A predictive atlas of disease onset from retinal fundus photographs

Early detection of high-risk individuals is crucial for healthcare systems to cope with changing demographics and an ever-increasing patient population. Images of the retinal fundus are a non- invasive, low-cost examination routinely collected and potentially scalable beyond ophthalmology. Prior work demonstrated the potential of retinal images for risk assessment for common cardiometabolic diseases, but it remains unclear whether this potential extends to a broader range of human diseases. Here, we extended a retinal foundation model (RETFound) to systematically explore the predictive potential of retinal images as a low-cost screening strategy for disease onset across >750 incident diseases in >60,000 individuals. For more than a third (n=308) of the diseases, we demonstrated improved discriminative performance compared to readily available patient characteristics. This included 281 diseases outside of ophthalmology, such as type 2 diabetes (Delta C-Index: UK Biobank +0.073 (0.068, 0.079)) or chronic obstructive pulmonary disease (Delta C-Index: UK Biobank +0.047 (0.039, 0.054)), showcasing the potential of retinal images to complement screening strategies more widely. Moreover, we externally validated these findings in 7,248 individuals from the EPIC-Norfolk Eye Study. Notably, retinal information did not improve the prediction for the onset of cardiovascular diseases compared to established primary prevention scores, demonstrating the need for rigorous benchmarking and disease-agnostic efforts to design cost-efficient screening strategies to improve population health. We demonstrated that predictive improvements were attributable to retinal vascularisation patterns and less obvious features, such as eye colour or lens morphology, by extracting image attributions from risk models and performing genome-wide association studies, respectively. Genetic findings further highlighted commonalities between eye-derived risk estimates and complex disorders, including novel loci, such as IMAP1, for iron homeostasis. In conclusion, we present the first comprehensive evaluation of predictive information derived from retinal fundus photographs, illustrating the potential and limitations of easily accessible and low-cost retinal images for risk assessment across common and rare diseases. ### Competing Interest Statement U.L. received grants from Bayer, Novartis, Amgen, consulting fees from Bayer, Sanofi, Amgen, Novartis, Daichy Sankyo, and honoraria from Novartis, Sanofi, Bayer, Amgen, Daichy Sankyo. J.D. received consulting fees from GENinCode UK Ltd, honoraria from Amgen, Boehringer Ingelheim, Merck, Pfizer, Aegerion, Novartis, Sanofi, Takeda, Novo Nordisk, Bayer, and is chief medical advisor to Our Future Health. R.E. received honoraria from Sanofi and consulting fees from Boehringer Ingelheim. APK has acted as a paid consultant or lecturer to Abbvie, Aerie, Allergan, Google Health, Heidelberg Engineering, Novartis, Reichert, Santen, Thea and Topcon. PJF received personal fees from Allergan, Carl Zeiss, Google/DeepMind and Santen, outside the submitted work. All other authors do declare no competing interests. O.Z. received grants from Bayer, Boehringer-Ingelheim, Novartis, consulting fees from Allergan/AbbVie, Bayer, Boehringer-Ingelheim, Novartis, Omeicos, Oxular, Roche, SamChungDang Pharma, and honoraria from Allergan/AbbVie, Bayer, Boehringer-Ingelheim, Novartis, Roche. ### Funding Statement The EPIC-Norfolk study (DOI 10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1 and MC-UU_12015/1) and Cancer Research UK (C864/A14136). This project has been funded by the Charite - Universitaetsmedizin Berlin and the Einstein Foundation Berlin, through the Einstein BIH Visiting Fellowship awarded to J.D. The study has been supported by the BMBF-funded Medical Informatics Initiative (HiGHmed, 01ZZ1802A29 - 01ZZ1802Z) and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) Project-ID 437531118 SFB 1470. APK is supported by a UK Research and Innovation Future Leaders Fellowship, an Alcon Research Institute Young Investigator Award and a Lister Institute for Preventive Medicine Award. This research was supported by the NIHR Biomedical Research Centre (BRC) at Moorfields Eye Hospital and the UCL Institute of Ophthalmology. PJF and APK received salary support from the NIHR BRC at Moorfields Eye Hospital. PJF received an unrestricted grant from the Alcon Research Institute, and support from the Richard Desmond Charitable Trust. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This research was conducted using data from UK Biobank, a major biomedical database (https://www.ukbiobank.ac.uk/) via application no. 51157 and 44448. Further, we used data from the EPIC-Norfolk (DOI 10.22025/2019.10.105.00004) study via the application of APK. Both studies have received ethical approval from their respective institutional review boards and have obtained informed consent from participants. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes UK Biobank data, including retinal fundus photographs, are available to bona fide researchers upon application at http://www.ukbiobank.ac.uk/using-the-resource/. Detailed information on predictors and endpoints used in this study is presented in Supplementary Tables 2-3. EPIC-Norfolk data are available for the scientific community, and researchers are invited to apply for data access at https://www.epic- norfolk.org.uk/for-researchers/data-sharing/data-requests/.