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基因关联分析中的精确MAX检验

Exact MAX tests in genetic association analysis

  • 摘要: 相较于常用的Pearson检验,Cochran-Armitage趋势检验(CAT检验)由于整合了遗传模式的信息,具有更高的功效。然而在实际应用中,真实的遗传模式通常未知,使用错误模式对应的CAT检验可能会显著降低检验功效。因此,对于遗传模式稳健且具有较高功效的检验方法的开发尤为重要。MAX型检验将不同遗传模式对应的CAT检验统计量取最大值作为检验统计量,具有稳健有效性。然而MAX型检验在原假设下的分布十分复杂,尽管可以通过大样本近似或置换方法获得,但前者的准确性受制于样本量大小,后者因其对重复模拟的需求而表现出相对较低的计算效率。为解决这一问题,本文提出了一种基于组合计数方法计算MAX型检验精确p值的新方法。模拟结果显示,我们提出的精确方法相比大样本近似方法更为准确,并且在计算效率上优于置换方法。计算的高效性和准确性使得该方法可扩展至大规模的全基因组关联分析。另外,我们还开发了相应的R程序包,该程序包可通过https://github.com/Myuan2019/MaXact/获取。

     

    Abstract: The three common genetic models (or modes of inheritance) in association analysis are the dominant, additive, and recessive models. It is known that the Cochran-Armitage trend test (CATT) which correctly incorporates information from genetic models, is more powerful than the commonly used Pearson’s chi-square test. However, the true genetic model is usually unknown in practice, and the power of the CAT test could be substantially reduced with a wrongly specified genetic model. To achieve a power that is close to that of a correctly specified CAT test, it is natural to apply trend tests under different possible genetic models and to report the most significant test result. This results in a MAX-type testing procedure, and it was found that this test is usually more powerful than the Pearson’s chi-square test. Although the significance (i.e., p value) of the MAX-type test can be accessed by either large sample approximation or permutation methods, requirements for sample size or simulation replicates are demanding with respect to accuracy and efficiency. This paper proposes an approach to calculate the exact p values of MAX-type tests based on the combinatorial counting method. The simulation results show that the exact method is more accurate than the large sample approximation methods and more computationally efficient than the permutation method, and our method can be readily applied to genome-wide association studies (GWASs). The proposed method is built in an R package, MaXact, which is available at the https://github.com/Myuan2019/MaXact/.

     

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