Statistical methods for haplotype-based matched case-control association studies

Kraft et al. [2005] proposed a method for matched haplotype-based association studies and compared the performances of six analytic strategies for estimating the odds ratio parameters using a conditional likelihood function. Zhang et al. [2006] modified the conditional likelihood and proposed a new method for matched haplotype-based association studies. The main assumptions of Zhang et al. were that the disease was rare, the population was in Hardy-Weinberg equilibrium (HWE), and the haplotypes were independent of the covariates and matching variable(s). In this article, we modify the estimation procedure proposed by Zhang et al. and introduce a fixation index so that the assumption of HWE is relaxed. Using the Wald test, we compare the current modified method with the procedure developed by Kraft et al. through simulations. The results show that the modified method is uniformly more powerful than that described in Kraft et al. Furthermore, the results indicate that the modified method is quite robust to the rare disease assumption.