Issues in genomic screening: critical values, sample sizes, and the ability to detect linkage

The aims of this study were to empirically investigate the ability of affected sib pairs (ASPs) to localize a gene through screening and to explore estimation of lod score critical values through resampling. To do so, we repartitioned 25 replicates of 100 simulated nuclear families into six data sets of sizes 100, 200, 300, 400, 500, and 1,000 and chose at most one mildly ASP per family. Using all marker data, we calculated maximum lod scores across the six-chromosome genome for each set. Then, we determined the cutoff value corresponding to a 5% genome-wide false positive rate using both the method of Lander and Kruglyak [1995] and a simple resampling algorithm that allows greater scan-specific flexibility. For chromosome 1, the ability of the ASPs to detect the region between markers 9 and 10 clearly increases with the sample size, and genome-wide significance is achieved for samples of size 400 or greater. Also, as expected, the critical values based on the less conservative resampling approach are generally slightly smaller than those from theoretical calculations based on the Ornstein-Uhlenbeck diffusion process of Lander and Kruglyak.