{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T18:04:12Z","timestamp":1784225052323,"version":"3.55.0"},"reference-count":85,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T00:00:00Z","timestamp":1780358400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Guangdong Basic Research Center of Excellence","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"Hainan Province Clinical Medical Center","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/501100004000","name":"Guangzhou Municipal Science and Technology Program key projects","doi-asserted-by":"publisher","award":["2025A04J7150"],"award-info":[{"award-number":["2025A04J7150"]}],"id":[{"id":"10.13039\/501100004000","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82371086"],"award-info":[{"award-number":["82371086"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82301253"],"award-info":[{"award-number":["82301253"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82571271"],"award-info":[{"award-number":["82571271"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2026A1515010675"],"award-info":[{"award-number":["2026A1515010675"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Guangdong Basic and Applied Basic Research Foundation","award":["2022A151511"],"award-info":[{"award-number":["2022A151511"]}]},{"name":"The Projects of Research Center for Sharp Vision at The Hong Kong Polytechnic University","award":["P0057931"],"award-info":[{"award-number":["P0057931"]}]},{"name":"The Health and Medical Research Fund-Research Fellowship Scheme","award":["07210207"],"award-info":[{"award-number":["07210207"]}]},{"name":"The Lumitin Vision to Brightness Research Funding for the Young and middle-aged Ophthalmologists","award":["BCF-KH-YK-20230803-03"],"award-info":[{"award-number":["BCF-KH-YK-20230803-03"]}]}],"content-domain":{"domain":["www.plosmedicine.org"],"crossmark-restriction":false},"short-container-title":["PLoS Med"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Retinal neurodegeneration is an early and independent feature of diabetic retinal disease and has been proposed as a window into the systemic neural consequences of diabetes, yet accessible molecular biomarkers and individualized prediction tools remain scarce. We aimed to identify circulating plasma protein signatures of diabetic retinal neurodegeneration (DRN) and to translate them into a clinically usable risk prediction system.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods and findings<\/jats:title>\n                    <jats:p>\n                      In this multi-cohort prospective observational study, we integrated high-throughput plasma proteomics with longitudinal optical coherence tomography (OCT) in two independent populations. The discovery cohort comprised 1,492 participants had baseline plasma proteomics and OCT, and 1,218 were followed with repeated OCT over 6 years in Guangzhou Diabetic Eye Study (GDES). DRN was quantified by the annualized OCT-derived retinal nerve fiber layer thinning rate. In multivariable analyses adjusted for age, sex, smoking, systolic blood pressure, HbA1c, and diabetes duration, we identified 71 plasma proteins associated with development and progression of DRN. These proteins mapped onto pathways governing inflammatory immune recruitment, extracellular matrix remodeling, and microvascular homeostasis, providing a plausible biological basis for DRN. We developed a proteomics-based DRN model (Pro-DRN) using eight machine learning (ML) algorithms, including XGBoost and LightGBM. In the independent test set, Pro-DRN achieved a C-index of 0.860, rising to 0.908 when integrated with clinical variables. Compared with six conventional models, Pro-DRN improved discrimination (\u0394C-index 0.137 to 0.159; all\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.001), reclassification (IDI 0.212 to 0.245; NRI 0.226 to 0.452; all\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.05). In the Hippisley model, the C-index increased from 0.739 (95% CI [0.670, 0.808]) to 0.898 (95% CI [0.858, 0.937]), with IDI 0.245 (95% CI [0.177, 0.318]), NRI 0.452 (95% CI [0.222, 0.673]) (both\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.001), and higher net benefit. The proteins most consistently driving