Linkage disequilibrium testing when linkage phase is unknown

Linkage disequilibrium, the nonrandom association of alleles from different loci, can provide valuable information oil the structure of haplotypes ill the genome mid is often the basis for evaluating the association of genomic variation with human traits mllamong unrelated subjects. But, linkage phase of genetic markers measured on unrelated subjects is typically unknown, and so measurement, of linkage disequilibrium, and testing whether it differs significantly from the null value of zero, requires statistical methods that call account for the ambiguity of unobserved haplotypes. A common method to test whether linkage disequilibrium differs significantly from zero is the likelihood-ratio statistic, which assumes Hardy-Weinberg equilibrium of the marker phenotype proportions. We show, by simulations, that this approach call he grossly biased, with either extremely conservative or liberal type I error rates. In contrast, we use simulations to show that a Composite statistic, proposed by Weir and Cockerham, maintains the correct type I error rate's, and, when comparisons are appropriate, has sisimilar power is the likelihood-ratio statistic. We extend the composite statistic to allow for more than two alleles per locus, providing a global composite statistic, which is a strong competitor to the usual likelihood-ratio statistic.