How to Read Protocol in Clinical Trials.gov
Research Methods & Reporting How to avoid common bug when using ClinicalTrials.gov in inquiry: ten issues to consider
BMJ 2018; 361 doi: https://doi.org/10.1136/bmj.k1452 (Published 25 May 2018) Cite this as: BMJ 2018;361:k1452
- Tony Tse , annotator for special projects1,
- Kevin Yard Fain , senior adviser for policy and researchi,
- Deborah A Zarin , director1
- oneNational Library of Medicine, National Institutes of Health, Department of Health and Human Services, Bethesda MD 20894, U.s.a.
- Correspondence to: K Thou Fain kevin.fain{at}nih.gov
- Accepted five March 2018
ClinicalTrials.gov is a spider web based resources providing admission to summary information on publicly and privately supported clinical studies on a wide range of diseases and conditions. The database, which is maintained by the National Library of Medicine at the National Institutes of Health (NIH), consists of a clinical study registry and results database—2 main components of the trial reporting arrangement.1 The goal of the trial reporting organization is to provide a public mechanism for identifying and characterising all trials conducted to answer specific biomedical questions (that is, the so-called denominator for all such trials) and their summary findings (that is, the evidence base of operations). Sponsors and investigators are responsible for submitting information about their studies to ClinicalTrials.gov. Ideally, complete and authentic key study information (eg, study design, recruitment information) is registered at the get-go of the report and updated throughout the research life cycle, and summary results are reported after the written report is completed.ii Achieving these goals depends on consistent and systematic reporting past sponsors and investigators. In practice, despite a substantial increase in reporting rates, connected suboptimal adherence to these principles means that accurate, complete, and timely information is non existence provided for all studies.345 ClinicalTrials.gov currently contains registration information for almost 270 000 studies in over 200 countries, and has posted summary results information for over 30 000 registered studies.
ClinicalTrials.gov is designed to provide a public list of initiated, ongoing, and completed studies, and to serve as a source of summary results information to complement the medical literature. The original focus was on facilitating identification and retrieval of data nigh specific studies on investigational drug products for potential report participants. Over time, other benefits of reporting accept become apparent including: fulfilment of ethical obligations to study volunteers who expect that participation volition contribute to medical scientific discipline; disclosure of all prespecified primary and secondary outcome measures, including those not reported in the peer reviewed publications, to demonstrate adherence to the written report protocol; and promotion of more efficient resource allotment of research resources by identifying gaps and overlaps. It has also become clear that the database provides a unique resources for those studying the clinical enquiry enterprise. For example, 404 research articles published between 2010 and 2015 reported using ClinicalTrials.gov data to study various topics, such every bit analyses of studies on specific conditions, and to back up research on ethics and adverse event reporting.half-dozen
Proper analyses crave an understanding of the database structure, its evolution over fourth dimension, the organisation of study records, and the various incentives and requirements that shape its content. We are often asked to review analyses that used ClinicalTrials.gov information and have adult x issues to consider based on our experience from these consultations. For additional data, we provide links to resource cloth in tabular array 1, and screenshots to help researchers use ClinicalTrials.gov in the online supplementary appendix.
Table 1
Linked information for fundamental ClinicalTrials.gov resources
Summary points
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ClinicalTrials.gov provides access to summary information on publicly and privately supported clinical studies on a wide range of diseases and conditions, and can be used to analyse research questions
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To utilise ClinicalTrials.gov as a data source for inquiry, researchers need to understand the database structure, its evolution over time, the organisation of report records, and the various incentives and rules that shape its content
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X issues for researchers to consider are presented to help them apply the ClinicalTrials.gov database more fully and consider the scientific appropriateness of their designs/methods to strengthen and expand public noesis in important inquiry areas.
