Post on 08-Aug-2020
transcript
This may be the author’s version of a work that was submitted/acceptedfor publication in the following source:
Korevaar, Daniel, Hooft, Lotty, Askie, Lisa, Barbour, Ginny, Faure, Helene,Gatsonis, Constantine, Hunter, Kylie, Kressel, Herbert, Lippman, Han-nah, McInnes, Matthew, Moher, David, Rifai, Nader, Cohen, Jeremie, &Bossuyt, Patrick(2017)Facilitating prospective registration of diagnostic accuracy studies: ASTARD initiative.Clinical Chemistry, 63(6), pp. 1-11.
This file was downloaded from: https://eprints.qut.edu.au/108237/
c© Consult author(s) regarding copyright matters
This work is covered by copyright. Unless the document is being made available under aCreative Commons Licence, you must assume that re-use is limited to personal use andthat permission from the copyright owner must be obtained for all other uses. If the docu-ment is available under a Creative Commons License (or other specified license) then referto the Licence for details of permitted re-use. It is a condition of access that users recog-nise and abide by the legal requirements associated with these rights. If you believe thatthis work infringes copyright please provide details by email to qut.copyright@qut.edu.au
Notice: Please note that this document may not be the Version of Record(i.e. published version) of the work. Author manuscript versions (as Sub-mitted for peer review or as Accepted for publication after peer review) canbe identified by an absence of publisher branding and/or typeset appear-ance. If there is any doubt, please refer to the published source.
https://doi.org/10.1373/clinchem.2017.272765
1
Facilitating Prospective Registration of Diagnostic Accuracy Studies:
A STARD Initiative
Running head: STARD for Registration
List of authors, academic degrees, positions, affiliations, and email addresses:
Daniël A. Korevaar, MD PhD, Physician researcher
Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical
Centre, University of Amsterdam, Amsterdam, the Netherlands.
d.a.korevaar@amc.uva.nl
Lotty Hooft, PhD, Co-director
Netherlands Trial Register and Cochrane Netherlands, Julius Center for Health Sciences and
Primary Care, University Medical Center Utrecht, University of Utrecht, Utrecht, the
Netherlands.
l.hooft@umcutrecht.nl
Lisa M. Askie, PhD MPH BN NICC RM RN, Director
Australian New Zealand Clinical Trials Registry (ANZCTR), Systematic Reviews and Health
Technology Assessment team, NHMRC Clinical Trials Centre, University of Sydney,
Sydney, Australia.
lisa.askie@ctc.usyd.edu.au
Virginia Barbour, MBBChir DPhil Professor
Office of Research Ethics and Integrity and Division of Technology, Information and
Learning Services, Queensland University of Technology (QUT) Brisbane, Australia.
ginny.barbour@qut.edu.au
Hélène Faure, Database Manager
2
ISRCTN registry, BioMed Central, London, UK.
helene.faure@biomedcentral.com
Constantine A. Gatsonis, PhD, Professor of biostatistics
Center for Statistical Sciences, Brown University School of Public Health, Providence,
Rhode Island, USA.
gatsonis@stat.brown.edu
Kylie E. Hunter, BA(Hons) MPH, Senior Project Officer
Australian New Zealand Clinical Trials Registry (ANZCTR), NHMRC Clinical Trials
Centre, University of Sydney, Sydney, Australia.
kylie.hunter@ctc.usyd.edu.au
Herbert Y. Kressel, MD, Editor-in-Chief Radiology
Department of Radiology, Beth Israel Deaconess Medical Center, Miriam H. Stoneman
Professor of Radiology, Harvard Medical School, Boston, Massachusetts, USA; Radiology
Editorial Office, Boston, Massachusetts, USA.
hkressel@rsna.org
Hannah Lippman, Database Editor
ISRCTN registry, BioMed Central, London, UK.
Hannah.Lippman@biomedcentral.com
Matthew D. McInnes, MD, Associate Professor
Department of Radiology, University of Ottawa, Ottawa, Canada.
mmcinnes@toh.on.ca
David Moher, PhD, Senior scientist
Centre for Journalology, Ottawa Hospital Research Institute, Ottawa, Canada; School of
Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa,
3
Canada.
dmoher@uottawa.ca
Nader Rifai, PhD, DABCC, FACB, Editor-in-Chief Clinical Chemistry
Department of Laboratory Medicine, Boston Children's Hospital, Harvard Medical School,
Boston, Massachusetts, USA; Clinical Chemistry Editorial Office, Boston, Massachusetts,
USA.
nader.rifai@childrens.harvard.edu
Jérémie F. Cohen, MD PhD, Postdoctoral research fellow
Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical
Centre, University of Amsterdam, Amsterdam, the Netherlands; INSERM UMR 1153 and
Department of Pediatrics, Necker Hospital, AP-HP, Paris Descartes University, Paris, France.
jeremie.cohen@inserm.fr
Patrick M. Bossuyt, PhD, Professor of clinical epidemiology
Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical
Centre, University of Amsterdam, Amsterdam, the Netherlands.
p.m.bossuyt@amc.nl
Corresponding author: Prof. Patrick M. Bossuyt
Department of Clinical Epidemiology, Biostatistics and Bioinformatics
Academic Medical Center - University of Amsterdam
PO Box 22700, 1100 DE Amsterdam, The Netherlands
Email: p.m.bossuyt@amc.nl
Phone: +31(20)566 3240 Fax: +31(20)691 2683
Article type: Special Report.
4
Word count (text only): 2,887.
Keywords: Trial registration; diagnostic accuracy; sensitivity and specificity; research waste.
