A method for incorporating ages at onset in affected sibpair linkage studies

Data with varying age at disease onset arise frequently in studies of mapping disease associated genes. Naively combining affected subjects with different ages at onset may result in a much reduced power in detecting the disease genes. In this paper we present a weighted score test statistic to detect the linkage between marker and latent disease loci using affected sibpairs, where the weight is used for assigning differential contribution due to the varying age at onset of each affected sibpair to the test statistic. We show that the weighted test has a correct type I error rate asymptotically. For an illustrative purpose, we analyze a data set from the 12th Genetic Analysis Workshop. The result shows that the weighted tests appear to be able to pinpoint the location of latent disease genes better than the mean IBD test with equal weight with respect to the age at onset. To avoid the potential power loss due to the improper weight, we propose to use a combined test statistic, taking the maximum of two tests, one that is weighted by the age-dependent penetrance function and the other that may be invariant to the age. We conduct an analytical study, comparing the combined test with weighted and equal weight with respect to age test. It shows that the combined test retains the most power of the better one of the two tests being combined. Copyright (C) 2002 S. Karger AG, Basel.