Pub Date : 2026-01-08DOI: 10.1016/j.xops.2026.101063
Lavinia Loss Henriques MD , Carolina Pelegrini Barbosa Gracitelli MD, PhD , Fernando Roberte Zanetti MD, MSc , Ricardo Luz Leitão Guerra MD, MSc
{"title":"Re: Most et al: Can Multimodal Large Language Models Diagnose Diabetic Retinopathy from Fundus Photos? A Quantitative Evaluation","authors":"Lavinia Loss Henriques MD , Carolina Pelegrini Barbosa Gracitelli MD, PhD , Fernando Roberte Zanetti MD, MSc , Ricardo Luz Leitão Guerra MD, MSc","doi":"10.1016/j.xops.2026.101063","DOIUrl":"10.1016/j.xops.2026.101063","url":null,"abstract":"","PeriodicalId":74363,"journal":{"name":"Ophthalmology science","volume":"6 3","pages":"Article 101063"},"PeriodicalIF":4.6,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146189816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-08DOI: 10.1016/j.xops.2026.101064
Jesse A. Most BA , Dirk-Uwe G. Bartsch PhD , Shyamanga Borooah FRCOphth, PhD
{"title":"Re: Henriques et al Correspondence Re: Most et al: Can Multimodal Large Language Models Diagnose Diabetic Retinopathy from Fundus Photos? A Quantitative Evaluation","authors":"Jesse A. Most BA , Dirk-Uwe G. Bartsch PhD , Shyamanga Borooah FRCOphth, PhD","doi":"10.1016/j.xops.2026.101064","DOIUrl":"10.1016/j.xops.2026.101064","url":null,"abstract":"","PeriodicalId":74363,"journal":{"name":"Ophthalmology science","volume":"6 3","pages":"Article 101064"},"PeriodicalIF":4.6,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146189728","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-07DOI: 10.1016/j.xops.2026.101065
Jack Phu MD, PhD , Henrietta Wang MPH , Jeremy C.K. Tan MD , Michael Kalloniatis MScOptom, PhD
<div><h3>Purpose</h3><div>To predict intrinsic measurement variability and reliability (any cause of data loss) in visual field (VF) results using a computer simulation model.</div></div><div><h3>Design</h3><div>Computer simulation study.</div></div><div><h3>Subjects</h3><div>One hundred thousand subjects simulated with empirical mean deviation, progression rate, variability, and reliability characteristics.</div></div><div><h3>Methods</h3><div>One hundred thousand subjects were simulated to undergo 4 VF tests per visit, 3 monthly, over 20 years (long-term condition) and 4 VF tests per visit daily over 28 days (short-term condition). Permutations of 1-4 tests per visit over 3-, 6-, and 12-monthly (long-term) and 1-, 2-, and 4-daily (short-term) review intervals were used. Visual field variabilities were estimated sequentially until 3 consecutive visits returned variabilities within 5% of each other using a rolling window. The same was applied to reliability. The last visit of the window denoted the critical time to estimating variability using the consecutive clinical criterion (TcV) and critical time to estimating reliability using the consecutive clinical criterion (TcR) estimation. Additionally, we identified the critical time at which 3 consecutive visits were within 5% of the ground truth (critical time to estimating variability using the consecutive clinical criterion and comparison with the ground truth [TgV] and critical time to estimating reliability using the consecutive clinical criterion and comparison with the ground truth [TgR]).</div></div><div><h3>Main Measures</h3><div>Critical time to estimating intrinsic variability and reliability.</div></div><div><h3>Results</h3><div>The most intensive long-term approach (4 tests/visit, 3 monthly) required a median of 6 years to reach TcV. In the long-term, most subjects arrived at TcR within 2 years, but short-term testing (even with 1 test per visit) required only 5 days of daily testing. More tests per visit and more frequent reviews shortened the critical time. Average differences between the estimated variability and reliability at TcV and TcR and their ground truth results were clinically small (within 1 decibel and 10%, respectively). Mean deviation, progression rate, and variability were significant predictors of TcV and TgV for long-term follow-up, with no clinically significant predictors for short-term variability (R<sup>2</sup> < 0.0001). Only reliability predicted TcR and TgR. Predictors had low coefficients of determination (<0.2).</div></div><div><h3>Conclusions</h3><div>Longitudinal estimates of variability are not likely achievable in clinical practice, but short-term intensive VF testing unaffected by progression can return variability and reliability rates within reasonable timeframes. We provide a framework for the effect of variability for the likelihood of detecting differences in VF results over time, given reliability rates.</div></div><div><h3>Financial Disclosu
