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BackgroundTo examine long-term retinal nerve fibre layer thickness (RNFLT) variability and associated clinical factors in African (AD) and European descent (ED) individuals with glaucoma.MethodsThis retrospective cohort study included glaucoma eyes of AD and ED from Diagnostic Innovations in Glaucoma Study/The African Descent and Glaucoma Evaluation Study with ≥4 visits/2 years of follow-up. We calculated optic nerve head RNFLT variability per-examination/visit as the absolute error of its residuals across follow-up. Full, baseline and parsimonious linear-mixed models were fit to evaluate the effects of clinical factors (demographics and ocular characteristics, prior/intervening glaucoma surgeries and cataract extraction (CE), RNFLT thinning rate, scan quality, visit/testing frequency, etc) on RNFLT variability in both races.ResultsThere were 376 and 625 eyes (226 and 349 participants) of AD and ED, and the mean (95% CI) RNFLT variability was 1.62 (1.52, 1.71) µm and 1.42 (1.34, 1.50) µm, respectively (p=0.002). AD and ED had some shared predictors of RNFLT variability, including intraocular pressure fluctuation and scan quality, although the effects varied (p

PurposeTo develop and evaluate a deep learning (DL) model to assess fundus photograph quality, and quantitatively measure its impact on automated POAG detection in independent study populations.MethodsImage quality ground truth was determined by manual review of 2815 fundus photographs of healthy and POAG eyes from the Diagnostic Innovations in Glaucoma Study and African Descent and Glaucoma Evaluation Study (DIGS/ADAGES), as well as 11,350 from the Ocular Hypertension Treatment Study (OHTS). Human experts assessed a photograph as high quality if of sufficient quality to determine POAG status and poor quality if not. A DL quality model was trained on photographs from DIGS/ADAGES and tested on OHTS. The effect of DL quality assessment on DL POAG detection was measured using area under the receiver operating characteristic (AUROC).ResultsThe DL quality model yielded an AUROC of 0.97 for differentiating between high- and low-quality photographs; qualitative human review affirmed high model performance. Diagnostic accuracy of the DL POAG model was significantly greater (P < 0.001) in good (AUROC, 0.87; 95% CI, 0.80-0.92) compared with poor quality photographs (AUROC, 0.77; 95% CI, 0.67-0.88).ConclusionsThe DL quality model was able to accurately assess fundus photograph quality. Using automated quality assessment to filter out low-quality photographs increased the accuracy of a DL POAG detection model.Translational relevanceIncorporating DL quality assessment into automated review of fundus photographs can help to decrease the burden of manual review and improve accuracy for automated DL POAG detection.

A longitudinal ophthalmic dataset was used to investigate multi-modal machine learning (ML) models incorporating patient demographics and history, clinical measurements, optical coherence tomography (OCT), and visual field (VF) testing in predicting glaucoma surgical interventions. The cohort included 369 patients who underwent glaucoma surgery and 592 patients who did not undergo surgery. The data types used for prediction included patient demographics, history of systemic conditions, medication history, ophthalmic measurements, 24-2 VF results, and thickness measurements from OCT imaging. The ML models were trained to predict surgical interventions and evaluated on independent data collected at a separate study site. The models were evaluated based on their ability to predict surgeries at varying lengths of time prior to surgical intervention. The highest performing predictions achieved an AUC of 0.93, 0.92, and 0.93 in predicting surgical intervention at 1 year, 2 years, and 3 years, respectively. The models were also able to achieve high sensitivity (0.89, 0.77, 0.86 at 1, 2, and 3 years, respectively) and specificity (0.85, 0.90, and 0.91 at 1, 2, and 3 years, respectively) at an 0.80 level of precision. The multi-modal models trained on a combination of data types predicted surgical interventions with high accuracy up to three years prior to surgery and could provide an important tool to predict the need for glaucoma intervention.

ObjectivesTo investigate the associations of alcohol consumption and smoking with the development of perimetric glaucoma in patients with suspected glaucoma.DesignA retrospective cohort study of patients suspected to have glaucoma enrolled in the Diagnostic Innovations in Glaucoma Study (DIGS) and the African Descent and Glaucoma Evaluation Study (ADAGES).SettingThree tertiary glaucoma centres in the USA.Participants825 eyes of 610 patients with glaucoma suspect eyes with normal visual fields (VF) at baseline were followed over an average of 9 years from the DIGS and ADAGES studies.Outcome measuresDevelopment of glaucoma was defined as occurrence of three consecutive abnormal VF tests during follow-up. Univariable and multivariable Cox regression models were used to investigate lifestyle-related factors associated with development of VF loss over time.ResultsVF tests were abnormal three times in a row in 235 (28.5%) eyes. Alcohol consumption was associated with a higher risk of developing glaucoma (HR 1.57, 95% CI 1.03 to 2.38, p=0.037). In men, the risk of developing glaucoma in alcohol drinkers (HR 1.92, 95% CI 1.00 to 3.68, p=0.048) was greater than non-alcohol drinkers. In individuals of African descent, the risk of developing glaucoma in alcohol drinkers (HR 1.79, 95% CI 1.02 to 3.15, p=0.043) was greater than non-alcohol drinkers. Age was a modifier of the relationship between smoking and glaucomatous VF defects (p=0.048). The risk of developing glaucoma in smokers (HR 1.73, 95% CI 1.10 to 2.72, p=0.019) was greater than never smokers after adjustment for confounding factors in older patients (age >61 years).ConclusionAlcohol consumption was associated with an increased risk of developing glaucoma, particularly in men and individuals of African descent. The risk of developing glaucoma among smokers suspected of having glaucoma was influenced by age, with older individuals having a higher risk than younger people.Trial registration numberNCT00221897 and NCT00221923.

PurposeTo determine the prevalence of fast global and central visual field (VF) progression in individuals with glaucoma under routine care.DesignObservational study.ParticipantsSix hundred ninety-three eyes of 461 individuals with glaucoma followed up over a median of 4.5 years.MethodsThis study included (1) patients at a private ophthalmology clinic in Melbourne, Australia, and (2) individuals in 2 prospective longitudinal observational studies across 3 sites in the United States. All individuals had a diagnosis of glaucoma and were under routine care, and had performed 5 or more reliable 24-2 VF tests over a 1- to 5-year period. Ordinary least squares regression analyses were used to calculate the rate of global mean deviation (MD) change over time and the rate of the mean total deviation values of the 12 test locations within the central 10° region (MTD10) for each eye.Main outcome measuresPrevalence of progression based on the rate of MD and the MTD10 change across various fixed cutoffs and cutoffs based on the estimated normal distribution (from the positive slopes).ResultsBased on the MD and the MTD10, 12.5% and 11.7% of the eyes, respectively, exhibited a rate of change that was less than -1.0 dB/year (being a rate that typically is defined as "fast progression" for MD values), and 29.0% of the eyes showed a change of less than -0.5 dB/year on MTD10. Furthermore, 12.7% and 9.1% of the eyes exhibited a rate of change that exceeded the 1% cutoff of the estimated normal distribution MD and the MTD10 values, respectively.ConclusionsThis study found that approximately 1 in 8 eyes with glaucoma receiving routine care showed fast progression based on global MD values (< -1.0 dB/year) and that nearly 1 in 3 eyes showed a < -0.5 dB/year decline centrally. These findings highlight the clinical importance of assessing progressive central VF loss and reinforce the need for new therapies to prevent functional disability in a notable proportion of individuals who continue to exhibit fast progression.Financial disclosure(s)Proprietary or commercial disclosure may be found after the references.

