Dudbridge Frank
MRC Human Genome Mapping Project Resource Centre, Hinxton, Cambridge, UK.
Genet Epidemiol. 2003 Sep;25(2):115-21. doi: 10.1002/gepi.10252.
Association tests of multilocus haplotypes are of interest both in linkage disequilibrium mapping and in candidate gene studies. For case-parent trios, I discuss the extension of existing multilocus methods to include ambiguous haplotypes in tests of models which distinguish between the cis and trans phase. A likelihood-ratio test is proposed, using the expectation-maximization (E-M) algorithm to account for haplotype ambiguities. Assumptions about the population structure are required, but realistic situations, including population stratification, which violate the assumptions lead to conservative tests. I describe a permutation procedure for the null hypothesis of interest, which controls for violation of the assumptions. For general pedigrees, I describe extensions of the pedigree disequilibrium test to include uncertain haplotypes. The summary statistics are replaced by their expected values over prior distributions of haplotype frequencies. If prior distributions are not available, a valid test is possible by using the E-M algorithm to estimate the null distribution of haplotype frequencies. Similar methods are available for quantitative traits. Exact permutation tests are difficult to construct in small samples, but an approximate procedure is appropriate in large samples, and can be used to account for dependencies between tests of multiple haplotypes and loci.
多位点单倍型的关联检验在连锁不平衡作图和候选基因研究中都备受关注。对于病例 - 父母三联体，我讨论了如何将现有的多位点方法进行扩展，以便在区分顺式和反式相位的模型检验中纳入模糊单倍型。本文提出了一种似然比检验方法，利用期望最大化（E - M）算法来处理单倍型的模糊性。虽然需要对群体结构做出假设，但包括群体分层在内的违反这些假设的现实情况会导致检验结果保守。我描述了一种针对感兴趣的零假设的置换程序，该程序可控制对假设的违反情况。对于一般家系，我描述了家系不平衡检验的扩展方法，以纳入不确定的单倍型。汇总统计量被其在单倍型频率先验分布上的期望值所取代。如果没有先验分布，可以通过使用E - M算法估计单倍型频率的零分布来进行有效检验。类似的方法也适用于数量性状。在小样本中难以构建精确的置换检验，但在大样本中近似程序是合适的，并且可用于处理多个单倍型和位点检验之间的相关性。
