Methods for genomic data with graphical structures

描述(由申请人提供)：该项目广泛的、长期的目标涉及开发新的统计方法和计算工具，用于对由重要的生物学问题和实验驱动的基因组数据进行统计和概率建模。本项目的具体目标是开发新的统计模型和方法，用于以图形结构分析基因组数据，重点放在分析遗传路径和网络的方法上，包括开发用于两个样本的非参数路径平滑检验和用于识别两个或多个实验条件之间具有扰动活性的路径的方差问题的分析，开发用于路径平滑的广义线性模型、Cox比例风险模型和加速失效时间模型的群体套索和群体阈值梯度下降正则化估计程序，以便识别与各种临床表型相关的路径。这些方法依赖于谱图理论、多变量数据分析的非参数方法和统计学习的正则化估计方法的新集成。新方法可以应用于不同类型的基因组数据，理想地将有助于识别各种复杂的人类疾病和复杂的生物过程背后的基因和生物途径。该项目还将调查这些方法的稳健性、功率和效率，并将它们与现有方法进行比较。此外，本项目将开发实用可行的计算机程序，以实施所提出的方法，通过应用于人类心力衰竭、心脏移植排斥反应和神经母细胞瘤的微阵列基因表达研究的真实数据来评估这些方法的性能。这里提出的工作将有助于统计学方法对具有图形结构的基因组数据进行建模，研究复杂的表型和生物系统，以及用于高维数据分析的方法，并提供对各种数据集所代表的每个临床领域的洞察，以评估这些新方法。根据这笔赠款开发的所有计划和详细的文件将通过万维网免费提供给感兴趣的研究人员。

DESCRIPTION (provided by applicant): The broad, long-term objective of this project concerns the development of novel statistical methods and computational tools for statistical and probabilistic modeling of genomic data motivated by important biological questions and experiments. The specific aim of the current project is to develop new statistical models and methods for analysis of genomic data with graphical structures, focusing on methods for analyzing genetic pathways and networks, including the development of nonparametric pathway-smooth tests for two-sample and analysis of variance problems for identifying pathways with perturbed activity between two or multiple experimental conditions, the development of group Lasso and group threshold gradient descent regularized estimation procedures for the pathway-smoothed generalized linear models, Cox proportional hazards models and the accelerated failure time models in order to identify pathways that are related to various clinical phenotypes. These methods hinge on novel integration of spectral graph theory, non-parametric methods for analysis of multivariate data and regularized estimation methods fro statistical learning. The new methods can be applied to different types of genomic data and will ideally facilitate the identification of genes and biological pathways underlying various complex human diseases and complex biological processes. The project will also investigate the robustness, power and efficiencies o these methods and compare them with existing methods. In addition, this project will develop practical a feasible computer programs in order to implement the proposed methods, to evaluate the performance o these methods through application to real data on microarray gene expression studies of human hear failure, cardiac allograft rejection and neuroblastoma. The work proposed here will contribute both statistical methodology to modeling genomic data with graphical structures, to studying complex phenotypes and biological systems and methods for high-dimensional data analysis, and offer insight into each of the clinical areas represented by the various data sets to evaluate these new methods. All programs developed under this grant and detailed documentation will be made available free-of-charge to interested researchers via the World Wide Web.