investigated breaches across all industries.[7] Additionally, a report by the Ponemon Institute found that almost 90 percent of respondents (involved in health plans and health care clearinghouses, as well as health care providers with EHRs) experienced a data breach in the past two years.[8] Another survey of health care information security professionals revealed that over 75 percent of health care organizations experienced a recent security incident.[9] The causes are multifactorial, involving both technology and people, and human error and cultural factors play increasingly critical roles.[10][11] Despite efforts to teach best-practice security behavior through training programs, recent surveys have revealed that one in five health care employees still write down their usernames and passwords on paper.[12]\nGiven the increasing importance of cybersecurity for safe, effective, and reliable health care delivery, there is a need to provide an overview of the literature at the intersection of cybersecurity and health care. Recent systematic reviews synthesized insights from 31 articles on cyber threats in health care[13] and aggregated strategies from 13 articles about responding to cyber incidents in health care organizations.[14] In this study, we conduct a large bibliometric review of the literature and describe the current state of research on various aspects of cybersecurity in health care in order to not only understand current trends but also identify gaps and guide future research efforts toward improving the security of our health care systems.\n\nMethods \nStudy eligibility criteria \nA comprehensive search was conducted using PubMed and Web of Science (WoS) for English-language peer-reviewed articles. We identified search keywords by adopting terminologies in The National Initiative for Cybersecurity Careers and Studies[15] and The British Standards Institution glossaries.[16] The list of keywords used follows.\nWoS (journal articles, all years):\n\n\u201cHealth*\u201d AND \u201cCybersecurity\u201d OR \u201cCyber Security\u201d OR \u201cCyber Attack*\u201d OR \u201cCyber Crisis*\u201d OR \u201cCyber Incident*\u201d OR \u201cCyber Infrastructure*\u201d OR \u201cCyber Operation*\u201d OR \u201cCyber Risk*\u201d OR \u201cCyber Threat*\u201d OR \u201cCyberspace*\u201d OR \u201cData Breach*\u201d OR \u201cData Security*\u201d OR \u201cFirewall*\u201d OR \u201cInformation Security*\u201d OR \u201cInformation Systems Security*\u201d OR \u201cInformation Technology Security*\u201d OR \u201cIT Security*\u201d OR \u201cMalware*\u201d OR \u201cPhishing*\u201d OR \u201cRansomware*\u201d OR \u201cSecurity Incident*\u201d OR \u201cInformation Assurance*\u201d\nPubMed (journal articles, all years, abstract availability):\n\n\u201cCybersecurity\u201d OR \u201cCyber Security\u201d OR \u201cCyber Attack\u201d OR \u201cCyber Crisis\u201d OR \u201cCyber Incident\u201d OR \u201cCyber Infrastructure\u201d OR \u201cCyber Operation\u201d OR \u201cCyber Risk\u201d OR \u201cCyber Threat\u201d OR \u201cCyberspace\u201d OR \u201cData Breach\u201d OR \u201cData Security\u201d OR \u201cFirewall\u201d OR \u201cInformation Security\u201d OR \u201cInformation Systems Security\u201d OR \u201cInformation Technology Security\u201d OR \u201cIT Security\u201d OR \u201cMalware\u201d OR \u201cPhishing\u201d OR \u201cRansomware\u201d OR \u201cSecurity Incident\u201d OR \u201cInformation Assurance\u201d\nKeywords that widened the search results far beyond the scope were rejected. For example, \u201cexploit\u201d and \u201cmalicious\u201d can be used in a cyber context, but they are more commonly used in unrelated contexts that add noise to the search. Such terms were not included because of their contribution to an overwhelming amount of irrelevant results.\nWe included articles published from the inception of PubMed in 1966 and WoS in 1900, all the way to September 2017. Articles were excluded if they did not clearly focus on cybersecurity or health care or if they were reviews or meta-analyses. Inclusion and exclusion criteria were formulated prior to the preliminary title and abstract screening. The eligibility criteria were intentionally nonspecific to obtain a complete picture of the existing relevant research. To increase our confidence in the inclusion criteria, we conducted an initial pilot screening of 100 articles.\n\nScreening selection \nScreening of titles and abstracts was conducted using the software package abstrackr.[17] Full texts of the \u201cmaybe\u201d articles were independently reviewed by two trained individuals to assess study eligibility. Disagreements about study inclusion were discussed until a consensus was reached. More details about our methodology are available in Multimedia Appendix 1.\n\nChronological clustering and trend analysis \nWe performed chronological analysis of the number of articles published per year and the number of authors per article. We topically clustered articles using 10 security domains created by the International Information Systems Security Certification Consortium to categorize each article (Multimedia Appendix 1). Each clustered article was further categorized as technological, managerial, legal, or interdisciplinary (if it fell into more than three categories). Features of the included articles, such as the publishing journal and number of citations, were recorded.\n\nText analysis \nAfter analyzing all the titles and abstracts, we removed words with high frequencies that were common in research articles but were not specific to our subject (e.g., \u201cpaper,\u201d \u201cusing,\u201d and \u201cresults\u201d). In addition, we merged the plural forms with singular forms of the same word and merged \u201chealthcare\u201d and \u201chealth care\u201d into \u201chealthcare.\u201d Subsequently, we created word clouds to visualize the word frequencies in titles and abstracts over time. Word frequency is represented by color and size, with darker, larger words representing higher occurrence.\nWe then assessed text titles and abstracts to generate a high-level concept map composed of specific words and the connections between them by using the software package Leximancer text analytics (version 4.5; Leximancer Pty Ltd, Brisbane, Australia). The software started with an unsupervised machine learning approach to extract a network of meaning from the data and developed a heat map that visually illustrated the end results. The method, underpinned by a naive Bayesian co-occurrence metric, considers how often two words co-occur as well as how often they occur apart.[18][19] Heat maps consist of \u201cthemes\u201d represented by bubbles and \u201cconcepts\u201d represented by grey dots. Concepts can be equated to a list of similar terms coalescing into a monothematic idea, and themes are clusters of these concepts. The lines between dots suggest a strong connection between two concepts.\n\nResults \nSearch results \nThe primary search on PubMed for papers containing terms pertaining to \u201ccyber\u201d yielded 1,480 articles, and the search on WoS yielded 810 articles. After removing 310 duplicates, the titles and abstracts of 1,980 articles were screened, which was facilitated by the Abstrackr software.[17] Based on the inclusion criteria, 1,262 articles were excluded in the first screening, reducing the results to 718 articles for full-text review. Eventually, a further screening removed additional articles to provide a final selection of 472 articles. Figure 1 presents the search method and results.\n\r\n\n\n\n\n\n\n\n\n\n\n Fig. 1 Search method and results\n\n\n\nChronological clustering and trend analysis \nFigure 2 presents the overall trend of all publications over time, from 1985 to September 2017; the first included article was published in 1979 but was excluded from the figure for better visualization. Figure 2 shows a steady increase in the number of articles published on cybersecurity in health care (Multimedia Appendix 1).\n\r\n\n\n\n\n\n\n\n\n\n\n Fig. 2 Annual number of published papers at the intersection of health care and cybersecurity (fitted trend line: y=0.9166e0.1252x; R\u00b2=0.82)\n\n\n\nFigure 3 shows the distribution among the three high-level categories: technological, managerial, and legal (Multimedia Appendix 1). The seven technological clusters made up more than half of all clusters, the two managerial clusters represented 32 percent, and the legal cluster represented 18 percent of all clusters.\n\r\n\n\n\n\n\n\n\n\n\n\n Fig. 3 Cluster distributions\n\n\n\nThe orange-shaded portion within each cluster in Figure 3 represents interdisciplinary articles (spanning multiple high-level categories). Although the topic of physical security had the lowest number of publications (Figure 3), it was the most interdisciplinary cluster (six out of the seven articles [85.7 percent] identified as interdisciplinary). The topic of legal, regulations, investigations, and compliance was the second most interdisciplinary cluster (59.8 percent of the articles in this category were interdisciplinary), followed by operations security (52.9 percent), business continuity and disaster recovery planning (50 percent), Information security governance and risk management (43.9 percent), and access control (30.6 percent). Although the topic of security architecture and design was the second most frequent cluster overall, only 22.2 percent of the articles were found to be interdisciplinary. The less interdisciplinary categories were in the topics of telecommunications and network security (18.9 percent), software development security (17.6 percent), and cryptography (four percent) (Multimedia Appendix 1).\nWe analyzed the publication trends over time in the 10 clusters (Figure 4). All clusters showed increased frequency, and some clusters such as security architecture and design, information security gGovernance and risk management, and cryptography demonstrated particularly steep increases in frequency.\n\r\n\n\n\n\n\n\n\n\n\n\n Fig. 4 Trend of 10 clusters over time\n\n\n\nJournal characteristics \nOverall, the 472 articles included were published in 239 unique journals. We ranked the journals according to the number of published articles and selected the journals with more than three articles, which resulted in a list of 17 journals (Table 1). According to the corresponding InCites Journal Citation Reports (JCR) categories[20], the top journals tended to focus on computer science, information systems, and medical informatics. The most popular JCR category, accounting for seven out of the 10 journals listed in JCR, was medical informatics. Six journals had a computer science category, specifically within information systems, interdisciplinary applications, or theory and methods. Five journals were from the health care sciences and services category. Only one of the top 15 journals was categorized as a biomedical engineering journal; one, as a math and computational biology journal; and one, as a radiology, nuclear medicine, and medical imaging journal.\nApproximately 73 percent of the 239 journals had only published one article at the intersection of cybersecurity and health care. The high number and diversity of the journals included along with the low publication rate suggest that there is currently no major niche for medical practice readership at the intersection of cybersecurity and health care due to the cross-disciplinary nature of the field.\n\r\n\n\n\n\n\n\n\n\nTable 1. Journals with the most articles\n\n\n\nJournal\n\n# of published papers\n\nIndexed categories (according to Journal Citation Reports)[20]\n\n\nStudies in Health Technology and Informatics\n\n47\n\nNot indexed\n\n\nInternational Journal of Medical Informatics\n\n24\n\nComputer science, information systems; Health care sciences & services; Medical informatics\n\n\nJournal of Medical Systems\n\n17\n\nHealth care sciences & services; Medical informatics\n\n\nJournal of Diabetes Science and Technology\n\n9\n\nNot indexed\n\n\nHealthcare Financial Management\n\n8\n\nNot indexed\n\n\nMedical Informatics\n\n8\n\nComputer science, information systems; Computer science, interdisciplinary applications; Medical informatics\n\n\nInternational Journal of Bio-Medical Computing\n\n8\n\nComputer science, interdisciplinary applications; Computer science, theory & methods; Engineering, biomedical; Medical informatics\n\n\nComputers & Security\n\n7\n\nComputer science, information systems\n\n\nJournal of the American Medical Informatics Association\n\n7\n\nComputer science, information systems; Computer science, interdisciplinary applications; Health care sciences & services; Medical informatics\n\n\nJournal of Healthcare Protection Management\n\n7\n\nNot indexed\n\n\nTelemedicine Journal and E-Health\n\n5\n\nHealth care sciences & services\n\n\nIEEE Journal of Biomedical and Health Informatics\n\n4\n\nComputer science, information systems; Computer science, interdisciplinary applications; Mathematical & computational biology; Medical informatics\n\n\nJournal of the American Health Information Management Association\n\n4\n\nNot indexed\n\n\nJournal of Digital Imaging\n\n4\n\nRadiology, nuclear medicine & medical imaging\n\n\nJournal of Healthcare Information Management\n\n4\n\nNot indexed\n\n\nJournal of Medical Internet Research\n\n4\n\nHealth care sciences & services; Medical informatics\n\n\nJournal of Medical Practice Management\n\n4\n\nNot indexed\n\n\n\nCharacteristics of the most cited articles \nTable 2 shows the most influential publications in the field of cybersecurity in health care, ranked by the number of citations as of September 2017. Six of the top 15 cited articles were published in five journals of the Institute of Electrical and Electronics Engineers. The clusters show a mix of article domains across the legal, managerial, and technological domains. The author-denoted keywords support this finding.\nOf the total clusters of the top 15 articles, 38 percent belonged to security architecture and design category. Cryptography was the next most popular cluster (17 percent); followed by legal, regulations, investigations, and compliance (13 percent); and access control (13 percent). Overall, 79 percent of the clusters were technological, 13 percent were legal, and eight percent were managerial. Additionally, 20 percent of the papers were interdisciplinary, with multiple clusters of distinct high-level categories. Notably, the list of most cited articles does not reflect the most recent articles, as citation of these articles is often significantly delayed.\n\n\n\n\n\n\n\nTable 2. Top 15 most cited articles\n\n\n\nRank\n\n# of citations\n\nTitle\n\nAuthors\n\nYear\n\nJournal\n\nClusters\n\nAuthor-denoted keywords\n\n\n1\n\n443\n\nData security and privacy in wireless body area networks\n\nLi, M.; Lou, W.J.; Ren, K.\n\n2010\n\nIEEE Wireless Communications\n\nTelecommunications and network security\n\nData security, Data privacy, Body sensor networks, Biomedical monitoring, Wireless sensor networks, Wearable sensors, Wireless communication, Medical services, Application software, Patient monitoring\n\n\n2\n\n304\n\nAnalyzing regulatory rules for privacy and security requirements\n\nBreaux, T.D. and Anton, A.I.\n\n2008\n\nIEEE Transactions on Software Engineering\n\nLegal, regulations, investigations and compliance\n\nData security and privacy, Laws and regulations, Compliance, Accountability, Requirements engineering\n\n\n3\n\n173\n\nMedical image security in a HIPAA mandated PACS environment\n\nCao, F.; Huang, H.K.; Zhou, X.Q.\n\n2003\n\nComputerized Medical Imaging and Graphics\n\nLegal, regulations, investigations and compliance; Security architecture and design\n\nData encryption, Picture archiving and communication system security, Image integrity, Digital imaging and communication in medicine, Compliance, Health insurance portability and accountability act\n\n\n4\n\n168\n\nSPOC: A Secure and Privacy-Preserving Opportunistic Computing Framework for Mobile-Healthcare Emergency\n\nLu, R.X.; Lin, X.D.; Shen, X.M.\n\n2013\n\nIEEE Transactions on Parallel and Distributed Systems\n\nAccess control; Security architecture and design\n\nMobile-healthcare emergency, Opportunistic computing, User-centric privacy access control, PPSPC\n\n\n5\n\n158\n\nAuthenticity and integrity of digital mammography images\n\nZhou, X.Q.; Huang, H.K.; Lou, S.L.\n\n2001\n\nIEEE Transactions on Medical Imaging\n\nCryptography, Telecommunications and network security\n\nData embedding and cryptography, Digital mammography, Image authenticity and integrity, Telemammography\n\n\n6\n\n131\n\nSecurity in health-care information systems--current trends\n\nSmith, E. and Eloff, J.H.\n\n1999\n\nInternational Journal of Medical Informatics\n\nAccess control, Information security governance and risk management\n\nHealth-care information systems security, Risk-analysis in health-care information systems, Access control for computerized health-care, Electronic patient record, International Medical Informatics Association, Managed health-care\n\n\n7\n\n112\n\nHow to ensure data security of an epidemiological follow-up: Quality assessment of an anonymous record linkage procedure\n\nQuantin, C.; Bouzelat, H.; Allaert, F.A. et al.\n\n1998\n\nInternational Journal of Medical Informatics\n\nCryptography, Security architecture and design\n\nData security, Computerized record, Linkage procedure\n\n\n8\n\n103\n\nIBE-Lite: A lightweight identity-based cryptography for body sensor networks\n\nTan, C.C.; Wang, H.D.; Zhong, S.; Li, Q.\n\n2009\n\nIEEE Transactions on Information Technology in Biomedicine\n\nSecurity architecture and design, Cryptography\n\nBody sensor network, Identity-based encryption, Privac, Security\n\n\n9\n\n89\n\nA security architecture for interconnecting health information systems\n\nGritzalis, D. and Lambrinoudakis, C.\n\n2004\n\nInternational Journal of Medical Informatics\n\nAccess control, Security architecture and design\n\nInformation systems security, Computer security, Medical data security, Medical Data Protection, Electronic healthcare records, Role-based access control\n\n\n10\n\n85\n\nBiometric methods for secure communications in body sensor networks: Resource-efficient key management and signal-level data scrambling\n\nBui, F.M. and Hatzinakos, D.\n\n2008\n\nEurasip Journal on Advances in Signal Processing\n\nSecurity architecture and design, Cryptography\n\nNot available\n\n\n11\n\n84\n\nmHealth data security: The need for HIPAA-compliant standardization\n\nLuxton, D.D.; Kayl, R.A.; Mishkind, M.C.\n\n2012\n\nTelemedicine Journal and E-Health\n\nSoftware development security; Legal, regulations, investigations and compliance\n\nSecurity, HIPAA, Encryption, Telehealth, Mobile health\n\n\n12\n\n82\n\nAnalysis of the security and privacy requirements of cloud-based electronic health records systems\n\nRodrigues, J.J.; de la Torre, I.; Fernandez, G.; Lopez-Coronado, M.\n\n2013\n\nJournal of Medical Internet Research\n\nSecurity architecture and design\n\nCloud-computing, eHealth, Electronic health records (EHRs), Privacy, Security\n\n\n13\n\n82\n\nHealth care management and information systems security: Awareness, training or education?\n\nKatsikas, S.K.\n\n2000\n\nInternational Journal of Medical Informatics\n\nInformation security governance and risk management\n\nHealth information systems, Information systems security, Health care management, Education, Training, Awareness\n\n\n14\n\n82\n\nSecuring m-healthcare social networks: Challenges, countermeasures and future directions\n\nZhou, J.; Cao, Z.F.; Dong, X.L. et al.\n\n2013\n\nIEEE Wireless Communications\n\nSecurity architecture and design\n\nMobile communication, Social network services, Medical services, Mobile computing, Personal digital assistants, Privacy, Network security, Electronic medical records\n\n\n15\n\n80\n\nPrivacy and data security in E-health: Requirements from the user's perspective\n\nWilkowska, W. and Ziefle, M.\n\n2012\n\nHealth Informatics Journal\n\nSecurity architecture and design\n\nE-health, Gender, Medical assistive technologies, Privacy, Security\n\n\n\nTest analysis \nThe text-mining analysis identified specific trends in the article texts. The map produced from all titles and abstracts is shown in Figure 5. The thematic bubbles are ranked by relevance based on a heat-map color scheme: hot colors indicate more important themes, and cool colors indicate less important themes. The relative positions of the bubbles indicate the relationship between aggregated ideas, reflecting how closely they are related to each other. The sizes of the bubbles are only set to include their grey dots, and the size of each grey dot (a common word within the theme) indicates its relative frequency. The lines between these dots signify connectivity and association of concepts.\n\r\n\n\n\n\n\n\n\n\n\n\n Fig. 5 Thematic map of all titles and abstracts (A) and concept cloud of all titles and abstracts (B)\n\n\n\nThe overlay of grey-dot concepts onto thematic bubbles allows for more specific analysis of terms. Technological terms emerge as the main theme in Figure 5, including words like \u201cencryption\u201d and \u201csoftware.\u201d Concept words within these themes highlighted the following common elements of an organization\u2019s informal technology structure related to cybersecurity: \u201cinternet,\u201d \u201cnetwork,\u201d \u201capplications,\u201d \u201crecords,\u201d \u201cbreaches,\u201d \u201ckey,\u201d and \u201celectronic.\u201d Managerial and legal terms were also identified as concepts (Figure 5). \u201cManagement\u201d was a concept within the \u201cinformation\u201d theme. \u201cPolicies\u201d and \u201cprocess\u201d were concepts in the risk theme and indicated the influence of risk analysis on the cybersecurity policies and procedures of organizations. \u201cHIPAA\u201d was a concept that stemmed from the \u201cinformation\u201d concept in the \u201cimportant\u201d theme.\nThe two central themes \u201csecurity\u201d and \u201cinformation\u201d included multiple, large grey-dot concepts that branched out into other thematic areas. There was an overlap between \u201csecurity\u201d and \u201cencryption,\u201d suggesting that encoding material is fundamental to security. An overlap between \u201csecurity\u201d and \u201cusers\u201d could imply that user control is imperative to security.\nFor further analysis of word frequencies, the articles from 1985 to 2017 were split into four time periods: 1985-1993, 1994-2001, 2002-2009, and 2010-2017 (September). Multimedia Appendix 1 presents the word clouds within the four time periods. The size of the word represents the frequency of its occurrence. The term \u201cprivacy\u201d increased in size in the last three time periods. \u201cInternet\u201d appeared in 1994-2001, around the time of the dot-com bubble. \u201cLegal\u201d was mentioned in 1985-1993, and \u201clegislation\u201d was found in 1994-2001. \u201cHIPAA\u201d appeared in 2002-2009 and again, although to a smaller extent, in 2010-2017.\nMaps of the four time periods were also created to identify trends over time (Figure 6). \u201cSecurity\u201d remained the most popular concept from 1985 to 2009, but was overtaken by \u201chealth care\u201d from 2010 to 2017 (the most popular concept is indicated by the red bubble). The time period maps in Multimedia Appendix 1 provide further details.\n\r\n\n\n\n\n\n\n\n\n\n\n Fig. 6 Thematic maps of titles and abstracts of articles in four time periods\n\n\n\nDiscussion \nOverview \nThis article provides an analysis of the literature at the intersection of cybersecurity and health care. In general, research in this area has been increasing over the past 20 years and is continually represented in a wide, distributed array of academic journals, reflecting the importance of cybersecurity. With the increase in cybersecurity attacks against hospitals and dependency of health care delivery on technology, we expect cybersecurity to continue to play a central role in health care delivery.\nDespite the increase in research and attention to cybersecurity, there are persistent shortcomings in the research on cybersecurity. For example, our research suggests that majority of the articles on cybersecurity focus on technology. In our domain-clustering analysis, technology\u2013focused articles accounted for more than half of all the clusters, whereas managerial articles accounted for only 32 percent. Similarly, in our journal analysis, 58 articles included in the 15 most published journals were from computer science journals and 12 articles were from health-focused journals. Notably, 79 percent of the top 15 most cited paper clusters were technological. This focus on the technological aspects of cybersecurity suggests that nontechnological variables (human\u2013based and organizational aspects, strategy, and management) may be understudied. Investment in technological tools should be the output of a robust cybersecurity strategy rather than the foundation.[21] An overwhelming majority of cybersecurity incidents are caused or propagated by people[22], and technological solutions can mitigate this risk to a limited extent.\nWe found discordance between the topics of the highly cited articles and the topical breakdown of our cluster analysis (these articles were published more than five years ago, implying that emergent threats are poorly captured). This finding suggests that articles on topics such as cryptography have significant traction, even though they are not widely present in the literature. On the other hand, only a few information security governance and compliance articles were frequently cited, despite accounting for a large portion of the literature. \nCybersecurity is most often examined with respect to privacy and compliance. Our results show that physical security is lacking in research, and only one percent of the literature is categorized under physical security. Not all cyber vulnerabilities are digital. Many physical threats contribute to breaches, and these threats potentially affect the physical safety of patients. Software development security, business continuity, and disaster recovery planning, each accounted for three percent of the studied articles. Further examination is needed on these topics, and our study suggests that incident recovery (critical to the success of recovery from incidents) is not a significant focus in the research community. Articles focusing on legality were the least represented. Moreover, federal cybersecurity guidance such as the publications of the National Institute of Standards and Technology was seldom observed in our text analysis. In addition, massive increases in cybersecurity spending[23] did not drive proportional growth in the literature.\nOur lexical analysis highlighted a separation of security processes and software terminology, with longer word distances between these themes. Additionally, the time period maps for 2002-2009 and 2010-2017 showed no overlap between the management and technological themes. More interdisciplinary research is needed to avoid gaps that arise from only analyzing managerial and technological security issues.\nUnlike medical research, which is set up to openly benefit human lives[24], cybersecurity is based on the premise of an active adversary. The presence of this adversary may, unfortunately, drive a school of thought that knowledge, especially specific strategies and tactics, should not be shared openly, which impedes the growth and utility of research in this field.\n\nLimitations and suggestions for future research \nOur review was limited to journal articles indexed in PubMed and WoS. Information retrieval was limited to articles that included the terms of the search strategy in their titles or abstracts; articles that used different terminology were not retrieved. Additionally, we only included articles with cybersecurity at the core of the study.\nOur review did not assess non-English language articles or documents other than journal articles (e.g., conference articles, white papers, or reports by governments or other organizations). A more comprehensive search could include these sources. Importantly, much of the work on cybersecurity and health care is operational and administrative, not academic. Information security professionals may not rely on academic literature as extensively as clinicians do when considering new diagnostics or therapeutics and may instead favor \u201con the job\u201d experience and industry best practices. Additionally, information security research performed within the health care ecosystem may not be publishable due to security-related concerns such as exposing an internal vulnerability. Understanding the published literature in this space is an important starting point, and hospitals and patients will benefit from transparency in research, wherever possible.\nFuture reviews can focus on individual clusters that were reviewed in our study to provide a more in-depth analysis of the cluster. For instance, they could look specifically at business continuity and disaster recovery planning or software development security. Such a detailed focus can help synthesize research findings and provide best practices. Studies may also analyze the gap in managerial research and the implications of a narrow technological focus. Furthermore, such studies can focus on different settings in health care, such as inpatient and outpatient care, translational research, health and wellness environments, and integration of mobile devices and networked systems.\n\nAbbreviations \nHIPAA: Health Insurance Portability and Accountability Act \nIEEE: Institute of Electrical and Electronics Engineers\nmHealth: mobile health\nNIST: National Institute of Standards and Technology\nPACS: picture archiving and communication system\nWoS: Web of Science\n\nMultimedia Appendix 1 \nDetails of the methodology: PDF\n\nAcknowledgements \nFinancial support for this study was provided by Cybersecurity at MIT Sloan (CAMS), also known as the Interdisciplinary Consortium for Improving Critical Infrastructure Cybersecurity.\n\nConflicts of interest \nNone declared.\n\nReferences \n\n\n\u2191 Jalali, M.S.; Kaiser, J.P. (2018). \"Cybersecurity in Hospitals: A Systematic, Organizational Perspective\". Journal of Medical Internet Research 20 (5): e10059. doi:10.2196\/10059. PMC PMC5996174. PMID 29807882. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5996174 .   \n\n\u2191 Gordon, W.J.; Fairhall, A.; Landman, A. (2017). \"Threats to Information Security - Public Health Implications\". New England Journal of Medicine 377 (8): 707\u20139. doi:10.1056\/NEJMp1707212. PMID 28700269.   \n\n\u2191 Perakslis, E.D. (2014). \"Cybersecurity in health care\". New England Journal of Medicine 371 (5): 395\u20137. doi:10.1056\/NEJMp1404358. PMID 25075831.   \n\n\u2191 Jarrett, M.P. (2017). \"Cybersecurity-A Serious Patient Care Concern\". JAMA 318 (14): 1319\u201320. doi:10.1001\/jama.2017.11986. PMID 28973258.   \n\n\u2191 Kramer, D.B.; Fu, K. (2017). \"Cybersecurity Concerns and Medical Devices: Lessons From a Pacemaker Advisory\". JAMA 318 (21): 2077\u201378. doi:10.1001\/jama.2017.15692. PMID 29049709.   \n\n\u2191 Furnell, S.; Emm, D. (2017). \"The ABC of ransomware protection\". Computer Fraud & Security 2017 (10): 5\u201311. doi:10.1016\/S1361-3723(17)30089-1.   \n\n\u2191 Verizon (2018). \"2018 Data Breach Investigations Report\" (PDF). Verizon. https:\/\/enterprise.verizon.com\/resources\/reports\/DBIR_2018_Report.pdf . Retrieved 01 September 2018 .   \n\n\u2191 Ponemon Institute, LLC (May 2016). \"Sixth Annual Benchmark Study on Privacy & Security of Healthcare Data\" (PDF). Ponemon Institute, LLC. https:\/\/www.ponemon.org\/local\/upload\/file\/Sixth%20Annual%20Patient%20Privacy%20%26%20Data%20Security%20Report%20FINAL%206.pdf . Retrieved 09 April 2018 .   \n\n\u2191 Healthcare Information and Management Systems Society (2018). \"2018 HIMSS Cybersecurity Survey\" (PDF). Healthcare Information and Management Systems Society. https:\/\/www.himss.org\/sites\/hde\/files\/d7\/u132196\/2018_HIMSS_Cybersecurity_Survey_Final_Report.pdf . Retrieved 30 July 2020 .   \n\n\u2191 Madnick, S.; Jalali, M.S.; Siegel, M. et al. (2017). \"Measuring Stakeholders\u2019 Perceptions of Cybersecurity for Renewable Energy Systems\". Proceedings from DARE 2016: Data Analytics for Renewable Energy Integration. Lecture Notes in Computer Science 10097: 67\u201377. doi:10.1007\/978-3-319-50947-1_7.   \n\n\u2191 Jalali, M.S.; Siegel, M.; Madnick, S. (2019). \"Decision-making and biases in cybersecurity capability development: Evidence from a simulation game experiment\". The Journal of Strategic Information Systems 28 (1): 66\u201382. doi:10.1016\/j.jsis.2018.09.003.   \n\n\u2191 \"One in Five Health Employees Willing to Sell Confidential Data to Unauthorized Parties, Accenture Survey Finds\". Accenture. 01 March 2018. https:\/\/newsroom.accenture.com\/news\/one-in-five-health-employees-willing-to-sell-confidential-data-to-unauthorized-parties-accenture-survey-finds.htm .   \n\n\u2191 Kruse, C.S.; Frederick, B.; Jacobson, T. et al. (2017). \"Cybersecurity in healthcare: A systematic review of modern threats and trends\". Technology and Health Care 25 (1): 1\u201310. doi:10.3233\/THC-161263. PMID 27689562.   \n\n\u2191 Jalali, M.S.; Russell, B.; Razak, S. et al. (2019). \"EARS to cyber incidents in health care\". JAMIA 26 (1): 81\u201390. doi:10.1093\/jamia\/ocy148. PMID 30517701.   \n\n\u2191 National Initiative for Cybersecurity Careers and Studies. \"Glossary\". National Initiative for Cybersecurity Careers and Studies. https:\/\/niccs.us-cert.gov\/about-niccs\/glossary . Retrieved 31 December 2018 .   \n\n\u2191 British Standards Institution. \"Glossary of cyber security terms\". British Standards Institution. https:\/\/www.bsigroup.com\/en-GB\/Cyber-Security\/Glossary-of-cyber-security-terms\/ . Retrieved 31 July 2018 .   \n\n\u2191 17.0 17.1 Wallace, B.C.; Small, K.; Brodley, C.E. (2012). \"Deploying an interactive machine learning system in an evidence-based practice center: abstrackr\". Proceedings of the 2nd ACM SIGHIT International Health Informatics Symposium: 819\u201324. doi:10.1145\/2110363.2110464.   \n\n\u2191 Smith, A.E.; Humphreys, M.S. (2006). \"Evaluation of unsupervised semantic mapping of natural language with Leximancer concept mapping\". Behavior Research Methods 38: 262\u201379. doi:10.3758\/BF03192778.   \n\n\u2191 Cheng, M. (2019). \"A comparative automated content analysis approach on the review of the sharing economy discourse in tourism and hospitality\". Current Issues in Tourism 22 (1): 35\u201349. doi:10.1080\/13683500.2017.1361908.   \n\n\u2191 20.0 20.1 Clarivate Analytics. \"Journal Citation Reports\". Clarivate Analytics. https:\/\/clarivate.com\/webofsciencegroup\/solutions\/journal-citation-reports\/ . Retrieved 29 October 2018 .   \n\n\u2191 Health Care Industry Cybersecurity Task Force (June 2017). \"Report on Improving Cybersecurity in the Health Care Industry\" (PDF). Assistant Secretary for Preparedness and Response. https:\/\/www.phe.gov\/Preparedness\/planning\/CyberTF\/Documents\/report2017.pdf .   \n\n\u2191 van Zadelhoff, M. (19 September 2016). \"The biggest cybersecurity threats are inside your company\". Harvard Business Review. https:\/\/hbr.org\/2016\/09\/the-biggest-cybersecurity-threats-are-inside-your-company . Retrieved 04 February 2019 .   \n\n\u2191 Gartner (07 December 2017). \"Gartner Forecasts Worldwide Security Spending Will Reach $96 Billion in 2018, Up 8 Percent from 2017\". Gartner. https:\/\/www.gartner.com\/en\/newsroom\/press-releases\/2017-12-07-gartner-forecasts-worldwide-security-spending-will-reach-96-billion-in-2018 . Retrieved 29 October 2018 .   \n\n\u2191 Ioannidis, J.P.; Greenland, S.; Hlatky, M.A. et al. (2014). \"Increasing value and reducing waste in research design, conduct, and analysis\". Lancet 383 (9912): 166\u201375. doi:10.1016\/S0140-6736(13)62227-8. PMC PMC4697939. PMID 24411645. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4697939 .   \n\n\nNotes \nThis presentation is faithful to the original, with only a few minor changes to presentation, grammar, and punctuation. In some cases important information was missing from the references, and that information was added. The original cited an Accenture YouTube video for the claim regarding users writing their credentials down; for this version a more informative press release, which links to the video, was used.\n\n\n\n\n\n\nSource: <a rel=\"external_link\" class=\"external\" href=\"https:\/\/www.limswiki.org\/index.php\/Journal:Health_care_and_cybersecurity:_Bibliometric_analysis_of_the_literature\">https:\/\/www.limswiki.org\/index.php\/Journal:Health_care_and_cybersecurity:_Bibliometric_analysis_of_the_literature<\/a>\n\t\t\t\t\tCategories: LIMSwiki journal articles (added in 2020)LIMSwiki journal articles (all)LIMSwiki journal articles on cybersecurityLIMSwiki journal articles on health informatics\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\n\t\t\t\t\n\t\t\t\n\t\t\n\t\t\n\t\t\tNavigation menu\n\t\t\t\t\t\n\t\t\tViews\n\n\t\t\t\n\t\t\t\t\n\t\t\t\tJournal\n\t\t\t\tDiscussion\n\t\t\t\tView source\n\t\t\t\tHistory\n\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\n\t\t\t\t\n\t\t\t\tPersonal tools\n\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\t\t\tLog in\n\t\t\t\t\t\t\t\t\t\t\t\t\tRequest account\n\t\t\t\t\t\t\t\t\t\t\t\n\t\t\t\t\n\t\t\t\n\t\t\t\n\t\t\t\t\n\t\t\t\n\t\t\t\t\n\t\tNavigation\n\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\tMain page\n\t\t\t\t\t\t\t\t\t\t\tRecent changes\n\t\t\t\t\t\t\t\t\t\t\tRandom page\n\t\t\t\t\t\t\t\t\t\t\tHelp\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\n\t\t\t\n\t\t\tSearch\n\n\t\t\t\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t \n\t\t\t\t\t\t\n\t\t\t\t\n\n\t\t\t\t\t\t\t\n\t\t\n\t\t\t\n\t\t\tTools\n\n\t\t\t\n\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\tWhat links here\n\t\t\t\t\t\t\t\t\t\t\tRelated changes\n\t\t\t\t\t\t\t\t\t\t\tSpecial pages\n\t\t\t\t\t\t\t\t\t\t\tPermanent link\n\t\t\t\t\t\t\t\t\t\t\tPage information\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\n\t\t\n\t\tPrint\/export\n\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\tCreate a book\n\t\t\t\t\t\t\t\t\t\t\tDownload as PDF\n\t\t\t\t\t\t\t\t\t\t\tDownload as Plain text\n\t\t\t\t\t\t\t\t\t\t\tPrintable version\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\n\t\t\n\t\tSponsors\n\t\t\n\t\t\t \r\n\n\t\r\n\n\t\r\n\n\t\n\t\r\n\n\t\r\n\n\t\n\t\r\n\n \n\t\r\n\n\t\n\t\r\n\n \n\t\n\t\r\n\n\t\n\t\n\t\r\n\n\t\r\n\n\t\r\n\n\t\n\t\r\n\n\t\r\n\t\t\n\t\t\n\t\t\t\n\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t This page was last modified on 5 May 2020, at 18:28.\n\t\t\t\t\t\t\t\t\tThis page has been accessed 507 times.\n\t\t\t\t\t\t\t\t\tContent is available under a Creative Commons Attribution-ShareAlike 4.0 International License unless otherwise noted.\n\t\t\t\t\t\t\t\t\tPrivacy policy\n\t\t\t\t\t\t\t\t\tAbout LIMSWiki\n\t\t\t\t\t\t\t\t\tDisclaimers\n\t\t\t\t\t\t\t\n\t\t\n\t\t\n\t\t\n\n","a4527a9687a2e4995aa12c37d0db8fb1_html":"<body class=\"mediawiki ltr sitedir-ltr ns-206 ns-subject page-Journal_Health_care_and_cybersecurity_Bibliometric_analysis_of_the_literature skin-monobook action-view\">\n<div id=\"rdp-ebb-globalWrapper\">\n\t\t<div id=\"rdp-ebb-column-content\">\n\t\t\t<div id=\"rdp-ebb-content\" class=\"mw-body\" role=\"main\">\n\t\t\t\t<a id=\"rdp-ebb-top\"><\/a>\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t<h1 id=\"rdp-ebb-firstHeading\" class=\"firstHeading\" lang=\"en\">Journal:Health care and cybersecurity: Bibliometric analysis of the literature<\/h1>\n\t\t\t\t\n\t\t\t\t<div id=\"rdp-ebb-bodyContent\" class=\"mw-body-content\">\n\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\n\n\t\t\t\t\t<!-- start content -->\n\t\t\t\t\t<div id=\"rdp-ebb-mw-content-text\" lang=\"en\" dir=\"ltr\" class=\"mw-content-ltr\">\n\n\n<h2><span class=\"mw-headline\" id=\"Abstract\">Abstract<\/span><\/h2>\n<p><b>Background<\/b>: Over the past decade, clinical care has become globally dependent on information technology. The <a href=\"https:\/\/www.limswiki.org\/index.php\/Cybersecurity\" title=\"Cybersecurity\" class=\"mw-redirect wiki-link\" data-key=\"ba653dc2a1384e5f9f6ac9dc1a740109\">cybersecurity<\/a> of <a href=\"https:\/\/www.limswiki.org\/index.php\/Health_informatics\" title=\"Health informatics\" class=\"wiki-link\" data-key=\"055eb51f53cfdbacc08ed150b266c9f4\">health care information systems<\/a> is now an essential component of safe, reliable, and effective health care delivery.\n<\/p><p><b>Objective<\/b>: The objective of this study was to provide an overview of the literature at the intersection of cybersecurity and health care delivery.\n<\/p><p><b>Methods<\/b>: A comprehensive search was conducted using PubMed and Web of Science for English-language peer-reviewed articles. We carried out chronological analysis, domain clustering analysis, and text analysis of the included articles to generate a high-level concept map composed of specific words and the connections between them.\n<\/p><p><b>Results<\/b>: Our final sample included 472 English-language journal articles. Our review results revealed that a majority of the articles were focused on technology. Technology\u2013focused articles made up more than half of all the clusters, whereas managerial articles accounted for only 32 percent of all clusters. This finding suggests that nontechnological variables (human\u2013based and organizational aspects, strategy, and management) may be understudied. In addition, <a href=\"https:\/\/www.limswiki.org\/index.php\/Software_development_security\" title=\"Software development security\" class=\"wiki-link\" data-key=\"20e75bd7ff6754e63e7ae5bb9e9ce4fb\">software development security<\/a>, business continuity, and disaster recovery planning each accounted for three percent of the studied articles. Our results also showed that publications on <a href=\"https:\/\/www.limswiki.org\/index.php\/Physical_security\" title=\"Physical security\" class=\"wiki-link\" data-key=\"39042dc985ec4e0cc5ea32e2852824b0\">physical security<\/a> account for only one percent of the literature, and research in this area is lacking. Cyber vulnerabilities are not all digital; many physical threats contribute to breaches and potentially affect the physical safety of patients.\n<\/p><p><b>Conclusions<\/b>: Our results revealed an overall increase in research on cybersecurity and identified major gaps and opportunities for future work.\n<\/p><p><b>Keywords<\/b>: bibliometric review, cybersecurity, health care, literature analysis, text mining \n<\/p>\n<h2><span class=\"mw-headline\" id=\"Introduction\">Introduction<\/span><\/h2>\n<p><a href=\"https:\/\/www.limswiki.org\/index.php\/Cybersecurity\" title=\"Cybersecurity\" class=\"mw-redirect wiki-link\" data-key=\"ba653dc2a1384e5f9f6ac9dc1a740109\">Cybersecurity<\/a> is an increasingly critical aspect of <a href=\"https:\/\/www.limswiki.org\/index.php\/Health_information_technology\" title=\"Health information technology\" class=\"wiki-link\" data-key=\"9c8ef822470559f757db89f3fa234cc0\">health care information technology<\/a> infrastructure. The rapid digitization of health care delivery, from <a href=\"https:\/\/www.limswiki.org\/index.php\/Electronic_health_record\" title=\"Electronic health record\" class=\"wiki-link\" data-key=\"f2e31a73217185bb01389404c1fd5255\">electronic health records<\/a> (EHR) and <a href=\"https:\/\/www.limswiki.org\/index.php\/Telehealth\" title=\"Telehealth\" class=\"wiki-link\" data-key=\"7fa3bb62d93e066945a25961f55f5642\">telehealth<\/a> to <a href=\"https:\/\/www.limswiki.org\/index.php\/MHealth\" title=\"MHealth\" class=\"wiki-link\" data-key=\"42415d515f590babb6158dc02b7b3f0a\">mobile health<\/a> (mHealth) and network-enabled , introduces risks related to cybersecurity vulnerabilities.<sup id=\"rdp-ebb-cite_ref-JalaliCyber18_1-0\" class=\"reference\"><a href=\"#cite_note-JalaliCyber18-1\">[1]<\/a><\/sup> These vulnerabilities are particularly worrisome because cyberattacks in a health care setting can result in the exposure of <a href=\"https:\/\/www.limswiki.org\/index.php\/Information_privacy\" title=\"Information privacy\" class=\"wiki-link\" data-key=\"185f6d9f874e48914b5789317408f782\">highly sensitive personal information<\/a> or cause disruptions in clinical care.<sup id=\"rdp-ebb-cite_ref-GordonThreats17_2-0\" class=\"reference\"><a href=\"#cite_note-GordonThreats17-2\">[2]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-PerakslisCyber14_3-0\" class=\"reference\"><a href=\"#cite_note-PerakslisCyber14-3\">[3]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-JarrettCyber17_4-0\" class=\"reference\"><a href=\"#cite_note-JarrettCyber17-4\">[4]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-KramerCyber17_5-0\" class=\"reference\"><a href=\"#cite_note-KramerCyber17-5\">[5]<\/a><\/sup> Cyberattacks may also affect the safety of patients, for example, by compromising the <a href=\"https:\/\/www.limswiki.org\/index.php\/Data_integrity\" title=\"Data integrity\" class=\"wiki-link\" data-key=\"382a9bb77ee3e36bb3b37c79ed813167\">integrity of data<\/a> or impairing medical device functionality. The WannaCry and NotPetya ransomware attacks and vulnerabilities in Medtronic Implantable Cardiac Device Programmers are recent examples that have resulted in impaired health care delivery capabilities.<sup id=\"rdp-ebb-cite_ref-FurnellTheABC17_6-0\" class=\"reference\"><a href=\"#cite_note-FurnellTheABC17-6\">[6]<\/a><\/sup>\n<\/p><p>Health care organizations are particularly vulnerable to cyber threats. Verizon\u2019s <i>2018 Data Breach Investigations Report<\/i> found that the health care field, in general, was most affected by data breaches, which accounted for 24 percent of all investigated breaches across all industries.<sup id=\"rdp-ebb-cite_ref-Verizon2018_7-0\" class=\"reference\"><a href=\"#cite_note-Verizon2018-7\">[7]<\/a><\/sup> Additionally, a report by the Ponemon Institute found that almost 90 percent of respondents (involved in health plans and health care clearinghouses, as well as health care providers with EHRs) experienced a data breach in the past two years.<sup id=\"rdp-ebb-cite_ref-PonemonSixth16_8-0\" class=\"reference\"><a href=\"#cite_note-PonemonSixth16-8\">[8]<\/a><\/sup> Another survey of health care information security professionals revealed that over 75 percent of health care organizations experienced a recent security incident.<sup id=\"rdp-ebb-cite_ref-HIMSS2018_9-0\" class=\"reference\"><a href=\"#cite_note-HIMSS2018-9\">[9]<\/a><\/sup> The causes are multifactorial, involving both technology and people, and human error and cultural factors play increasingly critical roles.<sup id=\"rdp-ebb-cite_ref-MadnickMeasuring17_10-0\" class=\"reference\"><a href=\"#cite_note-MadnickMeasuring17-10\">[10]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-JalaliDecision19_11-0\" class=\"reference\"><a href=\"#cite_note-JalaliDecision19-11\">[11]<\/a><\/sup> Despite efforts to teach best-practice security behavior through training programs, recent surveys have revealed that one in five health care employees still write down their usernames and passwords on paper.<sup id=\"rdp-ebb-cite_ref-AccentureOneIn18_12-0\" class=\"reference\"><a href=\"#cite_note-AccentureOneIn18-12\">[12]<\/a><\/sup>\n<\/p><p>Given the increasing importance of cybersecurity for safe, effective, and reliable health care delivery, there is a need to provide an overview of the literature at the intersection of cybersecurity and health care. Recent systematic reviews synthesized insights from 31 articles on cyber threats in health care<sup id=\"rdp-ebb-cite_ref-KruseCyber17_13-0\" class=\"reference\"><a href=\"#cite_note-KruseCyber17-13\">[13]<\/a><\/sup> and aggregated strategies from 13 articles about responding to cyber incidents in health care organizations.<sup id=\"rdp-ebb-cite_ref-JalaliEARS19_14-0\" class=\"reference\"><a href=\"#cite_note-JalaliEARS19-14\">[14]<\/a><\/sup> In this study, we conduct a large bibliometric review of the literature and describe the current state of research on various aspects of cybersecurity in health care in order to not only understand current trends but also identify gaps and guide future research efforts toward improving the security of our health care systems.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Methods\">Methods<\/span><\/h2>\n<h3><span class=\"mw-headline\" id=\"Study_eligibility_criteria\">Study eligibility criteria<\/span><\/h3>\n<p>A comprehensive search was conducted using PubMed and Web of Science (WoS) for English-language peer-reviewed articles. We identified search keywords by adopting terminologies in The National Initiative for Cybersecurity Careers and Studies<sup id=\"rdp-ebb-cite_ref-NICCSGlossary_15-0\" class=\"reference\"><a href=\"#cite_note-NICCSGlossary-15\">[15]<\/a><\/sup> and The British Standards Institution glossaries.<sup id=\"rdp-ebb-cite_ref-BSIGlossary_16-0\" class=\"reference\"><a href=\"#cite_note-BSIGlossary-16\">[16]<\/a><\/sup> The list of keywords used follows.\n<\/p><p><b>WoS (journal articles, all years)<\/b>:\n<\/p>\n<blockquote>\u201cHealth*\u201d AND \u201cCybersecurity\u201d OR \u201cCyber Security\u201d OR \u201cCyber Attack*\u201d OR \u201cCyber Crisis*\u201d OR \u201cCyber Incident*\u201d OR \u201cCyber Infrastructure*\u201d OR \u201cCyber Operation*\u201d OR \u201cCyber Risk*\u201d OR \u201cCyber Threat*\u201d OR \u201cCyberspace*\u201d OR \u201cData Breach*\u201d OR \u201cData Security*\u201d OR \u201cFirewall*\u201d OR \u201cInformation Security*\u201d OR \u201cInformation Systems Security*\u201d OR \u201cInformation Technology Security*\u201d OR \u201cIT Security*\u201d OR \u201cMalware*\u201d OR \u201cPhishing*\u201d OR \u201cRansomware*\u201d OR \u201cSecurity Incident*\u201d OR \u201cInformation Assurance*\u201d<\/blockquote>\n<p><b>PubMed (journal articles, all years, abstract availability)<\/b>:\n<\/p>\n<blockquote>\u201cCybersecurity\u201d OR \u201cCyber Security\u201d OR \u201cCyber Attack\u201d OR \u201cCyber Crisis\u201d OR \u201cCyber Incident\u201d OR \u201cCyber Infrastructure\u201d OR \u201cCyber Operation\u201d OR \u201cCyber Risk\u201d OR \u201cCyber Threat\u201d OR \u201cCyberspace\u201d OR \u201cData Breach\u201d OR \u201cData Security\u201d OR \u201cFirewall\u201d OR \u201cInformation Security\u201d OR \u201cInformation Systems Security\u201d OR \u201cInformation Technology Security\u201d OR \u201cIT Security\u201d OR \u201cMalware\u201d OR \u201cPhishing\u201d OR \u201cRansomware\u201d OR \u201cSecurity Incident\u201d OR \u201cInformation Assurance\u201d<\/blockquote>\n<p>Keywords that widened the search results far beyond the scope were rejected. For example, \u201cexploit\u201d and \u201cmalicious\u201d can be used in a cyber context, but they are more commonly used in unrelated contexts that add noise to the search. Such terms were not included because of their contribution to an overwhelming amount of irrelevant results.\n<\/p><p>We included articles published from the inception of PubMed in 1966 and WoS in 1900, all the way to September 2017. Articles were excluded if they did not clearly focus on cybersecurity or health care or if they were reviews or meta-analyses. Inclusion and exclusion criteria were formulated prior to the preliminary title and abstract screening. The eligibility criteria were intentionally nonspecific to obtain a complete picture of the existing relevant research. To increase our confidence in the inclusion criteria, we conducted an initial pilot screening of 100 articles.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Screening_selection\">Screening selection<\/span><\/h3>\n<p>Screening of titles and abstracts was conducted using the software package abstrackr.<sup id=\"rdp-ebb-cite_ref-WallaceDeploy12_17-0\" class=\"reference\"><a href=\"#cite_note-WallaceDeploy12-17\">[17]<\/a><\/sup> Full texts of the \u201cmaybe\u201d articles were independently reviewed by two trained individuals to assess study eligibility. Disagreements about study inclusion were discussed until a consensus was reached. More details about our methodology are available in Multimedia Appendix 1.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Chronological_clustering_and_trend_analysis\">Chronological clustering and trend analysis<\/span><\/h3>\n<p>We performed chronological analysis of the number of articles published per year and the number of authors per article. We topically clustered articles using 10 security domains created by the International Information Systems Security Certification Consortium to categorize each article (Multimedia Appendix 1). Each clustered article was further categorized as technological, managerial, legal, or interdisciplinary (if it fell into more than three categories). Features of the included articles, such as the publishing journal and number of citations, were recorded.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Text_analysis\">Text analysis<\/span><\/h3>\n<p>After analyzing all the titles and abstracts, we removed words with high frequencies that were common in research articles but were not specific to our subject (e.g., \u201cpaper,\u201d \u201cusing,\u201d and \u201cresults\u201d). In addition, we merged the plural forms with singular forms of the same word and merged \u201chealthcare\u201d and \u201chealth care\u201d into \u201chealthcare.\u201d Subsequently, we created word clouds to visualize the word frequencies in titles and abstracts over time. Word frequency is represented by color and size, with darker, larger words representing higher occurrence.\n<\/p><p>We then assessed text titles and abstracts to generate a high-level concept map composed of specific words and the connections between them by using the software package Leximancer text analytics (version 4.5; Leximancer Pty Ltd, Brisbane, Australia). The software started with an unsupervised machine learning approach to extract a network of meaning from the data and developed a heat map that visually illustrated the end results. The method, underpinned by a naive Bayesian co-occurrence metric, considers how often two words co-occur as well as how often they occur apart.<sup id=\"rdp-ebb-cite_ref-SmithEval06_18-0\" class=\"reference\"><a href=\"#cite_note-SmithEval06-18\">[18]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ChengAComp17_19-0\" class=\"reference\"><a href=\"#cite_note-ChengAComp17-19\">[19]<\/a><\/sup> Heat maps consist of \u201cthemes\u201d represented by bubbles and \u201cconcepts\u201d represented by grey dots. Concepts can be equated to a list of similar terms coalescing into a monothematic idea, and themes are clusters of these concepts. The lines between dots suggest a strong connection between two concepts.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Results\">Results<\/span><\/h2>\n<h3><span class=\"mw-headline\" id=\"Search_results\">Search results<\/span><\/h3>\n<p>The primary search on PubMed for papers containing terms pertaining to \u201ccyber\u201d yielded 1,480 articles, and the search on WoS yielded 810 articles. After removing 310 duplicates, the titles and abstracts of 1,980 articles were screened, which was facilitated by the Abstrackr software.<sup id=\"rdp-ebb-cite_ref-WallaceDeploy12_17-1\" class=\"reference\"><a href=\"#cite_note-WallaceDeploy12-17\">[17]<\/a><\/sup> Based on the inclusion criteria, 1,262 articles were excluded in the first screening, reducing the results to 718 articles for full-text review. Eventually, a further screening removed additional articles to provide a final selection of 472 articles. Figure 1 presents the search method and results.\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig1_Jalali_JofMedIntRes2019_21-2.png\" class=\"image wiki-link\" data-key=\"fe51a0f141e6d3e5a0df623e5cfd012f\"><img alt=\"Fig1 Jalali JofMedIntRes2019 21-2.png\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/0\/0a\/Fig1_Jalali_JofMedIntRes2019_21-2.png\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Fig. 1<\/b> Search method and results<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<h3><span class=\"mw-headline\" id=\"Chronological_clustering_and_trend_analysis_2\">Chronological clustering and trend analysis<\/span><\/h3>\n<p>Figure 2 presents the overall trend of all publications over time, from 1985 to September 2017; the first included article was published in 1979 but was excluded from the figure for better visualization. Figure 2 shows a steady increase in the number of articles published on cybersecurity in health care (Multimedia Appendix 1).\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig2_Jalali_JofMedIntRes2019_21-2.png\" class=\"image wiki-link\" data-key=\"b23a58b755df383b485c240214f9fd61\"><img alt=\"Fig2 Jalali JofMedIntRes2019 21-2.png\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/4\/44\/Fig2_Jalali_JofMedIntRes2019_21-2.png\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Fig. 2<\/b> Annual number of published papers at the intersection of health care and cybersecurity (fitted trend line: y=0.9166e0.1252x; R\u00b2=0.82)<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>Figure 3 shows the distribution among the three high-level categories: technological, managerial, and legal (Multimedia Appendix 1). The seven technological clusters made up more than half of all clusters, the two managerial clusters represented 32 percent, and the legal cluster represented 18 percent of all clusters.\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig3_Jalali_JofMedIntRes2019_21-2.png\" class=\"image wiki-link\" data-key=\"c721321ea95c272d1effa786882e8560\"><img alt=\"Fig3 Jalali JofMedIntRes2019 21-2.png\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/a\/ad\/Fig3_Jalali_JofMedIntRes2019_21-2.png\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Fig. 3<\/b> Cluster distributions<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>The orange-shaded portion within each cluster in Figure 3 represents interdisciplinary articles (spanning multiple high-level categories). Although the topic of physical security had the lowest number of publications (Figure 3), it was the most interdisciplinary cluster (six out of the seven articles [85.7 percent] identified as interdisciplinary). The topic of legal, regulations, investigations, and compliance was the second most interdisciplinary cluster (59.8 percent of the articles in this category were interdisciplinary), followed by operations security (52.9 percent), business continuity and disaster recovery planning (50 percent), Information security governance and risk management (43.9 percent), and access control (30.6 percent). Although the topic of security architecture and design was the second most frequent cluster overall, only 22.2 percent of the articles were found to be interdisciplinary. The less interdisciplinary categories were in the topics of telecommunications and network security (18.9 percent), software development security (17.6 percent), and cryptography (four percent) (Multimedia Appendix 1).\n<\/p><p>We analyzed the publication trends over time in the 10 clusters (Figure 4). All clusters showed increased frequency, and some clusters such as security architecture and design, information security gGovernance and risk management, and cryptography demonstrated particularly steep increases in frequency.\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig4_Jalali_JofMedIntRes2019_21-2.png\" class=\"image wiki-link\" data-key=\"2ad61316e0ea079fca6e4f9ee0fdec16\"><img alt=\"Fig4 Jalali JofMedIntRes2019 21-2.png\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/4\/4e\/Fig4_Jalali_JofMedIntRes2019_21-2.png\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Fig. 4<\/b> Trend of 10 clusters over time<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<h3><span class=\"mw-headline\" id=\"Journal_characteristics\">Journal characteristics<\/span><\/h3>\n<p>Overall, the 472 articles included were published in 239 unique journals. We ranked the journals according to the number of published articles and selected the journals with more than three articles, which resulted in a list of 17 journals (Table 1). According to the corresponding InCites Journal Citation Reports (JCR) categories<sup id=\"rdp-ebb-cite_ref-ClarivateJournal_20-0\" class=\"reference\"><a href=\"#cite_note-ClarivateJournal-20\">[20]<\/a><\/sup>, the top journals tended to focus on computer science, information systems, and <a href=\"https:\/\/www.limswiki.org\/index.php\/Medical_informatics\" title=\"Medical informatics\" class=\"mw-redirect wiki-link\" data-key=\"f89ecb3b26617b8c6e09bc5e050cfd5d\">medical informatics<\/a>. The most popular JCR category, accounting for seven out of the 10 journals listed in JCR, was medical informatics. Six journals had a computer science category, specifically within information systems, interdisciplinary applications, or theory and methods. Five journals were from the health care sciences and services category. Only one of the top 15 journals was categorized as a biomedical engineering journal; one, as a math and computational biology journal; and one, as a radiology, nuclear medicine, and medical imaging journal.