model performance included ACTA2, COL6A3, and HSPG2. For clinical translation, we deployed the locked model as an interactive, web-based risk-assessment tool to support early DRN screening and longitudinal monitoring. Cross-ethnic external validation in UK Biobank (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009502; recruited 2006\u20132010) reproduced core protein signals and consistent effect directions, confirming robustness across populations. Principal methodological limitation lies in single time point proteomic assessment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>In this multi-cohort study, we present a proteomics- and ML\u2013based precision prediction system for DRN. Pro-DRN substantially enhanced early risk stratification beyond conventional clinical factors and may support targeted screening and timely neuroprotective interventions, advancing molecularly guided strategies for diabetic eye disease prevention.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pmed.1004868","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T17:21:14Z","timestamp":1780420874000},"page":"e1004868","update-policy":"https:\/\/doi.org\/10.1371\/journal.pmed.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Plasma proteomic signatures of early retinal neurodegeneration in diabetes: a multi-cohort study"],"prefix":"10.1371","volume":"23","author":[{"given":"Huangdong","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0268-9563","authenticated-orcid":true,"given":"Ziyu","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4330-7841","authenticated-orcid":true,"given":"Shaopeng","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijing","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9997-7396","authenticated-orcid":true,"given":"Shaoying","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuoyao","family":"Xin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2343-084X","authenticated-orcid":true,"given":"Lei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuoting","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0907-0614","authenticated-orcid":true,"given":"Shida","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyong","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5273-3332","authenticated-orcid":true,"given":"Wei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,6,2]]},"reference":[{"issue":"15","key":"pmed.1004868.ref001","doi-asserted-by":"crossref","first-page":"3789","DOI":"10.1016\/j.cell.2024.06.029","article-title":"Diabetes mellitus-progress and opportunities in the evolving epidemic","volume":"187","author":"ED Abel","year":"2024","journal-title":"Cell"},{"issue":"8003","key":"pmed.1004868.ref002","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1038\/s41586-024-07019-6","article-title":"Genetic drivers of heterogeneity in type 2 diabetes pathophysiology","volume":"627","author":"K Suzuki","year":"2024","journal-title":"Nature"},{"issue":"1","key":"pmed.1004868.ref003","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1038\/s41572-025-00646-x","article-title":"Diabetic retinal disease","volume":"11","author":"S Sivaprasad","year":"2025","journal-title":"Nat Rev Dis Primers"},{"issue":"17","key":"pmed.1004868.ref004","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1056\/NEJMra1909637","article-title":"Evaluation and care of patients with diabetic retinopathy","volume":"382","author":"LM Jampol","year":"2020","journal-title":"N Engl J Med"},{"issue":"4","key":"pmed.1004868.ref005","article-title":"Diabetic retinopathy preferred practice pattern(R)","volume":"132","author":"JI Lim","year":"2025","journal-title":"Ophthalmology"},{"issue":"11","key":"pmed.1004868.ref006","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.2337\/db24-0107","article-title":"Deciphering the connection between microvascular damage and neurodegeneration in early diabetic retinopathy","volume":"73","author":"Q Yang","year":"2024","journal-title":"Diabetes"},{"issue":"19","key":"pmed.1004868.ref007","article-title":"Retinal neurodegeneration may precede microvascular changes characteristic of diabetic retinopathy in diabetes mellitus","volume":"113","author":"EH