Evaluating the Predictive Value of Biomarkers with Stratified Case‐Cohort Design

Abstract

Identification of novel biomarkers for risk assessment is important for both effective disease prevention and optimal treatment recommendation. Discovery relies on the precious yet limited resource of stored biological samples from large prospective cohort studies. Case-cohort sampling design provides a cost-effective tool in the context of biomarker evaluation, especially when the clinical condition of interest is rare. Existing statistical methods focus on making efficient inference on relative hazard parameters from the Cox regression model. Drawing on recent theoretical development on the weighted likelihood for semiparametric models under two-phase studies (Breslow and Wellner, 2007), we propose statistical methods to evaluate accuracy and predictiveness of a risk prediction biomarker, with censored time-to-event outcome under stratified case-cohort sampling. We consider nonparametric methods and a semiparametric method. We derive large sample properties of proposed estimators and evaluate their finite sample performance using numerical studies. We illustrate new procedures using data from Framingham Offspring Study to evaluate the accuracy of a recently developed risk score incorporating biomarker information for predicting cardiovascular disease.