Project Summary Although abstinence-oriented interventions remain the typical treatment choice for alcohol use disorder (AUD), relapse is common. Research in animals and humans shows that, in certain groups, short-term abstinence followed by reinstatement of drinking escalates, instead of reduces, subsequent alcohol use. This heterogeneity in response can in part explain poor AUD treatment effects, warranting personalized treatment rules for when to prescribe abstinence-oriented interventions. Co-occurring psychopathology complicates AUD, making it a prime factor on which to base clinical decision-making. The overall goal of this project is to utilize a novel psychopathology framework, the Hierarchical Taxonomy of Psychopathology (HiTOP), to predict the heterogeneous response to short-term abstinence and to examine shared neurobiological and genetic mechanisms underlying this response. The specific aims of this application are to 1) characterize individuals who benefit from, or are harmed by, short-term enforced abstinence based on HiTOP dimensions and underlying neurobiological and genetic mechanisms in a well-controlled laboratory paradigm and 2) Characterize individuals who show escalating patterns of alcohol consumption after natural periods of abstinence over a one-year period based on HiTOP dimensions and underlying neurobiological and genetic mechanisms. Modern cutting-edge subgroup discovery methodology will be leveraged which enables simultaneously modeling a large number of treatment-moderator interactions with complex, nonlinear moderation effects, to accurately estimate abstinence response. This cutting-edge methodology directly informs clinical decision making, enabling the creation of guidelines for predicting response to abstinence in practice. The proposed project is innovative and significant as it 1) studies heterogeneity in abstinence response, which might explain escalation in alcohol use, a highly significant and costly problem; 2) leverages the novel HiTOP framework for personalized alcohol treatment recommendations, which is easily assessed and can be easily applied to clinical settings; 3) applies cutting edge modern statistical methodology that addresses limitations of traditional methods in precision medicine and the urgent need for individualized treatment planning; 4) complements data-driven approaches with potential underlying neurobiological and genetic mechanisms; and 5) integrates a novel, well-controlled human laboratory paradigm with ecologically valid longitudinal follow-up of real-world reported alcohol patterns to further provide rich and robust findings. The long-term goal of this line of research is to develop guidelines to facilitate clinical practitioners’ decision- making concerning when to utilize abstinence-based interventions.