Abbreviations: AUC = area under the receiver operating characteristic curve; ICMJE =
International Committee of Medical Journal Editors; ISRCTN = International Standard
Randomised Controlled Trial Number; WHO = World Health Organization; STARD =
Standards for Reporting Diagnostic Accuracy; TRDS = Trial Registration Data Set.
5
Abstract
Although the introduction of prospective trial registration policies has been successful in
reducing waste in research, diagnostic accuracy studies are rarely registered. We describe
why diagnostic accuracy studies should be registered, and where and how this can be done.
Advantages of registration include that the identification of unpublished studies, prevention
of selective outcome reporting, prevention of unnecessary duplication of research,
collaboration between researchers and linkage of study materials. In a survey among
representatives of 16 major trial registries, such as ClinicalTrials.gov, ANZCTR (Australian
New Zealand Clinical Trials Registry) and the UK based ISRCTN registry (International
Standard Randomised Controlled Trial Number), 13 responded of which 8 (62%) indicated
they always accept registration of diagnostic accuracy studies, and 5 (38%) do so in some
cases. However all but one of them (92%) indicated that their registry currently does not
provide specific guidance for registering diagnostic accuracy studies. A second survey among
the 85 members of the STARD Group (Standards for Reporting Diagnostic Accuracy)
resulted in the identification of 14 essential protocol items and was used to develop guidance
on how these items can be registered in existing major trial registries. We propose that
investigators responsible for diagnostic accuracy studies should register their study, before
recruiting patients, in one of the existing major trial registries that are willing to host such
studies. We also propose that governmental, research and academic institutions providing
funding for and journals publishing diagnostic accuracy studies require such registration.
6
Introduction
Over the past decade, there have been growing concerns about a wide range of sources of
avoidable waste in biomedical research.[1] Examples include studies addressing low priority
clinical questions, study results that are unreported, and published study reports that are not
as informative as they could be.[1 2]
One approach to reduce research waste has been the introduction of prospective trial
registration policies.[3] In 2005, the International Committee of Medical Journal Editors
(ICMJE) declared that its member journals would only consider reports of trials for
publication if they had been registered in a publicly accessible trial registry prospectively,
before enrolment of the first study participant.[4] Subsequently, similar requirements have
been implemented by several governmental organizations, funders and academic
institutions.[2] These policies led to a large increase in registered studies,[5] and about half of
recently published trials now report a registration number.[6]
Unfortunately, registration rates remain low for diagnostic accuracy studies,[7 8] despite the
fact that the compelling rationale for prospective registration applies to this type of study
design.[9-12] One reason may be that registration policies have so far mainly addressed
randomized trials of interventions, while diagnostic accuracy studies, which compare medical
tests against a clinical reference standard, are often considered to be observational. Another
reason may be the unavailability of specific guidance for registration of these studies.
In this article, we set out why we believe that there is a need to register diagnostic accuracy
studies, and where and how this can be done. We provide guidance for authors and readers,
based on two online surveys (Figure 1).
What are diagnostic accuracy studies?
7
Diagnostic tests are indispensable in clinical practice. Physical examination, imaging
techniques, laboratory tests and other forms of medical testing inform clinicians about the
likelihood that a tested patient has the suspected target disease or condition, and guide
subsequent decisions about further testing or treatment.
Most diagnostic tests are not perfectly accurate in classifying patients as having the target
condition or not, and some of those tested will a have false positive or false negative test
result.[13] Diagnostic accuracy is typically evaluated by comparing test results with those of
a reference standard in a series of patients suspected of having a target condition. The
diagnostic accuracy of the test under investigation is then expressed in measures such as
sensitivity and specificity, positive and negative predictive values, likelihood ratios and area
under the receiver operating characteristic curve (AUC).[13]
Every year, thousands of these diagnostic accuracy studies are being undertaken. Some are
based on retrospective review of chart data, many others prospectively collect data in patients
who have specifically consented to these data being collected. Sometimes, evaluations of
diagnostic accuracy are incorporated into larger overarching projects that have also other,
non-diagnostic study objectives.[7]
Why register diagnostic accuracy studies?
There are numerous reasons why prospective registration of diagnostic accuracy studies is
beneficial for those involved in conducting research as well as those who rely on the research
findings.
Research transparency as an ethical obligation. Full disclosure of all study materials,
including the protocol, is increasingly considered to be an ethical obligation, not only toward
individuals who participated in the study on the understanding that their data would
8
contribute to scientific knowledge, but also toward future patients and public funders of
research, including tax payers.[14] The Declaration of Helsinki states: “Every research study
involving human subjects must be registered in a publicly accessible database before
recruitment of the first subject”.[15]
Identify unpublished studies. As described for trials of interventions, many initiated
diagnostic accuracy studies are never published, while others take years to get published.[8
16-19] This may lead to reporting bias when summarizing the available evidence in
systematic reviews, meta-analyses and clinical practice guidelines.[19] Such bias could result
in invalid implementation of medical tests in clinical practice and suboptimal clinical
decision making, potentially threatening patient safety and efficient use of healthcare funds.
