{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T19:22:19Z","timestamp":1764962539726,"version":"3.46.0"},"reference-count":25,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T00:00:00Z","timestamp":1764806400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"JSPS KAKENHI","doi-asserted-by":"publisher","award":["21K09751"],"award-info":[{"award-number":["21K09751"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Sensors"],"abstract":"<jats:p>The relationship between retinal images and intraocular cytokine profiles remains largely unexplored, and no prior work has systematically compared fundus- and OCT-based deep learning models for cytokine prediction. We aimed to predict intraocular cytokine concentrations using color fundus photographs (CFP) and retinal optical coherence tomography (OCT) with deep learning. Our pipeline consisted of image preprocessing, convolutional neural network\u2013based feature extraction, and regression modeling for each cytokine. Deep learning was implemented using AutoGluon, which automatically explored multiple architectures and converged on ResNet18, reflecting the small dataset size. Four approaches were tested: (1) CFP alone, (2) CFP plus demographic\/clinical features, (3) OCT alone, and (4) OCT plus these features. Prediction performance was defined as the mean coefficient of determination (R2) across 34 cytokines, and differences were evaluated using paired two-tailed t-tests. We used data from 139 patients (152 eyes) and 176 aqueous humor samples. The cohort consisted of 85 males (61%) with a mean age of 73 (SD 9.8). Diseases included 64 exudative age-related macular degeneration, 29 brolucizumab-associated endophthalmitis, 19 cataract surgeries, 15 retinal vein occlusion, and 8 diabetic macular edema. Prediction performance was generally poor, with mean R2 values below zero across all approaches. The CFP-only model (\u20130.19) outperformed CFP plus demographics (\u201324.1; p = 0.0373), and the OCT-only model (\u20130.18) outperformed OCT plus demographics (\u201314.7; p = 0.0080). No significant difference was observed between CFP and OCT (p = 0.9281). Notably, VEGF showed low predictability (31st with CFP, 12th with OCT).<\/jats:p>","DOI":"10.3390\/s25237382","type":"journal-article","created":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T18:42:02Z","timestamp":1764960122000},"page":"7382","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Intraocular Cytokine Level Prediction from Fundus Images and Optical Coherence Tomography"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5331-4730","authenticated-orcid":false,"given":"Hidenori","family":"Takahashi","sequence":"first","affiliation":[{"name":"Center for Cyber Medicine Research, University of Tsukuba, Tsukuba 305-8575, Japan"},{"name":"Department of Ophthalmology, Jichi Medical University, Shimotsuke 329-0498, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taiki","family":"Tsuge","sequence":"additional","affiliation":[{"name":"DeepEyeVision Inc., Shimotsuke 329-0498, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yusuke","family":"Kondo","sequence":"additional","affiliation":[{"name":"DeepEyeVision Inc., Shimotsuke 329-0498, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuo","family":"Yanagi","sequence":"additional","affiliation":[{"name":"Department of Visual Reconstructive Surgery, Yokohama City University, Yokohama 232-0024, Japan"},{"name":"Retina Research Group, Singapore Eye Research Institute, Singapore 168751, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4577-8169","authenticated-orcid":false,"given":"Satoru","family":"Inoda","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Jichi Medical University, Shimotsuke 329-0498, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shohei","family":"Morikawa","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Tsukuba, Tsukuba 305-8575, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7289-5016","authenticated-orcid":false,"given":"Yuki","family":"Senoo","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Nihon University, Tokyo 173-8610, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1132-6148","authenticated-orcid":false,"given":"Toshikatsu","family":"Kaburaki","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Jichi Medical University, Shimotsuke 329-0498, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9071-7018","authenticated-orcid":false,"given":"Tetsuro","family":"Oshika","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Tsukuba, Tsukuba 305-8575, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshihiko","family":"Yamasaki","sequence":"additional","affiliation":[{"name":"Department of Technology, the University of Tokyo, Tokyo 113-8656, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,4]]},"reference":[{"key":"ref_1","first-page":"1929","article-title":"Subfoveal Fibrovascular Membranes in Age-Related Macular Degeneration Express Vascular Endothelial Growth Factor","volume":"37","author":"Kvanta","year":"1996","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/S0002-9394(01)01269-7","article-title":"Increased Levels of Vascular Endothelial Growth Factor and Interleukin-6 in the Aqueous Humor of Diabetics with Macular Edema","volume":"133","author":"Funatsu","year":"2002","journal-title":"Am. J. Ophthalmol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1038\/sj.eye.6702498","article-title":"Aqueous Humour Levels of Cytokines Are Correlated with Vitreous Levels and Severity of Macular Oedema in Branch Retinal Vein Occlusion","volume":"22","author":"Noma","year":"2008","journal-title":"Eye"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1055\/s-2000-5803","article-title":"Increased Levels of Platelet-Derived Growth Factor in Vitreous Fluid of Patients with Proliferative Diabetic Retinopathy","volume":"108","author":"Freyberger","year":"2000","journal-title":"Exp. Clin. Endocrinol. Diabetes"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.ajo.2011.10.016","article-title":"Incidence of Legal Blindness from Age-Related Macular Degeneration in Denmark: Year 2000 to 2010","volume":"153","author":"Bloch","year":"2012","journal-title":"Am. J. Ophthalmol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Park, Y.G., Park, W.K., Kim, R.Y., Kim, M., and Park, Y.H. (2020). Serial Changes in the Aqueous IL-10 Level after Intravitreal Methotrexate Injection as an Indicator of Primary Vitreoretinal Lymphoma Recurrence. