Comparison of prospective and retrospective methods for haplotype inference in case-control studies

We compare bias and power of three methods for haplotype inference on disease risk using unphased genotype data from a case-control study. We examine the prospective score test of Schaid et al. ([2002] Am. J. Hum. Genet 70:425-434), a novel modification of the prospective estimating equations of Zhao et al. ([2003] Am. J. Hum. Genet. 72:1231-1250) and the retrospective likelihood of Epstein and Satten ([2003] Am. J. Hum. Genet. 73:1316-1329). We find that all three approaches are roughly comparable when the haplotype effect on disease odds follows a multiplicative model. However, for dominant and recessive models of haplotype effect, the retrospective-likelihood method has increased efficiency with respect to the prospective methods. As all three methods assume haplotype frequencies are in Hardy-Weinberg Equilibrium (HWE), we compare the robustness of each procedure to departures from HWE. We find the prospective methods are robust to departure from HWE, while the retrospective-likelihood method is biased for dominant and recessive models of haplotype effect. To remedy this limitation of the retrospective-likelihood method, we propose a modification that allows for a non-negative fixation index (common to all haplotype pairs) and show it dramatically reduces the bias of the retrospective likelihood when HWE is violated. Published 2004 Wiley-Liss, Inc.(dagger).