Classifying and quantifying changes in papilloedema using machine learning.

Background: Machine learning (ML) can differentiate papilloedema from normal optic discs using fundus photos. Currently, papilloedema severity is assessed using the descriptive, ordinal Frisén scale. We hypothesise that ML can quantify papilloedema and detect a treatment effect on papilloedema due to idiopathic intracranial hypertension. Methods: We trained a convolutional neural network to assign a Frisén grade to fundus photos taken from the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). We applied modified subject-based fivefold cross-validation to grade 2979 longitudinal images from 158 participants' study eyes (ie, the eye with the worst mean deviation) in the IIHTT. Compared with the human expert-determined grades, we hypothesise that ML-estimated grades can also demonstrate differential changes over time in the IIHTT study eyes between the treatment (acetazolamide (ACZ) plus diet) and placebo (diet only) groups. Findings: The average ML-determined grade correlated strongly with the reference standard (r=0.76, p<0.001; mean absolute error=0.54). At the presentation, treatment groups had similar expert-determined and ML-determined Frisén grades. The average ML-determined grade for the ACZ group (1.7, 95% CI 1.5 to 1.8) was significantly lower (p=0.0003) than for the placebo group (2.3, 95% CI 2.0 to 2.5) at the 6-month trial outcome. Interpretation: Supervised ML of fundus photos quantified the degree of papilloedema and changes over time reflecting the effects of ACZ. Given the increasing availability of fundus photography, neurologists will be able to use ML to quantify papilloedema on a continuous scale that incorporates the features of the Frisén grade to monitor interventions.

Ophthalmic drop waste due to self-imposed use cessation dates.

Self-imposed use cessation dates for multi-use eye drop bottles lead to significant drug waste and increased costs. We quantified the residual medication in eye drop bottles across three clinics in an academic ambulatory setting.

The Evolving Surgical Paradigm of Scleral Allograft Bio-Tissue Use in Ophthalmic Surgery: Techniques and Clinical Indications for Ab-Externo and Ab-Interno Scleral Reinforcement.

To review the latest surgical advances and evolving clinical use of scleral bio-tissue for reinforcement in the eye and review the published literature on novel surgical applications of scleral allograft bio-tissue. Conventional surgical procedures for scleral reinforcement using homologous scleral allograft have been traditionally ab-externo interventions comprising of anterior or posterior reinforcement of the sclera for clinical indications such as trauma, scleromalacia, glaucoma drainage device coverage, scleral perforation, buckle repair as well as posterior reinforcement for pathologic myopia and staphyloma. There have been a few novel ab-interno uses of scleral bio-tissue for reinforcement in both retina and glaucoma. Over the last decade, there has been an increase in peer-reviewed publications on scleral reinforcement, reflecting more interest in its clinical applications. With favorable biological and biomechanical properties, scleral allograft may be an ideal substrate for an array of new applications and surgical uses.

Use of Diagnostic Codes for Primary Open-Angle Glaucoma Polygenic Risk Score Construction in Electronic Health Record-linked Biobanks.