Sohn","year":"2016","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"pmed.1004868.ref008","doi-asserted-by":"crossref","first-page":"6064","DOI":"10.1038\/s41467-024-50309-w","article-title":"Eye-brain connections revealed by multimodal retinal and brain imaging genetics","volume":"15","author":"B Zhao","year":"2024","journal-title":"Nat Commun"},{"issue":"10","key":"pmed.1004868.ref009","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1001\/jamaneurol.2018.1563","article-title":"Association of retinal neurodegeneration on optical coherence tomography with dementia: a population-based study","volume":"75","author":"U Mutlu","year":"2018","journal-title":"JAMA Neurol"},{"issue":"10","key":"pmed.1004868.ref010","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1001\/jamaneurol.2018.1578","article-title":"Association of retinal nerve fiber layer thinning with current and future cognitive decline: a study using optical coherence tomography","volume":"75","author":"F Ko","year":"2018","journal-title":"JAMA Neurol"},{"issue":"731","key":"pmed.1004868.ref011","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.adg4517","article-title":"Phenome- and genome-wide analyses of retinal optical coherence tomography images identify links between ocular and systemic health","volume":"16","author":"SM Zekavat","year":"2024","journal-title":"Sci Transl Med"},{"issue":"7981","key":"pmed.1004868.ref012","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1038\/s41586-023-06555-x","article-title":"A foundation model for generalizable disease detection from retinal images","volume":"622","author":"Y Zhou","year":"2023","journal-title":"Nature"},{"issue":"8","key":"pmed.1004868.ref013","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/S2213-8587(15)00136-9","article-title":"New ophthalmologic imaging techniques for detection and monitoring of neurodegenerative changes in diabetes: a systematic review","volume":"3","author":"EEB De Clerck","year":"2015","journal-title":"Lancet Diabetes Endocrinol"},{"issue":"1","key":"pmed.1004868.ref014","article-title":"Atlas of the plasma proteome in health and disease in 53,026 adults","volume":"188","author":"Y-T Deng","year":"2025","journal-title":"Cell"},{"issue":"6716","key":"pmed.1004868.ref015","doi-asserted-by":"crossref","DOI":"10.1126\/science.ads5749","article-title":"The revolution in high-throughput proteomics and AI","volume":"385","author":"EJ Topol","year":"2024","journal-title":"Science"},{"issue":"8042","key":"pmed.1004868.ref016","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1038\/s41586-024-08280-5","article-title":"\u03c0-HuB: the proteomic navigator of the human body","volume":"636","author":"F He","year":"2024","journal-title":"Nature"},{"issue":"22","key":"pmed.1004868.ref017","doi-asserted-by":"crossref","first-page":"4868","DOI":"10.1016\/j.cell.2023.09.012","article-title":"Liquid-biopsy proteomics combined with AI identifies cellular drivers of eye aging and disease in vivo","volume":"186","author":"J Wolf","year":"2023","journal-title":"Cell"},{"issue":"8052","key":"pmed.1004868.ref018","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1038\/s41586-025-08584-0","article-title":"Mass-spectrometry-based proteomics: from single cells to clinical applications","volume":"638","author":"T Guo","year":"2025","journal-title":"Nature"},{"issue":"10","key":"pmed.1004868.ref019","doi-asserted-by":"crossref","DOI":"10.1016\/j.cell.2025.03.013","article-title":"Human proteome distribution atlas for tissue-specific plasma proteome dynamics","volume":"188","author":"E Malmstr\u00f6m","year":"2025","journal-title":"Cell"},{"issue":"1","key":"pmed.1004868.ref020","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/s43587-024-00753-6","article-title":"Plasma proteomics identify biomarkers and undulating changes of brain aging","volume":"5","author":"W-S Liu","year":"2025","journal-title":"Nat Aging"},{"issue":"3","key":"pmed.1004868.ref021","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1038\/s41591-024-03483-9","article-title":"Integrating the environmental and genetic architectures of aging and mortality","volume":"31","author":"MA Argentieri","year":"2025","journal-title":"Nat Med"},{"issue":"6","key":"pmed.1004868.ref022","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1038\/s43587-025-00872-8","article-title":"Large-scale