Statistical Methods for Microbiome and Metagenomics

摘要 该项目的广泛、长期目标涉及开发新的统计方法和联合统计方法。 用于人类微生物组和鸟枪元基因组数据的统计和概率建模的推定工具 受到重要的生物学问题和实验的激励。当前项目的具体目标是开发 用于分析16S rRNA的新的统计模型、新的推理程序和快速计算算法 以及大规模人类微生物组研究中的超基因组测序数据。该项目的重点是 基于模型的多样本微生物组组成定量方法的研究进展 用成分中介分析方法量化微生物组的中介效应 治疗/风险因素对结果的影响。此外，该项目还将开发新的统计方法 基于稀疏离散马尔可夫随机过程(MRF)模型的大规模多重测试推理 用于微生物相互作用网络的构建和差异网络分析。这些问题都是动态的。 被PI与宾夕法尼亚大学研究人员在儿童克罗恩病的元基因组研究上的密切合作所吸引 肥胖与慢性肾脏病(CKD)患者的疾病进展)。方法取决于小说 集成生物学见解和建模稀疏计数数据、高维成分的方法 数据分析和基于网络的分析，包括核范数惩罚最大似然估计 基于税收丰度估计、成分中介模型和马尔可夫随机梯度分布的微生物网络 二次网络分析。新方法既适用于16S rRNA，也适用于散弹枪亚基因组Se。 并将理想地促进微生物组成、亚组分和微生物的鉴定 各种复杂的人类疾病和生物过程背后的网络。该项目还将调查 比较了这些方法的稳健性、有效性和特殊性，并与现有的方法进行了比较。此外, 该项目将开发实用和可行的计算机程序，以实施拟议的方法- 并通过大量的模拟和分析来评价这些方法的性能。 通过PI与宾夕法尼亚大学医生和生物学家的合作，进行各种正在进行的微生物组研究。这个 本文提出的工作将有助于建立元基因组测序数据和HIGH模型的统计方法 维度组成数据，MFR模型的理论推断方法以及对每个模型的其他见解 由各种数据集表示的生物区域。根据此赠款开发的所有计划，并详细说明 文件将免费提供给感兴趣的研究人员。

Abstract The broad, long-term objective of this project concerns the development of novel statistical methods and com- putational tools for statistical and probabilistic modeling of human microbiome and shotgun metagenomic data motivated by important biological questions and experiments. The speci c aim of the current project is to develop new statistical models, novel inference procedures, and fast computational algorithms for the analysis of 16S rRNA and shotgun metagenomic sequencing data in large-scale human microbiome studies. The project focuses on the development of model-based multi-sample approaches for quantifying microbiome compositions and development methods of compositional mediation analysis in order to quantify the e ects of microbiome mediating the e ect of treatment/risk factor on outcomes. In addition, this project will also develop novel methods for statistical inference including large-scale multiple testing procedures on sparse discrete Markov random eld (MRF) models for microbial interaction network construction and for di erential network analysis. These problems are all moti- vated by the PI's close collaborations with Penn investigators on metagenomic studies of Crohn disease, childhood obesity and disease progression among patients with chronic kidney disease (CKD)). The methods hinge on novel integration of biological insights and methods for modeling sparse count data, high dimensional compositional data analysis and network-based analysis, including nuclear-norm penalized maximum likelihood estimation for tax abundance estimation, compositional mediation model and Markov random eld based microbial network and di erential network analysis. The new methods can be applied to both 16S rRNA and shotgun metagenomic se- quencing data and will ideally facilitate the identi cations of microbial composition, subcomposition and microbial networks underlying various complex human diseases and biological processes. The project will also investigate the robustness, power and eciencies of these methods and compare them with existing methods. In addition, this project will develop practical and feasible computer programs for the implementation of the proposed meth- ods, and for the evaluation of the performance of these methods through extensive simulatons and analysis of various on-going microbiome studies through the PI's collaborations with Penn physicians and biologists. The work proposed here will contribute statistical methodology for modeling metagenomic sequencing data and high dimensional compositional data, theoretical inference methods for the MFR models and o er insights into each of the biological areas represented by the various data sets. All programs developed under this grant and detailed documentation will be made available free-of-charge to interested researchers.