The Integrative Systems Biology Analysis Core (Price-Systems) will provide support for data analysis across Longevity Consortium (LC) projects, such as genetic variants generated by Perls-Centenarian and Schork- Disease Context, metabolomics data from Fiehn-Metabolomics, proteomics data from Orwoll-Proteomics and transcriptomics data from Miller-Mice/Cells in order to integrate them into several different models, which will be used to generate testable hypotheses centered on mechanistic network context. Our approaches will provide focused, tissue-specific analyses, thereby increasing the statistical power and insights of the LC. We will leverage a variety of network resources we have in hand and will update and expand all of these throughout the course of the project to provide access to the latest advancements in each area to the LC. The resources include: (a) genome-scale reconstructions of the human metabolic network (Brunk et al. 2018; Thiele et al. 2013) that will allow us to contextualize integrated analysis of metabolomics and genetic variants of the enzymes; (b) capability to contextualize this global network to any tissue, cell type, or condition for which we have sufficient expression data as we have already done for 126 different tissues and cell types in the human body using our mCADRE algorithm (Wang et al. 2012); (c) functional annotation of genetic variants from our atlas of inferred transcriptional regulatory networks (TRNs) and their binding sites along the genome using data from ENCODE DNase hypersensitivity footprinting information and large-scale transcriptomics repositories such as from GTEx (manuscript submitted). Another major capability provided by the Core will be to serve as an integrative analysis center that will perform systems biology analyses by integrating data that come from across LC projects, including analysis tools we have developed for longitudinal multi-omic analysis (mostly from blood) where we are currently analyzing multi-omic data (proteomes, metabolomes, clinical labs, microbiomes, wearable device data) from thousands of individuals (Hood and Price 2014; Price et al. 2017). Our core will focus on two primary aims to support the projects. First, we will deepen understanding of aging phenotypes across the LC by performing a series of integrative analyses, leveraging data across the projects and capabilities developed and deployed within the core. Second, we will expand, maintain, and distribute network reconstruction and analysis capabilities to the LC and broader scientific community. Taken together, the Price-Systems core will provide an important linkage across all the projects and cores to drive insights into aging from leveraging all of the data resources of the Longevity Consortium.
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