{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T06:07:00Z","timestamp":1791266820312,"version":"4.1.0"},"reference-count":22,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,10,16]],"date-time":"2023-10-16T00:00:00Z","timestamp":1697414400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["R01 EY021797"],"award-info":[{"award-number":["R01 EY021797"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["R01 EY028557"],"award-info":[{"award-number":["R01 EY028557"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000900","name":"California Institute for Regenerative Medicine","doi-asserted-by":"publisher","award":["TR2-01768"],"award-info":[{"award-number":["TR2-01768"]}],"id":[{"id":"10.13039\/100000900","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000900","name":"California Institute for Regenerative Medicine","doi-asserted-by":"publisher","award":["CLIN1-08686"],"award-info":[{"award-number":["CLIN1-08686"]}],"id":[{"id":"10.13039\/100000900","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000900","name":"California Institute for Regenerative Medicine","doi-asserted-by":"publisher","award":["CLIN2-11650"],"award-info":[{"award-number":["CLIN2-11650"]}],"id":[{"id":"10.13039\/100000900","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Limbal Stem Cell Deficiency (LSCD) is a blinding corneal disease characterized by the loss of function or deficiency in adult stem cells located at the junction between the cornea and the sclera (i.e., the limbus), namely the limbal stem cells (LSCs). Recent advances in <jats:italic>in vivo<\/jats:italic> imaging technology have improved disease diagnosis and staging to quantify several biomarkers of <jats:italic>in vivo<\/jats:italic> LSC function including epithelial thickness measured by anterior segment optical coherence tomography, and basal epithelial cell density and subbasal nerve plexus by <jats:italic>in vivo<\/jats:italic> confocal microscopy. A decrease in central corneal sub-basal nerve density and nerve fiber and branching number has been shown to correlate with the severity of the disease in parallel with increased nerve tortuosity. Yet, image acquisition and manual quantification require a high level of expertise and are time-consuming. Manual quantification presents inevitable interobserver variability.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The current study employs a novel deep learning approach to classify neuron morphology in various LSCD stages and healthy controls, by integrating images created through latent diffusion augmentation. The proposed model, a residual U-Net, is based in part on the InceptionResNetV2 transfer learning model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Deep learning was able to determine fiber number, branching, and fiber length with high accuracy (R2 of 0.63, 0.63, and 0.80, respectively). The model trained on images generated through latent diffusion on average outperformed the same model when trained on solely original images. The model was also able to detect LSCD with an AUC of 0.867, which showed slightly higher performance compared to classification using manually assessed metrics.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>The results suggest that utilizing latent diffusion to supplement training data may be effective in bolstering model performance. The results of the model emphasize the ability as well as the shortcomings of this novel deep learning approach to predict various nerve morphology metrics as well as LSCD disease severity.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmed.2023.1270570","type":"journal-article","created":{"date-parts":[[2023,10,16]],"date-time":"2023-10-16T05:01:50Z","timestamp":1697432510000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Latent diffusion augmentation enhances deep learning analysis of neuro-morphology in limbal stem cell deficiency"],"prefix":"10.3389","volume":"10","author":[{"given":"David","family":"Gibson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thai","family":"Tran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vidhur","family":"Raveendran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cl\u00e9mence","family":"Bonnet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"Siu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micah","family":"Vinet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theo","family":"Stoddard-Bennett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corey","family":"Arnold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie X.","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Speier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,10,16]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1038\/eye.1989.22","article-title":"Concept and application of limbal stem cells","volume":"3","author":"Tseng","year":"1989","journal-title":"Eye"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1097\/ICO.0000000000001820","article-title":"Global consensus on definition, classification, diagnosis, and staging of limbal stem cell deficiency","volume":"38","author":"Deng","year":"2019","journal-title":"Cornea"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1001\/archophthalmol.2011.378","article-title":"Characterization of Limbal stem cell deficiency by in vivo laser scanning confocal microscopy: a microstructural approach","volume":"130","author":"Deng","year":"2012","journal-title":"Arch Ophthalmol"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1291","DOI":"10.1097\/ICO.0000000000002358","article-title":"Global consensus on the management of limbal stem cell deficiency","volume":"39","author":"Deng","year":"2020","journal-title":"Cornea"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1483","DOI":"10.1097\/ICO.0000000000000914","article-title":"Existence of normal limbal epithelium in eyes with clinical signs of total limbal stem cell deficiency","volume":"35","author":"Chan","year":"2016","journal-title":"Cornea"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.1097\/ICO.0000000000001631","article-title":"A case of corneal neovascularization misdiagnosed as total limbal stem cell deficiency","volume":"37","author":"Le","year":"2018","journal-title":"Cornea"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/j.jtos.2021.12.005","article-title":"Biomarkers of in vivo limbal stem cell function","volume":"23","author":"Le","year":"2022","journal-title":"Ocul Surf"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1097\/ICO.0000000000001092","article-title":"Characterization of the corneal subbasal nerve plexus in limbal stem cell deficiency","volume":"36","author":"Chuephanich","year":"2017","journal-title":"Cornea"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1633","DOI":"10.1136\/bjophthalmol-2019-315231","article-title":"Central corneal basal cell density and nerve parameters in ocular surface disease and limbal stem cell deficiency: a review and meta-analysis","volume":"104","author":"Bhattacharya","year":"2020","journal-title":"Br J Ophthalmol"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"102","DOI":"10.3389\/fnana.2016.00102\/full","article-title":"Morphological neuron classification using machine learning","volume":"10","author":"Vasques","year":"2016","journal-title":"Front Neuroanat"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"530","DOI":"10.1038\/nrn.2017.85","article-title":"Neuronal cell-type classification: challenges, opportunities and the path forward","volume":"18","author":"Zeng","year":"2017","journal-title":"Nat Rev Neurosci"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1097\/ICO.0000000000002181","article-title":"Multiple-image deep learning analysis for neuropathy detection in corneal nerve images","volume":"39","author":"Scarpa","year":"2020","journal-title":"Cornea"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1007\/s00125-021-05617-x","article-title":"Artificial intelligence utilising corneal confocal microscopy for the diagnosis of peripheral neuropathy in diabetes mellitus and prediabetes","volume":"65","author":"Preston","year":"2022","journal-title":"Diabetologia"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"706","DOI":"10.21037\/atm.2020.03.134","article-title":"Deep learning-based automated diagnosis of fungal keratitis with in vivo confocal microscopy images","volume":"8","author":"Lv","year":"2020","journal-title":"Ann Transl Med"},{"key":"ref15","author":"Rombach","year":"2022"},{"key":"ref16","author":"Trabucco","year":"2023"},{"key":"ref17","author":"Khader","year":"2023"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1097\/ICO.0000000000001799","article-title":"Classification of Limbal stem cell deficiency using clinical and confocal grading","volume":"38","author":"Aravena","year":"2019","journal-title":"Cornea"},{"key":"ref19","author":"Radford","year":"2021"},{"key":"ref20","author":"Szegedy","year":"2016"},{"key":"ref21","author":"Deng","year":"2009"},{"key":"ref22","author":"Liu","year":"2022"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2023.1270570\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,16]],"date-time":"2023-10-16T05:01:53Z","timestamp":1697432513000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2023.1270570\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,16]]},"references-count":22,"alternative-id":["10.3389\/fmed.2023.1270570"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2023.1270570","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,16]]},"article-number":"1270570"}}