plasma proteomic profiling unveils diagnostic biomarkers and pathways for Alzheimer\u2019s disease","volume":"5","author":"G Heo","year":"2025","journal-title":"Nat Aging"},{"issue":"8","key":"pmed.1004868.ref023","doi-asserted-by":"crossref","first-page":"2703","DOI":"10.1038\/s41591-025-03798-1","article-title":"Plasma proteomics links brain and immune system aging with healthspan and longevity","volume":"31","author":"HS-H Oh","year":"2025","journal-title":"Nat Med"},{"issue":"6","key":"pmed.1004868.ref024","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1038\/s41591-024-03039-x","article-title":"Proteomic analysis of cardiorespiratory fitness for prediction of mortality and multisystem disease risks","volume":"30","author":"AS Perry","year":"2024","journal-title":"Nat Med"},{"issue":"7","key":"pmed.1004868.ref025","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1038\/s43587-024-00655-7","article-title":"Blood protein assessment of leading incident diseases and mortality in the UK Biobank","volume":"4","author":"DA Gadd","year":"2024","journal-title":"Nat Aging"},{"issue":"9","key":"pmed.1004868.ref026","doi-asserted-by":"crossref","first-page":"2450","DOI":"10.1038\/s41591-024-03164-7","article-title":"Proteomic aging clock predicts mortality and risk of common age-related diseases in diverse populations","volume":"30","author":"MA Argentieri","year":"2024","journal-title":"Nat Med"},{"issue":"9","key":"pmed.1004868.ref027","doi-asserted-by":"crossref","first-page":"2489","DOI":"10.1038\/s41591-024-03142-z","article-title":"Proteomic signatures improve risk prediction for common and rare diseases","volume":"30","author":"J Carrasco-Zanini","year":"2024","journal-title":"Nat Med"},{"issue":"7990","key":"pmed.1004868.ref028","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1038\/s41586-023-06802-1","article-title":"Organ aging signatures in the plasma proteome track health and disease","volume":"624","author":"HS-H Oh","year":"2023","journal-title":"Nature"},{"issue":"18","key":"pmed.1004868.ref029","doi-asserted-by":"crossref","first-page":"2819","DOI":"10.3390\/cells11182819","article-title":"Proteomic analysis of retinal mitochondria-associated ER membranes identified novel proteins of retinal degeneration in long-term diabetes","volume":"11","author":"JJ Wang","year":"2022","journal-title":"Cells"},{"issue":"3","key":"pmed.1004868.ref030","doi-asserted-by":"crossref","first-page":"505","DOI":"10.3390\/antiox11030505","article-title":"Vitreous humor proteome: targeting oxidative stress, inflammation, and neurodegeneration in vitreoretinal diseases","volume":"11","author":"FM Santos","year":"2022","journal-title":"Antioxidants (Basel)"},{"issue":"4","key":"pmed.1004868.ref031","doi-asserted-by":"crossref","DOI":"10.1167\/iovs.18-24122","article-title":"The proteomic landscape in the vitreous of patients with age-related and diabetic retinal disease","volume":"59","author":"C Schori","year":"2018","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"1","key":"pmed.1004868.ref032","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1038\/s41467-024-55035-x","article-title":"Photoreceptor metabolic window unveils eye-body interactions","volume":"16","author":"S Yang","year":"2025","journal-title":"Nat Commun"},{"issue":"1","key":"pmed.1004868.ref033","doi-asserted-by":"crossref","first-page":"6573","DOI":"10.1038\/s41467-023-42404-1","article-title":"Metabolic fingerprinting on retinal pigment epithelium thickness for individualized risk stratification of type 2 diabetes mellitus","volume":"14","author":"S Yang","year":"2023","journal-title":"Nat Commun"},{"issue":"7982","key":"pmed.1004868.ref034","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1038\/s41586-023-06563-x","article-title":"Large-scale plasma proteomics comparisons through genetics and disease associations","volume":"622","author":"GH Eldjarn","year":"2023","journal-title":"Nature"},{"issue":"7982","key":"pmed.1004868.ref035","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/s41586-023-06592-6","article-title":"Plasma proteomic associations with genetics and health in the UK Biobank","volume":"622","author":"BB