{"title":"Predicting Variability and Reliability in Visual Field Testing: Short- and Long-Term Approaches","authors":"Jack Phu MD, PhD , Henrietta Wang MPH , Jeremy C.K. Tan MD , Michael Kalloniatis MScOptom, PhD","doi":"10.1016/j.xops.2026.101065","DOIUrl":"10.1016/j.xops.2026.101065","url":null,"abstract":"<div><h3>Purpose</h3><div>To predict intrinsic measurement variability and reliability (any cause of data loss) in visual field (VF) results using a computer simulation model.</div></div><div><h3>Design</h3><div>Computer simulation study.</div></div><div><h3>Subjects</h3><div>One hundred thousand subjects simulated with empirical mean deviation, progression rate, variability, and reliability characteristics.</div></div><div><h3>Methods</h3><div>One hundred thousand subjects were simulated to undergo 4 VF tests per visit, 3 monthly, over 20 years (long-term condition) and 4 VF tests per visit daily over 28 days (short-term condition). Permutations of 1-4 tests per visit over 3-, 6-, and 12-monthly (long-term) and 1-, 2-, and 4-daily (short-term) review intervals were used. Visual field variabilities were estimated sequentially until 3 consecutive visits returned variabilities within 5% of each other using a rolling window. The same was applied to reliability. The last visit of the window denoted the critical time to estimating variability using the consecutive clinical criterion (TcV) and critical time to estimating reliability using the consecutive clinical criterion (TcR) estimation. Additionally, we identified the critical time at which 3 consecutive visits were within 5% of the ground truth (critical time to estimating variability using the consecutive clinical criterion and comparison with the ground truth [TgV] and critical time to estimating reliability using the consecutive clinical criterion and comparison with the ground truth [TgR]).</div></div><div><h3>Main Measures</h3><div>Critical time to estimating intrinsic variability and reliability.</div></div><div><h3>Results</h3><div>The most intensive long-term approach (4 tests/visit, 3 monthly) required a median of 6 years to reach TcV. In the long-term, most subjects arrived at TcR within 2 years, but short-term testing (even with 1 test per visit) required only 5 days of daily testing. More tests per visit and more frequent reviews shortened the critical time. Average differences between the estimated variability and reliability at TcV and TcR and their ground truth results were clinically small (within 1 decibel and 10%, respectively). Mean deviation, progression rate, and variability were significant predictors of TcV and TgV for long-term follow-up, with no clinically significant predictors for short-term variability (R<sup>2</sup> < 0.0001). Only reliability predicted TcR and TgR. Predictors had low coefficients of determination (<0.2).</div></div><div><h3>Conclusions</h3><div>Longitudinal estimates of variability are not likely achievable in clinical practice, but short-term intensive VF testing unaffected by progression can return variability and reliability rates within reasonable timeframes. We provide a framework for the effect of variability for the likelihood of detecting differences in VF results over time, given reliability rates.</div></div><div><h3>Financial Disclosu","PeriodicalId":74363,"journal":{"name":"Ophthalmology science","volume":"6 3","pages":"Article 101065"},"PeriodicalIF":4.6,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146189730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-06DOI: 10.1016/j.xops.2025.101062
Luning Yang PhD , Sen Lin MS , Yiwen Tao BS , Qi Pan MS , Tengda Cai MS , Yunyan Ye PhD , Jianhui Liu PhD , Yang Zhou PhD , Yongqing Shao MS , Quanyong Yi PhD , Zen Huat Lu PhD , Lie Chen PhD , Gareth McKay PhD , Richard Rankin PhD , Fan Li PhD , Weihua Meng PhD
Purpose
To characterize cell-type-specific transcriptional changes during human retinal aging and develop machine learning (ML) model for cellular age discrimination in a Chinese cohort.
Eighteen unfrozen retinas from 12 Chinese donors (9 young, 34-55 y; 9 old, 68-92 y).
Methods
Single-cell RNA sequencing (10x, v3.1) generated 223 612 cells, batch-corrected with single-cell variational inference; age-related signatures were defined by intersecting single-cell and pseudobulk differentially expressed genes (DEGs), then cell-type-specific panels were rank-ordered with L1-regularized logistic regression plus recursive feature elimination and interpreted through hallmark-pathway enrichment and transcription factor (TF) regulon mapping.
Main Outcome Measures
Age-related cellular composition shifts; cell-type-specific DEGs; ML classifier accuracy and feature rankings; TF regulon activity changes.
Results
Eleven major retinal cell populations were identified. Aging showed declining rod-to-cone ratios, reduced bipolar cell (BC) proportions among interneurons, and increased astrocyte abundance. Müller glial cells exhibited the most pronounced transcriptional changes, followed by BCs and rods. Machine learning classifiers achieved 80% to 96% accuracy across cell types (microglia 96%, horizontal cells [HCs] 93%, BCs 91%, cones 90%, rods 89%). Shared aging signatures included mitochondrial dysfunction and inflammatory activation. Cell-specific vulnerabilities emerged: mitochondria-centric stress in rods/BCs, proteostasis-retinoid metabolism in cones, and structural-RNA maintenance in HCs.
Conclusions
This study provides the first ML derived, cell-type-specific aging signatures for human retina in a Chinese cohort, revealing both conserved molecular hallmarks and distinctive cellular vulnerabilities that inform targeted therapeutic strategies for retinal aging.
Financial Disclosure(s)
The author has no/the authors have no proprietary or commercial interest in any materials discussed in this article.