History of ClinicalTrials.gov
The ClinicalTrials.gov report registry was launched in Feb 2000 in response to US federal constabulary requiring the NIH to "constitute, maintain, and operate a information banking concern of information on clinical trials for drugs for serious or life-threatening diseases and conditions . . . in a course that can be readily understood past members of the public".7 The database subsequently included other registration requirements such as the International Committee of Medical Periodical Editors (ICMJE) policy (table 2). The US Food and Drug Administration Amendments Act of 2007 (FDAAA) further extended the scope and legal requirements of the ClinicalTrials.gov registry, and mandated the creation of a results database, which became operational in September 2008.10 Regulations for implementing the FDAAA, which were issued in September 2016 and became effective on 18 Jan 2017, clarified ambiguous statutory provisions, and expanded the telescopic and requirements of the results database considerably.1113 To support the overall mission of the trial reporting organization beyond its legal mandates, ClinicalTrials.gov permits and encourages registration and results' reporting of all biomedical or health related enquiry studies (and data on expanded admission to experimental interventions) on humans that the sponsor or principal investigator indicates is in conformance with:
Table 2
Telescopic of key policies for clinical trial reporting to ClinicalTrials.gov*
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Any applicable regulations on the protection of humans, or ethics review (eg, institutional review lath approval), and
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Any other applicable regulations of the national or regional wellness authority.
In parallel, the number of international trial registries and reporting requirements has also grown (eg, the European union Clinical Trial Registry and European union registration and results reporting regulations14). The Globe Health Organisation's International Clinical Trials Registry Platform (ICTRP) search portal allows users to look for studies in the xvi primary registries of the WHO registry network and ClinicalTrials.gov, from which it downloads registration data weekly. The WHO ICTRP search portal identifies single studies registered in two or more than registries (that is, duplicate registrations) but when sponsors or investigators list unique registry identifiers on corresponding study records, only misses other duplicate registrations.xv Thus, searching the WHO ICTRP search portal might retrieve multiple records of the same study, which would touch various counts (eg, number of unique studies, or participants enrolled). Equally of March 2016, nigh two thirds of all trials available through the WHO ICTRP search portal were registered on ClinicalTrials.gov.iv
ClinicalTrials.gov database—the basics
Who is responsible for submitting study information?
The study sponsor is responsible for submitting, updating, and verifying study information to ClinicalTrials.gov throughout the study life bicycle (that is, "the responsible party").16 In general, the holder of an FDA investigational new drug application, or investigational device exemption for a study is considered to exist the sponsor. Otherwise, the sponsor is the entity or individual who initiates and has say-so over the study. A sponsor may designate a principal investigator as the responsible political party in sure circumstances. Nevertheless, if at whatever time the designated principal investigator can no longer serve as the responsible political party, accountability reverts to the sponsor.
When is the information submitted?
Studies are generally registered at the start of the written report, and then updated as the study is conducted. One time a study is completed, summary results can be entered. Although documents containing the protocol and statistical analysis plan are required to exist submitted to ClinicalTrials.gov as portable document format (PDF) files at the time of results' reporting for trials that are subject to the concluding dominion implementing the FDAAA, they can be uploaded for any registered written report at any time. The sponsor or principal investigator can update, right, add, or sometimes delete information from the study tape through the Protocol Registration and Results System 17 at any time. Earlier versions of written report records are attainable through the "history of changes" link nether "study details" on each record (figs S1 and S2). The "tabular view" displays both the current (last updated and posted) and original (initially registered) entries for the primary, secondary, and other outcome measures for easy comparing (fig S3).
How is the study information reviewed?
All written report data, which is cocky reported by the responsible party through the Protocol Registration and Results System, must meet established quality control review criteria before posting.xviii Automatic validation rules prevent submission of records that fail to meet certain technical requirements. Quality control staff manually review the information for consistency with remaining quality control criteria (for details, see issue 5). A unique ClinicalTrials.gov identifier (NCT number) is assigned to each study record.
10 problems to consider when planning an analysis
As with whatsoever scientific investigation that uses data in a resource designed to support unlike objectives, researchers must carefully consider if their inquiry questions can be adequately answered using the information in ClinicalTrials.gov. Whether the investigation will describe practices in the trial reporting arrangement (eg, how non-inferiority trials are reported19), or make inferences about the clinical research enterprise more than broadly (eg, how written report designs of cardiovascular trials differ from oncology trials20), researchers need to consider important attributes of the database (eg, information element definitions, requirements), and related extrinsic factors (eg, prevailing incentives that affect the sample of studies that are included in the database at any point in fourth dimension). In this section, we describe the x issues that researchers should consider when using ClinicalTrials.gov in research. The penultimate section of this commodity integrates some of these problems as dos and don'ts of using ClinicalTrials.gov information for enquiry.