Sun","year":"2023","journal-title":"Nature"},{"issue":"10","key":"pmed.1004868.ref036","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1001\/jamaophthalmol.2019.2537","article-title":"Longitudinal changes in the peripapillary retinal nerve fiber layer thickness of patients with type 2 diabetes","volume":"137","author":"HB Lim","year":"2019","journal-title":"JAMA Ophthalmol"},{"issue":"12","key":"pmed.1004868.ref037","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1167\/iovs.65.12.5","article-title":"Initial retinal nerve fiber layer loss and risk of diabetic retinopathy over a four-year period","volume":"65","author":"X Zhong","year":"2024","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"pmed.1004868.ref038","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.ajo.2024.08.039","article-title":"Retinal and choroidal phenotypes across novel subtypes of type 2 diabetes mellitus","volume":"269","author":"K Liu","year":"2025","journal-title":"Am J Ophthalmol"},{"issue":"12","key":"pmed.1004868.ref039","doi-asserted-by":"crossref","first-page":"2401","DOI":"10.1097\/IAE.0000000000003613","article-title":"Progressive peripapillary choroid thinning and retinal neurodegeneration in patients with diabetes: a 3-year cohort study","volume":"42","author":"S Zhang","year":"2022","journal-title":"Retina"},{"issue":"11","key":"pmed.1004868.ref040","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.1007\/s00125-022-05731-4","article-title":"Precision prognostics for the development of complications in diabetes","volume":"65","author":"C Schiborn","year":"2022","journal-title":"Diabetologia"},{"issue":"10","key":"pmed.1004868.ref041","doi-asserted-by":"crossref","first-page":"2525","DOI":"10.1007\/s00125-011-2257-7","article-title":"Individual risk assessment and information technology to optimise screening frequency for diabetic retinopathy","volume":"54","author":"T Aspelund","year":"2011","journal-title":"Diabetologia"},{"key":"pmed.1004868.ref042","doi-asserted-by":"crossref","DOI":"10.1136\/bmj.h5441","article-title":"Development and validation of risk prediction equations to estimate future risk of blindness and lower limb amputation in patients with diabetes: cohort study","volume":"351","author":"J Hippisley-Cox","year":"2015","journal-title":"BMJ"},{"issue":"2","key":"pmed.1004868.ref043","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1177\/1932296817706375","article-title":"Machine learning methods to predict diabetes complications","volume":"12","author":"A Dagliati","year":"2018","journal-title":"J Diabetes Sci Technol"},{"issue":"3","key":"pmed.1004868.ref044","doi-asserted-by":"crossref","first-page":"586","DOI":"10.2337\/dc17-2002","article-title":"Validation of risk equations for complications of type 2 diabetes (RECODe) using individual participant data from diverse longitudinal cohorts in the U.S","volume":"41","author":"S Basu","year":"2018","journal-title":"Diabetes Care"},{"issue":"1","key":"pmed.1004868.ref045","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1007\/s00125-020-05313-2","article-title":"Safety and cost-effectiveness of individualised screening for diabetic retinopathy: the ISDR open-label, equivalence RCT","volume":"64","author":"DM Broadbent","year":"2021","journal-title":"Diabetologia"},{"issue":"5","key":"pmed.1004868.ref046","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.2337\/dc12-0958","article-title":"Predicting macro- and microvascular complications in type 2 diabetes: the Japan Diabetes Complications Study\/the Japanese Elderly Diabetes Intervention Trial risk engine","volume":"36","author":"S Tanaka","year":"2013","journal-title":"Diabetes Care"},{"issue":"5","key":"pmed.1004868.ref047","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.2337\/dc22-1168","article-title":"Development and validation of a diabetic retinopathy risk stratification algorithm","volume":"46","author":"D Tarasewicz","year":"2023","journal-title":"Diabetes Care"},{"issue":"6","key":"pmed.1004868.ref048","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1007\/s00125-020-05134-3","article-title":"Prediction models for development of retinopathy in people with type 2 diabetes: systematic review and external validation in a Dutch primary care setting","volume":"63","author":"AA van der