{"doi":"10.1101/2025.07.03.25330767","title":"Quantification of Optical Coherence Tomography Features in >3500 Patients with Inherited Retinal Disease Reveals Novel Genotype-Phenotype Associations","abstract":"Abstract Purpose To quantify spectral-domain optical coherence tomography (SD-OCT) images cross-sectionally and longitudinally in a large cohort of molecularly characterized patients with inherited retinal disease (IRDs) from the UK. Design Retrospective study of imaging data. Participants Patients with a clinical and molecularly confirmed diagnosis of IRD who have undergone macular SD-OCT imaging at Moorfields Eye Hospital (MEH) between 2011 and 2019. We retrospectively identified 4,240 IRD patients from the MEH database (198 distinct IRD genes), including 69,664 SD-OCT macular volumes. Methods Eight features of interest were defined: retina, fovea, intraretinal cystic spaces (ICS), subretinal fluid (SRF), subretinal hyper-reflective material (SHRM), pigment epithelium detachment (PED), ellipsoid zone loss (EZ-loss) and retinal pigment epithelium loss (RPE-loss). Manual annotations of five b-scans per SD-OCT volume was performed for the retinal features by four graders based on a defined grading protocol. A total of 1,749 b-scans from 360 SD-OCT volumes across 275 patients were annotated for the eight retinal features for training and testing of a neural-network-based segmentation model, AIRDetect-OCT, which was then applied to the entire imaging dataset. Main Outcome Measures Performance of AIRDetect-OCT, comparing to inter-grader agreement was evaluated using Dice score on a held-out dataset. Feature prevalence, volume and area were analysed cross-sectionally and longitudinally. Results The inter-grader Dice score for manual segmentation was ≥90% for retina, ICS, SRF, SHRM and PED, >77% for both EZ-loss and RPE-loss. Model-grader agreement was >80% for segmentation of retina, ICS, SRF, SHRM, and PED, and >68% for both EZ-loss and RPE-loss. Automatic segmentation was applied to 272,168 b-scans across 7,405 SD-OCT volumes from 3,534 patients encompassing 176 unique genes. Accounting for age, male patients exhibited significantly more EZ-loss (19.6mm 2 vs 17.9mm 2 , p<2.8×10 -4 ) and RPE-loss (7.79mm 2 vs 6.15mm 2 , p<3.2×10 -6 ) than females. RPE-loss was significantly higher in Asian patients than other ethnicities (9.37mm 2 vs 7.29mm 2 , p<0.03). ICS average total volume was largest in RS1 (0.47mm 3 ) and NR2E3 (0.25mm 3 ), SRF in BEST1 (0.21mm 3 ) and PED in EFEMP1 (0.34mm 3 ). BEST1 and PROM1 showed significantly different patterns of EZ-loss (p<10 -4 ) and RPE-loss (p<0.02) comparing the dominant to the recessive forms. Sectoral analysis revealed significantly increased EZ-loss in the inferior quadrant compared to superior quadrant for RHO (Δ=-0.414 mm 2 , p=0.036) and EYS (Δ=-0.908 mm 2 , p=1.5×10 -4 ). In ABCA4 retinopathy, more severe genotypes (group A) were associated with faster progression of EZ-loss (2.80±0.62 mm 2 /yr), whilst the p.(Gly1961Glu) variant (group D) was associated with slower progression (0.56 ±0.18 mm 2 /yr). There were also sex differences within groups with males in group A experiencing significantly faster rates of progression of RPE-loss (2.48 ±1.40 mm 2 /yr vs 0.87 ±0.62 mm 2 /yr, p=0.047), but lower rates in groups B, C, and D. Conclusions AIRDetect-OCT, a novel deep learning algorithm, enables large-scale OCT feature quantification in IRD patients uncovering cross-sectional and longitudinal phenotype correlations with demographic and genotypic parameters.","journal":"medRxiv","year":2025,"id":555234,"datarank":0.2477509030315232,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.006335216166408102,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.006335216166408102,"corpus_percentile":39.99381140249091,"corpus_rank":7758,"citation_count":4,"citer_count":2,"citers_with_citation_signal":1,"citers_with_endowment":1,"datacite_reuse_total":0,"is_dataset":true,"is_dataset_confidence":0.8627,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":625433,"name":"Thales A. C. de