Quantifying bias due to allele misclassification in case-control studies of haplotypes
Quantifying bias due to allele misclassification in case-control studies of haplotypes
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DOI：
10.1002/gepi.20170
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发表时间：
2006-11-01
影响因子：
2.1
通讯作者：
Kraft, Peter
中科院分区：
文献类型：
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作者：
Govindarajulu, Usha S.;Spiegelman, Donna;Kraft, Peter
目的单核苷酸多态性（SNPs）单倍型频率估计中，基因分型错误会导致偏倚。在这里，我们认为SNP等位基因错误分类对单倍型优势比估计从病例对照研究无关individuals.Methods的影响，我们计算偏差分析，使用单倍型计数预期在病例和对照基因型错误分类。我们使用有限单倍型多样性区块内的经验单倍型频率评估了一系列单倍型分布中由于等位基因错误分类而导致的偏倚。我们还考虑了简单的两个和三个位点单倍型分布，以了解单倍型频率和SNPs数量对错误分类偏倚的影响。（> 5%频率）、实际基因分型错误率（错叫等位基因的机会为0.1-1%）和中等相对风险（2-4），偏倚总是朝向零，并且随着错误率的增加、优势比的增加而增加。对于常见的单倍型，偏差通常随着单倍型频率的增加而增加，而对于罕见的单倍型，偏差通常随着频率的降低而增加。当误判等位基因的几率为0.5%时，常见单倍型的单倍型特异性优势比的中位偏倚通常较小（对数优势比量表上< 4%），但某些单个单倍型的偏倚较大（10-20%）。偏向零导致损失的权力;相对效率使用的测试统计的基础上错误分类的单倍型数据相比，一个测试的基础上未观察到的真正的单倍型范围从大约60%到80%，并恶化与增加单倍型frequency.Conclusions的累积效应的小等位基因调用错误在多个位点可以引起显着的偏见，并降低功率在现实的情况下。这对利用多标记单倍型的候选基因关联研究的设计具有影响。
Objectives 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 multimarker haplotypes.