Heijden","year":"2020","journal-title":"Diabetologia"},{"issue":"7972","key":"pmed.1004868.ref049","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/s41586-023-06221-2","article-title":"Scientific discovery in the age of artificial intelligence","volume":"620","author":"H Wang","year":"2023","journal-title":"Nature"},{"issue":"4","key":"pmed.1004868.ref050","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/j.ophtha.2020.10.008","article-title":"Updating the staging system for diabetic retinal disease","volume":"128","author":"JK Sun","year":"2021","journal-title":"Ophthalmology"},{"issue":"9","key":"pmed.1004868.ref051","doi-asserted-by":"crossref","first-page":"2159","DOI":"10.2337\/dc22-0165","article-title":"Elevated retinol binding protein 3 concentrations are associated with decreased vitreous inflammatory cytokines, VEGF, and progression of diabetic retinopathy","volume":"45","author":"W Fickweiler","year":"2022","journal-title":"Diabetes Care"},{"issue":"1","key":"pmed.1004868.ref052","doi-asserted-by":"crossref","first-page":"136","DOI":"10.2337\/dc24-1260","article-title":"Reduced aqueous retinol-binding protein 3 concentration is associated with diabetic macular edema and progression of diabetic retinopathy","volume":"48","author":"T Chokshi","year":"2025","journal-title":"Diabetes Care"},{"issue":"499","key":"pmed.1004868.ref053","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aau6627","article-title":"Retinol binding protein 3 is increased in the retina of patients with diabetes resistant to diabetic retinopathy","volume":"11","author":"H Yokomizo","year":"2019","journal-title":"Sci Transl Med"},{"issue":"1","key":"pmed.1004868.ref054","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/s41584-018-0130-5","article-title":"Machine-learning-based patient-specific prediction models for knee osteoarthritis","volume":"15","author":"A Jamshidi","year":"2019","journal-title":"Nat Rev Rheumatol"},{"issue":"3","key":"pmed.1004868.ref055","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1093\/eurheartj\/ehz565","article-title":"Machine learning of clinical variables and coronary artery calcium scoring for the prediction of obstructive coronary artery disease on coronary computed tomography angiography: analysis from the CONFIRM registry","volume":"41","author":"SJ Al\u2019Aref","year":"2020","journal-title":"Eur Heart J"},{"issue":"7","key":"pmed.1004868.ref056","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.2337\/dc19-1743","article-title":"Predicting the risk of inpatient hypoglycemia with machine learning using electronic health records","volume":"43","author":"Y Ruan","year":"2020","journal-title":"Diabetes Care"},{"issue":"6","key":"pmed.1004868.ref057","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1001\/jamacardio.2021.0122","article-title":"Use of machine learning models to predict death after acute myocardial infarction","volume":"6","author":"R Khera","year":"2021","journal-title":"JAMA Cardiol"},{"issue":"6","key":"pmed.1004868.ref058","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1016\/j.cell.2021.01.015","article-title":"Precision medicine in 2030-seven ways to transform healthcare","volume":"184","author":"JC Denny","year":"2021","journal-title":"Cell"},{"issue":"4","key":"pmed.1004868.ref059","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1038\/s41574-020-00451-4","article-title":"Current understanding of the molecular and cellular pathology of diabetic retinopathy","volume":"17","author":"DA Antonetti","year":"2021","journal-title":"Nat Rev Endocrinol"},{"issue":"5","key":"pmed.1004868.ref060","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1016\/j.ophtha.2014.12.001","article-title":"Multimodal characterization of proliferative diabetic retinopathy reveals alterations in outer retinal function and structure","volume":"122","author":"GE Boynton","year":"2015","journal-title":"Ophthalmology"},{"key":"pmed.1004868.ref061","doi-asserted-by":"crossref","first-page":"103027","DOI":"10.1016\/j.redox.2024.103027","article-title":"Specific targeting of the NRF2\/\u03b2-TrCP axis promotes beneficial effects in NASH","volume":"69","author":"R Fern\u00e1ndez-Gin\u00e9s","year":"2024","journal-title":"Redox