1180 COMMENTARY Journal of the National Cancer Institute, Vol. 97, No. 16, August 17, 2005
Specimen availability may be related to tumor size and patient
outcome ( 12 ) , and the quantity, quality, and preservation method
of the specimen may affect feasibility of conducting certain
assays. There can also be biases or large variability inherent in
the assay results, depending on the particular assay methods used
( 13 – 17 ) . Statistical problems are commonplace. These problems
include underpowered studies or overly optimistic reporting of
effect sizes and signifi cance levels due to multiple testing, subset
analyses, and cutpoint optimization ( 18 ) .
Unfortunately, many tumor marker studies have not been
reported in a rigorous fashion, and published articles often lack
suffi cient information to allow adequate assessment of the qual-
ity of the study or the generalizability of study results. Such
reporting defi ciencies are increasingly being highlighted by sys-
tematic reviews of the published literature on particular markers
or cancers ( 19 – 25 ) .
The development of guidelines for the reporting of tumor
marker studies was a major recommendation of the National Can-
cer Institute – European Organisation for Research and Treatment
of Cancer (NCI-EORTC) First International Meeting on Cancer
Diagnostics (From Discovery to Clinical Practice: Diagnostic
Innovation, Implementation, and Evaluation) that was convened
in Nyborg, Denmark, in July 2000. The purpose of the meeting
was to discuss issues, accomplishments, and barriers in the fi eld
of cancer diagnostics. Poor study design and analysis, assay vari-
ability, and inadequate reporting of studies were identifi ed as some
of the major barriers to progress in this fi eld. One of the working
groups formed at the Nyborg meeting was charged with address-
ing statistical issues of poor design and analysis and with report-
ing of tumor marker prognostic studies. The guidelines that we
present in this commentary are the product of that committee. The
Program for the Assessment of Clinical Cancer Tests (PACCT)
Strategy Group of the U.S. NCI has also strongly endorsed this
effort ( http://www.cancerdiagnosis.nci.nih.gov/assessment ).
Reporting Recommendations for Tumor Marker
Prognostic Studies (REMARK)
Lisa M. McShane , Douglas G. Altman , Willi Sauerbrei , Sheila E. Taube ,
Massimo Gion , Gary M. Clark for the Statistics Subcommittee of the
NCI-EORTC Working Group on Cancer Diagnostics
Despite years of research and hundreds of reports on tumor
markers in oncology, the number of markers that have
emerged as clinically useful is pitifully small. Often, initially
reported studies of a marker show great promise, but subse-
quent studies on the same or related markers yield inconsis-
tent conclusions or stand in direct contradiction to the
promising results. It is imperative that we attempt to under-
stand the reasons that multiple studies of the same marker
lead to differing conclusions. A variety of methodologic prob-
lems have been cited to explain these discrepancies. Unfortu-
nately, many tumor marker studies have not been reported in
a rigorous fashion, and published articles often lack suffi cient
information to allow adequate assessment of the quality of the
study or the generalizability of study results. The development
of guidelines for the reporting of tumor marker studies was
a major recommendation of the National Cancer Institute –
European Organisation for Research and Treatment of Can-
cer (NCI-EORTC) First International Meeting on Cancer
Diagnostics in 2000. As for the successful CONSORT initia-
tive for randomized trials and for the STARD statement for
diagnostic studies, we suggest guidelines to provide relevant
information about the study design, preplanned hypotheses,
patient and specimen characteristics, assay methods, and
statistical analysis methods. In addition, the guidelines sug-
gest helpful presentations of data and important elements to
include in discussions. The goal of these guidelines is to encour-
age transparent and complete reporting so that the relevant
information will be available to others to help them to judge
the usefulness of the data and understand the context in which
the conclusions apply. [J Natl Cancer Inst 2005;97:1180–4]
Despite years of research and hundreds of reports on tumor
markers in oncology, the number of markers that have emerged
as clinically useful is pitifully small ( 1 – 3 ) . Often, initially re-
ported studies of a marker show great promise, but subsequent
studies on the same or related markers yield inconsistent conclu-
sions or stand in direct contradiction to the promising results.
It is imperative that we attempt to understand the reasons that
multiple studies of the same marker lead to differing conclusions.
A variety of problems have been cited to explain these discrep-
ancies, such as general methodologic differences, poor study
design, assays that are not standardized or lack reproducibility,
and inappropriate or misleading statistical analyses that are often
based on sample sizes too small to draw meaningful conclusions
( 4 – 11 ) . For example, in retrospective studies, patient populations
are often biased toward patients with available tumor specimens.
