Estimation of Multilocus Haplotype Effects Using Weighted Penalised Log‐Likelihood: Analysis of Five Sequence Variations at the Cholesteryl Ester Transfer Protein Gene Locus
- 7 March 2003
- journal article
- research article
- Published by Wiley in Annals of Human Genetics
- Vol. 67 (2), 175-184
- https://doi.org/10.1046/j.1469-1809.2003.00021.x
Abstract
Direct analyses of haplotype effects can be used to identify those specific combinations of alleles that are associated with a specific phenotype. We introduce a method for direct haplotype analysis that solves two problems that arise when haplotypes are analysed in populations of unrelated subjects. Instead of assigning a single, most likely, haplotype pair to multiple heterozygous subjects, all haplotype pairs compatible with their genotype were determined and the posterior probabilities of these pairs were calculated using Bayes’ theorem and estimated haplotype frequencies. For the individual patients, all possible haplotype pairs were included in the statistical analysis using the posterior probabilities as weights, which were re‐estimated in an iterative process together with the haplotype effects. The second problem of unstable haplotype effect estimates, due to the numerous haplotypes and the low frequency at which some occur, was solved by assuming that haplotypes sharing the same alleles show a similar effect and that the extent of this similarity relates to the number of alleles shared. These assumptions were incorporated in a weighted log‐likelihood model by introducing a penalty, where differences in effects of similar haplotypes were penalised. Using CETP gene haplotypes, consisting of five closely linked polymorphisms, and baseline CETP and HDL‐C concentrations from the REGRESS population, we demonstrated that the model resulted in more stable effects than estimates based on unambiguous patients only.Keywords
This publication has 32 references indexed in Scilit:
- Nested clade analysis: an extensively validated method for strong phylogeographic inferenceMolecular Ecology, 2008
- Haplotype analysis of the CETP gene: not TaqIB, but the closely linked -629C->A polymorphism and a novel promoter variant are independently associated with CETP concentrationHuman Molecular Genetics, 2003
- Haplotype frequency estimation in patient populations: The effect of departures from Hardy‐Weinberg proportions and collapsing over a locus in the HLA regionGenetic Epidemiology, 2002
- Effectiveness of computational methods in haplotype predictionHuman Genetics, 2001
- New Functional Promoter Polymorphism, CETP/−629, in Cholesteryl Ester Transfer Protein (CETP) Gene Related to CETP Mass and High Density Lipoprotein Cholesterol LevelsArteriosclerosis, Thrombosis, and Vascular Biology, 2000
- Analysis of lipoprotein lipase haplotypes reveals associations not apparent from analysis of the constituent lociAnnals of Human Genetics, 1999
- The effect of variation in the apolipoprotein B gene on plasma lipid and apolipoprotein B levels I. A likelihood‐based approach to cladistic analysisAnnals of Human Genetics, 1994
- High-Density Lipoprotein — The Clinical Implications of Recent StudiesNew England Journal of Medicine, 1989
- The general relationship between average effect and average excessGenetics Research, 1987
- Generalized Cross-Validation as a Method for Choosing a Good Ridge ParameterTechnometrics, 1979