Comparative Single Vesicle Analysis of Aqueous Humor Extracellular Vesicles before and after Radiation in Uveal Melanoma Eyes.

Small extracellular vesicles (sEVs) have been shown to promote tumorigenesis, treatment resistance, and metastasis in multiple cancer types; however, sEVs in the aqueous humor (AH) of uveal melanoma (UM) patients have never previously been profiled. In this study, we used single particle analysis to characterize sEV subpopulations in the AH of UM patients by quantifying their size, concentration, and phenotypes based on cell surface markers, specifically the tetraspanin co-expression patterns of CD9, CD63, and CD81. sEVs were analyzed from paired pre- and post-treatment (brachytherapy, a form of radiation) AH samples collected from 19 UM patients. In post-brachytherapy samples, two subpopulations, CD63/81+ and CD9/63/81+ sEVs, were significantly increased. These trends existed even when stratified by tumor location and GEP class 1 and class 2 (albeit not significant for GEP class 2). In this initial report of single vesicle profiling of sEVs in the AH of UM patients, we demonstrated that sEVs can be detected in the AH. We further identified two subpopulations that were increased post-brachytherapy, which may suggest radiation-induced release of these particles, potentially from tumor cells. Further study of the cargo carried by these sEV subpopulations may uncover important biomarkers and insights into tumorigenesis for UM.

Long-Term Risk and Prediction of Progression in Primary Angle Closure Suspect.

Importance: Identifying primary angle closure suspect (PACS) eyes at risk of angle closure is crucial for its management. However, the risk of progression and its prediction are still understudied in long-term longitudinal studies about PACS. Objective: To explore baseline predictors and develop prediction models for the 14-year risk of progression from PACS to primary angle closure (PAC). Design, Setting, and Participants: This cohort study involved participants from the Zhongshan Angle Closure Prevention trial who had untreated eyes with PACS. Baseline examinations included tonometry, ultrasound A-scan biometry, and anterior segment optical coherence tomography (AS-OCT) under both light and dark conditions. Primary angle closure was defined as peripheral anterior synechiae in 1 or more clock hours, intraocular pressure (IOP) greater than 24 mm Hg, or acute angle closure. Based on baseline covariates, logistic regression models were built to predict the risk of progression from PACS to PAC during 14 years of follow-up. Results: The analysis included 377 eyes from 377 patients (mean [SD] patient age at baseline, 58.28 [4.71] years; 317 females [84%]). By the 14-year follow-up visit, 93 eyes (25%) had progressed from PACS to PAC. In multivariable models, higher IOP (odds ratio [OR], 1.14 [95% CI, 1.04-1.25] per 1-mm Hg increase), shallower central anterior chamber depth (ACD; OR, 0.81 [95% CI, 0.67-0.97] per 0.1-mm increase), and shallower limbal ACD (OR, 0.96 [95% CI, 0.93-0.99] per 0.01 increase in peripheral corneal thickness) at baseline were associated with an increased 14-year risk of progression from PACS to PAC. As for AS-OCT measurements, smaller light-room trabecular-iris space area (TISA) at 500 µm from the scleral spur (OR, 0.86 [95% CI, 0.77-0.96] per 0.01-mm2 increase), smaller light-room angle recess area (ARA) at 750 µm from the scleral spur (OR, 0.93 [95% CI, 0.88-0.98] per 0.01-mm2 increase), and smaller dark-room TISA at 500 µm (OR, 0.89 [95% CI, 0.80-0.98] per 0.01-mm2 increase) at baseline were identified as predictors for the 14-year risk of progression. The prediction models based on IOP and central and limbal ACDs showed moderate performance (area under the receiver operating characteristic curve, 0.69; 95% CI, 0.63-0.75) in predicting progression from PACS to PAC, and inclusion of AS-OCT metrics did not improve the model's performance. Conclusions and Relevance: This cohort study suggests that higher IOP, shallower central and limbal ACDs, and smaller TISA at 500 µm and light-room ARA at 750 µm may serve as baseline predictors for progression to PAC in PACS eyes. Evaluating these factors can aid in customizing PACS management.

Multicentre analysis of nucleic acid quantification using aqueous humour liquid biopsy in uveal melanoma: implications for clinical testing.