Affi liations of authors: Biometric Research Branch (LMM) and Cancer
Diagnosis Program (SET), National Cancer Institute, Bethesda, MD; Medi-
cal Statistics Group, Cancer Research UK, Center for Statistics in Medicine,
Wolfson College, Oxford, UK (DGA); Institut fuer Medizinische Biometrie und
Medizinische Informatik, Universitaetsklinikum Freiburg, Germany (WS);
Centro Regionale Indicatori Biochimici di Tumore, Ospedale Civile, Venezia,
Italy (MG); OSI Pharmaceuticals, Inc., Boulder, CO (GMC).
Correspondence to: Lisa M. McShane, PhD, National Cancer Institute, Bio-
metric Research Branch, DCTD, Rm. 8126, Executive Plaza North, MSC 7434,
6130 Executive Blvd., Bethesda, MD 20892-7434 (e-mail: firstname.lastname@example.org ).
See “ Notes ” following “ References. ”
© The Author 2005. Published by Oxford University Press. All rights reserved.
For Permissions, please e-mail: email@example.com .
Journal of the National Cancer Institute, Vol. 97, No. 16, August 17, 2005 COMMENTARY 1181
The guidelines that we present in this commentary build on
earlier suggestions ( 21 , 26 – 29 ) and on educational publications
( 30 – 33 ) . They recommend elements and formats for presenta-
tion with the objectives of facilitating evaluation of the appro-
priateness and quality of study design, methods, analyses, and
improving the ability to compare results across studies. As for
the successful CONSORT initiative for randomized clinical tri-
als ( 34 ) , and the STARD statement for studies of diagnostic test
accuracy ( 35 ) , these guidelines suggest relevant information that
should be provided about the study design, preplanned hypoth-
eses, patient and specimen characteristics, assay methods, and
statistical analysis methods. In addition, the guidelines suggest
helpful presentations of data and important elements to include
in discussions. To be published elsewhere, in an explanatory
document, are specifi c justifi cations for the need for each of the
elements of the recommendations.
We have developed these reporting guidelines primarily for
studies evaluating a single tumor marker of interest, often includ-
ing adjustment for standard clinical prognostic variables. They
are largely relevant for studies exploring more than one marker,
but they are not intended to specifi cally address statistical con-
siderations in development of prognostic models from very large
numbers of candidate markers. The reason we chose to empha-
size prognostic marker studies is that they represent a large pro-
portion of the tumor marker literature and tend to be particularly
fraught with problems because they are often conducted on retro-
spective collections of specimens, and analyses may contain sub-
stantial exploratory components. For this commentary, we defi ne
prognostic markers to be markers that have an association with
some clinical outcome, typically a time-to-event outcome such
as overall survival or recurrence-free survival. (Some individuals
adhere to a stricter defi nition of prognostic marker as applying
only to the natural history of patients who received no treatment
following local therapy.) Prognostic markers may be considered
in the clinical management of a patient. For example, they may
be used as decision aids in determining whether a patient should
receive adjuvant chemotherapy or how aggressive that therapy
should be. Predictive markers are generally used to make more
specifi c choices between treatment options. Predictive markers
are used as indicators of the likely benefi t to a specifi c patient
of a specifi c treatment. For example, a predictive marker might
indicate that a patient expressing the marker will benefi t more
from a new treatment than from standard treatment, whereas a
patient not expressing the marker will derive little or no benefi t
from the new treatment. Predictive marker studies usually occur
later in the marker development process, and there are far fewer
published examples. Knowledge of specifi c treatments received
and of how those treatment decisions were made become even
more critical. In our judgment, the issues in reporting predictive
marker studies are complex and different enough from those of
prognostic marker studies that we are not willing to claim that
these guidelines give predictive marker studies adequate cover-
age, although we believe that most of the guidance is relevant to
such studies also.
The goal of these guidelines is to encourage transparent and
complete reporting so that the relevant information will be avail-
able to others to help them to judge the usefulness of the data
and understand the context in which the conclusions apply. These
guidelines are not intended to dictate specifi c designs or analysis
strategies. In general, there is more than one acceptable approach
to the design or analysis of a particular study, although these
guidelines should help to eliminate some clearly unacceptable
options, as have been discussed in other papers ( 7 , 26 , 33 , 36 ) . For
example, unacceptable options include reporting statistical sig-
nifi cance of a marker’s prognostic effect without acknowledging
that the signifi cance testing was preceded by extensive manipula-
tions involving derivation of data-dependent cutpoints or variable
selection procedures. High-quality reporting of a study cannot
transform a poorly designed or -analyzed study into a good one,
but it can help to identify the poor studies, and we believe it is
an important fi rst step in improving the overall quality of tumor
marker prognostic studies.
