Family-based association tests using genotype data with uncertainty.
Family-based association tests using genotype data with uncertainty.
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DOI：
10.1093/biostatistics/kxr045
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发表时间：
2012-04
期刊：
影响因子：
2.1
通讯作者：
Zhaoxia Yu
中科院分区：
文献类型：
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作者：
Zhaoxia Yu
基于家族的关联研究已被广泛用于确定疾病与遗传标记之间的关联。已知基因分型不确定性是直接基因分型或测序DNA变异和计算机插补数据的固有因素。即使不确定性与疾病状态无关，这种不确定性也可能导致基因分型错误和缺失，并可能对基于家庭的关联研究的功效和I型错误率产生负面影响。与使用不相关受试者的研究相比，很少有方法解决基于家系设计的基因分型不确定性问题。有限的尝试主要是为了纠正基因分型错误引起的偏倚。如果不适当地解决这个问题，传统的测试策略，即基于家庭的关联测试使用所谓的基因型，可以产生无效的统计推断。在这里，我们提出了一个新的测试，以解决在分析的情况下，父母的数据，通过使用高精度的调用和建模基因型特异性调用率的挑战。我们的模拟结果表明，与传统的策略和替代测试相比，我们的新测试有一个改进的性能存在很大的不确定性，并具有类似的性能时，不确定性水平较低。我们还证明了我们的新方法的优点，将其应用到从全基因组的情况下，父母的关联研究的插补标记。
Family-based association studies have been widely used to identify association between diseases and genetic markers. It is known that genotyping uncertainty is inherent in both directly genotyped or sequenced DNA variations and imputed data in silico. The uncertainty can lead to genotyping errors and missingness and can negatively impact the power and Type I error rates of family-based association studies even if the uncertainty is independent of disease status. Compared with studies using unrelated subjects, there are very few methods that address the issue of genotyping uncertainty for family-based designs. The limited attempts have mostly been made to correct the bias caused by genotyping errors. Without properly addressing the issue, the conventional testing strategy, i.e. family-based association tests using called genotypes, can yield invalid statistical inferences. Here, we propose a new test to address the challenges in analyzing case-parents data by using calls with high accuracy and modeling genotype-specific call rates. Our simulations show that compared with the conventional strategy and an alternative test, our new test has an improved performance in the presence of substantial uncertainty and has a similar performance when the uncertainty level is low. We also demonstrate the advantages of our new method by applying it to imputed markers from a genome-wide case-parents association study.