Nonalcoholic fatty liver disease (NAFLD) is a growing cause of end-stage liver disease. Despite many advances, there remains an unmet need to better understand the variable clinical course of affected subjects, the factors driving such variability and develop effective treatment to prevent cirrhosis due to nonalcoholic steatohepatitis (NASH). The NIDDK NASH Clinical Research Network (CRN) has performed four clinical trials, numerous ancillary studies and enrolled 3000+ subjects in to a prospective cohort database-2 study with protocol-mandated follow up, bio-sample collection and adjudicated outcomes assessment; this cohort has been followed up to 10+ years and outcomes are beginning to be seen. In this competitive renewal application from the VCU adult clinical center and the Emory University pediatric center, we will build on the gains from the current cycle by performing studies with the following aims: (1) To actively participate in NASH CRN activities and recruit/retain adult and pediatric subjects in ongoing and future consortium-wide and ancillary studies e.g. database-2 and STOP- NAFLD. These studies will generate critically needed outcomes data needed for biomarker development, holistic modeling of disease progression and to inform the design of long-term clinical trials. (2) To establish and lead “The NAFLD Atlas (TNA)” to guide models of disease development and progression, identification of novel biomarkers and Precision Medicine approaches for NASH. Here we provide a vision to integrate the clinical, laboratory, genomic, transcriptomic and lipidomic data being obtained by the CRN with histological- and clinical- outcomes data. This approach, analogous to the cancer genome atlas for cancers, will permit unprecedented multi-dimensional analytic approaches to accelerate the identification of new diagnostic and prognostic markers, new targets for pharmaceutical interventions and Precision Medicine approaches for the prevention and treatment of NASH. The infrastructure required for data formatting, storage, integrity, analytics and visualization for both CRN and the greater research community is outlined along with a viable “modular” funding model. Key external collaborators with the required skills and experience have joined this effort. (3) To lead and perform a NASH CRN-wide prospective, randomized, double-blind placebo-controlled clinical trial of Pioglitazone and Vitamin E (rrr α-tocopherol, 800 IU/day) in those with NASH with bridging fibrosis (PIVENS II). The premise for this trial includes the unmet need for therapies that prevent cirrhosis the driver of liver outcomes in NASH, the available data to support a role for pioglitazone and vitamin E for NASH and their independent mechanisms of action making them suitable for combination in a trial. The primary endpoint is the proportion of subjects who progress to cirrhosis; the trial population is selected based on their high risk of such progression and thus likelihood of benefit. To...