Two other novel designs use different ways of selecting controls to improve the power for detecting either main effects or interactions. The two-phase case-control design45 is useful where a surrogate for exposure is readily available but data on exact doses, confounders, or modifiers require additional expensive data collection46. (Note that the kinds of two-phase sampling designs described here are fundamentally different from the two-stage genotyping designs for GWA studies described below.) These designs entail independent subsampling on the basis of both disease status and the exposure surrogate variable from a first-phase case-control or cohort study. Data from both phases are combined in the analysis, with appropriate allowance for the biased sampling in phase two. The optimal design entails over-representing the rarer cells, typically the exposed cases. Although most applications have focused on its use for improving exposure characterization for main effects or for better control of confounding, it can also be highly efficient for studying interaction effects. For example, Li et al.47 used a two-phase design nested within the Atherosclerosis Risk in Communities (ARIC) study to study the interaction between