OBJECTIVE: Uveal melanoma (UM) tumour biopsy is limited by size and intratumour heterogeneity. We explored the potential of aqueous humour (AH) liquid biopsy for UM by quantifying analytes in samples collected at diagnosis and after brachytherapy to look for clinical correlations with tumour features. DESIGN: Case-series study. PARTICIPANTS: Sixty-six UM patients and 16 control subjects from a tertiary care hospital. METHODS: The study included 119 UM AH samples and 16 control samples analyzed for unprocessed analytes (i.e., dsDNA, miRNA, and protein) using Qubit fluorescence assays. RESULTS: Analytes were widely quantifiable among available UM AH samples (dsDNA: 94.1%; miRNA: 88.0%; protein: 95.2%) at significantly higher concentrations than among control samples (dsDNA, p = 0.008; miRNA, p < 0.0001; protein, p = 0.007). In samples taken at diagnosis, concentrations were higher at more advanced American Joint Cancer Commission stages; when comparing most advanced stage III with least advanced stage I, median dsDNA was 4 times greater (p < 0.0001), miRNA was 2 times greater (p = 0.001), and protein was 3 times greater (p < 0.0001). Analytes were quantifiable in >70% of diagnostic samples from eyes with tumours <2 mm tall. Height had a positive association with diagnostic analyte concentrations (dsDNA: R = 0.43, p = 0.0007; miRNA: R = 0.35, p = 0.01; protein: R = 0.39, p = 0.005). Samples taken after brachytherapy showed significantly higher concentrations than diagnostic samples (p < 0.01 for all). CONCLUSIONS: UM AH is a rich repository of analytes. Samples from eyes with more advanced stage and larger tumours had higher concentrations, though analytes also were quantifiable in eyes with smaller, less advanced tumours. Future analysis of AH analytes may be informative in the pursuit of personalized UM treatments.

Identifying, Understanding, and Addressing Disparities in Glaucoma Care in the United States.

Glaucoma is the leading cause of irreversible blindness worldwide, currently affecting around 80 million people. Glaucoma prevalence is rapidly rising in the United States due to an aging population. Despite recent advances in the diagnosis and treatment of glaucoma, significant disparities persist in disease detection, management, and outcomes among the diverse patient populations of the United States. Research on disparities is critical to identifying, understanding, and addressing societal and healthcare inequalities. Disparities research is especially important and impactful in the context of irreversible diseases such as glaucoma, where earlier detection and intervention are the primary approach to improving patient outcomes. In this article, we first review recent studies identifying disparities in glaucoma care that affect patient populations based on race, age, and gender. We then review studies elucidating and furthering our understanding of modifiable factors that contribute to these inequities, including socioeconomic status (particularly age and education), insurance product, and geographic region. Finally, we present work proposing potential strategies addressing disparities in glaucoma care, including teleophthalmology and artificial intelligence. We also discuss the presence of non-modifiable factors that contribute to differences in glaucoma burden and can confound the detection of glaucoma disparities. Translational Relevance: By recognizing underlying causes and proposing potential solutions, healthcare providers, policymakers, and other stakeholders can work collaboratively to reduce the burden of glaucoma and improve visual health and clinical outcomes in vulnerable patient populations.

Automated expert-level scleral spur detection and quantitative biometric analysis on the ANTERION anterior segment OCT system.

AIM: To perform an independent validation of deep learning (DL) algorithms for automated scleral spur detection and measurement of scleral spur-based biometric parameters in anterior segment optical coherence tomography (AS-OCT) images. METHODS: Patients receiving routine eye care underwent AS-OCT imaging using the ANTERION OCT system (Heidelberg Engineering, Heidelberg, Germany). Scleral spur locations were marked by three human graders (reference, expert and novice) and predicted using DL algorithms developed by Heidelberg Engineering that prioritise a false positive rate <4% (FPR4) or true positive rate >95% (TPR95). Performance of human graders and DL algorithms were evaluated based on agreement of scleral spur locations and biometric measurements with the reference grader. RESULTS: 1308 AS-OCT images were obtained from 117 participants. Median differences in scleral spur locations from reference locations were significantly smaller (p<0.001) for the FPR4 (52.6±48.6 µm) and TPR95 (55.5±50.6 µm) algorithms compared with the expert (61.1±65.7 µm) and novice (79.4±74.9 µm) graders. Intergrader reproducibility of biometric measurements was excellent overall for all four (intraclass correlation coefficient range 0.918-0.997). Intergrader reproducibility of the expert grader (0.567-0.965) and DL algorithms (0.746-0.979) exceeded that of the novice grader (0.146-0.929) for images with narrow angles defined by OCT measurement of angle opening distance 500 µm anterior to the scleral spur (AOD500)<150 µm. CONCLUSIONS: DL algorithms on the ANTERION approximate expert-level measurement of scleral spur-based biometric parameters in an independent patient population. These algorithms could enhance clinical utility of AS-OCT imaging, especially for evaluating patients with angle closure and performing intraocular lens calculations.

Investigating the determinants of iridolenticular contact area: a novel parameter for angle closure.