Guimarães","orcid":"0000-0002-7936-6851","position":1,"is_corresponding":false},{"id":1326698,"name":"Saoud Al‐Khuzaei","orcid":"0000-0002-2779-3202","position":2,"is_corresponding":false},{"id":439818,"name":"Malena Daich Varela","orcid":"0000-0003-4960-4510","position":3,"is_corresponding":false},{"id":727521,"name":"Mital Shah","orcid":"0000-0001-7496-6121","position":4,"is_corresponding":false},{"id":1326702,"name":"Gunjan Naik","orcid":"0000-0003-1296-1362","position":5,"is_corresponding":false},{"id":1326699,"name":"Sagnik Sen","orcid":"0000-0001-5835-5371","position":6,"is_corresponding":false},{"id":1326700,"name":"Pallavi Bagga","orcid":"0000-0001-5226-1948","position":7,"is_corresponding":false},{"id":1326701,"name":"Bernardo Mendes","orcid":"0009-0002-0416-6852","position":8,"is_corresponding":false},{"id":1453538,"name":"Y.H. Chan","orcid":"0009-0004-4911-4233","position":9,"is_corresponding":false},{"id":57105,"name":"Siying Lin","orcid":"0000-0003-1122-8396","position":10,"is_corresponding":false},{"id":1326703,"name":"Biraja Ghoshal","orcid":"0000-0001-5456-2197","position":11,"is_corresponding":false},{"id":1057490,"name":"Bart Liefers","orcid":"0000-0002-2763-6426","position":12,"is_corresponding":false},{"id":1326704,"name":"Dun Jack Fu","orcid":"0000-0003-2852-6912","position":13,"is_corresponding":false},{"id":384660,"name":"Michalis Georgiou","orcid":"0000-0001-6397-8071","position":14,"is_corresponding":false},{"id":74431,"name":"Alan Sousa da Silva","orcid":"0000-0003-1250-943X","position":15,"is_corresponding":false},{"id":1326705,"name":"Quang Nguyen","orcid":"0000-0003-2665-3125","position":16,"is_corresponding":false},{"id":1326706,"name":"Yichen Liu","orcid":"0000-0002-9563-9151","position":17,"is_corresponding":false},{"id":1326707,"name":"Dayyanah Sumodhee","orcid":"0000-0001-7274-6088","position":18,"is_corresponding":false},{"id":701738,"name":"Yu Fujinami‐Yokokawa","orcid":"0000-0001-7555-5797","position":19,"is_corresponding":false},{"id":557083,"name":"Praveen J. Patel","orcid":"0000-0001-8682-4067","position":20,"is_corresponding":false},{"id":1326708,"name":"Jennifer Furman","orcid":"0000-0002-0622-6989","position":21,"is_corresponding":false},{"id":1300328,"name":"Ismail Moghul","orcid":"0000-0003-3653-2327","position":22,"is_corresponding":false},{"id":572196,"name":"Mariya Moosajee","orcid":"0000-0003-1688-5360","position":23,"is_corresponding":false},{"id":56995,"name":"Juliana M. Ferraz Sallum","orcid":"0000-0002-7206-4447","position":24,"is_corresponding":false},{"id":727662,"name":"Samantha R. De Silva","orcid":"0000-0002-4455-2814","position":25,"is_corresponding":false},{"id":615009,"name":"Birgit Lorenz","orcid":"0000-0002-9737-8127","position":26,"is_corresponding":false},{"id":775662,"name":"Philipp Herrmann","orcid":null,"position":27,"is_corresponding":false},{"id":54586,"name":"Frank G. Holz","orcid":"0000-0001-8019-9272","position":28,"is_corresponding":false},{"id":701732,"name":"Kaoru Fujinami","orcid":"0000-0003-4248-0033","position":29,"is_corresponding":false},{"id":54643,"name":"Andrew R. Webster","orcid":"0000-0001-6915-9560","position":30,"is_corresponding":false},{"id":57033,"name":"Omar A. Mahroo","orcid":"0000-0003-1254-0832","position":31,"is_corresponding":false},{"id":1326709,"name":"Susan M. Downes","orcid":"0000-0001-7373-2665","position":32,"is_corresponding":false},{"id":762187,"name":"Savita Madhusudhan","orcid":"0000-0002-8203-0929","position":33,"is_corresponding":false},{"id":321510,"name":"Konstantinos Balaskas","orcid":"0000-0003-2034-8920","position":34,"is_corresponding":false},{"id":323449,"name":"Michel Michaelides","orcid":"0000-0002-1552-7046","position":35,"is_corresponding":false},{"id":638911,"name":"Nikolas Pontikos","orcid":"0000-0003-1782-4711","position":36,"is_corresponding":false},{"id":1326697,"name":"William Woof","orcid":"0000-0001-7555-329X","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":null,"created_at":"2026-07-19T02:54:59.329539Z","pmid":"40630585","pmcid":"PMC12236878","fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}