M ATERIALS AND M ETHODS
Initial ideas for key elements to be addressed in the guidelines
were assembled from literature citing empirical evidence of in-
adequate reporting or problematic analysis methods ( 9 , 18 , 36 , 37 )
that are based on published reviews of tumor marker studies.
Ideas were also generated by reviewing similar reporting guide -
lines that have been produced for other types of medical
research studies (CONSORT, QUOROM, MOOSE, and STARD)
( 34 , 35 , 38 , 39 ) . Three individuals from the working group (L.M.,
D.A., and G.C.) wrote a fi rst draft to serve as a starting point for
discussion by the full group. Comments on drafts were made by
the full group on a conference call and through multiple e-mail
exchanges. A very preliminary draft was presented to the PACCT
Strategy Group in January 2001. In response to comments, the
guidelines were shortened, reformatted, and recirculated to the
full committee. They were posted to the PACCT website ( http://
html ) for public comment and circulated to attendees of the
NCI-EORTC Second International Meeting on Cancer Diagnos-
tics (Conference on the Development of New Diagnostic Tools
for Cancer) that was held in Washington, DC, in June 2002. In
February 2003, three committee members (D.A., L.M., and W.S.)
met for 2 days to make further revisions. The version produced
in that February meeting was sent to the full committee for fi nal
comment. The version presented here incorporates those fi nal
comments and was approved by the full committee.
Table 1 shows the recommendations for reporting studies on
tumor markers. Specifi c items are grouped under headings Intro-
duction, Materials and Methods, Results, and Discussion, refl ect-
ing the relevant sections of a published scientifi c article. Further
details about the recommendations and explanatory material will
be provided elsewhere.
As noted in item 12, a diagram may be helpful to indicate
numbers of individuals included at different stages of a study. As
a minimum, such a diagram could show the number of patients
originally in the sample, the number remaining after exclusions,
and the numbers incorporated into univariate and multivariable
The reporting guidelines in this commentary are the result of
a collaborative effort among statisticians, clinicians, and labora-
tory scientists who are committed to improving and accelerating
1182 COMMENTARY Journal of the National Cancer Institute, Vol. 97, No. 16, August 17, 2005
the process by which tumor markers that provide useful informa-
tion for management of cancer patients are adopted into clini-
cal practice. In addition to the authors of this commentary, we
gratefully acknowledge the contributions of many individuals
with whom we have had informal discussions regarding these
guidelines and who have been supportive of this effort. All of us
participating in the development of these guidelines are actively
involved in the design, conduct, and analysis of studies involv-
ing tumor markers. We serve as editors and reviewers for many
scientifi c journals that publish tumor marker studies. We serve
on program committees for international meetings, as decision-
makers for funding agencies, and as participants in national and
international committees charged with evaluating and prioritizing
tumor markers for further study or making recommendations for
clinical use. We also are actively involved in our own research
involving tumor markers. As editors, reviewers, and program and
advisory committee members, we have struggled with having to
make decisions when insuffi cient information is provided about
study design or analysis methods. As individual investigators, we
have experienced the frustration of trying to interpret often con-
fusing literature to guide our own research programs.
There are consequences of poor study reporting for the
r esearch community as a whole. Poorly designed or inappro-
priately analyzed studies can attract undeserved attention when
they produce very dramatic but unfortunately incorrect results.
In contrast, some carefully designed and analyzed studies have
been overlooked because they produced less dramatic but
perhaps more accurate and realistic results. The poor quality of
reporting of prognostic marker studies may have contributed to
the relative scarcity of markers whose prognostic infl uence is
well supported. Thorough reporting is required no matter what
methods of design and analysis are used. Thorough reporting
does not solve problems of poor design or analysis that are being
reported; rather, it just fairly describes what problems may exist
and need to be considered in interpretation. It is our hope that
these guidelines will be embraced and used by journal editors,
reviewers, funding agencies, decision-making bodies, and indi-
Table 1. Reporting recommendations for tumor marker prognostic studies (REMARK)
1. State the marker examined, the study objectives, and any prespecifi ed hypotheses.
MATERIALS AND METHODS
2. Describe the characteristics (e.g., disease stage or comorbidities) of the study patients, including their source and inclusion and exclusion criteria.
