Upward bias in odds ratio estimates from genome-wide association studies
Upward bias in odds ratio estimates from genome-wide association studies
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DOI：
10.1002/gepi.20209
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发表时间：
2007-05-01
影响因子：
2.1
通讯作者：
Garner, Chad
中科院分区：
文献类型：
--
作者：
Garner, Chad
进行全基因组关联研究是为了确定复杂性状的未知基因。在随后的验证性研究中，报告了显示最具统计学意义的关联的多态性并进行了随访。除了相关性检验之外，统计分析还提供了每种多态性的基因型和表型之间关系的点估计，通常是病例对照关联研究中的优势比。检验的统计显著性与比值比的估计量完全相关。选择最极端的统计数据相当于选择最极端的比值比。给定统计显著性的值，估计量的值取决于估计量的标准误差和研究的能力。该报告表明，当权力较低时，全基因组关联研究或任何大规模关联研究的优势比估计将偏向于上升。全基因组关联研究往往缺乏动力，因为需要较低的a水平来宣布统计意义，并且已知表征复杂性状的个体遗传效应很小。等位基因频率低、样本量不足和遗传效应弱等因素导致优势比估计的标准误差大、功率低和优势比偏上。无论统计显著性阈值如何，具有高检测与真实比值比关联的能力的研究将很少或没有偏差。该结果对全基因组关联分析的解释和后续验证阶段的规划具有启示意义。
Genome-wide association studies are carried out to identify unknown genes for a complex trait. Polymorphisms showing the most statistically significant associations are reported and followed up in subsequent confirmatory studies. In addition to the test of association, the statistical analysis provides point estimates of the relationship between the genotype and phenotype at each polymorphism, typically an odds ratio in case-control association studies. The statistical significance of the test and the estimator of the odds ratio are completely correlated. Selecting the most extreme statistics is equivalent to selecting the most extreme odds ratios. The value of the estimator, given the value of the statistical significance depends on the standard error of the estimator and the power of the study. This report shows that when power is low, estimates of the odds ratio from a genome-wide association study, or any large-scale association study, will be upwardly biased. Genome-wide association studies are often underpowered given the low a levels required to declare statistical significance and the small individual genetic effects known to characterize complex traits. Factors such as low allele frequency, inadequate sample size and weak genetic effects contribute to large standard errors in the odds ratio estimates, low power and upwardly biased odds ratios. Studies that have high power to detect an association with the true odds ratio will have little or no bias, regardless of the statistical significance threshold. The results have implications for the interpretation of genome-wide association analysis and the planning of subsequent confirmatory stages.