ABSTRACT The reasons for individual variability in the physiologic response to dietary patterns are not well understood but hamper efforts to provide optimum diets to our population. There is an urgent need to understand the complex interaction of demographic, genetic, metabolic, behavioral, psychosocial, and environmental factors that affect the responses to dietary patterns in order to prevent and treat nutrition-related chronic diseases. The field of “precision nutrition” holds great promise for elucidating these interactions to eventually predict the optimal diet for an individual or groups of individuals. The overall objective of this application is to demonstrate that the University of Alabama at Birmingham (UAB) is uniquely positioned to join the consortium as a Nutrition for Precision Health Clinical Center (RFA-RM-21-005). The study team will collect a wide range of physiological and metabolic data from individuals in response to free-living (module 1) and controlled diets (modules 2 & 3), that will be used in analyses to determine potential predictors of response to diet. Sophisticated data methods (artificial intelligence, machine learning, mathematical modelling) will then be employed by the study group to identify the comprehensive phenotypes needed for individualizing diet prescriptions. We aim to accomplish the following three specific aims: Specific Aim 1 (module 1): Conduct an observational study of 2000 free-living individuals consuming their usual diet for 14 days. The physiologic responses to a standardized test meal challenge will be assessed while they are consuming their usual diet. Specific Aim 2 (module 2): Conduct a free-living controlled feeding study in 400 subjects fed three isocaloric diets varying in macronutrient composition at maintenance energy requirements. Diets are designed to elicit a wide range of responses among participants. The physiologic responses to standardized test meals and diet-specific meals will be measured at the end of each 14-day diet period. We will also collect measures of 24-hr glucose, 24-hr blood pressure, 24-hr physical activity, cardiorespiratory fitness, and sleep during each diet period. Specific Aim 3 (module 3): Conduct a domiciled controlled feeding study in 150 subjects of three isocaloric diets (same diets as in aim #1) fed at maintenance energy requirements. In addition to module 2 outcomes, assessments including room calorimetry, doubly labelled water, cardiorespiratory fitness, and muscle and fat biopsies will be completed in module 3 participants while they are domiciled in cottages at the Lakeshore Foundation Campus near UAB. Achieving these aims will create a database that allows sophisticated data analysis (e.g., AI, machine learning) to develop algorithms to match people to optimum diets. UAB, with access to >16,000 All of Us participants in Birmingham, outstanding facilities for conducting diet interventions, and an outstanding research team, can be a valued member of th...