PURPOSE: Polygenic risk scores (PRSs) likely predict risk and prognosis of glaucoma. We compared the PRS performance for primary open-angle glaucoma (POAG), defined using International Classification of Diseases (ICD) codes versus manual medical record review. DESIGN: Retrospective cohort study METHODS: We identified POAG cases in Mount Sinai BioMe and Mass General Brigham (MGB) biobank using ICD codes. We confirmed POAG based on optical coherence tomograms and visual fields. In a separate 5% sample, the absence of POAG was confirmed with intraocular pressure and cup-disc ratio criteria. We used genotype data and either self-reported glaucoma diagnoses or ICD-10 codes for glaucoma diagnoses from the UK Biobank and the lassosum method to compute a genome-wide POAG PRS. We compared the area under the curve (AUC) for POAG prediction based on ICD codes versus medical records. RESULTS: We reviewed 804 of 996 BioMe and 367 of 1,006 MGB ICD-identified cases. In BioMe and MGB, respectively: positive predictive value was 53% and 55%; negative predictive value was 96% and 97%; sensitivity was 97% and 97%; and specificity was 44% and 53%. Adjusted PRS AUCs for POAG using ICD codes vs. manual record review in BioMe were not statistically different (p≥0.21) by ancestry: 0.77 vs. 0.75 for African, 0.80 vs. 0.80 for Hispanic, and 0.81 vs. 0.81 for European. Results were similar in MGB (p≥0.18): 0.72 vs. 0.80 for African, 0.83 vs. 0.86 for Hispanic, and 0.74 vs. 0.73 for European. CONCLUSIONS: A POAG PRS performed similarly using either manual review or ICD codes in two EHR-linked biobanks; manual assessment of glaucoma status might be unnecessary for some PRS studies. However, caution should be exercised with using ICD codes for glaucoma diagnosis given their low specificity (44-53%) for manually confirmed cases of glaucoma.

The Association of Urinary Sodium Excretion with Glaucoma and Related Traits in a Large United Kingdom Population.

PURPOSE: Excessive dietary sodium intake has known adverse effects on intravascular fluid volume and systemic blood pressure, which may influence intraocular pressure (IOP) and glaucoma risk. This study aimed to assess the association of urinary sodium excretion, a biomarker of dietary intake, with glaucoma and related traits, and determine whether this relationship is modified by genetic susceptibility to disease. DESIGN: Cross-sectional observational and gene-environment interaction analyses in the population-based UK Biobank study. PARTICIPANTS: Up to 103 634 individuals (mean age: 57 years; 51% women) with complete urinary, ocular, and covariable data. METHODS: Urine sodium:creatinine ratio (UNa:Cr; mmol:mmol) was calculated from a midstream urine sample. Ocular parameters were measured as part of a comprehensive eye examination, and glaucoma case ascertainment was through a combination of self-report and linked national hospital records. Genetic susceptibility to glaucoma was calculated based on a glaucoma polygenic risk score comprising 2673 common genetic variants. Multivariable linear and logistic regression, adjusted for key sociodemographic, medical, anthropometric, and lifestyle factors, were used to model associations and gene-environment interactions. MAIN OUTCOME MEASURES: Corneal-compensated IOP, OCT derived macular retinal nerve fiber layer and ganglion cell-inner plexiform layer (GCIPL) thickness, and prevalent glaucoma. RESULTS: In maximally adjusted regression models, a 1 standard deviation increase in UNa:Cr was associated with higher IOP (0.14 mmHg; 95% confidence interval [CI], 0.12-0.17; P < 0.001) and greater prevalence of glaucoma (odds ratio, 1.11; 95% CI, 1.07-1.14; P < 0.001) but not macular retinal nerve fiber layer or ganglion cell-inner plexiform layer thickness. Compared with those with UNa:Cr in the lowest quintile, those in the highest quintile had significantly higher IOP (0.45 mmHg; 95% CI, 0.36-0.53, P < 0.001) and prevalence of glaucoma (odds ratio, 1.30; 95% CI, 1.17-1.45; P < 0.001). Stronger associations with glaucoma (P interaction = 0.001) were noted in participants with a higher glaucoma polygenic risk score. CONCLUSIONS: Urinary sodium excretion, a biomarker of dietary intake, may represent an important modifiable risk factor for glaucoma, especially in individuals at high underlying genetic risk. These findings warrant further investigation because they may have important clinical and public health implications. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Genome-first evaluation with exome sequence and clinical data uncovers underdiagnosed genetic disorders in a large healthcare system.