1. ClinicalTrials.gov includes more than "clinical trials"
Despite its name, the database includes 3 unlike types of study records.
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Interventional (or clinical trial). Participants are assigned prospectively to interventions as specified in a protocol to evaluate the effect of the interventions on biomedical and/or health related outcomes.16 U.s. federal reporting requirements and the ICMJE policy apply to clinical trials. Currently, 80% of registered records and 93% of records with posted results are clinical trials.
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Observational. Biomedical and/or wellness outcomes are assessed in predefined groups of written report participants receiving specific interventions, just non assigned by an investigator.sixteen Despite the lack of major reporting policies for observational studies, they account for twenty% of registered records, and seven% of records with posted results.21
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Expanded admission. US regulations require registration of expanded admission to certain FDA regulated drug or biological products for patients who do not qualify for enrolment in a clinical trial. ClinicalTrials.gov currently includes over 450 expanded access records.
Each study type is associated with a unique set of registration data elements (eg, the study phase data element is only available for interventional studies). For the residue of this commodity, we focus on clinical trials. Table S7 shows the mandatory registration and results information for clinical trials by category also as registration information elements that are part of the WHO ICTRP trial registration dataset. For a list of all mandatory and optional data elements for all of the written report types, see the ClinicalTrials.gov documents list data element definitions.16
2. Follow-on studies may be registered as dissever records
ClinicalTrials.gov defines a single study every bit a set of information collections and analyses governed past a unmarried protocol that includes a plan to analyse the same group of participants; each report is registered separately and represented by a single record with a unique NCT number. In dissimilarity, data collections or analyses that require re-consent and/or include participants who were not office of the original report are registered as separate studies. However, fifty-fifty though follow-on or extension study designs track participants after completion of an initial report to collect longer term data, responsible parties may register initial and follow-on studies as separate records. ClinicalTrials.gov currently does not provide a fashion to identify such pairs of records automatically, just clues tin be found in certain information elements, including: title/acronym (eg, "ABSORB" and "Absorb Extend"); brief summary (eg, "The main objective is to assess the rubber and tolerability . . . in participants . . . who completed Written report 205MS301"); and eligibility criteria (eg, "patient successfully completed cadre study CRFB002H2301").
3. Incentives for reporting trials change over time
Reporting incentives influence both the kinds of studies that are registered on ClinicalTrials.gov and the amount of information submitted, and change over fourth dimension. Any sample of registered records, including those with posted results, reflects the prevailing incentives for disclosing trial information, including laws, policies, and scientific norms/practices (table 2). Information technology is of import to consider how these evolving incentives might affect an assay. For example, the fact that more than device studies were registered in 2016 than in 2004 probably reflects, in part, the effect of the ICMJE policy and FDAAA, which makes information technology hard to determine if in that location had been an actual increase in the number of device studies conducted using information from ClinicalTrials.gov.
Similarly, the content of registered records also reflects the prevailing incentives. For instance, FDAAA required information about primary and secondary outcome measures, but did not specify timeframes for outcome measures. Timeframes became mandatory data elements in ClinicalTrials.gov in December 2012. Without this incentive, before December 2012, responsible parties often did not provide data about timeframes even though ClinicalTrials.gov had offered the option.22
4. ClinicalTrials.gov includes mandatory and optional data elements
Each record contains both mandatory and optional structured data elements. Mandatory information elements comprise the minimum amount of information needed to understand the study and its findings (table S7) and are annotated with ruby-red asterisks in the documents listing data chemical element definitions.16 Automated validation rules foreclose the submission of records with missing entries for data elements that were mandatory when registered, and identify obviously inconsistent data at the time of submission (eg, recruitment status gear up to "recruiting," but listed report outset date is in the futurity). Optional information elements are not reported in all posted records.
