Assessing environmental modifiers of disease risk associated with rare mutations

As disease-predisposing mutations are increasingly identified, there is growing need to assess the effects of lifestyle and environmental factors on disease risks in mutation carriers. Such assessment is difficult when the mutations are rare and evaluating them in large population samples is costly.

This paper describes four study designs for evaluating the effects of environmental exposures in carriers of rare disease-predisposing mutations.

The strengths and weaknesses of the designs are assessed, and strategies for analyzing the data obtained from such designs are considered.

When exposure effects in noncarriers are well-established and exposure is independent of carrier status in the population of disease-free controls, the case-only design provides a feasible and efficient method for inferring effects in carriers. When exposure effects in noncarriers are not well established, the most feasible design options are those that compare exposures in carrier cases to either untyped controls or to carrier controls. These two designs have complementary strengths and weaknesses; thus inferences are stronger when measures of association estimated using the two designs are consistent.