PurposeTo investigate the association of vision-related quality of life (VRQOL) with the central visual field and macular ganglion cell complex (GCC) thickness in healthy control participants, patients with preperimetric glaucoma, and patients with perimetric glaucoma.DesignRetrospective cross-sectional study.MethodsA total of 39 healthy, 34 preperimetric glaucoma, and 145 perimetric glaucoma patients completed the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ). A linear mixed-effect models was used to investigate the association between the glaucoma stage as measured by binocular 10-2 visual field mean sensitivity (VFMS) and GCC thickness with the Rasch-calibrated NEI-VFQ score.ResultsA total of 436 eyes from 218 participants (mean age = 67.2 [95% CI = 65.1 to 69.2] years) were enrolled. VRQOL calculated by the NEI-VFQ Rasch-calibrated score was worst for patients with perimetric glaucoma (50.7 [95% CI = 47.2 to 54.2]), followed by patients with preperimetric glaucoma (41.2 [95% CI = 34.5 to 47.9]) and healthy controls (29.3 [95% CI = 24.0 to 34.7]. Worse VRQOL had a moderate association with a worse global binocular 10-2 VFMS (-3.4 [95% CI = -5.0 to -1.9] dB per 1 score; P < .001; adjusted R2 = 0.27), but not with a thinner global GCC in the better eye (-0.1 [95% CI = -0.2 to 0.1] µm per 1 score; P =.0485; adjusted R2 = 0.17).ConclusionsThese findings suggest that patients with perimetric and preperimetric glaucoma have worse VRQOL than patients with healthy eyes. As compared to macular thickness measurements, the central visual field is more strongly associated with VRQOL and may better help to identify patients in need of intervention.

PurposeTo compare the diagnostic accuracy and explainability of a Vision Transformer deep learning technique, Data-efficient image Transformer (DeiT), and ResNet-50, trained on fundus photographs from the Ocular Hypertension Treatment Study (OHTS) to detect primary open-angle glaucoma (POAG) and identify the salient areas of the photographs most important for each model's decision-making process.DesignEvaluation of a diagnostic technology.Subjects participants and controlsOverall 66 715 photographs from 1636 OHTS participants and an additional 5 external datasets of 16 137 photographs of healthy and glaucoma eyes.MethodsData-efficient image Transformer models were trained to detect 5 ground-truth OHTS POAG classifications: OHTS end point committee POAG determinations because of disc changes (model 1), visual field (VF) changes (model 2), or either disc or VF changes (model 3) and Reading Center determinations based on disc (model 4) and VFs (model 5). The best-performing DeiT models were compared with ResNet-50 models on OHTS and 5 external datasets.Main outcome measuresDiagnostic performance was compared using areas under the receiver operating characteristic curve (AUROC) and sensitivities at fixed specificities. The explainability of the DeiT and ResNet-50 models was compared by evaluating the attention maps derived directly from DeiT to 3 gradient-weighted class activation map strategies.ResultsCompared with our best-performing ResNet-50 models, the DeiT models demonstrated similar performance on the OHTS test sets for all 5 ground-truth POAG labels; AUROC ranged from 0.82 (model 5) to 0.91 (model 1). Data-efficient image Transformer AUROC was consistently higher than ResNet-50 on the 5 external datasets. For example, AUROC for the main OHTS end point (model 3) was between 0.08 and 0.20 higher in the DeiT than ResNet-50 models. The saliency maps from the DeiT highlight localized areas of the neuroretinal rim, suggesting important rim features for classification. The same maps in the ResNet-50 models show a more diffuse, generalized distribution around the optic disc.ConclusionsVision Transformers have the potential to improve generalizability and explainability in deep learning models, detecting eye disease and possibly other medical conditions that rely on imaging for clinical diagnosis and management.

PrcisWith high specificity and less variability than perimetry, more frequent testing resulted in shorter time to detect progression, though a 6-month testing interval provides a reasonable trade-off for following glaucoma patients using optical coherence tomography (OCT).PurposeTo investigate the time to detect progression in glaucomatous eyes using different OCT test intervals.Materials and methodsParticipants with manifest glaucoma from the African Descent and Glaucoma Evaluation Study (ADAGES), a multicenter, prospective, observational cohort study, were included. A total of 2699 OCT tests from 171 glaucomatous and 149 normal eyes of 182 participants, with at least 5 tests and 2 years of follow-up, were analyzed. Computer simulations (n=10,000 eyes) were performed to estimate time to detect progression of global circumpapillary retinal nerve fiber layer thickness (cpRNFL) measured with OCT tests. Simulations were based on different testing paradigms (every 4, 6, 12, and 24 mo) and different rates of change (µm/year). Time to detect significant progression ( P

PurposeTo investigate the effect of smoking on rates of progressive visual field (VF) damage over time in glaucoma.DesignRetrospective cohort study.ParticipantsFive hundred eleven eyes of 354 patients with glaucoma followed up from multicenter glaucoma registries.MethodsIn this longitudinal study, 354 patients with primary open-angle glaucoma with a minimum of 3 years of follow-up and 5 VF tests were enrolled from the Diagnostic Innovations in Glaucoma Study and the African Descent and Glaucoma Evaluation Study. Univariate and multivariate linear mixed models were used to investigate the effects of smoking on rates of 24-2 VF mean deviation loss. Visual field progression was defined using pointwise linear and significant negative VF mean deviation loss. Logistic regression was used to identify baseline factors and whether different levels of smoking intensity were associated with VF progression. Kaplan-Meier survival analysis and the log-rank test were used to compare the cumulative risk ratio of progression between smoker and never smoker groups.Main outcome measuresVisual field progression.ResultsFive hundred eleven eyes of 354 patients were included over the median follow-up of 12.5 years. Median baseline age was 64.8 years. Of the 354 patients, 124 (35%) were Black, and 149 (42.1%) and 168 (59.8%) had reported a history of smoking or alcohol consumption, respectively. In a multivariate model, higher smoking intensity was associated with faster VF loss (coefficient, -0.05 decibels (dB)/year per 10 pack-years; 95% confidence interval [CI], -0.08 to -0.01 dB/year per 10 pack-years; P = 0.010). Developing VF progression in eyes of heavy smokers (≥ 20 pack-years) was 2.2 times more than in eyes of patients without smoking history (odds ratio, 2.21; 95% CI, 1.02-4.76; P = 0.044). Statistically significant differences were found between heavy smokers (≥ 20 pack-years) and never smokers by Kaplan-Meier analysis (P = 0.011, log-rank test).ConclusionsHeavy smokers are more likely to sustain VF loss in eyes with glaucoma. The prospective longitudinal design of this study supports the hypothesis that levels of smoking may be a significant predictor for glaucoma progression. Additionally, this information can be used for clinically relevant tobacco prevention and intervention messages.

