PROJECT SUMMARY Among SES- and race/ethnicity-related health disparities in the U.S., 11 preventable conditions cause >50% of mortality. Our preliminary modeling work suggests that only 9 prevention goals could attain 40% mortality reduction from these 11 conditions, a 20% mortality reduction overall, because of interdependencies and common pathways. For example, alcohol use disorder and/or heavy drinking (AUD/HD) impacts liver failure, but also sexual risk-taking and medication nonadherence. But achieving mortality reduction would require a radical transformation of preventive care, such as proposed here: personalization, navigation, and compensation. Personalization means maximizing individual-level benefit by modulating intervention characteristics in 3 three domains: (1) intensity of screening; (2) frequency of screening; and (3) intensity or duration of response, based on individual harm/benefit profile and preferences. Navigation means reducing barriers posed by fragmentation of health and social systems. Compensation means offsetting dependent care, time costs, and travel costs relating to care based on cost-attribution methods used in cost-effectiveness analysis. For this proposal, disparity-impacted means any SES, race/ethnicity, and sex strata among 35-64- year-olds with substantially raised mortality (=1% per year). This R34 (n=150) is preparatory for a post-R34- Goal of an n=15,000 5-year RCT which would have adequate power to test the hypothesis of 20% mortality reduction. While the R34’s scope includes all 9 health goals, it focuses especially on AUD/HD, HIV risk and cardiovascular (CV) risk. The overall objective of this administrative supplement is to preserve the parent proposal’s intention to complement self-report measures used in screening and identification of AUD/HD with quantitative data. Specifically, we seek to include biomarker testing for alcohol consumption, Phosphatidylethanol (PEth) and Ethyl Glucuronide (EtG), at baseline and final (12 month) study time points. Inclusion of these biomarkers is invaluable, it not only provides a more comprehensive and objective assessment of alcohol consumption, reducing the potential for underreporting or inaccuracies, but also more accurately identifies high-risk individuals who may be susceptible to alcohol-related health complications. Their inclusion contributes significantly to our study's overarching goal of tailoring interventions to address the unique health needs of each participant, ultimately leading to a more effective, cost-effective, and targeted approach to reducing mortality in this population.