Data elements, subelements, and submission requirements accept evolved (tabular array S8). For example, the main outcome measure data element, introduced as an optional gratuitous text field in 2005, was restructured in 2007 to include 3 split optional subelements for greater precision that paralleled the superlative three levels of the specification framework for reporting effect measures: title, including domain (eg, anxiety) and specific measurement (eg, Hamilton anxiety rating calibration); description, including specific metric (eg, change from baseline); and timeframe for the time indicate(s) at which the measurement is assessed for the specific metric.23 All three subelements became mandatory for study records submitted subsequently ane December 2012.
five. ClinicalTrials.gov conducts quality command review
Quality control review criteria ensure that entries are complete and meaningful, and show internal consistency and face up validity. These criteria with examples are described in publicly available documents.18 Several approaches are used to ensure consistency and standard implementation of the quality control review criteria across the review staff, including a comprehensive training plan, standardised review comments, and regular auditing of reviews by review staff members. At registration, the about common trouble identified past the quality control review is insufficient specificity of effect measures (eg, "safe"). At results reporting, the five most important problems by frequency of occurrence are invalid/inconsistent unit of measure, bereft information about a scale, internal inconsistencies betwixt different parts of a record, inclusion of written results or conclusions, and unclear baseline, or outcome measure.24
Because quality command review criteria evolve with policies, scientific practices (eg, new study designs), and experience, inconsistencies with the electric current criteria may exist in records posted earlier implementation of the relevant criteria. For example, older records may include primary outcome measures that do not run into current requirements for specificity.
Researchers must also keep in heed that, as with the peer review procedure, quality control review cannot ensure the veracity of the submitted information, or determine whether the entry is fully compliant with diverse policy or legal requirements. For example, discrepancies and inconsistencies take been found between summary results posted on ClinicalTrials.gov and other sources of results for the aforementioned trials (eg, peer reviewed publications, FDA review documents).252627 Although in many cases the data in ClinicalTrials.gov are more than complete and more structured,28 there is no mode to make up one's mind which (if either) version of the results is right.
half dozen. Records can be modified past the responsible party at any time
Responsible parties can add, edit, and sometimes delete information from a record at whatsoever fourth dimension, although all previous versions are publicly bachelor through the archive site. While some data elements are expected to change regularly over the study life bike (eg, recruitment status), others change infrequently (eg, report blueprint). ClinicalTrials.gov permits changes to allow the information displayed in records to reverberate the electric current state of a study, and to ensure accuracy. Thus, researchers demand to extract and relieve all data elements from an analysis to ensure future access to the dataset (eg, for audit or reanalysis). They also need to state clearly in their manuscripts when the data were extracted for analysis. Despite the adequacy to make changes to a record, many records are not updated in a timely way. For instance, as of Feb 2018, well-nigh 25 500 of 270 000 (9.four%) records listing an "unknown" recruitment condition, which indicates that posted information for a study previously listed as "recruiting," "not yet recruiting," or "active, not recruiting" has not been updated or verified inside the past ii years.
The near recent entry submitted for each data element is displayed on ClinicalTrials.gov, but all earlier versions of that tape back to the initial registration can be reviewed using the "history of changes" archival function in "study details" (fig S1), or the "change history" feature in the "tabular view". Depending on the goals of the analysis, it might be necessary to use information from historical versions of the record (eg, characterising the nature and frequency of primary changes in ClinicalTrials.gov records afterwards initial registration29).
7. ClinicalTrials.gov does not accept all information for all studies
An important overarching factor to consider is that ClinicalTrials.gov will always be incomplete in two ways: beginning, private studies may exist missing from the database and, second, study information may be missing from the records.345 Considering reporting policies are not comprehensive, and compliance will never be perfect, some trials in the clinical enquiry enterprise are not registered with ClinicalTrials.gov, or do non have any posted summary results. Thus, researchers using this database need to consider the representativeness of any sample of records, the types of inferences that tin be drawn about the clinical research enterprise (see consequence nine) from an analysis of the sampled records, and possible biases.