Population-based genomic screening may help diagnose individuals with disease-risk variants. Here, we perform a genome-first evaluation for nine disorders in 29,039 participants with linked exome sequences and electronic health records (EHRs). We identify 614 individuals with 303 pathogenic/likely pathogenic or predicted loss-of-function (P/LP/LoF) variants, yielding 644 observations; 487 observations (76%) lack a corresponding clinical diagnosis in the EHR. Upon further investigation, 75 clinically undiagnosed observations (15%) have evidence of symptomatic untreated disease, including familial hypercholesterolemia (3 of 6 [50%] undiagnosed observations with disease evidence) and breast cancer (23 of 106 [22%]). These genetic findings enable targeted phenotyping that reveals new diagnoses in previously undiagnosed individuals. Disease yield is greater with variants in penetrant genes for which disease is observed in carriers in an independent cohort. The prevalence of P/LP/LoF variants exceeds that of clinical diagnoses, and some clinically undiagnosed carriers are discovered to have disease. These results highlight the potential of population-based genomic screening.

Harvard Glaucoma Fairness: A Retinal Nerve Disease Dataset for Fairness Learning and Fair Identity Normalization.

Fairness (also known as equity interchangeably) in machine learning is important for societal well-being, but limited public datasets hinder its progress. Currently, no dedicated public medical datasets with imaging data for fairness learning are available, though underrepresented groups suffer from more health issues. To address this gap, we introduce Harvard Glaucoma Fairness (Harvard-GF), a retinal nerve disease dataset including 3,300 subjects with both 2D and 3D imaging data and balanced racial groups for glaucoma detection. Glaucoma is the leading cause of irreversible blindness globally with Blacks having doubled glaucoma prevalence than other races. We also propose a fair identity normalization (FIN) approach to equalize the feature importance between different identity groups. Our FIN approach is compared with various state-of-the-art fairness learning methods with superior performance in the racial, gender, and ethnicity fairness tasks with 2D and 3D imaging data, demonstrating the utilities of our dataset Harvard-GF for fairness learning. To facilitate fairness comparisons between different models, we propose an equity-scaled performance measure, which can be flexibly used to compare all kinds of performance metrics in the context of fairness. The dataset and code are publicly accessible via https://ophai.hms.harvard.edu/datasets/harvard-gf3300/.

Polygenic Risk Scores for Glaucoma Onset in the Ocular Hypertension Treatment Study.

Importance: Primary open-angle glaucoma (POAG) is a highly heritable disease, with 127 identified risk loci to date. Polygenic risk score (PRS) may provide a clinically useful measure of aggregate genetic burden and improve patient risk stratification. Objective: To assess whether a PRS improves prediction of POAG onset in patients with ocular hypertension. Design, Setting, and Participants: This was a post hoc analysis of the Ocular Hypertension Treatment Study. Data were collected from 22 US sites with a mean (SD) follow-up of 14.0 (6.9) years. A total of 1636 participants were followed up from February 1994 to December 2008; 1077 participants were enrolled in an ancillary genetics study, of which 1009 met criteria for this analysis. PRS was calculated using summary statistics from the largest cross-ancestry POAG meta-analysis, with weights trained using 8 813 496 variants from 449 186 cross-ancestry participants in the UK Biobank. Data were analyzed from July 2022 to December 2023. Exposures: From February 1994 to June 2002, participants were randomized to either topical intraocular pressure-lowering medication or close observation. After June 2002, both groups received medication. Main Outcomes and Measures: Outcome measures were hazard ratios for POAG onset. Concordance index and time-dependent areas under the receiver operating characteristic curve were used to compare the predictive performance of multivariable Cox proportional hazards models. Results: Of 1009 included participants, 562 (55.7%) were female, and the mean (SD) age was 55.9 (9.3) years. The mean (SD) PRS was significantly higher for 350 POAG converters (0.24 [0.95]) compared with 659 nonconverters (-0.12 [1.00]) (P < .001). POAG risk increased 1.36% (95% CI, 1.08-1.64) with each higher PRS decile, with conversion ranging from 9.52% (95% CI, 7.09-11.95) in the lowest PRS decile to 21.81% (95% CI, 19.37-24.25) in the highest decile. Comparison of low-risk and high-risk PRS tertiles showed a 2.0-fold increase in 20-year POAG risk for participants of European and African ancestries. In the subgroup randomized to delayed treatment, each increase in PRS decile was associated with a 0.52-year (95% CI, 0.01-1.03) decrease in age at diagnosis (P = .047). No significant linear association between PRS and age at POAG diagnosis was present in the early treatment group. Prediction models significantly improved with the addition of PRS as a covariate (C index = 0.77) compared with the Ocular Hypertension Treatment Study baseline model (C index = 0.75) (P < .001). Each 1-SD higher PRS conferred a mean hazard ratio of 1.25 (95% CI, 1.13-1.44) for POAG onset. Conclusions and Relevance: Higher PRS was associated with increased risk for POAG in patients with ocular hypertension. The inclusion of a PRS improved the prediction of POAG onset. Trial Registration: ClinicalTrials.gov Identifier: NCT00000125.

