AI-Assisted OCT Clinical Phenotypes of Diabetic Macular Edema: A Large Cohort Clustering Study

Edoardo Midena^{1

2}, Marco Lupidi³, Lisa Toto⁴, Giuseppe Covello⁵, Daniele Veritti^{6

7}, Elisabetta Pilotto¹, Maria Vittoria Cicinelli^{8

9}, Rosangela Lattanzio^{8

9}, Michele Figus⁵, Giulia Midena², Luca Danieli¹, Enrico Borrelli¹⁰, Michele Reibaldi¹⁰, Daniele Tognetto¹¹, Leandro Inferrera¹¹, Simone Donati¹², Settimio Rossi¹³, Paolo Melillo¹³, Paolo Lanzetta^{6

7}, Valentina Sarao^{6

7}, Giulia Gregori³, Carlo Cagini¹⁴, Chiara Maria Eandi^{15

16}, Adriano Carnevali¹⁷, Vincenzo Scorcia¹⁷, Emilia Maggio¹⁸, Grazia Pertile¹⁸, Ciro Costagliola¹⁹, Gilda Cennamo¹⁹, Paolo Mora²⁰, Roberto Dell'Omo²¹, Marzia Affatato²¹, Marzia Passamonti⁴, Mariacristina Parravano^{2

22}, Nicola Vito Lassandro², Marco Nassisi^{23

24}, Francesco Viola^{23

24}, Niccolò Castellino²⁵, Francesco Cappellani²⁶, Giuseppe Giannaccare²⁷, Francesco Boscia²⁸, Maria Oliva Grassi²⁸, Donatella Musetti²⁹, Valentina Folegani³⁰, Alessandro Invernizzi³⁰, Luca Rossetti³¹, Tommaso Bacci³², Federico Ricci³³, Marco Lombardo³³, Mary Romano^{34

35}, Nicola Valsecchi³⁶, Michele Coppola³⁷, Fabiano Cavarzeran¹, Luisa Frizziero¹

Affiliations

¹ Department of Ophthalmology, University of Padova, 35100 Padova, Italy.
² IRCCS-Fondazione Bietti, 00184 Rome, Italy.
³ Department of Experimental and Clinical Medicine, Polytechnic University of Marche, 60121 Ancona, Italy.
⁴ Ophthalmology Clinic, Department of Medicine and Science of Ageing, "G. d'Annunzio" University Chieti-Pescara, 66100 Chieti, Italy.
⁵ Ophthalmology, Department of Surgical, Medical, Molecular Pathology and Clinical Care Medicine, University of Pisa, 56126 Pisa, Italy.
⁶ Department of Medicine-Ophthalmology, University of Udine, 33100 Udine, Italy.
⁷ Istituto Europeo Di Microchirurgia Oculare-IEMO, 33100 Udine, Italy.
⁸ School of Medicine, Vita-Salute San Raffaele University, 20132 Milan, Italy.
⁹ Department of Ophthalmology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
¹⁰ Department of Ophthalmology, City of Health and Science Hospital, University of Turin, 10126 Turin, Italy.
¹¹ Eye Clinic, Department of Medical, Surgical Sciences and Health, University of Trieste, 34128 Trieste, Italy.
¹² Ophthalmology Unit, Circolo Hospital, Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy.
¹³ Multidisciplinary Department of Medical, Surgical and Dental Sciences, Eye Clinic, University of Campania "Luigi Vanvitelli", 81131 Naples, Italy.
¹⁴ Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy.
¹⁵ Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, 1004 Lausanne, Switzerland.
¹⁶ Department of Surgical Sciences, University of Torino, 10124 Torino, Italy.
¹⁷ Department of Ophthalmogy, University Magna Graecia of Catanzaro, Azienda Ospedaliera-Universitaria R. Dulbecco, 88100 Catanzaro, Italy.
¹⁸ Ophthalmology Unit, IRCCS Sacro Cuore Don Calabria Hospital Verona, 37024 Verona, Italy.
¹⁹ Eye Clinic, Department of Neurosciences, Reproductive Sciences and Dentistry, University of Naples Federico II, 80131 Naples, Italy.
²⁰ Ophthalmology Unit, University Hospital of Parma, 43126 Parma, Italy.
²¹ Department of Medicine and Health Sciences "Vincenzo Tiberio", University of Molise, 86100 Campobasso, Italy.
²² Faculty of Medicine, UniCamillus-Saint Camillus International University of Health Sciences, 00131 Rome, Italy.
²³ Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.
²⁴ Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy.
²⁵ Department of Ophthalmology, University of Catania, 95123 Catania, Italy.
²⁶ Department of Medicine and surgery, University of Enna "Kore", 94100 Enna, Italy.
²⁷ Eye Clinic, Department of Surgical Sciences, University of Cagliari, 09124 Cagliari, Italy.
²⁸ Department of Translational Biomedicine Neuroscience, University of Bari "Aldo Moro", 70121 Bari, Italy.
²⁹ Clinica Oculistica DiNOGMI, Università di Genova, Ospedale Policlinico San Martino IRCCS, 16132 Genova, Italy.
³⁰ Eye Clinic, Department of Biomedical and Clinical Sciences, Ospedale Luigi Sacco, University of Milan, 20157 Milan, Italy.
³¹ Eye Clinic, ASST Santi Paolo e Carlo-San Paolo Hospital, University of Milan, 20142 Milan, Italy.
³² Ophthalmology Unit, Department of Medicine, Surgery and Neuroscience, Siena University Hospital, 53100 Siena, Italy.
³³ Retinal Diseases Unit-PPTV, Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Roma, Italy.
³⁴ Department of Ophthalmology, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy.
³⁵ Multidisciplinary Department of Medical, Surgical and Dental Sciences University of Campania Luigi Vanvitelli, 80138 Neaples, Italy.
³⁶ Ophthalmology Unit, IRCCS Azienda Ospedaliera-Universitaria di Bologna, 40138 Bologna, Italy.
³⁷ IRCCS-San Gerardo, 20900 Monza, Italy.

