OphAgent: A Generalisable Ophthalmic Agentic System for Global Eye Care

OphAgent: A Generalisable Ophthalmic Agentic System for Global Eye Care | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Biological Sciences - Article OphAgent: A Generalisable Ophthalmic Agentic System for Global Eye Care Tien Yin Wong, Lie Ju, Jinyuan Wang, Zhonghua Wang, Yukun Zhou, and 67 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9189179/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Artificial intelligence holds the potential to transform ophthalmic assessment, yet its translation into clinical practice remains hindered by its limited ability to perform complex reasoning, utilize specialized tools, or provide transparent justifications. We introduce OphAgent, a multi-agent framework powered by large language models that mimics clinical workflows through dynamic diagnostic planning, knowledge base consultation, and multimodal image interpretation via structured inter-agent debate. Validated across four imaging modalities, 30+ conditions, and 11 diverse real-world datasets, OphAgent achieved 85% average accuracy in retinal diagnosis, surpassing current state-of-the-art multimodal large language models. In a large-scale global reader study with 311 ophthalmologists from 86 centres across 22 countries, spanning seven languages and settings from tertiary hospitals to resource-limited clinics, OphAgent improved diagnostic accuracy by up to 20% across 14 clinically significant tasks. Critically, these gains remained stable across geographic regions, experience levels, and languages, demonstrating robustness, fairness, and generalisability. OphAgent exemplifies an emerging paradigm where medical AI evolves from isolated prediction to collaborative clinical reasoning. By integrating reasoned clinical consultation with state-of-the-art diagnostic performance, the framework offers a scalable pathway toward more equitable, transparent, and trustworthy AI-enabled clinical decision support, with the potential to extend expert-level ophthalmic assessment across diverse healthcare settings. Health sciences/Diseases/Eye diseases Health sciences/Health care/Medical imaging Health sciences/Medical research/Translational research Full Text Additional Declarations Yes there is potential Competing Interest. Z.G. is on the scientific advisory board and a consultant for Optain Health and Airdoc. P.A.K. is a co-founder of Cascader Ltd. and has acted as a consultant for Skleo Health, insitro, Retina Consultants of America, Roche, Boehringer-Ingelheim, and Bitfount, and is an equity owner in Big Picture Medical. He has received speaker fees from Zeiss, Théa, Apellis, and Roche, travel support from Bayer and Roche, and grant funding from Roche. He has attended advisory boards for Topcon, Bayer, Boehringer-Ingelheim, and Roche. T.Y.W. is a consultant for AbbVie Pte Ltd., Aldropika Therapeutics, Bayer, Boehringer Ingelheim, Zeiss, Genentech, Iveric Bio, Novartis, Opthea Limited, Plano, Quaerite Biopharm Research Ltd., Roche, Sanofi, and Shanghai Henlius. He is an inventor, holds patents, and is a co-founder of EyRiS and Visre, which develop digital solutions for eye diseases. All potential conflicts of interest are managed under institutional policies of SingHealth and Tsinghua University. A.B. is a consultant for Théa. J.B.J. holds European patents EP 3 271 392 and WO 2025/056713 A1, Japanese patent JP 2021-119187, and U.S. Patent No. US 12,024,557 B2. J.H. has received travel support from Bayer and Roche, and speaker fees from Zeiss, Roche, and Bayer. L.M.Z. has received grants and nonfinancial support (equipment) from Heidelberg Engineering, Carl Zeiss Meditec, Optovue, Topcon, ICare Inc., and Optomed Inc., has served as a consultant for Topcon Medical Systems, and is a co-founder, inventor, board member, and equity holder of AISight Health Inc. F.A. is a founder of and holds equity in SIMA Surgical Intelligence Inc. S.P.J. holds European patent EP 3 271 392, Japanese patent JP 2021-119187, and U.S. Patent No. US 12,024,557 B2: Agents for use in the therapeutic or prophylactic treatment of myopia or hyperopia; and European patent application WO 2025/056713 A1: EGFR Antagonists for the treatment of diseases involving unwanted migration, proliferation, and metaplasia of retinal pigment epithelium (RPE) cells. M.H. is the Medical Officer for Optain Health. J.Z. is a Consultant for AbbVie, Adverum, Alcon, Alimera Sciences, Bausch & Lomb, Bayer, Brill Pharma, DORC, Esteve, Novartis, Oxular, Preceyes, Roche, Sandoz, Topcon, ULMA Medical Technologies and Zeiss. T.C. is consultant for Bayer, DORC and Horus and has received travel grant from Essilor and Roche. The remaining authors declare no competing interests. Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9189179","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":610574478,"identity":"13076e86-601d-4d1a-87e6-f8765d86e67d","order_by":0,"name":"Tien Yin 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18:12:43","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":14727729,"visible":true,"origin":"","legend":"Article File","description":"","filename":"OphAgentmanuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9189179/v1_covered_bc14f5d6-ca99-4e74-8e4c-16780cc8d776.pdf"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nZ.G. is on the scientific advisory board and a consultant for Optain Health and Airdoc. P.A.K. is a co-founder of Cascader Ltd. and has acted as a consultant for Skleo Health, insitro, Retina Consultants of America, Roche, Boehringer-Ingelheim, and Bitfount, and