title: Non-iterative, regression-based estimation of haplotype associations with censored survival outcomes.
abstract: The general availability of reliable and affordable genotyping technology has enabled genetic association studies to move beyond small case-control studies to large prospective studies. For prospective studies, genetic information can be integrated into the analysis via haplotypes, with focus on their association with a censored survival outcome. We develop non-iterative, regression-based methods to estimate associations between common haplotypes and a censored survival outcome in large cohort studies. Our non-iterative methods--weighted estimation and weighted haplotype combination--are both based on the Cox regression model, but differ in how the imputed haplotypes are integrated into the model. Our approaches enable haplotype imputation to be performed once as a simple data-processing step, and thus avoid implementation based on sophisticated algorithms that iterate between haplotype imputation and risk estimation. We show that non-iterative weighted estimation and weighted haplotype combination provide valid tests for genetic associations and reliable estimates of moderate associations between common haplotypes and a censored survival outcome, and are straightforward to implement in standard statistical software. We apply the methods to an analysis of HSPB7-CLCNKA haplotypes and risk of adverse outcomes in a prospective cohort study of outpatients with chronic heart failure.
authors.affiliation: University of Pennsylvania, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: French
authors.forename: Thomas
authors.initials: T
authors.lastname: Lumley
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Cappola
authors.forename: Nandita
authors.initials: N
authors.lastname: Mitra
mesh_terms: D000368:Aged; D000465:Algorithms; D018118:Chloride Channels / Q000235:genetics; D015331:Cohort Studies; D003198:Computer Simulation; D005260:Female; D056726:Genetic Association Studies; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics; D006239:Haplotypes; D006333:Heart Failure / Q000235:genetics* / Q000401:mortality*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D020641:Polymorphism, Single Nucleotide; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D012044:Regression Analysis; D016019:Survival Analysis
chemical_list: C489932:CLCNKA protein, human; D018118:Chloride Channels; D055551:HSP27 Heat-Shock Proteins; C550985:HSPB7 protein, human; D044140:Receptor, Angiotensin, Type 1