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可以预测哪个标记等位基因与疾病相关。最近提出了新的统计测试程序。 例如，传递/不平衡测试（TDT）一直是评估候选基因与疾病和标记之间的连锁/关联的流行且强大的方法。该方法结合了关联和链接的信息，以产生比用于在存在关联时检测链接的传统测试更大的能力。通过进行全基因组 TDT 筛选，它还有巨大的潜力在未来人类疾病的基因图谱中发挥重要作用。最近的文献显示，将 TDT 或其概括应用于各种复杂的基于家庭的数据的研究数量呈增加趋势，但这些方法都是临时的。非常需要对这些方法进行系统且合理的优化分析。 这项工作建立了一个通用的统计框架，可以包含所有程序、不同的数据集和其他相关知识，例如疾病信息、抽样设计和人口信息。 我们开发了一种通用统计理论，可以作为未来研究人员的指南，他们可以设计和开发自己的统计程序（遵循框架）以满足他们融入不同环境的需求。 该研究通过引入适用于每个核心家庭的有用 3x2 表格，提供了一种基于可能性的方法。很自然地采用条件性原则来导出和评估各种 TDT 类型程序和链接测试，并使用“局部最强大的测试”（LMPT）作为中心最优性标准。 这项研究概述了似然法，并演示了该方法在某些特殊情况下的工作原理。该研究提供了示例的推导和发现，这应该有助于更好地理解这些数据集产生的更具挑战性和更广泛的问题。 在培养从事这一日益重要的领域的博士生时，该研究为开发新的研究水平课程提供了基础。 拟议的研究旨在最终为未来的研究人员提供常规指南，并为基于家庭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.