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Association Analysis under Population Stratification: A Two-Stage Procedure Utilizing Population- and Family-Based Analyses

机译：人口分层下的关联分析：使用基于人口和家庭的分析的两阶段过程

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Objective: The association analysis based on a population-based case-control study is convenient and powerful, but may be biased under population stratification (PS), namely the study population consists of strata heterogeneous in disease rates and allele frequencies. On the other hand, a family-based (e.g. case-parents) study is robust against the PS bias, but may be less convenient to implement. We propose an association analysis that preserves the full robustness property of the family-based analysis while allowing for borrowing information from a population-based analysis. Methods: A two-stage procedure is proposed. In the first stage, one selects a population-based case-control sample and performs a traditional case-control association analysis. In the second stage, one randomly selects a subset of the first-stage cases and recruits their family controls (e.g. parents), and performs a family-based association analysis. An overall two-stage analysis is then performed to utilize information from the two stages. Results: The proposed two-stage analysis achieves higher power than the second-stage family-based analysis by utilizing information in the first-stage population study, while maintaining the full robustness of the family study and hence is still valid under PS. The proposal can also accommodate parental missingness when the case-parents study is used as the second-stage family study. Conclusion: The two-stage analysis facilitates efficient and robust association analysis under PS. Its computation- and cost-effectiveness render it very promising in genome-wide association studies. [PUBLICATION ABSTRACT]
机译：目的：基于人群病例对照研究的关联分析既方便又有效，但在人群分层（PS）下可能存在偏差，即研究人群由疾病发生率和等位基因频率异质的人群组成。另一方面，基于家庭的研究（例如，案例父母）对于PS偏见是有力的，但实施起来可能不太方便。我们提出一种关联分析，该分析保留了基于家庭的分析的完整鲁棒性，同时允许从基于人口的分析中借用信息。方法：提出了一个两阶段的程序。在第一阶段，选择一个基于人群的病例对照样本并执行传统的病例对照关联分析。在第二阶段，一个人随机选择一个第一阶段病例的子集，并招募他们的家庭控制（例如父母），并执行基于家庭的关联分析。然后执行总体两阶段分析，以利用来自两个阶段的信息。结果：通过在第一阶段人口研究中利用信息，提出的两阶段分析比第二阶段基于家庭的分析具有更高的功效，同时保持了家庭研究的充分鲁棒性，因此在PS下仍然有效。当案例父母研究被用作第二阶段家庭研究时，该建议还可以解决父母的缺失问题。结论：两阶段分析有助于在PS下进行高效而强大的关联分析。它的计算和成本效益使其在全基因组关联研究中非常有前途。 [出版物摘要]

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