A linkage strategy for detection of human quantitative-trait loci. II. Optimization of study designs based on extreme sib pairs and generalized relative risk ratios.

We are concerned here with practical issues in the application of extreme sib-pair (ESP) methods to quantitative traits. Two important factors-namely, the way extreme trait values are defined and the proportions in which different types of ESPs are pooled, in the analysis-are shown to determine the power and the cost effectiveness of a study design. We found that, in general, combining reasonable numbers of both extremely discordant and extremely concordant sib pairs that were available in the sample is more powerful and more cost effective than pursuing only a single type of ESP. We also found that dividing trait values with a less extreme threshold at one end or at both ends of the trait distribution leads to more cost-effective designs. The notion of generalized relative risk ratios (the lambda methods, as described in the first part of this series of two articles) is used to calculate the power and sample size for various choices of polychotomization of trait values and for the combination of different types of ESPs. A balance then can be struck among these choices, to attain an optimum design.