\n<\/p><p>Approximately 73 percent of the 239 journals had only published one article at the intersection of cybersecurity and health care. The high number and diversity of the journals included along with the low publication rate suggest that there is currently no major niche for medical practice readership at the intersection of cybersecurity and health care due to the cross-disciplinary nature of the field.\n<\/p><p><br \/>\n<\/p>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table class=\"wikitable\" border=\"1\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\" colspan=\"3\"><b>Table 1.<\/b> Journals with the most articles\n<\/td><\/tr>\n\n<tr>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">Journal\n<\/th>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\"># of published papers\n<\/th>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">Indexed categories (according to Journal Citation Reports)<sup id=\"rdp-ebb-cite_ref-ClarivateJournal_20-1\" class=\"reference\"><a href=\"#cite_note-ClarivateJournal-20\">[20]<\/a><\/sup>\n<\/th><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>Studies in Health Technology and Informatics<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">47\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Not indexed\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>International Journal of Medical Informatics<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">24\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Computer science, information systems; Health care sciences & services; Medical informatics\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>Journal of Medical Systems<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">17\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Health care sciences & services; Medical informatics\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>Journal of Diabetes Science and Technology<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">9\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Not indexed\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>Healthcare Financial Management<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">8\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Not indexed\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>Medical Informatics<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">8\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Computer science, information systems; Computer science, interdisciplinary applications; Medical informatics\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>International Journal of Bio-Medical Computing<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">8\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Computer science, interdisciplinary applications; Computer science, theory & methods; Engineering, biomedical; Medical informatics\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>Computers & Security<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">7\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Computer science, information systems\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>Journal of the American Medical Informatics Association<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">7\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Computer science, information systems; Computer science, interdisciplinary applications; Health care sciences & services; Medical informatics\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>Journal of Healthcare Protection Management<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">7\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Not indexed\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>Telemedicine Journal and E-Health<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">5\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Health care sciences & services\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>IEEE Journal of Biomedical and Health Informatics<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">4\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Computer science, information systems; Computer science, interdisciplinary applications; Mathematical & computational biology; Medical informatics\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>Journal of the American Health Information Management Association<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">4\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Not indexed\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>Journal of Digital Imaging<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">4\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Radiology, nuclear medicine & medical imaging\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>Journal of Healthcare Information Management<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">4\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Not indexed\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>Journal of Medical Internet Research<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">4\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Health care sciences & services; Medical informatics\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>Journal of Medical Practice Management<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">4\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Not indexed\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<h3><span class=\"mw-headline\" id=\"Characteristics_of_the_most_cited_articles\">Characteristics of the most cited articles<\/span><\/h3>\n<p>Table 2 shows the most influential publications in the field of cybersecurity in health care, ranked by the number of citations as of September 2017. Six of the top 15 cited articles were published in five journals of the Institute of Electrical and Electronics Engineers. The clusters show a mix of article domains across the legal, managerial, and technological domains. The author-denoted keywords support this finding.\n<\/p><p>Of the total clusters of the top 15 articles, 38 percent belonged to security architecture and design category. Cryptography was the next most popular cluster (17 percent); followed by legal, regulations, investigations, and compliance (13 percent); and access control (13 percent). Overall, 79 percent of the clusters were technological, 13 percent were legal, and eight percent were managerial. Additionally, 20 percent of the papers were interdisciplinary, with multiple clusters of distinct high-level categories. Notably, the list of most cited articles does not reflect the most recent articles, as citation of these articles is often significantly delayed.\n<\/p>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table class=\"wikitable\" border=\"1\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\" colspan=\"8\"><b>Table 2.<\/b> Top 15 most cited articles\n<\/td><\/tr>\n\n<tr>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">Rank\n<\/th>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\"># of citations\n<\/th>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">Title\n<\/th>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">Authors\n<\/th>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">Year\n<\/th>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">Journal\n<\/th>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">Clusters\n<\/th>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">Author-denoted keywords\n<\/th><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">1\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">443\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Data security and privacy in wireless body area networks\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Li, M.; Lou, W.J.; Ren, K.\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">2010\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>IEEE Wireless Communications<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Telecommunications and network security\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Data security, Data privacy, Body sensor networks, Biomedical monitoring, Wireless sensor networks, Wearable sensors, Wireless communication, Medical services, Application software, Patient monitoring\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">2\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">304\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Analyzing regulatory rules for privacy and security requirements\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Breaux, T.D. and Anton, A.I.\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">2008\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>IEEE Transactions on Software Engineering<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Legal, regulations, investigations and compliance\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Data security and privacy, Laws and regulations, Compliance, Accountability, Requirements engineering\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">3\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">173\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Medical image security in a HIPAA mandated PACS environment\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Cao, F.; Huang, H.K.; Zhou, X.Q.\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">2003\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>Computerized Medical Imaging and Graphics<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Legal, regulations, investigations and compliance; Security architecture and design\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Data encryption, Picture archiving and communication system security, Image integrity, Digital imaging and communication in medicine, Compliance, Health insurance portability and accountability act\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">4\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">168\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">SPOC: A Secure and Privacy-Preserving Opportunistic Computing Framework for Mobile-Healthcare Emergency\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Lu, R.X.; Lin, X.D.; Shen, X.M.\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">2013\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>IEEE Transactions on Parallel and Distributed Systems<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Access control; Security architecture and design\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Mobile-healthcare emergency, Opportunistic computing, User-centric privacy access control, PPSPC\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">5\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">158\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Authenticity and integrity of digital mammography images\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Zhou, X.Q.; Huang, H.K.; Lou, S.L.\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">2001\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>IEEE Transactions on Medical Imaging<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Cryptography, Telecommunications and network security\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Data embedding and cryptography, Digital mammography, Image authenticity and integrity, Telemammography\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">6\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">131\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Security in health-care information systems--current trends\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Smith, E. and Eloff, J.H.\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">1999\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>International Journal of Medical Informatics<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Access control, Information security governance and risk management\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Health-care information systems security, Risk-analysis in health-care information systems, Access control for computerized health-care, Electronic patient record, International Medical Informatics Association, Managed health-care\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">7\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">112\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">How to ensure data security of an epidemiological follow-up: Quality assessment of an anonymous record linkage procedure\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Quantin, C.; Bouzelat, H.; Allaert, F.A. <i>et al.<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">1998\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>International Journal of Medical Informatics<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Cryptography, Security architecture and design\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Data security, Computerized record, Linkage procedure\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">8\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">103\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">IBE-Lite: A lightweight identity-based cryptography for body sensor networks\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Tan, C.C.; Wang, H.D.; Zhong, S.; Li, Q.\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">2009\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>IEEE Transactions on Information Technology in Biomedicine<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Security architecture and design, Cryptography\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Body sensor network, Identity-based encryption, Privac, Security\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">9\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">89\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">A security architecture for interconnecting health information systems\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Gritzalis, D. and Lambrinoudakis, C.\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">2004\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>International Journal of Medical Informatics<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Access control, Security architecture and design\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Information systems security, Computer security, Medical data security, Medical Data Protection, Electronic healthcare records, Role-based access control\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">10\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">85\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Biometric methods for secure communications in body sensor networks: Resource-efficient key management and signal-level data scrambling\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Bui, F.M. and Hatzinakos, D.\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">2008\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>Eurasip Journal on Advances in Signal Processing<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Security architecture and design, Cryptography\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Not available\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">11\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">84\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">mHealth data security: The need for HIPAA-compliant standardization\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Luxton, D.D.; Kayl, R.A.; Mishkind, M.C.\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">2012\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>Telemedicine Journal and E-Health<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Software development security; Legal, regulations, investigations and compliance\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Security, HIPAA, Encryption, Telehealth, Mobile health\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">12\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">82\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Analysis of the security and privacy requirements of cloud-based electronic health records systems\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Rodrigues, J.J.; de la Torre, I.; Fernandez, G.; Lopez-Coronado, M.\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">2013\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>Journal of Medical Internet Research<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Security architecture and design\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Cloud-computing, eHealth, Electronic health records (EHRs), Privacy, Security\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">13\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">82\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Health care management and information systems security: Awareness, training or education?\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Katsikas, S.K.\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">2000\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>International Journal of Medical Informatics<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Information security governance and risk management\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Health information systems, Information systems security, Health care management, Education, Training, Awareness\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">14\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">82\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Securing m-healthcare social networks: Challenges, countermeasures and future directions\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Zhou, J.; Cao, Z.F.; Dong, X.L. <i>et al.<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">2013\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>IEEE Wireless Communications<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Security architecture and design\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Mobile communication, Social network services, Medical services, Mobile computing, Personal digital assistants, Privacy, Network security, Electronic medical records\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">15\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">80\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Privacy and data security in E-health: Requirements from the user's perspective\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Wilkowska, W. and Ziefle, M.\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">2012\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><i>Health Informatics Journal<\/i>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Security architecture and design\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">E-health, Gender, Medical assistive technologies, Privacy, Security\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<h3><span class=\"mw-headline\" id=\"Test_analysis\">Test analysis<\/span><\/h3>\n<p>The text-mining analysis identified specific trends in the article texts. The map produced from all titles and abstracts is shown in Figure 5. The thematic bubbles are ranked by relevance based on a heat-map color scheme: hot colors indicate more important themes, and cool colors indicate less important themes. The relative positions of the bubbles indicate the relationship between aggregated ideas, reflecting how closely they are related to each other. The sizes of the bubbles are only set to include their grey dots, and the size of each grey dot (a common word within the theme) indicates its relative frequency. The lines between these dots signify connectivity and association of concepts.\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig5_Jalali_JofMedIntRes2019_21-2.png\" class=\"image wiki-link\" data-key=\"cae18601f7368485c0689402895734b7\"><img alt=\"Fig5 Jalali JofMedIntRes2019 21-2.png\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/a\/a7\/Fig5_Jalali_JofMedIntRes2019_21-2.png\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Fig. 5<\/b> Thematic map of all titles and abstracts <b>(A)<\/b> and concept cloud of all titles and abstracts <b>(B)<\/b><\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>The overlay of grey-dot concepts onto thematic bubbles allows for more specific analysis of terms. Technological terms emerge as the main theme in Figure 5, including words like \u201cencryption\u201d and \u201csoftware.\u201d Concept words within these themes highlighted the following common elements of an organization\u2019s informal technology structure related to cybersecurity: \u201cinternet,\u201d \u201cnetwork,\u201d \u201capplications,\u201d \u201crecords,\u201d \u201cbreaches,\u201d \u201ckey,\u201d and \u201celectronic.\u201d Managerial and legal terms were also identified as concepts (Figure 5). \u201cManagement\u201d was a concept within the \u201cinformation\u201d theme. \u201cPolicies\u201d and \u201cprocess\u201d were concepts in the risk theme and indicated the influence of risk analysis on the cybersecurity policies and procedures of organizations. \u201cHIPAA\u201d was a concept that stemmed from the \u201cinformation\u201d concept in the \u201cimportant\u201d theme.\n<\/p><p>The two central themes \u201csecurity\u201d and \u201cinformation\u201d included multiple, large grey-dot concepts that branched out into other thematic areas. There was an overlap between \u201csecurity\u201d and \u201cencryption,\u201d suggesting that encoding material is fundamental to security. An overlap between \u201csecurity\u201d and \u201cusers\u201d could imply that user control is imperative to security.\n<\/p><p>For further analysis of word frequencies, the articles from 1985 to 2017 were split into four time periods: 1985-1993, 1994-2001, 2002-2009, and 2010-2017 (September). Multimedia Appendix 1 presents the word clouds within the four time periods. The size of the word represents the frequency of its occurrence. The term \u201cprivacy\u201d increased in size in the last three time periods. \u201cInternet\u201d appeared in 1994-2001, around the time of the dot-com bubble. \u201cLegal\u201d was mentioned in 1985-1993, and \u201clegislation\u201d was found in 1994-2001. \u201cHIPAA\u201d appeared in 2002-2009 and again, although to a smaller extent, in 2010-2017.\n<\/p><p>Maps of the four time periods were also created to identify trends over time (Figure 6). \u201cSecurity\u201d remained the most popular concept from 1985 to 2009, but was overtaken by \u201chealth care\u201d from 2010 to 2017 (the most popular concept is indicated by the red bubble). The time period maps in Multimedia Appendix 1 provide further details.\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig6_Jalali_JofMedIntRes2019_21-2.png\" class=\"image wiki-link\" data-key=\"759fdb4a257b640fd5ba9c821439ba93\"><img alt=\"Fig6 Jalali JofMedIntRes2019 21-2.png\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/d\/da\/Fig6_Jalali_JofMedIntRes2019_21-2.png\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Fig. 6<\/b> Thematic maps of titles and abstracts of articles in four time periods<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<h2><span class=\"mw-headline\" id=\"Discussion\">Discussion<\/span><\/h2>\n<h3><span class=\"mw-headline\" id=\"Overview\">Overview<\/span><\/h3>\n<p>This article provides an analysis of the literature at the intersection of cybersecurity and health care. In general, research in this area has been increasing over the past 20 years and is continually represented in a wide, distributed array of academic journals, reflecting the importance of cybersecurity. With the increase in cybersecurity attacks against hospitals and dependency of health care delivery on technology, we expect cybersecurity to continue to play a central role in health care delivery.\n<\/p><p>Despite the increase in research and attention to cybersecurity, there are persistent shortcomings in the research on cybersecurity. For example, our research suggests that majority of the articles on cybersecurity focus on technology. In our domain-clustering analysis, technology\u2013focused articles accounted for more than half of all the clusters, whereas managerial articles accounted for only 32 percent. Similarly, in our journal analysis, 58 articles included in the 15 most published journals were from computer science journals and 12 articles were from health-focused journals. Notably, 79 percent of the top 15 most cited paper clusters were technological. This focus on the technological aspects of cybersecurity suggests that nontechnological variables (human\u2013based and organizational aspects, strategy, and management) may be understudied. Investment in technological tools should be the output of a robust cybersecurity strategy rather than the foundation.<sup id=\"rdp-ebb-cite_ref-HCICTFReport17_21-0\" class=\"reference\"><a href=\"#cite_note-HCICTFReport17-21\">[21]<\/a><\/sup> An overwhelming majority of cybersecurity incidents are caused or propagated by people<sup id=\"rdp-ebb-cite_ref-vanZadelhoffTheBig16_22-0\" class=\"reference\"><a href=\"#cite_note-vanZadelhoffTheBig16-22\">[22]<\/a><\/sup>, and technological solutions can mitigate this risk to a limited extent.\n<\/p><p>We found discordance between the topics of the highly cited articles and the topical breakdown of our cluster analysis (these articles were published more than five years ago, implying that emergent threats are poorly captured). This finding suggests that articles on topics such as cryptography have significant traction, even though they are not widely present in the literature. On the other hand, only a few information security governance and compliance articles were frequently cited, despite accounting for a large portion of the literature. \n<\/p><p>Cybersecurity is most often examined with respect to privacy and compliance. Our results show that physical security is lacking in research, and only one percent of the literature is categorized under physical security. Not all cyber vulnerabilities are digital. Many physical threats contribute to breaches, and these threats potentially affect the physical safety of patients. Software development security, business continuity, and disaster recovery planning, each accounted for three percent of the studied articles. Further examination is needed on these topics, and our study suggests that incident recovery (critical to the success of recovery from incidents) is not a significant focus in the research community. Articles focusing on legality were the least represented. Moreover, federal cybersecurity guidance such as the publications of the National Institute of Standards and Technology was seldom observed in our text analysis. In addition, massive increases in cybersecurity spending<sup id=\"rdp-ebb-cite_ref-GartnerForecasts17_23-0\" class=\"reference\"><a href=\"#cite_note-GartnerForecasts17-23\">[23]<\/a><\/sup> did not drive proportional growth in the literature.\n<\/p><p>Our lexical analysis highlighted a separation of security processes and software terminology, with longer word distances between these themes. Additionally, the time period maps for 2002-2009 and 2010-2017 showed no overlap between the management and technological themes. More interdisciplinary research is needed to avoid gaps that arise from only analyzing managerial and technological security issues.\n<\/p><p>Unlike medical research, which is set up to openly benefit human lives<sup id=\"rdp-ebb-cite_ref-IoannidisIncreasing14_24-0\" class=\"reference\"><a href=\"#cite_note-IoannidisIncreasing14-24\">[24]<\/a><\/sup>, cybersecurity is based on the premise of an active adversary. The presence of this adversary may, unfortunately, drive a school of thought that knowledge, especially specific strategies and tactics, should not be shared openly, which impedes the growth and utility of research in this field.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Limitations_and_suggestions_for_future_research\">Limitations and suggestions for future research<\/span><\/h3>\n<p>Our review was limited to journal articles indexed in PubMed and WoS. Information retrieval was limited to articles that included the terms of the search strategy in their titles or abstracts; articles that used different terminology were not retrieved. Additionally, we only included articles with cybersecurity at the core of the study.\n<\/p><p>Our review did not assess non-English language articles or documents other than journal articles (e.g., conference articles, white papers, or reports by governments or other organizations). A more comprehensive search could include these sources. Importantly, much of the work on cybersecurity and health care is operational and administrative, not academic. Information security professionals may not rely on academic literature as extensively as clinicians do when considering new diagnostics or therapeutics and may instead favor \u201con the job\u201d experience and industry best practices. Additionally, information security research performed within the health care ecosystem may not be publishable due to security-related concerns such as exposing an internal vulnerability. Understanding the published literature in this space is an important starting point, and hospitals and patients will benefit from transparency in research, wherever possible.\n<\/p><p>Future reviews can focus on individual clusters that were reviewed in our study to provide a more in-depth analysis of the cluster. For instance, they could look specifically at business continuity and disaster recovery planning or software development security. Such a detailed focus can help synthesize research findings and provide best practices. Studies may also analyze the gap in managerial research and the implications of a narrow technological focus. Furthermore, such studies can focus on different settings in health care, such as inpatient and outpatient care, translational research, health and wellness environments, and integration of mobile devices and networked systems.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Abbreviations\">Abbreviations<\/span><\/h2>\n<p><b>HIPAA<\/b>: Health Insurance Portability and Accountability Act \n<\/p><p><b>IEEE<\/b>: Institute of Electrical and Electronics Engineers\n<\/p><p><b>mHealth<\/b>: mobile health\n<\/p><p><b>NIST<\/b>: National Institute of Standards and Technology\n<\/p><p><b>PACS<\/b>: picture archiving and communication system\n<\/p><p><b>WoS<\/b>: Web of Science\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Multimedia_Appendix_1\">Multimedia Appendix 1<\/span><\/h2>\n<p>Details of the methodology: <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.jmir.org\/api\/download?filename=e5210e57f25f9e07c2ca7c37d59a833b.pdf&alt_name=12644-235924-1-SP.pdf\" target=\"_blank\">PDF<\/a>\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Acknowledgements\">Acknowledgements<\/span><\/h2>\n<p>Financial support for this study was provided by Cybersecurity at MIT Sloan (CAMS), also known as the Interdisciplinary Consortium for Improving Critical Infrastructure Cybersecurity.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Conflicts_of_interest\">Conflicts of interest<\/span><\/h3>\n<p>None declared.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"References\">References<\/span><\/h2>\n<div class=\"reflist references-column-width\" style=\"-moz-column-width: 30em; -webkit-column-width: 30em; column-width: 30em; list-style-type: decimal;\">\n<ol class=\"references\">\n<li id=\"cite_note-JalaliCyber18-1\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-JalaliCyber18_1-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Jalali, M.S.; Kaiser, J.P. (2018). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5996174\" target=\"_blank\">\"Cybersecurity in Hospitals: A Systematic, Organizational Perspective\"<\/a>. <i>Journal of Medical Internet Research<\/i> <b>20<\/b> (5): e10059. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.2196%2F10059\" target=\"_blank\">10.2196\/10059<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC5996174\/\" target=\"_blank\">PMC5996174<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/29807882\" target=\"_blank\">29807882<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5996174\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5996174<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Cybersecurity+in+Hospitals%3A+A+Systematic%2C+Organizational+Perspective&rft.jtitle=Journal+of+Medical+Internet+Research&rft.aulast=Jalali%2C+M.S.%3B+Kaiser%2C+J.P.&rft.au=Jalali%2C+M.S.%3B+Kaiser%2C+J.P.&rft.date=2018&rft.volume=20&rft.issue=5&rft.pages=e10059&rft_id=info:doi\/10.2196%2F10059&rft_id=info:pmc\/PMC5996174&rft_id=info:pmid\/29807882&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC5996174&rfr_id=info:sid\/en.wikipedia.org:Journal:Health_care_and_cybersecurity:_Bibliometric_analysis_of_the_literature\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-GordonThreats17-2\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-GordonThreats17_2-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Gordon, W.J.; Fairhall, A.; Landman, A. (2017). \"Threats to Information Security - Public Health Implications\". <i>New England Journal of Medicine<\/i> <b>377<\/b> (8): 707\u20139. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1056%2FNEJMp1707212\" target=\"_blank\">10.1056\/NEJMp1707212<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/28700269\" target=\"_blank\">28700269<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Threats+to+Information+Security+-+Public+Health+Implications&rft.jtitle=New+England+Journal+of+Medicine&rft.aulast=Gordon%2C+W.J.%3B+Fairhall%2C+A.%3B+Landman%2C+A.&rft.au=Gordon%2C+W.J.%3B+Fairhall%2C+A.%3B+Landman%2C+A.&rft.date=2017&rft.volume=377&rft.issue=8&rft.pages=707%E2%80%939&rft_id=info:doi\/10.1056%2FNEJMp1707212&rft_id=info:pmid\/28700269&rfr_id=info:sid\/en.wikipedia.org:Journal:Health_care_and_cybersecurity:_Bibliometric_analysis_of_the_literature\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-PerakslisCyber14-3\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-PerakslisCyber14_3-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Perakslis, E.D. (2014). \"Cybersecurity in health care\". <i>New England Journal of Medicine<\/i> <b>371<\/b> (5): 395\u20137. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1056%2FNEJMp1404358\" target=\"_blank\">10.1056\/NEJMp1404358<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/25075831\" target=\"_blank\">25075831<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Cybersecurity+in+health+care&rft.jtitle=New+England+Journal+of+Medicine&rft.aulast=Perakslis%2C+E.D.&rft.au=Perakslis%2C+E.D.&rft.date=2014&rft.volume=371&rft.issue=5&rft.pages=395%E2%80%937&rft_id=info:doi\/10.1056%2FNEJMp1404358&rft_id=info:pmid\/25075831&rfr_id=info:sid\/en.wikipedia.org:Journal:Health_care_and_cybersecurity:_Bibliometric_analysis_of_the_literature\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-JarrettCyber17-4\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-JarrettCyber17_4-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Jarrett, M.P. (2017). \"Cybersecurity-A Serious Patient Care Concern\". <i>JAMA<\/i> <b>318<\/b> (14): 1319\u201320. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1001%2Fjama.2017.11986\" target=\"_blank\">10.1001\/jama.2017.11986<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/28973258\" target=\"_blank\">28973258<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Cybersecurity-A+Serious+Patient+Care+Concern&rft.jtitle=JAMA&rft.aulast=Jarrett%2C+M.P.&rft.au=Jarrett%2C+M.P.&rft.date=2017&rft.volume=318&rft.issue=14&rft.pages=1319%E2%80%9320&rft_id=info:doi\/10.1001%2Fjama.2017.11986&rft_id=info:pmid\/28973258&rfr_id=info:sid\/en.wikipedia.org:Journal:Health_care_and_cybersecurity:_Bibliometric_analysis_of_the_literature\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-KramerCyber17-5\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-KramerCyber17_5-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Kramer, D.B.; Fu, K. (2017). \"Cybersecurity Concerns and Medical Devices: Lessons From a Pacemaker Advisory\". <i>JAMA<\/i> <b>318<\/b> (21): 2077\u201378. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1001%2Fjama.2017.15692\" target=\"_blank\">10.1001\/jama.2017.15692<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/29049709\" target=\"_blank\">29049709<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Cybersecurity+Concerns+and+Medical+Devices%3A+Lessons+From+a+Pacemaker+Advisory&rft.jtitle=JAMA&rft.aulast=Kramer%2C+D.B.%3B+Fu%2C+K.&rft.au=Kramer%2C+D.B.%3B+Fu%2C+K.&rft.date=2017&rft.volume=318&rft.issue=21&rft.pages=2077%E2%80%9378&rft_id=info:doi\/10.1001%2Fjama.2017.15692&rft_id=info:pmid\/29049709&rfr_id=info:sid\/en.wikipedia.org:Journal:Health_care_and_cybersecurity:_Bibliometric_analysis_of_the_literature\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-FurnellTheABC17-6\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-FurnellTheABC17_6-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Furnell, S.; Emm, D. (2017). \"The ABC of ransomware protection\". <i>Computer Fraud & Security<\/i> <b>2017<\/b> (10): 5\u201311. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2FS1361-3723%2817%2930089-1\" target=\"_blank\">10.1016\/S1361-3723(17)30089-1<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=The+ABC+of+ransomware+protection&rft.jtitle=Computer+Fraud+%26+Security&rft.aulast=Furnell%2C+S.%3B+Emm%2C+D.&rft.au=Furnell%2C+S.%3B+Emm%2C+D.&rft.date=2017&rft.volume=2017&rft.issue=10&rft.pages=5%E2%80%9311&rft_id=info:doi\/10.1016%2FS1361-3723%2817%2930089-1&rfr_id=info:sid\/en.wikipedia.org:Journal:Health_care_and_cybersecurity:_Bibliometric_analysis_of_the_literature\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-Verizon2018-7\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-Verizon2018_7-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Verizon (2018). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/enterprise.verizon.com\/resources\/reports\/DBIR_2018_Report.pdf\" target=\"_blank\">\"2018 Data Breach Investigations Report\"<\/a> (PDF). Verizon<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/enterprise.verizon.com\/resources\/reports\/DBIR_2018_Report.pdf\" target=\"_blank\">https:\/\/enterprise.verizon.com\/resources\/reports\/DBIR_2018_Report.pdf<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 01 September 2018<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=2018+Data+Breach+Investigations+Report&rft.atitle=&rft.aulast=Verizon&rft.au=Verizon&rft.date=2018&rft.pub=Verizon&rft_id=https%3A%2F%2Fenterprise.verizon.com%2Fresources%2Freports%2FDBIR_2018_Report.pdf&rfr_id=info:sid\/en.wikipedia.org:Journal:Health_care_and_cybersecurity:_Bibliometric_analysis_of_the_literature\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-PonemonSixth16-8\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-PonemonSixth16_8-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Ponemon Institute, LLC (May 2016). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.ponemon.org\/local\/upload\/file\/Sixth%20Annual%20Patient%20Privacy%20%26%20Data%20Security%20Report%20FINAL%206.pdf\" target=\"_blank\">\"Sixth Annual Benchmark Study on Privacy & Security of Healthcare Data\"<\/a> (PDF). Ponemon Institute, LLC<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.ponemon.org\/local\/upload\/file\/Sixth%20Annual%20Patient%20Privacy%20%26%20Data%20Security%20Report%20FINAL%206.pdf\" target=\"_blank\">https:\/\/www.ponemon.org\/local\/upload\/file\/Sixth%20Annual%20Patient%20Privacy%20%26%20Data%20Security%20Report%20FINAL%206.pdf<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 09 April 2018<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Sixth+Annual+Benchmark+Study+on+Privacy+%26+Security+of+Healthcare+Data&rft.atitle=&rft.aulast=Ponemon+Institute%2C+LLC&rft.au=Ponemon+Institute%2C+LLC&rft.date=May+2016&rft.pub=Ponemon+Institute%2C+LLC&rft_id=https%3A%2F%2Fwww.ponemon.org%2Flocal%2Fupload%2Ffile%2FSixth%2520Annual%2520Patient%2520Privacy%2520%2526%2520Data%2520Security%2520Report%2520FINAL%25206.pdf&rfr_id=info:sid\/en.wikipedia.org:Journal:Health_care_and_cybersecurity:_Bibliometric_analysis_of_the_literature\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-HIMSS2018-9\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-HIMSS2018_9-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Healthcare Information and Management Systems Society (2018). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.himss.org\/sites\/hde\/files\/d7\/u132196\/2018_HIMSS_Cybersecurity_Survey_Final_Report.pdf\" target=\"_blank\">\"2018 HIMSS Cybersecurity Survey\"<\/a> (PDF). Healthcare Information and Management Systems Society<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.himss.org\/sites\/hde\/files\/d7\/u132196\/2018_HIMSS_Cybersecurity_Survey_Final_Report.pdf\" target=\"_blank\">https:\/\/www.himss.org\/sites\/hde\/files\/d7\/u132196\/2018_HIMSS_Cybersecurity_Survey_Final_Report.pdf<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 30 July 2020<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=2018+HIMSS+Cybersecurity+Survey&rft.atitle=&rft.aulast=Healthcare+Information+and+Management+Systems+Society&rft.au=Healthcare+Information+and+Management+Systems+Society&rft.date=2018&rft.pub=Healthcare+Information+and+Management+Systems+Society&rft_id=https%3A%2F%2Fwww.himss.org%2Fsites%2Fhde%2Ffiles%2Fd7%2Fu132196%2F2018_HIMSS_Cybersecurity_Survey_Final_Report.pdf&rfr_id=info:sid\/en.wikipedia.org:Journal:Health_care_and_cybersecurity:_Bibliometric_analysis_of_the_literature\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-MadnickMeasuring17-10\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-MadnickMeasuring17_10-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Madnick, S.; Jalali, M.S.; Siegel, M. et al. (2017). \"Measuring Stakeholders\u2019 Perceptions of Cybersecurity for Renewable Energy Systems\". <i>Proceedings from DARE 2016: Data Analytics for Renewable Energy Integration<\/i>. Lecture Notes in Computer Science <b>10097<\/b>: 67\u201377. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1007%2F978-3-319-50947-1_7\" target=\"_blank\">10.1007\/978-3-319-50947-1_7<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Measuring+Stakeholders%E2%80%99+Perceptions+of+Cybersecurity+for+Renewable+Energy+Systems&rft.jtitle=Proceedings+from+DARE+2016%3A+Data+Analytics+for+Renewable+Energy+Integration&rft.aulast=Madnick%2C+S.%3B+Jalali%2C+M.S.%3B+Siegel%2C+M.+et+al.&rft.au=Madnick%2C+S.%3B+Jalali%2C+M.S.%3B+Siegel%2C+M.+et+al.&rft.date=2017&rft.series=Lecture+Notes+in+Computer+Science&rft.volume=10097&rft.pages=67%E2%80%9377&rft_id=info:doi\/10.1007%2F978-3-319-50947-1_7&rfr_id=info:sid\/en.wikipedia.org:Journal:Health_care_and_cybersecurity:_Bibliometric_analysis_of_the_literature\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-JalaliDecision19-11\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-JalaliDecision19_11-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Jalali, M.S.; Siegel, M.; Madnick, S. (2019). \"Decision-making and biases in cybersecurity capability development: Evidence from a simulation game experiment\". <i>The Journal of Strategic Information Systems<\/i> <b>28<\/b> (1): 66\u201382. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.jsis.2018.09.003\" target=\"_blank\">10.1016\/j.jsis.2018.09.003<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Decision-making+and+biases+in+cybersecurity+capability+development%3A+Evidence+from+a+simulation+game+experiment&rft.jtitle=The+Journal+of+Strategic+Information+Systems&rft.aulast=Jalali%2C+M.S.%3B+Siegel%2C+M.%3B+Madnick%2C+S.&rft.au=Jalali%2C+M.S.%3B+Siegel%2C+M.%3B+Madnick%2C+S.&rft.date=2019&rft.volume=28&rft.issue=1&rft.pages=66%E2%80%9382&rft_id=info:doi\/10.1016%2Fj.jsis.2018.09.003&rfr_id=info:sid\/en.wikipedia.org:Journal:Health_care_and_cybersecurity:_Bibliometric_analysis_of_the_literature\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-AccentureOneIn18-12\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-AccentureOneIn18_12-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\"><a rel=\"external_link\" class=\"external text\" href=\"https:\/\/newsroom.accenture.com\/news\/one-in-five-health-employees-willing-to-sell-confidential-data-to-unauthorized-parties-accenture-survey-finds.htm\" target=\"_blank\">\"One in Five Health Employees Willing to Sell Confidential Data to Unauthorized Parties, Accenture Survey Finds\"<\/a>. Accenture. 01 March 2018<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/newsroom.accenture.com\/news\/one-in-five-health-employees-willing-to-sell-confidential-data-to-unauthorized-parties-accenture-survey-finds.htm\" target=\"_blank\">https:\/\/newsroom.accenture.com\/news\/one-in-five-health-employees-willing-to-sell-confidential-data-to-unauthorized-parties-accenture-survey-finds.htm<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=One+in+Five+Health+Employees+Willing+to+Sell+Confidential+Data+to+Unauthorized+Parties%2C+Accenture+Survey+Finds&rft.atitle=&rft.date=01+March+2018&rft.pub=Accenture&rft_id=https%3A%2F%2Fnewsroom.accenture.com%2Fnews%2Fone-in-five-health-employees-willing-to-sell-confidential-data-to-unauthorized-parties-accenture-survey-finds.htm&rfr_id=info:sid\/en.wikipedia.org:Journal:Health_care_and_cybersecurity:_Bibliometric_analysis_of_the_literature\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-KruseCyber17-13\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-KruseCyber17_13-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Kruse, C.S.; Frederick, B.; Jacobson, T. et al. (2017). \"Cybersecurity in healthcare: A systematic review of modern threats and trends\". <i>Technology and Health Care<\/i> <b>25<\/b> (1): 1\u201310. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.3233%2FTHC-161263\" target=\"_blank\">10.3233\/THC-161263<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/27689562\" target=\"_blank\">27689562<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Cybersecurity+in+healthcare%3A+A+systematic+review+of+modern+threats+and+trends&rft.jtitle=Technology+and+Health+Care&rft.aulast=Kruse%2C+C.S.%3B+Frederick%2C+B.%3B+Jacobson%2C+T.+et+al.&rft.au=Kruse%2C+C.S.%3B+Frederick%2C+B.%3B+Jacobson%2C+T.+et+al.&rft.date=2017&rft.volume=25&rft.issue=1&rft.pages=1%E2%80%9310&rft_id=info:doi\/10.3233%2FTHC-161263&rft_id=info:pmid\/27689562&rfr_id=info:sid\/en.wikipedia.org:Journal:Health_care_and_cybersecurity:_Bibliometric_analysis_of_the_literature\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-JalaliEARS19-14\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-JalaliEARS19_14-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Jalali, M.S.; Russell, B.; Razak, S. et al. (2019). \"EARS to cyber incidents in health care\". <i>JAMIA<\/i> <b>26<\/b> (1): 81\u201390. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1093%2Fjamia%2Focy148\" target=\"_blank\">10.1093\/jamia\/ocy148<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/30517701\" target=\"_blank\">30517701<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=EARS+to+cyber+incidents+in+health+care&rft.jtitle=JAMIA&rft.aulast=Jalali%2C+M.S.%3B+Russell%2C+B.%3B+Razak%2C+S.+et+al.&rft.au=Jalali%2C+M.S.%3B+Russell%2C+B.%3B+Razak%2C+S.+et+al.&rft.date=2019&rft.volume=26&rft.issue=1&rft.pages=81%E2%80%9390&rft_id=info:doi\/10.1093%2Fjamia%2Focy148&rft_id=info:pmid\/30517701&rfr_id=info:sid\/en.wikipedia.org:Journal:Health_care_and_cybersecurity:_Bibliometric_analysis_of_the_literature\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-NICCSGlossary-15\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-NICCSGlossary_15-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">National Initiative for Cybersecurity Careers and Studies. <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/niccs.us-cert.gov\/about-niccs\/glossary\" target=\"_blank\">\"Glossary\"<\/a>. National Initiative for Cybersecurity Careers and Studies<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/niccs.us-cert.gov\/about-niccs\/glossary\" target=\"_blank\">https:\/\/niccs.us-cert.gov\/about-niccs\/glossary<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 31 December 2018<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Glossary&rft.atitle=&rft.aulast=National+Initiative+for+Cybersecurity+Careers+and+Studies&rft.au=National+Initiative+for+Cybersecurity+Careers+and+Studies&rft.pub=National+Initiative+for+Cybersecurity+Careers+and+Studies&rft_id=https%3A%2F%2Fniccs.us-cert.gov%2Fabout-niccs%2Fglossary&rfr_id=info:sid\/en.wikipedia.org:Journal:Health_care_and_cybersecurity:_Bibliometric_analysis_of_the_literature\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-BSIGlossary-16\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-BSIGlossary_16-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">British Standards Institution. <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.bsigroup.com\/en-GB\/Cyber-Security\/Glossary-of-cyber-security-terms\/\" target=\"_blank\">\"Glossary of cyber security terms\"<\/a>. British Standards Institution<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.bsigroup.com\/en-GB\/Cyber-Security\/Glossary-of-cyber-security-terms\/\" target=\"_blank\">https:\/\/www.bsigroup.com\/en-GB\/Cyber-Security\/Glossary-of-cyber-security-terms\/<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 31 July 2018<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Glossary+of+cyber+security+terms&rft.atitle=&rft.aulast=British+Standards+Institution&rft.au=British+Standards+Institution&rft.pub=British+Standards+Institution&rft_id=https%3A%2F%2Fwww.bsigroup.com%2Fen-GB%2FCyber-Security%2FGlossary-of-cyber-security-terms%2F&rfr_id=info:sid\/en.wikipedia.org:Journal:Health_care_and_cybersecurity:_Bibliometric_analysis_of_the_literature\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-WallaceDeploy12-17\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-WallaceDeploy12_17-0\">17.0<\/a><\/sup> <sup><a href=\"#cite_ref-WallaceDeploy12_17-1\">17.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Wallace, B.C.; Small, K.; Brodley, C.E. (2012). \"Deploying an interactive machine learning system in an evidence-based practice center: abstrackr\". <i>Proceedings of the 2nd ACM SIGHIT International Health Informatics Symposium<\/i>: 819\u201324. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1145%2F2110363.2110464\" target=\"_blank\">10.1145\/2110363.2110464<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Deploying+an+interactive+machine+learning+system+in+an+evidence-based+practice+center%3A+abstrackr&rft.jtitle=Proceedings+of+the+2nd+ACM+SIGHIT+International+Health+Informatics+Symposium&rft.aulast=Wallace%2C+B.C.%3B+Small%2C+K.%3B+Brodley%2C+C.E.&rft.au=Wallace%2C+B.C.%3B+Small%2C+K.%3B+Brodley%2C+C.E.&rft.date=2012&rft.pages=819%E2%80%9324&rft_id=info:doi\/10.1145%2F2110363.2110464&rfr_id=info:sid\/en.wikipedia.org:Journal:Health_care_and_cybersecurity:_Bibliometric_analysis_of_the_literature\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-SmithEval06-18\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-SmithEval06_18-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Smith, A.E.; Humphreys, M.S. (2006). \"Evaluation of unsupervised semantic mapping of natural language with Leximancer concept mapping\". <i>Behavior Research Methods<\/i> <b>38<\/b>: 262\u201379. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.3758%2FBF03192778\" target=\"_blank\">10.3758\/BF03192778<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Evaluation+of+unsupervised+semantic+mapping+of+natural+language+with+Leximancer+concept+mapping&rft.jtitle=Behavior+Research+Methods&rft.aulast=Smith%2C+A.E.%3B+Humphreys%2C+M.S.&rft.au=Smith%2C+A.E.%3B+Humphreys%2C+M.S.&rft.date=2006&rft.volume=38&rft.pages=262%E2%80%9379&rft_id=info:doi\/10.3758%2FBF03192778&rfr_id=info:sid\/en.wikipedia.org:Journal:Health_care_and_cybersecurity:_Bibliometric_analysis_of_the_literature\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ChengAComp17-19\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-ChengAComp17_19-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Cheng, M. (2019). \"A comparative automated content analysis approach on the review of the sharing economy discourse in tourism and hospitality\". <i>Current Issues in Tourism<\/i> <b>22<\/b> (1): 35\u201349. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1080%2F13683500.2017.1361908\" target=\"_blank\">10.1080\/13683500.2017.1361908<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=A+comparative+automated+content+analysis+approach+on+the+review+of+the+sharing+economy+discourse+in+tourism+and+hospitality&rft.jtitle=Current+Issues+in+Tourism&rft.aulast=Cheng%2C+M.&rft.au=Cheng%2C+M.&rft.date=2019&rft.volume=22&rft.issue=1&rft.pages=35%E2%80%9349&rft_id=info:doi\/10.1080%2F13683500.2017.1361908&rfr_id=info:sid\/en.wikipedia.org:Journal:Health_care_and_cybersecurity:_Bibliometric_analysis_of_the_literature\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ClarivateJournal-20\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-ClarivateJournal_20-0\">20.0<\/a><\/sup> <sup><a href=\"#cite_ref-ClarivateJournal_20-1\">20.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation web\">Clarivate Analytics. <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/clarivate.com\/webofsciencegroup\/solutions\/journal-citation-reports\/\" target=\"_blank\">\"Journal Citation Reports\"<\/a>. Clarivate Analytics<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/clarivate.com\/webofsciencegroup\/solutions\/journal-citation-reports\/\" target=\"_blank\">https:\/\/clarivate.com\/webofsciencegroup\/solutions\/journal-citation-reports\/<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 29 October 2018<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Journal+Citation+Reports&rft.atitle=&rft.aulast=Clarivate+Analytics&rft.au=Clarivate+Analytics&rft.pub=Clarivate+Analytics&rft_id=https%3A%2F%2Fclarivate.com%2Fwebofsciencegroup%2Fsolutions%2Fjournal-citation-reports%2F&rfr_id=info:sid\/en.wikipedia.org:Journal:Health_care_and_cybersecurity:_Bibliometric_analysis_of_the_literature\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-HCICTFReport17-21\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-HCICTFReport17_21-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Health Care Industry Cybersecurity Task Force (June 2017). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.phe.gov\/Preparedness\/planning\/CyberTF\/Documents\/report2017.pdf\" target=\"_blank\">\"Report on Improving Cybersecurity in the Health Care Industry\"<\/a> (PDF). Assistant Secretary for Preparedness and Response<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.phe.gov\/Preparedness\/planning\/CyberTF\/Documents\/report2017.pdf\" target=\"_blank\">https:\/\/www.phe.gov\/Preparedness\/planning\/CyberTF\/Documents\/report2017.pdf<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Report+on+Improving+Cybersecurity+in+the+Health+Care+Industry&rft.atitle=&rft.aulast=Health+Care+Industry+Cybersecurity+Task+Force&rft.au=Health+Care+Industry+Cybersecurity+Task+Force&rft.date=June+2017&rft.pub=Assistant+Secretary+for+Preparedness+and+Response&rft_id=https%3A%2F%2Fwww.phe.gov%2FPreparedness%2Fplanning%2FCyberTF%2FDocuments%2Freport2017.pdf&rfr_id=info:sid\/en.wikipedia.org:Journal:Health_care_and_cybersecurity:_Bibliometric_analysis_of_the_literature\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-vanZadelhoffTheBig16-22\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-vanZadelhoffTheBig16_22-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">van Zadelhoff, M. (19 September 2016). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/hbr.org\/2016\/09\/the-biggest-cybersecurity-threats-are-inside-your-company\" target=\"_blank\">\"The biggest cybersecurity threats are inside your company\"<\/a>. <i>Harvard Business Review<\/i><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/hbr.org\/2016\/09\/the-biggest-cybersecurity-threats-are-inside-your-company\" target=\"_blank\">https:\/\/hbr.org\/2016\/09\/the-biggest-cybersecurity-threats-are-inside-your-company<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 04 February 2019<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=The+biggest+cybersecurity+threats+are+inside+your+company&rft.atitle=Harvard+Business+Review&rft.aulast=van+Zadelhoff%2C+M.&rft.au=van+Zadelhoff%2C+M.&rft.date=19+September+2016&rft_id=https%3A%2F%2Fhbr.org%2F2016%2F09%2Fthe-biggest-cybersecurity-threats-are-inside-your-company&rfr_id=info:sid\/en.wikipedia.org:Journal:Health_care_and_cybersecurity:_Bibliometric_analysis_of_the_literature\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-GartnerForecasts17-23\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-GartnerForecasts17_23-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Gartner (07 December 2017). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.gartner.com\/en\/newsroom\/press-releases\/2017-12-07-gartner-forecasts-worldwide-security-spending-will-reach-96-billion-in-2018\" target=\"_blank\">\"Gartner Forecasts Worldwide Security Spending Will Reach $96 Billion in 2018, Up 8 Percent from 2017\"<\/a>. Gartner<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.gartner.com\/en\/newsroom\/press-releases\/2017-12-07-gartner-forecasts-worldwide-security-spending-will-reach-96-billion-in-2018\" target=\"_blank\">https:\/\/www.gartner.com\/en\/newsroom\/press-releases\/2017-12-07-gartner-forecasts-worldwide-security-spending-will-reach-96-billion-in-2018<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 29 October 2018<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Gartner+Forecasts+Worldwide+Security+Spending+Will+Reach+%2496+Billion+in+2018%2C+Up+8+Percent+from+2017&rft.atitle=&rft.aulast=Gartner&rft.au=Gartner&rft.date=07+December+2017&rft.pub=Gartner&rft_id=https%3A%2F%2Fwww.gartner.com%2Fen%2Fnewsroom%2Fpress-releases%2F2017-12-07-gartner-forecasts-worldwide-security-spending-will-reach-96-billion-in-2018&rfr_id=info:sid\/en.wikipedia.org:Journal:Health_care_and_cybersecurity:_Bibliometric_analysis_of_the_literature\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-IoannidisIncreasing14-24\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-IoannidisIncreasing14_24-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Ioannidis, J.P.; Greenland, S.; Hlatky, M.A. et al. (2014). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4697939\" target=\"_blank\">\"Increasing value and reducing waste in research design, conduct, and analysis\"<\/a>. <i>Lancet<\/i> <b>383<\/b> (9912): 166\u201375. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2FS0140-6736%2813%2962227-8\" target=\"_blank\">10.1016\/S0140-6736(13)62227-8<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC4697939\/\" target=\"_blank\">PMC4697939<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/24411645\" target=\"_blank\">24411645<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4697939\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4697939<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Increasing+value+and+reducing+waste+in+research+design%2C+conduct%2C+and+analysis&rft.jtitle=Lancet&rft.aulast=Ioannidis%2C+J.P.%3B+Greenland%2C+S.%3B+Hlatky%2C+M.A.+et+al.&rft.au=Ioannidis%2C+J.P.%3B+Greenland%2C+S.%3B+Hlatky%2C+M.A.+et+al.