title: Test of association between haplotypes and phenotypes in case-control studies: examination of validity of the application of an algorithm for samples from cohort or clinical trials to case-control samples using simulated and real data.
abstract: The use of haplotype information in case-control studies is an area of focus for the research on the association between phenotypes and genetic polymorphisms. We examined the validity of the application of the likelihood-based algorithm, which was originally developed to analyze the data from cohort studies or clinical trials, to the data from case-control studies. This algorithm was implemented in a computer program called PENHAPLO. In this program, haplotype frequencies and penetrances are estimated using the expectation-maximization algorithm, and the haplotype-phenotype association is tested using the generalized likelihood ratio. We show that this algorithm was useful not only for cohort studies but also for case-control studies. Simulations under the null hypothesis (no association between haplotypes and phenotypes) have shown that the type I error rates were accurately estimated. The simulations under alternative hypotheses showed that PENHAPLO is a robust method for the analysis of the data from case-control studies even when the haplotypes were not in HWE, although real penetrances cannot be estimated. The power of PENHAPLO was higher than that of other methods using the likelihood-ratio test for the comparison of haplotype frequencies. Results of the analysis of real data indicated that a significant association between haplotypes in the SAA1 gene and AA-amyloidosis phenotype was observed in patients with rheumatoid arthritis, thereby suggesting the validity of the application of PENHAPLO for case-control data.
authors.affiliation: Algorithm Team Japan Biological Information Research Center, Japan Biological Informatics Consortium, Tokyo, Japan.
authors.forename: Shiori
authors.initials: S
authors.lastname: Furihata
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Ito
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kamatani
mesh_terms: D000465:Algorithms; D000686:Amyloidosis / Q000235:genetics; D001172:Arthritis, Rheumatoid / Q000235:genetics; D016022:Case-Control Studies; D015331:Cohort Studies; D003198:Computer Simulation; D003627:Data Interpretation, Statistical; D006239:Haplotypes; D006801:Humans; D016013:Likelihood Functions; D019683:Penetrance; D010641:Phenotype; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results