Biol"},{"issue":"2","key":"pmed.1004868.ref062","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/s41588-024-02052-7","article-title":"Integrative proteogenomic analysis identifies COL6A3-derived endotrophin as a mediator of the effect of obesity on coronary artery disease","volume":"57","author":"S Yoshiji","year":"2025","journal-title":"Nat Genet"},{"key":"pmed.1004868.ref063","doi-asserted-by":"crossref","first-page":"155629","DOI":"10.1016\/j.metabol.2023.155629","article-title":"High levels of intracellular endotrophin in adipocytes mediate COPII vesicle supplies to autophagosome to impair autophagic flux and contribute to systemic insulin resistance in obesity","volume":"145","author":"J Oh","year":"2023","journal-title":"Metabolism"},{"issue":"1","key":"pmed.1004868.ref064","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s40246-025-00730-z","article-title":"Exploring the hepatic-ophthalmic axis through immune modulation and cellular dynamics in diabetic retinopathy and non-alcoholic fatty liver disease","volume":"19","author":"S Zhang","year":"2025","journal-title":"Hum Genomics"},{"issue":"12","key":"pmed.1004868.ref065","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.186836","article-title":"The distal nephron biomarkers associate with diabetic kidney disease progression","volume":"10","author":"CL Tamargo","year":"2025","journal-title":"JCI Insight"},{"issue":"3","key":"pmed.1004868.ref066","doi-asserted-by":"crossref","DOI":"10.1172\/JCI139927","article-title":"Biomarkers of inflammation and repair in kidney disease progression","volume":"131","author":"J Puthumana","year":"2021","journal-title":"J Clin Invest"},{"issue":"3","key":"pmed.1004868.ref067","doi-asserted-by":"crossref","first-page":"381","DOI":"10.2337\/dc24-1696","article-title":"Large-scale plasma proteomics improves prediction of peripheral artery disease in individuals with type 2 diabetes: a prospective cohort study","volume":"48","author":"H Yu","year":"2025","journal-title":"Diabetes Care"},{"issue":"1","key":"pmed.1004868.ref068","doi-asserted-by":"crossref","first-page":"7720","DOI":"10.1038\/s41467-023-43125-1","article-title":"Choroidal and retinal thinning in chronic kidney disease independently associate with eGFR decline and are modifiable with treatment","volume":"14","author":"TE Farrah","year":"2023","journal-title":"Nat Commun"},{"issue":"2","key":"pmed.1004868.ref069","doi-asserted-by":"crossref","first-page":"273","DOI":"10.2337\/dc18-1809","article-title":"Retinopathy and RAAS activation: results from the Canadian Study of Longevity in Type 1 Diabetes","volume":"42","author":"JA Lovshin","year":"2019","journal-title":"Diabetes Care"},{"issue":"5","key":"pmed.1004868.ref070","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1016\/j.ophtha.2015.01.001","article-title":"Retinal nerve fiber layer loss is associated with urinary albumin excretion in patients with type 2 diabetes","volume":"122","author":"JA Choi","year":"2015","journal-title":"Ophthalmology"},{"issue":"1","key":"pmed.1004868.ref071","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1186\/s12916-021-02064-8","article-title":"Renal function and lipid metabolism are major predictors of circumpapillary retinal nerve fiber layer thickness-the LIFE-Adult Study","volume":"19","author":"FG Rauscher","year":"2021","journal-title":"BMC Med"},{"key":"pmed.1004868.ref072","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.ajo.2023.10.005","article-title":"Impacts of Chronic kidney disease on retinal neurodegeneration: a cross-cohort analysis","volume":"258","author":"X Guo","year":"2024","journal-title":"Am J Ophthalmol"},{"key":"pmed.1004868.ref073","doi-asserted-by":"crossref","first-page":"105592","DOI":"10.1016\/j.neubiorev.2024.105592","article-title":"The usefulness of the retina for identifying people with type 2 diabetes with prodromal stages of dementia","volume":"159","author":"A Ciudin","year":"2024","journal-title":"Neurosci Biobehav Rev"},{"issue":"12","key":"pmed.1004868.ref074","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.2337\/db23-0025","article-title":"Structural and metabolic retinal changes associated with mild cognitive impairment in type 2 diabetes","volume":"72","author":"FN