{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T19:57:05Z","timestamp":1789588625182,"version":"build-2803163510"},"posted":{"date-parts":[[2025,8,13]]},"group-title":"Health Informatics","reference-count":155,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T00:00:00Z","timestamp":1755043200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,8,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Disease heterogeneity and commonality pose significant challenges to precision medicine, as traditional approaches frequently focus on single disease entities and overlook shared mechanisms across conditions\n                  <jats:sup>1<\/jats:sup>\n                  . Inspired by pan-cancer\n                  <jats:sup>2<\/jats:sup>\n                  and multi-organ research\n                  <jats:sup>3<\/jats:sup>\n                  , we introduce the concept of \u201cpan-disease\u201d to investigate the heterogeneity and shared etiology in brain, eye, and heart diseases. Leveraging individual-level data from 129,340 participants, as well as summary-level data from the MULTI consortium, we applied a weakly-supervised deep learning model (Surreal-GAN\n                  <jats:sup>4,5<\/jats:sup>\n                  ) to multi-organ imaging, genetic, proteomic, and RNA-seq data, identifying 11 AI-derived biomarkers \u2013 called Multi-organ AI Endophenotypes (MAEs) \u2013 for the brain (Brain 1\u20136), eye (Eye 1\u20133), and heart (Heart 1\u20132), respectively. We found Brain 3 to be a risk factor for Alzheimer\u2019s disease (AD) progression and mortality, whereas Brain 5 was protective against AD progression. Crucially, in data from an anti-amyloid AD drug (solanezumab\n                  <jats:sup>6<\/jats:sup>\n                  ), heterogeneity in cognitive decline trajectories was observed across treatment groups. At week 240, patients with lower brain 1-3 expression had slower cognitive decline, whereas patients with higher expression had faster cognitive decline. A multi-layer causal pathway pinpointed Brain 1 as a mediational endophenotype\n                  <jats:sup>7<\/jats:sup>\n                  linking the FLRT2 protein to migraine, exemplifying novel therapeutic targets and pathways. Additionally, genes associated with Eye 1 and Eye 3 were enriched in cancer drug-related gene sets with causal links to specific cancer types and proteins. Finally, Heart 1 and Heart 2 had the highest mortality risk and unique medication history profiles, with Heart 1 showing favorable responses to antihypertensive medications and Heart 2 to digoxin treatment. The 11 MAEs provide novel AI dimensional representations for precision medicine and highlight the potential of AI-driven patient stratification for disease risk monitoring, clinical trials, and drug discovery.\n                <\/jats:p>","DOI":"10.1101\/2025.08.09.25333350","type":"posted-content","created":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T00:10:46Z","timestamp":1755130246000},"source":"Crossref","is-referenced-by-count":1,"title":["Multi-organ AI Endophenotypes Chart the Heterogeneity of Pan-disease in the Brain, Eye, and Heart"],"prefix":"10.64898","author":[{"name":"The MULTI consortium","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleix","family":"Boquet-Pujadas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippos","family":"Anagnostakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhijian","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3107-5550","authenticated-orcid":false,"given":"Ye Ella","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Duggan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guray","family":"Erus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dhivya","family":"Srinivasan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cassandra M.","family":"Joynes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjia","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Praveen J.","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5989-9853","authenticated-orcid":false,"given":"Keenan A.","family":"Walker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Zalesky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christos","family":"Davatzikos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2077-3070","authenticated-orcid":false,"given":"Junhao","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025081601551049000_2025.08.09.25333350v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41551-025-01412-w"},{"key":"2025081601551049000_2025.08.09.25333350v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-1969-6"},{"key":"2025081601551049000_2025.08.09.25333350v1.3","doi-asserted-by":"publisher","DOI":"10.1101\/2025.01.04.25319995"},{"key":"2025081601551049000_2025.08.09.25333350v1.4","unstructured":"Yang, Z. , Wen, J. & Davatzikos, C. 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