目的：表征人类视网膜衰老过程中细胞类型特异性转录变化，并在中国队列中建立细胞年龄判别的机器学习（ML）模型。设计：横断面，实验室为基础的观察性研究。参与者：来自12名中国供体的18例未冷冻视网膜（9例年轻，34-55岁；9例老年，68-92岁）。方法：单细胞RNA测序（10x, v3.1）产生223 612个细胞，用单细胞变分推理进行批量校正；通过交叉单细胞和假体差异表达基因（DEGs）定义年龄相关特征，然后使用l1正则化逻辑回归加递归特征消除对细胞类型特异性面板进行排序，并通过标记通路富集和转录因子（TF）调控子定位进行解释。主要观察指标：与年龄相关的细胞组成变化；cell-type-specific度;机器学习分类器精度和特征排名；TF调节活性改变。结果：鉴定出11个主要的视网膜细胞群。衰老表现为杆锥比下降，中间神经元中双极细胞（BC）比例减少，星形胶质细胞丰度增加。mller胶质细胞表现出最明显的转录变化，其次是BCs和杆状细胞。机器学习分类器在细胞类型上的准确率达到80%到96%（小胶质细胞96%，水平细胞[hc] 93%， bc 91%，锥细胞90%，杆状细胞89%）。共同的衰老特征包括线粒体功能障碍和炎症激活。细胞特异性的脆弱性出现了：杆状细胞/BCs中的线粒体中心应激，锥体中的蛋白质固定-类视黄酮代谢，以及hc中的结构- rna维持。结论：本研究在中国人群中首次提供了ML衍生的细胞类型特异性衰老特征，揭示了保守的分子特征和独特的细胞脆弱性，为视网膜衰老的靶向治疗策略提供了信息。财务披露：作者在本文中讨论的任何材料中没有任何专有或商业利益。
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Pub Date : 2026-01-06DOI: 10.1016/j.xops.2025.101061
Maverick Wenhao Wong MBBS , Huanye Li BEng , Yee Shan Dan MSc , Samantha CN. Lor , Raphael Soh MBBS , Quan V. Hoang MD, PhD , Rachel S. Chong MBBS, PhD
<div><h3>Objective</h3><div>To investigate the relationship between intraocular pressure (IOP) and antiglaucoma medications on both the incidence and progression of myopic macular degeneration (MMD), posterior staphyloma and axial length (AXL) elongation in highly myopic (HM) eyes.</div></div><div><h3>Design</h3><div>A retrospective multiethnic cohort study with cross-sectional and longitudinal analyses.</div></div><div><h3>Subjects, Participants, and/or Controls</h3><div>Nine hundred eighty-eight HM eyes from 518 multi-ethnic subjects assessed at the Singapore National Eye Centre (2017–2022). Eyes with glaucoma or on existing IOP-lowering therapy were excluded from the primary analyses. Secondary cross-sectional and longitudinal analyses included eyes with glaucoma to explore medication effects.</div></div><div><h3>Methods</h3><div>Intraocular pressure was measured with noncontact tonometry. Logistic and linear regression models assessed associations between IOP and MMD/staphyloma presence and progression and AXL elongation. Multivariate analysis was performed to identify independent predictors of progression, including effects of antiglaucoma medication use.</div></div><div><h3>Main Outcome Measures</h3><div>Presence and progression of MMD and staphyloma, current AXL, and AXL elongation as determined by imaging and clinical examination. Progression was defined by changes in MMD grade, atrophic lesions, or structural staphyloma features over time.</div></div><div><h3>Results</h3><div>In nonglaucomatous eyes, IOP was not significantly associated with the presence or progression of MMD, staphyloma, or AXL (all <em>P</em> > 0.05). Across all eyes, longer AXL was correlated with earlier spectacle onset, worse visual acuity, longer anterior chamber depth, presence of tilted disc, superior peripapillary atrophy, vitreomacular traction, staphyloma, epiretinal membrane, dome- or saddle-shaped macula, and lacquer crack (<em>P</em> < 0.05). In longitudinal analyses, baseline glaucoma medication use was significantly associated with reduced AXL elongation over time (β = –0.077, <em>P</em> = 0.036), independent of IOP, whereas tilted disc and staphyloma presence predicted greater elongation (<em>P</em> < 0.05). Myopic macular degeneration and staphyloma progression were primarily associated with structural factors, including presence of sloped fovea, macular retinoschisis, epiretinal membrane, and dome- or saddle-shaped macula at baseline (<em>P</em> < 0.05).</div></div><div><h3>Conclusions</h3><div>Intraocular pressure was not associated with pathologic myopia-related structural changes or AXL in HM eyes. In contrast, use of antiglaucoma medications was associated with reduced AXL elongation. These findings suggest the potential for IOP-independent pharmacologic modulation of AXL in HM eyes.</div></div><div><h3>Financial Disclosure(s)</h3><div>Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this
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Pub Date : 2026-01-05DOI: 10.1016/j.xops.2025.101059
Tai Yong Loh MBBS , Juling Sia MBBS , Wei Hing Seah MBBS , Lingyi Zhuang MBBS , Wenjun Song MD , Yue Qiu , Xiaofeng Shen M.Eng , Zhongqing Yu M.Eng , Ryan Tan MBBS , Nuo Tang MBBS , Yusra Asad MBBS , Colin Ming Hui Goh MBBS , Charmayne Xinyi Ang MBBS , Celyn Chng MBBS , Peiqi Lo MBBS , Pavan Paniharam MBBS , Ser Koon Goh MBBS , Hnin Hnin Oo MBBS , Min Wang MD, PhD , Rupesh Agrawal MD , Sandy Wenting Zhou MD
Purpose
To evaluate the performance of a customized deep learning algorithm for automated segmentation of nonperfusion area (NPA) on ultra-widefield swept-source OCTA (UWF SS-OCTA) and its utility in diabetic retinopathy (DR) severity assessment.