Registration facilitates the identification of unpublished studies, thereby providing an
opportunity to prevent this major source of research waste.[20] If a registered record is
available for the study, principal investigators can be contacted to obtain study results, and to
identify reasons for not publishing them. By helping the inclusion of unpublished studies in
systematic reviews, registration could also increase precision of summary estimates in meta-
analyses and power for assessing sources of heterogeneity. An analysis of 117 systematic
reviews assessing medical interventions published in 2012-2013 identified that 35%
contained a screen of trial registries for unpublished trials.[21]
Identify and prevent selective reporting within studies. Selective reporting of pre-defined
primary outcomes appears to be common among published diagnostic accuracy studies.[16]
Such selective publication may provide a distorted view of diagnostic accuracy, leading to
erroneous impressions of the usefulness of the test in clinical practice. If studies are
prospectively registered with pre-specified outcomes, peer reviewers and journal editors will
have the opportunity to identify and prevent selective reporting in study reports submitted for
publication. In a survey among peer reviewers, it was shown that one-third examined
9
corresponding trial registries and reported discrepancies with the peer-reviewed manuscript to
journal editors.[22] Unreported outcomes can be identified, and corresponding results can be
obtained by contacting the principal investigators.
Facilitate the peer review process. The registered record provides a more comprehensive
knowledge of the methods, allows for a comparison between what was originally proposed
and what was actually done, and facilitates the identification of potential reporting biases as
registered and reported outcomes can easily be compared.
Prevent unnecessary duplication of research and identify research gaps. Unpublished or
ongoing diagnostic accuracy studies may be unnecessarily duplicated if other researchers are
not aware of their existence.[10] Before initiating a new study, researchers and funders could
search trial registries to identify ongoing or completed studies with similar objectives. This
may help them in appreciating the research gaps that further studies could address. Such
practices may lead to a more efficient allocation of research funds and efforts. In addition,
unnecessary exposure of study participants to potentially harmful tests or other interventions
can be prevented.
Obtain additional study information. Reports of diagnostic accuracy studies are often
incomplete in their description of essential study design features, making it difficult for
readers to assess the risk of bias and the applicability of the study findings.[23 24] In such
cases, corresponding completed registered records may be useful as an additional source of
information on study methods, as has been shown for trials of therapeutic interventions.[25]
Facilitate collaboration between researchers. By facilitating the identification of studies that
are about to start or ongoing, registration has the potential to improve collaborations between
researchers that are operational in similar fields of research.
10
Facilitate study participant recruitment. Patients are among the main users of trial
registries.[26] Those willing to participate in scientific research, and clinicians looking for
relevant research projects for their patients to participate in, will have the opportunity to
identify and participate in eligible studies if these are registered.
Improve protocol and study quality. Diagnostic accuracy studies are particularly sensitive to
bias, which may jeopardize the trustworthiness of study results.[27] Registration can improve
protocol development, as it may encourage researchers to carefully consider a standardized
set of critical protocol elements that are likely to affect the results of their studies, thereby
improving the overall methodological quality of the study.
Facilitate linkage of study material. Increasingly, individual studies lead to multiple
reports.[28] Researchers can publish the trial protocol, report results in conference abstracts,
in applications with regulatory bodies, in patient information leaflets, on websites, and in one
or more full publications in biomedical journals. These reports often focus on different
research questions and outcomes, sometimes based on a subset of the total study group.
Linkage of reports that originate from the same study can be difficult.[28] This is challenging
for researchers who want to identify all the relevant evidence for a systematic review, and
may come across publications with potentially overlapping participants. Linkage will be
highly facilitated if all diagnostic accuracy studies have a unique registration number that is
included in any report generated from the study.
In contrast to randomized trials, as performed for pharmaceuticals, diagnostic accuracy
studies can also be retrospective in nature, relying on chart records or previously collected
data. Some of the benefits of registration may not fully apply to such retrospective studies,
such as the potential for collaboration, but many other advantages still apply, if the authors
register their study before they extract the data and start performing their analyses.
11
Where to register diagnostic accuracy studies?
No central trial register exists that focuses specifically on diagnostic accuracy studies, and we
do not see the need to start a separate register. We believe that registration of diagnostic
accuracy studies within existing major trial registries is a better option than developing a
registry specifically designed for such studies, because (1) these registries are widely known
and used in the scientific and clinical community, (2) some already contain numerous
diagnostic accuracy studies, (3) a limited number of large, well-designed registries has
practical advantages over many small ones that focus on specific types of research, and (4)
diagnostic accuracy studies are often part of broader studies that also contain non-diagnostic
outcomes.
The major existing trial registries are ClinicalTrials.gov, a service of the US National
Institutes of Health, and 15 Primary registries in the World Health Organization (WHO)
Registry Network (see http://www.who.int/ictrp/network/primary/en/). These are considered
as ‘Primary Registries’ because they “meet specific criteria for content, quality and validity,
accessibility, unique identification, technical capacity and administration”. At present,
ClinicalTrials.gov and the 15 Primary Registries in the WHO Registry Network primarily
focus on the registration of trials of therapeutic interventions, although some welcome studies
with other designs as well.
We performed an online survey among representatives of these 16 registries to assess their
policy towards registration of diagnostic accuracy studies (Figure 1). The survey and results
are provided in Supplemental Data 1 and 2. Thirteen registry representatives (81%)
responded; of these 8 (62%) indicated they always accept registration of diagnostic accuracy
12
studies, and 5 (38%) do so in some cases. A list of major trial registries where diagnostic
accuracy studies can be registered is provided in Table 1.
How to register diagnostic accuracy studies?
In our survey of trial registries, 12 of 13 (92%) respondents indicated that their registry
currently does not provide specific guidance for registering diagnostic accuracy studies, with
the UK based ISRCTN registry (International Standard Randomised Controlled Trial
Number) being the exception.[29] Lack of explicit instructions for registering diagnostic
accuracy studies may be an important reason for researchers to believe that it is difficult or
impossible to register these studies in existing trial registries.