BACKGROUND/AIMS: To identify ocular determinants of iridolenticular contact area (ILCA), a recently introduced swept-source optical coherence tomography (SSOCT) derived parameter, and assess the association between ILCA and angle closure. METHODS: In this population-based cross-sectional study, right eyes of 464 subjects underwent SSOCT (SS-1000, CASIA, Tomey Corporation, Nagoya, Japan) imaging in the dark. Eight out of 128 cross-sectional images (evenly spaced 22.5° apart) were selected for analysis. Matlab (Matworks, Massachusetts, USA) was used to measure ILCA, defined as the circumferential extent of contact area between the pigmented iris epithelium and anterior lens surface. Gonioscopic angle closure (GAC) was defined as non-visibility of the posterior trabecular meshwork in two or more angle quadrants. RESULTS: The mean age of subjects was 62±6.6 years, with the majority being female (65.5%). 143/464 subjects (28.6%) had GAC. In multivariable linear regression analysis, ILCA was significantly associated with anterior chamber width (ß=1.03, p=0.003), pupillary diameter (ß=-1.9, p<0.001) and iris curvature (ß=-17.35, p<0.001). ILCA was smaller in eyes with GAC compared with those with open angles (4.28±1.6 mm2 vs 6.02±2.71 mm2, p<0.001). ILCA was independently associated with GAC (ß=-0.03, p<0.001), iridotrabecular contact index (ß=-6.82, p<0.001) or angle opening distance (ß=0.02, p<0.001) after adjusting for covariates. The diagnostic performance of ILCA for detecting GAC was acceptable (AUC=0.69). CONCLUSIONS: ILCA is a significant predictor of angle closure independent of other biometric factors and may reflect unique anatomical information associated with pupillary block. ILCA represents a novel biometric risk factor in eyes with angle closure.

Classification of Angle Closure Severity by Hierarchical Cluster Analysis of Ocular Biometrics in the Dark and Light.

Purpose: The purpose of this study was to investigate the classification of angle closure eyes based on hierarchical cluster analysis of ocular biometrics measured in the dark and light using anterior segment optical coherence tomography (AS-OCT). Methods: Participants of the Chinese American Eye Study received complete eye examinations to identify primary angle closure suspects (PACS) and primary angle closure without/with glaucoma (PAC/G). AS-OCT was performed in the dark and light. Biometric parameters describing the angle, iris, lens, and anterior chamber were analyzed. Hierarchical clustering was performed using Ward's method. Post hoc logistic regression models were developed to identify biometric predictors of angle closure staging. Results: Analysis of 159 eyes with PACS (N = 120) or PAC/G (N = 39) produced 2 clusters in the dark and light. In both analyses, cluster 1 (N = 132 in the dark and N = 126 in the light) was characterized by smaller angle opening distance (AOD)750 and trabecular iris space area (TISA)750, greater iris curvature (IC), and greater lens vault (LV; P < 0.001) than cluster 2. The proportion of PAC/PACG to PACS eyes was significantly higher in cluster 1 than 2 in the light (36:90 and 3:30, respectively; P = 0.02), but not the dark (36:96 and 3:24, respectively; P = 0.08). On multivariable regression analyses, smaller TISA750 (odds ratio [OR] = 0.84 per 0.01 mm2) and AOD750 (OR = 0.93 per 0.01 mm) in the light and smaller TISA750 (OR = 0.86 per 0.01 mm2) in the dark conferred higher risk of PAC/G (P ≤ 0.02). Conclusions: Unsupervised cluster analysis of ocular biometrics can classify angle closure eyes by severity. Static biometrics measured in the light and dark are both predictive of PAC/G. Translational Relevance: Clustering of biometrics measured in the light could provide an alternative source of information to risk-stratify angle closure eyes for more severe disease.

Role of Static and Dynamic Ocular Biometrics Measured in the Dark and Light as Risk Factors for Angle Closure Progression.

