title: Quantifying bias due to allele misclassification in case-control studies of haplotypes.
abstract: OBJECTIVE
  Genotyping errors can induce biases in frequency estimates for haplotypes of single nucleotide polymorphisms (SNPs). Here, we considered the impact of SNP allele misclassification on haplotype odds ratio estimates from case-control studies of unrelated individuals.
  
  
  METHODS
  We calculated bias analytically, using the haplotype counts expected in cases and controls under genotype misclassification. We evaluated the bias due to allele misclassification across a range of haplotype distributions using empirical haplotype frequencies within blocks of limited haplotype diversity. We also considered simple two- and three-locus haplotype distributions to understand the impact of haplotype frequency and number of SNPs on misclassification bias.
  
  
  RESULTS
  We found that for common haplotypes (>5% frequency), realistic genotyping error rates (0.1-1% chance of miscalling an allele), and moderate relative risks (2-4), the bias was always towards the null and increases in magnitude with increasing error rate, increasing odds ratio. For common haplotypes, bias generally increased with increasing haplotype frequency, while for rare haplotypes, bias generally increased with decreasing frequency. When the chance of miscalling an allele is 0.5%, the median bias in haplotype-specific odds ratios for common haplotypes was generally small (<4% on the log odds ratio scale), but the bias for some individual haplotypes was larger (10-20%). Bias towards the null leads to a loss in power; the relative efficiency using a test statistic based upon misclassified haplotype data compared to a test based on the unobserved true haplotypes ranged from roughly 60% to 80%, and worsened with increasing haplotype frequency.
  
  
  CONCLUSIONS
  The cumulative effect of small allele-calling errors across multiple loci can induce noticeable bias and reduce power in realistic scenarios. This has implications for the design of candidate gene association studies that utilize multi-marker haplotypes.
authors.affiliation: Department of Biostatistics, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA. ugovinda@hsph.harvard.edu
authors.forename: Usha S
authors.initials: US
authors.lastname: Govindarajulu
authors.forename: Donna
authors.initials: D
authors.lastname: Spiegelman
authors.forename: Katie L
authors.initials: KL
authors.lastname: Miller
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
mesh_terms: D000483:Alleles; D015982:Bias; D016022:Case-Control Studies; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008957:Models, Genetic; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide