An overall test for association of a set of haplotypes with the phenotype involves a specific set of k SNPs. The null hypothesis of such a test is that none of the haplotypes defined by the k SNPs is associated with the phenotype. When the haplotype phase is unobserved, current methods incorporate specific assumptions about the degree of deviation from Hardy–Weinberg equilibrium. Here we employ a method that does not depend on the HWE assumption. The approach is termed the ‘composite haplotype method’, CHM (52). The idea behind the CHM approach is best explained for the case of a binary (e.g. case/control) phenotype. For two loci with alleles (A, a) and (B, b), the ‘composite frequency’ is the sum of intra-gametic, or haplotypic (PAB) and inter-gametic (PA/B) frequencies (73). The advantage in considering the composite sum is that unlike the haplotypic frequency, this sum is directly estimated by counting from the unphased data. Thus, the HWE assumption is not required, and furthermore, the uncertainty in estimation of the composite frequencies is confined to just the sampling variation and does not
