Detection of interaction involving identified genes: available study designs

Advances in molecular genetic techniques have led to an increased ability to examine gene-environment interactions. Studies to detect gene-environment interactions are motivated by different situations, including 1) most identified cancer genes having associated lifetime risks less than 100% (i.e., incomplete penetrance), 2) hereditary factors that control the metabolism of carcinogens that may modulate risk of disease as hypothesized in pharmacogenetics, and 3) inconsistent associations across studies between a cancer and a suspected risk factor. The above situations and others have led to increased study of interaction between genetic and environmental factors. Less studied so far, but with increased potential for the future, is interaction between identified genes. Gene-gene interaction studies would also be motivated by the situations described above. Approaches to detect gene-environment and gene-gene interactions are reviewed. Available risk estimates, required types of subjects, and feasibility of the proposed study designs are discussed; efficiency and power for interaction assessment are summarized where available. In general, most designs allow for estimating risk associated with a genetic factor, environmental factor, and interaction effect. Although power and efficiency for detecting interactions have been assessed for specific situations in some of the methods, further investigations are needed to define the efficiency spectra of each design.