&rft.date=2014&rft.volume=383&rft.issue=9912&rft.pages=166%E2%80%9375&rft_id=info:doi\/10.1016%2FS0140-6736%2813%2962227-8&rft_id=info:pmc\/PMC4697939&rft_id=info:pmid\/24411645&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC4697939&rfr_id=info:sid\/en.wikipedia.org:Journal:Health_care_and_cybersecurity:_Bibliometric_analysis_of_the_literature\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<\/ol><\/div>\n<h2><span class=\"mw-headline\" id=\"Notes\">Notes<\/span><\/h2>\n<p>This presentation is faithful to the original, with only a few minor changes to presentation, grammar, and punctuation. In some cases important information was missing from the references, and that information was added. The original cited an Accenture YouTube video for the claim regarding users writing their credentials down; for this version a more informative press release, which links to the video, was used.\n<\/p>\n<!-- \nNewPP limit report\nCached time: 20200707205048\nCache expiry: 86400\nDynamic content: false\nCPU time usage: 0.556 seconds\nReal time usage: 3.525 seconds\nPreprocessor visited node count: 18468\/1000000\nPreprocessor generated node count: 32700\/1000000\nPost\u2010expand include size: 134298\/2097152 bytes\nTemplate argument size: 45911\/2097152 bytes\nHighest expansion depth: 18\/40\nExpensive parser function count: 0\/100\n-->\n\n<!-- \nTransclusion expansion time report (%,ms,calls,template)\n100.00% 387.296 1 - -total\n 84.03% 325.431 1 - Template:Reflist\n 69.67% 269.811 24 - Template:Citation\/core\n 47.72% 184.816 14 - Template:Cite_journal\n 25.66% 99.373 10 - Template:Cite_web\n 10.00% 38.728 1 - Template:Infobox_journal_article\n 9.50% 36.803 1 - Template:Infobox\n 6.48% 25.090 80 - Template:Infobox\/row\n 6.07% 23.515 24 - Template:Citation\/identifier\n 4.04% 15.660 25 - Template:Citation\/make_link\n-->\n\n<!-- Saved in parser cache with key limswiki:pcache:idhash:11946-0!*!0!!en!5!* and timestamp 20200707205044 and revision id 39304\n -->\n<\/div><div class=\"printfooter\">Source: <a rel=\"external_link\" class=\"external\" href=\"https:\/\/www.limswiki.org\/index.php\/Journal:Health_care_and_cybersecurity:_Bibliometric_analysis_of_the_literature\">https:\/\/www.limswiki.org\/index.php\/Journal:Health_care_and_cybersecurity:_Bibliometric_analysis_of_the_literature<\/a><\/div>\n\t\t\t\t\t\t\t\t\t\t<!-- end content -->\n\t\t\t\t\t\t\t\t\t\t<div class=\"visualClear\"><\/div>\n\t\t\t\t<\/div>\n\t\t\t<\/div>\n\t\t<\/div>\n\t\t<!-- end of the left (by default at least) column -->\n\t\t<div class=\"visualClear\"><\/div>\n\t\t\t\t\t\n\t\t<\/div>\n\t\t\n\n<\/body>","a4527a9687a2e4995aa12c37d0db8fb1_images":["https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/0\/0a\/Fig1_Jalali_JofMedIntRes2019_21-2.png","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/4\/44\/Fig2_Jalali_JofMedIntRes2019_21-2.png","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/a\/ad\/Fig3_Jalali_JofMedIntRes2019_21-2.png","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/4\/4e\/Fig4_Jalali_JofMedIntRes2019_21-2.png","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/a\/a7\/Fig5_Jalali_JofMedIntRes2019_21-2.png","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/d\/da\/Fig6_Jalali_JofMedIntRes2019_21-2.png"],"a4527a9687a2e4995aa12c37d0db8fb1_timestamp":1594155044,"38f2f0437c54887eb841f892d039cb99_type":"article","38f2f0437c54887eb841f892d039cb99_title":"Epidemiological data challenges: Planning for a more robust future through data standards (Fairchild et al. 2018)","38f2f0437c54887eb841f892d039cb99_url":"https:\/\/www.limswiki.org\/index.php\/Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards","38f2f0437c54887eb841f892d039cb99_plaintext":"\n\n\t\t\n\t\t\t\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t\n\n\t\t\t\tJournal:Epidemiological data challenges: Planning for a more robust future through data standards\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t\tFrom LIMSWiki\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\tJump to: navigation, search\n\n\t\t\t\t\t\n\t\t\t\t\tFull article title\n \nEpidemiological data challenges: Planning for a more robust future through data standardsJournal\n \nFrontiers in Public HealthAuthor(s)\n \nFairchild, Geoffrey; Tasseff, Byron; Khalsa, Hari; Generous, Nicholas; Daughton, Ashlynn R.;\r\nVelappan, Nileena; Priedhorsky, Reid; Deshpande, AlinaAuthor affiliation(s)\n \nLos Alamos National LaboratoryPrimary contact\n \nEmail: gfairchild at lanl dot govEditors\n \nEfird, Jimmy T.Year published\n \n2018Volume and issue\n \n6Article #\n \n336DOI\n \n10.3389\/fpubh.2018.00336ISSN\n \n2296-2565Distribution license\n \nCreative Commons Attribution 4.0 InternationalWebsite\n \nhttps:\/\/www.frontiersin.org\/articles\/10.3389\/fpubh.2018.00336\/fullDownload\n \nhttps:\/\/www.frontiersin.org\/articles\/10.3389\/fpubh.2018.00336\/pdf (PDF)\n\nContents\n\n1 Abstract \n2 Introduction \n3 Discussion \n\n3.1 Interface challenges \n3.2 Data format challenges \n\n3.2.1 Data containers \n3.2.2 Element format \n\n\n3.3 Data reporting challenges \n\n\n4 Conclusions \n5 Acknowledgements \n\n5.1 Author contributions \n5.2 Funding \n5.3 Conflict of interest statement \n\n\n6 References \n7 Notes \n\n\n\nAbstract \nAccessible epidemiological data are of great value for emergency preparedness and response, understanding disease progression through a population, and building statistical and mechanistic disease models that enable forecasting. The status quo, however, renders acquiring and using such data difficult in practice. In many cases, a primary way of obtaining epidemiological data is through the internet, but the methods by which the data are presented to the public often differ drastically among institutions. As a result, there is a strong need for better data sharing practices. This paper identifies, in detail and with examples, the three key challenges one encounters when attempting to acquire and use epidemiological data: (1) interfaces, (2) data formatting, and (3) reporting. These challenges are used to provide suggestions and guidance for improvement as these systems evolve in the future. If these suggested data and interface recommendations were adhered to, epidemiological and public health analysis, modeling, and informatics work would be significantly streamlined, which can in turn yield better public health decision-making capabilities.\nKeywords: data, computational epidemiology, public health, disease modeling, informatics, disease surveillance\n\nIntroduction \nAt the heart of disease surveillance and modeling are epidemiological data. These data are generally presented as a time series of cases, T, for a geographic region, G, and for a demographic, D. The type of cases presented may vary depending on the context. For example, T may be a time series of confirmed or suspected cases, or it might be hospitalizations or deaths; in some circumstances, it may be a summation of some combination of these (e.g., confirmed + suspected cases). G is most commonly a political boundary; it might be a country, state\/province, county\/district, city, or sub-city region, such as a postal code or United States (U.S.) Census Bureau census tract. Depending on the context, D may simply be the the entire population of G, or it might be stratified by age, sex, race, education, or other relevant factors.\nEpidemiological data have a variety of uses. From a public health perspective, they can be used to gain an understanding of population-level disease progression. This understanding can in turn be used to aid in decision-making and allocation of resources. Recent outbreaks like Ebola and Zika have demonstrated the value of accessible epidemiological data for emergency preparedness and the need for better data sharing.[1] These data may influence vaccine distribution[2], and hospitals can anticipate surge capacity during an outbreak, allowing them to obtain extra temporary help if necessary.[3][4]\nFrom a modeler's perspective, high-quality reference data (also commonly referred to as \"ground truth data\") are needed to enable prediction and forecasting.[5] These data can be used to parameterize compartmental models[6] as well as stochastic agent-based models[7][8][9][10][11], and they can also be used to train and validate machine learning and statistical models.[12][13][14][15][16][17][18][19]\nThe internet has become the predominant way to publish, share, and collect epidemiological data. While data standards exist for observational studies[20] and clinical research[21], for example, no such standards exist for the publication of the kind of public health-related epidemiological data described above. Despite the strong need to share and consume data, there are many legal, technical, political, and cultural challenges in implementing a standardized epidemiological data framework.[22][23] As a result, the methods by which data are presented to the public often differ significantly among data-sharing institutions (e.g., public health departments, ministries of health, data collection or aggregation services). Moreover, these problems are not unique to epidemiological data; the issues described in this paper are common across many different disciplines.\nFirst, epidemiological data on the internet are presented to the user through a variety of interfaces. These interfaces vary widely not only in their appearance but also in their functionality. Some data are openly available through clear modern web interfaces, complete with well-documented programmer-friendly application programming interfaces (APIs), while others are displayed as static web pages that require error-prone and brittle web scraping. Still others are offered as machine-readable documents (e.g., comma-separate values [CSV], Microsoft Excel, Extensible Markup Language [XML], Adobe PDF). Finally, some necessitate contacting a human, who then prepares and sends the requested data manually.\nSecond, there are many data formats. Data containers (e.g., CSV, JavaScript Object Notation [JSON]) and element formats (e.g., timestamp format, location name format) may differ. Character encodings[24] (e.g., ASCII, UTF-8) and line endings[25] (e.g., \\r\\n, \\n) may also differ. Compounding these issues, formats can change over time (e.g., renaming or reordering spreadsheet columns). More broadly, these challenges are closely tied to schema, data model, and vocabulary standardization.\nFinally, there are differences among institutions in their reporting habits; even within a single institution, there are often reporting nuances among diseases. For example, one context may be reported monthly (e.g., Q fever in Australia), while another context is reported weekly (e.g., influenza in the U.S.) or even more finely (e.g., 2014 West African Ebola outbreak). Furthermore, what is meant by \u201cweekly\u201d in one context may be different than another context (e.g., CDC epi weeks vs. irregular reporting intervals in Poland, as described later).\nTogether, these challenges make large-scale public health data analysis and modeling significantly more difficult and time-consuming. Gathering, cleaning, and eliciting relevant data often require more time than the actual analysis itself. This paper discusses these three key technical challenges involving public health-related epidemiological data, in detail and with examples that were identified through detailed analysis of data deposition practices around the globe. Building from this analysis, we offer a framework of best practices comprised of modern standards that should be adhered to when releasing epidemiological data to the public. Such a framework will enable a more robust future for accurate and high-confidence epidemiological data and analysis.\n\nDiscussion \nInterface challenges \nThe interface is the mechanism by which data are presented to a user for consumption.\nEpidemiological data repositories implementing current best practices provide an interactive web-based searching and filtering interface that enables users to easily export desired data in a variety of formats. These are generally accompanied by an API that allows users to programmatically acquire desired data. For example, if one wants to download the latest influenza surveillance data weekly, instead of manually navigating an interactive web interface each week to export the data, the process could be automated by writing code that interacts with the API. Such an interface provides the simplest and most powerful method of data acquisition. Examples of this type of interface are the U.S. Centers for Disease Control and Prevention's (CDC) Data Catalog and the World Health Organization's (WHO) Global Health Observatory (GHO).\nWhile an interactive web-based interface coupled with an API is a best practice, it can be complex and expensive to implement. Many public health departments are under resource constraints and depend on older websites that tend to release data in one of two ways: 1) data are uploaded in some common format (e.g., CSV, Microsoft Excel, PDF) or 2) data are displayed in Hypertext Markup Language (HTML) tables. An example of the first is seen on Israel's Ministry of Health website, where data are provided weekly in Microsoft Excel formats.[26] An example of the second is seen on Australia's Department of Health website, where data are provided within simply-formatted HTML tables.[27]\nData uploaded in a common format can often be automatically downloaded and processed, and HTML tables can generally be automatically scraped and processed. While HTML scraping is often straightforward, there are some instances where it can be quite difficult. One example of a difficult-to-scrape data source is the Robert Koch Institute SurvStat 2.0 website.[28] Although the service is capable of providing epidemiological data at superior spatial and temporal resolutions (county- and week-level, respectively), the interface is not easily amenable to scraping. First, the HTTP requests formed by the ASP.NET application cannot be easily reverse-engineered; this necessitates the use of browser-automation software like Selenium, which enables automating website user interaction, such as mouse clicks and keyboard presses, for data scraping. Second, the selection of new filters, attributes, and display options results in a newly-refreshed page for each change; because many options are required to obtain each desired dataset, scraping can take a long time.\nAdditionally, while there may be no technical barriers to downloading or scraping data, there may be barriers relating to a website's terms of service (TOS). In some instances, the TOS may prevent users from scraping or downloading data en masse; this is sometimes done to prevent unreasonable load on the website, for example. Ignoring the TOS raises ethical issues that are often overlooked in research; after all, the goals of most epidemiological researchers are benevolent, and the data are public and usually funded by taxpayers. Ignoring a website's TOS could also raise logistical issues related to publishing and institutional review board (IRB) approval.\nA concern underlying all scraping efforts is that data scraping scripts are brittle. Web scraping relies on patterns in the HTML\/CSS source code of a website. If an institution modifies its layouts, even slightly, scrapers may exhibit unexpected behavior.\nIn some cases, a human must be contacted directly, who then prepares and sends the requested data. However, these manually requested and prepared data are often saddled with many restrictions. For example, when one of the authors contacted a ministry of health for more detailed epidemiological data, the data were offered with a five-page data request form that significantly restricted use and sharing of the data. Furthermore, it stated that it would take \u201cup to 3 months\u201d to be released because of the review and approval from the various data owners (local, state, and territory health departments). These types of restrictions and hurdles to data access prevent the development and adoption of advanced analytics.\nFinally, finding epidemiological data interfaces or data within an interface is often a time-consuming and error-prone task. For example, the Zika virus epidemic has resulted in increased global attention for Brazil, but it has not resulted in a single easy-to-understand machine-readable interface.[29] Until just recently, Brazil's Ministry of Health maintained two separate lists of mosquito-borne illness epidemiological bulletins.[30][31] Although these lists pointed to the exact same bulletins, the page archiving Boletim Epidemiol\u00f3gico[31] is consistently more up-to-date than the \"Epidemiological Situation\" page[30] (see Figures 1, 2). Having multiple interfaces increases the likelihood of human error when collecting epidemiological data. For instance, if one assumes that there is only one official source for Zika, the most current information may be overlooked.\n\r\n\n\n\n\n\n\n\n\n\n\n Fig. 1 Screenshot showing part of the mosquito-borne illness epidemiological bulletin list available at 'Boletim Epidemiol\u00f3gico'. This is the most current and complete list, with data available through the 38th week of 2016.\n\n\n\n\r\n\n\n\n\n\n\n\n\n\n\n Fig. 2 Screenshot showing part of the mosquito-borne illness epidemiological bulletin list available at the \"Epidemiological Situation\" page. This list only goes through week 21 of 2016 and is missing a number of weeks when compared to the list in Figure 1. This screenshot was taken at the same time as the one in Figure 1.\n\n\n\nData format challenges \nData containers \nFirst, data container issues must be addressed. For example, CSV files are among the simplest file types to parse; they are plain text files with a simple structure (i.e., columns are separated by a comma, rows are separated by a newline). Figure 3 demonstrates how epidemiological data might be provided in a CSV file. Any spreadsheet software can open CSV files natively, and most programming languages require no third-party libraries to read and write CSV files.\n\r\n\n\n\n\n\n\n\n\n\n\n Fig. 3 Sample epidemiological case count data in CSV format. CSV files are plain text files that allow tabular data to be laid out as rows separated by newlines and columns separated by commas. This time series does not contain real data and only exists for demonstration purposes.\n\n\n\nA conceptually similar file type to CSV is Microsoft Excel's XLSX. XLSX is a spreadsheet format developed by Microsoft and is a part of the Office Open XML (OOXML) specification. OOXML is a complex specification comprised of zipped XML files and other embedded data (e.g., images).[32] This format is common among public health practitioners due to the ubiquity of Microsoft Excel. For the programmer, however, this format presents a variety of challenges not present with CSV files. Due to the file type's complexity, a third-party library will be necessary in virtually all circumstances for reading\/writing XLSX files (e.g., xlrd and xlwt for Python or Apache POI for Java). Depending on the maturity of the library used, the file's formulas, pivot tables, and other complex features should be handled with varying degrees of trust.\nJSON is another common data container used on the internet (see Figure 4 for an example). For instance, JSON data are commonly returned when querying an API endpoint. JSON is easy and fast to use; many programming languages offer built-in JSON read\/write support (e.g., Python and Java). Additionally, similar to CSV, JSON is a plain text format that is human-readable. Unlike CSV, however, JSON is not limited to tabular data. JSON can represent more complex relationships between data and is conceptually more similar to XML. Due to its ubiquity and structure, a number of application-specific JSON standards are available. For example, GeoJSON[33] and TopoJSON[34] enable sharing geographic data. In 2016, Finnie et al. proposed EpiJSON, which offers a standardized way to encode epidemiological data.[35] Although EpiJSON shows promise, it is young and has yet to be broadly embraced. To make adoption simpler, open-source EpiJSON libraries could be developed for common programming languages; currently, the only such library exists for the programming language R[36], but additional libraries should be developed for Python, Java, and other languages commonly used for epidemiological data analysis.\n\r\n\n\n\n\n\n\n\n\n\n\n Fig. 4 Sample epidemiological case count data in a simple JSON format. Compared to CSV (demonstrated in Figure 3), JSON contains more structure that can more rigorously specify data relationships (including hierarchical relationships). Note that this is not EpiJSON; EpiJSON can be quite verbose (due to, for example, metadata specifications and GeoJSON-specified locations), and the authors felt a complete EpiJSON example would take up an unreasonable amount of space in this paper. As in Figure 3, this time series does not contain real data and only exists for demonstration purposes.\n\n\n\nPDF files provide a number of unique challenges in addition to complexity. Extraction of data is the biggest challenge, as epidemiological information is often provided in mixed formats: textual (e.g., paragraphs of descriptive text in a report), graphical (e.g., bar and line charts), and tabular. Simply extracting the text of a PDF correctly and in the right order can prove to be a non-trivial challenge. Named-entity recognition and extraction, a natural language processing task, can be used to elicit case counts from unstructured text[19], but this supervised machine learning task requires knowledge of the language in which the document is published, as well as epidemiological subject matter expertise. Graphical data are intended for the human eye. While graphical data can potentially be digitized using software like WebPlotDigitizer, this cannot always be reliably automated. Even tabular data, which visually appear structured, are typically difficult to extract due to the variety of ways a table can be presented in a PDF document.[37]\nFurthermore, PDF files need not even contain text. In a number of circumstances, the PDF files that institutions provide simply contain scanned images of documents. The resulting PDF simply contains the image, rather than the raw text that comprised the original document. For example, many of the weekly reports available through the Department of Health website for the Philippines[38] are PDFs of scanned documents.[39][40] Text can potentially be elicited with optical character recognition (OCR) software, but the quality of the resulting textual data will vary significantly depending on the quality of the scanned images.\nFinally, one must be aware of the character encoding when reading text. Since, at the basic level, computers represent all data using binary bits, there must be some binary representation of each character or symbol in an alphabet or language; the character encoding specifies how the raw bits stored in a file should be converted to readable text and vice versa.[24] While there are a number of possible encodings, ASCII, ISO-8859-1, and UTF-8 are among the most common encodings encountered in practice. In 2012, UTF-8 surpassed 60% adoption across the web[41] and is currently approaching the 90% mark.[42] Encoding differences are important; for example, while reading ASCII text as UTF-8 yields correct results, the converse does not.\n\nElement format \nData and time\nBeyond data container challenges, there are a number of element formatting differences that must be addressed. First and foremost are date and time formatting discrepancies. While the ISO 8601 date\/time standard has existed since 1988, it is often bypassed in favor of locale-dependent formats. For example, much of Europe follows the day-month-year convention, the U.S. follows the month-day-year convention, and China follows the year-month-day convention. Depending on the locale, 03-09-2005 may refer to March 9, 2005 or September 3, 2005. Additionally, not all locales use the Gregorian calendar. Thailand, for example, uses the Buddhist calendar. The current year, as represented by the Gregorian calendar, is 2018; a Thai timestamp would instead specify 2561. Finally, some locales use 24-h time, while others use 12-h time.\nIn addition to these timestamp parsing differences, there are significant implicit timestamp differences that must be understood. To understand these, one must first recognize that a timestamp on a typical disease curve usually implicitly refers to an interval of time (i.e., actual event-level epidemiological data are rare). To illustrate this, consider the time series in Table 1. \n\n\n\n\n\n\n\nTable 1. Sample historical weekly epidemiological time series consisting of timestamps and case counts\n\n\nTimestamp\n\nCases\n\n\n2014-08-07 00:00\n\n2\n\n\n2014-08-14 00:00\n\n5\n\n\n2014-08-21 00:00\n\n4\n\n\n\nEach timestamp can be interpreted using one of three possible interval types:\n\n Leading: The timestamp starts the interval, and the interval ends the \u201cinstant\u201d before the next specified timestamp. Table 2 shows how the time series in Table 1 would be transformed to an interval series with an interval type of leading.\n Trailing exclusive: The timestamp ends the interval but is not included in the interval; Table 3 demonstrates this transformation.\n Trailing inclusive: The timestamp ends the interval and is included in the interval; Table 4 shows this transformation.\n\n\n\n\n\n\nTable 2. Explicit transformation of Table 1 into a leading interval series; the interval start and end are inclusive and exclusive, respectively.\n\n\nInterval start\n\nInterval end\n\nCases\n\n\n2014-08-07 00:00\n\n2014-08-14 00:00\n\n2\n\n\n2014-08-14 00:00\n\n2014-08-21 00:00\n\n5\n\n\n2014-08-21 00:00\n\n2014-08-28 00:00\n\n4\n\n\n\n\n\n\n\n\n\nTable 3. Explicit transformation of Table 1 into a trailing exclusive interval series; the interval start and end are inclusive and exclusive, respectively.\n\n\nInterval start\n\nInterval end\n\nCases\n\n\n2014-07-31 00:00\n\n2014-08-07 00:00\n\n2\n\n\n2014-08-07 00:00\n\n2014-08-14 00:00\n\n5\n\n\n2014-08-14 00:00\n\n2014-08-21 00:00\n\n4\n\n\n\n\n\n\n\n\n\nTable 4. Explicit transformation of Table 1 into a trailing inclusive interval series; the interval start and end are inclusive and exclusive, respectively.\n\n\nInterval start\n\nInterval end\n\nCases\n\n\n2014-08-01 00:00\n\n2014-08-08 00:00\n\n2\n\n\n2014-08-08 00:00\n\n2014-08-15 00:00\n\n5\n\n\n2014-08-15 00:00\n\n2014-08-22 00:00\n\n4\n\n\n\nAs an example, the CDC standardizes reporting dates in the U.S. using the notion of an \u201cMMWR week\u201d or \u201cepi week.\u201d[43] MMWR weeks always begin on Sundays and end on Saturdays. Weeks can be numbered 1\u201353, and, as a result, many institutions choose to report them as such (e.g., the interval \"2016-05-15 00:00, 2016-05-22 00:00\" is reported as \u201c2016, week 20\u201d). However, while most U.S.-based health departments respect the weekly MMWR aggregation standard, many continue to report timestamps based on the MMWR week concept. For example, Figure 5 shows how Texas identifies its weekly influenza surveillance PDF reports by trailing inclusive timestamps rather than by MMWR week.\n\r\n\n\n\n\n\n\n\n\n\n\n Fig. 5 Screenshot taken from Texas' Department of State Health Services 2014\u20132015 weekly influenza reports web page.[44] Texas identifies its weekly influenza surveillance PDF reports by trailing inclusive timestamps rather than by MMWR week (e.g., \u201c10\/3\/15\u201d instead of \u201c2015, week 39\u201d). Interestingly, much of the data in each PDF uses MMWR week numbers rather than timestamps.\n\n\n\nOutside of the U.S., a variety of reporting date standards exist. In Japan, for example, the epi week starts on Monday and ends on Sunday.[45] In Poland, the reporting is even more different. Poland reports influenza cases four \u201cweeks\u201d a month, regardless of the length of the month. As a result, the intervals between reports are not regular. For example, the four influenza reports in May 2016 are shown in Table 5.\n\n\n\n\n\n\n\nTable 5. Influenza reporting intervals in Poland in May 2016. Instead of reporting data at regular intervals (e.g., every seven days), Poland reports data four \"weeks\" a month, regardless of the length of the month. This yields irregular interval durations. Here, the interval start and end are inclusive.\n\n\nInterval start\n\nInterval end\n\nDuration (days)\n\nSource\n\n\n2016-05-01\n\n2016-05-07\n\n7\n\n[46]\n\n\n2016-05-08\n\n2016-05-15\n\n8\n\n[47]\n\n\n2016-05-16\n\n2016-05-22\n\n7\n\n[48]\n\n\n2016-05-23\n\n2016-05-31\n\n9\n\n[49]\n\n\n\nOne remaining concern related to date and time is time zone. With the increasing use of internet data streams in disease forecasting and surveillance, it is important to be able to precisely place reference epidemiological data since associated internet data streams might be timestamped down to the second. Many data sources fail to report a time zone, so local time is often assumed. An incorrect time zone may impact analysis of high resolution data. For example, norovirus data are sometimes provided hourly[50][51], and time zone errors could have a potentially drastic negative effect on model results or analyses.\nGeography\nPolitical boundaries and names must be carefully managed. Subtle differences in names (e.g., Zurich vs. Z\u00fcrich) may lead to incorrect results during an analysis. The ISO 3166 standard defines country and principle subdivision (e.g., state or province) names, but it does not handle finer-than-subdivision regions, such as counties, districts, or cities.\nMoreover, political boundaries (and thus populations and demographics) change over time. For example, South Sudan's split from Sudan in 2011 decreased Sudan's population by more than ten million people and dramatically changed its political boundary. Computing the historical attack rate for a disease (e.g., influenza incidence per 100,000 people), for instance, must take into account these changes.\n\nData reporting challenges \nBeyond interface and data format challenges, there are challenges that lie within the bureaucratic reporting process for an epidemiological institution. Modern disease surveillance systems rely on complex reporting hierarchies; raw data are initially captured at each provider, who then anonymizes and aggregates data as necessary before sending it to the next level in the hierarchy (perhaps a local or state public health department).[52] This hierarchy can have many levels. Even in many of the most developed regions of the world, much of this process continues to be done by hand, although the push to electronic medical records is gaining traction. As a result, most disease surveillance systems across the world experience reporting lags of at least one to two weeks.\nThis reporting lag can, in some cases, affect both an intuitive understanding of the situation as well as computational forecasting models. In an effort to combat surveillance system reporting lag, a number of attempts have been made to \u201cfill in\u201d the gaps using internet data[13][14][15][17], but these studies require moderate to high levels of internet usage in the locales of interest, which are often not guaranteed.\nAnother issue is heterogeneous case definitions across jurisdictions. Many times, the case definitions used in epidemiological data are not clearly defined, and it is often difficult to navigate websites to identify the definitions. For example, many of the influenza surveillance systems in Europe use common, but not identical, case definitions.[53] Contextual differences in case definitions for Ebola[54] could make interpreting data for the 2014 West African Ebola outbreak difficult.\nOne must also be concerned about language issues. Data are often provided in the native language of the region of the world in which they originate. For example, Thailand's Bureau of Epidemiology website[55] is natively displayed in Thai but also offers an English version.[56] While online language translation services do exist (e.g., Google Translate), these are not always reliable, and they cannot easily translate text in images (e.g., a website header comprised of images). To assist with language issues, formal disease- and epidemiological-focused ontologies[57] can help; translations, abbreviations, and alternate names can be encoded in an ontology to help automatically map different records to the same concept.\nFurthermore, even within a single institution, there are often reporting nuances among diseases. For example, one context may be reported monthly, while another context may be reported weekly or daily. Some contexts may not be regularly reported; irregular reporting can lead to questions like \u201cIs the value for a missing timestamp zero or unknown?\u201d\nFinally, case count data are often retroactively updated as new data are made available. In other words, historical data are not fixed the first time they are published. For example, a case count data point published today may be updated next week or the following week, as new data appear. This problem, often called \u201cbackfill,\u201d is due to the number and variety of members that comprise the complex reporting hierarchy that modern disease surveillance systems rely on. If a surveillance member's computer system goes down temporarily, for example, it may not be able to submit its data until the following week. Backfill can in some cases drastically affect analyses, so analysts and modelers must be aware of this potential issue.[58][59]\n\nConclusions \nWe have identified three key challenges involving epidemiological data: 1) interface challenges, 2) data format challenges, and 3) data reporting challenges. Each of these challenges can be addressed to simplify the efforts of analysts and modelers. Here, we propose a framework of best practices comprised of modern standards that should be adhered to when releasing epidemiological data to the public:\n\nPresent the user with an interactive web interface to search and filter data. This interface should allow users to export data in common open formats (e.g., JSON using the EpiJSON standard, CSV).\nProvide a web-based API to allow automated data retrieval.\nAlways use ISO 8601 dates, times, timestamps, and durations. Timestamps should either explicitly provide the local time zone or be adjusted for UTC, as specified by the ISO 8601 standard.\nWhen providing time series, clearly define the interval type so that timestamps can be interpreted properly.\nWhen possible, use ISO 3166 location names.\nEnsure all data are encoded using UTF-8.\nEnsure the website can be run through an online language translation service (e.g., do not place important text in an image).\nWhen reporting case counts, the case definitions should be made explicit and clear.\nClearly distinguish between unknown and zero values.\nThese suggestions are not prescribing a single format or process; instead, these items provide a means for clearly defining and presenting epidemiological data to the public.\nWe implore the members of the global public health community to work together to create and follow standards for publishing data. Many institutions attempt to publish similar types of data using similar interfaces. In general, a user selects locations, diseases, optional time periods, and optional demographics in order to retrieve the desired data. Because many analysts and modelers have similar data desires, we feel this provides an opportunity for a generic shared epidemiological data access platform. Currently used by the CDC, one possibility might be Socrata, a platform that allows governments to share data openly. Socrata provides not only a modern interactive web interface but also an extensive API. Another option may be for public health institutions to collaboratively develop a free and open source solution that each could use. Such a platform may be more easily implemented by resource-constrained public health departments that have neither the time nor the money to develop their own solutions. Additionally, as web standards evolve, a shared data access platform could be updated in order to propagate these changes to each institution.\nIf a standard platform could be employed by institutions worldwide, then one could envision a future where global data could be easily collected without the challenges we currently face. This would in turn streamline epidemiological and public health analysis, modeling, and informatics, resulting in better public health decision-making capabilities.\nAdditionally, while this paper focuses on the public health and epidemiological communities, many of the challenges and solutions discussed here are not unique to them. Many of these same challenges are present whenever data of the same type are published globally by separate institutions that do not have an a priori agreed-upon set of standards. For example, weather and economic data have many of the same features as epidemiological data (e.g., locations, time intervals) and should also adhere to the ISO 8601 and 3166 standards, be encoded in UTF-8, and clearly distinguish between unknown and zero values.\nFinally, it is important to recognize that this paper focuses on capable public health institutions with enough funding to collect and disseminate their epidemiological data. It should be noted, however, that a number of regions worldwide do not meet this criterion and are struggling even to monitor and care for their constituent populations, let alone publish reliable data. Unfortunately, it is precisely in these underserved regions that the public health community often desires data. Until worldwide public health infrastructure improves significantly, the suggestions here will remain peripheral for many; thus, the problems and suggested solutions put forth in this paper are likely only to be relevant to well-funded institutions. While the solutions presented in this paper may not be as effective at present time due to the lack of coverage, we offer them in preparation for the expanding global coverage that is continuously occurring, and it is only a matter of time until 100% global internet coverage becomes a reality.\n\nAcknowledgements \nThis work was supported by the U.S. Department of Energy through the Los Alamos National Laboratory. Los Alamos National Laboratory is operated by Triad National Security, LLC, for the National Nuclear Security Administration of U.S. Department of Energy (Contract No. 89233218NCA000001).\n\nAuthor contributions \nGF and BT compiled the initial manuscript. All authors identified and described challenges and standards, and provided critical revisions of the manuscript.\n\nFunding \nThis work was supported by the Defense Threat Reduction Agency's Joint Science and Technology Office for Chemical and Biological Defense under project numbers CB3656 and CB10007.\n\nConflict of interest statement \nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nReferences \n\n\n\u2191 Chretien, J.P.; Rivers, C.M.; Johansson, M.A. (2016). \"Make Data Sharing Routine to Prepare for Public Health Emergencies\". PLoS One 13 (8): e1002109. doi:10.1371\/journal.pmed.1002109. PMC PMC4987038. PMID 27529422. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4987038 .   \n\n\u2191 Centers for Disease Control and Prevention (2018). \"Allocating and Targeting Pandemic Influenza Vaccine During an Influenza Pandemic\". U.S. Department of Health and Human Services. https:\/\/asprtracie.hhs.gov\/technical-resources\/resource\/2846\/guidance-on-allocating-and-targeting-pandemic-influenza-vaccine .   \n\n\u2191 Nap, R.E.; Andriessen, M.P.; Meessen, N.E. et al. (2007). \"Pandemic influenza and hospital resources\". Emerging Infectious Diseases 13 (11): 1714-9. doi:10.3201\/eid1311.070103. PMC PMC3375786. PMID 18217556. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3375786 .   \n\n\u2191 Hota, S.; Fried, E.; Burry, L. et al. (2010). \"Preparing your intensive care unit for the second wave of H1N1 and future surges\". Critical Care Medicine 38 (4 Suppl.): e110\u20139. doi:10.1097\/CCM.0b013e3181c66940. PMID 19935417.   \n\n\u2191 Moran, K.R.; Fairchild, G.; Generous, N. et al. (2016). \"Epidemic Forecasting is Messier Than Weather Forecasting: The Role of Human Behavior and Internet Data Streams in Epidemic Forecast\". Journal of Infectious Diseases 214 (Suppl. 4): S404-S408. doi:10.1093\/infdis\/jiw375. PMC PMC5181546. PMID 28830111. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5181546 .   \n\n\u2191 Hethcore, H.W. (2000). \"The Mathematics of Infectious Diseases\". SIAM Review 42 (4): 599\u2013653. doi:10.1137\/S0036144500371907.   \n\n\u2191 Eubank, S.; Guclu, H.; Kumar, V.S. et al. (2004). \"Modelling disease outbreaks in realistic urban social networks\". Nature 429 (6988): 180\u20134. doi:10.1038\/nature02541. PMID 15141212.   \n\n\u2191 Busset, K.R.; Chen, J.; Feng, X. et al. (2009). \"EpiFast: A fast algorithm for large scale realistic epidemic simulations on distributed memory systems\". Proceedings of the 23rd international conference on Supercomputing: 430\u201339. doi:10.1145\/1542275.1542336.   \n\n\u2191 Chao, D.L.; Halstead, S.B.; Halloran, M.E. et al. (2012). \"Controlling dengue with vaccines in Thailand\". PLoS Neglected Tropical Diseases 6 (10): e1876. doi:10.1371\/journal.pntd.0001876. PMC PMC3493390. PMID 23145197. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3493390 .   \n\n\u2191 Grefenstette, J.J.; Brown, S.T.; Rosenfeld, R. et al. (2013). \"FRED (a Framework for Reconstructing Epidemic Dynamics): An open-source software system for modeling infectious diseases and control strategies using census-based populations\". BMC Public Health 13: 940. doi:10.1186\/1471-2458-13-940. PMC PMC3852955. PMID 24103508. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3852955 .   \n\n\u2191 McMahon, B.H.; Manore, C.A.; Hyman, J.M. et al. (2014). \"Coupling Vector-host Dynamics with Weather Geography and Mitigation Measures to Model Rift Valley Fever in Africa\". Mathematical Modelling of Natural Phenomena 9 (2): 161\u201377. doi:10.1051\/mmnp\/20149211. PMC PMC4398965. PMID 25892858. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4398965 .   \n\n\u2191 Viboud, C.; Bo\u00eblle, P.Y.; Carrat, F. et al. (2003). \"Prediction of the spread of influenza epidemics by the method of analogues\". American Journal of Epidemiology 158 (10): 996-1006. doi:10.1093\/aje\/kwg239. PMID 14607808.   \n\n\u2191 13.0 13.1 Polgreen, P.M.; Chen, Y.; Pennock, D.M. et al. (2008). \"Using internet searches for influenza surveillance\". Clinical Infectious Diseases 47 (11): 1443-8. doi:10.1086\/593098. PMID 18954267.   \n\n\u2191 14.0 14.1 Ginsberg, J.; Mohebbi, M.H.; Patel, R.S. et al. (2009). \"Detecting influenza epidemics using search engine query data\". Nature 457 (7232): 1012-4. doi:10.1038\/nature07634. PMID 19020500.   \n\n\u2191 15.0 15.1 Signorini, A.; Segre, A.M.; Polgreen, P.M. et al. (2011). \"The use of Twitter to track levels of disease activity and public concern in the U.S. during the influenza A H1N1 pandemic\". PLoS One 6 (5): e19467. doi:10.1371\/journal.pone.0019467. PMC PMC3087759. PMID 21573238. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3087759 .   \n\n\u2191 Shaman, J.; Karspeck, A.; Yang, W. et al. (2013). \"Real-time influenza forecasts during the 2012-2013 season\". Nature Communications 4: 2837. doi:10.1038\/ncomms3837. PMC PMC3873365. PMID 24302074. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3873365 .   \n\n\u2191 17.0 17.1 Generous, N.; Fairchild, G.; Deshpande, A. et al. (2014). \"Global disease monitoring and forecasting with Wikipedia\". PLoS Computational Biology 10 (11): e1003892. doi:10.1371\/journal.pcbi.1003892. PMC PMC4231164. PMID 25392913. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4231164 .   \n\n\u2191 Hickmann, K.S.; Fairchild, G.; Priedhorsky, R. et al. (2015). \"Forecasting the 2013-2014 influenza season using Wikipedia\". PLoS Computational Biology 11 (5): e1004239. doi:10.1371\/journal.pcbi.1004239. PMC PMC4431683. PMID 25974758. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4431683 .   \n\n\u2191 19.0 19.1 Fairchild, G.; Del Valle, S.Y.; De Silva, L. et al. (2015). \"Eliciting Disease Data from Wikipedia Articles\". Proceedings of the 2015 International AAAI Conference on Weblogs and Social Media: 26\u201333. PMC PMC5511739. PMID 28721308. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5511739 .   \n\n\u2191 STROBE Initiative. \"STROBE Statement\". University of Bern. https:\/\/www.strobe-statement.org\/ . Retrieved 01 October 2018 .   \n\n\u2191 Clinical Data Interchange Standards Consortium. \"CDISC\". https:\/\/www.cdisc.org\/ . Retrieved 01 October 2018 .   \n\n\u2191 Pisani, E.; AbouZahr, C. (2010). \"Sharing health data: Good intentions are not enough\". Bulletin of the World Health Organization 88 (6): 462\u20136. doi:10.2471\/BLT.09.074393. PMC PMC2878150. PMID 20539861. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2878150 .   \n\n\u2191 Edelstein, M.; Sane, J. (17 April 2015). \"Overcoming Barriers to Data Sharing in Public Health: A Global Perspective\". Chatham House. https:\/\/www.chathamhouse.org\/publication\/overcoming-barriers-data-sharing-public-health-global-perspective .   \n\n\u2191 24.0 24.1 Zentgraf, D.C. (27 April 2015). \"What Every Programmer Absolutely, Positively Needs To Know About Encodings And Character Sets To Work With Text\". Kunststube. http:\/\/kunststube.net\/encoding\/ . Retrieved 23 August 2016 .   \n\n\u2191 Atwood, J. (18 January 2010). \"The Great Newline Schism\". Coding Horror. https:\/\/blog.codinghorror.com\/the-great-newline-schism\/ . Retrieved 01 October 2016 .   \n\n\u2191 Ministry of Health Isreal. \"Weekly and Periodic Epidemiological Reports\". https:\/\/www.health.gov.il\/UnitsOffice\/HD\/PH\/epidemiology\/Pages\/epidemiology_report.aspx?WPID=WPQ7&PN=1 . Retrieved 04 September 2016 .   \n\n\u2191 Australian Government Department of Health. \"Notifications of all diseases by Month\". National Notifiable Diseases Surveillance System. http:\/\/www9.health.gov.au\/cda\/source\/rpt_1_sel.cfm . Retrieved 04 September 2016 .   \n\n\u2191 Robert Koch Institute. \"SurvStat@RKI 2.0\". https:\/\/survstat.rki.de\/ . Retrieved 04 September 2016 .   \n\n\u2191 Coelho, F.C.; Code\u00e7o, C.T.; Cruz, O.G. et al. (2016). \"Epidemiological data accessibility in Brazil\". The Lancet Infectious Diseases 16 (5): 524\u20135. doi:10.1016\/S1473-3099(16)30007-X. PMID 27068487.   \n\n\u2191 30.0 30.1 Minist\u00e9rio da Sa\u00fade. \"Epidemiological Situation\". Preventing and combating Dengue, Chikungunya e Zika. Archived from the original on 03 July 2016. https:\/\/web.archive.org\/web\/20160703011414\/http:\/\/www.combateaedes.saude.gov.br\/en\/epidemiological-situation . Retrieved 19 January 2017 .   \n\n\u2191 31.0 31.1 Minist\u00e9rio da Sa\u00fade. \"Boletins epidemiol\u00f3gicos\". Governo do Brasil. https:\/\/www.saude.gov.br\/boletins-epidemiologicos . Retrieved 19 January 2017 .   \n\n\u2191 \"Office Open XML\". The Apache OpenOffice Wiki. https:\/\/wiki.openoffice.org\/wiki\/Office_Open_XML . Retrieved 18 August 2016 .   \n\n\u2191 GeoJSON Workgroup. \"GeoJSON\". https:\/\/geojson.org\/ . Retrieved 22 August 2016 .   \n\n\u2191 \"topojson\/topojson\". GitHub. https:\/\/github.com\/topojson\/topojson . Retrieved 22 August 2016 .   \n\n\u2191 Finnie, T.J.; South, A.; Bento, A. et al. (2016). \"EpiJSON: A unified data-format for epidemiology\". Epidemics 15: 20\u20136. doi:10.1016\/j.epidem.2015.12.002. PMC PMC7104924. PMID 27266846. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7104924 .   \n\n\u2191 \"Hackout2\/repijson\". GitHub. https:\/\/github.com\/Hackout2\/repijson . Retrieved 23 October 2018 .   \n\n\u2191 Khusro, S.; Latif, A.; Ullah, I. (2014). \"On methods and tools of table detection, extraction and annotation in PDF documents\". Journal of Information Science 41 (1): 41\u201357. doi:10.1177\/0165551514551903.   \n\n\u2191 Department of Health. \"Statistics\". Republic of the Phillipines.   \n\n\u2191 Epidemiology Bureau, Department of Health (05 July 2015). \"Dengue Cases - Morbidity Week 26 - June 26\u2013July 4, 2015\" (PDF). Republic of the Phillipines. http:\/\/www.doh.gov.ph\/sites\/default\/files\/statistics\/dengueMw26.compressed.pdf . Retrieved 13 December 2016 .   \n\n\u2191 Epidemiology Bureau, Department of Health (27 March 2016). \"Diphtheria Cases - Morbidity Week 12 - January 1\u2013March 26, 2016\" (PDF). Republic of the Phillipines. http:\/\/www.doh.gov.ph\/sites\/default\/files\/statistics\/DIPHTHERIA%20MW12.pdf . Retrieved 13 December 2016 .   \n\n\u2191 Davis, M. (03 February 2012). \"Unicode over 60 percent of the web\". Google Official Blog. https:\/\/googleblog.blogspot.com\/2012\/02\/unicode-over-60-percent-of-web.html . Retrieved 23 August 2016 .   \n\n\u2191 W3Techs. \"Usage statistics of character encodings for websites\". https:\/\/w3techs.com\/technologies\/overview\/character_encoding . Retrieved 23 August 2016 .   \n\n\u2191 U.S. Centers for Disease Control and Prevention. \"MMWR Weeks\" (PDF). https:\/\/wwwn.cdc.gov\/nndss\/document\/MMWR_week_overview.pdf . Retrieved 22 August 2016 .   \n\n\u2191 Texas Department of State Health Services. \"2014 - 2015 Texas Influenza Surveillance Activity Report\". Texas HHS. https:\/\/www.dshs.texas.gov\/idcu\/disease\/influenza\/surveillance\/2015\/ . Retrieved 20 December 2016 .   \n\n\u2191 National Institute of Infectious Diseases. \"Weeks Ending Log 2016\". Government of Japan. https:\/\/www.niid.go.jp\/niid\/en\/survei\/2225-idwr\/calendar\/6113-idwr-calendar-e-2016.html . Retrieved 13 December 2016 .   \n\n\u2191 National Institute of Public Health Poland (May 2016). \"Influenza and influenza-like illness in Poland, 5A\" (PDF). http:\/\/wwwold.pzh.gov.pl\/oldpage\/epimeld\/grypa\/2016\/I_16_05A.pdf . Retrieved 13 December 2016 .   \n\n\u2191 National Institute of Public Health Poland (May 2016). \"Influenza and influenza-like illness in Poland, 5B\" (PDF). http:\/\/wwwold.pzh.gov.pl\/oldpage\/epimeld\/grypa\/2016\/I_16_05B.pdf . Retrieved 13 December 2016 .   \n\n\u2191 National Institute of Public Health Poland (May 2016). \"Influenza and influenza-like illness in Poland, 5C\" (PDF). http:\/\/wwwold.pzh.gov.pl\/oldpage\/epimeld\/grypa\/2016\/I_16_05C.pdf . Retrieved 13 December 2016 .   \n\n\u2191 National Institute of Public Health Poland (May 2016). \"Influenza and influenza-like illness in Poland, 5D\" (PDF). http:\/\/wwwold.pzh.gov.pl\/oldpage\/epimeld\/grypa\/2016\/I_16_05D.pdf . Retrieved 13 December 2016 .   \n\n\u2191 Guzman-Herrador, B.; Heier, B.; Osborg, E. et al. (2011). \"Outbreak of norovirus infection in a hotel in Oslo, Norway, January 2011\". Euro Suveillance 16 (30): 19928. PMID 21813081.   \n\n\u2191 Mayet, A.; Andreo, V.; Bedubourg, G. et al. (2011). \"Food-borne outbreak of norovirus infection in a French military parachuting unit, April 2011\". Euro Suveillance 16 (30): 19930. PMID 21813082.   \n\n\u2191 Fairchild, G.C. (2014). \"Improving disease surveillance: Sentinel surveillance network design and novel uses of Wikipedia\". PhD (Doctor of Philosophy) thesis. University of Iowa. doi:10.17077\/etd.sfbu328x. https:\/\/ir.uiowa.edu\/etd\/1452\/ .   \n\n\u2191 Aguilera, J.F.; Paget, W.J.; Mosnier, A. et al. (2003). \"Heterogeneous case definitions used for the surveillance of influenza in Europe\". European Journal of Epidemiology 18 (8): 751\u20134. doi:10.1023\/a:1025337616327. PMID 12974549.   \n\n\u2191 World Health Organization (09 August 2014). \"Case defintion recommendations for ebola or Marburg virus diseases\" (PDF). World Health Organization. https:\/\/www.who.int\/csr\/resources\/publications\/ebola\/ebola-case-definition-contact-en.pdf . Retrieved 10 January 2017 .   \n\n\u2191 Thailand Bureau of Epidemiology (2016). \"Thailand Bureau of Epidemiology\". http:\/\/203.157.15.110\/boe\/ . Retrieved 23 August 2016 .   \n\n\u2191 Thailand Bureau of Epidemiology (2016). \"Thailand Bureau of Epidemiology - English\". http:\/\/203.157.15.110\/boeeng\/ . Retrieved 23 August 2016 .   \n\n\u2191 Institute for Genome Sciences, University of Maryland School of Medicine. \"Disease Ontology\". https:\/\/disease-ontology.org\/ . Retrieved 01 October 2018 .   \n\n\u2191 Farrow, D.C.; Brooks, L.C.; Hyun, S. et al. (2017). \"A human judgment approach to epidemiological forecasting\". PLoS Computational Biology 13 (3): e1005248. doi:10.1371\/journal.pcbi.1005248. PMC PMC5345757. PMID 28282375. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5345757 .   \n\n\u2191 Osthus, D.; Gattiker, J.; Priedhorsky, R. et al. (2019). \"Dynamic Bayesian Influenza Forecasting in the United States with Hierarchical Discrepancy (with Discussion)\". Bayesian Analysis 14 (1): 261\u2013312. doi:10.1214\/18-BA1117.   \n\n\nNotes \nThis presentation is faithful to the original, with only a few minor changes to presentation. In some cases important information was missing from the references, and that information was added. Footnotes in the original were turned into external links for this version. Where a URL from the original was found to no longer work, an archived version of the page was cited. In the case of the Thailand Bureau of Epidemiology sites, an archive of neither could be found.\n\n\n\n\n\n\nSource: <a rel=\"external_link\" class=\"external\" href=\"https:\/\/www.limswiki.org\/index.php\/Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\">https:\/\/www.limswiki.org\/index.php\/Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards<\/a>\n\t\t\t\t\tCategories: LIMSwiki journal articles (added in 2020)LIMSwiki journal articles (all)LIMSwiki journal articles on epidemiologyLIMSwiki journal articles on public health informatics\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\n\t\t\t\t\n\t\t\t\n\t\t\n\t\t\n\t\t\tNavigation menu\n\t\t\t\t\t\n\t\t\tViews\n\n\t\t\t\n\t\t\t\t\n\t\t\t\tJournal\n\t\t\t\tDiscussion\n\t\t\t\tView source\n\t\t\t\tHistory\n\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\n\t\t\t\t\n\t\t\t\tPersonal tools\n\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\t\t\tLog in\n\t\t\t\t\t\t\t\t\t\t\t\t\tRequest account\n\t\t\t\t\t\t\t\t\t\t\t\n\t\t\t\t\n\t\t\t\n\t\t\t\n\t\t\t\t\n\t\t\t\n\t\t\t\t\n\t\tNavigation\n\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\tMain page\n\t\t\t\t\t\t\t\t\t\t\tRecent changes\n\t\t\t\t\t\t\t\t\t\t\tRandom page\n\t\t\t\t\t\t\t\t\t\t\tHelp\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\n\t\t\t\n\t\t\tSearch\n\n\t\t\t\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t \n\t\t\t\t\t\t\n\t\t\t\t\n\n\t\t\t\t\t\t\t\n\t\t\n\t\t\t\n\t\t\tTools\n\n\t\t\t\n\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\tWhat links here\n\t\t\t\t\t\t\t\t\t\t\tRelated changes\n\t\t\t\t\t\t\t\t\t\t\tSpecial pages\n\t\t\t\t\t\t\t\t\t\t\tPermanent link\n\t\t\t\t\t\t\t\t\t\t\tPage information\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\n\t\t\n\t\tPrint\/export\n\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\tCreate a book\n\t\t\t\t\t\t\t\t\t\t\tDownload as PDF\n\t\t\t\t\t\t\t\t\t\t\tDownload as Plain text\n\t\t\t\t\t\t\t\t\t\t\tPrintable version\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\n\t\t\n\t\tSponsors\n\t\t\n\t\t\t \r\n\n\t\r\n\n\t\r\n\n\t\n\t\r\n\n\t\r\n\n\t\n\t\r\n\n \n\t\r\n\n\t\n\t\r\n\n \n\t\n\t\r\n\n\t\n\t\n\t\r\n\n\t\r\n\n\t\r\n\n\t\n\t\r\n\n\t\r\n\t\t\n\t\t\n\t\t\t\n\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t This page was last modified on 28 April 2020, at 16:02.\n\t\t\t\t\t\t\t\t\tThis page has been accessed 273 times.\n\t\t\t\t\t\t\t\t\tContent is available under a Creative Commons Attribution-ShareAlike 4.0 International License unless otherwise noted.\n\t\t\t\t\t\t\t\t\tPrivacy policy\n\t\t\t\t\t\t\t\t\tAbout LIMSWiki\n\t\t\t\t\t\t\t\t\tDisclaimers\n\t\t\t\t\t\t\t\n\t\t\n\t\t\n\t\t\n\n","38f2f0437c54887eb841f892d039cb99_html":"<body class=\"mediawiki ltr sitedir-ltr ns-206 ns-subject page-Journal_Epidemiological_data_challenges_Planning_for_a_more_robust_future_through_data_standards skin-monobook action-view\">\n<div id=\"rdp-ebb-globalWrapper\">\n\t\t<div id=\"rdp-ebb-column-content\">\n\t\t\t<div id=\"rdp-ebb-content\" class=\"mw-body\" role=\"main\">\n\t\t\t\t<a id=\"rdp-ebb-top\"><\/a>\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t<h1 id=\"rdp-ebb-firstHeading\" class=\"firstHeading\" lang=\"en\">Journal:Epidemiological data challenges: Planning for a more robust future through data standards<\/h1>\n\t\t\t\t\n\t\t\t\t<div id=\"rdp-ebb-bodyContent\" class=\"mw-body-content\">\n\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\n\n\t\t\t\t\t<!-- start content -->\n\t\t\t\t\t<div id=\"rdp-ebb-mw-content-text\" lang=\"en\" dir=\"ltr\" class=\"mw-content-ltr\">\n\n\n<h2><span class=\"mw-headline\" id=\"Abstract\">Abstract<\/span><\/h2>\n<p>Accessible <a href=\"https:\/\/www.limswiki.org\/index.php\/Epidemiology\" title=\"Epidemiology\" class=\"wiki-link\" data-key=\"123badb8bf0b37a513182dbcfc3875bc\">epidemiological<\/a> data are of great value for emergency preparedness and response, understanding disease progression through a population, and building statistical and mechanistic disease models that enable forecasting. The status quo, however, renders acquiring and using such data difficult in practice. In many cases, a primary way of obtaining epidemiological data is through the internet, but the methods by which the data are presented to the public often differ drastically among institutions. As a result, there is a strong need for better data sharing practices. This paper identifies, in detail and with examples, the three key challenges one encounters when attempting to acquire and use epidemiological data: (1) interfaces, (2) data formatting, and (3) reporting. These challenges are used to provide suggestions and guidance for improvement as these systems evolve in the future. If these suggested data and interface recommendations were adhered to, epidemiological and <a href=\"https:\/\/www.limswiki.org\/index.php\/Public_health\" title=\"Public health\" class=\"wiki-link\" data-key=\"81092e25c0bd359cedd1b9f9dc350c86\">public health<\/a> analysis, modeling, and <a href=\"https:\/\/www.limswiki.org\/index.php\/Public_health_informatics\" title=\"Public health informatics\" class=\"wiki-link\" data-key=\"f0372a80f101e9f6fd00490dc1ebcedd\">informatics<\/a> work would be significantly streamlined, which can in turn yield better public health decision-making capabilities.\n<\/p><p><b>Keywords<\/b>: data, computational epidemiology, public health, disease modeling, informatics, disease surveillance\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Introduction\">Introduction<\/span><\/h2>\n<p>At the heart of <a href=\"https:\/\/www.limswiki.org\/index.php\/Infectious_disease_informatics\" title=\"Infectious disease informatics\" class=\"wiki-link\" data-key=\"d318bbc2e54c35364b6d9d0c26f0be5d\">disease surveillance and modeling<\/a> are <a href=\"https:\/\/www.limswiki.org\/index.php\/Epidemiology\" title=\"Epidemiology\" class=\"wiki-link\" data-key=\"123badb8bf0b37a513182dbcfc3875bc\">epidemiological<\/a> data. These data are generally presented as a time series of cases, <i>T<\/i>, for a geographic region, <i>G<\/i>, and for a demographic, <i>D<\/i>. The type of cases presented may vary depending on the context. For example, <i>T<\/i> may be a time series of confirmed or suspected cases, or it might be hospitalizations or deaths; in some circumstances, it may be a summation of some combination of these (e.g., confirmed + suspected cases). <i>G<\/i> is most commonly a political boundary; it might be a country, state\/province, county\/district, city, or sub-city region, such as a postal code or United States (U.S.) Census Bureau census tract. Depending on the context, <i>D<\/i> may simply be the the entire population of <i>G<\/i>, or it might be stratified by age, sex, race, education, or other relevant factors.\n<\/p><p>Epidemiological data have a variety of uses. From a <a href=\"https:\/\/www.limswiki.org\/index.php\/Public_health\" title=\"Public health\" class=\"wiki-link\" data-key=\"81092e25c0bd359cedd1b9f9dc350c86\">public health<\/a> perspective, they can be used to gain an understanding of population-level disease progression. This understanding can in turn be used to aid in decision-making and allocation of resources. Recent outbreaks like Ebola and Zika have demonstrated the value of accessible epidemiological data for emergency preparedness and the need for better data sharing.