PURPOSE: To assess the role of static and dynamic ocular biometric parameters measured in the dark and light for predicting progression of primary angle closure suspect (PACS) to primary angle closure (PAC). DESIGN: Retrospective cohort study using prospective randomized controlled trial data from untreated, control eyes. METHODS: Zhongshan Angle Closure Prevention Trial subjects underwent anterior segment optical coherence tomography (AS-OCT) imaging in the dark and light. Static biometric parameters were measured, consisting of angle, iris, lens, and anterior chamber parameters. Dynamic change parameters were calculated by subtracting light measurements from dark measurements. Cox proportional hazards regression models were developed to assess risk factors for PACD progression. RESULTS: A total of 861 eyes of 861 participants were analyzed (36 progressors). On univariable analysis, TISA500 measurements in the light and dark were associated with progression (P < .001), whereas dynamic change parameters were not (P ≥ .08). In the primary multivariable model, older age (hazard ratio [HR] = 1.09 per year), higher intraocular pressure (IOP) (HR = 1.13 per mm Hg), and smaller TISA500 in the light (HR = 1.28 per 0.01 mm2) were significantly associated with greater risk of progression (P ≤ .04). Dark TISA500 had similar significance (HR = 1.28, P = .002) when replacing light TISA500. Risk of progression was more predictive among eyes in the lowest quartile of light TISA500 measurements (HR = 4.56, P < .001) compared to dark measurements (HR = 2.89, P = .003). CONCLUSION: Static parameters measured in the light are as predictive, and possibly more so, of angle closure progression as those measured in the dark. Ocular biometrics measured under light and dark conditions may provide additional information for risk-stratifying patients for angle closure progression.

Racial and Ethnic Differences in the Roles of Myopia and Ocular Biometrics as Risk Factors for Primary Open-Angle Glaucoma.

Purpose: Assess how the roles of refractive error (RE) and ocular biometrics as risk factors for primary open-angle glaucoma (POAG) differ by race and ethnicity. Methods: Data from the Los Angeles Latino Eye Study (LALES) and the Chinese American Eye Study (CHES), two population-based epidemiological studies, were retrospectively analyzed. Multivariable logistic regression and interaction term analyses were performed to assess relationships between POAG and its risk factors, including RE and axial length (AL), and to assess effect modification by race/ethnicity. Results: Analysis included 7601 phakic participants of LALES (47.3%) and CHES (52.7%) with age ≥ 50 years. Mean age was 60.6 ± 8.3 years; 60.9% were female. The prevalence and unadjusted risk of POAG were higher in LALES than CHES (6.0% and 4.0%, respectively; odds ratio [OR] = 1.55; P < 0.001). In the multivariable analysis, significant risk factors for POAG included Latino ethnicity (OR = 2.25; P < 0.001), refractive myopia (OR = 1.54 for mild, OR = 2.47 for moderate, OR = 3.94 for high compared to non-myopes; P ≤ 0.003), and longer AL (OR = 1.37 per mm; P < 0.001). AL (standardized regression coefficient [SRC] = 0.3) was 2.7-fold more strongly associated with POAG than high myopia status (SRC = 0.11). There was no modifying effect by race/ethnicity on the association between RE (per diopter) or AL (per millimeter) and POAG (P = 0.49). Conclusions: Although the POAG risk conferred by myopic RE and longer AL is similar between Latino and Chinese Americans, the difference in POAG prevalence between the two groups is narrowed by higher myopia prevalence among Chinese Americans. Racial/ethnic populations with higher myopia incidence may become disproportionately affected by POAG in the context of the global myopia epidemic.

Biometric Risk Factors for Angle Closure Progression After Laser Peripheral Iridotomy.

Importance: Laser peripheral iridotomy (LPI) is the most common primary treatment for primary angle closure disease (PACD). However, there are sparse data guiding the longitudinal care of PAC suspect (PACS) eyes after LPI. Objective: To elucidate the anatomic effects of LPI that are associated with a protective outcome against progression from PACS to PAC and acute angle closure (AAC) and to identify biometric factors that predict progression after LPI. Design, Setting, and Participants: This was a retrospective analysis of data from the Zhongshan Angle Closure Prevention (ZAP) trial, a study of mainland Chinese people aged 50 to 70 years with bilateral PACS who received LPI in 1 randomly selected eye. Gonioscopy and anterior-segment optical coherence tomography (AS-OCT) imaging were performed 2 weeks after LPI. Progression was defined as the development of PAC or an acute angle closure (AAC) attack. Cohort A included a random mix of treated and untreated eyes, and cohort B included only eyes treated with LPI. Univariable and multivariable Cox regression models were developed to assess biometric risk factors for progression in cohorts A and B. Data were analyzed from January 4 to December 22, 2022. Main Outcome and Measure: Six-year progression to PAC or AAC. Results: Cohort A included 878 eyes from 878 participants (mean [SD] age, 58.9 [5.0] years; 726 female [82.7%]) of whom 44 experienced progressive disease. In a multivariable analysis, treatment (hazard ratio [HR], 0.67; 95% CI, 0.34-1.33; P = .25) was no longer associated with progression after adjusting for age and trabecular iris space area at 500 µm (TISA at 500 µm) at the 2-week visit. Cohort B included 869 treated eyes from 869 participants (mean [SD] age, 58.9 [5.0] years; 717 female [82.5%]) of whom 19 experienced progressive disease. In multivariable analysis, TISA at 500 µm (HR, 1.33 per 0.01 mm2 smaller; 95% CI, 1.12-1.56; P = .001) and cumulative gonioscopy score (HR, 1.25 per grade smaller; 95% CI, 1.03-1.52; P = .02) at the 2-week visit were associated with progression. Persistent angle narrowing on AS-OCT (TISA at 500 µm ≤0.05 mm2; HR, 9.41; 95% CI, 3.39-26.08; P <.001) or gonioscopy (cumulative score ≤6; HR, 2.80; 95% CI, 1.13-6.93; P =.04) conferred higher risk of progression. Conclusions and Relevance: Study results suggest that persistent angle narrowing detected by AS-OCT or cumulative gonioscopy score was predictive of disease progression in PACS eyes after LPI. These findings suggest that AS-OCT and gonioscopy may be performed to identify patients at high risk of developing angle closure who may benefit from closer monitoring despite patent LPI.