Yet registering diagnostic accuracy studies can be as straightforward as registering a
randomized trial of a new drug. The WHO, which has encouraged trial registration for years,
has proposed a ‘Trial Registration Data Set’, containing 20 items that cover essential study
protocol information that must appear in a registered record for a trial to be considered fully
registered (see http://www.who.int/ictrp/network/trds/en/). Each Primary Registry in the
WHO Registry Network mentioned in Table 1 requires registered records to at least contain
these 20 items. The format of ClinicalTrials.gov is slightly different, although there is major
overlap between items that need to be registered here as well.
Since many items on WHO’s Trial Registration Data Set apply to any type of research
involving humans, there should be no barriers to registration of diagnostic accuracy studies.
Items unique to diagnostic accuracy studies can be incorporated in the Trial Registration Data
Set. To identify such items, we performed a second online survey, among the members of the
STARD (Standards for Reporting Diagnostic Accuracy) group (Figure 1). This group consists
of 85 experts in the field of diagnostic research (Box).[23 24 30]
13
The survey and results are provided in Supplemental Data 3 and 4. In brief, we built a list of
20 items potentially relevant when register a diagnostic accuracy study that are not currently
covered by WHO’s Trial Registration Data Set. This list was established based on the
STARD 2015 reporting guideline.[23 24 30] The items were proposed to survey respondents,
and they could indicate whether they felt that they should or should not be included in the
registered record of a diagnostic accuracy study. Items that were tagged as relevant by two
thirds or more of the respondents were included in our final list. Respondents also had the
opportunity to suggest items not included on the list. The inclusion of these items was
decided based on discussion by the authors of this manuscript, consisting of five trial registry
representatives (LMA, HF, KEH, HL, LH), three current or former editors-in-chief of
journals that publish diagnostic accuracy studies (VB, DM, NR), and five persons with broad
experience in performing diagnostic accuracy studies and systematic reviews thereof (DAK,
JFC, CAG, MDM, PMB).
Seventy-one STARD group members (84%) responded. Based on the survey results, we
recommend that 14 items that are currently not (explicitly) covered by WHO’s Trial
Registration Data Set are incorporated for diagnostic accuracy studies.
Table 2 provides the WHO’s Trial Registration Data Set, and a proposal of where and how
the 14 newly identified items can be mentioned when registering diagnostic accuracy studies,
and examples from existing registered records. This applies to 7 of the 20 items within
WHO’s Trial Registration Data Set; the current definition of the 13 other items equally
applies to diagnostic accuracy studies and does not need any modification.
The Trial Registration Data Set also contains several required or optional data fields related
to the ‘study type’ (item 15), where only fixed options can be selected, for example, whether
the study is ‘interventional’ or ‘observational’, or whether the ‘method of allocation’ is
‘randomized’or ‘non-randomized’. To improve uniformity across registered records, we
14
provide suggestions on how to address these required data fields for diagnostic accuracy
studies in Supplemental Data 5.
How complete are registered records of diagnostic accuracy studies currently?
With the list of 14 recommended items identified in this project, we evaluated the content of
recently registered diagnostic accuracy studies. Using the search term diagnostic accuracy,
we searched WHO’s International Clinical Trials Registry Platform Search Portal on
November 1st, 2016. This engine searches through trial registration data provided by the
Primary Registries and ClinicalTrials.gov. The 30 most recently registered records of
diagnostic accuracy studies were selected. For each record, one author (DAK) assessed if the
newly identified recommended items listed in Table 2 were reported, and in which data field;
difficult cases were discussed with a second author (PMB).
A summary of results is provided in Table 3, with results per registered record in
Supplemental Data 6. Some recommended items were almost always registered, for example:
identification of the record as a diagnostic accuracy study (item 1; 90%), the target condition
(item 2; 97%), and the index test whose diagnostic accuracy is under evaluation (item 3;
100%). Other recommended items were much less frequently registered, for example:
information available to the performers or readers of the index test (item 5; 47%),
information available to the assessors of the reference standard (item 6; 40%), the setting in
which patients will be recruited (item 8; 50%), how data will be collected (item 10; 47%),
and how participants will be sampled (item 11; 37%). We found that 6 records (20%)
contained at least 11 of the 14 recommended items, illustrating that it should be possible to
register all the information proposed in Table 2 in the existing format of trial registers.
15
Who do we want to reach, and who can use this guidance?
With this statement, we aim to reach several key stakeholders:
Researchers. We call on researchers to prospectively register their diagnostic accuracy
studies in one of the major trial registries. We suggest that the guidance proposed will help to
ensure that registered records are fully informative and made uniform across registries. Trial
registries. By hosting registered records of diagnostic accuracy studies, trial registries play a
crucial role. We call on existing major trial registries to ensure that registered records of
diagnostic accuracy studies are sufficiently informative. Registries could incorporate the
proposed guidance into their data field definitions, by adding statements such as: “For
diagnostic accuracy studies, please (also) report [...]”.
Journals. A substantial increase in the number of clinical trials registrations was observed
after the ICMJE implemented its clinical trial registration policy.[5] Here we call on journals
and publishers to actively encourage authors in registering their diagnostic accuracy studies.
This could be done by addressing registration in journals’ instructions to authors, adding a
statement such as: “We recommend researchers to prospectively register their diagnostic
accuracy studies in a publicly accessible trial registry, and to report the corresponding
registration number in the final study report”, or by making the reporting of a trial registration
number – if available – a mandatory field in the submission process and in the reporting of
the abstract.
Funders. Parties funding or employing researchers could strongly recommend or require
registration of diagnostic accuracy studies as a necessary condition for obtaining full funding
or ethical approval. The Wellcome Trust, an “independent global charitable foundation
dedicated to improving health through science, research and engagement with society”, for
example, requires all funded clinical trials to be registered.