<sup id=\"rdp-ebb-cite_ref-ChretianMake16_1-0\" class=\"reference\"><a href=\"#cite_note-ChretianMake16-1\">[1]<\/a><\/sup> These data may influence vaccine distribution<sup id=\"rdp-ebb-cite_ref-CDCAlloc18_2-0\" class=\"reference\"><a href=\"#cite_note-CDCAlloc18-2\">[2]<\/a><\/sup>, and <a href=\"https:\/\/www.limswiki.org\/index.php\/Hospital\" title=\"Hospital\" class=\"wiki-link\" data-key=\"b8f070c66d8123fe91063594befebdff\">hospitals<\/a> can anticipate surge capacity during an outbreak, allowing them to obtain extra temporary help if necessary.<sup id=\"rdp-ebb-cite_ref-NapPandemic07_3-0\" class=\"reference\"><a href=\"#cite_note-NapPandemic07-3\">[3]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-HotaPrep10_4-0\" class=\"reference\"><a href=\"#cite_note-HotaPrep10-4\">[4]<\/a><\/sup>\n<\/p><p>From a modeler's perspective, high-quality reference data (also commonly referred to as \"ground truth data\") are needed to enable prediction and forecasting.<sup id=\"rdp-ebb-cite_ref-MoranEpi16_5-0\" class=\"reference\"><a href=\"#cite_note-MoranEpi16-5\">[5]<\/a><\/sup> These data can be used to parameterize compartmental models<sup id=\"rdp-ebb-cite_ref-HethcoteTheMath00_6-0\" class=\"reference\"><a href=\"#cite_note-HethcoteTheMath00-6\">[6]<\/a><\/sup> as well as stochastic agent-based models<sup id=\"rdp-ebb-cite_ref-EubankModel04_7-0\" class=\"reference\"><a href=\"#cite_note-EubankModel04-7\">[7]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-BissetEpiFast09_8-0\" class=\"reference\"><a href=\"#cite_note-BissetEpiFast09-8\">[8]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ChaoControl12_9-0\" class=\"reference\"><a href=\"#cite_note-ChaoControl12-9\">[9]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-GrefenstetteFRED13_10-0\" class=\"reference\"><a href=\"#cite_note-GrefenstetteFRED13-10\">[10]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-McMahonCoupling14_11-0\" class=\"reference\"><a href=\"#cite_note-McMahonCoupling14-11\">[11]<\/a><\/sup>, and they can also be used to train and validate machine learning and statistical models.<sup id=\"rdp-ebb-cite_ref-ViboudPredict03_12-0\" class=\"reference\"><a href=\"#cite_note-ViboudPredict03-12\">[12]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-PolgreenUsing08_13-0\" class=\"reference\"><a href=\"#cite_note-PolgreenUsing08-13\">[13]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-GinsbergDetect09_14-0\" class=\"reference\"><a href=\"#cite_note-GinsbergDetect09-14\">[14]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-SignoriniTheUse11_15-0\" class=\"reference\"><a href=\"#cite_note-SignoriniTheUse11-15\">[15]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-ShamanReal13_16-0\" class=\"reference\"><a href=\"#cite_note-ShamanReal13-16\">[16]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-GenerousGlobal14_17-0\" class=\"reference\"><a href=\"#cite_note-GenerousGlobal14-17\">[17]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-HickmannFore15_18-0\" class=\"reference\"><a href=\"#cite_note-HickmannFore15-18\">[18]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-FairchildElicit15_19-0\" class=\"reference\"><a href=\"#cite_note-FairchildElicit15-19\">[19]<\/a><\/sup>\n<\/p><p>The internet has become the predominant way to publish, share, and collect epidemiological data. While data standards exist for observational studies<sup id=\"rdp-ebb-cite_ref-STROBEState18_20-0\" class=\"reference\"><a href=\"#cite_note-STROBEState18-20\">[20]<\/a><\/sup> and clinical research<sup id=\"rdp-ebb-cite_ref-CDISC18_21-0\" class=\"reference\"><a href=\"#cite_note-CDISC18-21\">[21]<\/a><\/sup>, for example, no such standards exist for the publication of the kind of public health-related epidemiological data described above. Despite the strong need to share and consume data, there are many legal, technical, political, and cultural challenges in implementing a standardized epidemiological data framework.<sup id=\"rdp-ebb-cite_ref-PisaniSharing10_22-0\" class=\"reference\"><a href=\"#cite_note-PisaniSharing10-22\">[22]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-EdelsteinOvercoming15_23-0\" class=\"reference\"><a href=\"#cite_note-EdelsteinOvercoming15-23\">[23]<\/a><\/sup> As a result, the methods by which data are presented to the public often differ significantly among data-sharing institutions (e.g., public health departments, ministries of health, data collection or aggregation services). Moreover, these problems are not unique to epidemiological data; the issues described in this paper are common across many different disciplines.\n<\/p><p>First, epidemiological data on the internet are presented to the user through a variety of interfaces. These interfaces vary widely not only in their appearance but also in their functionality. Some data are openly available through clear modern web interfaces, complete with well-documented programmer-friendly <a href=\"https:\/\/www.limswiki.org\/index.php\/Application_programming_interface\" title=\"Application programming interface\" class=\"wiki-link\" data-key=\"36fc319869eba4613cb0854b421b0934\">application programming interfaces<\/a> (APIs), while others are displayed as static web pages that require error-prone and brittle web scraping. Still others are offered as machine-readable documents (e.g., comma-separate values [CSV], Microsoft Excel, Extensible Markup Language [XML], Adobe PDF). Finally, some necessitate contacting a human, who then prepares and sends the requested data manually.\n<\/p><p>Second, there are many data formats. Data containers (e.g., CSV, JavaScript Object Notation [JSON]) and element formats (e.g., timestamp format, location name format) may differ. Character encodings<sup id=\"rdp-ebb-cite_ref-ZentgrafWhat15_24-0\" class=\"reference\"><a href=\"#cite_note-ZentgrafWhat15-24\">[24]<\/a><\/sup> (e.g., ASCII, UTF-8) and line endings<sup id=\"rdp-ebb-cite_ref-AtwoodTheGreat10_25-0\" class=\"reference\"><a href=\"#cite_note-AtwoodTheGreat10-25\">[25]<\/a><\/sup> (e.g., <tt>\\r\\n<\/tt>, <tt>\\n<\/tt>) may also differ. Compounding these issues, formats can change over time (e.g., renaming or reordering spreadsheet columns). More broadly, these challenges are closely tied to schema, data model, and vocabulary standardization.\n<\/p><p>Finally, there are differences among institutions in their reporting habits; even within a single institution, there are often reporting nuances among diseases. For example, one context may be reported monthly (e.g., Q fever in Australia), while another context is reported weekly (e.g., influenza in the U.S.) or even more finely (e.g., 2014 West African Ebola outbreak). Furthermore, what is meant by \u201cweekly\u201d in one context may be different than another context (e.g., CDC epi weeks vs. irregular reporting intervals in Poland, as described later).\n<\/p><p>Together, these challenges make large-scale public health data analysis and modeling significantly more difficult and time-consuming. Gathering, cleaning, and eliciting relevant data often require more time than the actual analysis itself. This paper discusses these three key technical challenges involving public health-related epidemiological data, in detail and with examples that were identified through detailed analysis of data deposition practices around the globe. Building from this analysis, we offer a framework of best practices comprised of modern standards that should be adhered to when releasing epidemiological data to the public. Such a framework will enable a more robust future for accurate and high-confidence epidemiological data and analysis.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Discussion\">Discussion<\/span><\/h2>\n<h3><span class=\"mw-headline\" id=\"Interface_challenges\">Interface challenges<\/span><\/h3>\n<p>The interface is the mechanism by which data are presented to a user for consumption.\n<\/p><p>Epidemiological data repositories implementing current best practices provide an interactive web-based searching and filtering interface that enables users to easily export desired data in a variety of formats. These are generally accompanied by an API that allows users to programmatically acquire desired data. For example, if one wants to download the latest influenza surveillance data weekly, instead of manually navigating an interactive web interface each week to export the data, the process could be automated by writing code that interacts with the API. Such an interface provides the simplest and most powerful method of data acquisition. Examples of this type of interface are the U.S. Centers for Disease Control and Prevention's (CDC) <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/data.cdc.gov\/\" target=\"_blank\">Data Catalog<\/a> and the World Health Organization's (WHO) <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.who.int\/data\/gho\" target=\"_blank\">Global Health Observatory<\/a> (GHO).\n<\/p><p>While an interactive web-based interface coupled with an API is a best practice, it can be complex and expensive to implement. Many public health departments are under resource constraints and depend on older websites that tend to release data in one of two ways: 1) data are uploaded in some common format (e.g., CSV, Microsoft Excel, PDF) or 2) data are displayed in Hypertext Markup Language (HTML) tables. An example of the first is seen on Israel's Ministry of Health website, where data are provided weekly in Microsoft Excel formats.<sup id=\"rdp-ebb-cite_ref-MHIWeekly16_26-0\" class=\"reference\"><a href=\"#cite_note-MHIWeekly16-26\">[26]<\/a><\/sup> An example of the second is seen on Australia's Department of Health website, where data are provided within simply-formatted HTML tables.<sup id=\"rdp-ebb-cite_ref-ADoHNotifications16_27-0\" class=\"reference\"><a href=\"#cite_note-ADoHNotifications16-27\">[27]<\/a><\/sup>\n<\/p><p>Data uploaded in a common format can often be automatically downloaded and processed, and HTML tables can generally be automatically scraped and processed. While HTML scraping is often straightforward, there are some instances where it can be quite difficult. One example of a difficult-to-scrape data source is the Robert Koch Institute SurvStat 2.0 website.<sup id=\"rdp-ebb-cite_ref-RKISurvStat_28-0\" class=\"reference\"><a href=\"#cite_note-RKISurvStat-28\">[28]<\/a><\/sup> Although the service is capable of providing epidemiological data at superior spatial and temporal resolutions (county- and week-level, respectively), the interface is not easily amenable to scraping. First, the HTTP requests formed by the ASP.NET application cannot be easily reverse-engineered; this necessitates the use of browser-automation software like <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.seleniumhq.org\/\" target=\"_blank\">Selenium<\/a>, which enables automating website user interaction, such as mouse clicks and keyboard presses, for data scraping. Second, the selection of new filters, attributes, and display options results in a newly-refreshed page for each change; because many options are required to obtain each desired dataset, scraping can take a long time.\n<\/p><p>Additionally, while there may be no technical barriers to downloading or scraping data, there may be barriers relating to a website's terms of service (TOS). In some instances, the TOS may prevent users from scraping or downloading data en masse; this is sometimes done to prevent unreasonable load on the website, for example. Ignoring the TOS raises ethical issues that are often overlooked in research; after all, the goals of most epidemiological researchers are benevolent, and the data are public and usually funded by taxpayers. Ignoring a website's TOS could also raise logistical issues related to publishing and institutional review board (IRB) approval.\n<\/p><p>A concern underlying all scraping efforts is that data scraping scripts are brittle. Web scraping relies on patterns in the HTML\/CSS source code of a website. If an institution modifies its layouts, even slightly, scrapers may exhibit unexpected behavior.\n<\/p><p>In some cases, a human must be contacted directly, who then prepares and sends the requested data. However, these manually requested and prepared data are often saddled with many restrictions. For example, when one of the authors contacted a ministry of health for more detailed epidemiological data, the data were offered with a five-page data request form that significantly restricted use and sharing of the data. Furthermore, it stated that it would take \u201cup to 3 months\u201d to be released because of the review and approval from the various data owners (local, state, and territory health departments). These types of restrictions and hurdles to data access prevent the development and adoption of advanced <a href=\"https:\/\/www.limswiki.org\/index.php\/Data_analysis\" title=\"Data analysis\" class=\"wiki-link\" data-key=\"545c95e40ca67c9e63cd0a16042a5bd1\">analytics<\/a>.\n<\/p><p>Finally, finding epidemiological data interfaces or data within an interface is often a time-consuming and error-prone task. For example, the Zika virus epidemic has resulted in increased global attention for Brazil, but it has not resulted in a single easy-to-understand machine-readable interface.<sup id=\"rdp-ebb-cite_ref-CoelhoEpidemi16_29-0\" class=\"reference\"><a href=\"#cite_note-CoelhoEpidemi16-29\">[29]<\/a><\/sup> Until just recently, Brazil's Ministry of Health maintained two separate lists of mosquito-borne illness epidemiological bulletins.<sup id=\"rdp-ebb-cite_ref-MSEpidemArch_30-0\" class=\"reference\"><a href=\"#cite_note-MSEpidemArch-30\">[30]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-MSBoletins_31-0\" class=\"reference\"><a href=\"#cite_note-MSBoletins-31\">[31]<\/a><\/sup> Although these lists pointed to the exact same bulletins, the page archiving <i>Boletim Epidemiol\u00f3gico<\/i><sup id=\"rdp-ebb-cite_ref-MSBoletins_31-1\" class=\"reference\"><a href=\"#cite_note-MSBoletins-31\">[31]<\/a><\/sup> is consistently more up-to-date than the \"Epidemiological Situation\" page<sup id=\"rdp-ebb-cite_ref-MSEpidemArch_30-1\" class=\"reference\"><a href=\"#cite_note-MSEpidemArch-30\">[30]<\/a><\/sup> (see Figures 1, 2). Having multiple interfaces increases the likelihood of human error when collecting epidemiological data. For instance, if one assumes that there is only one official source for Zika, the most current information may be overlooked.\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig1_Fairchild_FrontPubHealth2018_6.jpg\" class=\"image wiki-link\" data-key=\"58932831ab9c5da36dc7b175c7dadfd3\"><img alt=\"Fig1 Fairchild FrontPubHealth2018 6.jpg\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/0\/01\/Fig1_Fairchild_FrontPubHealth2018_6.jpg\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Fig. 1<\/b> Screenshot showing part of the mosquito-borne illness epidemiological bulletin list available at 'Boletim Epidemiol\u00f3gico'. This is the most current and complete list, with data available through the 38th week of 2016.<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig2_Fairchild_FrontPubHealth2018_6.jpg\" class=\"image wiki-link\" data-key=\"50b18b04a59d38332ff5411e1dcea086\"><img alt=\"Fig2 Fairchild FrontPubHealth2018 6.jpg\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/9\/9c\/Fig2_Fairchild_FrontPubHealth2018_6.jpg\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Fig. 2<\/b> Screenshot showing part of the mosquito-borne illness epidemiological bulletin list available at the \"Epidemiological Situation\" page. This list only goes through week 21 of 2016 and is missing a number of weeks when compared to the list in Figure 1. This screenshot was taken at the same time as the one in Figure 1.<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<h3><span class=\"mw-headline\" id=\"Data_format_challenges\">Data format challenges<\/span><\/h3>\n<h4><span class=\"mw-headline\" id=\"Data_containers\">Data containers<\/span><\/h4>\n<p>First, data container issues must be addressed. For example, CSV files are among the simplest file types to parse; they are plain text files with a simple structure (i.e., columns are separated by a comma, rows are separated by a newline). Figure 3 demonstrates how epidemiological data might be provided in a CSV file. Any spreadsheet software can open CSV files natively, and most programming languages require no third-party libraries to read and write CSV files.\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig3_Fairchild_FrontPubHealth2018_6.jpg\" class=\"image wiki-link\" data-key=\"60324968ae6740e5c35e4144d08319de\"><img alt=\"Fig3 Fairchild FrontPubHealth2018 6.jpg\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/a\/a9\/Fig3_Fairchild_FrontPubHealth2018_6.jpg\" width=\"389\" height=\"126\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Fig. 3<\/b> Sample epidemiological case count data in CSV format. CSV files are plain text files that allow tabular data to be laid out as rows separated by newlines and columns separated by commas. This time series does not contain real data and only exists for demonstration purposes.<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>A conceptually similar file type to CSV is Microsoft Excel's XLSX. XLSX is a spreadsheet format developed by Microsoft and is a part of the Office Open XML (OOXML) specification. OOXML is a complex specification comprised of zipped XML files and other embedded data (e.g., images).<sup id=\"rdp-ebb-cite_ref-ApacheOffice_32-0\" class=\"reference\"><a href=\"#cite_note-ApacheOffice-32\">[32]<\/a><\/sup> This format is common among public health practitioners due to the ubiquity of Microsoft Excel. For the programmer, however, this format presents a variety of challenges not present with CSV files. Due to the file type's complexity, a third-party library will be necessary in virtually all circumstances for reading\/writing XLSX files (e.g., <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/github.com\/python-excel\/xlrd\" target=\"_blank\">xlrd<\/a> and <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/github.com\/python-excel\/xlwt\" target=\"_blank\">xlwt<\/a> for Python or <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/poi.apache.org\/\" target=\"_blank\">Apache POI<\/a> for Java). Depending on the maturity of the library used, the file's formulas, pivot tables, and other complex features should be handled with varying degrees of trust.\n<\/p><p>JSON is another common data container used on the internet (see Figure 4 for an example). For instance, JSON data are commonly returned when querying an API endpoint. JSON is easy and fast to use; many programming languages offer built-in JSON read\/write support (e.g., Python and Java). Additionally, similar to CSV, JSON is a plain text format that is human-readable. Unlike CSV, however, JSON is not limited to tabular data. JSON can represent more complex relationships between data and is conceptually more similar to XML. Due to its ubiquity and structure, a number of application-specific JSON standards are available. For example, GeoJSON<sup id=\"rdp-ebb-cite_ref-GeoJSON_33-0\" class=\"reference\"><a href=\"#cite_note-GeoJSON-33\">[33]<\/a><\/sup> and TopoJSON<sup id=\"rdp-ebb-cite_ref-TopoJSON_34-0\" class=\"reference\"><a href=\"#cite_note-TopoJSON-34\">[34]<\/a><\/sup> enable sharing geographic data. In 2016, Finnie <i>et al.<\/i> proposed EpiJSON, which offers a standardized way to encode epidemiological data.<sup id=\"rdp-ebb-cite_ref-FinnieEpiJSON16_35-0\" class=\"reference\"><a href=\"#cite_note-FinnieEpiJSON16-35\">[35]<\/a><\/sup> Although EpiJSON shows promise, it is young and has yet to be broadly embraced. To make adoption simpler, open-source EpiJSON libraries could be developed for common programming languages; currently, the only such library exists for the <a href=\"https:\/\/www.limswiki.org\/index.php\/R_(programming_language)\" title=\"R (programming language)\" class=\"wiki-link\" data-key=\"1b0aa598f071aca4c5b4ee08d8bb2bde\">programming language R<\/a><sup id=\"rdp-ebb-cite_ref-RepiJSON_36-0\" class=\"reference\"><a href=\"#cite_note-RepiJSON-36\">[36]<\/a><\/sup>, but additional libraries should be developed for Python, Java, and other languages commonly used for epidemiological data analysis.\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig4_Fairchild_FrontPubHealth2018_6.jpg\" class=\"image wiki-link\" data-key=\"c411580cbd157c9d67acfd85f1e810e8\"><img alt=\"Fig4 Fairchild FrontPubHealth2018 6.jpg\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/7\/7a\/Fig4_Fairchild_FrontPubHealth2018_6.jpg\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Fig. 4<\/b> Sample epidemiological case count data in a simple JSON format. Compared to CSV (demonstrated in Figure 3), JSON contains more structure that can more rigorously specify data relationships (including hierarchical relationships). Note that this is not EpiJSON; EpiJSON can be quite verbose (due to, for example, metadata specifications and GeoJSON-specified locations), and the authors felt a complete EpiJSON example would take up an unreasonable amount of space in this paper. As in Figure 3, this time series does not contain real data and only exists for demonstration purposes.<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>PDF files provide a number of unique challenges in addition to complexity. Extraction of data is the biggest challenge, as epidemiological information is often provided in mixed formats: textual (e.g., paragraphs of descriptive text in a report), graphical (e.g., bar and line charts), and tabular. Simply extracting the text of a PDF correctly and in the right order can prove to be a non-trivial challenge. Named-entity recognition and extraction, a natural language processing task, can be used to elicit case counts from unstructured text<sup id=\"rdp-ebb-cite_ref-FairchildElicit15_19-1\" class=\"reference\"><a href=\"#cite_note-FairchildElicit15-19\">[19]<\/a><\/sup>, but this supervised machine learning task requires knowledge of the language in which the document is published, as well as epidemiological subject matter expertise. Graphical data are intended for the human eye. While graphical data can potentially be digitized using software like <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/automeris.io\/WebPlotDigitizer\/\" target=\"_blank\">WebPlotDigitizer<\/a>, this cannot always be reliably automated. Even tabular data, which visually appear structured, are typically difficult to extract due to the variety of ways a table can be presented in a PDF document.<sup id=\"rdp-ebb-cite_ref-KhusroOnMethods14_37-0\" class=\"reference\"><a href=\"#cite_note-KhusroOnMethods14-37\">[37]<\/a><\/sup>\n<\/p><p>Furthermore, PDF files need not even contain text. In a number of circumstances, the PDF files that institutions provide simply contain scanned images of documents. The resulting PDF simply contains the image, rather than the raw text that comprised the original document. For example, many of the weekly reports available through the Department of Health website for the Philippines<sup id=\"rdp-ebb-cite_ref-PDoHStatistics_38-0\" class=\"reference\"><a href=\"#cite_note-PDoHStatistics-38\">[38]<\/a><\/sup> are PDFs of scanned documents.<sup id=\"rdp-ebb-cite_ref-PDoHDengue15_39-0\" class=\"reference\"><a href=\"#cite_note-PDoHDengue15-39\">[39]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-PDoHDiphtheria16_40-0\" class=\"reference\"><a href=\"#cite_note-PDoHDiphtheria16-40\">[40]<\/a><\/sup> Text can potentially be elicited with optical character recognition (OCR) software, but the quality of the resulting textual data will vary significantly depending on the quality of the scanned images.\n<\/p><p>Finally, one must be aware of the character encoding when reading text. Since, at the basic level, computers represent all data using binary bits, there must be some binary representation of each character or symbol in an alphabet or language; the character encoding specifies how the raw bits stored in a file should be converted to readable text and vice versa.<sup id=\"rdp-ebb-cite_ref-ZentgrafWhat15_24-1\" class=\"reference\"><a href=\"#cite_note-ZentgrafWhat15-24\">[24]<\/a><\/sup> While there are a number of possible encodings, ASCII, ISO-8859-1, and UTF-8 are among the most common encodings encountered in practice. In 2012, UTF-8 surpassed 60% adoption across the web<sup id=\"rdp-ebb-cite_ref-DavisUnicode12_41-0\" class=\"reference\"><a href=\"#cite_note-DavisUnicode12-41\">[41]<\/a><\/sup> and is currently approaching the 90% mark.<sup id=\"rdp-ebb-cite_ref-W3TechsUsage16_42-0\" class=\"reference\"><a href=\"#cite_note-W3TechsUsage16-42\">[42]<\/a><\/sup> Encoding differences are important; for example, while reading ASCII text as UTF-8 yields correct results, the converse does not.\n<\/p>\n<h4><span class=\"mw-headline\" id=\"Element_format\">Element format<\/span><\/h4>\n<p><b>Data and time<\/b>\n<\/p><p>Beyond data container challenges, there are a number of element formatting differences that must be addressed. First and foremost are date and time formatting discrepancies. While the ISO 8601 date\/time standard has existed since 1988, it is often bypassed in favor of locale-dependent formats. For example, much of Europe follows the day-month-year convention, the U.S. follows the month-day-year convention, and China follows the year-month-day convention. Depending on the locale, 03-09-2005 may refer to March 9, 2005 or September 3, 2005. Additionally, not all locales use the Gregorian calendar. Thailand, for example, uses the Buddhist calendar. The current year, as represented by the Gregorian calendar, is 2018; a Thai timestamp would instead specify 2561. Finally, some locales use 24-h time, while others use 12-h time.\n<\/p><p>In addition to these timestamp parsing differences, there are significant implicit timestamp differences that must be understood. To understand these, one must first recognize that a timestamp on a typical disease curve usually implicitly refers to an interval of time (i.e., actual event-level epidemiological data are rare). To illustrate this, consider the time series in Table 1. \n<\/p>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table class=\"wikitable\" border=\"1\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\" colspan=\"2\"><b>Table 1.<\/b> Sample historical weekly epidemiological time series consisting of timestamps and case counts\n<\/td><\/tr>\n<tr>\n<th style=\"padding-left:10px; padding-right:10px;\">Timestamp\n<\/th>\n<th style=\"padding-left:10px; padding-right:10px;\">Cases\n<\/th><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><tt>2014-08-07 00:00<\/tt>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">2\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><tt>2014-08-14 00:00<\/tt>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">5\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><tt>2014-08-21 00:00<\/tt>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">4\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>Each timestamp can be interpreted using one of three possible interval types:\n<\/p>\n<ul><li> Leading: The timestamp starts the interval, and the interval ends the \u201cinstant\u201d before the next specified timestamp. Table 2 shows how the time series in Table 1 would be transformed to an interval series with an interval type of leading.<\/li>\n<li> Trailing exclusive: The timestamp ends the interval but is not included in the interval; Table 3 demonstrates this transformation.<\/li>\n<li> Trailing inclusive: The timestamp ends the interval and is included in the interval; Table 4 shows this transformation.<\/li><\/ul>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table class=\"wikitable\" border=\"1\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\" colspan=\"3\"><b>Table 2.<\/b> Explicit transformation of Table 1 into a leading interval series; the interval start and end are inclusive and exclusive, respectively.\n<\/td><\/tr>\n<tr>\n<th style=\"padding-left:10px; padding-right:10px;\">Interval start\n<\/th>\n<th style=\"padding-left:10px; padding-right:10px;\">Interval end\n<\/th>\n<th style=\"padding-left:10px; padding-right:10px;\">Cases\n<\/th><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><tt>2014-08-07 00:00<\/tt>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><tt>2014-08-14 00:00<\/tt>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">2\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><tt>2014-08-14 00:00<\/tt>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><tt>2014-08-21 00:00<\/tt>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">5\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><tt>2014-08-21 00:00<\/tt>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><tt>2014-08-28 00:00<\/tt>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">4\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table class=\"wikitable\" border=\"1\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\" colspan=\"3\"><b>Table 3.<\/b> Explicit transformation of Table 1 into a trailing exclusive interval series; the interval start and end are inclusive and exclusive, respectively.\n<\/td><\/tr>\n<tr>\n<th style=\"padding-left:10px; padding-right:10px;\">Interval start\n<\/th>\n<th style=\"padding-left:10px; padding-right:10px;\">Interval end\n<\/th>\n<th style=\"padding-left:10px; padding-right:10px;\">Cases\n<\/th><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><tt>2014-07-31 00:00<\/tt>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><tt>2014-08-07 00:00<\/tt>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">2\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><tt>2014-08-07 00:00<\/tt>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><tt>2014-08-14 00:00<\/tt>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">5\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><tt>2014-08-14 00:00<\/tt>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><tt>2014-08-21 00:00<\/tt>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">4\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table class=\"wikitable\" border=\"1\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\" colspan=\"3\"><b>Table 4.<\/b> Explicit transformation of Table 1 into a trailing inclusive interval series; the interval start and end are inclusive and exclusive, respectively.\n<\/td><\/tr>\n<tr>\n<th style=\"padding-left:10px; padding-right:10px;\">Interval start\n<\/th>\n<th style=\"padding-left:10px; padding-right:10px;\">Interval end\n<\/th>\n<th style=\"padding-left:10px; padding-right:10px;\">Cases\n<\/th><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><tt>2014-08-01 00:00<\/tt>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><tt>2014-08-08 00:00<\/tt>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">2\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><tt>2014-08-08 00:00<\/tt>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><tt>2014-08-15 00:00<\/tt>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">5\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><tt>2014-08-15 00:00<\/tt>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><tt>2014-08-22 00:00<\/tt>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">4\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>As an example, the CDC standardizes reporting dates in the U.S. using the notion of an \u201cMMWR week\u201d or \u201cepi week.\u201d<sup id=\"rdp-ebb-cite_ref-CDC_MMWR_43-0\" class=\"reference\"><a href=\"#cite_note-CDC_MMWR-43\">[43]<\/a><\/sup> MMWR weeks always begin on Sundays and end on Saturdays. Weeks can be numbered 1\u201353, and, as a result, many institutions choose to report them as such (e.g., the interval \"2016-05-15 00:00, 2016-05-22 00:00\" is reported as \u201c2016, week 20\u201d). However, while most U.S.-based health departments respect the weekly MMWR aggregation standard, many continue to report timestamps based on the MMWR week concept. For example, Figure 5 shows how Texas identifies its weekly influenza surveillance PDF reports by trailing inclusive timestamps rather than by MMWR week.\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig5_Fairchild_FrontPubHealth2018_6.jpg\" class=\"image wiki-link\" data-key=\"3942c3e2dafabc4cac87601200cc512e\"><img alt=\"Fig5 Fairchild FrontPubHealth2018 6.jpg\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/9\/98\/Fig5_Fairchild_FrontPubHealth2018_6.jpg\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Fig. 5<\/b> Screenshot taken from Texas' Department of State Health Services 2014\u20132015 weekly influenza reports web page.<sup id=\"rdp-ebb-cite_ref-TexasHHS2014_44-0\" class=\"reference\"><a href=\"#cite_note-TexasHHS2014-44\">[44]<\/a><\/sup> Texas identifies its weekly influenza surveillance PDF reports by trailing inclusive timestamps rather than by MMWR week (e.g., \u201c10\/3\/15\u201d instead of \u201c2015, week 39\u201d). Interestingly, much of the data in each PDF uses MMWR week numbers rather than timestamps.<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>Outside of the U.S., a variety of reporting date standards exist. In Japan, for example, the epi week starts on Monday and ends on Sunday.<sup id=\"rdp-ebb-cite_ref-NIIDCalendar12_45-0\" class=\"reference\"><a href=\"#cite_note-NIIDCalendar12-45\">[45]<\/a><\/sup> In Poland, the reporting is even more different. Poland reports influenza cases four \u201cweeks\u201d a month, regardless of the length of the month. As a result, the intervals between reports are not regular. For example, the four influenza reports in May 2016 are shown in Table 5.\n<\/p>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table class=\"wikitable\" border=\"1\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\" colspan=\"4\"><b>Table 5.<\/b> Influenza reporting intervals in Poland in May 2016. Instead of reporting data at regular intervals (e.g., every seven days), Poland reports data four \"weeks\" a month, regardless of the length of the month. This yields irregular interval durations. Here, the interval start and end are inclusive.\n<\/td><\/tr>\n<tr>\n<th style=\"padding-left:10px; padding-right:10px;\">Interval start\n<\/th>\n<th style=\"padding-left:10px; padding-right:10px;\">Interval end\n<\/th>\n<th style=\"padding-left:10px; padding-right:10px;\">Duration (days)\n<\/th>\n<th style=\"padding-left:10px; padding-right:10px;\">Source\n<\/th><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><tt>2016-05-01<\/tt>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><tt>2016-05-07<\/tt>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">7\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><sup id=\"rdp-ebb-cite_ref-NIPHPEpidem1_16_46-0\" class=\"reference\"><a href=\"#cite_note-NIPHPEpidem1_16-46\">[46]<\/a><\/sup>\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><tt>2016-05-08<\/tt>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><tt>2016-05-15<\/tt>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">8\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><sup id=\"rdp-ebb-cite_ref-NIPHPEpidem2_16_47-0\" class=\"reference\"><a href=\"#cite_note-NIPHPEpidem2_16-47\">[47]<\/a><\/sup>\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><tt>2016-05-16<\/tt>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><tt>2016-05-22<\/tt>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">7\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><sup id=\"rdp-ebb-cite_ref-NIPHPEpidem3_16_48-0\" class=\"reference\"><a href=\"#cite_note-NIPHPEpidem3_16-48\">[48]<\/a><\/sup>\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><tt>2016-05-23<\/tt>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><tt>2016-05-31<\/tt>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">9\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><sup id=\"rdp-ebb-cite_ref-NIPHPEpidem4_16_49-0\" class=\"reference\"><a href=\"#cite_note-NIPHPEpidem4_16-49\">[49]<\/a><\/sup>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>One remaining concern related to date and time is time zone. With the increasing use of internet data streams in disease forecasting and surveillance, it is important to be able to precisely place reference epidemiological data since associated internet data streams might be timestamped down to the second. Many data sources fail to report a time zone, so local time is often assumed. An incorrect time zone may impact analysis of high resolution data. For example, norovirus data are sometimes provided hourly<sup id=\"rdp-ebb-cite_ref-Guzman-HerradorOutbreak11_50-0\" class=\"reference\"><a href=\"#cite_note-Guzman-HerradorOutbreak11-50\">[50]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-MayetFood11_51-0\" class=\"reference\"><a href=\"#cite_note-MayetFood11-51\">[51]<\/a><\/sup>, and time zone errors could have a potentially drastic negative effect on model results or analyses.\n<\/p><p><b>Geography<\/b>\n<\/p><p>Political boundaries and names must be carefully managed. Subtle differences in names (e.g., Zurich vs. Z\u00fcrich) may lead to incorrect results during an analysis. The ISO 3166 standard defines country and principle subdivision (e.g., state or province) names, but it does not handle finer-than-subdivision regions, such as counties, districts, or cities.\n<\/p><p>Moreover, political boundaries (and thus populations and demographics) change over time. For example, South Sudan's split from Sudan in 2011 decreased Sudan's population by more than ten million people and dramatically changed its political boundary. Computing the historical attack rate for a disease (e.g., influenza incidence per 100,000 people), for instance, must take into account these changes.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Data_reporting_challenges\">Data reporting challenges<\/span><\/h3>\n<p>Beyond interface and data format challenges, there are challenges that lie within the bureaucratic reporting process for an epidemiological institution. Modern disease surveillance systems rely on complex reporting hierarchies; raw data are initially captured at each provider, who then anonymizes and aggregates data as necessary before sending it to the next level in the hierarchy (perhaps a local or state public health department).<sup id=\"rdp-ebb-cite_ref-FairchildImproving14_52-0\" class=\"reference\"><a href=\"#cite_note-FairchildImproving14-52\">[52]<\/a><\/sup> This hierarchy can have many levels. Even in many of the most developed regions of the world, much of this process continues to be done by hand, although the push to electronic medical records is gaining traction. As a result, most disease surveillance systems across the world experience reporting lags of at least one to two weeks.\n<\/p><p>This reporting lag can, in some cases, affect both an intuitive understanding of the situation as well as computational forecasting models. In an effort to combat surveillance system reporting lag, a number of attempts have been made to \u201cfill in\u201d the gaps using internet data<sup id=\"rdp-ebb-cite_ref-PolgreenUsing08_13-1\" class=\"reference\"><a href=\"#cite_note-PolgreenUsing08-13\">[13]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-GinsbergDetect09_14-1\" class=\"reference\"><a href=\"#cite_note-GinsbergDetect09-14\">[14]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-SignoriniTheUse11_15-1\" class=\"reference\"><a href=\"#cite_note-SignoriniTheUse11-15\">[15]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-GenerousGlobal14_17-1\" class=\"reference\"><a href=\"#cite_note-GenerousGlobal14-17\">[17]<\/a><\/sup>, but these studies require moderate to high levels of internet usage in the locales of interest, which are often not guaranteed.\n<\/p><p>Another issue is heterogeneous case definitions across jurisdictions. Many times, the case definitions used in epidemiological data are not clearly defined, and it is often difficult to navigate websites to identify the definitions. For example, many of the influenza surveillance systems in Europe use common, but not identical, case definitions.<sup id=\"rdp-ebb-cite_ref-AguileraHetero03_53-0\" class=\"reference\"><a href=\"#cite_note-AguileraHetero03-53\">[53]<\/a><\/sup> Contextual differences in case definitions for Ebola<sup id=\"rdp-ebb-cite_ref-WHOCase14_54-0\" class=\"reference\"><a href=\"#cite_note-WHOCase14-54\">[54]<\/a><\/sup> could make interpreting data for the 2014 West African Ebola outbreak difficult.\n<\/p><p>One must also be concerned about language issues. Data are often provided in the native language of the region of the world in which they originate. For example, Thailand's Bureau of Epidemiology website<sup id=\"rdp-ebb-cite_ref-TBEThailandNative16_55-0\" class=\"reference\"><a href=\"#cite_note-TBEThailandNative16-55\">[55]<\/a><\/sup> is natively displayed in Thai but also offers an English version.<sup id=\"rdp-ebb-cite_ref-TBEThailandEnglish16_56-0\" class=\"reference\"><a href=\"#cite_note-TBEThailandEnglish16-56\">[56]<\/a><\/sup> While online language translation services do exist (e.g., <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/translate.google.com\/\" target=\"_blank\">Google Translate<\/a>), these are not always reliable, and they cannot easily translate text in images (e.g., a website header comprised of images). To assist with language issues, formal disease- and epidemiological-focused ontologies<sup id=\"rdp-ebb-cite_ref-IGSDisease_57-0\" class=\"reference\"><a href=\"#cite_note-IGSDisease-57\">[57]<\/a><\/sup> can help; translations, abbreviations, and alternate names can be encoded in an ontology to help automatically map different records to the same concept.\n<\/p><p>Furthermore, even within a single institution, there are often reporting nuances among diseases. For example, one context may be reported monthly, while another context may be reported weekly or daily. Some contexts may not be regularly reported; irregular reporting can lead to questions like \u201cIs the value for a missing timestamp zero or unknown?\u201d\n<\/p><p>Finally, case count data are often retroactively updated as new data are made available. In other words, historical data are not fixed the first time they are published. For example, a case count data point published today may be updated next week or the following week, as new data appear. This problem, often called \u201cbackfill,\u201d is due to the number and variety of members that comprise the complex reporting hierarchy that modern disease surveillance systems rely on. If a surveillance member's computer system goes down temporarily, for example, it may not be able to submit its data until the following week. Backfill can in some cases drastically affect analyses, so analysts and modelers must be aware of this potential issue.<sup id=\"rdp-ebb-cite_ref-FarrowAHuman17_58-0\" class=\"reference\"><a href=\"#cite_note-FarrowAHuman17-58\">[58]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-OsthusDynamic19_59-0\" class=\"reference\"><a href=\"#cite_note-OsthusDynamic19-59\">[59]<\/a><\/sup>\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Conclusions\">Conclusions<\/span><\/h2>\n<p>We have identified three key challenges involving epidemiological data: 1) interface challenges, 2) data format challenges, and 3) data reporting challenges. Each of these challenges can be addressed to simplify the efforts of analysts and modelers. Here, we propose a framework of best practices comprised of modern standards that should be adhered to when releasing epidemiological data to the public:\n<\/p>\n<ol><li>Present the user with an interactive web interface to search and filter data. This interface should allow users to export data in common open formats (e.g., JSON using the EpiJSON standard, CSV).<\/li>\n<li>Provide a web-based API to allow automated data retrieval.<\/li>\n<li>Always use ISO 8601 dates, times, timestamps, and durations. Timestamps should either explicitly provide the local time zone or be adjusted for UTC, as specified by the ISO 8601 standard.<\/li>\n<li>When providing time series, clearly define the interval type so that timestamps can be interpreted properly.<\/li>\n<li>When possible, use ISO 3166 location names.<\/li>\n<li>Ensure all data are encoded using UTF-8.<\/li>\n<li>Ensure the website can be run through an online language translation service (e.g., do not place important text in an image).<\/li>\n<li>When reporting case counts, the case definitions should be made explicit and clear.<\/li>\n<li>Clearly distinguish between unknown and zero values.<\/li><\/ol>\n<p>These suggestions are not prescribing a single format or process; instead, these items provide a means for clearly defining and presenting epidemiological data to the public.\n<\/p><p>We implore the members of the global public health community to work together to create and follow standards for publishing data. Many institutions attempt to publish similar types of data using similar interfaces. In general, a user selects locations, diseases, optional time periods, and optional demographics in order to retrieve the desired data. Because many analysts and modelers have similar data desires, we feel this provides an opportunity for a generic shared epidemiological data access platform. Currently used by the CDC, one possibility might be <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.tylertech.com\/products\/socrata\" target=\"_blank\">Socrata<\/a>, a platform that allows governments to share data openly. Socrata provides not only a modern interactive web interface but also an extensive API. Another option may be for public health institutions to collaboratively develop a free and open source solution that each could use. Such a platform may be more easily implemented by resource-constrained public health departments that have neither the time nor the money to develop their own solutions. Additionally, as web standards evolve, a shared data access platform could be updated in order to propagate these changes to each institution.\n<\/p><p>If a standard platform could be employed by institutions worldwide, then one could envision a future where global data could be easily collected without the challenges we currently face. This would in turn streamline epidemiological and public health analysis, modeling, and informatics, resulting in better public health decision-making capabilities.\n<\/p><p>Additionally, while this paper focuses on the public health and epidemiological communities, many of the challenges and solutions discussed here are not unique to them. Many of these same challenges are present whenever data of the same type are published globally by separate institutions that do not have an a priori agreed-upon set of standards. For example, weather and economic data have many of the same features as epidemiological data (e.g., locations, time intervals) and should also adhere to the ISO 8601 and 3166 standards, be encoded in UTF-8, and clearly distinguish between unknown and zero values.\n<\/p><p>Finally, it is important to recognize that this paper focuses on capable public health institutions with enough funding to collect and disseminate their epidemiological data. It should be noted, however, that a number of regions worldwide do not meet this criterion and are struggling even to monitor and care for their constituent populations, let alone publish reliable data. Unfortunately, it is precisely in these underserved regions that the public health community often desires data. Until worldwide public health infrastructure improves significantly, the suggestions here will remain peripheral for many; thus, the problems and suggested solutions put forth in this paper are likely only to be relevant to well-funded institutions. While the solutions presented in this paper may not be as effective at present time due to the lack of coverage, we offer them in preparation for the expanding global coverage that is continuously occurring, and it is only a matter of time until 100% global internet coverage becomes a reality.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Acknowledgements\">Acknowledgements<\/span><\/h2>\n<p>This work was supported by the U.S. Department of Energy through the Los Alamos National Laboratory. Los Alamos National Laboratory is operated by Triad National Security, LLC, for the National Nuclear Security Administration of U.S. Department of Energy (Contract No. 89233218NCA000001).\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Author_contributions\">Author contributions<\/span><\/h3>\n<p>GF and BT compiled the initial manuscript. All authors identified and described challenges and standards, and provided critical revisions of the manuscript.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Funding\">Funding<\/span><\/h3>\n<p>This work was supported by the Defense Threat Reduction Agency's Joint Science and Technology Office for Chemical and Biological Defense under project numbers CB3656 and CB10007.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Conflict_of_interest_statement\">Conflict of interest statement<\/span><\/h3>\n<p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"References\">References<\/span><\/h2>\n<div class=\"reflist references-column-width\" style=\"-moz-column-width: 30em; -webkit-column-width: 30em; column-width: 30em; list-style-type: decimal;\">\n<ol class=\"references\">\n<li id=\"cite_note-ChretianMake16-1\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-ChretianMake16_1-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Chretien, J.P.; Rivers, C.M.; Johansson, M.A. (2016). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4987038\" target=\"_blank\">\"Make Data Sharing Routine to Prepare for Public Health Emergencies\"<\/a>. <i>PLoS One<\/i> <b>13<\/b> (8): e1002109. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1371%2Fjournal.pmed.1002109\" target=\"_blank\">10.1371\/journal.pmed.1002109<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC4987038\/\" target=\"_blank\">PMC4987038<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/27529422\" target=\"_blank\">27529422<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4987038\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4987038<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Make+Data+Sharing+Routine+to+Prepare+for+Public+Health+Emergencies&rft.jtitle=PLoS+One&rft.aulast=Chretien%2C+J.P.%3B+Rivers%2C+C.M.%3B+Johansson%2C+M.A.&rft.au=Chretien%2C+J.P.%3B+Rivers%2C+C.M.%3B+Johansson%2C+M.A.&rft.date=2016&rft.volume=13&rft.issue=8&rft.pages=e1002109&rft_id=info:doi\/10.1371%2Fjournal.pmed.1002109&rft_id=info:pmc\/PMC4987038&rft_id=info:pmid\/27529422&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC4987038&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-CDCAlloc18-2\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-CDCAlloc18_2-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Centers for Disease Control and Prevention (2018). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/asprtracie.hhs.gov\/technical-resources\/resource\/2846\/guidance-on-allocating-and-targeting-pandemic-influenza-vaccine\" target=\"_blank\">\"Allocating and Targeting Pandemic Influenza Vaccine During an Influenza Pandemic\"<\/a>. U.S. Department of Health and Human Services<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/asprtracie.hhs.gov\/technical-resources\/resource\/2846\/guidance-on-allocating-and-targeting-pandemic-influenza-vaccine\" target=\"_blank\">https:\/\/asprtracie.hhs.gov\/technical-resources\/resource\/2846\/guidance-on-allocating-and-targeting-pandemic-influenza-vaccine<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Allocating+and+Targeting+Pandemic+Influenza+Vaccine+During+an+Influenza+Pandemic&rft.atitle=&rft.aulast=Centers+for+Disease+Control+and+Prevention&rft.au=Centers+for+Disease+Control+and+Prevention&rft.date=2018&rft.pub=U.S.+Department+of+Health+and+Human+Services&rft_id=https%3A%2F%2Fasprtracie.hhs.gov%2Ftechnical-resources%2Fresource%2F2846%2Fguidance-on-allocating-and-targeting-pandemic-influenza-vaccine&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-NapPandemic07-3\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-NapPandemic07_3-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Nap, R.E.; Andriessen, M.P.; Meessen, N.E. et al. (2007). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3375786\" target=\"_blank\">\"Pandemic influenza and hospital resources\"<\/a>. <i>Emerging Infectious Diseases<\/i> <b>13<\/b> (11): 1714-9. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.3201%2Feid1311.070103\" target=\"_blank\">10.3201\/eid1311.070103<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC3375786\/\" target=\"_blank\">PMC3375786<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/18217556\" target=\"_blank\">18217556<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3375786\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3375786<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Pandemic+influenza+and+hospital+resources&rft.jtitle=Emerging+Infectious+Diseases&rft.aulast=Nap%2C+R.E.%3B+Andriessen%2C+M.P.%3B+Meessen%2C+N.E.+et+al.&rft.au=Nap%2C+R.E.%3B+Andriessen%2C+M.P.%3B+Meessen%2C+N.E.+et+al.&rft.date=2007&rft.volume=13&rft.issue=11&rft.pages=1714-9&rft_id=info:doi\/10.3201%2Feid1311.070103&rft_id=info:pmc\/PMC3375786&rft_id=info:pmid\/18217556&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC3375786&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-HotaPrep10-4\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-HotaPrep10_4-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Hota, S.; Fried, E.; Burry, L. et al. (2010). \"Preparing your intensive care unit for the second wave of H1N1 and future surges\". <i>Critical Care Medicine<\/i> <b>38<\/b> (4 Suppl.): e110\u20139. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1097%2FCCM.0b013e3181c66940\" target=\"_blank\">10.1097\/CCM.0b013e3181c66940<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/19935417\" target=\"_blank\">19935417<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Preparing+your+intensive+care+unit+for+the+second+wave+of+H1N1+and+future+surges&rft.jtitle=Critical+Care+Medicine&rft.aulast=Hota%2C+S.%3B+Fried%2C+E.%3B+Burry%2C+L.+et+al.&rft.au=Hota%2C+S.%3B+Fried%2C+E.%3B+Burry%2C+L.+et+al.&rft.date=2010&rft.volume=38&rft.issue=4+Suppl.&rft.pages=e110%E2%80%939&rft_id=info:doi\/10.1097%2FCCM.0b013e3181c66940&rft_id=info:pmid\/19935417&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-MoranEpi16-5\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-MoranEpi16_5-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Moran, K.R.; Fairchild, G.; Generous, N. et al. (2016). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5181546\" target=\"_blank\">\"Epidemic Forecasting is Messier Than Weather Forecasting: The Role of Human Behavior and Internet Data Streams in Epidemic Forecast\"<\/a>. <i>Journal of Infectious Diseases<\/i> <b>214<\/b> (Suppl. 4): S404-S408. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1093%2Finfdis%2Fjiw375\" target=\"_blank\">10.1093\/infdis\/jiw375<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC5181546\/\" target=\"_blank\">PMC5181546<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/28830111\" target=\"_blank\">28830111<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5181546\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5181546<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Epidemic+Forecasting+is+Messier+Than+Weather+Forecasting%3A+The+Role+of+Human+Behavior+and+Internet+Data+Streams+in+Epidemic+Forecast&rft.jtitle=Journal+of+Infectious+Diseases&rft.aulast=Moran%2C+K.R.%3B+Fairchild%2C+G.%3B+Generous%2C+N.+et+al.&rft.au=Moran%2C+K.R.%3B+Fairchild%2C+G.%3B+Generous%2C+N.+et+al.&rft.date=2016&rft.volume=214&rft.issue=Suppl.+4&rft.pages=S404-S408&rft_id=info:doi\/10.1093%2Finfdis%2Fjiw375&rft_id=info:pmc\/PMC5181546&rft_id=info:pmid\/28830111&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC5181546&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-HethcoteTheMath00-6\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-HethcoteTheMath00_6-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Hethcore, H.W. (2000). \"The Mathematics of Infectious Diseases\". <i>SIAM Review<\/i> <b>42<\/b> (4): 599\u2013653. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1137%2FS0036144500371907\" target=\"_blank\">10.1137\/S0036144500371907<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=The+Mathematics+of+Infectious+Diseases&rft.jtitle=SIAM+Review&rft.aulast=Hethcore%2C+H.W.&rft.au=Hethcore%2C+H.W.&rft.date=2000&rft.volume=42&rft.issue=4&rft.pages=599%E2%80%93653&rft_id=info:doi\/10.1137%2FS0036144500371907&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-EubankModel04-7\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-EubankModel04_7-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Eubank, S.; Guclu, H.; Kumar, V.S. et al. (2004). \"Modelling disease outbreaks in realistic urban social networks\". <i>Nature<\/i> <b>429<\/b> (6988): 180\u20134. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1038%2Fnature02541\" target=\"_blank\">10.1038\/nature02541<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/15141212\" target=\"_blank\">15141212<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Modelling+disease+outbreaks+in+realistic+urban+social+networks&rft.jtitle=Nature&rft.aulast=Eubank%2C+S.%3B+Guclu%2C+H.%3B+Kumar%2C+V.S.+et+al.&rft.au=Eubank%2C+S.%3B+Guclu%2C+H.%3B+Kumar%2C+V.S.+et+al.&rft.date=2004&rft.volume=429&rft.issue=6988&rft.pages=180%E2%80%934&rft_id=info:doi\/10.1038%2Fnature02541&rft_id=info:pmid\/15141212&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-BissetEpiFast09-8\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-BissetEpiFast09_8-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Busset, K.R.; Chen, J.; Feng, X. et al. (2009). \"EpiFast: A fast algorithm for large scale realistic epidemic simulations on distributed memory systems\". <i>Proceedings of the 23rd international conference on Supercomputing<\/i>: 430\u201339. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1145%2F1542275.1542336\" target=\"_blank\">10.1145\/1542275.1542336<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=EpiFast%3A+A+fast+algorithm+for+large+scale+realistic+epidemic+simulations+on+distributed+memory+systems&rft.jtitle=Proceedings+of+the+23rd+international+conference+on+Supercomputing&rft.aulast=Busset%2C+K.R.%3B+Chen%2C+J.%3B+Feng%2C+X.+et+al.&rft.au=Busset%2C+K.R.%3B+Chen%2C+J.%3B+Feng%2C+X.+et+al.&rft.date=2009&rft.pages=430%E2%80%9339&rft_id=info:doi\/10.1145%2F1542275.1542336&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ChaoControl12-9\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-ChaoControl12_9-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Chao, D.L.; Halstead, S.B.; Halloran, M.E. et al. (2012). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3493390\" target=\"_blank\">\"Controlling dengue with vaccines in Thailand\"<\/a>. <i>PLoS Neglected Tropical Diseases<\/i> <b>6<\/b> (10): e1876. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1371%2Fjournal.pntd.0001876\" target=\"_blank\">10.1371\/journal.pntd.0001876<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC3493390\/\" target=\"_blank\">PMC3493390<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/23145197\" target=\"_blank\">23145197<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3493390\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3493390<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Controlling+dengue+with+vaccines+in+Thailand&rft.jtitle=PLoS+Neglected+Tropical+Diseases&rft.aulast=Chao%2C+D.L.%3B+Halstead%2C+S.B.%3B+Halloran%2C+M.E.+et+al.&rft.au=Chao%2C+D.L.%3B+Halstead%2C+S.B.%3B+Halloran%2C+M.E.+et+al.&rft.date=2012&rft.volume=6&rft.issue=10&rft.pages=e1876&rft_id=info:doi\/10.1371%2Fjournal.pntd.0001876&rft_id=info:pmc\/PMC3493390&rft_id=info:pmid\/23145197&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC3493390&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-GrefenstetteFRED13-10\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-GrefenstetteFRED13_10-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Grefenstette, J.J.; Brown, S.T.; Rosenfeld, R. et al. (2013). