Robust Score Statistics for QTL Linkage Analysis

The traditional variance components approach for quantitative trait locus (QTL) linkage analysis is sensitive to violations of normality and fails for selected sampling schemes. Recently, a number of new methods have been developed for QTL mapping in humans. Most of the new methods are based on score statistics or regression-based statistics and are expected to be relatively robust to non-normality of the trait distribution and also to selected sampling, at least in terms of type I error. Whereas the theoretical development of these statistics is more or less complete, some practical issues concerning their implementation still need to be addressed. Here we study some of these issues such as the choice of denominator variance estimates, weighting of pedigrees, effect of parameter misspecification, effect of non-normality of the trait distribution, and effect of incorporating dominance. We present a comprehensive discussion of the theoretical properties of various denominator variance estimates and of the weighting issue and then perform simulation studies for nuclear families to compare the methods in terms of power and robustness. Based on our analytical and simulation results, we provide general guidelines regarding the choice of appropriate QTL mapping statistics in practical situations.