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American Journal of Epidemiology Advance Access published online on July 15, 2008
American Journal of Epidemiology, doi:10.1093/aje/kwn183
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American Journal of Epidemiology © The Author 2008. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

A Cautionary Note on the Evaluation of Biomarkers of Subtypes of a Single Disease

Adeniyi J. Adewale1, Qi Liu2, Irina Dinu2, Paul D. Lampe3, Bree L. Mitchell4 and Yutaka Yasui2

1 Merck Research Laboratories, North Wales, PA
2 Department of Public Health Sciences, School of Public Health, University of Alberta, Edmonton, Alberta, Canada
3 Fred Hutchinson Cancer Research Center, Seattle, WA
4 Biomedical Life Sciences Group, Intel Corporation, Santa Clara, CA

Correspondence to Dr. Yutaka Yasui, Department of Public Health Sciences, School of Public Health, University of Alberta, 13-103 Clinical Sciences Building, Edmonton, Alberta T6G 2G3, Canada (e-mail: yyasui{at}ualberta.ca).

Received for publication December 7, 2007. Accepted for publication May 22, 2008.

Heterogeneity in the molecular characteristics of a disease presents a challenge to investigators attempting to identify biomarkers of the disease. Preceding the biomarker discovery effort with stratification within a heterogeneous disease group, which amounts to grouping disease cases into more homogeneous subtypes, seems to be a natural strategy for discovering subtype-specific biomarkers. This is because biologically more homogeneous subgroups are presumably easier to distinguish from the nondiseased than the entire heterogeneous disease group. The misleading benefits of this two-step approach are illustrated using an example from a protein biomarker discovery project for breast cancer. A potential analytical pitfall in this framework is explained using a conditional probability argument.

biological markers; classification problem; conditional probability; cross-validation; mass spectrometry; misclassification

Abbreviations: MALDI-TOF, matrix-assisted laser desorption/ionization time-of-flight


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