Estimating covariate-adjusted measures of diagnostic accuracy based on pooled biomarker assessments

There is a need for epidemiological and medical researchers to identify new biomarkers (biological markers) that are useful in determining exposure levels and/or for the purposes of disease detection. Often this process is stunted by high testing costs associated with evaluating new biomarkers. Traditionally, biomarker assessments are individually tested within a target population. Pooling has been proposed to help alleviate the testing costs, where pools are formed by combining several individual specimens. Methods for using pooled biomarker assessments to estimate discriminatory ability have been developed. However, all these procedures have failed to acknowledge confounding factors. In this paper, we propose a regression methodology based on pooled biomarker measurements that allow the assessment of the discriminatory ability of a biomarker of interest. In particular, we develop covariate-adjusted estimators of the receiver-operating characteristic curve, the area under the curve, and Youden's index. We establish the asymptotic properties of these estimators and develop inferential techniques that allow one to assess whether a biomarker is a good discriminator between cases and controls, while controlling for confounders. The finite sample performance of the proposed methodology is illustrated through simulation. We apply our methods to analyze myocardial infarction (MI) data, with the goal of determining whether the pro-inflammatory cytokine interleukin-6 is a good predictor of MI after controlling for the subjects' cholesterol levels.