3. Describe treatments received and how chosen (e.g., randomized or rule-based).
4. Describe type of biological material used (including control samples) and methods of preservation and storage.
5. Specify the assay method used and provide (or reference) a detailed protocol, including specifi c reagents or kits used, quality control procedures,
reproducibility assessments, quantitation methods, and scoring and reporting protocols. Specify whether and how assays were performed blinded to the study
6. State the method of case selection, including whether prospective or retrospective and whether stratifi cation or matching (e.g., by stage of disease or age) was
used. Specify the time period from which cases were taken, the end of the follow-up period, and the median follow-up time.
7. Precisely defi ne all clinical endpoints examined.
8. List all candidate variables initially examined or considered for inclusion in models.
9. Give rationale for sample size; if the study was designed to detect a specifi ed effect size, give the target power and effect size.
Statistical analysis methods
10. Specify all statistical methods, including details of any variable selection procedures and other model-building issues, how model assumptions were verifi ed,
and how missing data were handled.
11. Clarify how marker values were handled in the analyses; if relevant, describe methods used for cutpoint determination.
12. Describe the fl ow of patients through the study, including the number of patients included in each stage of the analysis (a diagram may be helpful) and reasons
for dropout. Specifi cally, both overall and for each subgroup extensively examined report the numbers of patients and the number of events.
13. Report distributions of basic demographic characteristics (at least age and sex), standard (disease-specifi c) prognostic variables, and tumor marker, including
numbers of missing values.
Analysis and presentation
14. Show the relation of the marker to standard prognostic variables.
15. Present univariate analyses showing the relation between the marker and outcome, with the estimated effect (e.g., hazard ratio and survival probability).
Preferably provide similar analyses for all other variables being analyzed. For the effect of a tumor marker on a time-to-event outcome, a Kaplan – Meier plot
16. For key multivariable analyses, report estimated effects (e.g., hazard ratio) with confi dence intervals for the marker and, at least for the fi nal model, all other
variables in the model.
17. Among reported results, provide estimated effects with confi dence intervals from an analysis in which the marker and standard prognostic variables are
included, regardless of their statistical signifi cance.
18. If done, report results of further investigations, such as checking assumptions, sensitivity analyses, and internal validation.
19. Interpret the results in the context of the prespecifi ed hypotheses and other relevant studies; include a discussion of limitations of the study.
20. Discuss implications for future research and clinical value.
Journal of the National Cancer Institute, Vol. 97, No. 16, August 17, 2005 COMMENTARY 1183
These guidelines have been labeled as applying to clinical prog-
nostic studies. Not all of the elements apply to studies conducted
in earlier phases of marker development ( 40 ) , for example, early
marker studies seeking to fi nd an association between a new
marker and other clinical variables or existing prognostic factors.
However, our recommendation is that investigators conducting
early marker studies strive to adhere to as many of the reporting
guidelines as applicable in their situation, and the guidelines might
also suggest issues that will be important for them to consider
in planning follow-up studies on their investigational markers.
Studies of markers that can be used to predict the success of
particular therapies, such as molecular targeted therapies, need
additional considerations. It is our opinion that predictive marker
studies should generally be conducted within randomized trials
and should require a suffi cient (usually larger) effective sample
size and that assays should be in a more advanced state of devel-
opment. The CONSORT statement for randomized clinical trials
can serve as a starting point for reporting guidelines for predictive
marker studies, but more issues relating to the marker assays must
be addressed. It is our feeling that more stringent and specifi c
guidelines need to be developed for reporting studies of predictive
markers. Such studies will be considered in somewhat more detail
in the planned explanatory paper to be published elsewhere.
It may not be possible to report every detail for every study. For
example, it is often diffi cult to provide detailed patient inclusion/
exclusion criteria or treatment information in retrospective prog-
nostic marker studies using archived tumor specimens. The impact
of such missing information must be judged in the specifi c con-
text of the study and its stated conclusions. For example, a “ pure ”
prognostic study should be conducted in a group of patients who
have not received any systemic adjuvant therapy, but treatment in-
formation is often missing or unreliable in retrospective studies. In
these cases, it is important to recognize that apparent “ prognostic ”
effects may be infl uenced by potential treatment by marker inter-
actions. The key point is that there must be a clear statement of
what is and is not known. In addition, it was beyond the scope
of these guidelines to recommend specifi c details that should be
reported for each of the major classes of marker assays, for ex-
ample, immunohistochemistry, in situ hybridization methods, or
DNA-based assays. There is an ongoing effort to defi ne such assay-
specifi c checklists by another working group evolving from the
NCI-EORTC International Meetings on Cancer Diagnostics.
