Efficient semiparametric estimation of haplotype-disease associations in case-cohort and nested case-control studies

• Published in: Biostatistics (Oxford, England) Vol. 7; no. 3; pp. 486 - 502
• Main Authors: Zeng, D, Lin, D Y, Avery, C L, North, K E, Bray, M S
• Format: Journal Article
• Language: English
• Published: England Oxford Publishing Limited (England) 01-07-2006
• Subjects: Age of Onset; Algorithms; Case-Control Studies; Cohort Studies; Computer Simulation; Coronary Disease - genetics; Genetic Predisposition to Disease - genetics; Haplotypes - genetics; Humans; Models, Genetic; Polymorphism, Single Nucleotide; Proportional Hazards Models; Smoking - adverse effects
• ISSN: 1465-4644; 1468-4357
• DOI: 10.1093/biostatistics/kxj021

Estimating the effects of haplotypes on the age of onset of a disease is an important step toward the discovery of genes that influence complex human diseases. A haplotype is a specific sequence of nucleotides on the same chromosome of an individual and can only be measured indirectly through the genotype. We consider cohort studies which collect genotype data on a subset of cohort members through case-cohort or nested case-control sampling. We formulate the effects of haplotypes and possibly time-varying environmental variables on the age of onset through a broad class of semiparametric regression models. We construct appropriate nonparametric likelihoods, which involve both finite- and infinite-dimensional parameters. The corresponding nonparametric maximum likelihood estimators are shown to be consistent, asymptotically normal, and asymptotically efficient. Consistent variance-covariance estimators are provided, and efficient and reliable numerical algorithms are developed. Simulation studies demonstrate that the asymptotic approximations are accurate in practical settings and that case-cohort and nested case-control designs are highly cost-effective. An application to a major cardiovascular study is provided.