TYPE-I AND TYPE-II ERROR RATES FOR QUANTITATIVE TRAIT LOCI (QTL) MAPPING STUDIES USING RECOMBINANT INBRED MOUSE STRAINS

Effective mapping strategies for quantitative traits must allow for th e detection of the more important quantitative trait loci (QTLs) while minimizing false positives. Type I (false-positive) and Type II (fals e-negative) error rates were estimated from a computer simulation of Q TL mapping in the BXD recombinant inbred (RI) set comprising 26 strain s of mice, and comparisons made with theoretical predictions. The resu lts are generally applicable to other RI sets when corrections are mad e for differing strain numbers and marker densities. Regardless of the number or magnitude of simulated QTLs contributing to the trait varia nce, the p value necessary to provide genome-wide .05 Type I error pro tection was found to be about p = .0001. To provide adequate protectio n against both Type I (alpha = .0001) and Type II (beta = .2) errors, a QTL would have to account for more than half of the between-strain ( genetic) variance if the BXD or similar set was used alone. In contras t, a two-step mapping strategy was also considered, where RI strains a re used as a preliminary screen for QTLs to be specifically tested (co nfirmed) in an F-2 (or other) population. In this case, QTLs accountin g for similar to 16% of the between-strain variance could be detected with an 80% probability in the BXD set when alpha = 0.2. To balance th e competing goals of minimizing Type I and II errors, an economical st rategy is to adopt a more stringent alpha initially for the RI screen, since this requires only a limited genome search in the F-2 of the RI -implicated regions (similar to 10% of the F-2 genome when p < .01 in the RIs). If confirmed QTLs do not account in the aggregate for a suff icient proportion of the genetic variance, then a more relaxed alpha v alue can be used in the RI screen to increase the statistical power. T his flexibility in setting RI alpha values is appropriate only when ad equate protection against Type I errors comes from the F-2 (or other) confirmation test(s).