PrcisThe earlier a person quits smoking the more likely is the optic nerve be spared from damage.PurposeTo investigate the effect of smoking cessation on visual field (VF) progression in glaucoma.MethodsPrimary open angle glaucoma patients with a minimum of 3 years follow-up and 5 VFs were included. Linear mixed models were used to investigate the effects of smoking on the rates of 24-2 VF mean deviation loss after adjusting for confounding factors. Cox proportional hazard regression was used to identify whether different levels of smoking intensity were associated with VF progression with respect to different duration of quitting.ResultsFive hundred eleven eyes of 354 patients were included over the mean follow-up of 12.4 years. Mean baseline age (95% confidence interval) was 62.3 (61.2, 63.4) years. One hundred forty nine (42.1%) patients were smokers. In a multivariable model, smoking intensity was associated with faster VF loss (-0.06, 95% confidence interval (-0.10, -0.01) dB/year per 10 pack-years, P =0.01) among smokers. Heavy smokers (≥20 pack-years) who had quit ˂25 years prior had significantly greater odds of VF progression compared with never smokers (odds ratio=2.49 (1.01, 6.08); P =0.046). There was no significant difference in odds of VF progression in heavy smokers who had quit smoking more than 25 years compared with never smokers ( P =0.43). A significantly higher proportion of VF progression was found in heavy smokers who quit < 25 years compared with heavy smokers who quit ≥25 years by Kaplan-Meier analysis ( P =

PurposeTo evaluate the role of corneal hysteresis (CH) as a risk factor of central visual field (VF) progression in a cohort of glaucoma suspect and glaucoma patients.DesignProspective cohort study.MethodsTwo hundred forty-eight eyes of 143 subjects who were followed for an average of 4.8 years with a minimum of 5 visits with 10-2 and 24-2 VF tests were included. Univariable and multivariable linear mixed-effects models were used to identify characteristics associated with the rate of change over time in 10-2 and 24-2 mean deviation (MD). Mixed-effects logistic regression was used to evaluate characteristics associated with an increased likelihood of event-based 10-2 VF progression based on the clustered pointwise linear regression criterion.ResultsCH was significantly associated with 10-2 and 24-2 VF progression in the univariable trend-based analysis. In multivariable trend-based analyses, lower CH was associated with a faster rate of decline in 10-2 MD (0.07 dB/y per 1 mm Hg, P < .001) but not with 24-2 MD (P = .490). In multivariable event-based analysis, lower CH was associated with an increased likelihood of 10-2 VF progression (odds ratio = 1.35 per 1 mm Hg lower, P = .025). Similar results were found in eyes with early glaucomatous damage at the baseline (baseline: 24-2 MD ≥ -6 dB).ConclusionsLower CH was associated with a statistically significant, but relatively small, increased risk of central VF progression on the 10-2 test grid. Given the substantial influence of central VF impairment on the quality of life, clinicians should consider using CH to assess the risk of progression in patients with primary open-angle glaucoma including those with early disease.

PurposeTo compare the rates of visual field (VF) progression between individuals of Black and White race and to investigate whether treatment effects may help explain differences previously reported between racial groups.DesignMulticenter prospective observational cohort study.MethodsParticipants were patients in referral tertiary care glaucoma clinics with open angle glaucoma. Eyes were excluded who had

PurposeTo assess whether the predictive accuracy of machine learning algorithms using Kalman filtering for forecasting future values of global indices on perimetry can be enhanced by adding global retinal nerve fiber layer (RNFL) data and whether model performance is influenced by the racial composition of the training and testing sets.DesignRetrospective, longitudinal cohort study.ParticipantsPatients with open-angle glaucoma (OAG) or glaucoma suspects enrolled in the African Descent and Glaucoma Evaluation Study or Diagnostic Innovation in Glaucoma Study.MethodsWe developed a Kalman filter (KF) with tonometry and perimetry data (KF-TP) and another KF with tonometry, perimetry, and global RNFL data (KF-TPO), comparing these models with one another and with 2 linear regression (LR) models for predicting mean deviation (MD) and pattern standard deviation values 36 months into the future for patients with OAG and glaucoma suspects. We also compared KF model performance when trained on individuals of European and African descent and tested on patients of the same versus the other race.Main outcome measuresPredictive accuracy (percentage of MD values forecasted within the 95% repeatability interval) differences among the models.ResultsAmong 362 eligible patients, the mean ± standard deviation age at baseline was 71.3 ± 10.4 years; 196 patients (54.1%) were women; 202 patients (55.8%) were of European descent, and 139 (38.4%) were of African descent. Among patients with OAG (n = 296), the predictive accuracy for 36 months in the future was higher for the KF models (73.5% for KF-TP, 71.2% for KF-TPO) than for the LR models (57.5%, 58.0%). Predictive accuracy did not differ significantly between KF-TP and KF-TPO (P = 0.20). If the races of the training and testing set patients were aligned (versus nonaligned), the mean absolute prediction error of future MD improved 0.39 dB for KF-TP and 0.48 dB for KF-TPO.ConclusionsAdding global RNFL data to existing KFs minimally improved their predictive accuracy. Although KFs attained better predictive accuracy when the races of the training and testing sets were aligned, these improvements were modest. These findings will help to guide implementation of KFs in clinical practice.

PURPOSE: To uncover the mechanism of subconjunctival outflow in human patients. DESIGN: Cross-sectional study. SUBJECTS/PARTICIPANTS AND/OR CONTROLS: Fifteen subjects receiving subconjunctival anesthesia prior to intravitreal injection for routine clinical care. METHODS: Anterior segment OCT (AS-OCT) was performed in patients with various instances of conjunctival edema or subconjunctival fluid. Other subjects received a subconjunctival mixture of 0.005% indocyanine green and 2% lidocaine. After subconjunctival injection of the tracer/anesthetic mixture, blebs and associated outflow pathways were angiographically imaged and the time for appearance recorded. The pattern and structure of outflow pathways were studied using AS-OCT. Angiographic and AS-OCT results were compared to trabecular/conventional outflow imaging which demonstrates veins. MAIN OUTCOME MEASURES: Ocular surface lymphangiography and AS-OCT images. RESULTS: AS-OCT of the conjunctiva in a normal eye demonstrated thin non-edematous conjunctiva with absent intraconjunctival lumens or subconjunctival fluid. Subjects with a history of trabeculectomy, subconjunctival drug injection, or chemosis demonstrated thickened conjunctiva and intraconjunctival luminal pathways that contained valve-like structures. Tracer-based studies in patients demonstrated blebs with irregular subconjunctival bleb-related outflow patterns that arose in a time-dependent fashion. These angiographic pathways were luminal on OCT, sausage-shaped, and contained intraluminal valve-like structures. This was in contrast to trabecular/conventional outflow imaging where pathways were classically Y-shaped, of even-caliber, and lacked valve-like structures. DISCUSSION: Outflow pathways were seen in cases of conjunctival edema and after subconjunctival tracer injection. These pathways were lymphatic based upon pattern and structural study. Better understanding of bleb-related lymphatic outflow may lead to improved bleb-requiring glaucoma surgeries and subconjunctival drug delivery.

