Non-iterative, regression-based estimation of haplotype associations with censored survival outcomes

Stat Appl Genet Mol Biol. 2012 Feb 15;11(3):Article 4. doi: 10.1515/1544-6115.1764.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Algorithms
  • Chloride Channels / genetics
  • Cohort Studies
  • Computer Simulation
  • Female
  • Genetic Association Studies
  • HSP27 Heat-Shock Proteins / genetics
  • Haplotypes*
  • Heart Failure / genetics*
  • Heart Failure / mortality*
  • Humans
  • Male
  • Middle Aged
  • Models, Statistical*
  • Polymorphism, Single Nucleotide
  • Receptor, Angiotensin, Type 1 / genetics
  • Regression Analysis
  • Survival Analysis

Substances

  • CLCNKA protein, human
  • Chloride Channels
  • HSP27 Heat-Shock Proteins
  • HSPB7 protein, human
  • Receptor, Angiotensin, Type 1