16
Institutional review boards and ethics committees. At some centers, clinical trials must have
a registration number before they can get Institutional Review Board approval.[2] Ethics
committees outside of universities can also enforce this. Similar policies could apply to
diagnostic accuracy studies.
Conclusions
Prospective registration provides major opportunities to prevent research waste. The
arguments and guidance provided here can be used to facilitate prospective registration of
diagnostic accuracy studies, and improve registration rates. We propose that investigators
responsible for diagnostic accuracy studies register their study, before recruiting patients, in
one of the 13 existing major trial registries that are willing to host such studies. We also
propose that existing major trial registries consider incorporating the porposed items, as these
are unique to diagnostic accuracy studies, and that bodies funding and journals publishing
diagnostic accuracy studies require full, informative and prospective registration of such
studies.
17
Box: paper’s provenance
STARD is a reporting guideline originally published in 2003 by a large group of researchers
and journal editors with the aim of improving the reporting of diagnostic accuracy studies.
An updated version was recently published: STARD 2015. One of the 30 items on the
updated checklist is “Registration number and name of registry”, which is now recommended
to report in any study report of a diagnostic accuracy study.
The STARD Project Team (DAK, JFC, LH, PMB) decided that STARD should actively take
the lead in promoting registration of diagnostic accuracy studies. This formed the basis of
this article. In this process, the STARD Project Team collaborated closely with the other
authors of this article, who are representatives from trial registries (LMA, HF, KEH, HL,
LH), (former) editors-in-chief of journals that publish diagnostic accuracy studies (VB,
HYK, DM, NR), and researchers/clinicians in the field of diagnostic accuracy (CAG, MDM).
18
Acknowledgements
We thank the following collaborators for participating in the first survey, which aimed to
identify the policy of major trial registries towards registration of diagnostic accuracy studies:
Luiza Rosangela da Silva (Brazilian Clinical Trials Registry), Taixiang Wu (Chinese Clinical
Trial Registry), Gladys Jiménez Rivero (Cuban Public Registry of Clinical Trials), Noemie
Manent (EU Clinical Trials Register), Susanne Jena (German Clinical Trials Register),
Masoud Solaymani-Dodaran (Iranian Registry of Clinical Trials), Elizabeth Pienaar (Pan
African Clinical Trial Registry), Udaya Ranawaka (Sri Lanka Clinical Trials Registry),
Wasee Tulvatana (Thai Clinical Trials Registry) and Tony Tse (ClinicalTrials.gov). We thank
the members of the STARD 2015 group for participating in the second survey, which aimed
to identify important protocol items that need to be registered for diagnostic accuracy studies.
19
References
1. Macleod MR, Michie S, Roberts I, et al. Biomedical research: increasing value, reducing
waste. Lancet 2014;383(9912):101-04 doi: 10.1016/S0140-6736(13)62329-
6[published Online First: Epub Date]|.
2. Moher D, Glasziou P, Chalmers I, et al. Increasing value and reducing waste in biomedical
research: who's listening? Lancet 2016;387(10027):1573-86 doi: 10.1016/S0140-
6736(15)00307-4[published Online First: Epub Date]|.
3. Dickersin K, Rennie D. The evolution of trial registries and their use to assess the clinical
trial enterprise. JAMA 2012;307(17):1861-64 doi: 307/17/1861
[pii];10.1001/jama.2012.4230 [doi][published Online First: Epub Date]|.
4. De Angelis CD, Drazen JM, Frizelle FA, et al. Is this clinical trial fully registered?--A
statement from the International Committee of Medical Journal Editors. New England
journal of medicine 2005;352(23):2436-38 doi: NEJMe058127
[pii];10.1056/NEJMe058127 [doi][published Online First: Epub Date]|.
5. Viergever RF, Li K. Trends in global clinical trial registration: an analysis of numbers of
registered clinical trials in different parts of the world from 2004 to 2013. BMJ open
2015;5(9):e008932 doi: bmjopen-2015-008932 [pii];10.1136/bmjopen-2015-008932
[doi][published Online First: Epub Date]|.
6. van de Wetering FT, Scholten RJ, Haring T, et al. Trial registration numbers are
underreported in biomedical publications. PLoS one 2012;7(11):e49599 doi:
10.1371/journal.pone.0049599 [doi];PONE-D-12-18367 [pii][published Online First:
Epub Date]|.
7. Korevaar DA, Bossuyt PM, Hooft L. Infrequent and incomplete registration of test
accuracy studies: analysis of recent study reports. BMJ open 2014;4(1):e004596 doi:
10.1136/bmjopen-2013-004596[published Online First: Epub Date]|.
20
8. Korevaar DA, Cohen JF, Spijker R, et al. Reported estimates of diagnostic accuracy in
ophthalmology conference abstracts were not associated with full-text publication.
Journal of clinical epidemiology 2016;79:96-103 doi:
10.1016/j.jclinepi.2016.06.002[published Online First: Epub Date]|.
9. Altman DG. The time has come to register diagnostic and prognostic research. Clinical
chemistry 2014;60(4):580-82 doi: clinchem.2013.220335
[pii];10.1373/clinchem.2013.220335 [doi][published Online First: Epub Date]|.
10. Rifai N, Altman DG, Bossuyt PM. Reporting bias in diagnostic and prognostic studies:
time for action. Clinical chemistry 2008;54(7):1101-03 doi: 54/7/1101
[pii];10.1373/clinchem.2008.108993 [doi][published Online First: Epub Date]|.
