EFFICIENT STRATEGIES FOR GENOMIC SEARCHING USING THE AFFECTED-PEDIGREE-MEMBER METHOD OF LINKAGE ANALYSIS

The affected-pedigree-member (APM) method of linkage analysis is a non parametric statistic that tests for nonrandom cosegregation of a disea se and marker loci. The APM statistic is based on the observation that if a marker locus is near a disease-susceptibility locus, then affect ed individuals within a family should be more similar at the marker lo cus than is expected by chance. The APM statistic measures marker simi larity in terms of identity by state (IBS) of marker alleles; that is, two alleles are IBS if they are the same, regardless of their ancestr al origin. Since the APM statistic measures increased marker similarit y, it makes no assumptions concerning how the disease is inherited; th is can be an advantage when dealing with complex diseases for which th e mode of inheritance is difficult to determine. We investigate here t he power of the APM statistic to detect linkage in the context of a ge nomewide search. In such a search, the APM statistic is evaluated at a grid of markers. Then regions with high APM statistics are investigat ed more thoroughly by typing more markers in the region. Using simulat ed data, we investigate various search strategies and recommend an opt imal search strategy that maximizes the power to detect linkage while minimizing the false-positive rate and number of markers. We determine an optimal series of three increasing cut-points and an independent c riterion for significance.