Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park Durham, NC, USA ; Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill Chapel Hill, NC, USA.
Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park Durham, NC, USA.
Front Genet. 2015 Feb 10;6:15. doi: 10.3389/fgene.2015.00015. eCollection 2015.
The X chromosome is generally understudied in association studies, in part because the analyst has had limited methodological options. For nuclear-family-based association studies, most current methods extend the transmission disequilibrium test (TDT) to the X chromosome. We present a new method to study association in case-parent triads: the parent-informed likelihood ratio test for the X chromosome (PIX-LRT). Our method enables estimation of relative risks and takes advantage of parental genotype information and the sex of the affected offspring to increase statistical power to detect an effect. Under a parental exchangeability assumption for the X, if case-parent triads are complete, the parents of affected offspring provide an independent replication sample for estimates based on transmission distortion to their affected offspring. For each offspring sex we combine the parent-level and the offspring-level information to form a likelihood ratio test statistic; we then combine the two to form a combined test statistic. Our method can estimate relative risks under different modes of inheritance or a more general co-dominant model. In triads with missing parental genotypes, the method accounts for missingness with the Expectation-Maximization algorithm. We calculate non-centrality parameters to assess the power gain and robustness of our method compared to alternative methods. We apply PIX-LRT to publically available data from an international consortium of genotyped families affected by the birth defect oral cleft and find a strong, internally-replicated signal for a SNP marker related to cleft lip with or without cleft palate.
X 染色体在关联研究中通常研究不足，部分原因是分析人员的方法选择有限。对于基于核心家庭的关联研究，大多数当前方法将传递不平衡测试（TDT）扩展到 X 染色体。我们提出了一种新的方法来研究病例-父母三体型中的关联：X 染色体的亲本知情似然比检验（PIX-LRT）。我们的方法能够估计相对风险，并利用父母的基因型信息和患病后代的性别来增加检测效应的统计能力。在 X 染色体的父母交换假设下，如果病例-父母三体型完整，患病后代的父母为基于对其患病后代的传递偏差的估计提供了独立的复制样本。对于每个后代性别，我们将父母水平和后代水平的信息结合起来形成似然比检验统计量；然后我们将两者结合起来形成一个联合检验统计量。我们的方法可以在不同的遗传模式或更一般的共显性模型下估计相对风险。在缺失父母基因型的三体型中，该方法使用期望最大化算法来解释缺失值。我们计算非中心参数来评估我们的方法与替代方法相比的功效增益和稳健性。我们将 PIX-LRT 应用于由国际基因分型家庭联盟提供的公开数据，该联盟受出生缺陷口腔裂影响，发现与唇裂伴或不伴腭裂相关的 SNP 标记存在强烈的、内部复制的信号。