Refractive Error and Anterior Chamber Depth as Risk Factors in Primary Angle Closure Disease: The Chinese American Eye Study.

PRCIS: The risk of primary angle closure disease (PACD) rises rapidly with greater hyperopia while remaining relatively low for all degrees of myopia. Refractive error (RE) is useful for angle closure risk stratification in the absence of biometric data. PURPOSE: To assess the role of RE and anterior chamber depth (ACD) as risk factors in PACD. METHODS: Chinese American Eye Study participants received complete eye examinations including refraction, gonioscopy, amplitude-scan biometry, and anterior segment ocular coherence tomography imaging. PACD included primary angle closure suspect (≥3 quadrants of angle closure on gonioscopy) and primary angle closure/primary angle closure glaucoma (peripheral anterior synechiae or intraocular pressure >21 mm Hg). Logistic regression models were developed to assess associations between PACD and RE and/or ACD adjusted for sex and age. Locally weighted scatterplot smoothing curves were plotted to assess continuous relationships between variables. RESULTS: Three thousand nine hundred seventy eyes (3403 open angle and 567 PACD) were included. The risk of PACD increased with greater hyperopia [odds ratio (OR) = 1.41 per diopter (D); P < 0.001] and shallower ACD (OR = 1.75 per 0.1 mm; P < 0.001). Hyperopia (≥ + 0.5 D; OR = 5.03) and emmetropia (-0.5 D to +0.5 D; OR = 2.78) conferred a significantly higher risk of PACD compared with myopia (≤0.5 D). ACD (standardized regression coefficient = -0.54) was a 2.5-fold stronger predictor of PACD risk compared with RE (standardized regression coefficient = 0.22) when both variables were included in one multivariable model. The sensitivity and specificity of a 2.6 mm ACD cutoff for PACD were 77.5% and 83.2% and of a +2.0 D RE cutoff were 22.3% and 89.1%. CONCLUSION: The risk of PACD rises rapidly with greater hyperopia while remaining relatively low for all degrees of myopia. Although RE is a weaker predictor of PACD than ACD, it remains a useful metric to identify patients who would benefit from gonioscopy in the absence of biometric data.

A Mechanistic Model of Aqueous Humor Flow to Study Effects of Angle Closure on Intraocular Pressure.

Purpose: To study the relationship between the circumferential extent of angle closure and elevation in intraocular pressure (IOP) using a novel mechanistic model of aqueous humor (AH) flow. Methods: AH flow through conventional and unconventional outflow pathways was modeled using the unified Stokes and Darcy equations, which were solved using the finite element method. The severity and circumferential extent of angle closure were modeled by lowering the permeability of the outflow pathways. The IOP predicted by the model was compared with biometric and IOP data from the Chinese American Eye Study, wherein the circumferential extent of angle closure was determined using anterior segment OCT measurements of angle opening distance. Results: The mechanistic model predicted an initial linear rise in IOP with increasing extent of angle closure which became nonlinear when the extent of closure exceeded around one-half of the circumference. The nonlinear rise in IOP was associated with a nonlinear increase in AH outflow velocity in the open regions of the angle. These predictions were consistent with the nonlinear relationship between angle closure and IOP observed in the clinical data. Conclusions: IOP increases rapidly when the circumferential extent of angle closure exceeds 180°. Residual AH outflow may explain why not all angle closure eyes develop elevated IOP when angle closure is extensive. Translational Relevance: This study provides insight into the extent of angle closure that is clinically relevant and confers increased risk of elevated IOP. The proposed model can be utilized to study other mechanisms of impaired aqueous outflow.