Design
Cross-sectional study.
Subjects
A total of 180 eyes from 122 participants representing all grades of DR severity.
Methods
We developed a convolutional neural network based on a multiscale U-Net backbone with squeeze-and-excitation attention for segmentation of NPAs on en face SS-OCTA all-retinal-layer images from 3 scan patterns: 6 × 6 mm, 12 × 12 mm, and 29 × 24 mm. Ground-truth annotations of NPAs and nongradable area (NGA) on en face OCTA images were generated by 2 independent graders and adjudicated by a vitreoretinal specialist. A corresponding en face structural OCT image was incorporated to distinguish true NPAs from shadow artifacts. Segmentation outputs included NPA, NGA, and shadow artifacts. Pixel-level accuracy was assessed with the F1 score. Nonperfusion index (NPI) was defined as NPA/gradable area. The level of agreement between human-labeled and algorithm-predicted NPI was analyzed using Bland–Altman analysis.
Main Outcome Measures
Algorithm F1 score and NPI.
Results
The algorithm for NPA segmentation achieved a mean F1 score of 0.82 ± 0.01 in 6 × 6 mm, 0.84 ± 0.03 in 12 × 12 mm, and 0.83 ± 0.02 in 29 × 24 mm, with no significant difference across fields of view (P = 0.12). Algorithm-derived NPI strongly agreed with expert grading (intraclass correlation coefficient >0.979). Both human- and algorithm-derived NPI increased progressively with increased DR severity in all scan patterns demonstrated by the Kruskal–Wallis test (6 × 6 mm: human: P = 0.02; algorithm: P = 0.03; 12 × 12 mm: algorithm P < 0.001; human P < 0.001; 29 × 24 mm: algorithm: P < 0.001; human: P < 0.001) with the largest magnitude of increase in 29 × 24 mm scans. The algorithm for foveal avascular zone segmentation also achieved a mean F1 score of 0.88 ± 0.05 for 6 × 6 mm images and 0.85 ± 0.05 for 12 × 12 mm images.
Conclusions
This deep learning algorithm was validated on single-scan UWF SS-OCTA for automated NPA segmentation and quantification. It demonstrates high accuracy and scalability across multiple scan sizes, supporting its potential integration into objective DR OCTA biomarker analysis.
Financial Disclosure(s)
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
{"title":"Automated Nonperfusion Quantification in Diabetic Retinopathy on Ultra-Widefield Swept-Source OCT Angiography","authors":"Tai Yong Loh MBBS , Juling Sia MBBS , Wei Hing Seah MBBS , Lingyi Zhuang MBBS , Wenjun Song MD , Yue Qiu , Xiaofeng Shen M.Eng , Zhongqing Yu M.Eng , Ryan Tan MBBS , Nuo Tang MBBS , Yusra Asad MBBS , Colin Ming Hui Goh MBBS , Charmayne Xinyi Ang MBBS , Celyn Chng MBBS , Peiqi Lo MBBS , Pavan Paniharam MBBS , Ser Koon Goh MBBS , Hnin Hnin Oo MBBS , Min Wang MD, PhD , Rupesh Agrawal MD , Sandy Wenting Zhou MD","doi":"10.1016/j.xops.2025.101059","DOIUrl":"10.1016/j.xops.2025.101059","url":null,"abstract":"<div><h3>Purpose</h3><div>To evaluate the performance of a customized deep learning algorithm for automated segmentation of nonperfusion area (NPA) on ultra-widefield swept-source OCTA (UWF SS-OCTA) and its utility in diabetic retinopathy (DR) severity assessment.</div></div><div><h3>Design</h3><div>Cross-sectional study.</div></div><div><h3>Subjects</h3><div>A total of 180 eyes from 122 participants representing all grades of DR severity.</div></div><div><h3>Methods</h3><div>We developed a convolutional neural network based on a multiscale U-Net backbone with squeeze-and-excitation attention for segmentation of NPAs on en face SS-OCTA all-retinal-layer images from 3 scan patterns: 6 × 6 mm, 12 × 12 mm, and 29 × 24 mm. Ground-truth annotations of NPAs and nongradable area (NGA) on en face OCTA images were generated by 2 independent graders and adjudicated by a vitreoretinal specialist. A corresponding en face structural OCT image was incorporated to distinguish true NPAs from shadow artifacts. Segmentation outputs included NPA, NGA, and shadow artifacts. Pixel-level accuracy was assessed with the F1 score. Nonperfusion index (NPI) was defined as NPA/gradable area. The level of agreement between human-labeled and algorithm-predicted NPI was analyzed using Bland–Altman analysis.</div></div><div><h3>Main Outcome Measures</h3><div>Algorithm F1 score and NPI.</div></div><div><h3>Results</h3><div>The algorithm for NPA segmentation achieved a mean F1 score of 0.82 ± 0.01 in 6 × 6 mm, 0.84 ± 0.03 in 12 × 12 mm, and 0.83 ± 0.02 in 29 × 24 mm, with no significant difference across fields of view (<em>P</em> = 0.12). Algorithm-derived NPI strongly agreed with expert grading (intraclass correlation coefficient >0.979). Both human- and algorithm-derived NPI increased progressively with increased DR severity in all scan patterns demonstrated by the Kruskal–Wallis test (6 × 6 mm: human: <em>P</em> = 0.02; algorithm: <em>P</em> = 0.03; 12 × 12 mm: algorithm <em>P</em> < 0.001; human <em>P</em> < 0.001; 29 × 24 mm: algorithm: <em>P</em> < 0.001; human: <em>P</em> < 0.001) with the largest magnitude of increase in 29 × 24 mm scans. The algorithm for foveal avascular zone segmentation also achieved a mean F1 score of 0.88 ± 0.05 for 6 × 6 mm images and 0.85 ± 0.05 for 12 × 12 mm images.