Fifty-fifty when reported, posted records on ClinicalTrials.gov may contain incomplete data. One reason is that certain information elements may not have existed, may take had a unlike format or construction, or may accept been considered optional at the time the study information was initially submitted (meet event four). Even though ClinicalTrials.gov permits the modification of records at any time (see issue vi), incentives are often insufficient to motivate responsible parties to update entries in older records (meet issue iii). Therefore, researchers need to be aware of when data elements of interest were introduced and became mandatory, and the existing incentives. For example, an investigation of the reporting of principal upshot measures over time would need to consider the timing of various changes to the data element and the associated requirements.
viii. ClinicalTrials.gov information can be accessed in several ways
There are three ways to identify and recall a fix of study records direct from ClinicalTrials.gov:
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Basic fielded search: specify term(due south) by status/disease, facility location, or other terms (fig S4).
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Advanced search: enter search terms in any of over 20 structured fields, including study type (eg, "interventional", "observational"), recruitment status (eg, "recruiting", "completed"), intervention/treatment, and has posted results (fig S5).
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Download the search results: registration and results information from study records can be downloaded in a spreadsheet format, or as a single zero file containing the study records formatted using XML that researchers tin can afterward search with their own system and tools (fig S6).
Alternatively, researchers may adopt to use the Clinical Trials Transformation Initiative's database for amass analysis of ClinicalTrials.gov.30 This database contains the full set of registration and results information from ClinicalTrials.gov; researchers should note the update schedule of the database to make up one's mind its ceremoniousness for their item analysis.
9. Defining a sample of records to answer a specific question
Sample selection is integrally related to the analytical goals, and any intended inferences. Many analyses rely on ClinicalTrials.gov data to reach conclusions about the practices and characteristics of the clinical enquiry enterprise, simply the degree to which a sample of ClinicalTrials.gov records accurately represents the full population of studies inside the clinical inquiry enterprise varies by the prevailing reporting incentives (eg, by geographical region, over fourth dimension, and the blazon and characteristics of the study). For example, a recent press release announced that "Korea ranks sixth in globe in number of clinical trials" based on information from ClinicalTrials.gov.31 The analysis plainly did not account for the fact that ClinicalTrials.gov does not include all trials (effect 7), incentives for reporting past geographical location vary and change over time (result iii), or the existence of a primary registry in the WHO ICPTR registry network "for clinical trials (researches) to be conducted in Korea".
In dissimilarity, an investigation of publication rates amid NIH funded trials used a sample of ClinicalTrials.gov records for the analysis.32 Given that multiple reporting incentives apply to such trials (see issue 3), including FDAAA, ICMJE policy, and NIH'due south recommendation that grantees register their trials, the bear witness suggested that the sample from ClinicalTrials.gov was largely representative of NIH funded trials.
10. Using the ClinicalTrials.gov results database
Results information available from ClinicalTrials.gov is more circuitous than registration information. Some additional factors need to exist considered when using the results database.
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Obtaining and using information. Unlike registry data elements, which can hands be downloaded in a list or spreadsheet format (records equally rows and information elements as columns), almost of the results data elements are only available in XML because of the loftier degree of variability in the data structure of results data tables (eg, numbers of rows and columns). However, full protocols, statistical assay plans, and informed consent forms can be downloaded as PDF files. ClinicalTrials.gov started accepting these documents on 29 June 2017.
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Understanding the results reporting requirements. Researchers demand to empathize the results reporting requirements, which are different from the registration requirements, as well as changes to these requirements and relevant dates when the requirements became legally effective. For instance, although the deadline for results information is generally one year later the main completion date (date of terminal collection of data for the master outcome), results submission may be legally delayed by up to 2 more years in sure circumstances,11 and not required at all in other circumstances. Additionally, in some circumstances—for example, when data collection is ongoing for a secondary outcome measure at the primary completion date—partial results data for a study must be submitted until complete results information has been provided.
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Policies and compliance. When assessing the compliance of studies with results reporting policies, researchers should be clear about the relevant standards for the analysis, such equally general ethical principles versus more specific legal requirements for reporting. Determination of compliance with FDAAA or the final rule requires detailed understanding of the police force, the regulations, and their implementation.