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3852955\" target=\"_blank\">\"FRED (a Framework for Reconstructing Epidemic Dynamics): An open-source software system for modeling infectious diseases and control strategies using census-based populations\"<\/a>. <i>BMC Public Health<\/i> <b>13<\/b>: 940. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1186%2F1471-2458-13-940\" target=\"_blank\">10.1186\/1471-2458-13-940<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC3852955\/\" target=\"_blank\">PMC3852955<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/24103508\" target=\"_blank\">24103508<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3852955\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3852955<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=FRED+%28a+Framework+for+Reconstructing+Epidemic+Dynamics%29%3A+An+open-source+software+system+for+modeling+infectious+diseases+and+control+strategies+using+census-based+populations&rft.jtitle=BMC+Public+Health&rft.aulast=Grefenstette%2C+J.J.%3B+Brown%2C+S.T.%3B+Rosenfeld%2C+R.+et+al.&rft.au=Grefenstette%2C+J.J.%3B+Brown%2C+S.T.%3B+Rosenfeld%2C+R.+et+al.&rft.date=2013&rft.volume=13&rft.pages=940&rft_id=info:doi\/10.1186%2F1471-2458-13-940&rft_id=info:pmc\/PMC3852955&rft_id=info:pmid\/24103508&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC3852955&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-McMahonCoupling14-11\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-McMahonCoupling14_11-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">McMahon, B.H.; Manore, C.A.; Hyman, J.M. et al. (2014). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4398965\" target=\"_blank\">\"Coupling Vector-host Dynamics with Weather Geography and Mitigation Measures to Model Rift Valley Fever in Africa\"<\/a>. <i>Mathematical Modelling of Natural Phenomena<\/i> <b>9<\/b> (2): 161\u201377. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1051%2Fmmnp%2F20149211\" target=\"_blank\">10.1051\/mmnp\/20149211<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC4398965\/\" target=\"_blank\">PMC4398965<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/25892858\" target=\"_blank\">25892858<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4398965\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4398965<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Coupling+Vector-host+Dynamics+with+Weather+Geography+and+Mitigation+Measures+to+Model+Rift+Valley+Fever+in+Africa&rft.jtitle=Mathematical+Modelling+of+Natural+Phenomena&rft.aulast=McMahon%2C+B.H.%3B+Manore%2C+C.A.%3B+Hyman%2C+J.M.+et+al.&rft.au=McMahon%2C+B.H.%3B+Manore%2C+C.A.%3B+Hyman%2C+J.M.+et+al.&rft.date=2014&rft.volume=9&rft.issue=2&rft.pages=161%E2%80%9377&rft_id=info:doi\/10.1051%2Fmmnp%2F20149211&rft_id=info:pmc\/PMC4398965&rft_id=info:pmid\/25892858&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC4398965&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ViboudPredict03-12\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-ViboudPredict03_12-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Viboud, C.; Bo\u00eblle, P.Y.; Carrat, F. et al. (2003). \"Prediction of the spread of influenza epidemics by the method of analogues\". <i>American Journal of Epidemiology<\/i> <b>158<\/b> (10): 996-1006. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1093%2Faje%2Fkwg239\" target=\"_blank\">10.1093\/aje\/kwg239<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/14607808\" target=\"_blank\">14607808<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Prediction+of+the+spread+of+influenza+epidemics+by+the+method+of+analogues&rft.jtitle=American+Journal+of+Epidemiology&rft.aulast=Viboud%2C+C.%3B+Bo%C3%ABlle%2C+P.Y.%3B+Carrat%2C+F.+et+al.&rft.au=Viboud%2C+C.%3B+Bo%C3%ABlle%2C+P.Y.%3B+Carrat%2C+F.+et+al.&rft.date=2003&rft.volume=158&rft.issue=10&rft.pages=996-1006&rft_id=info:doi\/10.1093%2Faje%2Fkwg239&rft_id=info:pmid\/14607808&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-PolgreenUsing08-13\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-PolgreenUsing08_13-0\">13.0<\/a><\/sup> <sup><a href=\"#cite_ref-PolgreenUsing08_13-1\">13.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Polgreen, P.M.; Chen, Y.; Pennock, D.M. et al. (2008). \"Using internet searches for influenza surveillance\". <i>Clinical Infectious Diseases<\/i> <b>47<\/b> (11): 1443-8. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1086%2F593098\" target=\"_blank\">10.1086\/593098<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/18954267\" target=\"_blank\">18954267<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Using+internet+searches+for+influenza+surveillance&rft.jtitle=Clinical+Infectious+Diseases&rft.aulast=Polgreen%2C+P.M.%3B+Chen%2C+Y.%3B+Pennock%2C+D.M.+et+al.&rft.au=Polgreen%2C+P.M.%3B+Chen%2C+Y.%3B+Pennock%2C+D.M.+et+al.&rft.date=2008&rft.volume=47&rft.issue=11&rft.pages=1443-8&rft_id=info:doi\/10.1086%2F593098&rft_id=info:pmid\/18954267&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-GinsbergDetect09-14\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-GinsbergDetect09_14-0\">14.0<\/a><\/sup> <sup><a href=\"#cite_ref-GinsbergDetect09_14-1\">14.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Ginsberg, J.; Mohebbi, M.H.; Patel, R.S. et al. (2009). \"Detecting influenza epidemics using search engine query data\". <i>Nature<\/i> <b>457<\/b> (7232): 1012-4. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1038%2Fnature07634\" target=\"_blank\">10.1038\/nature07634<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/19020500\" target=\"_blank\">19020500<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Detecting+influenza+epidemics+using+search+engine+query+data&rft.jtitle=Nature&rft.aulast=Ginsberg%2C+J.%3B+Mohebbi%2C+M.H.%3B+Patel%2C+R.S.+et+al.&rft.au=Ginsberg%2C+J.%3B+Mohebbi%2C+M.H.%3B+Patel%2C+R.S.+et+al.&rft.date=2009&rft.volume=457&rft.issue=7232&rft.pages=1012-4&rft_id=info:doi\/10.1038%2Fnature07634&rft_id=info:pmid\/19020500&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-SignoriniTheUse11-15\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-SignoriniTheUse11_15-0\">15.0<\/a><\/sup> <sup><a href=\"#cite_ref-SignoriniTheUse11_15-1\">15.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Signorini, A.; Segre, A.M.; Polgreen, P.M. et al. (2011). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3087759\" target=\"_blank\">\"The use of Twitter to track levels of disease activity and public concern in the U.S. during the influenza A H1N1 pandemic\"<\/a>. <i>PLoS One<\/i> <b>6<\/b> (5): e19467. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1371%2Fjournal.pone.0019467\" target=\"_blank\">10.1371\/journal.pone.0019467<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC3087759\/\" target=\"_blank\">PMC3087759<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/21573238\" target=\"_blank\">21573238<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3087759\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3087759<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=The+use+of+Twitter+to+track+levels+of+disease+activity+and+public+concern+in+the+U.S.+during+the+influenza+A+H1N1+pandemic&rft.jtitle=PLoS+One&rft.aulast=Signorini%2C+A.%3B+Segre%2C+A.M.%3B+Polgreen%2C+P.M.+et+al.&rft.au=Signorini%2C+A.%3B+Segre%2C+A.M.%3B+Polgreen%2C+P.M.+et+al.&rft.date=2011&rft.volume=6&rft.issue=5&rft.pages=e19467&rft_id=info:doi\/10.1371%2Fjournal.pone.0019467&rft_id=info:pmc\/PMC3087759&rft_id=info:pmid\/21573238&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC3087759&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ShamanReal13-16\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-ShamanReal13_16-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Shaman, J.; Karspeck, A.; Yang, W. et al. (2013). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3873365\" target=\"_blank\">\"Real-time influenza forecasts during the 2012-2013 season\"<\/a>. <i>Nature Communications<\/i> <b>4<\/b>: 2837. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1038%2Fncomms3837\" target=\"_blank\">10.1038\/ncomms3837<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC3873365\/\" target=\"_blank\">PMC3873365<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/24302074\" target=\"_blank\">24302074<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3873365\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC3873365<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Real-time+influenza+forecasts+during+the+2012-2013+season&rft.jtitle=Nature+Communications&rft.aulast=Shaman%2C+J.%3B+Karspeck%2C+A.%3B+Yang%2C+W.+et+al.&rft.au=Shaman%2C+J.%3B+Karspeck%2C+A.%3B+Yang%2C+W.+et+al.&rft.date=2013&rft.volume=4&rft.pages=2837&rft_id=info:doi\/10.1038%2Fncomms3837&rft_id=info:pmc\/PMC3873365&rft_id=info:pmid\/24302074&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC3873365&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-GenerousGlobal14-17\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-GenerousGlobal14_17-0\">17.0<\/a><\/sup> <sup><a href=\"#cite_ref-GenerousGlobal14_17-1\">17.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Generous, N.; Fairchild, G.; Deshpande, A. et al. (2014). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4231164\" target=\"_blank\">\"Global disease monitoring and forecasting with Wikipedia\"<\/a>. <i>PLoS Computational Biology<\/i> <b>10<\/b> (11): e1003892. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1371%2Fjournal.pcbi.1003892\" target=\"_blank\">10.1371\/journal.pcbi.1003892<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC4231164\/\" target=\"_blank\">PMC4231164<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/25392913\" target=\"_blank\">25392913<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4231164\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4231164<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Global+disease+monitoring+and+forecasting+with+Wikipedia&rft.jtitle=PLoS+Computational+Biology&rft.aulast=Generous%2C+N.%3B+Fairchild%2C+G.%3B+Deshpande%2C+A.+et+al.&rft.au=Generous%2C+N.%3B+Fairchild%2C+G.%3B+Deshpande%2C+A.+et+al.&rft.date=2014&rft.volume=10&rft.issue=11&rft.pages=e1003892&rft_id=info:doi\/10.1371%2Fjournal.pcbi.1003892&rft_id=info:pmc\/PMC4231164&rft_id=info:pmid\/25392913&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC4231164&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-HickmannFore15-18\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-HickmannFore15_18-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Hickmann, K.S.; Fairchild, G.; Priedhorsky, R. et al. (2015). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4431683\" target=\"_blank\">\"Forecasting the 2013-2014 influenza season using Wikipedia\"<\/a>. <i>PLoS Computational Biology<\/i> <b>11<\/b> (5): e1004239. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1371%2Fjournal.pcbi.1004239\" target=\"_blank\">10.1371\/journal.pcbi.1004239<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC4431683\/\" target=\"_blank\">PMC4431683<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/25974758\" target=\"_blank\">25974758<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4431683\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC4431683<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Forecasting+the+2013-2014+influenza+season+using+Wikipedia&rft.jtitle=PLoS+Computational+Biology&rft.aulast=Hickmann%2C+K.S.%3B+Fairchild%2C+G.%3B+Priedhorsky%2C+R.+et+al.&rft.au=Hickmann%2C+K.S.%3B+Fairchild%2C+G.%3B+Priedhorsky%2C+R.+et+al.&rft.date=2015&rft.volume=11&rft.issue=5&rft.pages=e1004239&rft_id=info:doi\/10.1371%2Fjournal.pcbi.1004239&rft_id=info:pmc\/PMC4431683&rft_id=info:pmid\/25974758&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC4431683&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-FairchildElicit15-19\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-FairchildElicit15_19-0\">19.0<\/a><\/sup> <sup><a href=\"#cite_ref-FairchildElicit15_19-1\">19.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Fairchild, G.; Del Valle, S.Y.; De Silva, L. et al. (2015). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5511739\" target=\"_blank\">\"Eliciting Disease Data from Wikipedia Articles\"<\/a>. <i>Proceedings of the 2015 International AAAI Conference on Weblogs and Social Media<\/i>: 26\u201333. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC5511739\/\" target=\"_blank\">PMC5511739<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/28721308\" target=\"_blank\">28721308<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5511739\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5511739<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Eliciting+Disease+Data+from+Wikipedia+Articles&rft.jtitle=Proceedings+of+the+2015+International+AAAI+Conference+on+Weblogs+and+Social+Media&rft.aulast=Fairchild%2C+G.%3B+Del+Valle%2C+S.Y.%3B+De+Silva%2C+L.+et+al.&rft.au=Fairchild%2C+G.%3B+Del+Valle%2C+S.Y.%3B+De+Silva%2C+L.+et+al.&rft.date=2015&rft.pages=26%E2%80%9333&rft_id=info:pmc\/PMC5511739&rft_id=info:pmid\/28721308&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC5511739&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-STROBEState18-20\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-STROBEState18_20-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">STROBE Initiative. <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.strobe-statement.org\/\" target=\"_blank\">\"STROBE Statement\"<\/a>. University of Bern<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.strobe-statement.org\/\" target=\"_blank\">https:\/\/www.strobe-statement.org\/<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 01 October 2018<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=STROBE+Statement&rft.atitle=&rft.aulast=STROBE+Initiative&rft.au=STROBE+Initiative&rft.pub=University+of+Bern&rft_id=https%3A%2F%2Fwww.strobe-statement.org%2F&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-CDISC18-21\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-CDISC18_21-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Clinical Data Interchange Standards Consortium. <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.cdisc.org\/\" target=\"_blank\">\"CDISC\"<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.cdisc.org\/\" target=\"_blank\">https:\/\/www.cdisc.org\/<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 01 October 2018<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=CDISC&rft.atitle=&rft.aulast=Clinical+Data+Interchange+Standards+Consortium&rft.au=Clinical+Data+Interchange+Standards+Consortium&rft_id=https%3A%2F%2Fwww.cdisc.org%2F&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-PisaniSharing10-22\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-PisaniSharing10_22-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Pisani, E.; AbouZahr, C. (2010). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2878150\" target=\"_blank\">\"Sharing health data: Good intentions are not enough\"<\/a>. <i>Bulletin of the World Health Organization<\/i> <b>88<\/b> (6): 462\u20136. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.2471%2FBLT.09.074393\" target=\"_blank\">10.2471\/BLT.09.074393<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC2878150\/\" target=\"_blank\">PMC2878150<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/20539861\" target=\"_blank\">20539861<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2878150\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC2878150<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Sharing+health+data%3A+Good+intentions+are+not+enough&rft.jtitle=Bulletin+of+the+World+Health+Organization&rft.aulast=Pisani%2C+E.%3B+AbouZahr%2C+C.&rft.au=Pisani%2C+E.%3B+AbouZahr%2C+C.&rft.date=2010&rft.volume=88&rft.issue=6&rft.pages=462%E2%80%936&rft_id=info:doi\/10.2471%2FBLT.09.074393&rft_id=info:pmc\/PMC2878150&rft_id=info:pmid\/20539861&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC2878150&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-EdelsteinOvercoming15-23\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-EdelsteinOvercoming15_23-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Edelstein, M.; Sane, J. (17 April 2015). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.chathamhouse.org\/publication\/overcoming-barriers-data-sharing-public-health-global-perspective\" target=\"_blank\">\"Overcoming Barriers to Data Sharing in Public Health: A Global Perspective\"<\/a>. <i>Chatham House<\/i><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.chathamhouse.org\/publication\/overcoming-barriers-data-sharing-public-health-global-perspective\" target=\"_blank\">https:\/\/www.chathamhouse.org\/publication\/overcoming-barriers-data-sharing-public-health-global-perspective<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Overcoming+Barriers+to+Data+Sharing+in+Public+Health%3A+A+Global+Perspective&rft.atitle=Chatham+House&rft.aulast=Edelstein%2C+M.%3B+Sane%2C+J.&rft.au=Edelstein%2C+M.%3B+Sane%2C+J.&rft.date=17+April+2015&rft_id=https%3A%2F%2Fwww.chathamhouse.org%2Fpublication%2Fovercoming-barriers-data-sharing-public-health-global-perspective&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ZentgrafWhat15-24\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-ZentgrafWhat15_24-0\">24.0<\/a><\/sup> <sup><a href=\"#cite_ref-ZentgrafWhat15_24-1\">24.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation web\">Zentgraf, D.C. (27 April 2015). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/kunststube.net\/encoding\/\" target=\"_blank\">\"What Every Programmer Absolutely, Positively Needs To Know About Encodings And Character Sets To Work With Text\"<\/a>. <i>Kunststube<\/i><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/kunststube.net\/encoding\/\" target=\"_blank\">http:\/\/kunststube.net\/encoding\/<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 23 August 2016<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=What+Every+Programmer+Absolutely%2C+Positively+Needs+To+Know+About+Encodings+And+Character+Sets+To+Work+With+Text&rft.atitle=Kunststube&rft.aulast=Zentgraf%2C+D.C.&rft.au=Zentgraf%2C+D.C.&rft.date=27+April+2015&rft_id=http%3A%2F%2Fkunststube.net%2Fencoding%2F&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-AtwoodTheGreat10-25\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-AtwoodTheGreat10_25-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Atwood, J. (18 January 2010). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/blog.codinghorror.com\/the-great-newline-schism\/\" target=\"_blank\">\"The Great Newline Schism\"<\/a>. <i>Coding Horror<\/i><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/blog.codinghorror.com\/the-great-newline-schism\/\" target=\"_blank\">https:\/\/blog.codinghorror.com\/the-great-newline-schism\/<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 01 October 2016<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=The+Great+Newline+Schism&rft.atitle=Coding+Horror&rft.aulast=Atwood%2C+J.&rft.au=Atwood%2C+J.&rft.date=18+January+2010&rft_id=https%3A%2F%2Fblog.codinghorror.com%2Fthe-great-newline-schism%2F&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-MHIWeekly16-26\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-MHIWeekly16_26-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Ministry of Health Isreal. <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.health.gov.il\/UnitsOffice\/HD\/PH\/epidemiology\/Pages\/epidemiology_report.aspx?WPID=WPQ7&PN=1\" target=\"_blank\">\"Weekly and Periodic Epidemiological Reports\"<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.health.gov.il\/UnitsOffice\/HD\/PH\/epidemiology\/Pages\/epidemiology_report.aspx?WPID=WPQ7&PN=1\" target=\"_blank\">https:\/\/www.health.gov.il\/UnitsOffice\/HD\/PH\/epidemiology\/Pages\/epidemiology_report.aspx?WPID=WPQ7&PN=1<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 04 September 2016<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Weekly+and+Periodic+Epidemiological+Reports&rft.atitle=&rft.aulast=Ministry+of+Health+Isreal&rft.au=Ministry+of+Health+Isreal&rft_id=https%3A%2F%2Fwww.health.gov.il%2FUnitsOffice%2FHD%2FPH%2Fepidemiology%2FPages%2Fepidemiology_report.aspx%3FWPID%3DWPQ7%26PN%3D1&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ADoHNotifications16-27\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-ADoHNotifications16_27-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Australian Government Department of Health. <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www9.health.gov.au\/cda\/source\/rpt_1_sel.cfm\" target=\"_blank\">\"Notifications of all diseases by Month\"<\/a>. <i>National Notifiable Diseases Surveillance System<\/i><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www9.health.gov.au\/cda\/source\/rpt_1_sel.cfm\" target=\"_blank\">http:\/\/www9.health.gov.au\/cda\/source\/rpt_1_sel.cfm<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 04 September 2016<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Notifications+of+all+diseases+by+Month&rft.atitle=National+Notifiable+Diseases+Surveillance+System&rft.aulast=Australian+Government+Department+of+Health&rft.au=Australian+Government+Department+of+Health&rft_id=http%3A%2F%2Fwww9.health.gov.au%2Fcda%2Fsource%2Frpt_1_sel.cfm&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-RKISurvStat-28\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-RKISurvStat_28-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Robert Koch Institute. <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/survstat.rki.de\/\" target=\"_blank\">\"SurvStat@RKI 2.0\"<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/survstat.rki.de\/\" target=\"_blank\">https:\/\/survstat.rki.de\/<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 04 September 2016<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=SurvStat%40RKI+2.0&rft.atitle=&rft.aulast=Robert+Koch+Institute&rft.au=Robert+Koch+Institute&rft_id=https%3A%2F%2Fsurvstat.rki.de%2F&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-CoelhoEpidemi16-29\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-CoelhoEpidemi16_29-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Coelho, F.C.; Code\u00e7o, C.T.; Cruz, O.G. et al. (2016). \"Epidemiological data accessibility in Brazil\". <i>The Lancet Infectious Diseases<\/i> <b>16<\/b> (5): 524\u20135. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2FS1473-3099%2816%2930007-X\" target=\"_blank\">10.1016\/S1473-3099(16)30007-X<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/27068487\" target=\"_blank\">27068487<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Epidemiological+data+accessibility+in+Brazil&rft.jtitle=The+Lancet+Infectious+Diseases&rft.aulast=Coelho%2C+F.C.%3B+Code%C3%A7o%2C+C.T.%3B+Cruz%2C+O.G.+et+al.&rft.au=Coelho%2C+F.C.%3B+Code%C3%A7o%2C+C.T.%3B+Cruz%2C+O.G.+et+al.&rft.date=2016&rft.volume=16&rft.issue=5&rft.pages=524%E2%80%935&rft_id=info:doi\/10.1016%2FS1473-3099%2816%2930007-X&rft_id=info:pmid\/27068487&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-MSEpidemArch-30\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-MSEpidemArch_30-0\">30.0<\/a><\/sup> <sup><a href=\"#cite_ref-MSEpidemArch_30-1\">30.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation web\">Minist\u00e9rio da Sa\u00fade. <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/web.archive.org\/web\/20160703011414\/http:\/\/www.combateaedes.saude.gov.br\/en\/epidemiological-situation\" target=\"_blank\">\"Epidemiological Situation\"<\/a>. <i>Preventing and combating Dengue, Chikungunya e Zika<\/i>. Archived from <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.combateaedes.saude.gov.br\/en\/epidemiological-situation\" target=\"_blank\">the original<\/a> on 03 July 2016<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/web.archive.org\/web\/20160703011414\/http:\/\/www.combateaedes.saude.gov.br\/en\/epidemiological-situation\" target=\"_blank\">https:\/\/web.archive.org\/web\/20160703011414\/http:\/\/www.combateaedes.saude.gov.br\/en\/epidemiological-situation<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 19 January 2017<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Epidemiological+Situation&rft.atitle=Preventing+and+combating+Dengue%2C+Chikungunya+e+Zika&rft.aulast=Minist%C3%A9rio+da+Sa%C3%BAde&rft.au=Minist%C3%A9rio+da+Sa%C3%BAde&rft_id=https%3A%2F%2Fweb.archive.org%2Fweb%2F20160703011414%2Fhttp%3A%2F%2Fwww.combateaedes.saude.gov.br%2Fen%2Fepidemiological-situation&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-MSBoletins-31\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-MSBoletins_31-0\">31.0<\/a><\/sup> <sup><a href=\"#cite_ref-MSBoletins_31-1\">31.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation web\">Minist\u00e9rio da Sa\u00fade. <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.saude.gov.br\/boletins-epidemiologicos\" target=\"_blank\">\"Boletins epidemiol\u00f3gicos\"<\/a>. Governo do Brasil<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.saude.gov.br\/boletins-epidemiologicos\" target=\"_blank\">https:\/\/www.saude.gov.br\/boletins-epidemiologicos<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 19 January 2017<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Boletins+epidemiol%C3%B3gicos&rft.atitle=&rft.aulast=Minist%C3%A9rio+da+Sa%C3%BAde&rft.au=Minist%C3%A9rio+da+Sa%C3%BAde&rft.pub=Governo+do+Brasil&rft_id=https%3A%2F%2Fwww.saude.gov.br%2Fboletins-epidemiologicos&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ApacheOffice-32\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-ApacheOffice_32-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\"><a rel=\"external_link\" class=\"external text\" href=\"https:\/\/wiki.openoffice.org\/wiki\/Office_Open_XML\" target=\"_blank\">\"Office Open XML\"<\/a>. <i>The Apache OpenOffice Wiki<\/i><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/wiki.openoffice.org\/wiki\/Office_Open_XML\" target=\"_blank\">https:\/\/wiki.openoffice.org\/wiki\/Office_Open_XML<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 18 August 2016<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Office+Open+XML&rft.atitle=The+Apache+OpenOffice+Wiki&rft_id=https%3A%2F%2Fwiki.openoffice.org%2Fwiki%2FOffice_Open_XML&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-GeoJSON-33\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-GeoJSON_33-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">GeoJSON Workgroup. <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/geojson.org\/\" target=\"_blank\">\"GeoJSON\"<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/geojson.org\/\" target=\"_blank\">https:\/\/geojson.org\/<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 22 August 2016<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=GeoJSON&rft.atitle=&rft.aulast=GeoJSON+Workgroup&rft.au=GeoJSON+Workgroup&rft_id=https%3A%2F%2Fgeojson.org%2F&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-TopoJSON-34\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-TopoJSON_34-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\"><a rel=\"external_link\" class=\"external text\" href=\"https:\/\/github.com\/topojson\/topojson\" target=\"_blank\">\"topojson\/topojson\"<\/a>. <i>GitHub<\/i><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/github.com\/topojson\/topojson\" target=\"_blank\">https:\/\/github.com\/topojson\/topojson<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 22 August 2016<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=topojson%2Ftopojson&rft.atitle=GitHub&rft_id=https%3A%2F%2Fgithub.com%2Ftopojson%2Ftopojson&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-FinnieEpiJSON16-35\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-FinnieEpiJSON16_35-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Finnie, T.J.; South, A.; Bento, A. et al. (2016). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7104924\" target=\"_blank\">\"EpiJSON: A unified data-format for epidemiology\"<\/a>. <i>Epidemics<\/i> <b>15<\/b>: 20\u20136. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.epidem.2015.12.002\" target=\"_blank\">10.1016\/j.epidem.2015.12.002<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC7104924\/\" target=\"_blank\">PMC7104924<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/27266846\" target=\"_blank\">27266846<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7104924\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC7104924<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=EpiJSON%3A+A+unified+data-format+for+epidemiology&rft.jtitle=Epidemics&rft.aulast=Finnie%2C+T.J.%3B+South%2C+A.%3B+Bento%2C+A.+et+al.&rft.au=Finnie%2C+T.J.%3B+South%2C+A.%3B+Bento%2C+A.+et+al.&rft.date=2016&rft.volume=15&rft.pages=20%E2%80%936&rft_id=info:doi\/10.1016%2Fj.epidem.2015.12.002&rft_id=info:pmc\/PMC7104924&rft_id=info:pmid\/27266846&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC7104924&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-RepiJSON-36\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-RepiJSON_36-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\"><a rel=\"external_link\" class=\"external text\" href=\"https:\/\/github.com\/Hackout2\/repijson\" target=\"_blank\">\"Hackout2\/repijson\"<\/a>. <i>GitHub<\/i><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/github.com\/Hackout2\/repijson\" target=\"_blank\">https:\/\/github.com\/Hackout2\/repijson<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 23 October 2018<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Hackout2%2Frepijson&rft.atitle=GitHub&rft_id=https%3A%2F%2Fgithub.com%2FHackout2%2Frepijson&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-KhusroOnMethods14-37\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-KhusroOnMethods14_37-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Khusro, S.; Latif, A.; Ullah, I. (2014). \"On methods and tools of table detection, extraction and annotation in PDF documents\". <i>Journal of Information Science<\/i> <b>41<\/b> (1): 41\u201357. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1177%2F0165551514551903\" target=\"_blank\">10.1177\/0165551514551903<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=On+methods+and+tools+of+table+detection%2C+extraction+and+annotation+in+PDF+documents&rft.jtitle=Journal+of+Information+Science&rft.aulast=Khusro%2C+S.%3B+Latif%2C+A.%3B+Ullah%2C+I.&rft.au=Khusro%2C+S.%3B+Latif%2C+A.%3B+Ullah%2C+I.&rft.date=2014&rft.volume=41&rft.issue=1&rft.pages=41%E2%80%9357&rft_id=info:doi\/10.1177%2F0165551514551903&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-PDoHStatistics-38\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-PDoHStatistics_38-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Department of Health. \"Statistics\". Republic of the Phillipines.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Statistics&rft.atitle=&rft.aulast=Department+of+Health&rft.au=Department+of+Health&rft.pub=Republic+of+the+Phillipines&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-PDoHDengue15-39\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-PDoHDengue15_39-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Epidemiology Bureau, Department of Health (05 July 2015). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.doh.gov.ph\/sites\/default\/files\/statistics\/dengueMw26.compressed.pdf\" target=\"_blank\">\"Dengue Cases - Morbidity Week 26 - June 26\u2013July 4, 2015\"<\/a> (PDF). Republic of the Phillipines<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.doh.gov.ph\/sites\/default\/files\/statistics\/dengueMw26.compressed.pdf\" target=\"_blank\">http:\/\/www.doh.gov.ph\/sites\/default\/files\/statistics\/dengueMw26.compressed.pdf<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 13 December 2016<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Dengue+Cases+-+Morbidity+Week+26+-+June+26%E2%80%93July+4%2C+2015&rft.atitle=&rft.aulast=Epidemiology+Bureau%2C+Department+of+Health&rft.au=Epidemiology+Bureau%2C+Department+of+Health&rft.date=05+July+2015&rft.pub=Republic+of+the+Phillipines&rft_id=http%3A%2F%2Fwww.doh.gov.ph%2Fsites%2Fdefault%2Ffiles%2Fstatistics%2FdengueMw26.compressed.pdf&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-PDoHDiphtheria16-40\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-PDoHDiphtheria16_40-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Epidemiology Bureau, Department of Health (27 March 2016). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.doh.gov.ph\/sites\/default\/files\/statistics\/DIPHTHERIA%20MW12.pdf\" target=\"_blank\">\"Diphtheria Cases - Morbidity Week 12 - January 1\u2013March 26, 2016\"<\/a> (PDF). Republic of the Phillipines<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.doh.gov.ph\/sites\/default\/files\/statistics\/DIPHTHERIA%20MW12.pdf\" target=\"_blank\">http:\/\/www.doh.gov.ph\/sites\/default\/files\/statistics\/DIPHTHERIA%20MW12.pdf<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 13 December 2016<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Diphtheria+Cases+-+Morbidity+Week+12+-+January+1%E2%80%93March+26%2C+2016&rft.atitle=&rft.aulast=Epidemiology+Bureau%2C+Department+of+Health&rft.au=Epidemiology+Bureau%2C+Department+of+Health&rft.date=27+March+2016&rft.pub=Republic+of+the+Phillipines&rft_id=http%3A%2F%2Fwww.doh.gov.ph%2Fsites%2Fdefault%2Ffiles%2Fstatistics%2FDIPHTHERIA%2520MW12.pdf&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-DavisUnicode12-41\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-DavisUnicode12_41-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Davis, M. (03 February 2012). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/googleblog.blogspot.com\/2012\/02\/unicode-over-60-percent-of-web.html\" target=\"_blank\">\"Unicode over 60 percent of the web\"<\/a>. <i>Google Official Blog<\/i><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/googleblog.blogspot.com\/2012\/02\/unicode-over-60-percent-of-web.html\" target=\"_blank\">https:\/\/googleblog.blogspot.com\/2012\/02\/unicode-over-60-percent-of-web.html<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 23 August 2016<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Unicode+over+60+percent+of+the+web&rft.atitle=Google+Official+Blog&rft.aulast=Davis%2C+M.&rft.au=Davis%2C+M.&rft.date=03+February+2012&rft_id=https%3A%2F%2Fgoogleblog.blogspot.com%2F2012%2F02%2Funicode-over-60-percent-of-web.html&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-W3TechsUsage16-42\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-W3TechsUsage16_42-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">W3Techs. <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/w3techs.com\/technologies\/overview\/character_encoding\" target=\"_blank\">\"Usage statistics of character encodings for websites\"<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/w3techs.com\/technologies\/overview\/character_encoding\" target=\"_blank\">https:\/\/w3techs.com\/technologies\/overview\/character_encoding<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 23 August 2016<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Usage+statistics+of+character+encodings+for+websites&rft.atitle=&rft.aulast=W3Techs&rft.au=W3Techs&rft_id=https%3A%2F%2Fw3techs.com%2Ftechnologies%2Foverview%2Fcharacter_encoding&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-CDC_MMWR-43\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-CDC_MMWR_43-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">U.S. Centers for Disease Control and Prevention. <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/wwwn.cdc.gov\/nndss\/document\/MMWR_week_overview.pdf\" target=\"_blank\">\"<i>MMWR<\/i> Weeks\"<\/a> (PDF)<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/wwwn.cdc.gov\/nndss\/document\/MMWR_week_overview.pdf\" target=\"_blank\">https:\/\/wwwn.cdc.gov\/nndss\/document\/MMWR_week_overview.pdf<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 22 August 2016<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=%27%27MMWR%27%27+Weeks&rft.atitle=&rft.aulast=U.S.+Centers+for+Disease+Control+and+Prevention&rft.au=U.S.+Centers+for+Disease+Control+and+Prevention&rft_id=https%3A%2F%2Fwwwn.cdc.gov%2Fnndss%2Fdocument%2FMMWR_week_overview.pdf&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-TexasHHS2014-44\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-TexasHHS2014_44-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Texas Department of State Health Services. <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.dshs.texas.gov\/idcu\/disease\/influenza\/surveillance\/2015\/\" target=\"_blank\">\"2014 - 2015 Texas Influenza Surveillance Activity Report\"<\/a>. Texas HHS<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.dshs.texas.gov\/idcu\/disease\/influenza\/surveillance\/2015\/\" target=\"_blank\">https:\/\/www.dshs.texas.gov\/idcu\/disease\/influenza\/surveillance\/2015\/<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 20 December 2016<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=2014+-+2015+Texas+Influenza+Surveillance+Activity+Report&rft.atitle=&rft.aulast=Texas+Department+of+State+Health+Services&rft.au=Texas+Department+of+State+Health+Services&rft.pub=Texas+HHS&rft_id=https%3A%2F%2Fwww.dshs.texas.gov%2Fidcu%2Fdisease%2Finfluenza%2Fsurveillance%2F2015%2F&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-NIIDCalendar12-45\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-NIIDCalendar12_45-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">National Institute of Infectious Diseases. <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.niid.go.jp\/niid\/en\/survei\/2225-idwr\/calendar\/6113-idwr-calendar-e-2016.html\" target=\"_blank\">\"Weeks Ending Log 2016\"<\/a>. Government of Japan<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.niid.go.jp\/niid\/en\/survei\/2225-idwr\/calendar\/6113-idwr-calendar-e-2016.html\" target=\"_blank\">https:\/\/www.niid.go.jp\/niid\/en\/survei\/2225-idwr\/calendar\/6113-idwr-calendar-e-2016.html<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 13 December 2016<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Weeks+Ending+Log+2016&rft.atitle=&rft.aulast=National+Institute+of+Infectious+Diseases&rft.au=National+Institute+of+Infectious+Diseases&rft.pub=Government+of+Japan&rft_id=https%3A%2F%2Fwww.niid.go.jp%2Fniid%2Fen%2Fsurvei%2F2225-idwr%2Fcalendar%2F6113-idwr-calendar-e-2016.html&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-NIPHPEpidem1_16-46\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-NIPHPEpidem1_16_46-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">National Institute of Public Health Poland (May 2016). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/wwwold.pzh.gov.pl\/oldpage\/epimeld\/grypa\/2016\/I_16_05A.pdf\" target=\"_blank\">\"Influenza and influenza-like illness in Poland, 5A\"<\/a> (PDF)<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/wwwold.pzh.gov.pl\/oldpage\/epimeld\/grypa\/2016\/I_16_05A.pdf\" target=\"_blank\">http:\/\/wwwold.pzh.gov.pl\/oldpage\/epimeld\/grypa\/2016\/I_16_05A.pdf<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 13 December 2016<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Influenza+and+influenza-like+illness+in+Poland%2C+5A&rft.atitle=&rft.aulast=National+Institute+of+Public+Health+Poland&rft.au=National+Institute+of+Public+Health+Poland&rft.date=May+2016&rft_id=http%3A%2F%2Fwwwold.pzh.gov.pl%2Foldpage%2Fepimeld%2Fgrypa%2F2016%2FI_16_05A.pdf&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-NIPHPEpidem2_16-47\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-NIPHPEpidem2_16_47-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">National Institute of Public Health Poland (May 2016). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/wwwold.pzh.gov.pl\/oldpage\/epimeld\/grypa\/2016\/I_16_05B.pdf\" target=\"_blank\">\"Influenza and influenza-like illness in Poland, 5B\"<\/a> (PDF)<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/wwwold.pzh.gov.pl\/oldpage\/epimeld\/grypa\/2016\/I_16_05B.pdf\" target=\"_blank\">http:\/\/wwwold.pzh.gov.pl\/oldpage\/epimeld\/grypa\/2016\/I_16_05B.pdf<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 13 December 2016<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Influenza+and+influenza-like+illness+in+Poland%2C+5B&rft.atitle=&rft.aulast=National+Institute+of+Public+Health+Poland&rft.au=National+Institute+of+Public+Health+Poland&rft.date=May+2016&rft_id=http%3A%2F%2Fwwwold.pzh.gov.pl%2Foldpage%2Fepimeld%2Fgrypa%2F2016%2FI_16_05B.pdf&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-NIPHPEpidem3_16-48\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-NIPHPEpidem3_16_48-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">National Institute of Public Health Poland (May 2016). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/wwwold.pzh.gov.pl\/oldpage\/epimeld\/grypa\/2016\/I_16_05C.pdf\" target=\"_blank\">\"Influenza and influenza-like illness in Poland, 5C\"<\/a> (PDF)<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/wwwold.pzh.gov.pl\/oldpage\/epimeld\/grypa\/2016\/I_16_05C.pdf\" target=\"_blank\">http:\/\/wwwold.pzh.gov.pl\/oldpage\/epimeld\/grypa\/2016\/I_16_05C.pdf<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 13 December 2016<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Influenza+and+influenza-like+illness+in+Poland%2C+5C&rft.atitle=&rft.aulast=National+Institute+of+Public+Health+Poland&rft.au=National+Institute+of+Public+Health+Poland&rft.date=May+2016&rft_id=http%3A%2F%2Fwwwold.pzh.gov.pl%2Foldpage%2Fepimeld%2Fgrypa%2F2016%2FI_16_05C.pdf&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-NIPHPEpidem4_16-49\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-NIPHPEpidem4_16_49-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">National Institute of Public Health Poland (May 2016). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/wwwold.pzh.gov.pl\/oldpage\/epimeld\/grypa\/2016\/I_16_05D.pdf\" target=\"_blank\">\"Influenza and influenza-like illness in Poland, 5D\"<\/a> (PDF)<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/wwwold.pzh.gov.pl\/oldpage\/epimeld\/grypa\/2016\/I_16_05D.pdf\" target=\"_blank\">http:\/\/wwwold.pzh.gov.pl\/oldpage\/epimeld\/grypa\/2016\/I_16_05D.pdf<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 13 December 2016<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Influenza+and+influenza-like+illness+in+Poland%2C+5D&rft.atitle=&rft.aulast=National+Institute+of+Public+Health+Poland&rft.au=National+Institute+of+Public+Health+Poland&rft.date=May+2016&rft_id=http%3A%2F%2Fwwwold.pzh.gov.pl%2Foldpage%2Fepimeld%2Fgrypa%2F2016%2FI_16_05D.pdf&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-Guzman-HerradorOutbreak11-50\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-Guzman-HerradorOutbreak11_50-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Guzman-Herrador, B.; Heier, B.; Osborg, E. et al. (2011). \"Outbreak of norovirus infection in a hotel in Oslo, Norway, January 2011\". <i>Euro Suveillance<\/i> <b>16<\/b> (30): 19928. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/21813081\" target=\"_blank\">21813081<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Outbreak+of+norovirus+infection+in+a+hotel+in+Oslo%2C+Norway%2C+January+2011&rft.jtitle=Euro+Suveillance&rft.aulast=Guzman-Herrador%2C+B.%3B+Heier%2C+B.%3B+Osborg%2C+E.+et+al.&rft.au=Guzman-Herrador%2C+B.%3B+Heier%2C+B.%3B+Osborg%2C+E.+et+al.&rft.date=2011&rft.volume=16&rft.issue=30&rft.pages=19928&rft_id=info:pmid\/21813081&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-MayetFood11-51\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-MayetFood11_51-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Mayet, A.; Andreo, V.; Bedubourg, G. et al. (2011). \"Food-borne outbreak of norovirus infection in a French military parachuting unit, April 2011\". <i>Euro Suveillance<\/i> <b>16<\/b> (30): 19930. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/21813082\" target=\"_blank\">21813082<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Food-borne+outbreak+of+norovirus+infection+in+a+French+military+parachuting+unit%2C+April+2011&rft.jtitle=Euro+Suveillance&rft.aulast=Mayet%2C+A.%3B+Andreo%2C+V.%3B+Bedubourg%2C+G.+et+al.&rft.au=Mayet%2C+A.%3B+Andreo%2C+V.%3B+Bedubourg%2C+G.+et+al.&rft.date=2011&rft.volume=16&rft.issue=30&rft.pages=19930&rft_id=info:pmid\/21813082&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-FairchildImproving14-52\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-FairchildImproving14_52-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Fairchild, G.C. (2014). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/ir.uiowa.edu\/etd\/1452\/\" target=\"_blank\">\"Improving disease surveillance: Sentinel surveillance network design and novel uses of Wikipedia\"<\/a>. <i>PhD (Doctor of Philosophy) thesis<\/i>. University of Iowa. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.17077%2Fetd.sfbu328x\" target=\"_blank\">10.17077\/etd.sfbu328x<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/ir.uiowa.edu\/etd\/1452\/\" target=\"_blank\">https:\/\/ir.uiowa.edu\/etd\/1452\/<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Improving+disease+surveillance%3A+Sentinel+surveillance+network+design+and+novel+uses+of+Wikipedia&rft.atitle=PhD+%28Doctor+of+Philosophy%29+thesis&rft.aulast=Fairchild%2C+G.C.&rft.au=Fairchild%2C+G.C.&rft.date=2014&rft.pub=University+of+Iowa&rft_id=info:doi\/10.17077%2Fetd.sfbu328x&rft_id=https%3A%2F%2Fir.uiowa.edu%2Fetd%2F1452%2F&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-AguileraHetero03-53\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-AguileraHetero03_53-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Aguilera, J.F.; Paget, W.J.; Mosnier, A. et al. (2003). \"Heterogeneous case definitions used for the surveillance of influenza in Europe\". <i>European Journal of Epidemiology<\/i> <b>18<\/b> (8): 751\u20134. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1023%2Fa%3A1025337616327\" target=\"_blank\">10.1023\/a:1025337616327<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/12974549\" target=\"_blank\">12974549<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Heterogeneous+case+definitions+used+for+the+surveillance+of+influenza+in+Europe&rft.jtitle=European+Journal+of+Epidemiology&rft.aulast=Aguilera%2C+J.F.%3B+Paget%2C+W.J.%3B+Mosnier%2C+A.+et+al.&rft.au=Aguilera%2C+J.F.%3B+Paget%2C+W.J.%3B+Mosnier%2C+A.+et+al.&rft.date=2003&rft.volume=18&rft.issue=8&rft.pages=751%E2%80%934&rft_id=info:doi\/10.1023%2Fa%3A1025337616327&rft_id=info:pmid\/12974549&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-WHOCase14-54\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-WHOCase14_54-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">World Health Organization (09 August 2014). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/www.who.int\/csr\/resources\/publications\/ebola\/ebola-case-definition-contact-en.pdf\" target=\"_blank\">\"Case defintion recommendations for ebola or Marburg virus diseases\"<\/a> (PDF). World Health Organization<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/www.who.int\/csr\/resources\/publications\/ebola\/ebola-case-definition-contact-en.pdf\" target=\"_blank\">https:\/\/www.who.int\/csr\/resources\/publications\/ebola\/ebola-case-definition-contact-en.pdf<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 10 January 2017<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Case+defintion+recommendations+for+ebola+or+Marburg+virus+diseases&rft.atitle=&rft.aulast=World+Health+Organization&rft.au=World+Health+Organization&rft.date=09+August+2014&rft.pub=World+Health+Organization&rft_id=https%3A%2F%2Fwww.who.int%2Fcsr%2Fresources%2Fpublications%2Febola%2Febola-case-definition-contact-en.pdf&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-TBEThailandNative16-55\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-TBEThailandNative16_55-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Thailand Bureau of Epidemiology (2016). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/203.157.15.110\/boe\/\" target=\"_blank\">\"Thailand Bureau of Epidemiology\"<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/203.157.15.110\/boe\/\" target=\"_blank\">http:\/\/203.157.15.110\/boe\/<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 23 August 2016<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Thailand+Bureau+of+Epidemiology&rft.atitle=&rft.aulast=Thailand+Bureau+of+Epidemiology&rft.au=Thailand+Bureau+of+Epidemiology&rft.date=2016&rft_id=http%3A%2F%2F203.157.15.110%2Fboe%2F&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-TBEThailandEnglish16-56\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-TBEThailandEnglish16_56-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Thailand Bureau of Epidemiology (2016). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/203.157.15.110\/boeeng\/\" target=\"_blank\">\"Thailand Bureau of Epidemiology - English\"<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/203.157.15.110\/boeeng\/\" target=\"_blank\">http:\/\/203.157.15.110\/boeeng\/<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 23 August 2016<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Thailand+Bureau+of+Epidemiology+-+English&rft.atitle=&rft.aulast=Thailand+Bureau+of+Epidemiology&rft.au=Thailand+Bureau+of+Epidemiology&rft.date=2016&rft_id=http%3A%2F%2F203.157.15.110%2Fboeeng%2F&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-IGSDisease-57\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-IGSDisease_57-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Institute for Genome Sciences, University of Maryland School of Medicine. <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/disease-ontology.org\/\" target=\"_blank\">\"Disease Ontology\"<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/disease-ontology.org\/\" target=\"_blank\">https:\/\/disease-ontology.org\/<\/a><\/span><span class=\"reference-accessdate\">. Retrieved 01 October 2018<\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=Disease+Ontology&rft.atitle=&rft.aulast=Institute+for+Genome+Sciences%2C+University+of+Maryland+School+of+Medicine&rft.au=Institute+for+Genome+Sciences%2C+University+of+Maryland+School+of+Medicine&rft_id=https%3A%2F%2Fdisease-ontology.org%2F&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-FarrowAHuman17-58\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-FarrowAHuman17_58-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Farrow, D.C.; Brooks, L.C.; Hyun, S. et al. (2017). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5345757\" target=\"_blank\">\"A human judgment approach to epidemiological forecasting\"<\/a>. <i>PLoS Computational Biology<\/i> <b>13<\/b> (3): e1005248. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1371%2Fjournal.pcbi.1005248\" target=\"_blank\">10.1371\/journal.pcbi.1005248<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC5345757\/\" target=\"_blank\">PMC5345757<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/28282375\" target=\"_blank\">28282375<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5345757\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5345757<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=A+human+judgment+approach+to+epidemiological+forecasting&rft.jtitle=PLoS+Computational+Biology&rft.aulast=Farrow%2C+D.C.%3B+Brooks%2C+L.C.%3B+Hyun%2C+S.+et+al.&rft.au=Farrow%2C+D.C.%3B+Brooks%2C+L.C.%3B+Hyun%2C+S.+et+al.&rft.date=2017&rft.volume=13&rft.issue=3&rft.pages=e1005248&rft_id=info:doi\/10.1371%2Fjournal.pcbi.1005248&rft_id=info:pmc\/PMC5345757&rft_id=info:pmid\/28282375&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC5345757&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-OsthusDynamic19-59\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-OsthusDynamic19_59-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Osthus, D.; Gattiker, J.; Priedhorsky, R. et al. (2019). \"Dynamic Bayesian Influenza Forecasting in the United States with Hierarchical Discrepancy (with Discussion)\". <i>Bayesian Analysis<\/i> <b>14<\/b> (1): 261\u2013312. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1214%2F18-BA1117\" target=\"_blank\">10.1214\/18-BA1117<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Dynamic+Bayesian+Influenza+Forecasting+in+the+United+States+with+Hierarchical+Discrepancy+%28with+Discussion%29&rft.jtitle=Bayesian+Analysis&rft.aulast=Osthus%2C+D.%3B+Gattiker%2C+J.%3B+Priedhorsky%2C+R.+et+al.&rft.au=Osthus%2C+D.%3B+Gattiker%2C+J.%3B+Priedhorsky%2C+R.+et+al.&rft.date=2019&rft.volume=14&rft.issue=1&rft.pages=261%E2%80%93312&rft_id=info:doi\/10.1214%2F18-BA1117&rfr_id=info:sid\/en.wikipedia.org:Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<\/ol><\/div>\n<h2><span class=\"mw-headline\" id=\"Notes\">Notes<\/span><\/h2>\n<p>This presentation is faithful to the original, with only a few minor changes to presentation. In some cases important information was missing from the references, and that information was added. Footnotes in the original were turned into external links for this version. Where a URL from the original was found to no longer work, an archived version of the page was cited. In the case of the Thailand Bureau of Epidemiology sites, an archive of neither could be found.\n<\/p>\n<!-- \nNewPP limit report\nCached time: 20200707205044\nCache expiry: 86400\nDynamic content: false\nCPU time usage: 1.132 seconds\nReal time usage: 2.553 seconds\nPreprocessor visited node count: 42217\/1000000\nPreprocessor generated node count: 38924\/1000000\nPost\u2010expand include size: 323110\/2097152 bytes\nTemplate argument size: 108751\/2097152 bytes\nHighest expansion depth: 18\/40\nExpensive parser function count: 0\/100\n-->\n\n<!-- \nTransclusion expansion time report (%,ms,calls,template)\n100.00% 981.984 1 - -total\n 90.41% 887.779 1 - Template:Reflist\n 78.88% 774.632 59 - Template:Citation\/core\n 41.38% 406.328 27 - Template:Cite_journal\n 40.74% 400.034 32 - Template:Cite_web\n 5.98% 58.756 62 - Template:Citation\/identifier\n 4.62% 45.415 70 - Template:Citation\/make_link\n 4.40% 43.202 1 - Template:Infobox_journal_article\n 4.25% 41.775 1 - Template:Infobox\n 2.96% 29.095 80 - Template:Infobox\/row\n-->\n\n<!-- Saved in parser cache with key limswiki:pcache:idhash:11891-0!*!0!!en!5!* and timestamp 20200707205041 and revision id 39163\n -->\n<\/div><div class=\"printfooter\">Source: <a rel=\"external_link\" class=\"external\" href=\"https:\/\/www.limswiki.org\/index.php\/Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards\">https:\/\/www.limswiki.org\/index.php\/Journal:Epidemiological_data_challenges:_Planning_for_a_more_robust_future_through_data_standards<\/a><\/div>\n\t\t\t\t\t\t\t\t\t\t<!-- end content -->\n\t\t\t\t\t\t\t\t\t\t<div class=\"visualClear\"><\/div>\n\t\t\t\t<\/div>\n\t\t\t<\/div>\n\t\t<\/div>\n\t\t<!-- end of the left (by default at least) column -->\n\t\t<div class=\"visualClear\"><\/div>\n\t\t\t\t\t\n\t\t<\/div>\n\t\t\n\n<\/body>","38f2f0437c54887eb841f892d039cb99_images":["https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/0\/01\/Fig1_Fairchild_FrontPubHealth2018_6.jpg","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/9\/9c\/Fig2_Fairchild_FrontPubHealth2018_6.jpg","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/a\/a9\/Fig3_Fairchild_FrontPubHealth2018_6.jpg","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/7\/7a\/Fig4_Fairchild_FrontPubHealth2018_6.jpg","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/9\/98\/Fig5_Fairchild_FrontPubHealth2018_6.jpg"],"38f2f0437c54887eb841f892d039cb99_timestamp":1594155041,"dbbafbdedf3c364c6925d8378915086c_type":"article","dbbafbdedf3c364c6925d8378915086c_title":"Strengthening public health surveillance through blockchain technology (Bhattacharya et al. 2019)","dbbafbdedf3c364c6925d8378915086c_url":"https:\/\/www.limswiki.org\/index.php\/Journal:Strengthening_public_health_surveillance_through_blockchain_technology","dbbafbdedf3c364c6925d8378915086c_plaintext":"\n\n\t\t\n\t\t\t\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t\n\n\t\t\t\tJournal:Strengthening public health surveillance through blockchain technology\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t\tFrom LIMSWiki\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\tJump to: navigation, search\n\n\t\t\t\t\t\n\t\t\t\t\tFull article title\n \nStrengthening public health surveillance through blockchain technologyJournal\n \nAIMS Public HealthAuthor(s)\n \nBhattacharya, Sudip; Singh, Amarjeet; Hossain, Md MahbubAuthor affiliation(s)\n \nHimalayan Institute of Medical Sciences, Postgraduate Institute of Medical Education and Research,\r\nTexas A & M UniversityPrimary contact\n \nEmail: docbilu at gmail dot comYear published\n \n2019Volume and issue\n \n6(3)Page(s)\n \n326-333DOI\n \n10.3934\/publichealth.2019.3.326ISSN\n \n2327-8994Distribution license\n \nCreative Commons Attribution 4.0 InternationalWebsite\n \nhttp:\/\/www.aimspress.com\/article\/10.3934\/publichealth.2019.3.326Download\n \nhttp:\/\/www.aimspress.com\/article\/10.3934\/publichealth.2019.3.326\/pdf (PDF)\n\nContents\n\n1 Abstract \n2 Introduction \n3 Blockchain and its applications \n4 Types and uses of blockchain \n5 Blockchain technology in healthcare \n6 Limitations \n7 Discussions and conclusions \n8 Acknowledgements \n\n8.1 Conflict of interest \n\n\n9 References \n10 Notes \n\n\n\nAbstract \nBlockchain technology is a decentralized system of recording data and performing transactions which is increasingly being used across many industries, including healthcare. It has several unique features like the validation of transaction processes, prevention of systems failure from any single point of transaction, and approval of data sharing with optimal security, to name a few. At the hospital level, blockchain technologies are used in electronic medical records systems, insurance claims systems, billing management processes, and so on. Moreover, this technology is helpful to manage logistic and human resources to achieve the quality of care in learning health systems. In many countries, blockchain is being used to promote patient-centered care by sharing patient data for remote monitoring and management. Furthermore, blockchain technology has the potential to strengthen disease surveillance systems in cases of disease outbreaks resulting in local and global health emergencies. In such conditions, blockchain can be used to identify health security concerns, analyze preventive measures, and facilitate decision-making processes to act rapidly and effectively. Despite its limitations, research, and practice based on blockchain technology have shown promises to strengthen health systems around the world, with a potential to reduce the global burden of diseases, mortality, morbidity, and economic costs.\nKeywords: blockchain technology, telemedicine, medical informatics, disease outbreaks, population surveillance\n\nIntroduction \nIn the twenty-first century, many scientific innovations have changed the means of day-to-day communication, transactions, and decision-making. Blockchain is such a technology, which is being considered as one of the most significant inventions since the development of the internet.[1] It is also popularly termed as the next generation of \u201cinternet of things.\u201d[2] The rise of Bitcoin and other cryptocurrencies have certainly helped blockchain to gain the spotlight across the globe. However, experts believe that blockchain is more than cryptocurrencies and that it may offer greater benefits to the users of complex systems.[1][3] Blockchain technology is commonly used for online money transfers and bank payments. It is also used in automobile manufacturing, cybersecurity, exit poll development, educational endevors, insurance systems, and time trend forecasting.[4] Recently, blockchain technology has gained popularity several other domains, including health systems. This is because it offers a safer and decentralized database that can operate independently from a centralized administrator.[3] According to Angraal et al., a unique selling point of the blockchain system is that once digital validation takes place, the network itself streamlines and validates the subsequent process of transaction. It safeguards the transaction history and allows data to be transferred directly between third parties.[5]\nIn this article, we discuss how blockchain technology works and how it can be used in complex situations like strengthening public health surveillance.