Pedersen","year":"2023","journal-title":"Diabetes"},{"issue":"1","key":"pmed.1004868.ref075","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.tem.2021.10.008","article-title":"Common pathways in dementia and diabetic retinopathy: understanding the mechanisms of diabetes-related cognitive decline","volume":"33","author":"K Little","year":"2022","journal-title":"Trends Endocrinol Metab"},{"issue":"1","key":"pmed.1004868.ref076","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s40478-018-0654-6","article-title":"Optic nerve thinning and neurosensory retinal degeneration in the rTg4510 mouse model of frontotemporal dementia","volume":"7","author":"IF Harrison","year":"2019","journal-title":"Acta Neuropathol Commun"},{"issue":"1","key":"pmed.1004868.ref077","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1186\/s13195-019-0542-8","article-title":"Retinal thinning of inner sub-layers is associated with cortical atrophy in a mouse model of Alzheimer\u2019s disease: a longitudinal multimodal in vivo study","volume":"11","author":"S Chiquita","year":"2019","journal-title":"Alzheimers Res Ther"},{"issue":"11","key":"pmed.1004868.ref078","doi-asserted-by":"crossref","first-page":"3926","DOI":"10.2337\/db13-1673","article-title":"Neuroretinal dysfunction with intact blood-retinal barrier and absent vasculopathy in type 1 diabetes","volume":"63","author":"A Reis","year":"2014","journal-title":"Diabetes"},{"issue":"1","key":"pmed.1004868.ref079","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1186\/s12883-021-02215-7","article-title":"Study of the collagen type VI alpha 3 (COL6A3) gene in Parkinson\u2019s disease","volume":"21","author":"C-Y Jin","year":"2021","journal-title":"BMC Neurol"},{"issue":"8","key":"pmed.1004868.ref080","doi-asserted-by":"crossref","first-page":"2578","DOI":"10.1038\/s41591-025-03831-3","article-title":"Disruption of the cerebrospinal fluid-plasma protein balance in cognitive impairment and aging","volume":"31","author":"A Farinas","year":"2025","journal-title":"Nat Med"},{"issue":"2","key":"pmed.1004868.ref081","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1038\/s41591-023-02702-z","article-title":"A deep learning system for predicting time to progression of diabetic retinopathy","volume":"30","author":"L Dai","year":"2024","journal-title":"Nat Med"},{"issue":"10","key":"pmed.1004868.ref082","doi-asserted-by":"crossref","first-page":"2886","DOI":"10.1038\/s41591-024-03139-8","article-title":"Integrated image-based deep learning and language models for primary diabetes care","volume":"30","author":"J Li","year":"2024","journal-title":"Nat Med"},{"key":"pmed.1004868.ref083","article-title":"Optimal frequency of retinopathy screening in adolescents with type 1 diabetes \u2013 Markov modeling approach based on 30 years of data","author":"AS Januszewski","year":"2022","journal-title":"Diabetes Care"},{"issue":"2","key":"pmed.1004868.ref084","doi-asserted-by":"crossref","first-page":"457","DOI":"10.2337\/db18-0682","article-title":"Effects of topically administered neuroprotective drugs in early stages of diabetic retinopathy: results of the EUROCONDOR clinical trial","volume":"68","author":"R Sim\u00f3","year":"2019","journal-title":"Diabetes"},{"issue":"5","key":"pmed.1004868.ref085","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1001\/jamaneurol.2025.0353","article-title":"GLP-1RA and SGLT2i medications for Type 2 diabetes and alzheimer disease and related dementias","volume":"82","author":"H Tang","year":"2025","journal-title":"JAMA Neurol"}],"updated-by":[{"DOI":"10.1371\/journal.pmed.1005180","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000}}],"container-title":["PLOS Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pmed.1004868","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T12:10:17Z","timestamp":1782475817000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pmed.1004868"}},"subtitle":[],"editor":[{"given":"Weiping","family":"Jia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,6,2]]},"references-count":85,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6,2]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pmed.1004868","relation":{},"ISSN":["1549-1676"],"issn-type":[{"value":"1549-1676","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,2]]}}}