Original Contribution Using Risk-based Sampling to Enrich Cohorts for Endpoints, Genes, and Exposures

Targeting the first-degree relatives of people with a particular complex disease can offer a powerful approach to building a risk-based cohort for prospective studies of etiologic factors. Such a cohort provides both a sizable increase in the rate of accrual of newly incident cases, enriching for risk factors that are known or even unknown, and a high level of motivation among participants. A nationwide study of breast cancer in the United States and Puerto Rico, the Sister Study, made up of women who are each the sister of a woman with breast cancer, exemplifies this approach. In this paper, the authors provide power calculations to aid in the design of such studies and quantify their benefits for detecting both genetic variants related to risk and interactive effects of genetic and environmental factors. While the risk-based cohort can have markedly increased prevalences of rare causative alleles, most of the power advantages for this design is due to the increased rate of accrual of newly incident cases rather than the increase in any one individual allele. cohort studies; disease susceptibility; genes; prospective studies; risk; sampling studies Most diseases are complex because both genetic and en-vironmental factors contribute to their etiology, and many are difficult to study prospectively because they are uncom-mon. Retrospective case-control studies offer important ad