Joint effects of genetic and environmental factors have been increasingly recognized in the development of many complex human diseases. Despite the popularity of case-control and caseonly designs, longitudinal cohort studies that can capture time-varying outcome and exposure information have long been recommended for gene-environment (GxE) interactions. To date, literature on sampling designs for longitudinal studies of GxE interaction is quite limited. We therefore consider designs that can

more »

... oritize a subsample of the existing cohort for retrospective genotyping on the basis of currently available outcome, exposure and covariate data. In this work, we propose stratified sampling based on summaries of individual exposures and outcome trajectories, and develop a full conditional likelihood (FCL) approach for estimation that adjusts for the biased sample. We compare the performance of our proposed design and analysis to combinations of different sampling designs and estimation approaches via simulation. We observe that the FCL provides improved estimates for the GxE interaction and joint exposure effects over uncorrected complete-case analysis, and the exposure enriched outcome trajectory dependent design outperforms other designs in terms of estimation efficiency and power for detection of the GxE interaction. We also illustrate our design and analysis using data from the Normative Aging Study, an ongoing longitudinal cohort study initiated by the Veterans Administration in 1963.