Robustness and power of the maximum-likelihood-binomial and maximum-likelihood-score methods, in multipoint linkage analysis of affected-sibship data.
The maximum-likelihood-binomial (MLB) method, based on the binomial distribution of parental marker alleles among affected offspring, recently was shown to provide promising results by two-point linkage analysis of affected-sibship data. In this article, we extend the MLB method to multipoint linkage analysis, using the general framework of hidden Markov models. Furthermore, we perform a large simulation study to investigate the robustness and power of the MLB method, compared with those of the maximum-likelihood-score (MLS) method as implemented in MAPMAKER/SIBS, in the multipoint analysis of different affected-sibship samples. Analyses of multiple-affected sibships by means of the MLS were conducted by consideration of all possible sib pairs, with (weighted MLS [MLSw]) or without (unweighted MLS [MLSu]) application of a classic weighting procedure. In simulations under the null hypothesis, the MLB provided very consistent type I errors regardless of the type of family sample (sib pairs or multiple-affected sibships), as did the MLS for samples with sib pairs only. When samples included multiple-affected sibships, the MLSu led to inflation of low type I errors, whereas the MLSw yielded very conservative tests. Power comparisons showed that the MLB generally was more powerful than the MLS, except in recessive models with allele frequencies <.3. Missing parental marker data did not strongly influence type I error and power results in these multipoint analyses. The MLB approach, which in a natural way accounts for multiple-affected sibships and which provides a simple likelihood-ratio test for linkage, is an interesting alternative for multipoint analysis of sibships.
Abel
L
L
INSERM U.436, Mathematical and Statistical Modeling in Biology and Medicine, Hôpital Pitié-Salpêtrière, Paris, France. abel@biomath.jussieu.fr
Müller-Myhsok
B
B
D003198:Computer Simulation; D005799:Genes, Dominant; D005808:Genes, Recessive; D005819:Genetic Markers; D006801:Humans; D016013:Likelihood Functions; D008126:Lod Score; D008957:Models, Genetic; D015233:Models, Statistical; D009679:Nuclear Family; D015203:Reproducibility of Results
D005819:Genetic Markers