Nonparametric simulation-based statistics for detecting linkage in general pedigrees.

We present here four nonparametric statistics for linkage analysis that test whether pairs of affected relatives share marker alleles more often than expected. These statistics are based on simulating the null distribution of a given statistic conditional on the unaffecteds' marker genotypes. Each statistic uses a different measure of marker sharing: the SimAPM statistic uses the simulation-based affected-pedigree-member measure based on identity-by-state (IBS) sharing. The SimKIN (kinship) measure is 1.0 for identity-by-descent (IBD) sharing, 0.0 for no IBD status sharing, and the kinship coefficient when the IBD status is ambiguous. The simulation-based IBD (SimIBD) statistic uses a recursive algorithm to determine the probability of two affecteds sharing a specific allele IBD. The SimISO statistic is identical to SimIBD, except that it also measures marker similarity between unaffected pairs. We evaluated our statistics on data simulated under different two-locus disease models, comparing our results to those obtained with several other nonparametric statistics. Use of IBD information produces dramatic increases in power over the SimAPM method, which uses only IBS information. The power of our best statistic in most cases meets or exceeds the power of the other nonparametric statistics. Furthermore, our statistics perform comparisons between all affected relative pairs within general pedigrees and are not restricted to sib pairs or nuclear families.