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

By Furihata, Shiori; Ito, Toshikazu et al. | Genetics, November 2006 | Go to article overview

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


Furihata, Shiori, Ito, Toshikazu, Kamatani, Naoyuki, Genetics


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.

(ProQuest Information and Learning: ... denotes formulae omitted.)

THE importance of the analysis of polymorphism data based on linkage disequilibrium and haplotype structure has increased with the number of available single-nucleotide polymorphism (SNP) markers. Some studies have suggested that phenotypes of individuals are associated with a diplotype configuration (a combination of haplotypes) rather than a SNP genotype (HORIKAWA et al. 2000; SUGIURA et al. 2002; Tanaka et al. 2002; URANO et al. 2002; KAWAGUCHI et al. 2003). Since neither haplotypes nor diplotype configurations of a subject are usually observed, the haplotype frequencies of the population are inferred using algorithms.

For the analysis of data from either cohort studies or clinical trials, we developed an algorithm for an association test between individual qualitative phenotypes and specific haplotypes (ITO et al. 2004). This algorithm estimates diplotype-based penetrances in dominant, recessive, or general relative risk modes; further, it estimates the frequencies in a population.

On the basis of the expectation-maximization (EM) method, the algorithm was implemented in the computer program PENHAPLO. The proportions of affected and unaffected individuals with different diplotype configurations can be compared using posterior distribution given themaximum-likelihood estimates of population haplotype frequencies as priors. A number of computer programs have been developed for inferring haplotype frequencies in a population (STEPHENS et al. 2001; KITAMURA et al. 2002; NIU et al. 2002; QIN et al. 2002; STEPHENS and DONNELLY 2003). One advantage of using PENHAPLO is that the diplotype configuration of each individual need not be determined to test the association between the haplotypes and phenotypes. Rather, the diplotype configurations of some subjects can remain ambiguous. Our previous results showed that PENHAPLO is particularly useful for the analysis of cohort data on the association between haplotypes and phenotypes (ITO et al. 2004).

A case-control study is another type of useful clinical study for detecting the association between haplotypes and phenotypes. Several methods have been proposed for the analysis of case-control studies on the basis of haplotypes (FALLIN et al. 2001; SCHAID et al. 2002; ZAYKIN et al. 2002; EPSTEIN and SATTEN 2003; STRAM et al. 2003). FALLIN et al. (2001) estimated haplotype frequencies for cases and controls separately; then, they applied omnibus tests to assess the differences in the overall haplotype frequency profiles between cases and controls. …

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