is an equity owner in Big Picture Medical. He has received speaker fees from Zeiss, Théa, Apellis, and Roche, travel support from Bayer and Roche, and grant funding from Roche. He has attended advisory boards for Topcon, Bayer, Boehringer-Ingelheim, and Roche. T.Y.W. is a consultant for AbbVie Pte Ltd., Aldropika Therapeutics, Bayer, Boehringer Ingelheim, Zeiss, Genentech, Iveric Bio, Novartis, Opthea Limited, Plano, Quaerite Biopharm Research Ltd., Roche, Sanofi, and Shanghai Henlius. He is an inventor, holds patents, and is a co-founder of EyRiS and Visre, which develop digital solutions for eye diseases. All potential conflicts of interest are managed under institutional policies of SingHealth and Tsinghua University. A.B. is a consultant for Théa. J.B.J. holds European patents EP 3 271 392 and WO 2025/056713 A1, Japanese patent JP 2021-119187, and U.S. Patent No. US 12,024,557 B2. J.H. has received travel support from Bayer and Roche, and speaker fees from Zeiss, Roche, and Bayer. L.M.Z. has received grants and nonfinancial support (equipment) from Heidelberg Engineering, Carl Zeiss Meditec, Optovue, Topcon, ICare Inc., and Optomed Inc., has served as a consultant for Topcon Medical Systems, and is a co-founder, inventor, board member, and equity holder of AISight Health Inc. F.A. is a founder of and holds equity in SIMA Surgical Intelligence Inc. S.P.J. holds European patent EP 3 271 392, Japanese patent JP 2021-119187, and U.S. Patent No. US 12,024,557 B2: Agents for use in the therapeutic or prophylactic treatment of myopia or hyperopia; and European patent application WO 2025/056713 A1: EGFR Antagonists for the treatment of diseases involving unwanted migration, proliferation, and metaplasia of retinal pigment epithelium (RPE) cells. M.H. is the Medical Officer for Optain Health. J.Z. is a Consultant for AbbVie, Adverum, Alcon, Alimera Sciences, Bausch \u0026 Lomb, Bayer, Brill Pharma, DORC, Esteve, Novartis, Oxular, Preceyes, Roche, Sandoz, Topcon, ULMA Medical Technologies and Zeiss. T.C. is consultant for Bayer, DORC and Horus and has received travel grant from Essilor and Roche. The remaining authors declare no competing interests.","formattedTitle":"OphAgent: A Generalisable Ophthalmic Agentic System for Global Eye Care","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-9189179/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9189179/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Artificial intelligence holds the potential to transform ophthalmic assessment, yet its translation into clinical practice remains hindered by its limited ability to perform complex reasoning, utilize specialized tools, or provide transparent justifications. We introduce OphAgent, a multi-agent framework powered by large language models that mimics clinical workflows through dynamic diagnostic planning, knowledge base consultation, and multimodal image interpretation via structured inter-agent debate. Validated across four imaging modalities, 30+ conditions, and 11 diverse real-world datasets, OphAgent achieved 85% average accuracy in retinal diagnosis, surpassing current state-of-the-art multimodal large language models. In a large-scale global reader study with 311 ophthalmologists from 86 centres across 22 countries, spanning seven languages and settings from tertiary hospitals to resource-limited clinics, OphAgent improved diagnostic accuracy by up to 20% across 14 clinically significant tasks. Critically, these gains remained stable across geographic regions, experience levels, and languages, demonstrating robustness, fairness, and generalisability. OphAgent exemplifies an emerging paradigm where medical AI evolves from isolated prediction to collaborative clinical reasoning. By integrating reasoned clinical consultation with state-of-the-art diagnostic performance, the framework offers a scalable pathway toward more equitable, transparent, and trustworthy AI-enabled clinical decision support, with the potential to extend expert-level ophthalmic assessment across diverse healthcare settings.","manuscriptTitle":"OphAgent: A Generalisable Ophthalmic Agentic System for Global Eye Care","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-14 18:12:11","doi":"10.21203/rs.3.rs-9189179/v1","editorialEvents":[],"status":"published","journal":{"display":false,"email":"[email protected]","identity":"nature","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nature","sideBox":"Learn more about [Nature](http://www.nature.com/nature/)","snPcode":"","submissionUrl":"","title":"Nature","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"5ef0023c-9259-4127-abac-5d4dd32a64ee","owner":[],"postedDate":"April 14th, 2026","published":true,"recentEditorialEvents":[{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-05-11T05:31:40+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-05-07T10:36:00+00:00","index":4,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-05-04T10:50:57+00:00","index":3,"fulltext":"This content is not available."}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":64959947,"name":"Health sciences/Diseases/Eye diseases"},{"id":64959948,"name":"Health sciences/Health care/Medical imaging"},{"id":64959949,"name":"Health sciences/Medical research/Translational research"}],"tags":[],"updatedAt":"2026-04-14T18:12:12+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-14 18:12:11","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9189179","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9189179","identity":"rs-9189179","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}