\n\nBlockchain and its applications \nA blockchain is defined as \u201ca distributed system (decentralized) which performs the dual function of recording and storing the records of the transaction. In this blockchain, the data is located in a network of personal computers called \u2018nodes\u2019 without any central control.\u201d (Figure 1). The main advantage of this decentralized technology is that all the dealings or variations in the data are captured with real-time updates across the network.[6] The information that gets stored in each node is similar and permanent. It can't be distorted. Hence, this technology is transparent and autonomous, and as such it improves the quality of shared data between different stakeholders.[7] In this system, to validate the transaction, cryptographic algorithms are used.[8] This is different from a \u201ctrust-in-the-third-party\u201d mechanism, where an online transaction takes place when two willing parties approve the transaction by use of a digital signature.[2] Moreover, blockchain overcomes the challenge of \u201csingle point failure,\u201d which is common in centralized information management systems.[9] Currently, however, the average centralized healthcare system lacks the advantages offered by blockchain, including transparency and trust, data security and privacy, cost-effectiveness, and verifiability of data, as well as fast and real-time data transfer to all trusted parties.[10]\n\r\n\n\n\n\n\n\n\n\n\n\n Figure 1. Centralized (a) and decentralized network (b)\n\n\n\nTypes and uses of blockchain \nThere are two main types of blockchains:\n1. Open-access blockchains, which makes all records visible to the stakeholders; and\n2. Limited-access blockchains, which restricts the access of data\/information.[11]\nOpen-access blockchains are more appropriate to the health sector. Presently, cryptocurrency such as Bitcoin (some of the most popular applications of blockchain technology) depends on this type of technology.[12]\n\nBlockchain technology in healthcare \nBlockchain has commonly been used in four primary ways in healthcare: in electronic medical record (EMR) implementations at the hospital level, for resource management in health systems, for patient-level applications, and for disease surveillance at the community level.\n1. Hospitals and EMRs: Blockchain is one of the popular technologies used in EMRs found in modern hospital ecosystems in industrialized nations. Blockchain's ability to improve decentralization, data provenance, and robustness has made it suitable for storing, managing, and sharing protected health information in EMRs.[13] For example, an electronic health chain (or interoperable health blockchain) could be based on a blockchain-based EMR system which uses IBM's Hyperledger Fabric modular blockchain framework.[14] This technology helps to achieve scalable data security and optimize the performance of the EMR system. Arguably, blockchain may also be considered for improving transactions in billing and managing insurance claims, as well as surveillance measures like nosocomial infection surveillance.[14] The advantage of this technology is that a lot of data can rapidly be stored, processed, and shared with stakeholders without any link failure\/delay.[15] According to Peterson et al., it can also reform health database interoperability with built-in authentication controls, which lowers the risk of data theft.[12]\n2. Resource management in health systems: Blockchain can facilitate managing logistics and human resources in healthcare systems. For example, counterfeit medications and instruments below standard can be supplied to healthcare systems from external vendors. Use of blockchain can validate the quality standards at different nodes of the supply chain and inform the respective authorities about suspected discrepancies.[16] Moreover, human resource management in the digital age requires storing and using employee data for attendance, vacation scheduling, performance appraisal, and security measures with complex authentication processes. Use of blockchain can make such processes efficient and contribute to the development of smarter health services organizations.\n3. Patient-level applications: Due to its decentralized features protecting data safety concerns, blockchain is increasingly being used to share health data with patients and their caregivers. Such patient empowerment initiatives are also fostering meaningful use of health information technology and improving patient-provider communication across digital platforms.[17] Furthermore, blockchain-based mHealth interventions are enabling remote patient monitoring through use of biosensors, thus bridging the access gaps in patient-level health services.[18]\n4. Community disease surveillance: Surveillance is defined as the \u201csystematic, ongoing collection, collation, and analysis of data and the timely dissemination of information to those who need to know so that the action can be taken.\u201d[19] It is done for both communicable diseases and non-communicable diseases by all national health systems according to their national priorities as per WHO's International Health Regulations (IHR). For example, deadly viruses like Nipah can travel across the globe within 36 hours and may lead to a pandemic, further compromised by rapid and uncontrolled urbanization and globalization.[20] Communicable disease surveillance is an ongoing, complex, and inefficient process, because a huge number of self-regulating organizations report to a centralized information system. As such, it remains a challenging task to maintain seamless information flow in a timely manner.[21][22] Moreover, sufficient incentive is rarely provided to routine staff. \nThe sequence of events that occur after a healthcare worker reports a potential case is depicted in Figure 2.\n\r\n\n\n\n\n\n\n\n\n\n\n Figure 2. Sequence of events in disease surveillance system\n\n\n\nBlockchain could help independent organizations to manage data more efficiently during pandemics.[23] It could also help track information for ongoing public health emergencies, like road traffic accidents, illicit drug use, opioid misuse, and so on.[24] When blockchain technology is used in a public health domain, these networks might be able to automate secure data sharing and storage at different levels of healthcare organizations.\nThis technology has a potential to give real-time data\/information by sensing potential outbreaks or bioterrorism. Hence, if vaccinations, antibiotics, and other disease control measures are instituted promptly, massive casualties can be prevented. For example, fake news on social media against vaccination have critically impacted public health in recent years.[25] Huckle and White reported a blockchain-based approach to identify the origins of such harmful content and identify the population at risk in digital communication.[26] This highlights the potential of blockchain to improve public health surveillance in the era of digitalization.\nToday many countries use machine learning techniques in surveillance. However, there are certain unique and added advantages of blockchain technology over machine learning techniques. For example, blockchain predominantly blocks malicious activities, like data hacking and duplication.[27] Additionally, the combination of blockchain technology with artificial intelligence (AI) is the proverbial \"cherry on top\" for the medical research and health sectors.[28]\nThere is also tremendous scope for integration with geographic information systems (GIS) to expedite routine epidemic investigations, as well as drug and vaccine supply chain management. The other critical aspect is that by ensuring transparency and correct reporting, as in the case of reporting deaths from an outbreak, blockchain overcomes the existing limitations of local health information systems. The following illustration (Figure 3) shows how the application of blockchain in surveillance systems enhances activities for ensuring health security.\n\r\n\n\n\n\n\n\n\n\n\n\n Figure 3. Application of block chain in surveillance system\n\n\n\nAs shown in Figure 3, the disease control actions of prevention, detection, and response, aided by blockchain, have their scope broadened for real-time surveillance and detection of non-communicable diseases (NCD). This also lends to the goals of the Global Health Security Agenda (GHSA) and its Action Package working groups.[29]\nBy applying real-time surveillance, defining and tracking the early risk factors for NCDs can be improved. Additionally, by building up the capacity of medical units, the challenges of emergency response can be overcome through effective supply chain systems.[30] A summary of other NCD real-time surveillance activities within the framework of the GHSA are shown in Table 1.\n\n\n\n\n\n\n\nTable 1. Real time surveillance for NCDs within the Global Health Security Agenda\n\n\nGHSA category\n\nGHSA action package\n\nNCD-related activity\n\n\nDetect\n\nReal-time surveillance\n\n\n1. Strengthen cancer registries\r\n\n2. Support tobacco use surveillance\r\n\n3. Birth defects surveillance due to zika virus\r\n\n4. Include NCD indicators in current surveillance systems\r\n\n5. Support inclusion of electronic medical records\r\n\n6. Implement for health data\n\n\n\n\nLimitations \nBlockchain technology has several limitations which include use of the technology without adequate security and privacy measures, lack of frameworks for implementation and regulation, and concerns for cost-effectiveness and interoperability.[31] These challenges can be overcome by gradual improvements in scalability and upgradeability.\n\nDiscussions and conclusions \nThe case of Taiwan is an excellent example of the application of this revolutionary blockchain technology.[32] In Estonia, the complete public health infrastructure is being operated using blockchain.[33] Other examples include countries such as the United Kingdom, United States, and Canada, where such real-time surveillance systems have been implemented in many of their departments. In England, at the national level, they have implemented it in their Emergency Department Syndromic Surveillance System (EDSSS). Emergency department syndromic surveillance has also been implemented by Canada at the regional level. Another excellent example of this application is the European Antimicrobial Resistance Surveillance Network.[23][34] Hence, we may conclude that blockchain applications can retain the prime characteristics of ideal disease surveillance. It can be more effective and rapid than traditional surveillance in terms of coverage, durability, consensus, selective privacy, uniqueness, and timing. Blockchain technology holds great promise in overpopulated and low-income countries like India, Pakistan, and Africa (where the health systems are prone to epidemic and pandemic) by strengthening the capacity of the countries with simplified early warning surveillance for diseases of epidemic potential by reducing the mortality, morbidity, and economic costs. It is high time to incorporate blockchain technology within the existing surveillance systems of at least low-income countries in order to strengthen their health systems.\n\nAcknowledgements \nWe acknowledge all the present and previous authors (working in the field of blockchain technology, especially Dr Vijay Kumar Chattu), contributors and sources, who helped us directly or indirectly for preparing this manuscript. All the authors had contributed equally during preparation of this manuscript (concept, design, literature review, and editing).\n\nConflict of interest \nAll authors declare no conflicts of interest in this paper.\n\nReferences \n\n\n\u2191 1.0 1.1 Chen, G.; Xu, B.; Lu, M. et al. (2018). \"Exploring blockchain technology and its potential applications for education\". Smart Learning Environments 5: 1. doi:10.1186\/s40561-017-0050-x.   \n\n\u2191 2.0 2.1 Alam, T. (2019). \"IoT-Fog: A Communication Framework using Blockchain in the Internet of Things\". International Journal of Recent Technology and Engineering 7 (6): 833-838. http:\/\/www.ijrte.org\/download\/volume-7-issue-6\/ .   \n\n\u2191 3.0 3.1 Meinert, E.; Alturkistani, A.; Foley, K.A. et al. (2019). \"Blockchain Implementation in Health Care: Protocol for a Systematic Review\". JMIR Research Protocols 8 (2): e10994. doi:10.2196\/10994. PMC PMC6384534. PMID 30735146. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6384534 .   \n\n\u2191 Campbell-Verduyn, M. (2017). Bitcoin and Beyond: Cryptocurrencies, Blockchains, and Global Governance. Routledge. pp. 221. ISBN 9780415792141.   \n\n\u2191 Angraal, S.; Krumholz, H.M.; Schulz, W.L. et al. (2017). \"Blockchain Technology: Applications in Health Care\". Circulation: Cardiovascular Quality and Outcomes 10 (9): e003800. doi:10.1161\/CIRCOUTCOMES.117.003800. PMID 28912202.   \n\n\u2191 Rathee, G.; Sharma, A.; Kumar, R. et al. (2019). \"A Secure Communicating Things Network Framework for Industrial IoT using Blockchain Technology\". Ad Hoc Networks 94: 101933. doi:10.1016\/j.adhoc.2019.101933.   \n\n\u2191 Crosby, M.; Nachiappan; Pattenayak, P. et al. (2016). \"BlockChain Technology: Beyond Bitcoin\" (PDF). Applied Innovation Review (2): 6\u201319. http:\/\/scet.berkeley.edu\/wp-content\/uploads\/AIR-2016-Blockchain.pdf .   \n\n\u2191 Sharma, A.; Kumar, R. (2019). \"Service-Level Agreement\u2014Energy Cooperative Quickest Ambulance Routing for Critical Healthcare Services\". Arabian Journal for Science and Engineering 44: 3831\u20133848. doi:10.1007\/s13369-018-3687-z.   \n\n\u2191 Li, I.-C.; Liao, T.-C. (2017). \"A Survey of Blockchain Security Issues and Challenges\". International Journal of Network Security 19 (5): 653\u2013659. doi:10.6633\/IJNS.201709.19(5).01.   \n\n\u2191 Vazirani, A.A.; O'Donoghue, O.; Brindley, D. et al. (2019). \"Implementing Blockchains for Efficient Health Care: Systematic Review\". Journal of Medical Internet Research 21 (2): e12439. doi:10.2196\/12439. PMC PMC6390185. PMID 30747714. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6390185 .   \n\n\u2191 Beck, R.; Avital, M.; Rossi, M. et al. (2017). \"Blockchain Technology in Business and Information Systems Research\". Business & Information Systems Engineering 59: 381\u201384. doi:10.1007\/s12599-017-0505-1.   \n\n\u2191 12.0 12.1 Peterson, K. (September 2016). \"A Blockchain-Based Approach to Health Information Exchange Networks\". Use of Blockchain in Healthcare and Research Workshop. https:\/\/oncprojectracking.healthit.gov\/wiki\/display\/TechLabI\/Use+of+Blockchain+in+Healthcare+and+Research+Workshop .   \n\n\u2191 Sharma, A.; Kumar, R. (2017). \"An optimal routing scheme for critical healthcare HTH services \u2014 An IOT perspective\". Proceedings from the Fourth International Conference on Image Information Processing: 1\u20135. doi:10.1109\/ICIIP.2017.8313784.   \n\n\u2191 14.0 14.1 Roman-Belmonte, J.M.; De la Corte-Rodriguez, H.; Rodriguez-Merchan, E.C. (2018). \"How blockchain technology can change medicine\". Postgraduate Medicine 130 (4): 420-427. doi:10.1080\/00325481.2018.1472996. PMID 29727247.   \n\n\u2191 Ekblaw, A.; Azaria, A.; Halamka, J.D. et al. (August 2016). \"A Case Study for Blockchain in Healthcare: \u201cMedRec\u201d prototype for electronic health records and medical research data\". 2nd International Conference on Open & Big Data 2016. pp. 1\u201313. https:\/\/dci.mit.edu\/research\/blockchain-medical-records .   \n\n\u2191 Tseng, J.H.; Liao, Y.C.; Chong, B. et al. (2018). \"Governance on the Drug Supply Chain via Gcoin Blockchain\". International Journal of Environmental Research and Public Health 15 (6): E1055. doi:10.3390\/ijerph15061055. PMC PMC6025275. PMID 29882861. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6025275 .   \n\n\u2191 Engelhardt, M.A. (2017). \"Hitching Healthcare to the Chain: An Introduction to Blockchain Technology in the Healthcare Sector\". Technology Innovation Management Review 7 (10): 22\u201334. doi:10.22215\/timreview\/1111.   \n\n\u2191 Saravanan, M.; Shubha, R.; Marks, A.M. et al. (2017). \"SMEAD: A secured mobile enabled assisting device for diabetics monitoring\". Proceedings of the 2017 IEEE International Conference on Advanced Networks and Telecommunications Systems: 1\u20136. doi:10.1109\/ANTS.2017.8384099.   \n\n\u2191 Last, J.M., ed. (2001). \"A Dictionary of Epidemiology\". Oxford University Press. ISBN 9780195141696. https:\/\/books.google.com\/books?id=RPaQY8cG4N4C .   \n\n\u2191 Fan, V.Y.; Jamison, D.T.; Summers, L.H. (2018). \"Pandemic risk: how large are the expected losses?\". Bulletin of the World Health Organization 96 (2): 129\u201334. doi:10.2471\/BLT.17.199588.   \n\n\u2191 Islam, N.; Faheem, Y.; Din, I.U. et al. (2019). \"A blockchain-based fog computing framework for activity recognition as an application to e-Healthcare services\". Future Generation Computer Systems 100: 569\u201378. doi:10.1016\/j.future.2019.05.059.   \n\n\u2191 Khan, S.U.; Islam, N.; Jan, Z. et al. (2019). \"An e-Health care services framework for the detection and classification of breast cancer in breast cytology images as an IoMT application\". Future Generation Computer Systems 98: 286\u201396. doi:10.1016\/j.future.2019.01.033.   \n\n\u2191 23.0 23.1 Chattu, V.K.; Nanda, A.; Chattu, S.K. et al. (2019). \"The Emerging Role of Blockchain Technology Applications in Routine Disease Surveillance Systems to Strengthen Global Health Security\". Big Data and Cognitive Computing 3 (2): 25. doi:10.3390\/bdcc3020025.   \n\n\u2191 Katuwal, G.J.; Pandey, S.; Hennessey, M. et al. (2018). \"Applications of Blockchain in Healthcare: Current Landscape & Challenges\". arXiv: 1\u201317. https:\/\/arxiv.org\/abs\/1812.02776 .   \n\n\u2191 Jervelund, S.S. (2018). \"How social media is transforming the spreading of knowledge: Implications for our perceptions concerning vaccinations and migrant health\". Scandanavian Journal of Public Health 46 (2): 167-169. doi:10.1177\/1403494818760139.   \n\n\u2191 Huckle, S.; White, M. (2017). \"Fake News: A Technological Approach to Proving the Origins of Content, Using Blockchains\". Big Data 5 (4): 356\u201371. doi:10.1089\/big.2017.0071.   \n\n\u2191 Rahouti, M.; Xiong, K.; Ghani, N. (2018). \"Bitcoin Concepts, Threats, and Machine-Learning Security Solutions\". IEEE Access 6: 67189-67205. doi:10.1109\/ACCESS.2018.2874539.   \n\n\u2191 Mamoshina, P.; Ojomoko, L.; Yanovich, Y. et al. (2017). \"Converging blockchain and next-generation artificial intelligence technologies to decentralize and accelerate biomedical research and healthcare\". Oncotarget 9 (5): 5665-5690. doi:10.18632\/oncotarget.22345. PMC PMC5814166. PMID 29464026. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5814166 .   \n\n\u2191 Global Health Security Agenda (2019). \"About the GHSA\". https:\/\/ghsagenda.org\/home\/about-the-ghsa\/ .   \n\n\u2191 Kostova, D.; Husain, M.J.; Sugerman, D. et al. (2017). \"Synergies between Communicable and Noncommunicable Disease Programs to Enhance Global Health Security\". Emerging Infectious Diseases 23 (13): S40\u2013S46. doi:10.3201\/eid2313.170581. PMC PMC5711304. PMID 29155655. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5711304 .   \n\n\u2191 Boulos, M.N.K.; Wilson, J.T.; Clauson, K.A. (2018). \"Geospatial blockchain: Promises, challenges, and scenarios in health and healthcare\". International Journal of Health Geographics 17: 25. doi:10.1186\/s12942-018-0144-x.   \n\n\u2191 Jian, S.W.; Chen, C.M.; Lee, C.Y. et al. (2017). \"Real-Time Surveillance of Infectious Diseases: Taiwan's Experience\". Health Security 15 (2): 144\u201353. doi:10.1089\/hs.2016.0107. PMC 28418738. PMID PMC5404256. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=28418738 .   \n\n\u2191 Mettler, M. (2016). \"Blockchain technology in healthcare: The revolution starts here\". Proceedings of the 2016 IEEE 18th International Conference on e-Health Networking, Applications and Services: 1\u20133. doi:10.1109\/HealthCom.2016.7749510.   \n\n\u2191 Abat, C.; Chaudet, H.; Colson, P. et al. (2015). \"Real-Time Microbiology Laboratory Surveillance System to Detect Abnormal Events and Emerging Infections, Marseille, France\". Emergency Infectious Diseases 21 (8): 1302-10. doi:10.3201\/eid2108.141419. PMC 26196165. PMID PMC4517727. http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=26196165 .   \n\n\nNotes \nThis presentation is faithful to the original, with only a few minor changes to presentation. In some cases important information was missing from the references, and that information was added. A reference was added for the GHSA in this version.\n\n\n\n\n\n\nSource: <a rel=\"external_link\" class=\"external\" href=\"https:\/\/www.limswiki.org\/index.php\/Journal:Strengthening_public_health_surveillance_through_blockchain_technology\">https:\/\/www.limswiki.org\/index.php\/Journal:Strengthening_public_health_surveillance_through_blockchain_technology<\/a>\n\t\t\t\t\tCategories: LIMSwiki journal articles (added in 2020)LIMSwiki journal articles (all)LIMSwiki journal articles on cybersecurityLIMSwiki journal articles on epidemiologyLIMSwiki journal articles on public health informatics\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\n\t\t\t\t\n\t\t\t\n\t\t\n\t\t\n\t\t\tNavigation menu\n\t\t\t\t\t\n\t\t\tViews\n\n\t\t\t\n\t\t\t\t\n\t\t\t\tJournal\n\t\t\t\tDiscussion\n\t\t\t\tView source\n\t\t\t\tHistory\n\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\n\t\t\t\t\n\t\t\t\tPersonal tools\n\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\t\t\tLog in\n\t\t\t\t\t\t\t\t\t\t\t\t\tRequest account\n\t\t\t\t\t\t\t\t\t\t\t\n\t\t\t\t\n\t\t\t\n\t\t\t\n\t\t\t\t\n\t\t\t\n\t\t\t\t\n\t\tNavigation\n\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\tMain page\n\t\t\t\t\t\t\t\t\t\t\tRecent changes\n\t\t\t\t\t\t\t\t\t\t\tRandom page\n\t\t\t\t\t\t\t\t\t\t\tHelp\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\n\t\t\t\n\t\t\tSearch\n\n\t\t\t\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t \n\t\t\t\t\t\t\n\t\t\t\t\n\n\t\t\t\t\t\t\t\n\t\t\n\t\t\t\n\t\t\tTools\n\n\t\t\t\n\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\tWhat links here\n\t\t\t\t\t\t\t\t\t\t\tRelated changes\n\t\t\t\t\t\t\t\t\t\t\tSpecial pages\n\t\t\t\t\t\t\t\t\t\t\tPermanent link\n\t\t\t\t\t\t\t\t\t\t\tPage information\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\n\t\t\n\t\tPrint\/export\n\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\tCreate a book\n\t\t\t\t\t\t\t\t\t\t\tDownload as PDF\n\t\t\t\t\t\t\t\t\t\t\tDownload as Plain text\n\t\t\t\t\t\t\t\t\t\t\tPrintable version\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\n\t\t\n\t\tSponsors\n\t\t\n\t\t\t \r\n\n\t\r\n\n\t\r\n\n\t\n\t\r\n\n\t\r\n\n\t\n\t\r\n\n \n\t\r\n\n\t\n\t\r\n\n \n\t\n\t\r\n\n\t\n\t\n\t\r\n\n\t\r\n\n\t\r\n\n\t\n\t\r\n\n\t\r\n\t\t\n\t\t\n\t\t\t\n\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t This page was last modified on 12 May 2020, at 17:36.\n\t\t\t\t\t\t\t\t\tThis page has been accessed 747 times.\n\t\t\t\t\t\t\t\t\tContent is available under a Creative Commons Attribution-ShareAlike 4.0 International License unless otherwise noted.\n\t\t\t\t\t\t\t\t\tPrivacy policy\n\t\t\t\t\t\t\t\t\tAbout LIMSWiki\n\t\t\t\t\t\t\t\t\tDisclaimers\n\t\t\t\t\t\t\t\n\t\t\n\t\t\n\t\t\n\n","dbbafbdedf3c364c6925d8378915086c_html":"<body class=\"mediawiki ltr sitedir-ltr ns-206 ns-subject page-Journal_Strengthening_public_health_surveillance_through_blockchain_technology skin-monobook action-view\">\n<div id=\"rdp-ebb-globalWrapper\">\n\t\t<div id=\"rdp-ebb-column-content\">\n\t\t\t<div id=\"rdp-ebb-content\" class=\"mw-body\" role=\"main\">\n\t\t\t\t<a id=\"rdp-ebb-top\"><\/a>\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t<h1 id=\"rdp-ebb-firstHeading\" class=\"firstHeading\" lang=\"en\">Journal:Strengthening public health surveillance through blockchain technology<\/h1>\n\t\t\t\t\n\t\t\t\t<div id=\"rdp-ebb-bodyContent\" class=\"mw-body-content\">\n\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\n\n\t\t\t\t\t<!-- start content -->\n\t\t\t\t\t<div id=\"rdp-ebb-mw-content-text\" lang=\"en\" dir=\"ltr\" class=\"mw-content-ltr\">\n\n\n<h2><span class=\"mw-headline\" id=\"Abstract\">Abstract<\/span><\/h2>\n<p><a href=\"https:\/\/www.limswiki.org\/index.php\/Blockchain\" title=\"Blockchain\" class=\"wiki-link\" data-key=\"ae8b186c311716aca561aaee91944f8e\">Blockchain<\/a> technology is a decentralized system of recording data and performing transactions which is increasingly being used across many industries, including healthcare. It has several unique features like the validation of transaction processes, prevention of systems failure from any single point of transaction, and approval of data sharing with optimal security, to name a few. At the <a href=\"https:\/\/www.limswiki.org\/index.php\/Hospital\" title=\"Hospital\" class=\"wiki-link\" data-key=\"b8f070c66d8123fe91063594befebdff\">hospital<\/a> level, blockchain technologies are used in <a href=\"https:\/\/www.limswiki.org\/index.php\/Electronic_medical_record\" title=\"Electronic medical record\" class=\"wiki-link\" data-key=\"99a695d2af23397807da0537d29d0be7\">electronic medical records<\/a> systems, insurance claims systems, billing management processes, and so on. Moreover, this technology is helpful to manage logistic and human resources to achieve the quality of care in learning health systems. In many countries, blockchain is being used to promote patient-centered care by sharing patient data for <a href=\"https:\/\/www.limswiki.org\/index.php\/Remote_patient_monitoring\" title=\"Remote patient monitoring\" class=\"wiki-link\" data-key=\"459438aa577ac442814a6c6946908980\">remote monitoring<\/a> and management. Furthermore, blockchain technology has the potential to strengthen disease surveillance systems in cases of disease outbreaks resulting in local and global health emergencies. In such conditions, blockchain can be used to identify health security concerns, analyze preventive measures, and facilitate decision-making processes to act rapidly and effectively. Despite its limitations, research, and practice based on blockchain technology have shown promises to strengthen health systems around the world, with a potential to reduce the global burden of diseases, mortality, morbidity, and economic costs.\n<\/p><p><b>Keywords<\/b>: blockchain technology, telemedicine, medical informatics, disease outbreaks, population surveillance\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Introduction\">Introduction<\/span><\/h2>\n<p>In the twenty-first century, many scientific innovations have changed the means of day-to-day communication, transactions, and decision-making. <a href=\"https:\/\/www.limswiki.org\/index.php\/Blockchain\" title=\"Blockchain\" class=\"wiki-link\" data-key=\"ae8b186c311716aca561aaee91944f8e\">Blockchain<\/a> is such a technology, which is being considered as one of the most significant inventions since the development of the internet.<sup id=\"rdp-ebb-cite_ref-ChenExploring18_1-0\" class=\"reference\"><a href=\"#cite_note-ChenExploring18-1\">[1]<\/a><\/sup> It is also popularly termed as the next generation of \u201c<a href=\"https:\/\/www.limswiki.org\/index.php\/Internet_of_things\" title=\"Internet of things\" class=\"wiki-link\" data-key=\"13e0b826fa1770fe4bea72e3cb942f0f\">internet of things<\/a>.\u201d<sup id=\"rdp-ebb-cite_ref-AlamIoT18_2-0\" class=\"reference\"><a href=\"#cite_note-AlamIoT18-2\">[2]<\/a><\/sup> The rise of Bitcoin and other cryptocurrencies have certainly helped blockchain to gain the spotlight across the globe. However, experts believe that blockchain is more than cryptocurrencies and that it may offer greater benefits to the users of complex systems.<sup id=\"rdp-ebb-cite_ref-ChenExploring18_1-1\" class=\"reference\"><a href=\"#cite_note-ChenExploring18-1\">[1]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-MeinertBlock19_3-0\" class=\"reference\"><a href=\"#cite_note-MeinertBlock19-3\">[3]<\/a><\/sup> Blockchain technology is commonly used for online money transfers and bank payments. It is also used in automobile manufacturing, <a href=\"https:\/\/www.limswiki.org\/index.php\/Cybersecurity\" title=\"Cybersecurity\" class=\"mw-redirect wiki-link\" data-key=\"ba653dc2a1384e5f9f6ac9dc1a740109\">cybersecurity<\/a>, exit poll development, educational endevors, insurance systems, and time trend forecasting.<sup id=\"rdp-ebb-cite_ref-Campbell-VerduynBit17_4-0\" class=\"reference\"><a href=\"#cite_note-Campbell-VerduynBit17-4\">[4]<\/a><\/sup> Recently, blockchain technology has gained popularity several other domains, including health systems. This is because it offers a safer and decentralized database that can operate independently from a centralized administrator.<sup id=\"rdp-ebb-cite_ref-MeinertBlock19_3-1\" class=\"reference\"><a href=\"#cite_note-MeinertBlock19-3\">[3]<\/a><\/sup> According to Angraal <i>et al.<\/i>, a unique selling point of the blockchain system is that once digital validation takes place, the network itself streamlines and validates the subsequent process of transaction. It safeguards the transaction history and allows data to be transferred directly between third parties.<sup id=\"rdp-ebb-cite_ref-AngraalBlock17_5-0\" class=\"reference\"><a href=\"#cite_note-AngraalBlock17-5\">[5]<\/a><\/sup>\n<\/p><p>In this article, we discuss how blockchain technology works and how it can be used in complex situations like strengthening public health surveillance.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Blockchain_and_its_applications\">Blockchain and its applications<\/span><\/h2>\n<p>A blockchain is defined as \u201ca distributed system (decentralized) which performs the dual function of recording and storing the records of the transaction. In this blockchain, the data is located in a network of personal computers called \u2018nodes\u2019 without any central control.\u201d (Figure 1). The main advantage of this decentralized technology is that all the dealings or variations in the data are captured with real-time updates across the network.<sup id=\"rdp-ebb-cite_ref-RatheeASecure19_6-0\" class=\"reference\"><a href=\"#cite_note-RatheeASecure19-6\">[6]<\/a><\/sup> The information that gets stored in each node is similar and permanent. It can't be distorted. Hence, this technology is transparent and autonomous, and as such it improves the quality of shared data between different stakeholders.<sup id=\"rdp-ebb-cite_ref-CrosbyBlock16_7-0\" class=\"reference\"><a href=\"#cite_note-CrosbyBlock16-7\">[7]<\/a><\/sup> In this system, to validate the transaction, cryptographic algorithms are used.<sup id=\"rdp-ebb-cite_ref-SharmaService19_8-0\" class=\"reference\"><a href=\"#cite_note-SharmaService19-8\">[8]<\/a><\/sup> This is different from a \u201ctrust-in-the-third-party\u201d mechanism, where an online transaction takes place when two willing parties approve the transaction by use of a digital signature.<sup id=\"rdp-ebb-cite_ref-AlamIoT18_2-1\" class=\"reference\"><a href=\"#cite_note-AlamIoT18-2\">[2]<\/a><\/sup> Moreover, blockchain overcomes the challenge of \u201csingle point failure,\u201d which is common in centralized information management systems.<sup id=\"rdp-ebb-cite_ref-LinASurv17_9-0\" class=\"reference\"><a href=\"#cite_note-LinASurv17-9\">[9]<\/a><\/sup> Currently, however, the average centralized healthcare system lacks the advantages offered by blockchain, including transparency and trust, data security and privacy, cost-effectiveness, and verifiability of data, as well as fast and real-time data transfer to all trusted parties.<sup id=\"rdp-ebb-cite_ref-VaziraniImplementing19_10-0\" class=\"reference\"><a href=\"#cite_note-VaziraniImplementing19-10\">[10]<\/a><\/sup>\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig1_Bhattacharya_AIMSPubHlth2019_6-3.png\" class=\"image wiki-link\" data-key=\"759c1ea30eb248c4c3b5d874e5b1d5ec\"><img alt=\"Fig1 Bhattacharya AIMSPubHlth2019 6-3.png\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/2\/26\/Fig1_Bhattacharya_AIMSPubHlth2019_6-3.png\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Figure 1.<\/b> Centralized (<b>a<\/b>) and decentralized network (<b>b<\/b>)<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<h2><span class=\"mw-headline\" id=\"Types_and_uses_of_blockchain\">Types and uses of blockchain<\/span><\/h2>\n<p>There are two main types of blockchains:\n<\/p><p>1. Open-access blockchains, which makes all records visible to the stakeholders; and\n<\/p><p>2. Limited-access blockchains, which restricts the access of data\/information.<sup id=\"rdp-ebb-cite_ref-BeckBlock17_11-0\" class=\"reference\"><a href=\"#cite_note-BeckBlock17-11\">[11]<\/a><\/sup>\n<\/p><p>Open-access blockchains are more appropriate to the health sector. Presently, cryptocurrency such as Bitcoin (some of the most popular applications of blockchain technology) depends on this type of technology.<sup id=\"rdp-ebb-cite_ref-PetersonABlock16_12-0\" class=\"reference\"><a href=\"#cite_note-PetersonABlock16-12\">[12]<\/a><\/sup>\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Blockchain_technology_in_healthcare\">Blockchain technology in healthcare<\/span><\/h2>\n<p>Blockchain has commonly been used in four primary ways in healthcare: in <a href=\"https:\/\/www.limswiki.org\/index.php\/Electronic_medical_record\" title=\"Electronic medical record\" class=\"wiki-link\" data-key=\"99a695d2af23397807da0537d29d0be7\">electronic medical record<\/a> (EMR) implementations at the hospital level, for resource management in health systems, for patient-level applications, and for disease surveillance at the community level.\n<\/p><p>1. <i>Hospitals and EMRs<\/i>: Blockchain is one of the popular technologies used in EMRs found in modern hospital ecosystems in industrialized nations. Blockchain's ability to improve decentralization, data provenance, and robustness has made it suitable for storing, managing, and sharing <a href=\"https:\/\/www.limswiki.org\/index.php\/Information_privacy\" title=\"Information privacy\" class=\"wiki-link\" data-key=\"185f6d9f874e48914b5789317408f782\">protected health information<\/a> in EMRs.<sup id=\"rdp-ebb-cite_ref-SharmaAnOptimal17_13-0\" class=\"reference\"><a href=\"#cite_note-SharmaAnOptimal17-13\">[13]<\/a><\/sup> For example, an electronic health chain (or interoperable health blockchain) could be based on a blockchain-based EMR system which uses IBM's Hyperledger Fabric modular blockchain framework.<sup id=\"rdp-ebb-cite_ref-Roman-BelmonteHow18_14-0\" class=\"reference\"><a href=\"#cite_note-Roman-BelmonteHow18-14\">[14]<\/a><\/sup> This technology helps to achieve scalable data security and optimize the performance of the EMR system. Arguably, blockchain may also be considered for improving transactions in billing and managing insurance claims, as well as surveillance measures like nosocomial infection surveillance.<sup id=\"rdp-ebb-cite_ref-Roman-BelmonteHow18_14-1\" class=\"reference\"><a href=\"#cite_note-Roman-BelmonteHow18-14\">[14]<\/a><\/sup> The advantage of this technology is that a lot of data can rapidly be stored, processed, and shared with stakeholders without any link failure\/delay.<sup id=\"rdp-ebb-cite_ref-EkblawACase16_15-0\" class=\"reference\"><a href=\"#cite_note-EkblawACase16-15\">[15]<\/a><\/sup> According to Peterson <i>et al.<\/i>, it can also reform health database interoperability with built-in authentication controls, which lowers the risk of data theft.<sup id=\"rdp-ebb-cite_ref-PetersonABlock16_12-1\" class=\"reference\"><a href=\"#cite_note-PetersonABlock16-12\">[12]<\/a><\/sup>\n<\/p><p>2. <i>Resource management in health systems<\/i>: Blockchain can facilitate managing logistics and human resources in healthcare systems. For example, counterfeit medications and instruments below standard can be supplied to healthcare systems from external vendors. Use of blockchain can validate the quality standards at different nodes of the supply chain and inform the respective authorities about suspected discrepancies.<sup id=\"rdp-ebb-cite_ref-TsengGovern18_16-0\" class=\"reference\"><a href=\"#cite_note-TsengGovern18-16\">[16]<\/a><\/sup> Moreover, human resource management in the digital age requires storing and using employee data for attendance, vacation scheduling, performance appraisal, and security measures with complex authentication processes. Use of blockchain can make such processes efficient and contribute to the development of smarter health services organizations.\n<\/p><p>3. <i>Patient-level applications<\/i>: Due to its decentralized features protecting data safety concerns, blockchain is increasingly being used to share health data with patients and their caregivers. Such patient empowerment initiatives are also fostering meaningful use of health information technology and improving patient-provider communication across digital platforms.<sup id=\"rdp-ebb-cite_ref-EngelhardtHitch17_17-0\" class=\"reference\"><a href=\"#cite_note-EngelhardtHitch17-17\">[17]<\/a><\/sup> Furthermore, blockchain-based <a href=\"https:\/\/www.limswiki.org\/index.php\/MHealth\" title=\"MHealth\" class=\"wiki-link\" data-key=\"42415d515f590babb6158dc02b7b3f0a\">mHealth<\/a> interventions are enabling remote patient monitoring through use of <a href=\"https:\/\/www.limswiki.org\/index.php\/Remote_patient_monitoring\" title=\"Remote patient monitoring\" class=\"wiki-link\" data-key=\"459438aa577ac442814a6c6946908980\">biosensors<\/a>, thus bridging the access gaps in patient-level health services.<sup id=\"rdp-ebb-cite_ref-SaravananSMEAD17_18-0\" class=\"reference\"><a href=\"#cite_note-SaravananSMEAD17-18\">[18]<\/a><\/sup>\n<\/p><p>4. <i>Community disease surveillance<\/i>: Surveillance is defined as the \u201csystematic, ongoing collection, collation, and analysis of data and the timely dissemination of information to those who need to know so that the action can be taken.\u201d<sup id=\"rdp-ebb-cite_ref-LastADict01_19-0\" class=\"reference\"><a href=\"#cite_note-LastADict01-19\">[19]<\/a><\/sup> It is done for both communicable diseases and non-communicable diseases by all national health systems according to their national priorities as per WHO's International Health Regulations (IHR). For example, deadly viruses like Nipah can travel across the globe within 36 hours and may lead to a pandemic, further compromised by rapid and uncontrolled urbanization and globalization.<sup id=\"rdp-ebb-cite_ref-FanPandemic18_20-0\" class=\"reference\"><a href=\"#cite_note-FanPandemic18-20\">[20]<\/a><\/sup> Communicable disease surveillance is an ongoing, complex, and inefficient process, because a huge number of self-regulating organizations report to a centralized information system. As such, it remains a challenging task to maintain seamless information flow in a timely manner.<sup id=\"rdp-ebb-cite_ref-IslamABlock19_21-0\" class=\"reference\"><a href=\"#cite_note-IslamABlock19-21\">[21]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-KhanAnEhealth19_22-0\" class=\"reference\"><a href=\"#cite_note-KhanAnEhealth19-22\">[22]<\/a><\/sup> Moreover, sufficient incentive is rarely provided to routine staff. \n<\/p><p>The sequence of events that occur after a healthcare worker reports a potential case is depicted in Figure 2.\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig2_Bhattacharya_AIMSPubHlth2019_6-3.png\" class=\"image wiki-link\" data-key=\"5e63543610f339fef886c064d5f2a17c\"><img alt=\"Fig2 Bhattacharya AIMSPubHlth2019 6-3.png\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/8\/81\/Fig2_Bhattacharya_AIMSPubHlth2019_6-3.png\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Figure 2.<\/b> Sequence of events in disease surveillance system<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>Blockchain could help independent organizations to manage data more efficiently during pandemics.<sup id=\"rdp-ebb-cite_ref-ChattuTheEmerg19_23-0\" class=\"reference\"><a href=\"#cite_note-ChattuTheEmerg19-23\">[23]<\/a><\/sup> It could also help track information for ongoing public health emergencies, like road traffic accidents, illicit drug use, opioid misuse, and so on.<sup id=\"rdp-ebb-cite_ref-KatuwalApp18_24-0\" class=\"reference\"><a href=\"#cite_note-KatuwalApp18-24\">[24]<\/a><\/sup> When blockchain technology is used in a public health domain, these networks might be able to automate secure data sharing and storage at different levels of healthcare organizations.\n<\/p><p>This technology has a potential to give real-time data\/information by sensing potential outbreaks or bioterrorism. Hence, if vaccinations, antibiotics, and other disease control measures are instituted promptly, massive casualties can be prevented. For example, fake news on social media against vaccination have critically impacted public health in recent years.<sup id=\"rdp-ebb-cite_ref-JervelundHowSoc18_25-0\" class=\"reference\"><a href=\"#cite_note-JervelundHowSoc18-25\">[25]<\/a><\/sup> Huckle and White reported a blockchain-based approach to identify the origins of such harmful content and identify the population at risk in digital communication.<sup id=\"rdp-ebb-cite_ref-HuckleFake17_26-0\" class=\"reference\"><a href=\"#cite_note-HuckleFake17-26\">[26]<\/a><\/sup> This highlights the potential of blockchain to improve public health surveillance in the era of digitalization.\n<\/p><p>Today many countries use machine learning techniques in surveillance. However, there are certain unique and added advantages of blockchain technology over machine learning techniques. For example, blockchain predominantly blocks malicious activities, like data hacking and duplication.<sup id=\"rdp-ebb-cite_ref-RahoutiBitcoin18_27-0\" class=\"reference\"><a href=\"#cite_note-RahoutiBitcoin18-27\">[27]<\/a><\/sup> Additionally, the combination of blockchain technology with <a href=\"https:\/\/www.limswiki.org\/index.php\/Artificial_intelligence\" title=\"Artificial intelligence\" class=\"wiki-link\" data-key=\"0c45a597361ca47e1cd8112af676276e\">artificial intelligence<\/a> (AI) is the proverbial \"cherry on top\" for the medical research and health sectors.<sup id=\"rdp-ebb-cite_ref-MamoshinaConverg17_28-0\" class=\"reference\"><a href=\"#cite_note-MamoshinaConverg17-28\">[28]<\/a><\/sup>\n<\/p><p>There is also tremendous scope for integration with <a href=\"https:\/\/www.limswiki.org\/index.php\/Geographic_information_system\" title=\"Geographic information system\" class=\"wiki-link\" data-key=\"8981ab93f8ebf0730c3b38949b39ad99\">geographic information systems<\/a> (GIS) to expedite routine epidemic investigations, as well as drug and vaccine supply chain management. The other critical aspect is that by ensuring transparency and correct reporting, as in the case of reporting deaths from an outbreak, blockchain overcomes the existing limitations of local health information systems. The following illustration (Figure 3) shows how the application of blockchain in surveillance systems enhances activities for ensuring health security.\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig3_Bhattacharya_AIMSPubHlth2019_6-3.png\" class=\"image wiki-link\" data-key=\"f69bfa6d6c3006c72c38ed4057064dec\"><img alt=\"Fig3 Bhattacharya AIMSPubHlth2019 6-3.png\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/3\/3a\/Fig3_Bhattacharya_AIMSPubHlth2019_6-3.png\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Figure 3.<\/b> Application of block chain in surveillance system<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>As shown in Figure 3, the disease control actions of prevention, detection, and response, aided by blockchain, have their scope broadened for real-time surveillance and detection of non-communicable diseases (NCD). This also lends to the goals of the Global Health Security Agenda (GHSA) and its Action Package working groups.<sup id=\"rdp-ebb-cite_ref-GHSAAbout_29-0\" class=\"reference\"><a href=\"#cite_note-GHSAAbout-29\">[29]<\/a><\/sup>\n<\/p><p>By applying real-time surveillance, defining and tracking the early risk factors for NCDs can be improved. Additionally, by building up the capacity of medical units, the challenges of emergency response can be overcome through effective supply chain systems.<sup id=\"rdp-ebb-cite_ref-KostovaSynergies17_30-0\" class=\"reference\"><a href=\"#cite_note-KostovaSynergies17-30\">[30]<\/a><\/sup> A summary of other NCD real-time surveillance activities within the framework of the GHSA are shown in Table 1.\n<\/p>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table class=\"wikitable\" border=\"1\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\" colspan=\"3\"><b>Table 1.<\/b> Real time surveillance for NCDs within the Global Health Security Agenda\n<\/td><\/tr>\n<tr>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">GHSA category\n<\/th>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">GHSA action package\n<\/th>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">NCD-related activity\n<\/th><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Detect\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Real-time surveillance\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">\n<p>1. Strengthen cancer registries<br \/>\n2. Support tobacco use surveillance<br \/>\n3. Birth defects surveillance due to zika virus<br \/>\n4. Include NCD indicators in current surveillance systems<br \/>\n5. Support inclusion of electronic medical records<br \/>\n6. Implement for health data\n<\/p>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<h2><span class=\"mw-headline\" id=\"Limitations\">Limitations<\/span><\/h2>\n<p>Blockchain technology has several limitations which include use of the technology without adequate security and privacy measures, lack of frameworks for implementation and regulation, and concerns for cost-effectiveness and interoperability.<sup id=\"rdp-ebb-cite_ref-BoulosGeospatial18_31-0\" class=\"reference\"><a href=\"#cite_note-BoulosGeospatial18-31\">[31]<\/a><\/sup> These challenges can be overcome by gradual improvements in scalability and upgradeability.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Discussions_and_conclusions\">Discussions and conclusions<\/span><\/h2>\n<p>The case of Taiwan is an excellent example of the application of this revolutionary blockchain technology.<sup id=\"rdp-ebb-cite_ref-JianReal17_32-0\" class=\"reference\"><a href=\"#cite_note-JianReal17-32\">[32]<\/a><\/sup> In Estonia, the complete public health infrastructure is being operated using blockchain.<sup id=\"rdp-ebb-cite_ref-MettlerBlock16_33-0\" class=\"reference\"><a href=\"#cite_note-MettlerBlock16-33\">[33]<\/a><\/sup> Other examples include countries such as the United Kingdom, United States, and Canada, where such real-time surveillance systems have been implemented in many of their departments. In England, at the national level, they have implemented it in their Emergency Department Syndromic Surveillance System (EDSSS). Emergency department syndromic surveillance has also been implemented by Canada at the regional level. Another excellent example of this application is the European Antimicrobial Resistance Surveillance Network.<sup id=\"rdp-ebb-cite_ref-ChattuTheEmerg19_23-1\" class=\"reference\"><a href=\"#cite_note-ChattuTheEmerg19-23\">[23]<\/a><\/sup><sup id=\"rdp-ebb-cite_ref-AbatReal15_34-0\" class=\"reference\"><a href=\"#cite_note-AbatReal15-34\">[34]<\/a><\/sup> Hence, we may conclude that blockchain applications can retain the prime characteristics of ideal disease surveillance. It can be more effective and rapid than traditional surveillance in terms of coverage, durability, consensus, selective privacy, uniqueness, and timing. Blockchain technology holds great promise in overpopulated and low-income countries like India, Pakistan, and Africa (where the health systems are prone to epidemic and pandemic) by strengthening the capacity of the countries with simplified early warning surveillance for diseases of epidemic potential by reducing the mortality, morbidity, and economic costs. It is high time to incorporate blockchain technology within the existing surveillance systems of at least low-income countries in order to strengthen their health systems.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Acknowledgements\">Acknowledgements<\/span><\/h2>\n<p>We acknowledge all the present and previous authors (working in the field of blockchain technology, especially Dr Vijay Kumar Chattu), contributors and sources, who helped us directly or indirectly for preparing this manuscript. All the authors had contributed equally during preparation of this manuscript (concept, design, literature review, and editing).\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Conflict_of_interest\">Conflict of interest<\/span><\/h3>\n<p>All authors declare no conflicts of interest in this paper.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"References\">References<\/span><\/h2>\n<div class=\"reflist references-column-width\" style=\"-moz-column-width: 30em; -webkit-column-width: 30em; column-width: 30em; list-style-type: decimal;\">\n<ol class=\"references\">\n<li id=\"cite_note-ChenExploring18-1\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-ChenExploring18_1-0\">1.0<\/a><\/sup> <sup><a href=\"#cite_ref-ChenExploring18_1-1\">1.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Chen, G.; Xu, B.; Lu, M. et al. (2018). \"Exploring blockchain technology and its potential applications for education\". <i>Smart Learning Environments<\/i> <b>5<\/b>: 1. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1186%2Fs40561-017-0050-x\" target=\"_blank\">10.1186\/s40561-017-0050-x<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Exploring+blockchain+technology+and+its+potential+applications+for+education&rft.jtitle=Smart+Learning+Environments&rft.aulast=Chen%2C+G.%3B+Xu%2C+B.%3B+Lu%2C+M.+et+al.&rft.au=Chen%2C+G.%3B+Xu%2C+B.%3B+Lu%2C+M.+et+al.&rft.date=2018&rft.volume=5&rft.pages=1&rft_id=info:doi\/10.1186%2Fs40561-017-0050-x&rfr_id=info:sid\/en.wikipedia.org:Journal:Strengthening_public_health_surveillance_through_blockchain_technology\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-AlamIoT18-2\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-AlamIoT18_2-0\">2.0<\/a><\/sup> <sup><a href=\"#cite_ref-AlamIoT18_2-1\">2.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Alam, T. (2019). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ijrte.org\/download\/volume-7-issue-6\/\" target=\"_blank\">\"IoT-Fog: A Communication Framework using Blockchain in the Internet of Things\"<\/a>. <i>International Journal of Recent Technology and Engineering<\/i> <b>7<\/b> (6): 833-838<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.ijrte.org\/download\/volume-7-issue-6\/\" target=\"_blank\">http:\/\/www.ijrte.org\/download\/volume-7-issue-6\/<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=IoT-Fog%3A+A+Communication+Framework+using+Blockchain+in+the+Internet+of+Things&rft.jtitle=International+Journal+of+Recent+Technology+and+Engineering&rft.aulast=Alam%2C+T.&rft.au=Alam%2C+T.&rft.date=2019&rft.volume=7&rft.issue=6&rft.pages=833-838&rft_id=http%3A%2F%2Fwww.ijrte.org%2Fdownload%2Fvolume-7-issue-6%2F&rfr_id=info:sid\/en.wikipedia.org:Journal:Strengthening_public_health_surveillance_through_blockchain_technology\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-MeinertBlock19-3\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-MeinertBlock19_3-0\">3.0<\/a><\/sup> <sup><a href=\"#cite_ref-MeinertBlock19_3-1\">3.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Meinert, E.; Alturkistani, A.; Foley, K.A. et al. (2019). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6384534\" target=\"_blank\">\"Blockchain Implementation in Health Care: Protocol for a Systematic Review\"<\/a>. <i>JMIR Research Protocols<\/i> <b>8<\/b> (2): e10994. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.2196%2F10994\" target=\"_blank\">10.2196\/10994<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6384534\/\" target=\"_blank\">PMC6384534<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/30735146\" target=\"_blank\">30735146<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6384534\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6384534<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Blockchain+Implementation+in+Health+Care%3A+Protocol+for+a+Systematic+Review&rft.jtitle=JMIR+Research+Protocols&rft.aulast=Meinert%2C+E.%3B+Alturkistani%2C+A.%3B+Foley%2C+K.A.+et+al.&rft.au=Meinert%2C+E.%3B+Alturkistani%2C+A.%3B+Foley%2C+K.A.+et+al.&rft.date=2019&rft.volume=8&rft.issue=2&rft.pages=e10994&rft_id=info:doi\/10.2196%2F10994&rft_id=info:pmc\/PMC6384534&rft_id=info:pmid\/30735146&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC6384534&rfr_id=info:sid\/en.wikipedia.org:Journal:Strengthening_public_health_surveillance_through_blockchain_technology\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-Campbell-VerduynBit17-4\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-Campbell-VerduynBit17_4-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation book\">Campbell-Verduyn, M. (2017). <i>Bitcoin and Beyond: Cryptocurrencies, Blockchains, and Global Governance<\/i>. Routledge. pp. 221. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/International_Standard_Book_Number\" data-key=\"f64947ba21e884434bd70e8d9e60bae6\">ISBN<\/a> 9780415792141.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=book&rft.btitle=Bitcoin+and+Beyond%3A+Cryptocurrencies%2C+Blockchains%2C+and+Global+Governance&rft.aulast=Campbell-Verduyn%2C+M.&rft.au=Campbell-Verduyn%2C+M.&rft.date=2017&rft.pages=pp.%26nbsp%3B221&rft.pub=Routledge&rft.isbn=9780415792141&rfr_id=info:sid\/en.wikipedia.org:Journal:Strengthening_public_health_surveillance_through_blockchain_technology\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-AngraalBlock17-5\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-AngraalBlock17_5-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Angraal, S.; Krumholz, H.M.; Schulz, W.L. et al. (2017). \"Blockchain Technology: Applications in Health Care\". <i>Circulation: Cardiovascular Quality and Outcomes<\/i> <b>10<\/b> (9): e003800. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1161%2FCIRCOUTCOMES.117.003800\" target=\"_blank\">10.1161\/CIRCOUTCOMES.117.003800<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/28912202\" target=\"_blank\">28912202<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Blockchain+Technology%3A+Applications+in+Health+Care&rft.jtitle=Circulation%3A+Cardiovascular+Quality+and+Outcomes&rft.aulast=Angraal%2C+S.%3B+Krumholz%2C+H.M.%3B+Schulz%2C+W.L.+et+al.&rft.au=Angraal%2C+S.%3B+Krumholz%2C+H.M.%3B+Schulz%2C+W.L.+et+al.&rft.date=2017&rft.volume=10&rft.issue=9&rft.pages=e003800&rft_id=info:doi\/10.1161%2FCIRCOUTCOMES.117.003800&rft_id=info:pmid\/28912202&rfr_id=info:sid\/en.wikipedia.org:Journal:Strengthening_public_health_surveillance_through_blockchain_technology\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-RatheeASecure19-6\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-RatheeASecure19_6-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Rathee, G.; Sharma, A.; Kumar, R. et al. (2019). \"A Secure Communicating Things Network Framework for Industrial IoT using Blockchain Technology\". <i>Ad Hoc Networks<\/i> <b>94<\/b>: 101933. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.adhoc.2019.101933\" target=\"_blank\">10.1016\/j.adhoc.2019.101933<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=A+Secure+Communicating+Things+Network+Framework+for+Industrial+IoT+using+Blockchain+Technology&rft.jtitle=Ad+Hoc+Networks&rft.aulast=Rathee%2C+G.%3B+Sharma%2C+A.%3B+Kumar%2C+R.+et+al.&rft.au=Rathee%2C+G.%3B+Sharma%2C+A.%3B+Kumar%2C+R.+et+al.&rft.date=2019&rft.volume=94&rft.pages=101933&rft_id=info:doi\/10.1016%2Fj.adhoc.2019.101933&rfr_id=info:sid\/en.wikipedia.org:Journal:Strengthening_public_health_surveillance_through_blockchain_technology\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-CrosbyBlock16-7\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-CrosbyBlock16_7-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Crosby, M.; Nachiappan; Pattenayak, P. et al. (2016). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/scet.berkeley.edu\/wp-content\/uploads\/AIR-2016-Blockchain.pdf\" target=\"_blank\">\"BlockChain Technology: Beyond Bitcoin\"<\/a> (PDF). <i>Applied Innovation Review<\/i> (2): 6\u201319<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/scet.berkeley.edu\/wp-content\/uploads\/AIR-2016-Blockchain.pdf\" target=\"_blank\">http:\/\/scet.berkeley.edu\/wp-content\/uploads\/AIR-2016-Blockchain.pdf<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=BlockChain+Technology%3A+Beyond+Bitcoin&rft.jtitle=Applied+Innovation+Review&rft.aulast=Crosby%2C+M.%3B+Nachiappan%3B+Pattenayak%2C+P.+et+al.&rft.au=Crosby%2C+M.%3B+Nachiappan%3B+Pattenayak%2C+P.+et+al.&rft.date=2016&rft.issue=2&rft.pages=6%E2%80%9319&rft_id=http%3A%2F%2Fscet.berkeley.edu%2Fwp-content%2Fuploads%2FAIR-2016-Blockchain.pdf&rfr_id=info:sid\/en.wikipedia.org:Journal:Strengthening_public_health_surveillance_through_blockchain_technology\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-SharmaService19-8\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-SharmaService19_8-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Sharma, A.; Kumar, R. (2019). \"Service-Level Agreement\u2014Energy Cooperative Quickest Ambulance Routing for Critical Healthcare Services\". <i>Arabian Journal for Science and Engineering<\/i> <b>44<\/b>: 3831\u20133848. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1007%2Fs13369-018-3687-z\" target=\"_blank\">10.1007\/s13369-018-3687-z<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Service-Level+Agreement%E2%80%94Energy+Cooperative+Quickest+Ambulance+Routing+for+Critical+Healthcare+Services&rft.jtitle=Arabian+Journal+for+Science+and+Engineering&rft.aulast=Sharma%2C+A.%3B+Kumar%2C+R.&rft.au=Sharma%2C+A.%3B+Kumar%2C+R.&rft.date=2019&rft.volume=44&rft.pages=3831%E2%80%933848&rft_id=info:doi\/10.1007%2Fs13369-018-3687-z&rfr_id=info:sid\/en.wikipedia.org:Journal:Strengthening_public_health_surveillance_through_blockchain_technology\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-LinASurv17-9\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-LinASurv17_9-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Li, I.-C.; Liao, T.-C. (2017). \"A Survey of Blockchain Security Issues and Challenges\". <i>International Journal of Network Security<\/i> <b>19<\/b> (5): 653\u2013659. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.6633%2FIJNS.201709.19%285%29.01\" target=\"_blank\">10.6633\/IJNS.201709.19(5).01<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=A+Survey+of+Blockchain+Security+Issues+and+Challenges&rft.jtitle=International+Journal+of+Network+Security&rft.aulast=Li%2C+I.-C.%3B+Liao%2C+T.-C.&rft.au=Li%2C+I.-C.%3B+Liao%2C+T.-C.&rft.date=2017&rft.volume=19&rft.issue=5&rft.pages=653%E2%80%93659&rft_id=info:doi\/10.6633%2FIJNS.201709.19%285%29.01&rfr_id=info:sid\/en.wikipedia.org:Journal:Strengthening_public_health_surveillance_through_blockchain_technology\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-VaziraniImplementing19-10\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-VaziraniImplementing19_10-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Vazirani, A.A.; O'Donoghue, O.; Brindley, D. et al. (2019). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6390185\" target=\"_blank\">\"Implementing Blockchains for Efficient Health Care: Systematic Review\"<\/a>. <i>Journal of Medical Internet Research<\/i> <b>21<\/b> (2): e12439. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.2196%2F12439\" target=\"_blank\">10.2196\/12439<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6390185\/\" target=\"_blank\">PMC6390185<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/30747714\" target=\"_blank\">30747714<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6390185\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6390185<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Implementing+Blockchains+for+Efficient+Health+Care%3A+Systematic+Review&rft.jtitle=Journal+of+Medical+Internet+Research&rft.aulast=Vazirani%2C+A.A.%3B+O%27Donoghue%2C+O.%3B+Brindley%2C+D.+et+al.&rft.au=Vazirani%2C+A.A.%3B+O%27Donoghue%2C+O.%3B+Brindley%2C+D.+et+al.