Curtis David, Xu Ke
Academic Department of Psychiatry, Queen Mary's School of Medicine and Dentistry, London, UK.
BMC Genet. 2007 Jun 27;8:38. doi: 10.1186/1471-2156-8-38.
Tests for association between a haplotype and disease are commonly performed using a likelihood ratio test for heterogeneity between case and control haplotype frequencies. Using data from a study of association between heroin dependence and the DRD2 gene, we obtained estimated haplotype frequencies and the associated likelihood ratio statistic using two different computer programs, MLOCUS and GENECOUNTING. We also carried out permutation testing to assess the empirical significance of the results obtained.
Both programs yielded similar, though not identical, estimates for the haplotype frequencies. MLOCUS produced a p value of 1.810-15 and GENECOUNTING produced a p value of 5.410-4. Permutation testing produced a p value 2.8*10-4.
The fact that very large differences occur between the likelihood ratio statistics from the two programs may reflect the fact that the haplotype frequencies for the combined group are not constrained to be equal to the weighted averages of the frequencies for the cases and controls, as they would be if they were directly observed rather than being estimated. Minor differences in haplotype frequency estimates can result in very large differences in the likelihood ratio statistic and associated p value.
单倍型与疾病之间的关联性测试通常使用病例组和对照组单倍型频率之间的异质性似然比检验来进行。利用一项关于海洛因依赖与DRD2基因关联性研究的数据，我们使用两种不同的计算机程序MLOCUS和GENECOUNTING获得了估计的单倍型频率以及相关的似然比统计量。我们还进行了置换检验以评估所得结果的经验显著性。
两个程序得出的单倍型频率估计值相似但不完全相同。MLOCUS得出的p值为1.8×10⁻¹⁵，GENECOUNTING得出的p值为5.4×10⁻⁴。置换检验得出的p值为2.8×10⁻⁴。
两个程序的似然比统计量之间存在非常大的差异这一事实可能反映出，合并组的单倍型频率并不一定等于病例组和对照组频率的加权平均值（如果是直接观察而非估计得到的单倍型频率，就会是这种情况）。单倍型频率估计的微小差异可能会导致似然比统计量和相关p值出现非常大的差异。