Anterior segment biometric measurements explain misclassifications by a deep learning classifier for detecting gonioscopic angle closure.

BACKGROUND/AIMS: To identify biometric parameters that explain misclassifications by a deep learning classifier for detecting gonioscopic angle closure in anterior segment optical coherence tomography (AS-OCT) images. METHODS: Chinese American Eye Study (CHES) participants underwent gonioscopy and AS-OCT of each angle quadrant. A subset of CHES AS-OCT images were analysed using a deep learning classifier to detect positive angle closure based on manual gonioscopy by a reference human examiner. Parameter measurements were compared between four prediction classes: true positives (TPs), true negatives (TNs), false positives (FPs) and false negatives (FN). Logistic regression models were developed to differentiate between true and false predictions. Performance was assessed using area under the receiver operating curve (AUC) and classifier accuracy metrics. RESULTS: 584 images from 127 participants were analysed, yielding 271 TPs, 224 TNs, 77 FPs and 12 FNs. Parameter measurements differed (p<0.001) between prediction classes among anterior segment parameters, including iris curvature (IC) and lens vault (LV), and angle parameters, including angle opening distance (AOD). FP resembled TP more than FN and TN in terms of anterior segment parameters (steeper IC and higher LV), but resembled TN more than TP and FN in terms of angle parameters (wider AOD). Models for detecting FP (AUC=0.752) and FN (AUC=0.838) improved classifier accuracy from 84.8% to 89.0%. CONCLUSIONS: Misclassifications by an OCT-based deep learning classifier for detecting gonioscopic angle closure are explained by disagreement between anterior segment and angle parameters. This finding could be used to improve classifier performance and highlights differences between gonioscopic and AS-OCT definitions of angle closure.

Generalisability and performance of an OCT-based deep learning classifier for community-based and hospital-based detection of gonioscopic angle closure.

PURPOSE: To assess the generalisability and performance of a deep learning classifier for automated detection of gonioscopic angle closure in anterior segment optical coherence tomography (AS-OCT) images. METHODS: A convolutional neural network (CNN) model developed using data from the Chinese American Eye Study (CHES) was used to detect gonioscopic angle closure in AS-OCT images with reference gonioscopy grades provided by trained ophthalmologists. Independent test data were derived from the population-based CHES, a community-based clinic in Singapore, and a hospital-based clinic at the University of Southern California (USC). Classifier performance was evaluated with receiver operating characteristic curve and area under the receiver operating characteristic curve (AUC) metrics. Interexaminer agreement between the classifier and two human examiners at USC was calculated using Cohen's kappa coefficients. RESULTS: The classifier was tested using 640 images (311 open and 329 closed) from 127 Chinese Americans, 10 165 images (9595 open and 570 closed) from 1318 predominantly Chinese Singaporeans and 300 images (234 open and 66 closed) from 40 multiethnic USC patients. The classifier achieved similar performance in the CHES (AUC=0.917), Singapore (AUC=0.894) and USC (AUC=0.922) cohorts. Standardising the distribution of gonioscopy grades across cohorts produced similar AUC metrics (range 0.890-0.932). The agreement between the CNN classifier and two human examiners (Ò =0.700 and 0.704) approximated interexaminer agreement (Ò =0.693) in the USC cohort. CONCLUSION: An OCT-based deep learning classifier demonstrated consistent performance detecting gonioscopic angle closure across three independent patient populations. This automated method could aid ophthalmologists in the assessment of angle status in diverse patient populations.

Angle closure extent, anterior segment dimensions and intraocular pressure.

AIM: To investigate the association between the extent of iridotrabecular contact and other quantitative anterior segment dimensions measured by swept-source optical coherence tomography (SS-OCT; CASIA SS-1000, Tomey, Nagoya, Japan) with intraocular pressure (IOP). METHODS: Cross-sectional study. All subjects who were ≥50 years with no history of glaucoma, ocular surgery or trauma, underwent SS-OCT imaging (eight equally spaced radial scans), Goldman applanation tonometry and gonioscopy on the same day. We measured iridotrabecular contact (ITC) index and area, total volume of trabeculo-iris space area and angle opening distance at 500 and 750 from the scleral spur (TISA 500 and 750, AOD 500 and 750, respectively), anterior chamber depth (ACD), volume, area and width, pupil diameter, lens vault and iris volume.Their relationship with IOP (dependent variable) was assessed by locally weighted scatterplot smoothing (Lowess) regression with change-point analysis and generalised additive models adjusted for confounders. RESULTS: 2027 right eyes of mostly Chinese Singaporeans (90%) were analysed. ITC index above a threshold of ~60% (95% CI 34% to 92%) was significantly associated with higher IOP. Independent of the extent of ITC, ACD was also significantly associated with higher IOP below a threshold of 2.5 mm (95% CI 2.33 mm to 2.71 mm). Greater ITC index and shallower ACD had a joint association with IOP. A model including ACD and ITC index was more predictive of IOP than a model considering these variables separately, particularly for women with gonioscopically closed angles (R2 52.7%, p<0.05). CONCLUSIONS: The extent of angle closure and the ACD below a certain threshold had a significant joint association with IOP. These parameters, as biometrical surrogates of mechanical obstruction of the aqueous outflow, may jointly contribute to elevated IOP, particularly in women with gonioscopic angle closure.

