The impact of genotype calling errors on family-based studies.
The impact of genotype calling errors on family-based studies.
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DOI：
10.1038/srep28323
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发表时间：
2016-06-22
影响因子：
4.6
通讯作者：
Chen W
中科院分区：
文献类型：
--
作者：
Yan Q;Chen R;Sutcliffe JS;Cook EH;Weeks DE;Li B;Chen W
基于家系的测序研究在富集罕见变异、控制群体分层以及提高基因型判读方面具有独特优势。标准的基因型判读算法不太可能正确判读罕见变异，常常错误地将杂合子判读为参考纯合子。这种非随机误差对罕见变异的关联检验的影响尚不清楚，尤其是在基于传递的检验中。在本研究中，我们调查了基因分型误差对基于家系的序列数据的罕见变异关联检验的影响。我们进行了全面分析，以研究在基于家系的测序研究中，基因型判读误差如何使用各种实际参数影响基于传递的关联检验的一类错误和统计功效。在模拟研究中，我们发现有偏的基因型判读误差不仅导致一类错误膨胀，还造成关联检验的功效损失。我们进一步使用来自一个自闭症项目的外显子组序列数据证实了我们的观察结果。我们得出结论，在分析基于家系的序列数据时，非对称的基因型判读误差需要仔细考虑，并且我们提供了减轻检验偏差的实用指导。
Family-based sequencing studies have unique advantages in enriching rare variants, controlling population stratification, and improving genotype calling. Standard genotype calling algorithms are less likely to call rare variants correctly, often mistakenly calling heterozygotes as reference homozygotes. The consequences of such non-random errors on association tests for rare variants are unclear, particularly in transmission-based tests. In this study, we investigated the impact of genotyping errors on rare variant association tests of family-based sequence data. We performed a comprehensive analysis to study how genotype calling errors affect type I error and statistical power of transmission-based association tests using a variety of realistic parameters in family-based sequencing studies. In simulation studies, we found that biased genotype calling errors yielded not only an inflation of type I error but also a power loss of association tests. We further confirmed our observation using exome sequence data from an autism project. We concluded that non-symmetric genotype calling errors need careful consideration in the analysis of family-based sequence data and we provided practical guidance on ameliorating the test bias.