Li H, Hsu L
Department of Medicine, Rowe Program in Human Genetics, University of California, Davis, CA 95616-8500, USA.
Ann Hum Genet. 2000 May;64(Pt 3):239-54. doi: 10.1017/S000348000000806X.
Information on the age of a patient at disease onset, an important feature of complex diseases, is often collected in studies designed to map the disease genes. Penetrance-model-free methods, requiring no specification of penetrance functions, have been used extensively for detecting linkage and association between marker and disease loci. In this paper, we conduct an analytical study to examine the effects of incorporation of age at onset information on the power of two commonly used penetrance-model-free methods, the affected sib-pair (ASP) and transmission/disequilibrium tests (TDT). Assuming a Cox model with a major gene effect for the age at onset, we quantify analytically how age at onset affects the identity by descent (IBD) probabilities, the mean IBD values, and the expected numbers of alleles transmitted from heterozygous parents to affected children under various genetic models. We show that the power of the mean IBD test and the TDT can be greatly affected by the ages at onset of affected siblings or children used in the study. Generally, the most powerful test for ASPs is that based on affected sib pairs both having early disease onset and for TDT analyses is that based on trios with early-onset children. Naively combining affected sib pairs with different ages at onset or parent-children trios with different ages at onset of affected children can result in reduced power for detecting linkage or association. These results may be used to guide collection and analysis of sib pairs or families for diseases with variable age at onset.
疾病发病时患者的年龄信息是复杂疾病的一个重要特征，在旨在定位疾病基因的研究中经常会收集该信息。无需指定外显率函数的无外显率模型方法已被广泛用于检测标记与疾病位点之间的连锁和关联。在本文中，我们进行了一项分析研究，以检验纳入发病年龄信息对两种常用的无外显率模型方法——受累同胞对（ASP）法和传递/不平衡检验（TDT）法的检验效能的影响。假设发病年龄存在主基因效应的Cox模型，我们通过分析量化了发病年龄在各种遗传模型下如何影响同源等位基因（IBD）概率、平均IBD值以及从杂合子父母传递给受累子女的等位基因期望数。我们表明，平均IBD检验和TDT的检验效能会受到研究中使用的受累同胞或子女的发病年龄的极大影响。一般来说，对ASP最具检验效能的是基于两个发病早的受累同胞对，而对TDT分析而言，最具检验效能的是基于有早发病子女的三联体。盲目地将发病年龄不同的受累同胞对或受累子女发病年龄不同的亲子三联体组合在一起，可能会导致检测连锁或关联的效能降低。这些结果可用于指导对发病年龄可变的疾病的同胞对或家系进行收集和分析。
