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In this work, we propose a novel clustering approach to partition US counties into different clusters based on similarities in their SDOH\u2013CVD associations, providing a data-driven regional partition to inform region-specific interventions. To enhance the interpretability of the clustering result, we adopt the SDOH framework from the Agency for Healthcare Research and Quality to group SDOH variables into 5 domains, and build on this to develop an SDOH-domain-aware regularization (SDAR), which identifies the most influential variables within each SDOH domain tailored for each cluster. By embedding SDAR into the clustering process via a regularized expectation-maximization algorithm, our approach enables simultaneous clustering, parameter estimation, and variable selection, thereby mitigating error propagation across stages. We validate the method through theoretical developments and simulations. Applied to a national longitudinal dataset of US county-level SDOH and CVD mortality, our approach discovered 7 distinct clusters, each characterized by a unique set of SDOH drivers spanning multiple SDOH domains. Notably, 2 of these clusters exhibited elevated CVD mortality and inverse SDOH\u2013CVD associations compared to the other 5. These findings reveal complex regional heterogeneity in SDOH\u2013CVD associations, yielding insights to guide multi-domain, region-specific strategies for CVD management.<\/jats:p>","DOI":"10.1093\/biostatistics\/kxag042","type":"journal-article","created":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T11:40:29Z","timestamp":1789818029000},"source":"Crossref","is-referenced-by-count":0,"title":["Disentangling regional heterogeneity in social determinants\u2013cardiovascular disease associations in the US: a high-dimensional county clustering approach"],"prefix":"10.1093","volume":"27","author":[{"given":"Fangzhi","family":"Luo","sequence":"first","affiliation":[{"name":"University of Georgia Department of Epidemiology and Biostatistics, College of Public Health, , 101 Buck Road , Athens, GA 30602,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heejung","family":"Son","sequence":"additional","affiliation":[{"name":"University of South 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