Dos and don'ts of using ClinicalTrials.gov data for research
one. Don't assume that studies registered on ClinicalTrials.gov are an unbiased reflection of the clinical research enterprise
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Studies reported to ClinicalTrials.gov are an incomplete sample of the clinical research enterprise. The degree of bias introduced by a sample of records varies according to the strength of the incentives and norms for reporting studies with certain characteristics. Fundamental factors include intervention type (eg, drugs versus behavioural interventions), funding source, date of report initiation or completion, geographical location, and regulatory jurisdiction.
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Researchers conducting analyses aimed at showing differences or changes in the clinical research enterprise demand to consider carefully how reliance on the samples of studies available from ClinicalTrials.gov might innovate biases in the analyses.
2. Don't use the wrong data elements to operationally define a sample
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Many concepts used in analyses of the clinical research enterprise can be addressed past several different data elements in ClinicalTrials.gov. The choice of information elements will affect the meaning and the interpretation of an analysis—sometimes substantially.
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Earlier establishing an operational definition for a concept, researchers should fully review the definitions of the data elements, and understand the consequences of all possible options; examples of several mutual concepts are shown in tabular array 3.
Table 3
Common concepts and implications of selecting dissimilar information elements for a concept
iii. Think carefully when selecting an analysis population
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Many analyses can be summarised as ratios using the number of studies with a sure characteristic as the numerator, and the overall number of studies of interest (analysis population) every bit the denominator. The selection of an analysis population influences the validity of any conclusions and their relevance to the enquiry question. For example, when determining the percentage of studies that accept results posted on ClinicalTrials.gov, choosing all registered studies as the analysis population provides a methodologically straightforward finding merely does not account for of import factors. Selection of all studies completed since the start of the results database, or those legally required to report results to ClinicalTrials.gov as the analysis population (and comparable numerators) would guess the usefulness of the results database in providing summary results and compliance with the law, respectively.
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The choice of analysis population is also of import when using a data chemical element that is missing from many studies (eg, a new or optional data element). A denominator of all studies versus a denominator of only those studies that have a value entered for that data chemical element will provide dissimilar results.
4. Don't forget that information well-nigh a given trial in a record may have changed over time
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Study records change over time as the study itself is implemented and completed. Decisions about when to use the currently displayed entry for a information element versus a previously submitted entry (available through historical versions of records from the archive site) should be based on the goals of the assay. For example, assessing concordance between prespecified and published primary outcome measures requires the entry originally registered at the start of the written report rather than the most contempo, updated entry on the public site.
Conclusion
The ClinicalTrials.gov database is a powerful tool for agreement various aspects of registration and results reporting, equally well equally the underlying characteristics and practices of the trial reporting organisation, and clinical inquiry enterprise. Nonetheless, information technology is easy to misuse the information inadvertently and depict invalid conclusions, especially considering the database does not contain all clinical trials in the clinical research enterprise. Equally with any other analysis using an existing information resources designed to support different goals, researchers must carefully articulate the specific research question and determine the suitability of the database to answer the question. It is important that researchers understand the characteristics and nuances of the database, including the evolution of reporting incentives. By following these recommendations, researchers can use the ClinicalTrials.gov database more fully in scientifically advisable ways, which in turn can strengthen and expand public knowledge of these important research areas.
Acknowledgments
We thank Rebecca J Williams for her disquisitional review of the revised manuscript and for the many helpful suggestions. The views expressed in this article are those of the authors and do not necessarily reverberate the positions of the NIH.
Footnotes
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Contributors: TT, KF, and DAZ conceived the thought, drafted the manuscript, or critically revised the manuscript for important intellectual content, gave concluding approval of the version to exist published, and are accountable for all aspects of the piece of work. The corresponding writer attests that all listed authors encounter authorship criteria and that no others meeting the criteria accept been omitted
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Funding: The authors are supported past the Intramural Research Program of the National Institutes of Health, National Library of Medicine.
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Competing interests: We have read and understood the BMJ Group policy on declaration of interests and declare the post-obit interests: none.
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Provenance and peer review: Deputed; externally peer reviewed.
This is an Open up Admission article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC four.0) license, which permits others to distribute, remix, accommodate, build upon this piece of work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/four.0/.
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Source: https://www.bmj.com/content/361/bmj.k1452
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