11. Rifai N, Bossuyt PM, Ioannidis JP, et al. Registering diagnostic and prognostic trials of
tests: is it the right thing to do? Clinical chemistry 2014;60(9):1146-52 doi:
clinchem.2014.226100 [pii];10.1373/clinchem.2014.226100 [doi][published Online
First: Epub Date]|.
12. Hooft L, Assendelft WJ, Hoeksema HL, et al. [A national prospective trial register for
randomised controlled trials: ethical and practical necessity]. Nederlands tijdschrift
voor geneeskunde 2004;148(38):1866-69
13. Linnet K, Bossuyt PM, Moons KG, et al. Quantifying the accuracy of a diagnostic test or
marker. Clinical chemistry 2012;58(9):1292-301 doi: clinchem.2012.182543
[pii];10.1373/clinchem.2012.182543 [doi][published Online First: Epub Date]|.
14. Hooft L, Bossuyt PM. Prospective registration of marker evaluation studies: time to act.
Clinical chemistry 2011;57(12):1684-86 doi: clinchem.2011.176230
[pii];10.1373/clinchem.2011.176230 [doi][published Online First: Epub Date]|.
21
15. World Medical A. World Medical Association Declaration of Helsinki: ethical principles
for medical research involving human subjects. JAMA 2013;310(20):2191-94 doi:
10.1001/jama.2013.281053[published Online First: Epub Date]|.
16. Korevaar DA, Ochodo EA, Bossuyt PM, et al. Publication and reporting of test accuracy
studies registered in ClinicalTrials.gov. Clinical chemistry 2014;60(4):651-59 doi:
clinchem.2013.218149 [pii];10.1373/clinchem.2013.218149 [doi][published Online
First: Epub Date]|.
17. Brazzelli M, Lewis SC, Deeks JJ, et al. No evidence of bias in the process of publication
of diagnostic accuracy studies in stroke submitted as abstracts. Journal of clinical
epidemiology 2009;62(4):425-30 doi: S0895-4356(08)00228-X
[pii];10.1016/j.jclinepi.2008.06.018 [doi][published Online First: Epub Date]|.
18. Wilson C, Kerr D, Noel-Storr A, et al. Associations with publication and assessing
publication bias in dementia diagnostic test accuracy studies. International journal of
geriatric psychiatry 2015;30(12):1250-56 doi: 10.1002/gps.4283 [doi][published
Online First: Epub Date]|.
19. Korevaar DA, van Es N, Zwinderman AH, et al. Time to publication among completed
diagnostic accuracy studies: associated with reported accuracy estimates. BMC
medical research methodology 2016;16(1):68 doi: 10.1186/s12874-016-0177-
4[published Online First: Epub Date]|.
20. van Enst WA, Scholten RJ, Hooft L. Identification of additional trials in prospective trial
registers for Cochrane systematic reviews. PLoS one 2012;7(8):e42812 doi:
10.1371/journal.pone.0042812 [doi];PONE-D-12-10497 [pii][published Online First:
Epub Date]|.
22
21. Jones CW, Keil LG, Weaver MA, et al. Clinical trials registries are under-utilized in the
conduct of systematic reviews: a cross-sectional analysis. Syst Rev 2014;3:126 doi:
10.1186/2046-4053-3-126[published Online First: Epub Date]|.
22. Mathieu S, Chan AW, Ravaud P. Use of trial register information during the peer review
process. PLoS one 2013;8(4):e59910 doi: 10.1371/journal.pone.0059910 [doi];PONE-
D-12-38579 [pii][published Online First: Epub Date]|.
23. Bossuyt PM, Reitsma JB, Bruns DE, et al. STARD 2015: An Updated List of Essential
Items for Reporting Diagnostic Accuracy Studies. Clinical chemistry
2015;61(12):1446-52 doi: 10.1373/clinchem.2015.246280[published Online First:
Epub Date]|.
24. Cohen JF, Korevaar DA, Altman DG, et al. STARD 2015 guidelines for reporting
diagnostic accuracy studies: explanation and elaboration. BMJ open
2016;6(11):e012799 doi: 10.1136/bmjopen-2016-012799[published Online First:
Epub Date]|.
25. Scherer RW, Huynh L, Ervin AM, et al. ClinicalTrials.gov registration can supplement
information in abstracts for systematic reviews: a comparison study. BMC medical
research methodology 2013;13:79 doi: 1471-2288-13-79 [pii];10.1186/1471-2288-13-
79 [doi][published Online First: Epub Date]|.
26. Hunter K, Vu T, Sausa R, et al. Australian New Zealand Clinical Trials Registry
(ANZCTR) user survey results from 2009 and 2015. Cochrane Colloquium. Vienna,
2015.
27. Whiting PF, Rutjes AW, Westwood ME, et al. A systematic review classifies sources of
bias and variation in diagnostic test accuracy studies. Journal of clinical epidemiology
2013;66(10):1093-104 doi: S0895-4356(13)00200-X
[pii];10.1016/j.jclinepi.2013.05.014 [doi][published Online First: Epub Date]|.
23
28. Altman DG, Furberg CD, Grimshaw JM, et al. Linked publications from a single trial: a
thread of evidence. Trials 2014;15:369 doi: 10.1186/1745-6215-15-369[published
Online First: Epub Date]|.
29. Lippman H. Diagnostic accuracy: 60% of the time, it works every time. BioMed Central
blog network 2016.
30. Korevaar DA, Cohen JF, Reitsma JB, et al. Updating standards for reporting diagnostic
accuracy: the development of STARD 2015. Research Integrity and Peer Review
2016;1(1):7
24
Table 1. Major trial registries where diagnostic accuracy studies can be registered.
