Project Summary Michelle T. Long, MD, is a faculty member of the Boston Medical Center, Division of Gastroenterology and an Assistant Professor at the Boston University (BU) School of Medicine. Her research has focused on non-alcoholic fatty liver disease (NAFLD) as measured by computed tomography scan in the Framingham Heart Study (FHS). In her prior work, she has evaluated the association between NAFLD and physical activity and NAFLD and sub- clinical measures of cardiovascular disease (CVD) in the FHS cohort. Her work in these areas has resulted in 4 first author publications including the development and validation of a simple clinical diagnostic score for hepatic steatosis called the Framingham Steatosis Index. Her recent study utilizing blood-based non-invasive hepatic fibrosis markers in the FHS determined that the available fibrosis markers give widely disparate predictions of the risk for significant hepatic fibrosis when applied to this community-based cohort. NAFLD associated hepatic fibrosis is an important public health problem. More than 15 million Americans are estimated to suffer from hepatic fibrosis from NAFLD which worsens metabolic disease and increases the risk of liver- related and CVD- related death. Studies to date examining NAFLD in community-based cohorts in the United States have relied on imaging modalities that are insensitive to hepatic fibrosis. Dr. Long's proposal will focus on testing three hypotheses; 1) FHS participants with hepatic fibrosis, as measured by vibration-controlled transient elastography (VCTE), have a more adverse CVD risk factor profile compared to those with no fibrosis, 2) Genetic determinants for the risk of hepatic fibrosis are identifiable by genome wide association studies and 3) A diagnostic model based on clinical and genetic traits distinguishes NAFLD patients with and without fibrosis as defined by VCTE and the model performs well when applied to an external validation cohort. The study of the clinical and genetic traits associated with hepatic fibrosis in the community will lead to insights into disease mechanisms, biomarker development, and novel therapeutic targets, which has the potential to improve public health. This study will be performed as an ancillary study of approximately 3,500 FHS Third Generation and OMNI 2 cohort participants who are undergoing evaluation for hepatic fibrosis using VCTE. Dr. Long’s ultimate career goal is to use epidemiological insights for two purposes: a) identify potential novel drug targets; and b) develop tools to identify high risk NAFLD patients to prevent disease progression. To complete this proposal and progress towards these goals, Dr. Long has developed a five year mentored career development program that incorporates both didactic and formal research training guided by two well established investigators with expertise in clinical and translational research in CVD and NAFLD. She will receive formal didactic training in epidemiology, advanced biostatistics, predictive modeling, and implementation science through the BU School of Public Health. With this additional education and guidance, as well as the supportive environment provided by BU, Dr. Long will be well positioned to complete this proposal and develop into an independent clinical investigator.

Project Narrative: Non-alcoholic fatty liver disease (NAFLD) associated hepatic fibrosis likely affects 15 million Americans and is associated with poor outcomes. It remains poorly understood why certain patients with NAFLD progress to fibrosis while others have a relatively benign disease course. The proposed research will provide novel insights into determining the utility of transient elastography as a screening tool and also insights into biomarker development, understanding disease mechanisms, and identification of new potential therapeutic targets for hepatic fibrosis.