</div></div><div><h3>Conclusions</h3><div>This deep learning algorithm was validated on single-scan UWF SS-OCTA for automated NPA segmentation and quantification. It demonstrates high accuracy and scalability across multiple scan sizes, supporting its potential integration into objective DR OCTA biomarker analysis.</div></div><div><h3>Financial Disclosure(s)</h3><div>Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.</div></div>","PeriodicalId":74363,"journal":{"name":"Ophthalmology science","volume":"6 3","pages":"Article 101059"},"PeriodicalIF":4.6,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146189243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<div><h3>Purpose</h3><div>To identify genetic variants in posterior staphylomas in eyes with pathologic myopia using whole exome sequencing and to determine possible molecular mechanisms contributing to the pathogenesis.</div></div><div><h3>Design</h3><div>An observational, case-control study.</div></div><div><h3>Participants</h3><div>Two hundred sixty-four unrelated Japanese patients with myopia (≤ –0.50 diopters) and posterior staphyloma, which was diagnosed by ultra-widefield OCT, 3-dimensional magnetic resonance imaging, and Optos imaging.</div></div><div><h3>Methods</h3><div>Whole exome sequencing was performed on genomic DNA from peripheral blood. After variant filtering, the allelic frequencies were compared with control data obtained from East Asian subsets of the 1000 Genomes Project Phase III, the Exome Aggregation Consortium, and the Japanese Multi-Omics Reference Panel using Fisher exact test. A gene panel was constructed based on 13 staphyloma-associated disorders. Variants showing significant frequency differences (<em>P</em> ≤ 0.05) and an overlap of the gene panel were analyzed using gene set enrichment analysis with the DAVID Knowledgebase (v2023q4). Protein–protein interaction analysis was performed to assess functional associations.</div></div><div><h3>Main Outcome Measures</h3><div>The statistically associated variants and genes, gene set enrichment analysis results, protein–protein interaction networks, and involvement of basement membrane structures, including the inner limiting membrane (ILM) and Bruch membrane, were studied.</div></div><div><h3>Results</h3><div>Whole exome sequencing identified 16 656 missense variants in 8628 genes. Comparative allele frequency analyses with public databases revealed 3925 variants that had significantly higher allelic frequencies in the subjects. Of these, 81 genes overlapped with a curated staphyloma-related gene panel and were subjected to gene set enrichment analysis. The findings showed enrichment in basement membrane, extracellular matrix, and collagen-related pathways. The <em>COL4A5, COL18A1, COL2A1</em>, and <em>COL9A3</em> genes are concurrently enriched across these pathways. A missense variant in <em>COL4A5</em> was identified in 27 patients, and 96.3% of whom were females. Protein–protein interaction analysis demonstrated functional connections among these 4 genes.</div></div><div><h3>Conclusions</h3><div>Variants in the <em>COL4A5, COL18A1, COL2A1, and COL9A3</em> genes probably contribute to the pathogenesis of a posterior staphyloma through the disruption of collagen synthesis and basement membrane integrity. This was especially effective for the ILM and Bruch membrane. The <em>COL4A5</em> variant may cause an ocular-predominant phenotype in heterozygous female carriers, independent of the classical features of Alport syndrome.</div></div><div><h3>Financial Disclosure(s)</h3><div>The authors have no proprietary or commercial interest in any materials discussed in this artic
