Morton N E, Collins A
Human Genetics, University of Southampton, Level G, Princess Anne Hospital, Coxford Road, Southampton SO16 5YA, United Kingdom.
Proc Natl Acad Sci U S A. 1998 Sep 15;95(19):11389-93. doi: 10.1073/pnas.95.19.11389.
Family-based procedures such as the transmission disequilibrium test (TDT) were motivated by concern that sample-based methods to map disease genes by allelic association are not robust to population stratification, migration, and admixture. Other factors to consider in designing a study of allelic association are specification of gene action in a weakly parametric model, efficiency, diagnostic reliability for hypernormal individuals, interest in linkage and imprinting, and sibship composition. Family-based samples lend themselves to the TDT despite its inefficiency compared with cases and unrelated normal controls. The TDT has an efficiency of 1/2 for parent-offspring pairs and 2/3 for father-mother-child trios. Against cases and hypernormal controls, the efficiency is only 1/6 on the null hypothesis. Although dependent on marker gene frequency and other factors, efficiency for hypernormal controls is always greater than for random controls. Efficiency of the TDT is increased in multiplex families and by inclusion of normal sibs, approaching a case-control design with normal but not hypernormal controls. Isolated cases favor unrelated controls, and only in exceptional populations would avoidance of stratification justify a family-based design to map disease genes by allelic association.
基于家系的方法，如传递不平衡检验（TDT），其产生的动机是担心通过等位基因关联来定位疾病基因的基于样本的方法对群体分层、迁移和混合不具有稳健性。在设计等位基因关联研究时需要考虑的其他因素包括在弱参数模型中基因作用的规范、效率、超正常个体的诊断可靠性、对连锁和印记的兴趣以及同胞组成。尽管与病例和无关正常对照相比效率较低，但基于家系的样本适用于TDT。对于亲子对，TDT的效率为1/2，对于父母-子女三联体，效率为2/3。在无效假设下，与病例和超正常对照相比，效率仅为1/6。尽管效率取决于标记基因频率和其他因素，但超正常对照的效率总是高于随机对照。在多病家系中以及纳入正常同胞时，TDT的效率会提高，接近使用正常而非超正常对照的病例对照设计。散发病例倾向于选择无关对照，只有在特殊人群中，避免分层才会证明基于家系的设计通过等位基因关联来定位疾病基因是合理的。
