Abstract
Tumor biomarker studies may generate insights into the biological characteristics that drive the clinical behavior of a cancer. Publication bias and hidden multiple hypotheses testing distort the assessment of the true value of biomarkers. Publication bias from preferential reporting of 'positive' findings is well recognized. Hidden multihypothesis testing arises from several biomarkers being tested by different teams using the same samples. The more hypotheses (that is, biomarker association with outcome) tested, the greater the risk of false-positive findings. These biases inflate the potential clinical validity and utility of published biomarkers while negative results often remain hidden. Trial registries have been developed where all phase II and phase III trials should be listed regardless of study outcome. However, such steps have not been taken to reduce such bias in tumor biomarker research. We propose that a registry should be created for biomarker studies initially focused on studies that use specimens from randomized trials. Further development could include nonrandomized studies and deposition of raw data similar to existing genomic data repositories. The benefits of a comprehensive biomarker study registry include more balanced evaluation of proposed markers, fewer false positive leads in research, and hopefully more rapid identification of promising candidate biomarkers.
Key Points
-
Publication bias and hidden multiple hypotheses testing distort the assessment of the true value of biomarkers
-
Development of a biomarker study registry could decrease publication biases, as shown in the field of therapeutic trials
-
There is a need for a registry that would include all biomarker studies including the negative ones
-
Such a registry could collect key information from each biomarker study, including the main results of the study together with the statistical methods
-
It could be a stepwise project starting with biomarker studies from randomized trials
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Begg, C. et al. Improving the quality of reporting of randomized controlled trials. The CONSORT statement. JAMA 276, 637–639 (1996).
McCray, A. T. & Ide, N. C. Design and implementation of a national clinical trials registry. J. Am. Med. Inform. Assoc. 7, 313–323 (2000).
Altman, D. G. & Riley, R. D. Primer: an evidence-based approach to prognostic markers. Nat. Clin. Pract. Oncol. 2, 466–472 (2005).
Simon, R. M., Paik, S. & Hayes, D. F. Use of archived specimens in evaluation of prognostic and predictive biomarkers. J. Natl Cancer Inst. 101, 1446–1452 (2009).
Simon, R. Development and evaluation of therapeutically relevant predictive classifiers using gene expression profiling. J. Natl Cancer Inst. 98, 1169–1171 (2006).
Simon, R. Development and validation of therapeutically relevant multi-gene biomarker classifiers. J. Natl Cancer Inst. 97, 866–867 (2005).
Simon, R. & Altman, D. G. Statistical aspects of prognostic factor studies in oncology. Br. J. Cancer 69, 979–985 (1994).
McShane, L. M. et al. Reporting recommendations for tumor marker prognostic studies (REMARK). Nat. Clin. Pract. Oncol. 2, 416–422 (2005).
Song, F. et al. Dissemination and publication of research findings: an updated review of related biases. Health Technol. Assess. 14, 1–193 (2010).
Kyzas, P. A., Loizou, K. T. & Ioannidis, J. P. Selective reporting biases in cancer prognostic factor studies. J. Natl Cancer Inst. 97, 1043–1055 (2005).
Penault-Llorca, F. et al. Ki67 expression and docetaxel efficacy in patients with estrogen receptor-positive breast cancer. J. Clin. Oncol. 27, 2809–2815 (2009).
Simon, R. Evaluating prognostic factor studies, in Prognostic factors in cancer. 2nd edn (eds Gospodarowicz, M. K., Henson, D. E. & Hutter, R. V. P. et al.) 49–56 (Wiley–Liss, New York, 2001).
Simon, R. M., Paik, S. & Hayes, D. F. Use of archived specimens in evaluation of prognostic and predictive biomarkers. J. Natl Cancer Inst. 101, 1446–1452 (2009).
Hayes, D. F. et al. Tumor marker utility grading system: a framework to evaluate clinical utility of tumor markers. J. Natl Cancer Inst. 88, 1456–1466 (1996).
