Testing for risk and protective trends in genetic analyses of HIV acquisition.
Testing for risk and protective trends in genetic analyses of HIV acquisition.
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HIV 感染遗传分析中的风险和保护趋势测试。
DOI：
10.1093/biostatistics/kxu044
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发表时间：
2015
期刊：
影响因子：
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通讯作者：
Allen,AndrewS
中科院分区：
文献类型：
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作者：
Mccarthy,JaniceM;Shea,PatrickR;Goldstein,DavidB;Allen,AndrewS
HIV-1获得的宿主遗传学研究对于确定药物和疫苗开发的新靶点至关重要。此类研究的分析通常侧重于对三个不同群体进行成对比较：HIV-1阳性个体、HIV-1高风险血清阴性个体和人群对照。因为有一个明确的预期，风险或保护性等位基因的基因频率将如何在三组中排序，我们能够构建一个统计框架，提供了一个一致的增加功率在广泛的风险/保护作用的大小。在本文中，我们开发了测试，约束备择假设，以适当地反映风险或保护趋势，共同在三个组，并表明，他们导致了显着增加的力量，天真的成对的方法。我们开发了似然比和得分统计，测试三组的遗传效应，同时限制备择假设，以反映生物动机的风险或保护趋势。这两个统计量（似然比和得分）的渐近分布。我们通过使用HIV-1获取的生物动机模型进行广泛的模拟研究来调查我们方法的性能，并发现我们提出的方法导致功率增加约10- 28%。我们通过分析CCR 532突变对HIV感染的影响来说明我们的方法。
Host genetics studies of HIV-1 acquisition are critically important for the identification of new targets for drug and vaccine development. Analyses of such studies typically focus on pairwise comparisons of three different groups: HIV-1 positive individuals, HIV-1 high-risk seronegative individuals, and population controls. Because there is a clear expectation of how gene frequencies of risk or protective alleles would be ordered in the three groups, we are able to construct a statistical framework that offers a consistent increase in power over a wide-range of the magnitude of risk/protective effects. In this paper, we develop tests that constrain the alternative hypothesis to appropriately reflect risk or protective trends jointly across the three groups and show that they lead to a substantial increase in power over the naive pairwise approach. We develop both likelihood-ratio and score statistics that test for genetic effects across the three groups while constraining the alternative hypothesis to reflect biologically motivated trends of risk or protection. The asymptotic distribution of both statistics (likelihood ratio and score) is derived. We investigate the performance of our approach via extensive simulation studies using a biologically motivated model of HIV-1 acquisition, and find that our proposed approach leads to an increase in power of roughly 10–28%. We illustrate our approach with an analysis of the effect of theCCR532mutation on HIV acquisition.