Relationship Between Oral Health and Glaucoma Traits in the United Kingdom.

PRCIS: In this cross-sectional analysis of UK Biobank participants, we find no adverse association between self-reported oral health conditions and either glaucoma or elevated intraocular pressures. PURPOSE: Poor oral health may cause inflammation, which accelerates the progression of neurodegenerative diseases. We investigated the relationship between oral health and glaucoma. PATIENTS: United Kingdom Biobank participants. METHODS: This is a cross-sectional analysis of participants categorized by self-reported oral health status. Multivariable linear and logistic regression models were used. Primary analysis examined the association with glaucoma prevalence. Secondary analyses examined associations with IOP, macular retinal nerve fiber layer (mRNFL), and ganglion cell inner plexiform layer (mGCIPL) thicknesses, and interaction terms with multitrait glaucoma polygenic risk scores (MTAG PRS) or intraocular pressure (IOP) PRS. RESULTS: A total of 170,815 participants (34.3%) reported current oral health problems, including painful or bleeding gums, toothache, loose teeth, and/or denture wear. A In all, 33,059, 33,004, 14,652, and 14,613 participants were available for analysis of glaucoma, IOP, mRNFL, and mGCIPL, respectively. No association between oral health and glaucoma was identified [odds ratio (OR): 1.04, 95% CI: 0.95-1.14]. IOPs were slightly lower among those with oral disease (-0.08 mm Hg, 95% CI: -0.15, -0.009); specifically, among those with loose teeth ( P =0.03) and denture-wearers ( P <0.0001). mRNFL measurements were lower among those with oral health conditions (-0.14 µm, 95% CI: -0.27, -0.0009), but mGCIPL measurements ( P =0.96) were not significantly different. A PRS for IOP or glaucoma did not modify relations between oral health and IOP or glaucoma ( P for interactions ≥​​​​0.17). CONCLUSIONS: Self-reported oral health was not associated with elevated IOP or an increased risk of glaucoma. Future studies should confirm the null association between clinically diagnosed oral health conditions and glaucoma.

Assessment of a Large Language Model's Responses to Questions and Cases About Glaucoma and Retina Management.