PurposeTo investigate the characteristics and rate of central visual field loss after optic disc hemorrhage (DH).DesignProspective cohort study.MethodsThree hundred forty-three eyes of 220 subjects who had ≥3 years of follow-up with a minimum of 5 visits with 10-2 and 24-2 visual field (VF) were recruited. Rates of 10-2 mean deviation (MD) loss in each hemifield and predefined zones were compared using linear mixed-effects models in DH and non-DH eyes. Clustered pointwise regression analysis was also used to define central VF progressors and compared with 24-2 VF loss using guided progression analysis.ResultsThirty-nine eyes with DH and 304 eyes without DH had a mean follow-up of 5.2 years. Eyes with DH had rates of 10-2 MD loss that were 3 times faster than non-DH eyes (mean difference -0.36 dB/year [95% confidence interval 0.54-0.18]; P < .001) and were 3.7 times more likely to progress (P = .002). A larger proportion of glaucomatous eyes showed central VF progression rather than peripheral VF progression in the DH group (30.8% vs. 20.5%) compared with the non-DH group (10.9% vs. 9.2%). In early glaucoma, the rate of 10-2 MD loss was 5.5 times faster in DH eyes than in non-DH eyes (P < .001). Superonasal and superotemporal central VF regions progressed more rapidly than other regions, especially in DH eyes.ConclusionCentral VF loss is accelerated in glaucoma eyes with DH and it corresponds topographically to the DH location. In patients with glaucoma with DH, one should consider supplementing 10-2 VFs with 24-2 VFS to monitor the disease.

PurposeTo compare spectral-domain optical coherence tomography (SDOCT) measured circumpapillary retinal nerve fiber layer (cpRNFL) among 4 glaucomatous optic disc phenotypes in early glaucoma.DesignClinical cohort study METHODS: In this study, 218 early glaucoma eyes that had at least 3 years of follow-up and a minimum of 4 SDOCT scans were recruited. The optic discs were classified into 4 types based on appearance: 76 generalized cup enlargement (GE), 53 focal ischemic (FI), 22 myopic glaucomatous (MY), and 67 senile sclerotic (SS). A linear mixed effects model was used to compare the rates of global and regional cpRNFL thinning among optic disc phenotypes.ResultsAfter adjusting for confounders, the SS group (mean [95% CI]: -1.01 [-1.30, -0.73] µm/y) had the fastest mean rate of global cpRNFL thinning followed by FI (-0.77 [-0.97, -0.57] µm/y), MY (0.59 [-0.81, -0.36] µm/y), and GE (-0.58 [-0.75, -0.40] µm/y) at P < .001. The inferior temporal sector had the fastest rate of cpRNFL thinning among the regional measurements except for the MY group (-0.68 [-1.10, -0.26] µm/y, P = .002). In the multivariable analysis, GE (P = .002) and MY (P = .010) phenotypes were associated with significantly slower global rates of cpRNFL thinning compared with the SS phenotype.ConclusionsRates of cpRNFL thinning were different among the 4 glaucomatous optic disc phenotypes. Those patients with early glaucoma with SS phenotype have the fastest cpRNFL thinning. These patients may benefit from more frequent monitoring and the need to advance therapy if cpRNFL thinning is detected.

PurposeTo evaluate the thinning of the circumpapillary retinal nerve fiber layer (cpRNFL) and macular ganglion cell-inner plexiform layer (mGCIPL) in primary open-angle glaucoma eyes with and without a history of disc hemorrhage (DH).DesignObservational cohort study.ParticipantsThirty-nine 39 eyes (34 participants) with DH and 117 eyes (104 participants) without DH from the Diagnostic Innovations in Glaucoma Study and the African Decent and Glaucoma Evaluation Study.MethodsParticipants had at least 1.5 years of follow-up, with a minimum of 3 visits with biannual spectral-domain OCT cpRNFL and mGCIPL thickness measurements and visual fields (VFs). The rates of cpRNFL and mGCIPL thinning were calculated using mixed-effects models. The dynamic range-based normalized rates of cpRNFL and mGCIPL thinning were calculated and compared between the DH and non-DH groups.Main outcome measuresRates of cpRNFL and mGCIPL thinning.ResultsThe rate of mGCIPL thinning was significantly faster in the DH group compared with the non-DH group (-0.62 μm/year vs. -0.38 μm/year; P = 0.024). The rate of cpRNFL thinning in the DH quadrant and rate of mGCIPL thinning in the inferotemporal sector in the DH group were faster than the corresponding regions in the non-DH group after adjusting for intraocular pressure (-1.33 μm/year vs. -0.58 μm/year; P = 0.053) and race (-0.82 μm/year vs. -0.44 μm/year; P = 0.048). In the DH group, percent rate of loss was significantly faster for the mGCIPL than the cpRNFL (-1.59 %/year vs. -1.31 %/year; P = 0.046). Rates of mGCIPL thinning were associated weakly with mean deviation slope, VF index slope, and guided progression analysis (GPA). The areas under the receiver operating characteristic curve for VF progression were 0.75 for mGCIPL and 0.56 for cpRNFL in the DH group.ConclusionsThe rate of mGCIPL and cpRNFL thinning was faster in DH eyes than non-DH eyes. Compared with cpRNFL, mGCIPL showed higher proportional rates of thinning and greater association with functional progression. In addition to cpRNFL, clinicians should consider incorporating mGCIPL imaging to monitor glaucoma progression, especially in glaucoma eyes with DH.

PurposeTo examine whether glaucomatous central visual field abnormalities can be more effectively detected using a qualitative, expert evaluation of the 10-2 test compared with the topographically corresponding central 12 locations of the 24-2 test (C24-2).DesignCross-sectional study.MethodsEyes with a glaucomatous optic nerve appearance or ocular hypertension (n = 523) and healthy eyes (n = 107) were included as cases and control subjects, respectively. The 10-2 and C24-2 visual field results of all eyes were graded by 4 glaucoma specialists for the probability that central visual field abnormalities were present.ResultsThe sensitivity of the 10-2 and C24-2 tests for detecting the cases at 95% specificity were not significantly different (e.g., 32.2% and 31.4%, respectively, for grader 1, P = .87; all graders P ≥ .25). At 95% specificity, the pattern standard deviation values from these tests had a similar sensitivity to the qualitative evaluation for the C24-2 test for all graders (P ≥ .083), but it had a significantly higher sensitivity than the qualitative evaluation for the 10-2 test for 3 graders (P ≤ .016).ConclusionsThe similarity in performance of the 10-2 and C24-2 test suggests that the increased sampling density of the former does not significantly improve the detection of central visual field abnormalities, even when based on expert assessment. These findings should not be taken to mean that the 10-2 test is not useful, but it underscores the need for its utility to be clearly established before incorporating it as routine glaucoma standard of care.

