Randomization tests of disease-marker associations

A powerful test for population association of a disease with alleles at a bi-allelic marker locus is the transmission/disequilibrium test ( TDT ). A generalization of the test to multi-allelic marker locus is proposed which utilizes the maximal association of individual alleles with the disease, given by the maximum TDT statistic, TDT _(max). To overcome the multiple testing problem encountered when using the maximal association to test the null hypothesis of no disease-marker association, a randomization procedure is developed. An investigation of the power of the test suggests that the randomization procedure performs almost as well as a recently proposed likelihood based test of linkage disequilibrium. The advantage of the new test is that it can be applied sequentially, based on a one-sided version of the TDT statistic, for investigating patterns of association of several individual alleles with the disease.