Optimal number and orientation of anterior segment OCT images to measure ocular biometric parameters in angle closure eyes: the Chinese American Eye Study.

PURPOSE: To assess the optimal number and orientation of anterior segment optical coherence tomography (AS-OCT) images for accurately measuring ocular biometric parameters in angle closure eyes. METHODS: Subjects with angle closure, defined as >3 quadrants of non-visible pigmented trabecular meshwork on static gonioscopy, were selected from the Chinese American Eye Study. Mean angle opening distance (AOD500) was calculated using four images (0°-180°, 45°-225°, 90°-270° and 135°-315° meridians) from one eye per subject. Ten eyes from each quartile of AOD500 measurements were randomly selected for detailed 32-image analysis of 10 biometric parameters, including AOD500, iris curvature (IC), anterior chamber depth (ACD), lens vault (LV), and anterior chamber area (ACA). Mean and range of measurements from 1, 2, 4, 8 or 16 images were compared with 32-image values for all parameters. RESULTS: 40 out of 335 eyes with angle closure were selected for 32-image analysis. Deviation from the 32-image mean was between 0.44% and 19.31% with one image, decreasing to 0.08% to 4.21% with two images for all parameters. Deviation from the 32-image range of measurements was between 54.67% to 88.94% with one image, decreasing to <7.00% with eight images for all parameters except ACD and ACA. Orienting the first image analysed along the 25°-205° meridian better approximated the range of measurements when four or fewer images were analysed. CONCLUSIONS: Sectoral anatomical variations in angle closure eyes are easily misrepresented based on current AS-OCT imaging conventions. A revised multi-image approach can better capture the mean and range of biometric measurements.

Age-Related Changes in Dynamic Iris Behavior Assessed Using a Programmable Closed-Loop Iris Control System.

Purpose: The purpose of this study was to develop and test a programmable closed-loop system for tracking, modulating, and assessing dynamic iris behavior, including in the mid-dilated position. Methods: A programmable closed-loop iris control system was developed by customizing an ANTERION OCT device (Heidelberg Engineering, Heidelberg, Germany). Custom software was developed to store camera and optical coherence tomography (OCT) images, track pupillary diameter (PD), control a light-emitting diode (LED), and modulate ambient lighting to maintain the iris in a dilated, constricted, or mid-dilated position in real-time. Study participants underwent 3 consecutive 65-second scan sessions. Dynamic iris behavior in the form of peak constriction velocity (PCV) and mid-dilated iris activity (MDIA) were calculated and analyzed offline. Results: Among 58 participants, 56 (96.6%) were eligible for analysis based on achieving and maintaining mean PD within ±10% of the calculated mid-dilated PD. Mean participant age was 49.8 ± 18.9 years. Mean PCV was 3.92 ± 0.83 mm/s, and mean MDIA was 0.37 ± 0.15 mm. The mean difference between the calculated and achieved mid-dilated PD was 0.166 ± 0.192 mm. There were significant negative correlations between PCV and age (slope = -0.022, P < 0.001) and MDIA and age (slope = -0.004, P < 0.001). Success rates were lower (69.0%) but relationships between dynamic iris behavior and age were similar based on achieving and maintaining mean PD within ±5% of the calculated mid-dilated PD. Conclusions: A programmable closed-loop iris control system can modulate dynamic iris behavior and maintain the iris in a mid-dilated position. Pupillary constriction velocity and iris activity in the mid-dilated position decrease with age. Translational Relevance: This system can be applied to study dynamic disease processes involving the iris and establish novel biometric measures that could serve as risk factors for acute and chronic primary angle closure glaucoma (PACG).

Detection of Nonglaucomatous Macula Findings With Ganglion Cell Analysis Printouts vs Full Macular Cube Scans.

