title: Efficient semiparametric estimation of haplotype-disease associations in case-cohort and nested case-control studies.
abstract: 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.
authors.affiliation: Department of Biostatistics, CB# 7420, University of North Carolina, Chapel Hill, NC 27599-7420, USA.
authors.forename: D
authors.initials: D
authors.lastname: Zeng
authors.forename: D Y
authors.initials: DY
authors.lastname: Lin
authors.forename: C L
authors.initials: CL
authors.lastname: Avery
authors.forename: K E
authors.initials: KE
authors.lastname: North
authors.forename: M S
authors.initials: MS
authors.lastname: Bray
mesh_terms: D017668:Age of Onset; D000465:Algorithms; D016022:Case-Control Studies; D015331:Cohort Studies; D003198:Computer Simulation; D003327:Coronary Disease / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012907:Smoking / Q000009:adverse effects