Importance: Large language models (LLMs) are revolutionizing medical diagnosis and treatment, offering unprecedented accuracy and ease surpassing conventional search engines. Their integration into medical assistance programs will become pivotal for ophthalmologists as an adjunct for practicing evidence-based medicine. Therefore, the diagnostic and treatment accuracy of LLM-generated responses compared with fellowship-trained ophthalmologists can help assess their accuracy and validate their potential utility in ophthalmic subspecialties. Objective: To compare the diagnostic accuracy and comprehensiveness of responses from an LLM chatbot with those of fellowship-trained glaucoma and retina specialists on ophthalmological questions and real patient case management. Design, Setting, and Participants: This comparative cross-sectional study recruited 15 participants aged 31 to 67 years, including 12 attending physicians and 3 senior trainees, from eye clinics affiliated with the Department of Ophthalmology at Icahn School of Medicine at Mount Sinai, New York, New York. Glaucoma and retina questions (10 of each type) were randomly selected from the American Academy of Ophthalmology's commonly asked questions Ask an Ophthalmologist. Deidentified glaucoma and retinal cases (10 of each type) were randomly selected from ophthalmology patients seen at Icahn School of Medicine at Mount Sinai-affiliated clinics. The LLM used was GPT-4 (version dated May 12, 2023). Data were collected from June to August 2023. Main Outcomes and Measures: Responses were assessed via a Likert scale for medical accuracy and completeness. Statistical analysis involved the Mann-Whitney U test and the Kruskal-Wallis test, followed by pairwise comparison. Results: The combined question-case mean rank for accuracy was 506.2 for the LLM chatbot and 403.4 for glaucoma specialists (n = 831; Mann-Whitney U = 27976.5; P < .001), and the mean rank for completeness was 528.3 and 398.7, respectively (n = 828; Mann-Whitney U = 25218.5; P < .001). The mean rank for accuracy was 235.3 for the LLM chatbot and 216.1 for retina specialists (n = 440; Mann-Whitney U = 15518.0; P = .17), and the mean rank for completeness was 258.3 and 208.7, respectively (n = 439; Mann-Whitney U = 13123.5; P = .005). The Dunn test revealed a significant difference between all pairwise comparisons, except specialist vs trainee in rating chatbot completeness. The overall pairwise comparisons showed that both trainees and specialists rated the chatbot's accuracy and completeness more favorably than those of their specialist counterparts, with specialists noting a significant difference in the chatbot's accuracy (z = 3.23; P = .007) and completeness (z = 5.86; P < .001). Conclusions and Relevance: This study accentuates the comparative proficiency of LLM chatbots in diagnostic accuracy and completeness compared with fellowship-trained ophthalmologists in various clinical scenarios. The LLM chatbot outperformed glaucoma specialists and matched retina specialists in diagnostic and treatment accuracy, substantiating its role as a promising diagnostic adjunct in ophthalmology.

Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma.

Primary open-angle glaucoma (POAG), characterized by retinal ganglion cell death, is a leading cause of irreversible blindness worldwide. However, its molecular and cellular causes are not well understood. Elevated intraocular pressure (IOP) is a major risk factor, but many patients have normal IOP. Colocalization and Mendelian randomization analysis of >240 POAG and IOP genome-wide association study (GWAS) loci and overlapping expression and splicing quantitative trait loci (e/sQTLs) in 49 GTEx tissues and retina prioritizes causal genes for 60% of loci. These genes are enriched in pathways implicated in extracellular matrix organization, cell adhesion, and vascular development. Analysis of single-nucleus RNA-seq of glaucoma-relevant eye tissues reveals that the POAG and IOP colocalizing genes and genome-wide associations are enriched in specific cell types in the aqueous outflow pathways, retina, optic nerve head, peripapillary sclera, and choroid. This study nominates IOP-dependent and independent regulatory mechanisms, genes, and cell types that may contribute to POAG pathogenesis.

Recent developments of telemedicine in glaucoma.

PURPOSE OF REVIEW: Telemedicine has an increasingly significant role in the fields of ophthalmology and glaucoma. This review covers recent advancements in the development and optimization of teleglaucoma techniques and applications. RECENT FINDINGS: Glaucoma monitoring and diagnosis via remote tonometry, perimetry, and fundus imaging have become a possibility based on recent developments. Many applications work in combination with smart devices, virtual reality, and artificial intelligence and have been tested in patient populations against conventional "reference-standard" measurement tools, demonstrating promising results. Of note, there is still much progress to be made in teleglaucoma and telemedicine at large, such as accessibility to internet, broadband, and smart devices, application affordability, and reimbursement for remote services. However, continued development and optimization of these applications suggest that the implementation of remote monitoring will be a mainstay for glaucoma patient care. SUMMARY: Especially since the beginning of the COVID-19 pandemic, remote patient care has taken on an important role in medicine and ophthalmology. Remote versions of tonometry, perimetry, and fundus imaging may allow for a more patient-centered and accessible future for glaucoma care.