&rft.date=2019&rft.volume=21&rft.issue=2&rft.pages=e12439&rft_id=info:doi\/10.2196%2F12439&rft_id=info:pmc\/PMC6390185&rft_id=info:pmid\/30747714&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC6390185&rfr_id=info:sid\/en.wikipedia.org:Journal:Strengthening_public_health_surveillance_through_blockchain_technology\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-BeckBlock17-11\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-BeckBlock17_11-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Beck, R.; Avital, M.; Rossi, M. et al. (2017). \"Blockchain Technology in Business and Information Systems Research\". <i>Business & Information Systems Engineering<\/i> <b>59<\/b>: 381\u201384. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1007%2Fs12599-017-0505-1\" target=\"_blank\">10.1007\/s12599-017-0505-1<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Blockchain+Technology+in+Business+and+Information+Systems+Research&rft.jtitle=Business+%26+Information+Systems+Engineering&rft.aulast=Beck%2C+R.%3B+Avital%2C+M.%3B+Rossi%2C+M.+et+al.&rft.au=Beck%2C+R.%3B+Avital%2C+M.%3B+Rossi%2C+M.+et+al.&rft.date=2017&rft.volume=59&rft.pages=381%E2%80%9384&rft_id=info:doi\/10.1007%2Fs12599-017-0505-1&rfr_id=info:sid\/en.wikipedia.org:Journal:Strengthening_public_health_surveillance_through_blockchain_technology\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-PetersonABlock16-12\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-PetersonABlock16_12-0\">12.0<\/a><\/sup> <sup><a href=\"#cite_ref-PetersonABlock16_12-1\">12.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation web\">Peterson, K. (September 2016). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/oncprojectracking.healthit.gov\/wiki\/display\/TechLabI\/Use+of+Blockchain+in+Healthcare+and+Research+Workshop\" target=\"_blank\">\"A Blockchain-Based Approach to Health Information Exchange Networks\"<\/a>. <i>Use of Blockchain in Healthcare and Research Workshop<\/i><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/oncprojectracking.healthit.gov\/wiki\/display\/TechLabI\/Use+of+Blockchain+in+Healthcare+and+Research+Workshop\" target=\"_blank\">https:\/\/oncprojectracking.healthit.gov\/wiki\/display\/TechLabI\/Use+of+Blockchain+in+Healthcare+and+Research+Workshop<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=A+Blockchain-Based+Approach+to+Health+Information+Exchange+Networks&rft.atitle=Use+of+Blockchain+in+Healthcare+and+Research+Workshop&rft.aulast=Peterson%2C+K.&rft.au=Peterson%2C+K.&rft.date=September+2016&rft_id=https%3A%2F%2Foncprojectracking.healthit.gov%2Fwiki%2Fdisplay%2FTechLabI%2FUse%2Bof%2BBlockchain%2Bin%2BHealthcare%2Band%2BResearch%2BWorkshop&rfr_id=info:sid\/en.wikipedia.org:Journal:Strengthening_public_health_surveillance_through_blockchain_technology\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-SharmaAnOptimal17-13\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-SharmaAnOptimal17_13-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Sharma, A.; Kumar, R. (2017). \"An optimal routing scheme for critical healthcare HTH services \u2014 An IOT perspective\". <i>Proceedings from the Fourth International Conference on Image Information Processing<\/i>: 1\u20135. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1109%2FICIIP.2017.8313784\" target=\"_blank\">10.1109\/ICIIP.2017.8313784<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=An+optimal+routing+scheme+for+critical+healthcare+HTH+services+%E2%80%94+An+IOT+perspective&rft.jtitle=Proceedings+from+the+Fourth+International+Conference+on+Image+Information+Processing&rft.aulast=Sharma%2C+A.%3B+Kumar%2C+R.&rft.au=Sharma%2C+A.%3B+Kumar%2C+R.&rft.date=2017&rft.pages=1%E2%80%935&rft_id=info:doi\/10.1109%2FICIIP.2017.8313784&rfr_id=info:sid\/en.wikipedia.org:Journal:Strengthening_public_health_surveillance_through_blockchain_technology\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-Roman-BelmonteHow18-14\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-Roman-BelmonteHow18_14-0\">14.0<\/a><\/sup> <sup><a href=\"#cite_ref-Roman-BelmonteHow18_14-1\">14.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Roman-Belmonte, J.M.; De la Corte-Rodriguez, H.; Rodriguez-Merchan, E.C. (2018). \"How blockchain technology can change medicine\". <i>Postgraduate Medicine<\/i> <b>130<\/b> (4): 420-427. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1080%2F00325481.2018.1472996\" target=\"_blank\">10.1080\/00325481.2018.1472996<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/29727247\" target=\"_blank\">29727247<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=How+blockchain+technology+can+change+medicine&rft.jtitle=Postgraduate+Medicine&rft.aulast=Roman-Belmonte%2C+J.M.%3B+De+la+Corte-Rodriguez%2C+H.%3B+Rodriguez-Merchan%2C+E.C.&rft.au=Roman-Belmonte%2C+J.M.%3B+De+la+Corte-Rodriguez%2C+H.%3B+Rodriguez-Merchan%2C+E.C.&rft.date=2018&rft.volume=130&rft.issue=4&rft.pages=420-427&rft_id=info:doi\/10.1080%2F00325481.2018.1472996&rft_id=info:pmid\/29727247&rfr_id=info:sid\/en.wikipedia.org:Journal:Strengthening_public_health_surveillance_through_blockchain_technology\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-EkblawACase16-15\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-EkblawACase16_15-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Ekblaw, A.; Azaria, A.; Halamka, J.D. et al. (August 2016). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/dci.mit.edu\/research\/blockchain-medical-records\" target=\"_blank\">\"A Case Study for Blockchain in Healthcare: \u201cMedRec\u201d prototype for electronic health records and medical research data\"<\/a>. <i>2nd International Conference on Open & Big Data 2016<\/i>. pp. 1\u201313<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/dci.mit.edu\/research\/blockchain-medical-records\" target=\"_blank\">https:\/\/dci.mit.edu\/research\/blockchain-medical-records<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=A+Case+Study+for+Blockchain+in+Healthcare%3A+%E2%80%9CMedRec%E2%80%9D+prototype+for+electronic+health+records+and+medical+research+data&rft.atitle=2nd+International+Conference+on+Open+%26+Big+Data+2016&rft.aulast=Ekblaw%2C+A.%3B+Azaria%2C+A.%3B+Halamka%2C+J.D.+et+al.&rft.au=Ekblaw%2C+A.%3B+Azaria%2C+A.%3B+Halamka%2C+J.D.+et+al.&rft.date=August+2016&rft.pages=pp.+1%E2%80%9313&rft_id=https%3A%2F%2Fdci.mit.edu%2Fresearch%2Fblockchain-medical-records&rfr_id=info:sid\/en.wikipedia.org:Journal:Strengthening_public_health_surveillance_through_blockchain_technology\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-TsengGovern18-16\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-TsengGovern18_16-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Tseng, J.H.; Liao, Y.C.; Chong, B. et al. (2018). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6025275\" target=\"_blank\">\"Governance on the Drug Supply Chain via Gcoin Blockchain\"<\/a>. <i>International Journal of Environmental Research and Public Health<\/i> <b>15<\/b> (6): E1055. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.3390%2Fijerph15061055\" target=\"_blank\">10.3390\/ijerph15061055<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6025275\/\" target=\"_blank\">PMC6025275<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/29882861\" target=\"_blank\">29882861<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6025275\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC6025275<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Governance+on+the+Drug+Supply+Chain+via+Gcoin+Blockchain&rft.jtitle=International+Journal+of+Environmental+Research+and+Public+Health&rft.aulast=Tseng%2C+J.H.%3B+Liao%2C+Y.C.%3B+Chong%2C+B.+et+al.&rft.au=Tseng%2C+J.H.%3B+Liao%2C+Y.C.%3B+Chong%2C+B.+et+al.&rft.date=2018&rft.volume=15&rft.issue=6&rft.pages=E1055&rft_id=info:doi\/10.3390%2Fijerph15061055&rft_id=info:pmc\/PMC6025275&rft_id=info:pmid\/29882861&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC6025275&rfr_id=info:sid\/en.wikipedia.org:Journal:Strengthening_public_health_surveillance_through_blockchain_technology\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-EngelhardtHitch17-17\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-EngelhardtHitch17_17-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Engelhardt, M.A. (2017). \"Hitching Healthcare to the Chain: An Introduction to Blockchain Technology in the Healthcare Sector\". <i>Technology Innovation Management Review<\/i> <b>7<\/b> (10): 22\u201334. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.22215%2Ftimreview%2F1111\" target=\"_blank\">10.22215\/timreview\/1111<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Hitching+Healthcare+to+the+Chain%3A+An+Introduction+to+Blockchain+Technology+in+the+Healthcare+Sector&rft.jtitle=Technology+Innovation+Management+Review&rft.aulast=Engelhardt%2C+M.A.&rft.au=Engelhardt%2C+M.A.&rft.date=2017&rft.volume=7&rft.issue=10&rft.pages=22%E2%80%9334&rft_id=info:doi\/10.22215%2Ftimreview%2F1111&rfr_id=info:sid\/en.wikipedia.org:Journal:Strengthening_public_health_surveillance_through_blockchain_technology\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-SaravananSMEAD17-18\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-SaravananSMEAD17_18-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Saravanan, M.; Shubha, R.; Marks, A.M. et al. (2017). \"SMEAD: A secured mobile enabled assisting device for diabetics monitoring\". <i>Proceedings of the 2017 IEEE International Conference on Advanced Networks and Telecommunications Systems<\/i>: 1\u20136. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1109%2FANTS.2017.8384099\" target=\"_blank\">10.1109\/ANTS.2017.8384099<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=SMEAD%3A+A+secured+mobile+enabled+assisting+device+for+diabetics+monitoring&rft.jtitle=Proceedings+of+the+2017+IEEE+International+Conference+on+Advanced+Networks+and+Telecommunications+Systems&rft.aulast=Saravanan%2C+M.%3B+Shubha%2C+R.%3B+Marks%2C+A.M.+et+al.&rft.au=Saravanan%2C+M.%3B+Shubha%2C+R.%3B+Marks%2C+A.M.+et+al.&rft.date=2017&rft.pages=1%E2%80%936&rft_id=info:doi\/10.1109%2FANTS.2017.8384099&rfr_id=info:sid\/en.wikipedia.org:Journal:Strengthening_public_health_surveillance_through_blockchain_technology\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-LastADict01-19\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-LastADict01_19-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Last, J.M., ed. (2001). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/books.google.com\/books?id=RPaQY8cG4N4C\" target=\"_blank\">\"A Dictionary of Epidemiology\"<\/a>. Oxford University Press. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/International_Standard_Book_Number\" data-key=\"f64947ba21e884434bd70e8d9e60bae6\">ISBN<\/a> 9780195141696<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/books.google.com\/books?id=RPaQY8cG4N4C\" target=\"_blank\">https:\/\/books.google.com\/books?id=RPaQY8cG4N4C<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=A+Dictionary+of+Epidemiology&rft.atitle=&rft.date=2001&rft.pub=Oxford+University+Press&rft.isbn=9780195141696&rft_id=https%3A%2F%2Fbooks.google.com%2Fbooks%3Fid%3DRPaQY8cG4N4C&rfr_id=info:sid\/en.wikipedia.org:Journal:Strengthening_public_health_surveillance_through_blockchain_technology\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-FanPandemic18-20\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-FanPandemic18_20-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Fan, V.Y.; Jamison, D.T.; Summers, L.H. (2018). \"Pandemic risk: how large are the expected losses?\". <i>Bulletin of the World Health Organization<\/i> <b>96<\/b> (2): 129\u201334. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.2471%2FBLT.17.199588\" target=\"_blank\">10.2471\/BLT.17.199588<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Pandemic+risk%3A+how+large+are+the+expected+losses%3F&rft.jtitle=Bulletin+of+the+World+Health+Organization&rft.aulast=Fan%2C+V.Y.%3B+Jamison%2C+D.T.%3B+Summers%2C+L.H.&rft.au=Fan%2C+V.Y.%3B+Jamison%2C+D.T.%3B+Summers%2C+L.H.&rft.date=2018&rft.volume=96&rft.issue=2&rft.pages=129%E2%80%9334&rft_id=info:doi\/10.2471%2FBLT.17.199588&rfr_id=info:sid\/en.wikipedia.org:Journal:Strengthening_public_health_surveillance_through_blockchain_technology\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-IslamABlock19-21\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-IslamABlock19_21-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Islam, N.; Faheem, Y.; Din, I.U. et al. (2019). \"A blockchain-based fog computing framework for activity recognition as an application to e-Healthcare services\". <i>Future Generation Computer Systems<\/i> <b>100<\/b>: 569\u201378. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.future.2019.05.059\" target=\"_blank\">10.1016\/j.future.2019.05.059<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=A+blockchain-based+fog+computing+framework+for+activity+recognition+as+an+application+to+e-Healthcare+services&rft.jtitle=Future+Generation+Computer+Systems&rft.aulast=Islam%2C+N.%3B+Faheem%2C+Y.%3B+Din%2C+I.U.+et+al.&rft.au=Islam%2C+N.%3B+Faheem%2C+Y.%3B+Din%2C+I.U.+et+al.&rft.date=2019&rft.volume=100&rft.pages=569%E2%80%9378&rft_id=info:doi\/10.1016%2Fj.future.2019.05.059&rfr_id=info:sid\/en.wikipedia.org:Journal:Strengthening_public_health_surveillance_through_blockchain_technology\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-KhanAnEhealth19-22\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-KhanAnEhealth19_22-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Khan, S.U.; Islam, N.; Jan, Z. et al. (2019). \"An e-Health care services framework for the detection and classification of breast cancer in breast cytology images as an IoMT application\". <i>Future Generation Computer Systems<\/i> <b>98<\/b>: 286\u201396. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1016%2Fj.future.2019.01.033\" target=\"_blank\">10.1016\/j.future.2019.01.033<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=An+e-Health+care+services+framework+for+the+detection+and+classification+of+breast+cancer+in+breast+cytology+images+as+an+IoMT+application&rft.jtitle=Future+Generation+Computer+Systems&rft.aulast=Khan%2C+S.U.%3B+Islam%2C+N.%3B+Jan%2C+Z.+et+al.&rft.au=Khan%2C+S.U.%3B+Islam%2C+N.%3B+Jan%2C+Z.+et+al.&rft.date=2019&rft.volume=98&rft.pages=286%E2%80%9396&rft_id=info:doi\/10.1016%2Fj.future.2019.01.033&rfr_id=info:sid\/en.wikipedia.org:Journal:Strengthening_public_health_surveillance_through_blockchain_technology\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-ChattuTheEmerg19-23\"><span class=\"mw-cite-backlink\">\u2191 <sup><a href=\"#cite_ref-ChattuTheEmerg19_23-0\">23.0<\/a><\/sup> <sup><a href=\"#cite_ref-ChattuTheEmerg19_23-1\">23.1<\/a><\/sup><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Chattu, V.K.; Nanda, A.; Chattu, S.K. et al. (2019). \"The Emerging Role of Blockchain Technology Applications in Routine Disease Surveillance Systems to Strengthen Global Health Security\". <i>Big Data and Cognitive Computing<\/i> <b>3<\/b> (2): 25. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.3390%2Fbdcc3020025\" target=\"_blank\">10.3390\/bdcc3020025<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=The+Emerging+Role+of+Blockchain+Technology+Applications+in+Routine+Disease+Surveillance+Systems+to+Strengthen+Global+Health+Security&rft.jtitle=Big+Data+and+Cognitive+Computing&rft.aulast=Chattu%2C+V.K.%3B+Nanda%2C+A.%3B+Chattu%2C+S.K.+et+al.&rft.au=Chattu%2C+V.K.%3B+Nanda%2C+A.%3B+Chattu%2C+S.K.+et+al.&rft.date=2019&rft.volume=3&rft.issue=2&rft.pages=25&rft_id=info:doi\/10.3390%2Fbdcc3020025&rfr_id=info:sid\/en.wikipedia.org:Journal:Strengthening_public_health_surveillance_through_blockchain_technology\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-KatuwalApp18-24\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-KatuwalApp18_24-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Katuwal, G.J.; Pandey, S.; Hennessey, M. et al. (2018). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/arxiv.org\/abs\/1812.02776\" target=\"_blank\">\"Applications of Blockchain in Healthcare: Current Landscape & Challenges\"<\/a>. <i>arXiv<\/i>: 1\u201317<span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/arxiv.org\/abs\/1812.02776\" target=\"_blank\">https:\/\/arxiv.org\/abs\/1812.02776<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Applications+of+Blockchain+in+Healthcare%3A+Current+Landscape+%26+Challenges&rft.jtitle=arXiv&rft.aulast=Katuwal%2C+G.J.%3B+Pandey%2C+S.%3B+Hennessey%2C+M.+et+al.&rft.au=Katuwal%2C+G.J.%3B+Pandey%2C+S.%3B+Hennessey%2C+M.+et+al.&rft.date=2018&rft.pages=1%E2%80%9317&rft_id=https%3A%2F%2Farxiv.org%2Fabs%2F1812.02776&rfr_id=info:sid\/en.wikipedia.org:Journal:Strengthening_public_health_surveillance_through_blockchain_technology\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-JervelundHowSoc18-25\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-JervelundHowSoc18_25-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Jervelund, S.S. (2018). \"How social media is transforming the spreading of knowledge: Implications for our perceptions concerning vaccinations and migrant health\". <i>Scandanavian Journal of Public Health<\/i> <b>46<\/b> (2): 167-169. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1177%2F1403494818760139\" target=\"_blank\">10.1177\/1403494818760139<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=How+social+media+is+transforming+the+spreading+of+knowledge%3A+Implications+for+our+perceptions+concerning+vaccinations+and+migrant+health&rft.jtitle=Scandanavian+Journal+of+Public+Health&rft.aulast=Jervelund%2C+S.S.&rft.au=Jervelund%2C+S.S.&rft.date=2018&rft.volume=46&rft.issue=2&rft.pages=167-169&rft_id=info:doi\/10.1177%2F1403494818760139&rfr_id=info:sid\/en.wikipedia.org:Journal:Strengthening_public_health_surveillance_through_blockchain_technology\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-HuckleFake17-26\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-HuckleFake17_26-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Huckle, S.; White, M. (2017). \"Fake News: A Technological Approach to Proving the Origins of Content, Using Blockchains\". <i>Big Data<\/i> <b>5<\/b> (4): 356\u201371. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1089%2Fbig.2017.0071\" target=\"_blank\">10.1089\/big.2017.0071<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Fake+News%3A+A+Technological+Approach+to+Proving+the+Origins+of+Content%2C+Using+Blockchains&rft.jtitle=Big+Data&rft.aulast=Huckle%2C+S.%3B+White%2C+M.&rft.au=Huckle%2C+S.%3B+White%2C+M.&rft.date=2017&rft.volume=5&rft.issue=4&rft.pages=356%E2%80%9371&rft_id=info:doi\/10.1089%2Fbig.2017.0071&rfr_id=info:sid\/en.wikipedia.org:Journal:Strengthening_public_health_surveillance_through_blockchain_technology\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-RahoutiBitcoin18-27\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-RahoutiBitcoin18_27-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Rahouti, M.; Xiong, K.; Ghani, N. (2018). \"Bitcoin Concepts, Threats, and Machine-Learning Security Solutions\". <i>IEEE Access<\/i> <b>6<\/b>: 67189-67205. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1109%2FACCESS.2018.2874539\" target=\"_blank\">10.1109\/ACCESS.2018.2874539<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Bitcoin+Concepts%2C+Threats%2C+and+Machine-Learning+Security+Solutions&rft.jtitle=IEEE+Access&rft.aulast=Rahouti%2C+M.%3B+Xiong%2C+K.%3B+Ghani%2C+N.&rft.au=Rahouti%2C+M.%3B+Xiong%2C+K.%3B+Ghani%2C+N.&rft.date=2018&rft.volume=6&rft.pages=67189-67205&rft_id=info:doi\/10.1109%2FACCESS.2018.2874539&rfr_id=info:sid\/en.wikipedia.org:Journal:Strengthening_public_health_surveillance_through_blockchain_technology\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-MamoshinaConverg17-28\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-MamoshinaConverg17_28-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Mamoshina, P.; Ojomoko, L.; Yanovich, Y. et al. (2017). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5814166\" target=\"_blank\">\"Converging blockchain and next-generation artificial intelligence technologies to decentralize and accelerate biomedical research and healthcare\"<\/a>. <i>Oncotarget<\/i> <b>9<\/b> (5): 5665-5690. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.18632%2Foncotarget.22345\" target=\"_blank\">10.18632\/oncotarget.22345<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC5814166\/\" target=\"_blank\">PMC5814166<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/29464026\" target=\"_blank\">29464026<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5814166\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5814166<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Converging+blockchain+and+next-generation+artificial+intelligence+technologies+to+decentralize+and+accelerate+biomedical+research+and+healthcare&rft.jtitle=Oncotarget&rft.aulast=Mamoshina%2C+P.%3B+Ojomoko%2C+L.%3B+Yanovich%2C+Y.+et+al.&rft.au=Mamoshina%2C+P.%3B+Ojomoko%2C+L.%3B+Yanovich%2C+Y.+et+al.&rft.date=2017&rft.volume=9&rft.issue=5&rft.pages=5665-5690&rft_id=info:doi\/10.18632%2Foncotarget.22345&rft_id=info:pmc\/PMC5814166&rft_id=info:pmid\/29464026&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC5814166&rfr_id=info:sid\/en.wikipedia.org:Journal:Strengthening_public_health_surveillance_through_blockchain_technology\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-GHSAAbout-29\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-GHSAAbout_29-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation web\">Global Health Security Agenda (2019). <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/ghsagenda.org\/home\/about-the-ghsa\/\" target=\"_blank\">\"About the GHSA\"<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"https:\/\/ghsagenda.org\/home\/about-the-ghsa\/\" target=\"_blank\">https:\/\/ghsagenda.org\/home\/about-the-ghsa\/<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&rft.genre=bookitem&rft.btitle=About+the+GHSA&rft.atitle=&rft.aulast=Global+Health+Security+Agenda&rft.au=Global+Health+Security+Agenda&rft.date=2019&rft_id=https%3A%2F%2Fghsagenda.org%2Fhome%2Fabout-the-ghsa%2F&rfr_id=info:sid\/en.wikipedia.org:Journal:Strengthening_public_health_surveillance_through_blockchain_technology\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-KostovaSynergies17-30\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-KostovaSynergies17_30-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Kostova, D.; Husain, M.J.; Sugerman, D. et al. (2017). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5711304\" target=\"_blank\">\"Synergies between Communicable and Noncommunicable Disease Programs to Enhance Global Health Security\"<\/a>. <i>Emerging Infectious Diseases<\/i> <b>23<\/b> (13): S40\u2013S46. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.3201%2Feid2313.170581\" target=\"_blank\">10.3201\/eid2313.170581<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC5711304\/\" target=\"_blank\">PMC5711304<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/29155655\" target=\"_blank\">29155655<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5711304\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=PMC5711304<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Synergies+between+Communicable+and+Noncommunicable+Disease+Programs+to+Enhance+Global+Health+Security&rft.jtitle=Emerging+Infectious+Diseases&rft.aulast=Kostova%2C+D.%3B+Husain%2C+M.J.%3B+Sugerman%2C+D.+et+al.&rft.au=Kostova%2C+D.%3B+Husain%2C+M.J.%3B+Sugerman%2C+D.+et+al.&rft.date=2017&rft.volume=23&rft.issue=13&rft.pages=S40%E2%80%93S46&rft_id=info:doi\/10.3201%2Feid2313.170581&rft_id=info:pmc\/PMC5711304&rft_id=info:pmid\/29155655&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3DPMC5711304&rfr_id=info:sid\/en.wikipedia.org:Journal:Strengthening_public_health_surveillance_through_blockchain_technology\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-BoulosGeospatial18-31\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-BoulosGeospatial18_31-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Boulos, M.N.K.; Wilson, J.T.; Clauson, K.A. (2018). \"Geospatial blockchain: Promises, challenges, and scenarios in health and healthcare\". <i>International Journal of Health Geographics<\/i> <b>17<\/b>: 25. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1186%2Fs12942-018-0144-x\" target=\"_blank\">10.1186\/s12942-018-0144-x<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Geospatial+blockchain%3A+Promises%2C+challenges%2C+and+scenarios+in+health+and+healthcare&rft.jtitle=International+Journal+of+Health+Geographics&rft.aulast=Boulos%2C+M.N.K.%3B+Wilson%2C+J.T.%3B+Clauson%2C+K.A.&rft.au=Boulos%2C+M.N.K.%3B+Wilson%2C+J.T.%3B+Clauson%2C+K.A.&rft.date=2018&rft.volume=17&rft.pages=25&rft_id=info:doi\/10.1186%2Fs12942-018-0144-x&rfr_id=info:sid\/en.wikipedia.org:Journal:Strengthening_public_health_surveillance_through_blockchain_technology\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-JianReal17-32\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-JianReal17_32-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Jian, S.W.; Chen, C.M.; Lee, C.Y. et al. (2017). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=28418738\" target=\"_blank\">\"Real-Time Surveillance of Infectious Diseases: Taiwan's Experience\"<\/a>. <i>Health Security<\/i> <b>15<\/b> (2): 144\u201353. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1089%2Fhs.2016.0107\" target=\"_blank\">10.1089\/hs.2016.0107<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/28418738\/\" target=\"_blank\">28418738<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/PMC5404256\" target=\"_blank\">PMC5404256<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=28418738\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=28418738<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Real-Time+Surveillance+of+Infectious+Diseases%3A+Taiwan%27s+Experience&rft.jtitle=Health+Security&rft.aulast=Jian%2C+S.W.%3B+Chen%2C+C.M.%3B+Lee%2C+C.Y.+et+al.&rft.au=Jian%2C+S.W.%3B+Chen%2C+C.M.%3B+Lee%2C+C.Y.+et+al.&rft.date=2017&rft.volume=15&rft.issue=2&rft.pages=144%E2%80%9353&rft_id=info:doi\/10.1089%2Fhs.2016.0107&rft_id=info:pmc\/28418738&rft_id=info:pmid\/PMC5404256&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3D28418738&rfr_id=info:sid\/en.wikipedia.org:Journal:Strengthening_public_health_surveillance_through_blockchain_technology\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-MettlerBlock16-33\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-MettlerBlock16_33-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Mettler, M. (2016). \"Blockchain technology in healthcare: The revolution starts here\". <i>Proceedings of the 2016 IEEE 18th International Conference on e-Health Networking, Applications and Services<\/i>: 1\u20133. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.1109%2FHealthCom.2016.7749510\" target=\"_blank\">10.1109\/HealthCom.2016.7749510<\/a>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Blockchain+technology+in+healthcare%3A+The+revolution+starts+here&rft.jtitle=Proceedings+of+the+2016+IEEE+18th+International+Conference+on+e-Health+Networking%2C+Applications+and+Services&rft.aulast=Mettler%2C+M.&rft.au=Mettler%2C+M.&rft.date=2016&rft.pages=1%E2%80%933&rft_id=info:doi\/10.1109%2FHealthCom.2016.7749510&rfr_id=info:sid\/en.wikipedia.org:Journal:Strengthening_public_health_surveillance_through_blockchain_technology\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<li id=\"cite_note-AbatReal15-34\"><span class=\"mw-cite-backlink\"><a href=\"#cite_ref-AbatReal15_34-0\">\u2191<\/a><\/span> <span class=\"reference-text\"><span class=\"citation Journal\">Abat, C.; Chaudet, H.; Colson, P. et al. (2015). <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=26196165\" target=\"_blank\">\"Real-Time Microbiology Laboratory Surveillance System to Detect Abnormal Events and Emerging Infections, Marseille, France\"<\/a>. <i>Emergency Infectious Diseases<\/i> <b>21<\/b> (8): 1302-10. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/Digital_object_identifier\" data-key=\"ae6d69c760ab710abc2dd89f3937d2f4\">doi<\/a>:<a rel=\"external_link\" class=\"external text\" href=\"http:\/\/dx.doi.org\/10.3201%2Feid2108.141419\" target=\"_blank\">10.3201\/eid2108.141419<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Central\" data-key=\"c85bdffd69dd30e02024b9cc3d7679e2\">PMC<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/26196165\/\" target=\"_blank\">26196165<\/a>. <a rel=\"nofollow\" class=\"external text wiki-link\" href=\"http:\/\/en.wikipedia.org\/wiki\/PubMed_Identifier\" data-key=\"1d34e999f13d8801964a6b3e9d7b4e30\">PMID<\/a> <a rel=\"external_link\" class=\"external text\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/PMC4517727\" target=\"_blank\">PMC4517727<\/a><span class=\"printonly\">. <a rel=\"external_link\" class=\"external free\" href=\"http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=26196165\" target=\"_blank\">http:\/\/www.pubmedcentral.nih.gov\/articlerender.fcgi?tool=pmcentrez&artid=26196165<\/a><\/span>.<\/span><span class=\"Z3988\" title=\"ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Real-Time+Microbiology+Laboratory+Surveillance+System+to+Detect+Abnormal+Events+and+Emerging+Infections%2C+Marseille%2C+France&rft.jtitle=Emergency+Infectious+Diseases&rft.aulast=Abat%2C+C.%3B+Chaudet%2C+H.%3B+Colson%2C+P.+et+al.&rft.au=Abat%2C+C.%3B+Chaudet%2C+H.%3B+Colson%2C+P.+et+al.&rft.date=2015&rft.volume=21&rft.issue=8&rft.pages=1302-10&rft_id=info:doi\/10.3201%2Feid2108.141419&rft_id=info:pmc\/26196165&rft_id=info:pmid\/PMC4517727&rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3D26196165&rfr_id=info:sid\/en.wikipedia.org:Journal:Strengthening_public_health_surveillance_through_blockchain_technology\"><span style=\"display: none;\"> <\/span><\/span><\/span>\n<\/li>\n<\/ol><\/div>\n<h2><span class=\"mw-headline\" id=\"Notes\">Notes<\/span><\/h2>\n<p>This presentation is faithful to the original, with only a few minor changes to presentation. In some cases important information was missing from the references, and that information was added. A reference was added for the GHSA in this version.\n<\/p>\n<!-- \nNewPP limit report\nCached time: 20200707205041\nCache expiry: 86400\nDynamic content: false\nCPU time usage: 0.610 seconds\nReal time usage: 1.254 seconds\nPreprocessor visited node count: 26364\/1000000\nPreprocessor generated node count: 37547\/1000000\nPost\u2010expand include size: 199019\/2097152 bytes\nTemplate argument size: 68704\/2097152 bytes\nHighest expansion depth: 18\/40\nExpensive parser function count: 0\/100\n-->\n\n<!-- \nTransclusion expansion time report (%,ms,calls,template)\n100.00% 540.904 1 - -total\n 87.22% 471.768 1 - Template:Reflist\n 73.64% 398.322 34 - Template:Citation\/core\n 67.18% 363.370 29 - Template:Cite_journal\n 8.11% 43.846 4 - Template:Cite_web\n 7.55% 40.853 44 - Template:Citation\/identifier\n 7.15% 38.657 1 - Template:Infobox_journal_article\n 6.81% 36.814 1 - Template:Infobox\n 4.58% 24.748 80 - Template:Infobox\/row\n 4.03% 21.795 36 - Template:Citation\/make_link\n-->\n\n<!-- Saved in parser cache with key limswiki:pcache:idhash:11954-0!*!0!!en!5!* and timestamp 20200707205040 and revision id 39434\n -->\n<\/div><div class=\"printfooter\">Source: <a rel=\"external_link\" class=\"external\" href=\"https:\/\/www.limswiki.org\/index.php\/Journal:Strengthening_public_health_surveillance_through_blockchain_technology\">https:\/\/www.limswiki.org\/index.php\/Journal:Strengthening_public_health_surveillance_through_blockchain_technology<\/a><\/div>\n\t\t\t\t\t\t\t\t\t\t<!-- end content -->\n\t\t\t\t\t\t\t\t\t\t<div class=\"visualClear\"><\/div>\n\t\t\t\t<\/div>\n\t\t\t<\/div>\n\t\t<\/div>\n\t\t<!-- end of the left (by default at least) column -->\n\t\t<div class=\"visualClear\"><\/div>\n\t\t\t\t\t\n\t\t<\/div>\n\t\t\n\n<\/body>","dbbafbdedf3c364c6925d8378915086c_images":["https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/2\/26\/Fig1_Bhattacharya_AIMSPubHlth2019_6-3.png","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/8\/81\/Fig2_Bhattacharya_AIMSPubHlth2019_6-3.png","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/3\/3a\/Fig3_Bhattacharya_AIMSPubHlth2019_6-3.png"],"dbbafbdedf3c364c6925d8378915086c_timestamp":1594155040,"6916dfabf162fd46a0d0c48e26b03db4_type":"article","6916dfabf162fd46a0d0c48e26b03db4_title":"BlueTrace: A privacy-preserving protocol for community-driven contact tracing across borders (Bay et al. 2020)","6916dfabf162fd46a0d0c48e26b03db4_url":"https:\/\/www.limswiki.org\/index.php\/Journal:BlueTrace:_A_privacy-preserving_protocol_for_community-driven_contact_tracing_across_borders","6916dfabf162fd46a0d0c48e26b03db4_plaintext":"\n\n\t\t\n\t\t\t\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t\n\n\t\t\t\tJournal:BlueTrace: A privacy-preserving protocol for community-driven contact tracing across borders\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t\tFrom LIMSWiki\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\tJump to: navigation, search\n\n\t\t\t\t\t\n\t\t\t\t\tFull article title\n \nBlueTrace: A privacy-preserving protocol for community-driven contact tracing across bordersAuthor(s)\n \nBay, Jason; Kek, Joel; Tan, Alvin; Hau, Chai S.; Yongquan, Lai; Tan, Janice; Quy, Tang A.Author affiliation(s)\n \nSingapore's Government Technology AgencyPrimary contact\n \nEmail: info at bluetrace dot ioYear published\n \n2020Page(s)\n \n1\u20139Distribution license\n \nReproduced with written permissionWebsite\n \nhttps:\/\/bluetrace.io\/Download\n \nhttps:\/\/bluetrace.io\/static\/bluetrace_whitepaper-938063656596c104632def383eb33b3c.pdf (PDF)\n\n\n\n\n \n This article is not a peer-reviewed journal article but rather a white paper. The content should not be considered established information without consulting multiple experts in the associated field. However, the journal-style format was the most appropriate for reproducing the paper on this wiki. \n\n\nContents\n\n1 Abstract \n2 Context \n3 Overview of BlueTrace \n4 Data protection and privacy safeguards \n5 How BlueTrace works \n\n5.1 User registration and assignment of UserID \n5.2 Generation of TempIDs \n5.3 BLE handshake flow \n5.4 Scanning and advertising cycles \n5.5 Blacklisting \n5.6 Encounter message \n5.7 Storage of encounter history \n5.8 Contact tracing flow \n5.9 Data analysis flow \n5.10 Withdraw of consent \n\n\n6 Protocol design considerations \n\n6.1 Bluetooth or GPS \n6.2 Generation of TempID by backend service vs. on device \n6.3 Centralised vs decentralised contact tracing \n6.4 Human-in-the-loop vs. human-out-of-the-loop \n\n\n7 Implementation challenges \n\n7.1 iOS background Bluetooth limitations \n7.2 Difference in transmission power across devices \n\n\n8 Federation and interoperability \n\n8.1 Guiding principles \n8.2 Registry of BlueTrace Health Authorities \n8.3 Generation of TempIDs \n8.4 Processing of BlueTrace encounter history across health authorities \n\n\n9 Security considerations \n\n9.1 Encounter message replay\/relay attack \n9.2 Bluetooth vulnerabilities \n\n\n10 Legal considerations \n11 Conclusion \n12 Notes \n\n\n\nAbstract \nTraceTogether is the first national deployment of a Bluetooth-based contact tracing system in the world. It was developed by Singapore\u2019s Government Technology Agency and the Ministry of Health to help the country better respond to epidemics. \nFollowing its release, more than 50 governments have expressed interest in adopting or adapting TraceTogether for their countries. Responding to this interest, we are releasing an overview of BlueTrace, the privacy-preserving protocol that underpins TraceTogether, as well as OpenTrace, a reference implementation. \nOpenTrace comprises the source code for an iOS app, an Android app, a cloud-based backend, and baseline signal strength calibration data. This will be made available to the open source community at github.com\/opentrace-community on 9 April 2020.\n\nContext \nContact tracing is an important tool for reducing the spread of infectious diseases. Its goal is to reduce a disease\u2019s effective reproductive number (R) by identifying people who have been exposed to the virus through an infected person and contacting them to provide early detection, tailored guidance, and timely treatment. By stopping virus transmission chains, contact tracing helps \u201cflatten the curve\u201d and reduces the peak burden of a disease on the healthcare system. Contact tracing forms an essential part of Singapore\u2019s response to the COVID-19 pandemic.\n\nOverview of BlueTrace \nBlueTrace is a protocol for logging Bluetooth encounters between participating devices to facilitate contact tracing, while protecting the users\u2019 personal data and privacy.\nWhen two participating devices encounter each other, they exchange non-personally identifiable messages that contain temporary identifiers. The identifiers rotate frequently to prevent third parties from tracking users. The user\u2019s encounter history is stored locally on their device; none of this data can be directly accessed by the health authority.\nIf a user is infected or is the subject of contact tracing, they will be asked to share their encounter history with the relevant health authority with the use of a PIN. (A verification code may optionally be provided, to authenticate the health authority official\u2019s request.) Only the health authority has the ability to decrypt the shared encounter history to obtain and use personally-identifiable information and to subsequently filter for close contacts and notify potentially infected users.\nBlueTrace is designed to supplement manual contact tracing by addressing its key limitation: an infected person can only report contacts they are acquainted with and remember having met. BlueTrace could also allow for contact tracing to be more scalable and less resource-intensive.\nBlueTrace also allows a federated network of credentialed health authorities to each maintain distinct user bases, while allowing for contact tracing between users from different health authority jurisdictions (more later in the section \"Federation and interoperability\").\n\nData protection and privacy safeguards \nWe believe that even during pandemics, public health and personal privacy should not be a binary choice. BlueTrace is designed to safeguard user privacy and give users control of their data. The protocol includes the following privacy safeguards:\n\n Limited collection of personally-identifiable information: The only personally-identifiable information collected is a phone number, which is securely stored by the health authority.\n Local storage of encounter history: Each user\u2019s encounter history is stored exclusively on their own device. The health authority only has access to this history when an infected person chooses to share it.\n Prevention of third-party tracking: Third parties cannot use BlueTrace communications to track users over time. A device\u2019s temporary identifier rotates frequently, preventing malicious actors from tracking individual users over time by sniffing for BlueTrace messages.\n Revocable consent: Users have control of their personal data. When they withdraw consent, all personally-identifiable data stored at the health authority is deleted. All encounter history will thus cease to be linked to the user.\nHow BlueTrace works \nUser registration and assignment of UserID \nWhen the user of a BlueTrace-implementing app registers with their phone number, the back-end service generates a unique, randomised UserID and associates it with the user\u2019s phone number (Figure 1).\n\r\n\n\n\n\n\n\n\n\n\n\n Figure 1. User registration\n\n\n\nPhone numbers are the only personally-identifiable information required from the user. The phone numbers are used to contact users if they are found to have had prolonged exposure to an infected person. Alternative implementations of BlueTrace that do not require a phone number are possible, however. These might rely on push notification tokens to alert individual users (see the next section \"Protocol design considerations\").\n\nGeneration of TempIDs \nBlueTrace devices log encounters with each other by exchanging messages over Bluetooth. To protect users\u2019 privacy, these messages cannot reveal a user's identity. Additionally, in order to prevent users from being tracked over time by third parties, these messages cannot contain static identifiers. However, when an infected user uploads these messages to the health authority, the authority must be able to obtain contact information from the messages.\nBlueTrace addresses this by having users exchange temporary IDs (TempIDs). Each TempID comprises a UserID, created time, and expiry time encrypted symmetrically with AES-256-GCM and then Base64-encoded (Figure 2). Only the health authority holds the secret key to encrypt and decrypt TempIDs. Each TempID is generated with a random initialisation vector (IV).\n\r\n\n\n\n\n\n\n\n\n\n\n Figure 2. Format of TempID\n\n\n\nTempIDs have a short lifetime (we recommend 15 minutes). This helps to mitigate the impact of replay attacks by reducing the window of opportunity for exploitation. If malicious users impersonate other users by rebroadcasting their messages, they will only be able to do so for a short time before the message expires. This duration would likely be below the threshold duration of close contact, and hence not result in false positives (more later in the section \"Encounter Message replay\/relay attacks\").\nIn order to ensure that devices have a supply of valid TempIDs even when the internet connection is unstable, devices pull batches of forward-dated TempIDs from the health authority\u2019s back-end service each time (Figure 3).\n\r\n\n\n\n\n\n\n\n\n\n\n Figure 3. TempIDs sent to device\n\n\n\nBLE handshake flow \nBlueTrace devices exchange messages over the Bluetooth Low Energy (BLE) protocol. In BLE parlance, devices can take on peripheral or central roles. Peripherals advertise services, and centrals scan for peripherals\u2019 advertisements to connect to their services. Services are a collection of data, such as characteristics, which are specific data that can be exchanged between devices, through read and writes performed by a central role. The data exchanged by BlueTrace devices in each \u201chandshake\u201d is called an \"encounter message.\"\nDevices using BlueTrace act as both a central and a peripheral and may alternate between these roles. When two devices connect, the central reads the peripheral\u2019s encounter message and then writes back its own encounter message; each connection allows for a two-way exchange of data between the central and peripheral (Figure 4). Allowing for two-way communications promotes symmetry and addresses the limitation where some devices (and possibly wearables) are only able to function as peripherals.\n\r\n\n\n\n\n\n\n\n\n\n\n Figure 4. BLE handshake flow\n\n\n\nScanning and advertising cycles \nBlueTrace devices scan and advertise on configurable cycles. Scanning occurs with a duty cycle around 15 to 20%, during which devices scan for other BlueTrace devices as central. Devices may optionally introduce random jitter into the length and duty ratio of each scanning cycle to avoid lockstep behaviour.\nAdvertising occurs with a higher duty cycle of around 90 to 100%. We recommend a shorter duty cycle for scanning to conserve resources. We also recommend that the sum of both scanning and advertising duty cycles be greater than one to ensure that devices have the opportunity to see each other.\n\nBlacklisting \nTo ensure an even distribution of Bluetooth \u201chandshakes\u201d with as many nearby BlueTrace devices as possible, BlueTrace devices should implement a blacklist of recently seen devices and not attempt to connect to them for the duration of the blacklist period. On both Android and iOS devices, the length of this blacklist period is between one and two scanning cycles.\nNote that the blacklist can be negated by peripherals that perform device identifier randomisation regularly. On some Android devices, this can happen extremely frequently. Such devices tend to be scanned by centrals repeatedly, preventing an even distribution of encounters with nearby devices.\nWe are experimenting with different methods of preventing repetitive connections. We will incorporate recommended solutions within this document and make the corresponding contributions to the OpenTrace reference implementation in due course.\n\nEncounter message \nThe encounter message is a UTF-8-encoded JSON file. The fields in the JSON file differ slightly depending on the direction of communication.\nThe peripheral\u2019s encounter message is advertised by the peripheral as a characteristic value, so that a central can scan for and read it after discovering the peripheral and its valid vharacteristic. It is in the following format (as of Version 2):\n\n\n{\n \/\/ TempID of the peripheral\n "id": "Fj5jfbTtDySw8JoVsCmeul0wsoIcJKRPV0HtEFUlNvNg6C3wyGj8R1utPbw+Iz8tqAdpbxR1nSvr+ILXPG==",\n \/\/ Device model of the peripheral, to calibrate distance estimates\n "mp": "Samsung S8",\n \/\/ Organisation code indicating the country and health authority with which the peripheral is enrolled\n "o": "SG_MOH",\n \/\/ Version of the BlueTrace protocol that the peripheral is running\n "v": 2\n}\n\n\nThe central\u2019s encounter message is returned to the peripheral as a characteristic value, that a central writes back to the peripheral before closing the connection. It is in the following format (as of Version 2):\n\n\n{\n \/\/ TempID of the central\n "id": "Fj5jfbTtDySw8JoVsCmeul0wsoIcJKRPV0 HtEFUlNvNg6C3wyGj8R1utPbw+Iz8tqAdpbxR1nSvr+ILXPG==",\n \/\/ Device model of the central, to calibrate distance estimates\n "mc": "iPhone X",\n \/\/ Received Signal Strength Indicator (RSSI) as measured by the central of the peripheral\n "rs": -60,\n \/\/ Organisation code indicating the country and health authority with which the Central is enrolled\n "o": "SG_MOH",\n \/\/ Version of the BlueTrace protocol that the central is running\n "v": 2\n}\n\n\nThe main difference is that the message originating from central contains the RSSI field. This is necessary because although the central and peripheral communicate in both directions, only the central can record RSSI. Thus, the central records the RSSI reading of the peripheral, and then returns this information to the peripheral so that both devices have symmetric knowledge, and so that the RSSI and device model can be used to estimate distance subsequently.\nIn testing, we have encountered a message size limit with some devices. This message format fits well within that constraint. If there is a need to accommodate devices with smaller message size limits, it is possible to use a byte array instead of JSON, and also to base64 decode the TempID.\nMigrations to new message formats are possible by advertising multiple characteristics within the service, each corresponding to a different protocol version. This way, devices maintain backward compatibility while allowing the protocol to evolve (Figure 5).\n\r\n\n\n\n\n\n\n\n\n\n\n Figure 5. Protocol evolution by advertising multiple characteristics\n\n\n\nStorage of encounter history \nBoth central and peripheral devices store each \u201chandshake\u201d as an entry in its encounter history for a certain number of days (for OpenTrace, 21 days) before deletion. Devices can also be configured to log when a scan is performed, to differentiate between the absence of scanning and the absence of nearby devices.\n\nContact tracing flow \nWhen patients have been confirmed to be infected, health authorities ask them if they have the app installed. If they do, they are asked to upload their encounter history to the health authority (Figure 6).\n\r\n\n\n\n\n\n\n\n\n\n\n Figure 6. Upload of encounter history to health authority\n\n\n\nTo protect users and the system from fraudulent uploads, an authorisation code is provided by the health authority and entered through the app in order to obtain a valid token to transmit the logs.\n\nData analysis flow \nThe health authority decrypts the TempID for each encounter in the uploaded encounter history in order to obtain the UserID and validity period. It then verifies that the encounter timestamp for each TempID falls within its validity period. The health authority then filters for close contacts based on the disease\u2019s epidemiological parameters: time of exposure (measured by the length of a continuous cluster of encounters) and distance (measured by the received signal strength reading).\nIn Singapore, the contact tracing process involves an interview with the patient, where the patients are asked to recall where they have been and who they have been in contact with recently. This information is used together with the BlueTrace data to adjust the proximity and duration filtering thresholds based on the patient-reported location and context. The health authority then contacts individuals assessed to have a high likelihood of exposure to the disease, to provide medical guidance and care. \nNote that this workflow can be automated and decentralised without affecting interoperability with other BlueTrace implementations. However, we do not recommend this, and we have therefore not implemented it in OpenTrace. (For further discussion, see the next section \"Protocol design considerations\").\n\nWithdraw of consent \nWe believe users should be in control of their personal data and have the ability to delete this from the system. If a user withdraws consent to use their personal data, their UserID and phone number should be deleted from the back-end database. Since the phone number is the only source of identity, deleting it will render useless all of this user\u2019s TempIDs that were previously sent to other devices.\n\nProtocol design considerations \nBluetooth or GPS \nBluetooth and GPS contact tracing solutions were both considered. Table 1 illustrates the main differences.\n\n\n\n\n\n\n\nTable 1. Comparison between Bluetooth and GPS contact tracing\n\n\nAspect\n\nBluetooth\n\nGPS\n\n\nGeneral approach\n\nDevices log encounters with other devices. Infected users upload their encounter history.\n\nDevices log their GPS location. Infected users upload their location history.\n\n\nAccuracy (As a reference, widely-accepted epidemiological parameter for close contact with COVID-19 patient is 30 minutes at a distance of less than two metres.)\n\nAble to approximate close contacts within two metres by filtering encounters by signal strength.\r\n \r\nNote that Bluetooth has a range of 10 metres in indoor environments, but RSSI follows inverse square law and drops off quickly with distance. However, calibration is necessary for maximal effectiveness as different devices transmit at different powers.\n\nUnable to filter for proximity.\r\n \r\nNote that GPS has accuracy of 10 metres, which decreases in urban environments with tall buildings. Limited vertical accuracy (for floor detection) means that most people within a single skyscraper would register within the margin of error. GPS also exhibiys poor accuracy in moving or underground environments like a subway train.\n\n\nAdoption challenges\n\nRequires high adoption to be effective, because effectiveness is a quadratic function of adoption.\n\nRequires high adoption to be effective, because effectiveness is a quadratic function of adoption unless other data sources are incorporated. Public wariness and possible alarm about tracking location data of individuals could hamper adoption.\n\n\nBattery use\n\nLow\n\nMedium\n\n\n\nBluetooth was chosen because it is able to classify close contacts with a significantly lower false positive rate than GPS. Given that GPS accuracy decreases in indoor environments, entire shopping malls, or skyscrapers would be within the margin of error of a single GPS point. Furthermore, adoption could be hampered by the public wariness of location tracking and increased battery drain.\n\nGeneration of TempID by backend service vs. on device \nIn the reference implementation, TempIDs are cryptographically generated by the backend service. The downside is that this requires devices to connect periodically to the internet. We account for periods without connectivity by issuing a batch of TempIDs at a time.\nAn alternative to this approach would be for the UserID to be stored on the device, and for TempIDs to be generated locally using an asymmetric encryption key, with the backend service holding the corresponding decryption key. The asymmetric encryption key can be generated by the backend service and sent to the user device using registration. However, we found that this cryptographic scheme increased the computational requirement on devices beyond the OS-allocated limits, especially when in background execution mode.\nApart from minimising on-device compute requirements, server-side TempID generation has a secondary benefit of allowing the health authority to understand adoption and usage levels of the app by logging the issuance of daily batches of TempIDs, as well as the app's potential effectiveness in epidemic control. This could then be used to inform public health policy interventions.\n\nCentralised vs decentralised contact tracing \nBlueTrace envisages a blend of decentralised proximity data collection and logging, with a centralised contact tracing capability.\nEncounter messages and encounter histories are exchanged and stored in a decentralised, peer-to-peer manner, without the participation of a central server. We defer the centralised collection and processing of data to the last possible moment\u2014when a diagnosis of COVID-19 is made\u2014and then provide this data to the trusted public health authority in the OpenTrace reference implementation. Depending on the prevailing trust environment within which public health institutions operate, other jurisdictions may have different considerations that may favour a similar hybrid model or one that is completely decentralised.\nWe see various challenges with a purely decentralised contact tracing system. Individuals falsely declaring themselves infected would cause unnecessary anxiety and panic in other users and erode trust in the system. Some form of authorisation for users to either flag themselves as positive COVID-19 cases, or to upload encounter history, is therefore necessary to protect against abuse. Ultimately, this type of authorisation will have to be provided by a credentialed health institution or healthcare worker, who may or may not be part of a public health authority\u2019s infectious disease surveillance system, but would likely have to obtain the upload authorisation code through a chain of trust rooted in a centralised public health authority. This also has the benefit of ensuring that relevant information about the epidemic and the effect and effectiveness of such contact tracing systems is provided to the public health authority, to aid in planning public health interventions.\nFinally, another advantage of a centralised approach is keeping humans in the loop in making the assessment of the appropriate follow-up actions.\n\nHuman-in-the-loop vs. human-out-of-the-loop \nIt is possible to implement the BlueTrace protocol and have automated notification of probable close contacts of persons who have been diagnosed with COVID-19. In theory, we appreciate the privacy and scalability benefits of doing so. In practice, our ongoing conversations with public health authority officials performing epidemic surveillance and conducting contact tracing operations compel us to recommend otherwise.\nAn automated algorithm will necessarily generate both false negatives and false positives. A human contact tracer will similarly make mistakes. However, because a human contact tracer would seek to incorporate information beyond just physical proximity, he\/she can correct for systematic biases introduced by a purely automated notification system.\nEncounters between individuals can be classified into close, casual, and transient contacts for epidemiological purposes, based on proximity and duration of contact. However, these classifications depend on factors such as location and environment. For example, short-duration encounters in enclosed spaces without fresh ventilation often constitute close contact, even if encounter proximity and duration do not meet algorithmic thresholds. Since Bluetooth-based contact tracing solutions do not, by themselves, record location and environment data, this information needs to be obtained through other means: a human-led contact tracing interview.\nA human-in-the-loop system is also necessary to allow judgment to be applied, given the high likelihood of pre-symptomatic transmission of the SARS-CoV-2 virus. Since time is of the essence, contact tracers may preemptively wish to trace selected second-degree close contacts of a COVID-19 patient, in cases where there is a high likelihood of exposure and infection, even if the first-degree close contact has yet to test positive. For example, there may be epidemiological value in tracing close contacts of a close relative of an infected person.\nWe note that a human-out-of-the-loop system will certainly yield better results than having no system at all, but where a competent human-in-the-loop system with sufficient capacity exists, we caution against an over-reliance on technology.\nFinally, the experience of Singapore\u2019s contact tracers suggest that contact tracing should remain a human-fronted process. Contact tracing involves an intensive sequence of difficult and anxiety-laden conversations, and it is the role of a contact tracer to explain how a close contact might have been exposed\u2014while respecting patient privacy\u2014and provide assurance and guidance on next steps.\nSingapore\u2019s contact tracers are on the frontline of the fight against COVID-19; they are able to do this because they incorporate multiple sources of information, demonstrate sensitivity in their conversations with Singaporeans who have had probable exposure to SARS-CoV-2, and help to minimise unnecessary anxiety and unproductive panic. These are considerations that an automated algorithm may have difficulty explaining to worried users.\n\nImplementation challenges \niOS background Bluetooth limitations \nWhile the Android version of the OpenTrace reference implementation functions fully as both central and peripheral while the app is in both foreground and background execution modes, the iOS version of OpenTrace is bound by restrictions that iOS has on background Bluetooth functionality.\nWhen in the background, the iOS app advertises in a proprietary advertisement format that is not part of the Bluetooth standard and thus not readable by non-iOS devices. It is also unable to scan for other BlueTrace devices in any meaningful way.\nThe current workaround is to encourage iOS users to keep their app in the foreground, especially when in higher-risk environments. Within the OpenTrace reference implementation, we have implemented a \u201cpower saver mode,\u201d where users can flip the phone upside down to dim the screen so the app uses less battery power while in the foreground. Users, particularly inactive users, also receive push notifications to remind them to use the app, especially during commuting peak hours. The app also prompts the user if inadequate permissions are granted or Bluetooth is turned off, resulting in the app being unable to function normally.\n\nDifference in transmission power across devices \nBlueTrace uses RSSI readings to approximate distance. However, through tests of devices in anechoic chambers, we have established that the variance in transmission power across popular mobile devices can be as large as 30 dB (1000x). During testing, we have also discovered that transmission power varies little between different devices of the same model and is minimally affected by mobile phone cases. In order to account for this difference, we have taken reference signal strength readings for popular mobile devices in Singapore. We use this to calibrate RSSI readings when classifying encounters by proximity.\nWe have shared this data at github.com\/opentrace-community. We invite developers and handset manufacturers to contribute to this so that it can serve as a universal calibration table of device transmission powers for any Bluetooth contact tracing solution.\n\nFederation and interoperability \nFederation is a common and natural extension of national systems, and BlueTrace welcomes collaboration with the international community to facilitate community-driven cross-border contact tracing. BlueTrace was designed with interoperability in mind while maintaining flexibility for adopters of its protocol. Where possible, the protocol allows health authorities to customise and adapt the protocol to suit their use cases.