{"title":"Determining Genetic Cause of Posterior Staphylomas in Eyes with Pathologic Myopia by Whole Exome Sequencing","authors":"Ziye Wang MD , Changyu Chen MD, PhD , Yijin Wu MD , Yuki Nagata PhD , Toshihiro Tanaka MD, PhD , Shiqi Xie MD, PhD , Hongshuang Lu MD, PhD , Yining Wang MD , Jianping Xiong MD, PhD , Liwen Zhang MD , Koju Kamoi MD, PhD , Kyoko Ohno-Matsui MD, PhD","doi":"10.1016/j.xops.2025.101058","DOIUrl":"10.1016/j.xops.2025.101058","url":null,"abstract":"<div><h3>Purpose</h3><div>To identify genetic variants in posterior staphylomas in eyes with pathologic myopia using whole exome sequencing and to determine possible molecular mechanisms contributing to the pathogenesis.</div></div><div><h3>Design</h3><div>An observational, case-control study.</div></div><div><h3>Participants</h3><div>Two hundred sixty-four unrelated Japanese patients with myopia (≤ –0.50 diopters) and posterior staphyloma, which was diagnosed by ultra-widefield OCT, 3-dimensional magnetic resonance imaging, and Optos imaging.</div></div><div><h3>Methods</h3><div>Whole exome sequencing was performed on genomic DNA from peripheral blood. After variant filtering, the allelic frequencies were compared with control data obtained from East Asian subsets of the 1000 Genomes Project Phase III, the Exome Aggregation Consortium, and the Japanese Multi-Omics Reference Panel using Fisher exact test. A gene panel was constructed based on 13 staphyloma-associated disorders. Variants showing significant frequency differences (<em>P</em> ≤ 0.05) and an overlap of the gene panel were analyzed using gene set enrichment analysis with the DAVID Knowledgebase (v2023q4). Protein–protein interaction analysis was performed to assess functional associations.</div></div><div><h3>Main Outcome Measures</h3><div>The statistically associated variants and genes, gene set enrichment analysis results, protein–protein interaction networks, and involvement of basement membrane structures, including the inner limiting membrane (ILM) and Bruch membrane, were studied.</div></div><div><h3>Results</h3><div>Whole exome sequencing identified 16 656 missense variants in 8628 genes. Comparative allele frequency analyses with public databases revealed 3925 variants that had significantly higher allelic frequencies in the subjects. Of these, 81 genes overlapped with a curated staphyloma-related gene panel and were subjected to gene set enrichment analysis. The findings showed enrichment in basement membrane, extracellular matrix, and collagen-related pathways. The <em>COL4A5, COL18A1, COL2A1</em>, and <em>COL9A3</em> genes are concurrently enriched across these pathways. A missense variant in <em>COL4A5</em> was identified in 27 patients, and 96.3% of whom were females. Protein–protein interaction analysis demonstrated functional connections among these 4 genes.</div></div><div><h3>Conclusions</h3><div>Variants in the <em>COL4A5, COL18A1, COL2A1, and COL9A3</em> genes probably contribute to the pathogenesis of a posterior staphyloma through the disruption of collagen synthesis and basement membrane integrity. This was especially effective for the ILM and Bruch membrane. The <em>COL4A5</em> variant may cause an ocular-predominant phenotype in heterozygous female carriers, independent of the classical features of Alport syndrome.</div></div><div><h3>Financial Disclosure(s)</h3><div>The authors have no proprietary or commercial interest in any materials discussed in this artic","PeriodicalId":74363,"journal":{"name":"Ophthalmology science","volume":"6 3","pages":"Article 101058"},"PeriodicalIF":4.6,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146079752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-05DOI: 10.1016/j.xops.2025.101060
Yunchan Hwang SM , Muhammad Usman Jamil MD , Kwang Min Woo MD , Stephanie M. Kaiser BA , Fatima Babiker MD , Philip J. Rosenfeld MD, PhD , Nadia K. Waheed MD , James G. Fujimoto PhD
Purpose
To investigate choriocapillaris (CC) blood flow speed in regions associated with hypertransmission defects (hyperTDs) in nonexudative age-related macular degeneration (AMD) using variable interscan time analysis (VISTA) OCT angiography (OCTA).
Design
Retrospective cross-sectional analysis of a prospectively collected cohort.
Subjects
Thirty-one eyes from 29 subjects with nonexudative AMD.
Methods
Patients with age-related macular degeneration were imaged using a 600 kHz A-scan rate prototype swept-source OCT with a 5 × 5 mm field of view and 5 B-scan repeats (1.25 ms interscan time). Hypertransmission defects were traced on choroidal en face projections and categorized by their greatest linear dimension (GLD): large (≥250 μm), medium (63–250 μm), and small (<63 μm). Choriocapillaris blood flow speed was quantified using VISTA, which measures OCTA signal saturation dynamics across multiple interscan times. Variable interscan time analysis flow speed (VFS) was evaluated at the macula and within hyperTDs. Choriocapillaris flow speed impairment (ΔVFS) for each hyperTD was calculated as the difference between its VFS and the macular average. To assess spatial extent, ΔVFS was assessed beyond lesion boundaries. Traditional metrics of OCTA signal and flow deficits (FDs) were also evaluated.
