Augmented case‐only designs for randomized clinical trials with failure time endpoints

Summary Under suitable assumptions and by exploiting the independence between inherited genetic susceptibility and treatment assignment, the case‐only design yields efficient estimates for subgroup treatment effects and gene‐treatment interaction in a Cox model. However it cannot provide estimates of the genetic main effect and baseline hazards, that are necessary to compute the absolute disease risk. For two‐arm, placebo‐controlled trials with rare failure time endpoints, we consider augmenting the case‐only design with random samples of controls from both arms, as in the classical case‐cohort sampling scheme, or with a random sample of controls from the active treatment arm only. The latter design is motivated by vaccine trials for cost‐effective use of resources and specimens so that host genetics and vaccine‐induced immune responses can be studied simultaneously in a bigger set of participants. We show that these designs can identify all parameters in a Cox model and that the efficient case‐only estimator can be incorporated in a two‐step plug‐in procedure. Results in simulations and a data example suggest that incorporating case‐only estimators in the classical case‐cohort design improves the precision of all estimated parameters; sampling controls only in the active treatment arm attains a similar level of efficiency.