Comparison of Structural and Functional Features in Primary Angle Closure and Open Angle Glaucomas.

PRCIS: Using a large data set, we showed structural and functional differences between primary angle closure glaucoma (PACG) and primary open angle glaucoma (POAG). Primary angle closure glaucoma has relative structural preservation and worse functional loss inferiorly. PURPOSE: To identify structural and functional differences in PACG and POAG. MATERIALS AND METHODS: In this large cross-sectional study, differences in structural and functional damage were assessed among patients with POAG and PACG with optical coherence tomography and reliable visual field testing. RESULTS: In all, 283 patients with PACG and 4110 patients with POAG were included. Despite similar mean deviation on visual fields (mean [SD] -7.73 [7.92] vs. -7.53 [6.90] dB, P =0.72), patients with PACG had thicker global retinal nerve fiber layer (RNFL), smaller cup volume, smaller cup-to-disc ratio, and larger rim area than POAG (77 [20] vs. 71 [14] µm, 0.32 [0.28] vs. 0.40 [0.29] mm 3 , 0.6 [0.2] vs. 0.7 [0.1], 1.07 [0.40] vs. 0.89 [0.30] mm 2 , P <0.001 for all), while patients with POAG had more pronounced inferior RNFL thinning (82 [24] vs. 95 [35] µm, P <0.001). In a multivariable analysis, hyperopia [odds ratio (OR): 1.24, confidence interval (CI): 1.13-1.37], smaller cup-to-disc ratio (OR: 0.69, CI: 0.61-0.78), thicker inferior RNFL (OR: 1.15, CI: 1.06-1.26) and worse mean deviation (OR: 0.95, CI: 0.92-0.98) were associated with PACG. Functionally, POAG was associated with superior paracentral loss and PACG with inferior field loss. After adjusting for average RNFL thickness, PACG was associated with more diffuse loss than POAG (total deviation differences 1.26-3.2 dB). CONCLUSIONS: Patients with PACG had less structural damage than patients with POAG despite similar degrees of functional loss. Regional differences in patterns of functional and structural loss between POAG and PACG may improve disease monitoring for these glaucoma subtypes.

Lessons From The Glaucoma Foundation Think Tank 2023: A Patient-Centric Approach to Glaucoma.

PRCIS: The main takeaways also included that BIG DATA repositories and AI are important combinatory tools to foster novel strategies to prevent and stabilize glaucoma and, in the future, recover vision loss from the disease. PURPOSE: To summarize the main topics discussed during the 28th Annual Glaucoma Foundation Think Tank Meeting "A Patient-Centric Approach to Glaucoma" held in New York on June 9 and 10, 2023. METHODS: The highlights of the sessions on BIG DATA, genetics, modifiable lifestyle risk factors, female sex hormones, and neuroprotection in the field of primary open angle glaucoma (POAG) were summarized. RESULTS: The researchers discussed the importance of BIG DATA repositories available at national and international levels for POAG research, including the United Kingdom Biobank. Combining genotyped large cohorts worldwide, facilitated by artificial intelligence (AI) and machine-learning approaches, led to the milestone discovery of 312 genome-wide significant disease loci for POAG. While these loci could be combined into a polygenic risk score with clinical utility, Think Tank meeting participants also provided analytical epidemiological evidence that behavioral risk factors modify POAG polygenetic risk, citing specific examples related to caffeine and alcohol use. The impact of female sex hormones on POAG pathophysiology was discussed, as was neuroprotection and the potential use of AI to help mitigate specific challenges faced in clinical trials and speed approval of neuroprotective agents. CONCLUSIONS: The experts agreed on the importance of genetics in defining individual POAG risk and highlighted the additional crucial role of lifestyle, gender, blood pressure, and vascular risk factors. The main takeaways also included that BIG DATA repositories and AI are important combinatory tools to foster novel strategies to prevent and stabilize glaucoma and, in the future, recover vision loss from the disease.