Main Outcome Measures
Choriocapillaris blood flow speed impairment (ΔVFS) within and around hyperTDs.
Results
The macular average CC VFS was 1.47 ± 0.34 ms–1, with no significant difference between eyes with (n = 14) and without (n = 17) hyperTDs. A total of 88 hyperTDs were analyzed: 19 large, 28 medium, and 41 small. Large hyperTDs showed significant CC flow impairment (ΔVFS = –0.37 ± 0.18 ms–1, Padjusted < 0.0001), with impairment extending 100 μm beyond lesion boundaries (Padjusted = 0.0061). Medium-sized hyperTDs demonstrated moderate impairment (ΔVFS = –0.30 ± 0.47 ms–1, Padjusted = 0.031), while small hyperTDs did not. In linear mixed-effects modeling, large and medium hyperTDs were associated with significant reductions in flow speed (–0.40 ms–1, P = 0.014; –0.31 ms–1, P = 0.030, respectively), corresponding to approximately 25% decreases from macular average. OCT angiography signal and FD metrics also detected size-dependent flow impairment.
Conclusions
Large hyperTDs in nonexudative AMD exhibit reduced CC flow speed extending beyond the lesion boundary. Longitudinal studies will investigate whether CC flow predicts onset and progression of hyperTDs.
Financial Disclosure(s)
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
{"title":"Large Hypertransmission Defects Exhibit Choriocapillaris Flow Speed Impairment in Nonexudative Age-Related Macular Degeneration","authors":"Yunchan Hwang SM , Muhammad Usman Jamil MD , Kwang Min Woo MD , Stephanie M. Kaiser BA , Fatima Babiker MD , Philip J. Rosenfeld MD, PhD , Nadia K. Waheed MD , James G. Fujimoto PhD","doi":"10.1016/j.xops.2025.101060","DOIUrl":"10.1016/j.xops.2025.101060","url":null,"abstract":"<div><h3>Purpose</h3><div>To investigate choriocapillaris (CC) blood flow speed in regions associated with hypertransmission defects (hyperTDs) in nonexudative age-related macular degeneration (AMD) using variable interscan time analysis (VISTA) OCT angiography (OCTA).</div></div><div><h3>Design</h3><div>Retrospective cross-sectional analysis of a prospectively collected cohort.</div></div><div><h3>Subjects</h3><div>Thirty-one eyes from 29 subjects with nonexudative AMD.</div></div><div><h3>Methods</h3><div>Patients with age-related macular degeneration were imaged using a 600 kHz A-scan rate prototype swept-source OCT with a 5 × 5 mm field of view and 5 B-scan repeats (1.25 ms interscan time). Hypertransmission defects were traced on choroidal en face projections and categorized by their greatest linear dimension (GLD): large (≥250 μm), medium (63–250 μm), and small (<63 μm). Choriocapillaris blood flow speed was quantified using VISTA, which measures OCTA signal saturation dynamics across multiple interscan times. Variable interscan time analysis flow speed (VFS) was evaluated at the macula and within hyperTDs. Choriocapillaris flow speed impairment (ΔVFS) for each hyperTD was calculated as the difference between its VFS and the macular average. To assess spatial extent, ΔVFS was assessed beyond lesion boundaries. Traditional metrics of OCTA signal and flow deficits (FDs) were also evaluated.</div></div><div><h3>Main Outcome Measures</h3><div>Choriocapillaris blood flow speed impairment (ΔVFS) within and around hyperTDs.</div></div><div><h3>Results</h3><div>The macular average CC VFS was 1.47 ± 0.34 ms<sup>–1</sup>, with no significant difference between eyes with (n = 14) and without (n = 17) hyperTDs. A total of 88 hyperTDs were analyzed: 19 large, 28 medium, and 41 small. Large hyperTDs showed significant CC flow impairment (ΔVFS = –0.37 ± 0.18 ms<sup>–1</sup>, P<sub>adjusted</sub> < 0.0001), with impairment extending 100 μm beyond lesion boundaries (P<sub>adjusted</sub> = 0.0061). Medium-sized hyperTDs demonstrated moderate impairment (ΔVFS = –0.30 ± 0.47 ms<sup>–1</sup>, P<sub>adjusted</sub> = 0.031), while small hyperTDs did not. In linear mixed-effects modeling, large and medium hyperTDs were associated with significant reductions in flow speed (–0.40 ms<sup>–1</sup>, <em>P</em> = 0.014; –0.31 ms<sup>–1</sup>, <em>P</em> = 0.030, respectively), corresponding to approximately 25% decreases from macular average. OCT angiography signal and FD metrics also detected size-dependent flow impairment.</div></div><div><h3>Conclusions</h3><div>Large hyperTDs in nonexudative AMD exhibit reduced CC flow speed extending beyond the lesion boundary. Longitudinal studies will investigate whether CC flow predicts onset and progression of hyperTDs.</div></div><div><h3>Financial Disclosure(s)</h3><div>Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.</div></div>","PeriodicalId":74363,"journal":{"name":"Ophthalmology science","volume":"6 3","pages":"Article 101060"},"PeriodicalIF":4.6,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146189727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-30DOI: 10.1016/j.xops.2025.101057
Darvy Dang MOrth , Meghna Burmi MD , Xavier Hadoux PhD , Daniel McKay MBBS , Maxime Jannaud MEng , Myra B. McGuinness PhD , Peter van Wijngaarden PhD , Roderick O’Day DMedSci
Purpose
Accurate choroidal tumor border mapping is required for their management. We compared border mapping accuracy between unimodal assessment (color fundus photography [CFP] or scanning laser ophthalmoscopy [SLO]) against a multimodal assessment (CFP, SLO, and OCT) and identified tumor characteristics that affect performance.