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-73111-2"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1016\/j.ophtha.2021.01.019","article-title":"Machine Learning Approach for Intraocular Disease Prediction Based on Aqueous Humor Immune Mediator Profiles","volume":"128","author":"Nezu","year":"2021","journal-title":"Ophthalmology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1167\/iovs.66.3.38","article-title":"An Approach to Predict Intraocular Diseases by Machine Learning Based on Vitreous Humor Immune Mediator Profile","volume":"66","author":"Sugawara","year":"2025","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"102216","DOI":"10.1016\/j.xcrm.2025.102216","article-title":"AI-Enabled Molecular Phenotyping and Prognostic Predictions in Lung Cancer Through Multimodal Clinical Information Integration","volume":"6","author":"Lu","year":"2025","journal-title":"Cell Rep. Med."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Miladinovi\u0107, A., Biscontin, A., Aj\u010devi\u0107, M., Kresevic, S., Accardo, A., Marangoni, D., Tognetto, D., and Inferrera, L. (2024). Evaluating deep learning models for classifying OCT images with limited data and noisy labels. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-81127-1"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2722","DOI":"10.1111\/dom.15587","article-title":"Prediction of Cardiovascular Risk Factors from Retinal Fundus Photographs: Validation of a Deep Learning Algorithm in a Prospective Non-Interventional Study in Kenya","volume":"26","author":"White","year":"2024","journal-title":"Diabetes Obes. Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1136\/bjophthalmol-2014-306051","article-title":"Effects of Posterior Vitreous Detachment on Aqueous Humour Levels of VEGF and Inflammatory Cytokines","volume":"99","author":"Takahashi","year":"2015","journal-title":"Br. J. Ophthalmol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/s00417-015-3006-2","article-title":"Effect of Posterior Vitreous Detachment on Aqueous Humor Level of Vascular Endothelial Growth Factor in Exudative Age-Related Macular Degeneration Patients","volume":"254","author":"Nomura","year":"2016","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1136\/bjophthalmol-2017-310284","article-title":"Changes in Multiple Cytokine Concentrations in the Aqueous Humor of Neovascular Age-Related Macular Degeneration after Two Months of Ranibizumab Therapy","volume":"102","author":"Sakamoto","year":"2018","journal-title":"Br. J. Ophthalmol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Arai, Y., Takahashi, H., Inoda, S., Tan, X., Sakamoto, S., Inoue, Y., Fujino, Y., Kawashima, H., and Yanagi, Y. (2020). Aqueous Humour Proteins and Treatment Outcomes of Anti-VEGF Therapy in Neovascular Age-Related Macular Degeneration. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0229342"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Hayashi, T., Takahashi, H., Inoda, S., Shimizu, T., Kobayashi, A., Kawashima, H., Yamaguchi, T., and Yamagami, S. (2021). Aqueous Humour Cytokine Profiles after Descemet\u2019s Membrane Endothelial Keratoplasty. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-96566-3"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1007\/s00417-021-05445-0","article-title":"Cytokine Profiles of Macular Neovascularization in the Elderly Based on a Classification from a Pachychoroid\/Drusen Perspective","volume":"260","author":"Inoda","year":"2021","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2465","DOI":"10.1007\/s00417-023-06038-9","article-title":"Cytokine Profiles in the Aqueous Humor Following Brolucizumab Administration for Exudative Age-Related Macular Degeneration","volume":"261","author":"Terao","year":"2023","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1167\/iovs.65.1.8","article-title":"Factors Associated with Intraocular Inflammation in Neovascular Age-Related Macular Degeneration Patients Treated with Brolucizumab","volume":"65","author":"Hashimoto","year":"2024","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1007\/s00417-025-06738-4","article-title":"Effectiveness and Cytokine Profile of Combined Anti-Vascular Endothelial Growth Factor and Corticosteroid Therapy for Chronic Retinal Vein Occlusion","volume":"263","author":"Arai","year":"2025","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1167\/tvst.14.2.21","article-title":"Effect of Combination Use of Aqueous Humor Secretion Inhibitor Eye Drops on Aflibercept Level: A Preliminary Analysis","volume":"14","author":"Inoda","year":"2025","journal-title":"Transl. Vis. Sci. Technol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Nonogaki, R., Ota, H., Takeuchi, J., Nakano, Y., Sajiki, A.F., Todoroki, T., Nakamura, K., Kaneko, H., and Nishiguchi, K.M. (2024). Analysis of the Aqueous Humor Before and After the Administration of Faricimab in Patients with nAMD. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-83473-6"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Kadoh, Y., Takayanagi, Y., Sugihara, K., Kaidzu, S., Takai, Y., and Tanito, M. (2025). Aqueous Humor Cytokine Profiling Reveals Distinct Roles for Serum Amyloid A, Interleukin-8, and Endothelin-1 in Pseudoexfoliation Syndrome and Glaucoma. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26041461"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Asakage, M., Noma, H., Yasuda, K., Goto, H., and Shimura, M. (2025). The Dynamics of Inflammatory Factors in Patients with or without IOI after Brolucizumab Treatment. Medicina, 61.","DOI":"10.3390\/medicina61030372"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1690","DOI":"10.1016\/S0161-6420(03)00568-2","article-title":"Vitreous Levels of Interleukin-6 and Vascular Endothelial Growth Factor Are Related to Diabetic Macular Edema","volume":"110","author":"Funatsu","year":"2003","journal-title":"Ophthalmology"}],"container-title":["Sensors"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8220\/25\/23\/7382\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T18:52:57Z","timestamp":1764960777000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8220\/25\/23\/7382"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,4]]},"references-count":25,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["s25237382"],"URL":"https:\/\/doi.org\/10.3390\/s25237382","relation":{},"ISSN":["1424-8220"],"issn-type":[{"value":"1424-8220","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,4]]}}}