Sample Size Requirements for Association Studies of Gene-Gene Interaction

TLDR

Gene‑gene interaction studies in complex diseases require adequate sample sizes to be successful. The study investigates sample size requirements for gene‑gene interaction across four study designs. All four designs estimate interaction on a multiplicative scale, serving as the basis for comparing sample size needs. Case‑only and case‑parent designs need fewer samples than case‑control or case‑sibling designs, e.g., 116 cases versus 270 matched pairs for an asthma study, and a free software tool is available at http://hydra.usc.edu/gxe.

Abstract

In the study of complex diseases, it may be important to test hypotheses related to gene-gene (G × G) interaction. The success of such studies depends critically on obtaining adequate sample sizes. In this paper, the author investigates sample size requirements for studies of G × G interaction, focusing on four study designs: the matched-case-control design, the case-sibling design, the case-parent design, and the case-only design. All four designs provide an estimate of interaction on a multiplicative scale, which is used as a unifying theme in the comparison of sample size requirements. Across a variety of genetic models, the case-only and case-parent designs require fewer sampling units (cases and case-parent trios, respectively) than the case-control (pairs) or case-sibling (pairs) design. For example, the author describes an asthma study of two common recessive genes for which 270 matched case-control pairs would be required to detect a G × G interaction of moderate magnitude with 80% power. By comparison, the same study would require 319 case-sibling pairs but only 146 trios in the case-parent design or 116 cases in the case-only design. A software program that computes sample size for studies of G × G interaction and for studies of gene-environment (G × E) interaction is freely available (http://hydra.usc.edu/gxe).