Registry Website Condition for registration of diagnostic accuracy
studies
Registries that always accept registration of diagnostic accuracy studies:
Australian New Zealand Clinical Trials
Registry www.anzctr.org.au/ -
Brazilian Clinical Trials Registry www.ensaiosclinicos.gov.br/ -
Chinese Clinical Trial Registry www.chictr.org/en/ -
German Clinical Trials Register drks-neu.uniklinik-
freiburg.de/drks_web/ -
ISRCTN registry www.isrctn.com/
“The ISRCTN registry is a primary clinical trial
registry recognized by WHO and ICMJE that accepts
all clinical research studies (whether proposed, ongoing
or completed), providing content validation and
curation and the unique identification number
necessary for publication.”
Netherlands National Trial Register www.trialregister.nl/ -
Thai Clinical Trials Registry www.clinicaltrials.in.th/ -
ClinicalTrials.gov www.clinicaltrials.gov
“ClinicalTrials.gov accepts registration of all studies
that ‘are in conformance with applicable human
subjects or ethics review regulations (or equivalent)
and applicable regulations of the national (or regional)
health authority (or equivalent).’”
Registries that in some cases accept registration of diagnostic accuracy studies:
Cuban Public Registry of Clinical Trials registroclinico.sld.cu/
“The Cuban Public Registry of Clinical Trials does not
have a specific data set for this type of trials, but if the
trial fulfills the fields it is possible to register it.”
EU Clinical Trials Register www.clinicaltrialsregister.eu/
“If the study is also a clinical trial. This means that
there is an investigational medical product being
administered to the subjects taking part in the trial.”
Iranian Registry of Clinical Trials www.irct.ir/ “If they comply with the WHO’s definition of clinical
trials.”
Pan African Clinical Trial Registry www.pactr.org/ “Currently Pan African Clinical Trial Registry only
accepts RCTs and CCTs.”
Sri Lanka Clinical Trials Registry trials.slctr.lk/ “Where there is a clear intervention being tested.”
Registries that did not respond in our survey:
Clinical Research Information Service,
Korea cris.nih.go.kr/ -
Clinical Trials Registry – India ctri.nic.in/ -
Japan Primary Registries Network rctportal.niph.go.jp/ -
Table legend: WHO=World Health Organization; ICMJE=International Committee of
Medical Journal Editors; RCT=randomized clinical trial; CCT=controlled clinical trial.
25
Table 2. WHO’s Trial Registration Data Set (TRDS), modified for diagnostic accuracy
studies.
Item on TRDSa Modifications for diagnostic accuracy studies Examples from existing registered records of
diagnostic accuracy studies
1. Primary Registry and Trial
Identifying Number As defined for trials in WHO’s TRDS.
2. Date of Registration in Primary
Registry As defined for trials in WHO’s TRDS.
3. Secondary Identifying
Numbers As defined for trials in WHO’s TRDS.
4. Source(s) of Monetary or
Material Support As defined for trials in WHO’s TRDS.
5. Primary Sponsor As defined for trials in WHO’s TRDS.
6. Secondary Sponsor(s) As defined for trials in WHO’s TRDS.
7. Contact for Public Queries As defined for trials in WHO’s TRDS.
8. Contact for Scientific Queries As defined for trials in WHO’s TRDS.
9. Public Title As defined for trials in WHO’s TRDS.
10. Scientific Title
Item 1:
Include ‘diagnostic accuracy’ or one or more
accuracy measures in the title
(e.g. sensitivity, specificity, predictive value,
likelihood ratio, AUC).
“The diagnostic accuracy of exhaled breath
fingerprinting by eNose in diagnosing asthma
and atopy.”
(NTR1398)
11. Countries of Recruitment As defined for trials in WHO’s TRDS.
12. Health Condition(s) or
Problem(s) Studied
Item 2:
List the target condition that the diagnostic tests
should detect, or the target event to predict.
“Health condition(s) or problem(s) studied:
endometriosis”
(ACTRN12616001106426)
13. Intervention(s)
Item 3:
Index test: Provide an informative description of
the index test under evaluation. Include (if
applicable) the generic name and/or commercial
name.
“Device: VitalScan Magnetocardiograph. A
passive, non-contact, mobile medical device
that measures, displays, stores, and retrieves
magnetic fluctuations caused by heart activity at
a patient's bedside.”
(NCT02921438)
Item 4:
Reference standard: Provide an informative
description of the reference standard. Include (if
applicable) the generic name and/or commercial
name.
“Reference standard: Automated blood culture
technology, in place as standard NHS care in
microbiology laboratories at participating sites,
and performed prospectively as part of usual
clinical care.”
(ISRCTN97997760)
Item 5:
Index test: Describe the information available to the
performers or readers of the index test
(e.g. clinical information, other test results, results
of the reference standard).
“All patients will undergo both of these
diagnostic tests, though the order will be
randomised. Interpreting physicians of each
study will be blinded to the results of the other.”
(ACTRN12616001016426)
Item 6:
Reference standard: Describe the information
available to the assessors of the reference standard
“A second sonographer, blinded to all clinical
information and the primary sonographer's
ultrasound interpretation, will review the de-
identified ultrasound images remotely.”
26
(e.g. clinical information, other test results, results
of the index test).
(NCT02190981)
Item 7:
Index test: Describe the intended use and clinical
role relative to other tests in the existing clinical
pathway
“Current recommendations to rule out a heart
attack are based upon the patient having a
normal ECG (heart-tracing) and the absence of
a protein in the blood called troponin, which is
released when the heart muscle is injured.
