Two-stage extreme phenotype sequencing design for discovering and testing common and rare genetic variants: efficiency and power.
Two-stage extreme phenotype sequencing design for discovering and testing common and rare genetic variants: efficiency and power.
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DOI：
10.1159/000337300
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发表时间：
2012
期刊：
影响因子：
1.8
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Kang G;Lin D;Hakonarson H;Chen J
下一代测序技术为识别罕见的易感性变体提供了前所未有的机会。对大量受试者进行全基因组测序在财政上尚不可行，两阶段设计已被提倡为一个实际的选择。在第一阶段，通过对少数精心挑选的个体的全基因组进行测序来发现变异。在第二阶段，对大量个体的发现的变异进行基因分型以评估关联。具有极端表型的个体通常在阶段I被选择。使用无关个体的模拟数据，我们探索了两个重要方面的两个阶段的设计：发现常见和罕见的单核苷酸多态性（SNP）在第一阶段的效率和不完整的SNP发现在第一阶段的影响，在第二阶段的测试关联的权力。我们应用总和检验和得分平方和检验来评估两阶段设计的功效。我们从广泛的模拟研究和对GAW17数据集的分析中获得了以下结果。当第一阶段包括性状值比第99.7至第99分位数更极端的个体时，如果罕见的因果变异具有大的效应量，则两阶段设计可以达到与一阶段设计相同甚至更高的功效。在这些测试中，发现了不到一半的总SNP，包括超过一半的因果SNP，其中包括几乎所有次要等位基因频率（MAF）≥ 5%的SNP，超过一半的MAF在1%和5%之间的SNP，以及不到一半的MAF <1%的SNP。虽然一个阶段的设计可能是更可取的，以确定多个罕见的变异具有小到中等的效果大小，我们的观察支持使用两阶段的设计作为一个具有成本效益的选择，为下一代测序研究。
Next-generation sequencing technology provides an unprecedented opportunity to identify rare susceptibility variants. It is not yet financially feasible to perform whole-genome sequencing on a large number of subjects, and a two-stage design has been advocated to be a practical option. In stage I, variants are discovered by sequencing the whole genomes of a small number of carefully selected individuals. In stage II, the discovered variants of a large number of individuals are genotyped to assess association. Individuals with extreme phenotypes are typically selected in stage I. Using simulated data for unrelated individuals, we explore two important aspects of this two-stage design: the efficiency of discovering common and rare single-nucleotide polymorphisms (SNPs) in stage I and the impact of incomplete SNP discovery in stage I on the power of testing associations in stage II. We apply a sum test and a sum of squared score test for gene-based association analyses evaluating the power of the two-stage design. We obtained the following results from extensive simulation studies and analysis of the GAW17 dataset. When individuals with trait values more extreme than the 99.7 to 99th quantile are included in stage I, the two-stage design could achieve the same as or even higher power than one-stage design if the rare causal variants have large effect sizes. In such tests, fewer than half of the total SNPs including more than half of the causal SNPs were discovered, which included nearly all SNPs with minor allele frequencies (MAFs) ≥ 5%, more than half of the SNPs with MAFs between 1% and 5%, and fewer than half of the SNPs with MAFs <1%. Although a one-stage design may be preferable to identify multiple rare variants having small to moderate effect sizes, our observations support using the two-stage design as a cost-effective option for next-generation sequencing studies.
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