\n\nGuiding principles \nBlueTrace\u2019s guiding principles on federation and interoperability are:\n\n Each health authority should be allowed to administer their own set of users separate from other authorities. The user identity and contact information belonging to users of one health authority should never be exposed to another health authority.\n Each health authority can use its own algorithm for generating TempIDs and determining the validity period of the TempID. The TempID should allow the health authority to obtain the associated user\u2019s contact details.\n Each health authority is responsible for the storage and protection of users\u2019 identifiers and shared encounter history.\n Each health authority\u2019s mobile client app must perform communication exchanges using the BlueTrace encounter message format.\n OpenTrace has a set of default configurations for scanning and advertising cycles, but each health authority has the flexibility to configure the scanning and advertising cycle as it deems fit.\nRegistry of BlueTrace Health Authorities \nA registry of BlueTrace Health Authorities consolidates the list of international participating authorities. The registry contains information about the participating authority such as name, organisation code, contact person details, and an endpoint to allow anonymised information to be exchanged between authorities. The organisation code which is sent as part of the encounter exchange message follows a specific format: ISO 3166 country code (two characters) followed by an organisation unit (three characters) with an underscore separator, e.g. SG_MOH. In countries where there are multiple health authorities, the organisation unit can be used for intra-country federation. \nInterested health authorities will need to email a request to BlueTrace at info@bluetrace.io before being added to the global registry. BlueTrace recommends that only a single Health Authority BlueTrace app be installed and activated on a user device for maximum effectiveness.\nAll Health Authorities that are part of the BlueTrace registry are required to implement several requirements: be able to exchange TempID for PseudoID, and be able to be notified of PseudoIDs that have close contact.\n\nGeneration of TempIDs \nBlueTrace maintains interoperability while preserving flexibility for each health authority [Figure 7]. Each authority has its own user base, datastore, and algorithm to generate TempIDs for its users. BlueTrace does not limit the information collected during registration as long as the user can be traced back to a valid phone number or can otherwise be alerted. This could be through a push notification. The two different mobile clients communicate via the BlueTrace Protocol and transfer encounter messages. Each encounter message received by the device is then logged and stored.\n\r\n\n\n\n\n\n\n\n\n\n\n Figure 7. Interoperability between two health authorities\n\n\n\nProcessing of BlueTrace encounter history across health authorities \nWhen a patient is diagnosed with COVID-19, the patient will be approached by the health authority to upload their data. The data which contains TempIDs and records belonging to other authorities as well as its own is then processed by the backend. The differentiation is done through the organisation code indicated in the exchange message.\nThe health authority refers to the registry of BlueTrace health authorities and forwards the TempID and timestamp to the endpoint corresponding to the organisation code. The TempID will be validated by ensuring that its timestamp falls within its validity period. The endpoint then returns a PseudoID. The PseudoID allows correlating to a unique individual for analysis in place of a TempID which changes frequently. It could be a hash of the user\u2019s UserID or a randomly generated unique identifier that is mapped to the user\u2019s UserID. Once the PseudoID is assessed to be a close contact of the infected patient, the foreign health authority, which issued the PseudoID will be informed of the close contact period and duration and can then follow-up as necessary. The process is illustrated in Figure 8 below.\n\r\n\n\n\n\n\n\n\n\n\n\n Figure 8. Upload and processing of BlueTrace records\n\n\n\nSecurity considerations \nEncounter message replay\/relay attack \nThe BlueTrace protocol relies heavily on the exchange of messages through Bluetooth. This makes it susceptible to replay and relay attacks as an attacker has free access to capture the message being transmitted from a BlueTrace user\u2019s mobile device. The attacker can replicate the message (but is unable to modify the TempID) and replay\/relay it across multiple locations to make it appear as if the compromised user had close contact with many other devices. BlueTrace minimises this attack vector for replay (but not relay) attacks by reducing the validity of each TempIDs to 15 minutes (which strikes a balance between threat mitigation and computation intensity). If an expired TempID is collected by a BlueTrace user, when it gets uploaded to the backend, the backend service will reject the record after checking the timestamp and validity of the TempID. In addition, the attacker will need to stay within BLE range continuously, in order to capture the latest encounter message from the BlueTrace user.\nUltimately, protecting against a replay\/relay attack is performed not through a technical solution but through a process solution. In the Singapore implementation, a human contact tracer will corroborate the circumstances under which an encounter has occurred, when contacting the flagged close contact, as discussed previously in regards to the human-in-the-loop vs. human-out-of-the-loop design decision.\n\nBluetooth vulnerabilities \nMany smartphone users today use Bluetooth to connect their phones with peripherals such as smart watches, headphones, etc. While it is unlikely that the use of a BlueTrace app by itself introduces additional vulnerabilities, vulnerabilities are occasionally discovered in the underlying technology that BlueTrace depends on, i.e., Bluetooth. These vulnerabilities have to be patched at the operating system-level, and we therefore urge users to ensure that their operating systems are regularly patched. BlueTrace apps may consider notifying users if an outdated operating system is detected in order to prompt users to update them.\n\nLegal considerations \nWe note that data protection and privacy regulations differ from country to country. Health authorities that wish to deploy a BlueTrace-implementing app, whether built on top of OpenTrace or not, should seek separate legal advice on the appropriate consent mechanisms and data protection provisions in the design of the specific implementation of BlueTrace that is contemplated. Nothing in this white paper or protocol specification should be construed as legal advice in any domestic or international context.\n\nConclusion \nWe hope that our description of the BlueTrace protocol, with occasional references to how it is being implemented in Singapore, provides insight to others seeking to deploy Bluetooth-based contact tracing solutions in their own communities. We have documented the protocol and system design choices with a view to enabling globally interoperable, community-driven contact tracing. These will necessarily have to be adapted to the prevailing domestic context for each BlueTrace-implementing system. Bluetooth-based contact tracing is not a silver bullet for dealing with the COVID-19 pandemic; it must ultimately coexist and support the pandemic response plans and processes of the public health authorities guiding us through these difficult times. \nWe welcome suggestions on this white paper and protocol at info@bluetrace.io.\n\nNotes \nThis presentation is faithful to the original, with only a few minor changes presentation. Some grammar was corrected for clarity. Written permission to reproduce this white paper was received prior to publishing on LIMSwiki.\n\n\n\n\n\n\nSource: <a rel=\"external_link\" class=\"external\" href=\"https:\/\/www.limswiki.org\/index.php\/Journal:BlueTrace:_A_privacy-preserving_protocol_for_community-driven_contact_tracing_across_borders\">https:\/\/www.limswiki.org\/index.php\/Journal:BlueTrace:_A_privacy-preserving_protocol_for_community-driven_contact_tracing_across_borders<\/a>\n\t\t\t\t\tCategories: LIMSwiki journal articles (added in 2020)LIMSwiki journal articles (all)LIMSwiki journal articles on cybersecurityLIMSwiki journal articles on epidemiologyLIMSwiki journal articles on public health informatics\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\n\t\t\t\t\n\t\t\t\n\t\t\n\t\t\n\t\t\tNavigation menu\n\t\t\t\t\t\n\t\t\tViews\n\n\t\t\t\n\t\t\t\t\n\t\t\t\tJournal\n\t\t\t\tDiscussion\n\t\t\t\tView source\n\t\t\t\tHistory\n\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\n\t\t\t\t\n\t\t\t\tPersonal tools\n\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\t\t\tLog in\n\t\t\t\t\t\t\t\t\t\t\t\t\tRequest account\n\t\t\t\t\t\t\t\t\t\t\t\n\t\t\t\t\n\t\t\t\n\t\t\t\n\t\t\t\t\n\t\t\t\n\t\t\t\t\n\t\tNavigation\n\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\tMain page\n\t\t\t\t\t\t\t\t\t\t\tRecent changes\n\t\t\t\t\t\t\t\t\t\t\tRandom page\n\t\t\t\t\t\t\t\t\t\t\tHelp\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\n\t\t\t\n\t\t\tSearch\n\n\t\t\t\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t \n\t\t\t\t\t\t\n\t\t\t\t\n\n\t\t\t\t\t\t\t\n\t\t\n\t\t\t\n\t\t\tTools\n\n\t\t\t\n\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\tWhat links here\n\t\t\t\t\t\t\t\t\t\t\tRelated changes\n\t\t\t\t\t\t\t\t\t\t\tSpecial pages\n\t\t\t\t\t\t\t\t\t\t\tPermanent link\n\t\t\t\t\t\t\t\t\t\t\tPage information\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\n\t\t\n\t\tPrint\/export\n\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\tCreate a book\n\t\t\t\t\t\t\t\t\t\t\tDownload as PDF\n\t\t\t\t\t\t\t\t\t\t\tDownload as Plain text\n\t\t\t\t\t\t\t\t\t\t\tPrintable version\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\n\t\t\n\t\tSponsors\n\t\t\n\t\t\t \r\n\n\t\r\n\n\t\r\n\n\t\n\t\r\n\n\t\r\n\n\t\n\t\r\n\n \n\t\r\n\n\t\n\t\r\n\n \n\t\n\t\r\n\n\t\n\t\n\t\r\n\n\t\r\n\n\t\r\n\n\t\n\t\r\n\n\t\r\n\t\t\n\t\t\n\t\t\t\n\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t This page was last modified on 15 May 2020, at 01:48.\n\t\t\t\t\t\t\t\t\tThis page has been accessed 597 times.\n\t\t\t\t\t\t\t\t\tContent is available under a Creative Commons Attribution-ShareAlike 4.0 International License unless otherwise noted.\n\t\t\t\t\t\t\t\t\tPrivacy policy\n\t\t\t\t\t\t\t\t\tAbout LIMSWiki\n\t\t\t\t\t\t\t\t\tDisclaimers\n\t\t\t\t\t\t\t\n\t\t\n\t\t\n\t\t\n\n","6916dfabf162fd46a0d0c48e26b03db4_html":"<body class=\"mediawiki ltr sitedir-ltr ns-206 ns-subject page-Journal_BlueTrace_A_privacy-preserving_protocol_for_community-driven_contact_tracing_across_borders skin-monobook action-view\">\n<div id=\"rdp-ebb-globalWrapper\">\n\t\t<div id=\"rdp-ebb-column-content\">\n\t\t\t<div id=\"rdp-ebb-content\" class=\"mw-body\" role=\"main\">\n\t\t\t\t<a id=\"rdp-ebb-top\"><\/a>\n\t\t\t\t\n\t\t\t\t\n\t\t\t\t<h1 id=\"rdp-ebb-firstHeading\" class=\"firstHeading\" lang=\"en\">Journal:BlueTrace: A privacy-preserving protocol for community-driven contact tracing across borders<\/h1>\n\t\t\t\t\n\t\t\t\t<div id=\"rdp-ebb-bodyContent\" class=\"mw-body-content\">\n\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\n\n\t\t\t\t\t<!-- start content -->\n\t\t\t\t\t<div id=\"rdp-ebb-mw-content-text\" lang=\"en\" dir=\"ltr\" class=\"mw-content-ltr\">\n\n\n\n<h2><span class=\"mw-headline\" id=\"Abstract\">Abstract<\/span><\/h2>\n<p>TraceTogether is the first national deployment of a <a href=\"https:\/\/en.wikipedia.org\/wiki\/Bluetooth\" class=\"extiw wiki-link\" title=\"wikipedia:Bluetooth\" data-key=\"bf7b2ce888d74d287b869156ab12eee2\">Bluetooth<\/a>-based <a href=\"https:\/\/www.limswiki.org\/index.php\/Contact_tracing\" title=\"Contact tracing\" class=\"wiki-link\" data-key=\"6527a70b24b6f9b489bcec301240b0d8\">contact tracing<\/a> system in the world. It was developed by Singapore\u2019s Government Technology Agency and the Ministry of Health to help the country better respond to <a href=\"https:\/\/www.limswiki.org\/index.php\/Epidemiology\" title=\"Epidemiology\" class=\"wiki-link\" data-key=\"123badb8bf0b37a513182dbcfc3875bc\">epidemics<\/a>. \n<\/p><p>Following its release, more than 50 governments have expressed interest in adopting or adapting TraceTogether for their countries. Responding to this interest, we are releasing an overview of BlueTrace, the privacy-preserving protocol that underpins TraceTogether, as well as OpenTrace, a reference implementation. \n<\/p><p>OpenTrace comprises the source code for an iOS app, an Android app, a <a href=\"https:\/\/www.limswiki.org\/index.php\/Cloud_computing\" title=\"Cloud computing\" class=\"wiki-link\" data-key=\"fcfe5882eaa018d920cedb88398b604f\">cloud-based<\/a> backend, and baseline signal strength calibration data. This will be made available to the open source community at <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/github.com\/opentrace-community\" target=\"_blank\">github.com\/opentrace-community<\/a> on 9 April 2020.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Context\">Context<\/span><\/h2>\n<p><a href=\"https:\/\/www.limswiki.org\/index.php\/Contact_tracing\" title=\"Contact tracing\" class=\"wiki-link\" data-key=\"6527a70b24b6f9b489bcec301240b0d8\">Contact tracing<\/a> is an important tool for reducing the spread of infectious diseases. Its goal is to reduce a disease\u2019s <a href=\"https:\/\/en.wikipedia.org\/wiki\/Basic_reproduction_number#Notes\" class=\"extiw wiki-link\" title=\"wikipedia:Basic reproduction number\" data-key=\"1d3cd38d51f94e5df1cfd0331c00b907\">effective reproductive number<\/a> (R) by identifying people who have been exposed to the virus through an infected person and contacting them to provide early detection, tailored guidance, and timely treatment. By stopping virus transmission chains, contact tracing helps \u201cflatten the curve\u201d and reduces the peak burden of a disease on the healthcare system. Contact tracing forms an essential part of Singapore\u2019s response to the <a href=\"https:\/\/www.limswiki.org\/index.php\/COVID-19\" title=\"COVID-19\" class=\"mw-redirect wiki-link\" data-key=\"da9bd20c492b2a17074ad66c2fe25652\">COVID-19<\/a> <a href=\"https:\/\/www.limswiki.org\/index.php\/Pandemic\" title=\"Pandemic\" class=\"wiki-link\" data-key=\"bd9a48e6c6e41b6d603ee703836b01f1\">pandemic<\/a>.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Overview_of_BlueTrace\">Overview of BlueTrace<\/span><\/h2>\n<p>BlueTrace is a protocol for logging <a href=\"https:\/\/en.wikipedia.org\/wiki\/Bluetooth\" class=\"extiw wiki-link\" title=\"wikipedia:Bluetooth\" data-key=\"bf7b2ce888d74d287b869156ab12eee2\">Bluetooth<\/a> encounters between participating devices to facilitate contact tracing, while protecting the users\u2019 personal data and <a href=\"https:\/\/www.limswiki.org\/index.php\/Information_privacy\" title=\"Information privacy\" class=\"wiki-link\" data-key=\"185f6d9f874e48914b5789317408f782\">privacy<\/a>.\n<\/p><p>When two participating devices encounter each other, they exchange non-personally identifiable messages that contain temporary identifiers. The identifiers rotate frequently to prevent third parties from tracking users. The user\u2019s encounter history is stored locally on their device; none of this data can be directly accessed by the health authority.\n<\/p><p>If a user is infected or is the subject of contact tracing, they will be asked to share their encounter history with the relevant health authority with the use of a PIN. (A verification code may optionally be provided, to authenticate the health authority official\u2019s request.) Only the health authority has the ability to decrypt the shared encounter history to obtain and use personally-identifiable information and to subsequently filter for close contacts and notify potentially infected users.\n<\/p><p>BlueTrace is designed to supplement manual contact tracing by addressing its key limitation: an infected person can only report contacts they are acquainted with and remember having met. BlueTrace could also allow for contact tracing to be more scalable and less resource-intensive.\n<\/p><p>BlueTrace also allows a federated network of credentialed health authorities to each maintain distinct user bases, while allowing for contact tracing between users from different health authority jurisdictions (more later in the section \"Federation and interoperability\").\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Data_protection_and_privacy_safeguards\">Data protection and privacy safeguards<\/span><\/h2>\n<p>We believe that even during pandemics, <a href=\"https:\/\/www.limswiki.org\/index.php\/Public_health\" title=\"Public health\" class=\"wiki-link\" data-key=\"81092e25c0bd359cedd1b9f9dc350c86\">public health<\/a> and personal privacy should not be a binary choice. BlueTrace is designed to safeguard user privacy and give users control of their data. The protocol includes the following privacy safeguards:\n<\/p>\n<ul><li> <i>Limited collection of personally-identifiable information<\/i>: The only personally-identifiable information collected is a phone number, which is securely stored by the health authority.<\/li>\n<li> <i>Local storage of encounter history<\/i>: Each user\u2019s encounter history is stored exclusively on their own device. The health authority only has access to this history when an infected person chooses to share it.<\/li>\n<li> <i>Prevention of third-party tracking<\/i>: Third parties cannot use BlueTrace communications to track users over time. A device\u2019s temporary identifier rotates frequently, preventing malicious actors from tracking individual users over time by sniffing for BlueTrace messages.<\/li>\n<li> <i>Revocable consent<\/i>: Users have control of their personal data. When they withdraw consent, all personally-identifiable data stored at the health authority is deleted. All encounter history will thus cease to be linked to the user.<\/li><\/ul>\n<h2><span class=\"mw-headline\" id=\"How_BlueTrace_works\">How BlueTrace works<\/span><\/h2>\n<h3><span class=\"mw-headline\" id=\"User_registration_and_assignment_of_UserID\">User registration and assignment of UserID<\/span><\/h3>\n<p>When the user of a BlueTrace-implementing app registers with their phone number, the back-end service generates a unique, randomised UserID and associates it with the user\u2019s phone number (Figure 1).\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig1_BayWhitePaper2020.png\" class=\"image wiki-link\" data-key=\"e30fd3ef536102257b4703e0b31ff9a8\"><img alt=\"Fig1 BayWhitePaper2020.png\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/0\/04\/Fig1_BayWhitePaper2020.png\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Figure 1.<\/b> User registration<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>Phone numbers are the only personally-identifiable information required from the user. The phone numbers are used to contact users if they are found to have had prolonged exposure to an infected person. Alternative implementations of BlueTrace that do not require a phone number are possible, however. These might rely on <a href=\"https:\/\/en.wikipedia.org\/wiki\/Push_technology#Push_notification\" class=\"extiw wiki-link\" title=\"wikipedia:Push technology\" data-key=\"fe4fc5bdd085168737ec45a5c1f8ec3d\">push notification<\/a> tokens to alert individual users (see the next section \"Protocol design considerations\").\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Generation_of_TempIDs\">Generation of TempIDs<\/span><\/h3>\n<p>BlueTrace devices log encounters with each other by exchanging messages over Bluetooth. To protect users\u2019 privacy, these messages cannot reveal a user's identity. Additionally, in order to prevent users from being tracked over time by third parties, these messages cannot contain static identifiers. However, when an infected user uploads these messages to the health authority, the authority must be able to obtain contact information from the messages.\n<\/p><p>BlueTrace addresses this by having users exchange temporary IDs (TempIDs). Each TempID comprises a UserID, created time, and expiry time <a href=\"https:\/\/www.limswiki.org\/index.php\/Encryption\" title=\"Encryption\" class=\"wiki-link\" data-key=\"86a503652ed5cc9d8e2b0252a480b5e1\">encrypted<\/a> symmetrically with <a href=\"https:\/\/en.wikipedia.org\/wiki\/Galois\/Counter_Mode\" class=\"extiw wiki-link\" title=\"wikipedia:Galois\/Counter Mode\" data-key=\"3a977c3cd464eaf8b70b34f082edb030\">AES-256-GCM<\/a> and then <a href=\"https:\/\/en.wikipedia.org\/wiki\/Base64\" class=\"extiw wiki-link\" title=\"wikipedia:Base64\" data-key=\"286ec691b4a2b1be5d7d0467f81f0c5d\">Base64<\/a>-encoded (Figure 2). Only the health authority holds the secret key to encrypt and decrypt TempIDs. Each TempID is generated with a random <a href=\"https:\/\/en.wikipedia.org\/wiki\/Initialization_vector\" class=\"extiw wiki-link\" title=\"wikipedia:Initialization vector\" data-key=\"e9505830284bce988702d91f44e8a2cb\">initialisation vector<\/a> (IV).\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig2_BayWhitePaper2020.png\" class=\"image wiki-link\" data-key=\"030fff1ac5ab2c6d6a727b8043433e76\"><img alt=\"Fig2 BayWhitePaper2020.png\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/8\/8b\/Fig2_BayWhitePaper2020.png\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Figure 2.<\/b> Format of TempID<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>TempIDs have a short lifetime (we recommend 15 minutes). This helps to mitigate the impact of replay attacks by reducing the window of opportunity for exploitation. If malicious users impersonate other users by rebroadcasting their messages, they will only be able to do so for a short time before the message expires. This duration would likely be below the threshold duration of close contact, and hence not result in false positives (more later in the section \"Encounter Message replay\/relay attacks\").\n<\/p><p>In order to ensure that devices have a supply of valid TempIDs even when the internet connection is unstable, devices pull batches of forward-dated TempIDs from the health authority\u2019s back-end service each time (Figure 3).\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig3_BayWhitePaper2020.png\" class=\"image wiki-link\" data-key=\"cf89078d0cb05625535abcc1d66dde02\"><img alt=\"Fig3 BayWhitePaper2020.png\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/6\/65\/Fig3_BayWhitePaper2020.png\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Figure 3.<\/b> TempIDs sent to device<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<h3><span class=\"mw-headline\" id=\"BLE_handshake_flow\">BLE handshake flow<\/span><\/h3>\n<p>BlueTrace devices exchange messages over the <a href=\"https:\/\/en.wikipedia.org\/wiki\/Bluetooth_Low_Energy\" class=\"extiw wiki-link\" title=\"wikipedia:Bluetooth Low Energy\" data-key=\"497a25d1c8517b65afe41ce62592d90b\">Bluetooth Low Energy<\/a> (BLE) protocol. In BLE parlance, devices can take on peripheral or central roles. Peripherals advertise services, and centrals scan for peripherals\u2019 advertisements to connect to their services. Services are a collection of data, such as characteristics, which are specific data that can be exchanged between devices, through read and writes performed by a central role. The data exchanged by BlueTrace devices in each \u201c<a href=\"https:\/\/en.wikipedia.org\/wiki\/Handshaking\" class=\"extiw wiki-link\" title=\"wikipedia:Handshaking\" data-key=\"4315b7983177f15eb105c9ecf2eebb45\">handshake<\/a>\u201d is called an \"encounter message.\"\n<\/p><p>Devices using BlueTrace act as both a central and a peripheral and may alternate between these roles. When two devices connect, the central reads the peripheral\u2019s encounter message and then writes back its own encounter message; each connection allows for a two-way exchange of data between the central and peripheral (Figure 4). Allowing for two-way communications promotes symmetry and addresses the limitation where some devices (and possibly wearables) are only able to function as peripherals.\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig4_BayWhitePaper2020.png\" class=\"image wiki-link\" data-key=\"f74a46b88a24a35fd17729ed35dd3d18\"><img alt=\"Fig4 BayWhitePaper2020.png\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/9\/95\/Fig4_BayWhitePaper2020.png\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Figure 4.<\/b> BLE handshake flow<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<h3><span class=\"mw-headline\" id=\"Scanning_and_advertising_cycles\">Scanning and advertising cycles<\/span><\/h3>\n<p>BlueTrace devices scan and advertise on configurable cycles. Scanning occurs with a duty cycle around 15 to 20%, during which devices scan for other BlueTrace devices as central. Devices may optionally introduce random <a href=\"https:\/\/en.wikipedia.org\/wiki\/Packet_delay_variation\" class=\"extiw wiki-link\" title=\"wikipedia:Packet delay variation\" data-key=\"1f492fec070daa01d05e9f220753b245\">jitter<\/a> into the length and duty ratio of each scanning cycle to avoid lockstep behaviour.\n<\/p><p>Advertising occurs with a higher duty cycle of around 90 to 100%. We recommend a shorter duty cycle for scanning to conserve resources. We also recommend that the sum of both scanning and advertising duty cycles be greater than one to ensure that devices have the opportunity to see each other.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Blacklisting\">Blacklisting<\/span><\/h3>\n<p>To ensure an even distribution of Bluetooth \u201chandshakes\u201d with as many nearby BlueTrace devices as possible, BlueTrace devices should implement a blacklist of recently seen devices and not attempt to connect to them for the duration of the blacklist period. On both Android and iOS devices, the length of this blacklist period is between one and two scanning cycles.\n<\/p><p>Note that the blacklist can be negated by peripherals that perform device identifier randomisation regularly. On some Android devices, this can happen extremely frequently. Such devices tend to be scanned by centrals repeatedly, preventing an even distribution of encounters with nearby devices.\n<\/p><p>We are experimenting with different methods of preventing repetitive connections. We will incorporate recommended solutions within this document and make the corresponding contributions to the OpenTrace reference implementation in due course.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Encounter_message\">Encounter message<\/span><\/h3>\n<p>The encounter message is a <a href=\"https:\/\/en.wikipedia.org\/wiki\/UTF-8\" class=\"extiw wiki-link\" title=\"wikipedia:UTF-8\" data-key=\"c6b9b54c8f22f85d7056f9ef0590bfbc\">UTF-8<\/a>-encoded <a href=\"https:\/\/en.wikipedia.org\/wiki\/JSON\" class=\"extiw wiki-link\" title=\"wikipedia:JSON\" data-key=\"e0022d8edede1d399deb288231b10aad\">JSON<\/a> file. The fields in the JSON file differ slightly depending on the direction of communication.\n<\/p><p>The peripheral\u2019s encounter message is advertised by the peripheral as a characteristic value, so that a central can scan for and read it after discovering the peripheral and its valid vharacteristic. It is in the following format (as of Version 2):\n<\/p>\n<pre><tt>\n{\n \/\/ TempID of the peripheral\n "id": "Fj5jfbTtDySw8JoVsCmeul0wsoIcJKRPV0HtEFUlNvNg6C3wyGj8R1utPbw+Iz8tqAdpbxR1nSvr+ILXPG==",\n \/\/ Device model of the peripheral, to calibrate distance estimates\n "mp": "Samsung S8",\n \/\/ Organisation code indicating the country and health authority with which the peripheral is enrolled\n "o": "SG_MOH",\n \/\/ Version of the BlueTrace protocol that the peripheral is running\n "v": 2\n}\n<\/tt>\n<\/pre>\n<p>The central\u2019s encounter message is returned to the peripheral as a characteristic value, that a central writes back to the peripheral before closing the connection. It is in the following format (as of Version 2):\n<\/p>\n<pre><tt>\n{\n \/\/ TempID of the central\n "id": "Fj5jfbTtDySw8JoVsCmeul0wsoIcJKRPV0 HtEFUlNvNg6C3wyGj8R1utPbw+Iz8tqAdpbxR1nSvr+ILXPG==",\n \/\/ Device model of the central, to calibrate distance estimates\n "mc": "iPhone X",\n \/\/ Received Signal Strength Indicator (RSSI) as measured by the central of the peripheral\n "rs": -60,\n \/\/ Organisation code indicating the country and health authority with which the Central is enrolled\n "o": "SG_MOH",\n \/\/ Version of the BlueTrace protocol that the central is running\n "v": 2\n}\n<\/tt>\n<\/pre>\n<p>The main difference is that the message originating from central contains the RSSI field. This is necessary because although the central and peripheral communicate in both directions, only the central can record RSSI. Thus, the central records the RSSI reading of the peripheral, and then returns this information to the peripheral so that both devices have symmetric knowledge, and so that the RSSI and device model can be used to estimate distance subsequently.\n<\/p><p>In testing, we have encountered a message size limit with some devices. This message format fits well within that constraint. If there is a need to accommodate devices with smaller message size limits, it is possible to use a byte array instead of JSON, and also to base64 decode the TempID.\n<\/p><p>Migrations to new message formats are possible by advertising multiple characteristics within the service, each corresponding to a different protocol version. This way, devices maintain backward compatibility while allowing the protocol to evolve (Figure 5).\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig5_BayWhitePaper2020.png\" class=\"image wiki-link\" data-key=\"cc7e75b450ec0b74b16c4399320e31a4\"><img alt=\"Fig5 BayWhitePaper2020.png\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/1\/19\/Fig5_BayWhitePaper2020.png\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Figure 5.<\/b> Protocol evolution by advertising multiple characteristics<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<h3><span class=\"mw-headline\" id=\"Storage_of_encounter_history\">Storage of encounter history<\/span><\/h3>\n<p>Both central and peripheral devices store each \u201chandshake\u201d as an entry in its encounter history for a certain number of days (for OpenTrace, 21 days) before deletion. Devices can also be configured to log when a scan is performed, to differentiate between the absence of scanning and the absence of nearby devices.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Contact_tracing_flow\">Contact tracing flow<\/span><\/h3>\n<p>When patients have been confirmed to be infected, health authorities ask them if they have the app installed. If they do, they are asked to upload their encounter history to the health authority (Figure 6).\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig6_BayWhitePaper2020.png\" class=\"image wiki-link\" data-key=\"554ac2b65c867a2078437e7ce5a2e9d8\"><img alt=\"Fig6 BayWhitePaper2020.png\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/0\/07\/Fig6_BayWhitePaper2020.png\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Figure 6.<\/b> Upload of encounter history to health authority<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>To protect users and the system from fraudulent uploads, an authorisation code is provided by the health authority and entered through the app in order to obtain a valid token to transmit the logs.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Data_analysis_flow\">Data analysis flow<\/span><\/h3>\n<p>The health authority decrypts the TempID for each encounter in the uploaded encounter history in order to obtain the UserID and validity period. It then verifies that the encounter timestamp for each TempID falls within its validity period. The health authority then filters for close contacts based on the disease\u2019s epidemiological parameters: time of exposure (measured by the length of a continuous cluster of encounters) and distance (measured by the received signal strength reading).\n<\/p><p>In Singapore, the contact tracing process involves an interview with the patient, where the patients are asked to recall where they have been and who they have been in contact with recently. This information is used together with the BlueTrace data to adjust the proximity and duration filtering thresholds based on the patient-reported location and context. The health authority then contacts individuals assessed to have a high likelihood of exposure to the disease, to provide medical guidance and care. \n<\/p><p>Note that this workflow can be automated and decentralised without affecting interoperability with other BlueTrace implementations. However, we do not recommend this, and we have therefore not implemented it in OpenTrace. (For further discussion, see the next section \"Protocol design considerations\").\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Withdraw_of_consent\">Withdraw of consent<\/span><\/h3>\n<p>We believe users should be in control of their personal data and have the ability to delete this from the system. If a user withdraws consent to use their personal data, their UserID and phone number should be deleted from the back-end database. Since the phone number is the only source of identity, deleting it will render useless all of this user\u2019s TempIDs that were previously sent to other devices.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Protocol_design_considerations\">Protocol design considerations<\/span><\/h2>\n<h3><span class=\"mw-headline\" id=\"Bluetooth_or_GPS\">Bluetooth or GPS<\/span><\/h3>\n<p>Bluetooth and GPS contact tracing solutions were both considered. Table 1 illustrates the main differences.\n<\/p>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table class=\"wikitable\" border=\"1\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\" colspan=\"3\"><b>Table 1.<\/b> Comparison between Bluetooth and GPS contact tracing\n<\/td><\/tr>\n<tr>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">Aspect\n<\/th>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">Bluetooth\n<\/th>\n<th style=\"background-color:#e2e2e2; padding-left:10px; padding-right:10px;\">GPS\n<\/th><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><b>General approach<\/b>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Devices log encounters with other devices. Infected users upload their encounter history.\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Devices log their GPS location. Infected users upload their location history.\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><b>Accuracy<\/b> (As a reference, widely-accepted epidemiological parameter for close contact with COVID-19 patient is 30 minutes at a distance of less than two metres.)\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Able to approximate close contacts within two metres by filtering encounters by signal strength.<br \/> <br \/>Note that Bluetooth has a range of 10 metres in indoor environments, but RSSI follows inverse square law and drops off quickly with distance. However, calibration is necessary for maximal effectiveness as different devices transmit at different powers.\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Unable to filter for proximity.<br \/> <br \/>Note that GPS has accuracy of 10 metres, which decreases in urban environments with tall buildings. Limited vertical accuracy (for floor detection) means that most people within a single skyscraper would register within the margin of error. GPS also exhibiys poor accuracy in moving or underground environments like a subway train.\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><b>Adoption challenges<\/b>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Requires high adoption to be effective, because effectiveness is a quadratic function of adoption.\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Requires high adoption to be effective, because effectiveness is a quadratic function of adoption unless other data sources are incorporated. Public wariness and possible alarm about tracking location data of individuals could hamper adoption.\n<\/td><\/tr>\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"><b>Battery use<\/b>\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Low\n<\/td>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\">Medium\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<p>Bluetooth was chosen because it is able to classify close contacts with a significantly lower false positive rate than GPS. Given that GPS accuracy decreases in indoor environments, entire shopping malls, or skyscrapers would be within the margin of error of a single GPS point. Furthermore, adoption could be hampered by the public wariness of location tracking and increased battery drain.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Generation_of_TempID_by_backend_service_vs._on_device\">Generation of TempID by backend service vs. on device<\/span><\/h3>\n<p>In the reference implementation, TempIDs are cryptographically generated by the backend service. The downside is that this requires devices to connect periodically to the internet. We account for periods without connectivity by issuing a batch of TempIDs at a time.\n<\/p><p>An alternative to this approach would be for the UserID to be stored on the device, and for TempIDs to be generated locally using an asymmetric encryption key, with the backend service holding the corresponding decryption key. The asymmetric encryption key can be generated by the backend service and sent to the user device using registration. However, we found that this cryptographic scheme increased the computational requirement on devices beyond the OS-allocated limits, especially when in background execution mode.\n<\/p><p>Apart from minimising on-device compute requirements, server-side TempID generation has a secondary benefit of allowing the health authority to understand adoption and usage levels of the app by logging the issuance of daily batches of TempIDs, as well as the app's potential effectiveness in epidemic control. This could then be used to inform public health policy interventions.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Centralised_vs_decentralised_contact_tracing\">Centralised vs decentralised contact tracing<\/span><\/h3>\n<p>BlueTrace envisages a blend of decentralised proximity data collection and logging, with a centralised contact tracing capability.\n<\/p><p>Encounter messages and encounter histories are exchanged and stored in a decentralised, peer-to-peer manner, without the participation of a central server. We defer the centralised collection and processing of data to the last possible moment\u2014when a diagnosis of COVID-19 is made\u2014and then provide this data to the trusted public health authority in the OpenTrace reference implementation. Depending on the prevailing trust environment within which public health institutions operate, other jurisdictions may have different considerations that may favour a similar hybrid model or one that is completely decentralised.\n<\/p><p>We see various challenges with a purely decentralised contact tracing system. Individuals falsely declaring themselves infected would cause unnecessary anxiety and panic in other users and erode trust in the system. Some form of authorisation for users to either flag themselves as positive COVID-19 cases, or to upload encounter history, is therefore necessary to protect against abuse. Ultimately, this type of authorisation will have to be provided by a credentialed health institution or healthcare worker, who may or may not be part of a public health authority\u2019s infectious disease surveillance system, but would likely have to obtain the upload authorisation code through a chain of trust rooted in a centralised public health authority. This also has the benefit of ensuring that relevant information about the epidemic and the effect and effectiveness of such contact tracing systems is provided to the public health authority, to aid in planning public health interventions.\n<\/p><p>Finally, another advantage of a centralised approach is keeping humans in the loop in making the assessment of the appropriate follow-up actions.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Human-in-the-loop_vs._human-out-of-the-loop\">Human-in-the-loop vs. human-out-of-the-loop<\/span><\/h3>\n<p>It is possible to implement the BlueTrace protocol and have automated notification of probable close contacts of persons who have been diagnosed with COVID-19. In theory, we appreciate the privacy and scalability benefits of doing so. In practice, our ongoing conversations with public health authority officials performing epidemic surveillance and conducting contact tracing operations compel us to recommend otherwise.\n<\/p><p>An automated algorithm will necessarily generate both false negatives and false positives. A human contact tracer will similarly make mistakes. However, because a human contact tracer would seek to incorporate information beyond just physical proximity, he\/she can correct for systematic biases introduced by a purely automated notification system.\n<\/p><p>Encounters between individuals can be classified into close, casual, and transient contacts for <a href=\"https:\/\/www.limswiki.org\/index.php\/Epidemiology\" title=\"Epidemiology\" class=\"wiki-link\" data-key=\"123badb8bf0b37a513182dbcfc3875bc\">epidemiological<\/a> purposes, based on proximity and duration of contact. However, these classifications depend on factors such as location and environment. For example, short-duration encounters in enclosed spaces without fresh ventilation often constitute close contact, even if encounter proximity and duration do not meet algorithmic thresholds. Since Bluetooth-based contact tracing solutions do not, by themselves, record location and environment data, this information needs to be obtained through other means: a human-led contact tracing interview.\n<\/p><p>A human-in-the-loop system is also necessary to allow judgment to be applied, given the high likelihood of pre-symptomatic transmission of the <a href=\"https:\/\/www.limswiki.org\/index.php\/SARS-CoV-2\" title=\"SARS-CoV-2\" class=\"mw-redirect wiki-link\" data-key=\"6c6b78479de2c640028696ed32948526\">SARS-CoV-2<\/a> virus. Since time is of the essence, contact tracers may preemptively wish to trace selected second-degree close contacts of a COVID-19 patient, in cases where there is a high likelihood of exposure and infection, even if the first-degree close contact has yet to test positive. For example, there may be epidemiological value in tracing close contacts of a close relative of an infected person.\n<\/p><p>We note that a human-out-of-the-loop system will certainly yield better results than having no system at all, but where a competent human-in-the-loop system with sufficient capacity exists, we caution against an over-reliance on technology.\n<\/p><p>Finally, the experience of Singapore\u2019s contact tracers suggest that contact tracing should remain a human-fronted process. Contact tracing involves an intensive sequence of difficult and anxiety-laden conversations, and it is the role of a contact tracer to explain how a close contact might have been exposed\u2014while respecting patient privacy\u2014and provide assurance and guidance on next steps.\n<\/p><p>Singapore\u2019s contact tracers are on the frontline of the fight against COVID-19; they are able to do this because they incorporate multiple sources of information, demonstrate sensitivity in their conversations with Singaporeans who have had probable exposure to SARS-CoV-2, and help to minimise unnecessary anxiety and unproductive panic. These are considerations that an automated algorithm may have difficulty explaining to worried users.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Implementation_challenges\">Implementation challenges<\/span><\/h2>\n<h3><span class=\"mw-headline\" id=\"iOS_background_Bluetooth_limitations\">iOS background Bluetooth limitations<\/span><\/h3>\n<p>While the Android version of the OpenTrace reference implementation functions fully as both central and peripheral while the app is in both foreground and background execution modes, the iOS version of OpenTrace is bound by restrictions that iOS has on background Bluetooth functionality.\n<\/p><p>When in the background, the iOS app advertises in a proprietary advertisement format that is not part of the Bluetooth standard and thus not readable by non-iOS devices. It is also unable to scan for other BlueTrace devices in any meaningful way.\n<\/p><p>The current workaround is to encourage iOS users to keep their app in the foreground, especially when in higher-risk environments. Within the OpenTrace reference implementation, we have implemented a \u201cpower saver mode,\u201d where users can flip the phone upside down to dim the screen so the app uses less battery power while in the foreground. Users, particularly inactive users, also receive push notifications to remind them to use the app, especially during commuting peak hours. The app also prompts the user if inadequate permissions are granted or Bluetooth is turned off, resulting in the app being unable to function normally.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Difference_in_transmission_power_across_devices\">Difference in transmission power across devices<\/span><\/h3>\n<p>BlueTrace uses RSSI readings to approximate distance. However, through tests of devices in anechoic chambers, we have established that the variance in transmission power across popular mobile devices can be as large as 30 dB (1000x). During testing, we have also discovered that transmission power varies little between different devices of the same model and is minimally affected by mobile phone cases. In order to account for this difference, we have taken reference signal strength readings for popular mobile devices in Singapore. We use this to calibrate RSSI readings when classifying encounters by proximity.\n<\/p><p>We have shared this data at <a rel=\"external_link\" class=\"external text\" href=\"https:\/\/github.com\/opentrace-community\" target=\"_blank\">github.com\/opentrace-community<\/a>. We invite developers and handset manufacturers to contribute to this so that it can serve as a universal calibration table of device transmission powers for any Bluetooth contact tracing solution.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Federation_and_interoperability\">Federation and interoperability<\/span><\/h2>\n<p>Federation is a common and natural extension of national systems, and BlueTrace welcomes collaboration with the international community to facilitate community-driven cross-border contact tracing. BlueTrace was designed with interoperability in mind while maintaining flexibility for adopters of its protocol. Where possible, the protocol allows health authorities to customise and adapt the protocol to suit their use cases.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Guiding_principles\">Guiding principles<\/span><\/h3>\n<p>BlueTrace\u2019s guiding principles on federation and interoperability are:\n<\/p>\n<ul><li> Each health authority should be allowed to administer their own set of users separate from other authorities. The user identity and contact information belonging to users of one health authority should never be exposed to another health authority.<\/li>\n<li> Each health authority can use its own algorithm for generating TempIDs and determining the validity period of the TempID. The TempID should allow the health authority to obtain the associated user\u2019s contact details.<\/li>\n<li> Each health authority is responsible for the storage and protection of users\u2019 identifiers and shared encounter history.<\/li>\n<li> Each health authority\u2019s mobile client app must perform communication exchanges using the BlueTrace encounter message format.<\/li>\n<li> OpenTrace has a set of default configurations for scanning and advertising cycles, but each health authority has the flexibility to configure the scanning and advertising cycle as it deems fit.<\/li><\/ul>\n<h3><span class=\"mw-headline\" id=\"Registry_of_BlueTrace_Health_Authorities\">Registry of BlueTrace Health Authorities<\/span><\/h3>\n<p>A registry of BlueTrace Health Authorities consolidates the list of international participating authorities. The registry contains information about the participating authority such as name, organisation code, contact person details, and an endpoint to allow anonymised information to be exchanged between authorities. The organisation code which is sent as part of the encounter exchange message follows a specific format: <a href=\"https:\/\/en.wikipedia.org\/wiki\/ISO_3166\" class=\"extiw wiki-link\" title=\"wikipedia:ISO 3166\" data-key=\"aead2efe674c2779068e49de12a07697\">ISO 3166<\/a> country code (two characters) followed by an organisation unit (three characters) with an underscore separator, e.g. SG_MOH. In countries where there are multiple health authorities, the organisation unit can be used for intra-country federation. \n<\/p><p>Interested health authorities will need to email a request to BlueTrace at info@bluetrace.io before being added to the global registry. BlueTrace recommends that only a single Health Authority BlueTrace app be installed and activated on a user device for maximum effectiveness.\n<\/p><p>All Health Authorities that are part of the BlueTrace registry are required to implement several requirements: be able to exchange TempID for PseudoID, and be able to be notified of PseudoIDs that have close contact.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Generation_of_TempIDs_2\">Generation of TempIDs<\/span><\/h3>\n<p>BlueTrace maintains interoperability while preserving flexibility for each health authority [Figure 7]. Each authority has its own user base, datastore, and algorithm to generate TempIDs for its users. BlueTrace does not limit the information collected during registration as long as the user can be traced back to a valid phone number or can otherwise be alerted. This could be through a push notification. The two different mobile clients communicate via the BlueTrace Protocol and transfer encounter messages. Each encounter message received by the device is then logged and stored.\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig7_BayWhitePaper2020.png\" class=\"image wiki-link\" data-key=\"3fab6b4e747a8c615952bb21ed7c6010\"><img alt=\"Fig7 BayWhitePaper2020.png\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/3\/3f\/Fig7_BayWhitePaper2020.png\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Figure 7.<\/b> Interoperability between two health authorities<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<h3><span class=\"mw-headline\" id=\"Processing_of_BlueTrace_encounter_history_across_health_authorities\">Processing of BlueTrace encounter history across health authorities<\/span><\/h3>\n<p>When a patient is diagnosed with COVID-19, the patient will be approached by the health authority to upload their data. The data which contains TempIDs and records belonging to other authorities as well as its own is then processed by the backend. The differentiation is done through the organisation code indicated in the exchange message.\n<\/p><p>The health authority refers to the registry of BlueTrace health authorities and forwards the TempID and timestamp to the endpoint corresponding to the organisation code. The TempID will be validated by ensuring that its timestamp falls within its validity period. The endpoint then returns a PseudoID. The PseudoID allows correlating to a unique individual for analysis in place of a TempID which changes frequently. It could be a hash of the user\u2019s UserID or a randomly generated unique identifier that is mapped to the user\u2019s UserID. Once the PseudoID is assessed to be a close contact of the infected patient, the foreign health authority, which issued the PseudoID will be informed of the close contact period and duration and can then follow-up as necessary. The process is illustrated in Figure 8 below.\n<\/p><p><br \/>\n<a href=\"https:\/\/www.limswiki.org\/index.php\/File:Fig8_BayWhitePaper2020.png\" class=\"image wiki-link\" data-key=\"37f580fc2e1c876407a03fb0a481185b\"><img alt=\"Fig8 BayWhitePaper2020.png\" src=\"https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/7\/78\/Fig8_BayWhitePaper2020.png\" style=\"width: 100%;max-width: 400px;height: auto;\" \/><\/a>\n<\/p>\n<div style=\"clear:both;\"><\/div>\n<table style=\"\">\n<tr>\n<td style=\"vertical-align:top;\">\n<table border=\"0\" cellpadding=\"5\" cellspacing=\"0\" style=\"\">\n\n<tr>\n<td style=\"background-color:white; padding-left:10px; padding-right:10px;\"> <blockquote><b>Figure 8.<\/b> Upload and processing of BlueTrace records<\/blockquote>\n<\/td><\/tr>\n<\/table>\n<\/td><\/tr><\/table>\n<h2><span class=\"mw-headline\" id=\"Security_considerations\">Security considerations<\/span><\/h2>\n<h3><span class=\"mw-headline\" id=\"Encounter_message_replay.2Frelay_attack\">Encounter message replay\/relay attack<\/span><\/h3>\n<p>The BlueTrace protocol relies heavily on the exchange of messages through Bluetooth. This makes it susceptible to <a href=\"https:\/\/en.wikipedia.org\/wiki\/Replay_attack\" class=\"extiw wiki-link\" title=\"wikipedia:Replay attack\" data-key=\"ee088a5feb682e36784690a2e8af2c5a\">replay<\/a> and <a href=\"https:\/\/en.wikipedia.org\/wiki\/Relay_attack\" class=\"extiw wiki-link\" title=\"wikipedia:Relay attack\" data-key=\"14b72dcf636be12c0518f5a7b236cfc9\">relay attacks<\/a> as an attacker has free access to capture the message being transmitted from a BlueTrace user\u2019s mobile device. The attacker can replicate the message (but is unable to modify the TempID) and replay\/relay it across multiple locations to make it appear as if the compromised user had close contact with many other devices. BlueTrace minimises this attack vector for replay (but not relay) attacks by reducing the validity of each TempIDs to 15 minutes (which strikes a balance between threat mitigation and computation intensity). If an expired TempID is collected by a BlueTrace user, when it gets uploaded to the backend, the backend service will reject the record after checking the timestamp and validity of the TempID. In addition, the attacker will need to stay within BLE range continuously, in order to capture the latest encounter message from the BlueTrace user.\n<\/p><p>Ultimately, protecting against a replay\/relay attack is performed not through a technical solution but through a process solution. In the Singapore implementation, a human contact tracer will corroborate the circumstances under which an encounter has occurred, when contacting the flagged close contact, as discussed previously in regards to the human-in-the-loop vs. human-out-of-the-loop design decision.\n<\/p>\n<h3><span class=\"mw-headline\" id=\"Bluetooth_vulnerabilities\">Bluetooth vulnerabilities<\/span><\/h3>\n<p>Many smartphone users today use Bluetooth to connect their phones with peripherals such as smart watches, headphones, etc. While it is unlikely that the use of a BlueTrace app by itself introduces additional vulnerabilities, vulnerabilities are occasionally discovered in the underlying technology that BlueTrace depends on, i.e., Bluetooth. These vulnerabilities have to be patched at the operating system-level, and we therefore urge users to ensure that their operating systems are regularly patched. BlueTrace apps may consider notifying users if an outdated operating system is detected in order to prompt users to update them.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Legal_considerations\">Legal considerations<\/span><\/h2>\n<p>We note that data protection and privacy regulations differ from country to country. Health authorities that wish to deploy a BlueTrace-implementing app, whether built on top of OpenTrace or not, should seek separate legal advice on the appropriate consent mechanisms and data protection provisions in the design of the specific implementation of BlueTrace that is contemplated. Nothing in this white paper or protocol specification should be construed as legal advice in any domestic or international context.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Conclusion\">Conclusion<\/span><\/h2>\n<p>We hope that our description of the BlueTrace protocol, with occasional references to how it is being implemented in Singapore, provides insight to others seeking to deploy Bluetooth-based contact tracing solutions in their own communities. We have documented the protocol and system design choices with a view to enabling globally interoperable, community-driven contact tracing. These will necessarily have to be adapted to the prevailing domestic context for each BlueTrace-implementing system. Bluetooth-based contact tracing is not a silver bullet for dealing with the COVID-19 pandemic; it must ultimately coexist and support the pandemic response plans and processes of the public health authorities guiding us through these difficult times. \n<\/p><p>We welcome suggestions on this white paper and protocol at info@bluetrace.io.\n<\/p>\n<h2><span class=\"mw-headline\" id=\"Notes\">Notes<\/span><\/h2>\n<p>This presentation is faithful to the original, with only a few minor changes presentation. Some grammar was corrected for clarity. Written permission to reproduce this white paper was received prior to publishing on LIMSwiki.\n<\/p>\n<!-- \nNewPP limit report\nCached time: 20200707205040\nCache expiry: 86400\nDynamic content: false\nCPU time usage: 0.379 seconds\nReal time usage: 2.159 seconds\nPreprocessor visited node count: 2231\/1000000\nPreprocessor generated node count: 13418\/1000000\nPost\u2010expand include size: 10417\/2097152 bytes\nTemplate argument size: 3760\/2097152 bytes\nHighest expansion depth: 8\/40\nExpensive parser function count: 0\/100\n-->\n\n<!-- \nTransclusion expansion time report (%,ms,calls,template)\n100.00% 52.134 1 - -total\n 72.03% 37.550 1 - Template:Infobox_journal_article\n 68.49% 35.705 1 - Template:Infobox\n 44.90% 23.407 80 - Template:Infobox\/row\n 15.91% 8.297 8 - Template:Clear\n 9.10% 4.742 1 - Template:Ombox\n 5.33% 2.780 1 - Template:Ombox\/core\n-->\n\n<!-- Saved in parser cache with key limswiki:pcache:idhash:11959-0!*!0!!en!5!* and timestamp 20200707205038 and revision id 39462\n -->\n<\/div><div class=\"printfooter\">Source: <a rel=\"external_link\" class=\"external\" href=\"https:\/\/www.limswiki.org\/index.php\/Journal:BlueTrace:_A_privacy-preserving_protocol_for_community-driven_contact_tracing_across_borders\">https:\/\/www.limswiki.org\/index.php\/Journal:BlueTrace:_A_privacy-preserving_protocol_for_community-driven_contact_tracing_across_borders<\/a><\/div>\n\t\t\t\t\t\t\t\t\t\t<!-- end content -->\n\t\t\t\t\t\t\t\t\t\t<div class=\"visualClear\"><\/div>\n\t\t\t\t<\/div>\n\t\t\t<\/div>\n\t\t<\/div>\n\t\t<!-- end of the left (by default at least) column -->\n\t\t<div class=\"visualClear\"><\/div>\n\t\t\t\t\t\n\t\t<\/div>\n\t\t\n\n<\/body>","6916dfabf162fd46a0d0c48e26b03db4_images":["https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/thumb\/9\/97\/Emblem-important-yellow.svg\/80px-Emblem-important-yellow.svg.png","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/0\/04\/Fig1_BayWhitePaper2020.png","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/8\/8b\/Fig2_BayWhitePaper2020.png","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/6\/65\/Fig3_BayWhitePaper2020.png","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/9\/95\/Fig4_BayWhitePaper2020.png","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/1\/19\/Fig5_BayWhitePaper2020.png","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/0\/07\/Fig6_BayWhitePaper2020.png","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/3\/3f\/Fig7_BayWhitePaper2020.png","https:\/\/s3.limswiki.org\/www.limswiki.org\/images\/7\/78\/Fig8_BayWhitePaper2020.png"],"6916dfabf162fd46a0d0c48e26b03db4_timestamp":1594155038,"9674a1c05ba2ed4bfad7b32dd79b0788":{"type":"chapter","title":"1. 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