Importance: Ganglion cell analysis (GCA) of ocular coherence tomography (OCT) imaging is routinely used to detect and monitor glaucomatous damage of the ganglion cell complex in the macula. The GCA printout provides qualitative and quantitative data about the macular ganglion cell-inner plexiform layer and a single B-scan of the retina through the fovea. However, the full macular cube scan, including all 128 B-scans, is available for review. The macular cube scan provides considerable information about nonglaucomatous ocular pathology that may be missed if clinicians review only the GCA printout. Objective: To determine the frequency and type of nonglaucomatous macular findings that are observable in the full macular cube scan but not the GCA printout. Design, Setting, and Participants: A retrospective cross-sectional analysis of GCA printouts and full macular cube scans to detect nonglaucomatous macular pathology at a tertiary care academic center. Consecutive patients undergoing ganglion cell complex imaging during routine glaucoma evaluations over a 1-week period in a multi-clinician glaucoma clinic. Main Outcomes and Measures: The prevalence and type of nonglaucomatous macular pathology visible on the GCA printout or macular cube scan. Results: Among 105 patients (mean (SD) age, 67 (15.46) years; 63 [60%] female and 42 [40%] male) 201 eyes were imaged (64 [31.7%] with suspected glaucoma, 126 [62.4%] with open-angle glaucoma, 6 [3.0%] with closed-angle glaucoma, and 6 [3.0%] with other glaucoma). GCA printouts and macular cube scans revealed nonglaucomatous macular pathology in 65 eyes (32.2%). Of these, 25 eyes (38.5%) included findings that were not visible on the GCA printout. Of the cases not visible on the printout, 16 eyes (64.0% ) included macular pathology that required further evaluation. Conclusions and Relevance: The findings indicate that nonglaucomatous macular pathology may be missed based on GCA printouts alone. While it may be beneficial to review the full macular cube to detect potentially vision-threatening disease and ensure proper patient care, this study cannot determine if this missed pathology affects clinical outcomes.

High-Frequency Ultrasound Elastography to Assess the Nonlinear Elastic Properties of the Cornea and Ciliary Body.

Mechanical properties of the anterior anatomical structures of the eye, such as the cornea and ciliary body, play a key role in the ocular function and homeostasis. However, measuring the biomechanical properties of the anterior ocular structures, especially deeper structures, such as the ciliary body, remains a challenge due to the lack of high-resolution imaging tools. Herein, we implement a mechanical shaker-based high-frequency ultrasound elastography technique that can track the induced elastic wave propagation to assess the linear and nonlinear elastic properties of anterior ocular structures. The findings of this study advance our understanding of the role of anterior ocular structures in the pathogenesis of different ocular disorders, such as glaucoma.

Repeatability and Reproducibility of 4.5 by 4.5 mm Peripapillary Optical Coherence Tomography Angiography Scans in Glaucoma and Non-Glaucoma Eyes.

PRCIS: Peripapillary vessel parameters from optical coherence tomography angiography (OCTA) 4.5×4.5 mm scans in nonglaucomatous and glaucomatous eyes showed high repeatability and reproducibility, with higher reliability for commercially developed OCTA parameters compared with custom OCTA parameters. PURPOSE: The purpose of this study was to assess intrasession repeatability versus intersession reproducibility of peripapillary vessel parameters from 4.5×4.5 mm OCTA scans in nonglaucomatous eyes and glaucomatous eyes. MATERIALS AND METHODS: In a longitudinal study, peripapillary OCTA scans were quantified using research-oriented custom quantification software that calculated vessel area density (VAD) and flux and clinic-oriented commercially developed software (Cirrus 11.0) that calculated perfusion density (PD) and flux index (FI). Intrasession repeatability and intersession reproducibility were evaluated using within-eye coefficient of variation (CV W ) and intraclass correlation coefficient (ICC). RESULTS: With 127 nonglaucomatous eyes, intrasession CV W for VAD, PD, flux, and FI were 1.900%, 1.174%, 2.787%, and 1.425%, respectively. The intersession CV W were 2.039%, 1.606%, 4.053%, and 2.798%, respectively. Intrasession ICC ranged from 0.903 to 0.956, and intersession ICC ranged from 0.850 to 0.896. Among 144 glaucomatous eyes, intrasession CV W for VAD, PD, flux, and FI were: 3.841%, 1.493%, 5.009%, and 2.432%, respectively. The intersession CV W were 4.991%, 2.155%, 6.360%, and 3.458%, respectively. Intrasession ICC ranged from 0.956 to 0.969, and intersession ICC ranged from 0.918 to 0.964. CONCLUSIONS: Among nonglaucomatous and glaucomatous eyes, the majority of peripapillary OCTA vessel parameters from 4.5×4.5 mm scans had greater intrasession repeatability than intersession reproducibility. There was a greater agreement for the commercially developed quantification parameters than for their custom quantification counterparts.