PROJECT SUMMARY The purpose of this U19 Program Project (U19) is to comprehensively identify osteoporosis risk genes/bacterial species and their functional products from the human genome and gut microbiome. We will characterize their functions through comprehensive trans-omics integrative analyses of the data generated both from this renewal project and from our ongoing U19 (U19 AG055373, 9/15/2017-). This program involves extensive data management and complex analyses, requiring organic and simultaneous consideration of data from multiple component projects and demanding powerful and innovative analysis methodology. Thus, a Biostatistics & Bioinformatics Core (BBC) is necessary focusing on the use of both existing and the development of novel, integrative analysis approaches. The Objective of the BBC is to serve as a backbone support core for experimental design refinement, data quality control, management, imputation, integration, and interpretation, and to serve as a synergizer to foster data and information exchange and collaboration across individual projects/cores within the U19. Built upon the Core members’ long-term productive collaborations, the BBC will provide services through the following Specific Aims: 1) To deliver efficient support and services for data management, including high-quality data entry and database management, query and maintenance, data quality control, safety, monitoring, sharing, etc. 2) To provide strong support for and conduct extensive biostatistics and bioinformatics, especially multi- and trans- omics data imputation and integrative analyses. Closely working with the U19 investigators, the BBC will support both single-level omics data analyses and integrative analyses of multi-level omics data. Particularly, the BBC will pioneer a sophisticated integrative analysis strategy. This highly innovative strategy will link gut microbiome DNA, human host DNA, miRNA, methylation, and metabolomic data anchored via gene-based mRNA hubs to construct unified functional multi-omics modules and regulatory networks/pathways for both osteoblastogenic and osteoclastogenic lineage cells. These re-constructed functional modules and regulatory networks/pathways will then be used in disease association/causality analyses for osteoporosis risk. 3) To evaluate, validate, and apply novel, robust and powerful integrative analysis methods for the identification and characterization of (epi-)genes and variants, gut microbiome bacterial species, and gene/pathway functions for osteoporosis. The novel methods developed in-house (e.g., through recent R01’s funded to Core Director – Dr. Wang) under rigorous statistical frameworks, together with those developed by other groups in the field, will be comparatively used. These methods will characterize and incorporate crosstalks/interactions among-omics, along with prior biological information, to study causal relationships between multi-omics data and diseases. The innovative methods will be app...