Haplotype-based association analysis in cohort and nested case-control studies.
Genetic epidemiologic studies often collect genotype data at multiple loci within a genomic region of interest from a sample of unrelated individuals. One popular method for analyzing such data is to assess whether haplotypes, i.e., the arrangements of alleles along individual chromosomes, are associated with the disease phenotype or not. For many study subjects, however, the exact haplotype configuration on the pair of homologous chromosomes cannot be derived with certainty from the available locus-specific genotype data (phase ambiguity). In this article, we consider estimating haplotype-specific association parameters in the Cox proportional hazards model, using genotype, environmental exposure, and the disease endpoint data collected from cohort or nested case-control studies. We study alternative Expectation-Maximization algorithms for estimating haplotype frequencies from cohort and nested case-control studies. Based on a hazard function of the disease derived from the observed genotype data, we then propose a semiparametric method for joint estimation of relative-risk parameters and the cumulative baseline hazard function. The method is greatly simplified under a rare disease assumption, for which an asymptotic variance estimator is also proposed. The performance of the proposed estimators is assessed via simulation studies. An application of the proposed method is presented, using data from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study.
Chen
Jinbo
J
Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, Rockville, Maryland 20852, USA. chenjin@mail.nih.gov
Chatterjee
Nilanjan
N
D000465:Algorithms; D016022:Case-Control Studies; D015331:Cohort Studies; D004781:Environmental Exposure; D016021:Epidemiologic Studies; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D009369:Neoplasms / Q000453:epidemiology / Q000235:genetics; D016016:Proportional Hazards Models; D012307:Risk Factors