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doi:10.1534/genetics.105.054452
A more recent version of this article appeared on November 1, 2006.
REGULAR RESEARCH PAPERS |
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
Shiori Furihata 1, Toshikazu Ito 1 and Naoyuki Kamatani 2*
1 Mitsubishi Research Institute, Inc.
2 Tokyo Women's Medical University
* To whom correspondence should be addressed. E-mail: kamatani{at}ior.twmu.ac.jp.
Submitted on December 7, 2005
Revised on May 30, 2006
Accepted on 1 September 2006
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 f 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.
Key Words: EM algorithm, association test, case-control study, diplotype, haplotype
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