PurposeTo compare change over time in eye-specific optical coherence tomography (OCT) retinal nerve fiber layer (RNFL)-based region-of-interest (ROI) maps developed using unsupervised deep-learning auto-encoders (DL-AE) to circumpapillary RNFL (cpRNFL) thickness for the detection of glaucomatous progression.MethodsForty-four progressing glaucoma eyes (by stereophotograph assessment), 189 nonprogressing glaucoma eyes (by stereophotograph assessment), and 109 healthy eyes were followed for ≥3 years with ≥4 visits using OCT. The San Diego Automated Layer Segmentation Algorithm was used to automatically segment the RNFL layer from raw three-dimensional OCT images. For each longitudinal series, DL-AEs were used to generate individualized eye-based ROI maps by identifying RNFL regions of likely progression and no change. Sensitivities and specificities for detecting change over time and rates of change over time were compared for the DL-AE ROI and global cpRNFL thickness measurements derived from a 2.22-mm to 3.45-mm annulus centered on the optic disc.ResultsThe sensitivity for detecting change in progressing eyes was greater for DL-AE ROIs than for global cpRNFL annulus thicknesses (0.90 and 0.63, respectively). The specificity for detecting not likely progression in nonprogressing eyes was similar (0.92 and 0.93, respectively). The mean rates of change in DL-AE ROI were significantly faster than for cpRNFL annulus thickness in progressing eyes (-1.28 µm/y vs. -0.83 µm/y) and nonprogressing eyes (-1.03 µm/y vs. -0.78 µm/y).ConclusionsEye-specific ROIs identified using DL-AE analysis of OCT images show promise for improving assessment of glaucomatous progression.Translational relevanceThe detection and monitoring of structural glaucomatous progression can be improved by considering eye-specific regions of likely progression identified using deep learning.

PurposeThe purpose of this study was to determine if the rate of change in the depth of the surface of the lamina cribrosa due to glaucomatous remodeling differs between glaucoma patients of African descent (AD) and European descent (ED).MethodsThere were 1122 images taken longitudinally over an average of 3 years (range = 0.9-4.1 years) from 122 patients with glaucoma followed in the African Descent and Glaucoma Evaluation Study (ADAGES) and Diagnostic Intervention and Glaucoma Study (DIGS) were automatically segmented to compute anterior lamina cribrosa surface depth (ALCSD). The rate of ALCSD change was compared across racial groups after adjusting for baseline characteristics known to be associated with ALCSD or disease progression (visual field, ALCSD, corneal thickness, optic disk size, and age).ResultsAfter adjusting for all other covariates, the ED group had significantly greater ALCSD posterior migration (deepening) than the AD group (difference = 2.57 µm/year, P = 0.035). There was a wider range of ALCSD change in the ED compared with the AD group, and more individuals had greater magnitude of both deepening and shallowing. No other covariates measured at baseline had independent effects on the longitudinal changes in ALCSD (baseline visual field severity, baseline ALCSD, corneal thickness, Bruch's membrane opening [BMO] area, or age).ConclusionsGlaucomatous remodeling of the lamina cribrosa differs between AD and ED patients with glaucoma. Unlike the cross-sectional associations seen with aging, in which a deeper ALCSD was seen with age in the ED group, glaucomatous remodeling in this longitudinal study resulted in more posterior migration of ALCSD in ED compared to AD patients.

PurposeTo investigate central visual field (VF) defects among 4 phenotypes of glaucomatous optic discs.DesignCross-sectional study.MethodsOptic disc phenotypes were determined in eyes with definite or suspected glaucoma that had a 24-2 VF with mean deviation (MD) better than -12 dB and a 10-2 VF. 10-2 VFs were classified as abnormal based on a cluster criterion. Additionally, the average of the total deviation values at each 10-2 test point was compared by optic disc phenotype.ResultsThe following 4 glaucomatous optic disc phenotypes were identified in 448 eyes of 309 patients: focal ischemic (FI) (n = 121); generalized cup enlargement (GE) (n = 109); myopic glaucoma (MY) (n = 66); and senile sclerotic (SS) (n = 152). Although 24-2 VF MD values were similar among optic disc phenotypes, GE eyes had higher 10-2 VF MD (P = .004), as well as lower 24-2 VF pattern standard deviations (PSD) (P < .001) and VF 10-2 PSD (P < .001) than the other phenotypes. The prevalence of an abnormal VF 10-2 was highest in FI eyes (78.5%) and lowest in GE eyes (50.5%) (P < .001). In glaucoma suspects, the prevalence of an abnormal 10-2 VF was highest in the MY eyes (31.2%) and FI eyes (23.5%) and lowest in GE eyes (8.6%). In mild glaucoma, the prevalence of abnormal 10-2 VF test results was highest in FI eyes (79.2%) and lowest in GE eyes (44.4%) (P = .013).ConclusionsThe severity and prevalence of central VF loss varied among different glaucomatous optic disc phenotypes. Glaucomatous eyes with FI and MY optic disc phenotypes are more likely to have 10-2 VF loss, particularly in early disease, and especially may benefit from testing with both 10-2 and 24-2 VF tests.

In the description of the automated delineation algorithm, it was incorrectly stated that measurements were made 1.8 µm from the BMO centroid, whereas the correct value was 18 µm. The affected sentence is in the Image Acquisition and Processing section of the Methods and originally read: “The mean of ALCSD measurements from all 48 B-scans within 1.8 µm of the center of the BMO from each individual eye was used for the analysis after qualitative review of the accuracy of the BMO and ALCSD segmentation.” The error has been corrected in the article online and does not affect the conclusions of the article.

Glaucoma disproportionately affects individuals of African descent. Prior studies of the PIEZO1 mechanoreceptor have suggested a possible role in glaucoma pathophysiology. Here, we investigated associations between a Piezo1 gain-of-function variant common in individuals of African descent with glaucoma-related phenotypes. We analyzed whole genome sequences to identify Piezo1 variants and their frequencies among 1565 human participants. For the most common variant (e756del), we compared phenotypes between heterozygotes, homozygotes, and wildtypes. Longitudinal mixed effects models of visual field mean deviation (MD) and retinal nerve fiber layer (RNFL) thickness were used to evaluate progression. Based on trends in the models, further investigation was conducted using Piezo1 gain-of-function mice. About 30% of African descent individuals had at least one e756del allele. There were trends suggesting e756del was associated with higher IOPs, thinner RNFLs, lower optic nerve head capillary densities, and greater decreases in MD and RNFL thickness over time, but these did not reach statistical significance. Among mice, increased Piezo1 activity was not significantly associated with IOP or retinal ganglion cell density. Our study confirms that the Piezo1 e756del gain-of-function variant is a frequent polymorphism present in African descent individuals but is unrelated to examined differences in glaucoma phenotypes. Ongoing work is needed to elucidate the role of Piezo1-mediated mechanotransduction in glaucoma.