Troponin is currently measured between 6 and
12 hours from Emergency Department
presentation. The majority of tests are normal
but this wait leads to excessive patient anxiety,
unnecessary prolongation of hospital stay and
ED overcrowding. The development of a
diagnostic pathway that allows more rapid
assessment of patients with chest pain and
prevents unnecessary hospital admission will
have a profound benefit on healthcare services.
This study aims to test the safety of a novel
diagnostic pathway for the rapid assessment of
patients with chest pain that allows the rapid
rule-out of heart attack. This pathway is based
upon the very recent development of a new
blood test that detects heart injury called the
high-sensitivity Troponin (hs-Tn) assay.”
(ISRCTN21109279)
14. Key Inclusion and Exclusion
Criteria
Item 8:
Setting: Describe the setting in which patients will
be recruited
(e.g. primary care facilities, university hospital’s
emergency department).
“Patients with clinical suspected pulmonary
embolism; Simplified Well's score >4
(pulmonary emblism) or D-dimer value
≥500ng/ml; Patients that undergo MCTPA
(Multidetector Computed Tomography
Angiography) in the Emergency Department for
suspected pulmonary embolism.”
(NCT01635257)
Item 9:
Participant recruitment: Describe on what basis
potentially eligible participants will be identified
(e.g. symptoms, results from previous tests, from
patient registries).
15. Study Typeb
Item 10:
Data collection: Describe how data will be
collected
(e.g. prospectively, retrospectively).
“Retrospective analysis of a quality
measurement project examining the quality of
vital parameter measurement in consecutive
patients ≥75 years presenting to the emergency
department.” (NCT01639430)
Item 11:
Participant sampling: Describe how participants
will be sampled
(e.g. a consecutive series, a random series, a
convenience sample, other).
16. Date of First Enrollment As defined for trials in WHO’s TRDS.
17. Target Sample Size As defined for trials in WHO’s TRDS.
18. Recruitment Status As defined for trials in WHO’s TRDS.
19. Primary Outcome(s) Item 12:
Study’s primary outcome measures:
“Sensitivity and specificity of the Thessaly test,
in determining the presence of meniscal tears,
27
*Name of the outcome: Include the index test(s)
whose diagnostic accuracy is evaluated, and the
target condition.
*Metric or method of measurement: Include (if
applicable) which estimates of diagnostic accuracy
will be calculated for the primary outcome
(e.g. sensitivity and specificity, or positive and
negative predictive values).
*Timepoint(s) of primary interest: ;
For prognostic and predictive tests, define the
follow-up period of interest
(e.g. events within 12 months after the index test
was performed);
For diagnostic tests, this can be at the time of the
index test or reference standard.
when employed by General Practitioners.”
(ISRCTN43527822)
“Accuracy (sensitivity and specificity) of
ultrasound scan as a tool for early detection of
superficial endometriosis.”
(ACTRN12616001106426)
“Predictive accuracy of copeptin, C reactive
Protein (CRP) and procalcitonin in terms of
developing organ failure, necrosis and/or
superinfection and mortality [Time Frame:
Duration of hospitalization]”
(NCT01293318)
20. Key Secondary Outcomes
Item 13:
Describe any pre-defined analyses of variability in
diagnostic accuracy
(e.g. across clinical subgroups).
“Sensitivity/specificity measures for the urine
test will be determined in subgroups of patients
who have a kidney transplant or a combined
pancreas/kidney transplant.”
(NCT01315067)
Item 14:
-Describe any other outcomes of secondary interest.
“Any adverse events reported by the patient in
the week following the procedure.”
(NCT02498041)
“Inter-rater agreement: The study will quantify
the rate of inter-rater agreement between the
clinician performing the point-of-care
ultrasound and a blinded reviewer of the
ultrasound images”.
(NCT02190981)
Table legend:
aWHO’s Trial Registration Data Set is available at http://www.who.int/ictrp/network/trds/en/.
WHO=World Health Organization.
bWHO’s Trial Registration Data Set also contains several required or optional data fields
related to the ‘study type’ (item 15), where only fixed options can be selected (e.g., whether
the study is ‘interventional’ or ‘observational’). Suggestions on how to address these for
diagnostic accuracy studies are provided in Supplemental Data 5.
28
Table 3. Completeness of registered records of diagnostic accuracy studies (n=30).
Item Description Information registered
1 Include ‘diagnostic accuracy’ or one or more accuracy measures in the title 27 (90%)
2 List the target condition that the diagnostic tests should detect, or the target event to predict 29 (97%)
3 Index test: Provide an informative description of the index test under evaluation. 30 (100%)
4 Reference standard: Provide an informative description of the reference standard. 19 (63%)
5 Index test: Describe the information available to the performers or readers of the index test 14 (47%)
6 Reference standard: Describe the information available to the assessors of the reference standard 12 (40%)
7 Index test: Describe the intended use and clinical role relative to other tests in the existing clinical pathway 18 (60%)
8 Setting: Describe the setting in which patients will be recruited 15 (50%)
9 Participant recruitment: Describe on what basis potentially eligible participants will be identified 22 (73%)
10 Data collection: Describe how data will be collected 14 (47%)
11 Participant sampling: Describe how participants will be sampled 11 (37%)
12 Study’s primary outcome measures 20 (67%)
13 Describe any pre-defined analyses of variability in diagnostic accuracy 2 (7%)
14 Describe any other outcomes of secondary interest 19 (63%)
29
Figure 1. Two online surveys formed the basis for this project.