De Angelis, C. et al. International Committee of Medical Journal Editors. Clinical trial registration: a statement from the International Committee of Medical Journal Editors. N. Engl. J. Med. 351, 1250–1251 (2004).
Zarin, D. A., Tse, T. & Ide, N. C. Trial Registration at ClinicalTrials.gov between May and October 2005. N. Engl. J. Med. 353, 2779–2787 (2005).
Mathieu, S., Boutron, I., Moher, D., Altman, D. G. & Ravaud, P. Comparison of registered and published primary outcomes in randomized controlled trials. JAMA 302, 977–984 (2009).
Ross, J. S., Mulvey, G. K., Hines, E. M., Nissen, S. E. & Krumholz, H. M. Trial publication after registration in ClinicalTrials.Gov: a cross-sectional analysis. PLoS Med. 6, e1000144 (2009).
Williams, R. J., Tse, T., Harlan, W. R. & Zarin, D. A. Registration of observational studies: is it time? CMAJ 182, 1638–1642 (2010).
Ioannidis, J. P. Why most published research findings are false. PLoS Med. 2, e124 (2005).
Simon, R. et al. Design and analysis of DNA microarray investigations. (Springer-Verlag, New York, 2004).
Conforti, R. et al. Breast cancer molecular subclassification and estrogen receptor expression to predict efficacy of adjuvant anthracyclines-based chemotherapy: a biomarker study from two randomized trials. Ann. Oncol. 18, 1477–1483 (2007).
Andre, F. et al. CXCR4 expression in early breast cancer and risk of distant recurrence. Oncologist 14, 1182–1188 (2009).
Meslin, F. et al. Efficacy of adjuvant chemotherapy according to Prion protein expression in patients with estrogen receptor-negative breast cancer. Ann. Oncol. 18, 1793–1798 (2007).
Andre, F. et al. Expression patterns and predictive value of phosphorylated AKT in early-stage breast cancer. Ann. Oncol. 19, 315–320 (2008).
Acknowledgements
The authors thank Mitch Dowsett and J. Milburn Jessup for very helpful discussions.
Author information
Authors and Affiliations
Contributions
F. Andre, L. M. McShane, S. Michiels, D. F. Ransohoff, D. G. Altman, J. S. Reis-Filho, D. F. Hayes and L. Pusztai all contributed to researching the data for this article, to discussions relating to the article content, writing and reviewing/editing of the manuscript before submission and during the revision process.
Corresponding author
Ethics declarations
Competing interests
D. F. Hayes declares he has personal financial interest (stock ownership, membership on advisory board, on the board of directors and other relationships for Halcyon Diagnostics and Oncimmune LLC. He is also a consultant for Biomarker Strategies, Compendia Bioscience, and Chugai Pharmaceuticals. D. F. Hayes has also received sponsorship or is a principle or co-investigator for trials sponsored by GlaxoSmithKline, Johnson & Johnson, Novartis, and Pfizer. The other authors declare no competing interests.
Rights and permissions
About this article
Cite this article
Andre, F., McShane, L., Michiels, S. et al. Biomarker studies: a call for a comprehensive biomarker study registry. Nat Rev Clin Oncol 8, 171–176 (2011). https://doi.org/10.1038/nrclinonc.2011.4
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrclinonc.2011.4
This article is cited by
-
Re-evaluation of publicly available gene-expression databases using machine-learning yields a maximum prognostic power in breast cancer
Scientific Reports (2023)
-
Structured reporting to improve transparency of analyses in prognostic marker studies
BMC Medicine (2022)
-
Comment on ‘BAG-1 as a biomarker in early breast cancer prognosis: a systematic review with meta-analyses'
British Journal of Cancer (2018)
-
Overinterpretation and misreporting of prognostic factor studies in oncology: a systematic review
British Journal of Cancer (2018)
-
Prevention of selective outcome reporting: let us start from the beginning
European Journal of Clinical Pharmacology (2016)