PMID: 41302929
PMCID: PMC12653931
DOI: 10.3390/jcm14227893

AI-Assisted OCT Clinical Phenotypes of Diabetic Macular Edema: A Large Cohort Clustering Study

Edoardo Midena et al. J Clin Med. 2025.

. 2025 Nov 7;14(22):7893.

doi: 10.3390/jcm14227893.

Authors

Affiliations

¹ Department of Ophthalmology, University of Padova, 35100 Padova, Italy.
² IRCCS-Fondazione Bietti, 00184 Rome, Italy.
³ Department of Experimental and Clinical Medicine, Polytechnic University of Marche, 60121 Ancona, Italy.
⁴ Ophthalmology Clinic, Department of Medicine and Science of Ageing, "G. d'Annunzio" University Chieti-Pescara, 66100 Chieti, Italy.
⁵ Ophthalmology, Department of Surgical, Medical, Molecular Pathology and Clinical Care Medicine, University of Pisa, 56126 Pisa, Italy.
⁶ Department of Medicine-Ophthalmology, University of Udine, 33100 Udine, Italy.
⁷ Istituto Europeo Di Microchirurgia Oculare-IEMO, 33100 Udine, Italy.
⁸ School of Medicine, Vita-Salute San Raffaele University, 20132 Milan, Italy.
⁹ Department of Ophthalmology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
¹⁰ Department of Ophthalmology, City of Health and Science Hospital, University of Turin, 10126 Turin, Italy.
¹¹ Eye Clinic, Department of Medical, Surgical Sciences and Health, University of Trieste, 34128 Trieste, Italy.
¹² Ophthalmology Unit, Circolo Hospital, Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy.
¹³ Multidisciplinary Department of Medical, Surgical and Dental Sciences, Eye Clinic, University of Campania "Luigi Vanvitelli", 81131 Naples, Italy.
¹⁴ Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy.
¹⁵ Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, 1004 Lausanne, Switzerland.
¹⁶ Department of Surgical Sciences, University of Torino, 10124 Torino, Italy.
¹⁷ Department of Ophthalmogy, University Magna Graecia of Catanzaro, Azienda Ospedaliera-Universitaria R. Dulbecco, 88100 Catanzaro, Italy.
¹⁸ Ophthalmology Unit, IRCCS Sacro Cuore Don Calabria Hospital Verona, 37024 Verona, Italy.
¹⁹ Eye Clinic, Department of Neurosciences, Reproductive Sciences and Dentistry, University of Naples Federico II, 80131 Naples, Italy.
²⁰ Ophthalmology Unit, University Hospital of Parma, 43126 Parma, Italy.
²¹ Department of Medicine and Health Sciences "Vincenzo Tiberio", University of Molise, 86100 Campobasso, Italy.
²² Faculty of Medicine, UniCamillus-Saint Camillus International University of Health Sciences, 00131 Rome, Italy.
²³ Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.
²⁴ Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy.
²⁵ Department of Ophthalmology, University of Catania, 95123 Catania, Italy.
²⁶ Department of Medicine and surgery, University of Enna "Kore", 94100 Enna, Italy.
²⁷ Eye Clinic, Department of Surgical Sciences, University of Cagliari, 09124 Cagliari, Italy.
²⁸ Department of Translational Biomedicine Neuroscience, University of Bari "Aldo Moro", 70121 Bari, Italy.
²⁹ Clinica Oculistica DiNOGMI, Università di Genova, Ospedale Policlinico San Martino IRCCS, 16132 Genova, Italy.
³⁰ Eye Clinic, Department of Biomedical and Clinical Sciences, Ospedale Luigi Sacco, University of Milan, 20157 Milan, Italy.
³¹ Eye Clinic, ASST Santi Paolo e Carlo-San Paolo Hospital, University of Milan, 20142 Milan, Italy.
³² Ophthalmology Unit, Department of Medicine, Surgery and Neuroscience, Siena University Hospital, 53100 Siena, Italy.
³³ Retinal Diseases Unit-PPTV, Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Roma, Italy.
³⁴ Department of Ophthalmology, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy.
³⁵ Multidisciplinary Department of Medical, Surgical and Dental Sciences University of Campania Luigi Vanvitelli, 80138 Neaples, Italy.
³⁶ Ophthalmology Unit, IRCCS Azienda Ospedaliera-Universitaria di Bologna, 40138 Bologna, Italy.
³⁷ IRCCS-San Gerardo, 20900 Monza, Italy.

