Robust tests for matched case-control genetic association studies

Background: The Cochran-Armitage trend test (CATT) is powerful in detecting association between a susceptible marker and a disease. This test, however, may suffer from a substantial loss of power when the underlying genetic model is unknown and incorrectly specified. Thus, it is useful to derive tests obtaining the plausible power against all common genetic models. For this purpose, the genetic model selection (GMS) and genetic model exclusion (GME) methods were proposed recently. Simulation results showed that GMS and GME can obtain the plausible power against three common genetic models while the overall type I error is well controlled. Results: Although GMS and GME are powerful statistically, they could be seriously affected by known confounding factors such as gender, age and race. Therefore, in this paper, via comparing the difference of Hardy-Weinberg disequilibrium coefficients between the cases and the controls within each sub-population, we propose the stratified genetic model selection (SGMS) and exclusion (SGME) methods which could eliminate the effect of confounding factors by adopting a matching framework. Our goal in this paper is to investigate the robustness of the proposed statistics and compare them with other commonly used efficiency robust tests such as MAX3 and chi(2) with 2 degrees of freedom (df) test in matched case-control association designs through simulation studies. Conclusion: Simulation results showed that if the mean genetic effect of the heterozygous genotype is between those of the two homozygous genotypes, then the proposed tests and MAX3 are preferred. Otherwise, chi(2) with 2 df test may be used. To illustrate the robust procedures, the proposed tests are applied to a real matched pair case-control etiologic study of sarcoidosis.