The reporting guidelines presented here are the result of a collaborative effort among statisticians, clinicians, and laboratory scientists who are committed to improving and accelerating the process by which tumour markers that provide useful information for management of cancer patients are adopted into clinical practice. In addition to the authors of this paper, 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 involving tumour markers. Collectively, we serve as editors and reviewers for numerous scientific journals that publish tumour marker studies, we serve on programme committees for international meetings, as decision-makers for funding agencies, participants in national and international committees charged with evaluating and prioritising tumour markers for further study or making recommendations for clinical use, and are actively involved in our own research involving tumour markers. As editors, reviewers, and programme and advisory committee members, we have struggled with having to make decisions when insufficient information is provided about study design or analysis methods. As individual investigators, we have experienced the frustration of trying to interpret often confusing literature to guide our own research programmes.
There are consequences of poor study reporting for the research community as a whole. Poorly designed or inappropriately analysed studies can attract undeserved attention when they produce very dramatic, but unfortunately incorrect results. In contrast, some carefully designed and analysed 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 influence 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 individual investigators.
These guidelines have been labelled as applying to clinical prognostic studies. Not all of the elements apply to studies conducted in earlier phases of marker development (Hammond and Taube, 2002
), for example early marker studies seeking to correlate a new marker with other clinical variables or existing prognostic factors. However, our recommendation is that investigators conducting early marker studies should 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 randomised trials, require a sufficient (usually larger) effective sample size, and assays should be in a more advanced state of development. The CONSORT statement for randomised clinical trials can serve as a starting point for reporting guidelines for predictive marker studies, but additional issues relating to the marker assays must be addressed. It is our feeling that more stringent and specific 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.
It may not be possible to report every detail for every study. For example, it is often difficult to provide detailed patient inclusion/exclusion criteria or treatment information in retrospective prognostic marker studies using archived tumour specimens. The impact of such missing information must be judged in the specific context 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 information is often missing or unreliable in retrospective studies. In these cases, it is important to recognise that apparent ‘prognostic' effects may be influenced by potential treatment by marker interactions. The key point is that there must be a clear statement of what is and what is not known. In addition, it was beyond the scope of these guidelines to recommend specific details that should be reported for each of the major classes of marker assays, for example, immunohistochemistry, in situ hybridisation methods, or DNA-based assays. There is an ongoing effort to define such assay-specific 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 available may simply propagate bad science. Good study design and data quality have to come first. We do recognise the potential benefits of promoting full public access to good quality data. It would allow verification of published analysis methods and results and would facilitate alternative analyses and meta-analyses. Attainment of these goals would be helped significantly if guidelines 10 and 11 were strictly applied, so that statistical analysis methods were described in sufficient 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 supplementary material available outside of the main published report, for example, on the journal's or author's website.
While 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 reduce 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. Furthermore, we consider it as a prerequisite for a thoughtful presentation and interpretation of the results of a specific 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, analysed, or reported studies which send researchers 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 we received from the several journals who have agreed to simultaneously publish this paper. There is a clear recognition in the community that the time has come (if not long overdue) to improve the quality of tumour marker study reporting 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 tumour marker research will evolve, these guidelines will have to evolve to address new study paradigms and new assay technologies. It is our hope that publication of these guidelines will generate vigorous discussion leading to continually improved versions and ultimately to improved quality of tumour marker studies.