PMID: 41302929
PMCID: PMC12653931
DOI: 10.3390/jcm14227893

Abstract

Purpose: To characterize, using clustering analysis, the OCT morphological and clinical phenotypes of diabetic macular edema (DME) in a very large population (>2000 DME eyes) using standardized and validated OCT-based biomarkers. Methods: A cross-sectional study was conducted on OCT scans collected from 2355 eyes of 1688 patients with DME and performed during real-world clinical practice. OCT scans were automatically analyzed by a software able to automatically quantify OCT key biomarkers: intraretinal fluid (IRF), subretinal fluid (SRF), hyperreflective retinal foci (I-HRF), and external limiting membrane (ELM) and ellipsoid zone (EZ) interruption. Clustering analysis was performed using the above-mentioned biomarkers, including the distribution of IRF across the three ETDRS rings. Results: The overall population was predominantly composed of type 2 diabetes patients (89%), with a mean diabetes duration of 15.6 ± 10.7 years and mean best corrected visual acuity (BCVA) of 63 ± 18 ETDRS letters. Multivariate clustering identified four morphological phenotypes with distinct patterns of fluid distribution associated with different I-HRF counts, SRF volume, and percentages of ELM/EZ integrity (p < 0.0001). Conclusions: This large OCT analysis identified distinct morphological subtypes of DME, confirming the clinical relevance of key imaging biomarkers. The distribution and severity of DME features differ among clusters, supporting the importance of OCT-based phenotyping in tailoring treatment strategies and understanding disease evolution.

Keywords: biomarkers; clinical phenotypes; clustering analysis; diabetic macular edema; ellipsoid zone; external limiting membrane; hyperreflective retinal foci; intraretinal fluid; optical coherence tomography; subretinal fluid.

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Conflict of interest statement

This study was promoted by the Italian Retina Society (SIR) and the authors declare no conflicts of interest for this study.

References

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1. Schmidt-Erfurth U., Garcia-Arumi J., Bandello F., Berg K., Chakravarthy U., Gerendas B.S., Jonas J., Larsen M., Tadayoni R., Loewenstein A. Guidelines for the Management of Diabetic Macular Edema by the European Society of Retina Specialists (EURETINA) Ophthalmologica. 2017;237:185–222. doi: 10.1159/000458539. - DOI - PubMed

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AI-Assisted OCT Clinical Phenotypes of Diabetic Macular Edema: A Large Cohort Clustering Study

Affiliations

AI-Assisted OCT Clinical Phenotypes of Diabetic Macular Edema: A Large Cohort Clustering Study

Authors

Affiliations

Abstract

Conflict of interest statement

References

LinkOut - more resources

Full Text Sources

Miscellaneous