Estrogen dysregulation, intraocular pressure, and glaucoma risk.

Characterized by optic nerve atrophy due to retinal ganglion cell (RGC) death, glaucoma is the leading cause of irreversible blindness worldwide. Of the major risk factors for glaucoma (age, ocular hypertension, and genetics), only elevated intraocular pressure (IOP) is modifiable, which is largely regulated by aqueous humor outflow through the trabecular meshwork. Glucocorticoids such as dexamethasone have long been known to elevate IOP and lead to glaucoma. However, several recent studies have reported that steroid hormone estrogen levels inversely correlate with glaucoma risk, and that variants in estrogen signaling genes have been associated with glaucoma. As a result, estrogen dysregulation may contribute to glaucoma pathogenesis, and estrogen signaling may protect against glaucoma. The mechanism for estrogen-related protection against glaucoma is not completely understood but likely involves both regulation of IOP homeostasis and neuroprotection of RGCs. Based upon its known activities, estrogen signaling may promote IOP homeostasis by affecting extracellular matrix turnover, focal adhesion assembly, actin stress fiber formation, mechanosensation, and nitric oxide production. In addition, estrogen receptors in the RGCs may mediate neuroprotective functions. As a result, the estrogen signaling pathway may offer a therapeutic target for both IOP control and neuroprotection. This review examines the evidence for a relationship between estrogen and IOP and explores the possible mechanisms by which estrogen maintains IOP homeostasis.

Generative Artificial Intelligence Through ChatGPT and Other Large Language Models in Ophthalmology: Clinical Applications and Challenges.

The rapid progress of large language models (LLMs) driving generative artificial intelligence applications heralds the potential of opportunities in health care. We conducted a review up to April 2023 on Google Scholar, Embase, MEDLINE, and Scopus using the following terms: "large language models," "generative artificial intelligence," "ophthalmology," "ChatGPT," and "eye," based on relevance to this review. From a clinical viewpoint specific to ophthalmologists, we explore from the different stakeholders' perspectives-including patients, physicians, and policymakers-the potential LLM applications in education, research, and clinical domains specific to ophthalmology. We also highlight the foreseeable challenges of LLM implementation into clinical practice, including the concerns of accuracy, interpretability, perpetuating bias, and data security. As LLMs continue to mature, it is essential for stakeholders to jointly establish standards for best practices to safeguard patient safety. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Calcium Channel Blocker Use and Associated Glaucoma and Related Traits Among UK Biobank Participants.

