Unbiased application of the transmission/disequilibrium test to multilocus haplotypes
Unbiased application of the transmission/disequilibrium test to multilocus haplotypes
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DOI：
10.1086/302915
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发表时间：
2000-06-01
影响因子：
9.8
通讯作者：
Clayton, DG
中科院分区：
文献类型：
--
作者：
Dudbridge, F;Koeleman, BPC;Clayton, DG
当传递/不平衡检验（TDT）应用于多位点单倍型时，可能会在某些双亲在某个位点具有相同杂合基因型的家系中引入偏倚。由于单倍型只能从特定的后代中推导出来，因此两个亲本单倍型的传递不是独立的，因此会发生偏倚。我们通过计算一个家庭内的传播计数的正确方差，使用来自多个兄弟姐妹的信息（如果他们可用），获得一个无偏的TDT。在存在连锁的情况下，保留了对兄弟姐妹之间依赖性的现有校正。为了获得一个无偏的多单体型TDT，我们必须计数从一个随机选择的父母或计数所有的传输和经验估计的显着性水平。或者，我们可以使用缺失数据技术来估计不确定的单倍型，但这些方法对人群分层不鲁棒。使用来自1型糖尿病胰岛素基因区域的数据的说明表明，TDT的有效性和功效可能会因分析方法而异。
When the transmission/disequilibrium test (TDT) is applied to multilocus haplotypes, a bias may be introduced in some families for which both parents have the same heterozygous genotype at some locus. The bias occurs because haplotypes can only be deduced from certain offspring, with the result that the transmissions of the two parental haplotypes are not independent. We obtain an unbiased TDT for individual haplotypes by calculating the correct variance for the transmission count within a family, using information from multiple siblings if they are available. An existing correction for dependence between siblings in the presence of linkage is retained. To obtain an unbiased multihaplotype TDT, we must either count transmissions from one randomly chosen parent or count all transmissions and estimate the significance level empirically. Alternatively, we may use missing-data techniques to estimate uncertain haplotypes, but these methods are not robust to population stratification. An illustration using data from the insulin-gene region in type 1 diabetes shows that the validity and power of the TDT may vary by an order of magnitude, depending on the method of analysis.