PurposeTo use optical coherence tomography (OCT) to 3-dimensionally characterize the optic nerve head (ONH) in peripapillary scleral bowing in non-highly myopic healthy eyes.DesignCross-sectional, multicenter study.MethodsA total of 362 non-highly myopic (+6 diopters [D] > spherical equivalent > -6D) eyes of 362 healthy subjects from 20-90 years old underwent OCT ONH radial B-scan imaging. Bruch's membrane (BM), BM opening (BMO), anterior scleral canal opening (ASCO), and the peripapillary scleral surface were segmented. BMO and ASCO planes were fit, and their centroids, major axes, ovality, areas and offsets were determined. Peripapillary scleral bowing was characterized by 2 parameters: peripapillary scleral slope (ppSS) of 3 anterior peripapillary scleral segments (0-300, 300-700, and 700-1,000 μm from the ASCO centroid); and ASCO depth relative to a peripapillary scleral reference plane (ASCOD-ppScleral). Peripapillary choroidal thickness (ppCT) was calculated relative to the ASCO as the minimum distance between the anterior scleral surface and BM.ResultsBoth ppSS and ASCOD-ppScleral ranged from slightly inward through profoundly outward in direction. Both parameters increased with age and were independently associated with decreased ppCT.ConclusionsIn non-highly myopic healthy eyes, outward peripapillary scleral bowing achieved substantial levels, was markedly increased with age, and was independently associated with decreased peripapillary choroidal thickness. These findings provide a normative foundation for characterizing this anatomy in cases of high myopia and glaucoma and in eyes with optic disc tilt, torsion, and peripapillary atrophy.

PRECIS: In this prospective cohort study, disc hemorrhages were associated with more severe central damage on 24-2 and 10-2 visual fields (VFs), and faster progression globally on 24-2 VFs and centrally on 10-2 VFs. PURPOSE: To study the relationship between disc hemorrhage (DH) and the presence and progression of glaucomatous central VF damage. METHODS: Cross-sectional and longitudinal analyses were performed on data from the African Descent and Glaucoma Evaluation Study (ADAGES) cohort. Two masked investigators reviewed disc photographs for the presence and location of DH. 24-2 central VF damage was based on the number of test locations within the central 10 degrees of the 24-2 field pattern deviation and their mean total deviation (MTD). 10-2 central VF damage was based on pattern deviation and MTD. Main outcome measures were the association between DH and presence of central VF damage and between DH and worsening of VF. RESULTS: DH was detected in 21 of 335 eyes (6.2%). In the cross-sectional analysis, DH was significantly associated with more severe central damage on 24-2 [incidence rate ratio=1.47; 95% confidence interval (CI)=1.02-2.12; P=0.035] and 10-2 VFs (incidence rate ratio=1.81; 95% CI=1.26-2.60; P=0.001). In the longitudinal analysis, DH eyes progressed faster than non-DH eyes based on 24-2 global MTD rates (difference in slopes, β=-0.06; 95% CI=-0.11 to -0.01; P=0.009) and 10-2 MTD rates (β=-0.10; 95% CI=-0.14 to -0.06; P< 0.001), but not 24-2 central MTD rates (β=-0.02; 95% CI=-0.078 to 0.026; P=0.338). CONCLUSION: DH was associated with the presence and progression of central VF defects. DH identification should prompt intensive central VF monitoring and surveillance with 10-2 fields to detect progression.

PrecisIn this longitudinal prospective cohort study of open-angle glaucoma patients, intraocular pressure (IOP) parameters (mean, fluctuation, and maximum) had a similar effect on glaucomatous progression in the central and peripheral visual field (VF) regions.PurposeTo study the effects of IOP on rates of glaucomatous central versus peripheral VF progression.MethodsThe African Descent and Glaucoma Evaluation Study (ADAGES) is a longitudinal prospective cohort study that recruited patients from 3 centers. A sample of those with established glaucoma were included in this study. The mean peripheral sensitivity (MPS) and the mean central sensitivity (MCS) were defined based upon the average total deviation of the peripheral and central (10 degrees) points of the 24-2 VF, respectively. Progression was based upon central and peripheral change from linear mixed-effects models. The relationships between VF progression and IOP mean, maximum, and fluctuation as continuous variables were also investigated. Main outcome measures were MPS and MCS progression rates.ResultsA total of 452 eyes of 344 patients were studied. The mean number of VFs (SD) for each eye was 13.3 (6.4) over 9.1 (3.7) years. The mean baseline MD was -5.1 (3.9) dB and the mean rate of MD change was -0.26 dB/y [95% confidence interval (CI): -0.33 to -0.20, P

PurposeTo compare performance of independently developed deep learning algorithms for detecting glaucoma from fundus photographs and to evaluate strategies for incorporating new data into models.MethodsTwo fundus photograph datasets from the Diagnostic Innovations in Glaucoma Study/African Descent and Glaucoma Evaluation Study and Matsue Red Cross Hospital were used to independently develop deep learning algorithms for detection of glaucoma at the University of California, San Diego, and the University of Tokyo. We compared three versions of the University of California, San Diego, and University of Tokyo models: original (no retraining), sequential (retraining only on new data), and combined (training on combined data). Independent datasets were used to test the algorithms.ResultsThe original University of California, San Diego and University of Tokyo models performed similarly (area under the receiver operating characteristic curve = 0.96 and 0.97, respectively) for detection of glaucoma in the Matsue Red Cross Hospital dataset, but not the Diagnostic Innovations in Glaucoma Study/African Descent and Glaucoma Evaluation Study data (0.79 and 0.92; P < .001), respectively. Model performance was higher when classifying moderate-to-severe compared with mild disease (area under the receiver operating characteristic curve = 0.98 and 0.91; P < .001), respectively. Models trained with the combined strategy generally had better performance across all datasets than the original strategy.ConclusionsDeep learning glaucoma detection can achieve high accuracy across diverse datasets with appropriate training strategies. Because model performance was influenced by the severity of disease, labeling, training strategies, and population characteristics, reporting accuracy stratified by relevant covariates is important for cross study comparisons.Translational relevanceHigh sensitivity and specificity of deep learning algorithms for moderate-to-severe glaucoma across diverse populations suggest a role for artificial intelligence in the detection of glaucoma in primary care.