Importance: Calcium channel blocker (CCB) use has been associated with an increased risk of glaucoma in exploratory studies. Objective: To examine the association of systemic CCB use with glaucoma and related traits among UK Biobank participants. Design, Setting, and Participants: This population-based cross-sectional study included UK Biobank participants with complete data (2006-2010) for analysis of glaucoma status, intraocular pressure (IOP), and optical coherence tomography (OCT)-derived inner retinal layer thicknesses. Data analysis was conducted in January 2023. Exposure: Calcium channel blocker use was assessed in a baseline touchscreen questionnaire and confirmed during an interview led by a trained nurse. Main Outcomes and Measures: The primary outcome measures included glaucoma status, corneal-compensated IOP, and 2 OCT-derived inner retinal thickness parameters (macular retinal nerve fiber layer [mRNFL] and macular ganglion cell-inner plexiform layer [mGCIPL] thicknesses). We performed logistic regression and linear regression analyses to test for associations with glaucoma status and IOP and OCT-derived inner retinal thickness parameters, respectively. Results: This study included 427 480 adults. Their median age was 58 (IQR, 50-63) years, and more than half (54.1%) were women. There were 33 175 CCB users (7.8%). Participants who had complete data for glaucoma status (n = 427 480), IOP (n = 97 100), and OCT-derived inner retinal layer thicknesses (n = 41 023) were eligible for respective analyses. After adjustment for key sociodemographic, medical, anthropometric, and lifestyle factors, use of CCBs (but not other antihypertensive agents) was associated with greater odds of glaucoma (odds ratio [OR], 1.39 [95% CI, 1.14 to 1.69]; P = .001). Calcium channel blocker use was also associated with thinner mGCIPL (-0.34 µm [95% CI, -0.54 to -0.15 µm]; P = .001) and mRNFL (-0.16 µm [95% CI, -0.30 to -0.02 µm]; P = .03) thicknesses but not IOP (-0.01 mm Hg [95% CI, -0.09 to 0.07 mm Hg]; P = .84). Conclusions and Relevance: In this study, an adverse association between CCB use and glaucoma was observed, with CCB users having, on average, 39% higher odds of glaucoma. Calcium channel blocker use was also associated with thinner mGCIPL and mRNFL thicknesses, providing a structural basis that supports the association with glaucoma. The lack of association of CCB use with IOP suggests that an IOP-independent mechanism of glaucomatous neurodegeneration may be involved. Although a causal relationship has not been established, CCB replacement or withdrawal may be considered should glaucoma progress despite optimal care.

Polygenic Risk Score Improves Prediction of Primary Open Angle Glaucoma Onset in the Ocular Hypertension Treatment Study.

Objective or Purpose: Primary open-angle glaucoma (POAG) is a highly heritable disease with 127 identified risk loci. Polygenic risks score (PRS) offers a measure of aggregate genetic burden. In this study, we assess whether PRS improves risk stratification in patients with ocular hypertension. Design: A post-hoc analysis of the Ocular Hypertension Treatment Study (OHTS) data. Setting Participants and/or Controls: 1636 participants were followed from 1994 to 2020 across 22 sites. The PRS was computed for 1009 OHTS participants using summary statistics from largest cross-ancestry POAG metanalysis with weights trained using 8,813,496 variants from 488,395 participants in the UK Biobank. Methods Interventions or Testing: Survival regression analysis, with endpoint as development of POAG, predicted disease onset from PRS incorporating baseline covariates. Main Outcomes and Measures: Outcome measures were hazard ratios for POAG onset. Concordance index and time-dependent AUC were used to compare the predictive performance of multivariable Cox-Proportional Hazards models. Results: Mean PRS was significantly higher for POAG-converters (0.24 ± 0.95) than for non-converters (-0.12 ± 1.00) (p < 0.01). POAG risk increased 1.36% with each higher PRS decile, with conversion ranging from 9.5% in the lowest PRS decile to 21.8% in the highest decile. Comparison of low- and high-risk PRS tertiles showed a 1.8-fold increase in 20-year POAG risk for participants of European and African ancestries (p<0.01). In the subgroup randomized to delayed treatment, each increase in PRS decile was associated with a 0.52-year decrease in age at diagnosis, (p=0.05). No significant linear relationship between PRS and age at POAG diagnosis was present in the early treatment group. Prediction models significantly improved with the addition of PRS as a covariate (C-index = 0.77) compared to OHTS baseline model (C-index=0.75) (p<0.01). One standard deviation higher PRS conferred a mean hazard ratio of 1.25 (CI=[1.13, 1.44]) for POAG onset. Conclusions: Higher PRS is associated with increased risk for, and earlier development of POAG in patients with ocular hypertension. Early treatment may mitigate the risk from high genetic burden, delaying clinically detectable disease by up to 5.2 years. The inclusion of a PRS improves the prediction of POAG onset.