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 affec ted sib pairs (ASPs) to localize a gene through screening and to explore es timation of lod score critical values through resampling. To do so, we repa rtitioned 25 replicates of 100 simulated nuclear families into six data set s 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 acr oss 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 w ith the sample size, and genome-wide significance is achieved for samples o f size 400 or greater. Also, as expected, the critical values based on the less conservative resampling approach are generally slightly smaller than t hose from theoretical calculations based on the Ornstein-Uhlenbeck diffusio n process of lander and Kruglyak. (C) 1999 Wiley-Liss, Inc.