PurposeTo investigate the relationship between corneal hysteresis (CH) and anterior lamina cribrosa surface (ALCS) displacement over time in a cohort of patients with glaucoma.DesignProspective observational case series.MethodsIn this study, 147 eyes from 96 glaucoma or glaucoma suspect patients were followed for a mean of 3.5 years and 7.9 visits. Baseline CH measurements were obtained using the Ocular Response Analyzer (ORA; Reichert Ophthalmic Instruments Inc, Depew, New York, USA). The mean anterior lamina cribrosa surface depth (ALCSD) and choroidal thickness were by automated segmentation of spectral-domain optical coherence tomography (SD-OCT) scans. The rate of change of ALCSD was calculated using linear mixed effects models. Relationship between baseline CH and follow-up ALCSD rate of change was adjusted for confounding factors, including age, intraocular pressure (IOP), and choroidal thickness.ResultsThe mean baseline CH was 9.4 mm Hg (95% confidence interval [CI] 9.1-9.7). Overall, the ALCS was displaced posteriorly at a rate of 0.78 μm/y (95% CI -1.82, 0.26). Seventeen eyes (11.5%) showed a significant posterior displacement of ALCS, whereas 22 eyes (15.0%) showed a significant anterior displacement of ALCS. The choroidal thickness thinned at a rate of -1.09 μm/y during the follow-up (P = .001). Multivariable mixed modeling showed that choroidal thinning, lower IOP change, and lower corneal hysteresis were significantly associated with posterior ALCS displacement over time (P = .034, P = .037, and P = .048). Each 1 mm lower CH was associated with 0.66 μm/y posterior displacement of the ALCS.ConclusionsLower corneal hysteresis was significantly associated with posterior displacement of the anterior lamina cribrosa over time. These data provide additional support for lower corneal hysteresis being a risk factor for glaucoma progression.

PurposeTo develop and evaluate a deep learning system for differentiating between eyes with and without glaucomatous visual field damage (GVFD) and predicting the severity of GFVD from spectral domain OCT (SD OCT) optic nerve head images.DesignEvaluation of a diagnostic technology.ParticipantsA total of 9765 visual field (VF) SD OCT pairs collected from 1194 participants with and without GVFD (1909 eyes).MethodsDeep learning models were trained to use SD OCT retinal nerve fiber layer (RNFL) thickness maps, RNFL en face images, and confocal scanning laser ophthalmoscopy (CSLO) images to identify eyes with GVFD and predict quantitative VF mean deviation (MD), pattern standard deviation (PSD), and mean VF sectoral pattern deviation (PD) from SD OCT data.Main outcome measuresDeep learning models were compared with mean RNFL thickness for identifying GVFD using area under the curve (AUC), sensitivity, and specificity. For predicting MD, PSD, and mean sectoral PD, models were evaluated using R2 and mean absolute error (MAE).ResultsIn the independent test dataset, the deep learning models based on RNFL en face images achieved an AUC of 0.88 for identifying eyes with GVFD and 0.82 for detecting mild GVFD significantly (P < 0.001) better than using mean RNFL thickness measurements (AUC = 0.82 and 0.73, respectively). Deep learning models outperformed standard RNFL thickness measurements in predicting all quantitative VF metrics. In predicting MD, deep learning models based on RNFL en face images achieved an R2 of 0.70 and MAE of 2.5 decibels (dB) compared with 0.45 and 3.7 dB for RNFL thickness measurements. In predicting mean VF sectoral PD, deep learning models achieved high accuracy in the inferior nasal (R2 = 0.60) and superior nasal (R2 = 0.67) sectors, moderate accuracy in inferior (R2 = 0.26) and superior (R2 = 0.35) sectors, and lower accuracy in the central (R2 = 0.15) and temporal (R2 = 0.12) sectors.ConclusionsDeep learning models had high accuracy in identifying eyes with GFVD and predicting the severity of functional loss from SD OCT images. Accurately predicting the severity of GFVD from SD OCT imaging can help clinicians more effectively individualize the frequency of VF testing to the individual patient.

PurposeTo compare the rates of retinal nerve fiber layer (RNFL) thinning after intraocular pressure (IOP) lowering procedures in eyes with or without disc hemorrhage (DH) history.DesignObservational cohort study.MethodsA total of 166 primary open angle glaucoma (POAG) eyes and glaucoma suspect eyes (37 eyes with DH history (DH group) and 129 eyes without DH (non-DH group)) were included from the African Decent and Glaucoma Evaluation Study (ADAGES) and the Diagnostic Innovations in Glaucoma Study (DIGS). Subjects underwent stereoscopic optic disc photography annually and spectral-domain optical coherence tomography (OCT) RNFL thickness measurements every 6 months. The rates of RNFL thinning were compared in eyes with and without DH using univariate and multivariable linear mixed effects models.Main outcome measuresThe rates of RNFL thinning.ResultsThe mean follow-up of DH group and non-DH group was 4.6 years and 4.2 years, respectively. DH group had more procedures (2.4 vs. 1.9, P= 0.080) before follow-up, and more medications (1.8 vs. 1.4, P= 0.052) and lower mean IOP (12.69 mmHg vs. 14.41 mmHg, P= 0.012) during follow-up compared to non-DH group. When mean IOP was adjusted as a covariate in the model, the RNFL thinning rate in the DH group was 2-fold faster than in the non-DH group (-0.61 μm /year vs. -0.33 μm /year, P= 0.025). Higher mean IOP during follow-up was associated with a faster rate of RNFL thinning after procedures.ConclusionsPOAG or glaucoma suspect eyes with a history of DH should be carefully followed after IOP-lowering procedures. Additional IOP-lowering may be needed to slow structural progression of the DH eyes to the same rate as the non-DH eyes.

PurposeTo assess anterior scleral canal opening (ASCO) offset relative to Bruch's membrane opening (BMO) (ASCO/BMO offset) so as to determine neural canal direction, obliqueness, and minimum cross-sectional area (NCMCA) in 362 healthy eyes.DesignCross-sectional study.MethodsAfter optical coherence tomography optic nerve head and retinal nerve fiber layer thickness (RNFLT) imaging, BMO and ASCO were manually segmented. Planes, centroids, size, and shape were calculated. Neural canal direction was defined by projecting the neural canal axis vector (connecting BMO and ASCO centroids) onto the BMO plane. Neural canal obliqueness was defined by the angle between the neural canal axis and the BMO plane perpendicular vector. NCMCA was defined by projecting BMO and ASCO points onto a neural canal axis perpendicular plane and measuring the area of overlap. The angular distance between superior and inferior peak RNFLT was measured, and correlations between RFNLT, BMO, ASCO, ASCO/BMO offset, and NCMCA were assessed.ResultsMean (SD) NCMCA was significantly smaller than either the BMO or ASCO area (1.33 (0.42), 1.82 (0.38), 2.22 (0.43) mm2, respectively), and most closely correlated to RNFLT (P < .001, R2 = 0.158). Neural canal direction was most commonly superior-nasal (55%). Mean neural canal obliqueness was 39.4° (17.3°). The angular distance between superior and inferior peak RNFLT correlated to neural canal direction (P ≤ .008, R2 = 0.093).ConclusionsASCO/BMO offset underlies neural canal direction, obliqueness, and NCMCA. RNFLT is more strongly correlated to NCMCA than to BMO or ASCO, and its peripapillary distribution is influenced by neural canal direction.

