Ma Li, Wong Wing Hung, Owen Art B
Department of Statistical Science, Duke University, Durham, N.C. 27708-0251, USA.
Hum Hered. 2012;73(1):52-61. doi: 10.1159/000335937. Epub 2012 Mar 2.
Linkage and association analysis based on haplotype transmission disequilibrium can be more informative than single marker analysis. Several works have been proposed in recent years to extend the transmission disequilibrium test (TDT) to haplotypes. Among them, a powerful approach called the evolutionary tree TDT (ET-TDT) incorporates information about the evolutionary relationship among haplotypes using the cladogram of the locus.
In this work we extend this approach by taking into consideration the sparsity of causal mutations in the evolutionary history. We first introduce the notion of a Bradley-Terry (BT) graph representation of a haplotype locus. The most important property of the BT graph is that sparsity of the edge set of the graph corresponds to small number of causal mutations in the evolution of the haplotypes. We then propose a method to test the null hypothesis of no linkage and association against sparse alternatives under which a small number of edges on the BT graph have non-nil effects.
We compare the performance of our approach to that of the ET-TDT through a power study, and show that incorporating sparsity of causal mutations can significantly improve the power of a haplotype-based TDT.
基于单倍型传递不平衡的连锁和关联分析可能比单标记分析提供更多信息。近年来，已经提出了几项工作将传递不平衡检验（TDT）扩展到单倍型。其中，一种称为进化树TDT（ET-TDT）的强大方法利用基因座的分支图纳入了关于单倍型之间进化关系的信息。
在这项工作中，我们通过考虑进化历史中因果突变的稀疏性来扩展这种方法。我们首先引入单倍型基因座的布拉德利-特里（BT）图表示的概念。BT图的最重要属性是图的边集的稀疏性对应于单倍型进化中少量的因果突变。然后，我们提出一种方法来检验无连锁和关联的原假设，以对抗稀疏备择假设，在该假设下，BT图上的少量边具有非零效应。
我们通过功效研究将我们的方法与ET-TDT方法的性能进行比较，并表明纳入因果突变的稀疏性可以显著提高基于单倍型的TDT的功效。
