title: Combining biomarkers for classification with covariate adjustment.
abstract: Combining multiple markers can improve classification accuracy compared with using a single marker. In practice, covariates associated with markers or disease outcome can affect the performance of a biomarker or biomarker combination in the population. The covariate-adjusted receiver operating characteristic (ROC) curve has been proposed as a tool to tease out the covariate effect in the evaluation of a single marker; this curve characterizes the classification accuracy solely because of the marker of interest. However, research on the effect of covariates on the performance of marker combinations and on how to adjust for the covariate effect when combining markers is still lacking. In this article, we examine the effect of covariates on classification performance of linear marker combinations and propose to adjust for covariates in combining markers by maximizing the nonparametric estimate of the area under the covariate-adjusted ROC curve. The proposed method provides a way to estimate the best linear biomarker combination that is robust to risk model assumptions underlying alternative regression-model-based methods. The proposed estimator is shown to be consistent and asymptotically normally distributed. We conduct simulations to evaluate the performance of our estimator in cohort and case/control designs and compare several different weighting strategies during estimation with respect to efficiency. Our estimator is also compared with alternative regression-model-based estimators or estimators that maximize the empirical area under the ROC curve, with respect to bias and efficiency. We apply the proposed method to a biomarker study from an human immunodeficiency virus vaccine trial. Copyright © 2017 John Wiley & Sons, Ltd.
authors.affiliation: Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI, U.S.A.
authors.forename: Soyoung
authors.identifier: 0000-0003-1404-0575
authors.initials: S
authors.lastname: Kim
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, 98109, WA, U.S.A.
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology / Q000494:pharmacology; D019540:Area Under Curve; D015982:Bias; D015415:Biomarkers / Q000032:analysis*; D056808:Biostatistics; D016022:Case-Control Studies; D015331:Cohort Studies; D003198:Computer Simulation; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control; D006801:Humans; D016014:Linear Models; D016015:Logistic Models; D015233:Models, Statistical; D015999:Multivariate Analysis; D012372:ROC Curve; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data; D012044:Regression Analysis
chemical_list: D016915:AIDS Vaccines; D015415:Biomarkers
keywords: area under the ROC curve; biomarker combination; classification; covariate adjustment; receiver operating characteristic curve