应用相位图探讨病例对照遗传关联检验
Exploring Case-Control Genetic Association Tests Using Phase Diagrams
摘要：
背景资料：通过相图的概念，比较了两种常用的病例对照遗传分析的基因型检验方法，一种是Cochran-Armitage趋势检验（在$x=0.5$或CAT 0.5下进行CAT测试）和另一个（称为MAX2）是两个卡方检验结果的最大化：一个来自组合基线纯合子和杂合子的二乘二基因型计数表，另一个是杂合子和风险纯合子的组合。CAT0.5更适合于繁殖疾病模型，MAX2更适合于显性/隐性模型。研究方法：我们在疾病模型空间上定义CAT0.5-MAX2相图，使得MAX2比CAT0.5更强大的区域与CAT0.5更强大的区域分离，任务是选择适当的参数化以使分离成为可能。结果如下：我们发现，利用等位基因频率差（$δ_p$）和Hardy-Weinberg不平衡系数差（$δ_ε$）可以很好地分离两个阶段，并且阶段边界由角度$tan^{-1}(δ_p/δ_ε)$确定，这是对仅利用$δ_ε$进行疾病模型选择的改进。结论：我们认为，类似于CAT0.5-MAX2的相图在理解各种测试的功率性能、澄清模拟方案、总结病例对照数据集和猜测可能的遗传模式方面具有图形吸引力。
英文摘要：
Background: By a new concept called "phase diagram", we compare two commonly used genotype-based tests for case-control genetic analysis, one is a Cochran-Armitage trend test (CAT test at $x=0.5$, or CAT0.5) and another (called MAX2) is the maximization of two chi-square test results: one from the two-by-two genotype count table that combines the baseline homozygotes and heterozygotes, and another from the table that combines heterozygotes with risk homozygotes. CAT0.5 is more suitable for multiplicative disease models and MAX2 is better for dominant/recessive models. Methods: We define the CAT0.5-MAX2 phase diagram on the disease model space such that regions where MAX2 is more powerful than CAT0.5 are separated from regions where the CAT0.5 is more powerful, and the task is to choose the appropriate parameterization to make the separation possible. Results: We find that using the difference of allele frequencies ($δ_p$) and the difference of Hardy-Weinberg disequilibrium coefficients ($δ_ε$) can separate the two phases well, and the phase boundaries are determined by the angle $tan^{-1}(δ_p/δ_ε)$, which is an improvement over the disease model selection using $δ_ε$ only. Conclusions: We argue that phase diagrams similar to the one for CAT0.5-MAX2 have graphical appeals in understanding power performance of various tests, clarifying simulation schemes, summarizing case-control datasets, and guessing the possible mode of inheritance.
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