Design
A cross-sectional diagnostic accuracy study.
Participants
Sixty-four choroidal lesions (61% nevi, 39% melanomas; median basal diameter 5.65 mm, median thickness 1.85 mm) from 63 patients at tertiary ocular oncology clinics in Victoria, Australia. No separate control group was included.
Methods
Two ocular oncologists independently delineated lesion margins on CFP and SLO. Multimodal assessment was established by agreement. Agreement between unimodal and multimodal assessments was quantified using the 95th percentile Hausdorff Distance (HD95).
Main Outcome Measures
The HD95 in millimeters between unimodal and multimodal tumor borders. Dice coefficient summary statistics are also provided.
Results
Overall, unimodal CFP and SLO assessments had good agreement with multimodal assessments (median HD95 <1 mm for each grader and device). However, HD95 was >2 mm in 5% (grader 1) and 9% (grader 2) of CFP assessments and in 2% (grader 1) and 3% (grader 2) of SLO assessments. Nonpigmented and mixed-pigmented tumors showed significantly higher HD95 than pigmented lesions for most grader-modality pairs, particularly for grader 1 on CFP and SLO (P < 0.05).
Conclusions
Choroidal tumor margin assessment was accurate on CFP and SLO as compared with a multimodal assessment that included enhanced-depth imaging OCT (EDI-OCT). However, the borders of a subset of tumors, especially those with reduced pigmentation, were inaccurately determined when using fundus photography alone. Incorporating EDI-OCT into choroidal tumor border mapping may reduce these discrepancies.
Financial Disclosure(s)
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
{"title":"Discrepancies between Fundus Photography and Multimodal Imaging in Mapping of Choroidal Tumor Borders","authors":"Darvy Dang MOrth , Meghna Burmi MD , Xavier Hadoux PhD , Daniel McKay MBBS , Maxime Jannaud MEng , Myra B. McGuinness PhD , Peter van Wijngaarden PhD , Roderick O’Day DMedSci","doi":"10.1016/j.xops.2025.101057","DOIUrl":"10.1016/j.xops.2025.101057","url":null,"abstract":"<div><h3>Purpose</h3><div>Accurate choroidal tumor border mapping is required for their management. We compared border mapping accuracy between unimodal assessment (color fundus photography [CFP] or scanning laser ophthalmoscopy [SLO]) against a multimodal assessment (CFP, SLO, and OCT) and identified tumor characteristics that affect performance.</div></div><div><h3>Design</h3><div>A cross-sectional diagnostic accuracy study.</div></div><div><h3>Participants</h3><div>Sixty-four choroidal lesions (61% nevi, 39% melanomas; median basal diameter 5.65 mm, median thickness 1.85 mm) from 63 patients at tertiary ocular oncology clinics in Victoria, Australia. No separate control group was included.</div></div><div><h3>Methods</h3><div>Two ocular oncologists independently delineated lesion margins on CFP and SLO. Multimodal assessment was established by agreement. Agreement between unimodal and multimodal assessments was quantified using the 95th percentile Hausdorff Distance (HD95).</div></div><div><h3>Main Outcome Measures</h3><div>The HD95 in millimeters between unimodal and multimodal tumor borders. Dice coefficient summary statistics are also provided.</div></div><div><h3>Results</h3><div>Overall, unimodal CFP and SLO assessments had good agreement with multimodal assessments (median HD95 <1 mm for each grader and device). However, HD95 was >2 mm in 5% (grader 1) and 9% (grader 2) of CFP assessments and in 2% (grader 1) and 3% (grader 2) of SLO assessments. Nonpigmented and mixed-pigmented tumors showed significantly higher HD95 than pigmented lesions for most grader-modality pairs, particularly for grader 1 on CFP and SLO (<em>P</em> < 0.05).</div></div><div><h3>Conclusions</h3><div>Choroidal tumor margin assessment was accurate on CFP and SLO as compared with a multimodal assessment that included enhanced-depth imaging OCT (EDI-OCT). However, the borders of a subset of tumors, especially those with reduced pigmentation, were inaccurately determined when using fundus photography alone. Incorporating EDI-OCT into choroidal tumor border mapping may reduce these discrepancies.</div></div><div><h3>Financial Disclosure(s)</h3><div>Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.</div></div>","PeriodicalId":74363,"journal":{"name":"Ophthalmology science","volume":"6 3","pages":"Article 101057"},"PeriodicalIF":4.6,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146189244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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