Statistical Analysis of Linkage/Association on Family-Based Studies in Human Genetics

疾病基因和标记等位基因之间的等位基因关联允许预测哪个标记等位基因与疾病偶联。最近提出了一些新的统计检验方法。 例如，传递/不平衡检验（TDT）已经成为评价与疾病相关的候选基因与标记之间的连锁/关联的流行和有效的方法。这种方法结合了关联和链接的信息，以产生比传统测试更大的功率来检测关联时存在的链接。通过进行全基因组TDT筛选，它也有很大的潜力在未来人类疾病的基因定位中发挥重要作用。最近的文献已经看到了一个越来越多的趋势，研究的数量已经应用TDT或其推广到各种复杂的家庭为基础的数据，但这些方法是特设的。有一个系统的和明智的最佳分析这些方法的巨大需求。 这项工作建立了一个总的统计框架，可以纳入所有程序、不同的数据集和疾病信息、抽样设计和人口信息等其他相关知识。 我们开发了一个通用的统计理论，作为未来的调查人员，谁可以设计和开发自己的统计程序（以下框架），以满足他们的需要，纳入不同的环境中的指导方针。 该研究通过引入适用于每个核心家庭的有用的3x 2表提供了一种基于可能性的方法。这是自然的，采用条件性原则推导和评估各种TDT类型的程序和链接测试，使用“本地最强大的测试”（LMPT）作为一个中心的最优性标准。 本研究概述了似然方法，并演示了该方法在某些特殊情况下的工作原理。该研究提供了来自示例的推导和发现，这应该有助于更好地理解这些数据集所产生的更具挑战性和更广泛的问题。 在培养博士生在这个日益重要的领域工作，研究提供了基础，开发一个新的研究水平的课程。 拟议的研究旨在最终为未来的研究人员提供常规指南，并为以家庭为基础的研究提供理论基础。

The allelic association between disease genes and marker alleles allows predicting which marker allele is in coupling with the disease. There are novel statistical testing procedures proposed recently. For example, the Transmission/ Disequilibrium Testing ( TDT ) has been both a popular and powerful method to evaluate the linkage/ association between the candidate genes with disease and the markers. This approach combines the information of association and linkage to yield greater power than conventional tests for detecting linkage when the association is present. It also has great potential to play a major role in future gene mapping of human disorder, by carrying out genomewide TDT screens. Recent literature has seen an increasing trend in the number of studies that have applied TDT or its generalizations to a variety of complex family-based data, but these methods are ad hoc. There is a great need for a systematic and sensible optimal analysis of these methods. This work sets up a general statistical framework that can incorporate all procedures, different data sets and other related knowledge such as disease information, sampling designs and population information. We develop a general statistical theory, useful as a guideline for future investigators, who can design and develop their own statistical procedures (following the framework) to meet their needs in incorporating different environments. The research provides a likelihood-based approach by introducing a useful 3x2 table which applies to each nuclear family. It is natural to adopt the conditionality principle to derive and to evaluate a variety of TDT type procedures and linkage tests, using "Locally Most Powerful Testing" (LMPT ) as a central optimality criteria. This research outlines the likelihood approach and demonstrates how the method works in some special cases. The research provides the derivations and findings from the examples,which should shed light on a better understanding of the more challenging and broader problems arising from these data sets. In training doctoral students working on this increasingly important area, the research provides the basis to develop a new research level course. The proposed research intends to lead ultimately to routine guidelines for future investigators and to offer a theoretical basis for family-based studies.