Some of the reviewers suggested that the guidelines should
promote full public access to data, possibly even individual-level
data. We have chosen not to include this issue in the current scope
of the guidelines even though we view movement in this direction
as generally positive. One concern is that if a study was poorly
designed or inadequately reported, making its data publicly avail-
able may simply propagate bad science. Good study design and
data quality have to come fi rst. We do recognize the potential ben-
efi ts of promoting full public access to good-quality data. It would
allow verifi cation of published analysis methods and results and
would facilitate alternative analyses and meta-analyses. Attainment
of these goals would be helped substantially if guidelines 10 and
11 were strictly applied so that statistical analysis methods were
described in suffi cient detail to allow an individual independent
of the original research team to reproduce the results of the study
if supplied with the raw data. For extensive analyses, it is possible
that some of this information would have to be provided as supple-
mentary material available outside of the main published report,
for example on the journal’s or author’s Web site.
Although some might view adherence to these guidelines as
yet another burden in trying to publish or obtain funding, we
would argue that use of these guidelines is more likely to re-
duce burdens on the research community. Making clear what is
considered relevant and important to report in journal articles or
funding proposals will likely reduce review time, reduce requests
for revisions, and help to ensure a fair review process. Further-
more, we consider it as a prerequisite for a thoughtful presentation
and interpretation of the results of a specifi c study and a key aid
for a summary assessment of the effect of a marker in a review
paper. Most importantly, what greater reduction in burden could
there be than to eliminate some of the false leads generated by
poorly designed, analyzed, or reported studies that send research-
ers down unproductive paths, wasting years of time and money?
The ultimate usefulness of these guidelines will rely on how
widely they are adopted. We are heartened by the enthusiastic
responses that we received from the several journals who have
agreed to simultaneously publish this paper. There is a clear rec-
ognition in the community that the time has come (if not long
overdue) to improve the quality of tumor marker study report-
ing and conduct. We hope that many journals will adopt these
guidelines as part of their editorial requirements. To the extent
that does not happen immediately, we have to rely on authors
of journal articles and reviewers of those articles to initiate the
movement toward adherence to these guidelines.
We expect that just as tumor marker research will evolve,
these guidelines will have to evolve to address new study para-
digms and new assay technologies. It is our hope that publication
of these guidelines will generate vigorous discussion leading to
continually improved versions and, ultimately, improved quality
of tumor marker studies.
The guidelines presented in this paper are available at http://
html , as will be other recommendations from the group in due
course. As noted, a detailed explanatory paper is to be published
elsewhere, following the model of similar articles relating to the
CONSORT and STARD statements ( 41 – 42 ) .
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We are grateful to the U.S. National Cancer Institute and the European Organi-
zation for Research and Treatment of Cancer for their support of the NCI-EORTC
International Meetings on Cancer Diagnostics, from which the idea for these
guidelines originated. We thank the U.K. National Translational Cancer Research
Network for fi nancial support provided to D. G. Altman.
Members of the Statistics Subcommittee of the NCI-EORTC Working Group on
Cancer Diagnostics are: Douglas G. Altman, DSc (Co-chair), Medical Statistics
Group, Cancer Research UK, Centre for Statistics in Medicine, Wolfson College,
Oxford OX2 6UD, UK; Lisa M. McShane, PhD (Co-chair), Biometric Research
Branch, US National Cancer Institute, Bethesda, MD 20892; Gary M. Clark, PhD,
OSI Pharmaceuticals, Inc., Boulder, CO 80301; Jose Costa, MD, Yale Cancer Center,
New Haven, CT 06510-3202; Angelo Di Leo, MD, PhD, Department of Oncology,
Hospital of Prato, 59100 Prato, Italy; Massimo Gion, MD, Centro Regionale Indica-
tori Biochimici di Tumore, Ospedale Civile, 30122 Venezia, Italy; Robert J. Mayer,
MD, Dana-Farber Cancer Institute, Boston, MA 02115; Willi Sauerbrei, PhD, Insti-
tut fuer Medizinische Biometrie und Medizinische Informatik, Universitaetsklinikum
Freiburg, 79104 Freiburg, Germany; and Sheila E. Taube, PhD, Cancer Diagnosis
Program, US National Cancer Institute, Bethesda, MD 20892.
Manuscript received December 28, 2004; revised June 14, 2005; accepted
July 21, 2005.