Meta-Analysis of Multiple Regression Models and Rare Variant Gene-Gene Interaction Analysis for Next Generation Sequencing Data

该项目有两个主要目标，都与基因-基因相互作用有关。第一个目标是为多元回归分析提供一个元分析框架。默认应用程序将是交互分析。第二个主要目标是开发方法和提供分析软件，用于从下一代测序研究获得的稀有变异的基于集合的交互作用分析。交互作用分析的模型通常由多个参数定义。因此，需要对标准的全球气候变化综合分析框架进行扩展。最近描述了退化坡的合成，并将继续进行遗传学研究。应提供为多个回归模型设计的荟萃分析工具。该方法取决于参数协方差矩阵的可用性。框架应通过扩展现有的自有工具来支持，以提供这些矩阵。应研究荟萃分析方法的统计特性。一个国际数据分析项目正在议程上。稀有变异和基因相互作用是复杂疾病缺失的广义遗传性的潜在解释。因此，将这两种想法整合到一个联合分析框架中是一个直截了当的想法。我们的目标是解决不可避免的高维问题和计算挑战。现有的基于集合的方法，包括负荷检验以及回归或方差成分检验，应扩展到基因对的分析。应调查模拟相互作用项的无负荷试验。为了提高基于集合的稀有变异交互作用分析的能力，应采用我们最近提出的超乘性的单自由度检验。所有测试应在允许全基因组应用的独立工具中实施。应通过模拟研究来比较不同方法的能力。

The project has two major aims, both relating to gene-gene interaction. The first goal is to provide a meta-analysis framework for multiple regression analysis. The default application will be interaction analysis. The second major goal is to develop methods and provide analysis software for set-based interaction analysis of rare variants obtained from Next Generation Sequencing studies.Models for interaction analysis are typically defined by more than one parameter. Hence, extension of the standard GWAS meta-analysis framework is needed. Synthesis of regression slopes has recently been described and shall be carried over to genetic studies. A meta-analysis tool designed for multiple regression models shall be provided. The methodology depends on the availability of parameter covariance matrices. The framework shall be supported by extending existing own tools to provide these matrices. The statistical properties of the meta-analysis method shall be investigated. An international data analysis project is on the agenda.Rare variants and genetic interaction are potential explanations of the missing, broad-sense heritability of complex diseases. Therefore, it is a straightforward idea to integrate both ideas into a joint analysis framework. Our aim is to tackle the inevitably occurring high-dimensionality problem and computational challenges. Existing set-based methods, including burden tests as well as regression or variance component tests, shall be extended to the analysis of pairs of genes. Non-burden tests that model interaction terms shall be investigated. A one-degree-of-freedom test for supra-multiplicativity, recently proposed by us, shall be applied to improve power of set-based rare variant interaction analysis. All tests shall be implemented in a stand-alone tool that allows Genome-wide application. The power of different approaches shall be compared via a simulation study.