ImportancePrimary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders.ObjectivesTo perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma.Design, settings, and participantsA 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma.ExposuresGenetic variants associated with primary open-angle glaucoma.Main outcomes and measuresPresence of primary open-angle glaucoma. Genome-wide significance was defined as P C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P

Importance:Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders. Objectives:To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma. Design, Settings, and Participants:A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma. Exposures:Genetic variants associated with primary open-angle glaucoma. Main Outcomes and Measures:Presence of primary open-angle glaucoma. Genome-wide significance was defined as P C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P

PurposeTo determine if variation in anterior lamina cribrosa surface depth (ALCSD) differs between glaucoma patients of African (AD) and European descent (ED).MethodsA total of 178 eyes from 123 glaucoma patients in the African Descent and Glaucoma Evaluation Study (ADAGES) and Diagnostic Innovations in Glaucoma Study (DIGS) were included. ALCSD and choroidal thickness were measured using the San Diego Automated Layer Segmentation Algorithm (SALSA). ALCSD was defined by both Bruch's membrane opening (BMO)-based (ALCSD-BMO) and scleral-based (ALCSD-Scl) reference planes. Racial differences in ALCSD were evaluated using cross-sectional univariate and multivariable models.ResultsA deeper ALCSD-Scl was found in males (52.4 μm, P = 0.0401), AD individuals (78.6 μm, P = 0.0004), younger individuals (-3.1 μm/year, P < 0.0213), and eyes with larger discs (81.0 μm/mm2, P = 0.024), increased visual field loss (mean defect, MD: -6.4 μm/dB [decibel], P = 0.0106), and higher intraocular pressure (IOP: 14.1 μm/mm Hg, P = 0.0256). Significant deepening of ALSCD was observed with increasing IOP and visual field severity only in the AD group. Race modified the relationship between ALCSD-Scl and age (P = 0.0145) with ALCSD-Scl in AD individuals becoming more shallow with increasing age (-3.1 μm/year, P = 0.0213), while there was no significant association in the ED group (2.1 μm/mm Hg, P < 0.2026).ConclusionsThis study demonstrates that a deeper ALCSD, regardless of the ALCSD reference plane used, is associated with more severe glaucoma and higher IOP in the ADAGES cohort, particularly in individuals of AD. These results suggest that characterizing ALCSD morphology and its relationships to IOP, aging, and glaucoma progression may help explain racial differences in disease susceptibility.

PurposeTo compare the ability of 10-2 visual field tests and central 12 locations of the 24-2 tests (C24-2) to detect central visual field progression in glaucoma eyes with early central visual field abnormalities.DesignObservational cohort study.ParticipantsThree-hundred eyes of 180 participants with glaucoma or ocular hypertension.MethodsParticipants with both 10-2 and 24-2 tests performed on ≥3 visits over ≥1-year period were included to estimate the longitudinal variability of 10-2 and C24-2 visual field mean deviation (MD). The variability estimates were then used to reconstruct real-world visual field results by computer simulations, in a scenario where eyes had a baseline 10-2 and C24-2 MD was -2 dB and exhibited various rates of change (-0.25, -0.50, -0.75 and -1.00 dB/year), and the time to detect these changes were evaluated using trend-based analyses.Main outcome measuresTime required to detect progression.ResultsOverall, the time to detect central visual field progression was reduced by 7-9% using the 10-2 compared to C24-2 MD values, equivalent to a total reduction of 0.1-0.3 dB lost. For example, 90% of eyes with a central 10-2 or C24-2 MD loss of -0.50 dB/year would be detected after 5.0 and 5.5 years of semi-annual testing respectively, or after 3.4 and 3.7 years respectively for eyes with a -1.00 dB/year loss.ConclusionsTrend-based analyses using 10-2 MD resulted in a mild reduction (7-9%) in the time to detect central visual field progression compared to C24-2 MD in glaucoma eyes with early central visual field abnormalities. Further studies are needed to determine whether other progression analyses can better exploit the increased sampling of 10-2 tests. These findings provide evidence-based guidance on the potential value-add of 10-2 testing in the clinical management of glaucoma patients.

PurposeTo quantify peripapillary choroidal thickness (PCT) and the factors that influence it in healthy participants who represent the racial and ethnic composition of the U.S. population.MethodsA total of 362 healthy participants underwent optical coherence tomography (OCT) enhanced depth imaging of the optic nerve head with a 24 radial B-scan pattern aligned to the fovea to Bruch's membrane opening axis. Bruch's membrane, anterior scleral canal opening (ASCO), and the anterior scleral surface were manually segmented. PCT was measured at 100, 300, 500, 700, 900, and 1100 μm from the ASCO globally and within 12 clock-hour sectors. The effects of age, axial length, intraocular pressure, ethnicity, sex, sector, and ASCO area on PCT were assessed by ANOVA and univariable and multivariable regressions.ResultsGlobally, PCT was thicker further from the ASCO border and thinner with older age, longer axial length, larger ASCO area, European descent, and female sex. Among these effectors, age and axial length explained the greatest proportion of variance. The rate of age-related decline increased further from the ASCO border. Sectorally, the inferior-temporal sectors were thinnest (10.7%-20.0% thinner than the thickest sector) and demonstrated a higher rate of age-related loss (from 15.6% to 20.7% faster) at each ASCO distance.ConclusionsIn healthy eyes, PCT was thinnest in the inferior temporal sectors and thinner PCT was associated with older age, European descent, longer axial length, larger ASCO area, and female sex. Among these associations, age had the strongest influence, and its effect was greatest within the inferior temporal sectors.

PurposeTo describe the study protocol and baseline characteristics of the African Descent and Glaucoma Evaluation Study (ADAGES) III.DesignCross-sectional, case-control study.ParticipantsThree thousand two hundred sixty-six glaucoma patients and control participants without glaucoma of African or European descent were recruited from 5 study centers in different regions of the United States.MethodsIndividuals of African descent (AD) and European descent (ED) with primary open-angle glaucoma (POAG) and control participants completed a detailed demographic and medical history interview. Standardized height, weight, and blood pressure measurements were obtained. Saliva and blood samples to provide serum, plasma, DNA, and RNA were collected for standardized processing. Visual fields, stereoscopic disc photographs, and details of the ophthalmic examination were obtained and transferred to the University of California, San Diego, Data Coordinating Center for standardized processing and quality review.Main outcome measuresParticipant gender, age, race, body mass index, blood pressure, history of smoking and alcohol use in POAG patients and control participants were described. Ophthalmic measures included intraocular pressure, visual field mean deviation, central corneal thickness, glaucoma medication use, or past glaucoma surgery. Ocular conditions, including diabetic retinopathy, age-related macular degeneration, and past cataract surgery, were recorded.ResultsThe 3266 ADAGES III study participants in this report include 2146 AD POAG patients, 695 ED POAG patients, 198 AD control participants, and 227 ED control participants. The AD POAG patients and control participants were significantly younger (both, 67.4 years) than ED POAG patients and control participants (73.4 and 70.2 years, respectively). After adjusting for age, AD POAG patients had different phenotypic characteristics compared with ED POAG patients, including higher intraocular pressure, worse visual acuity and visual field mean deviation, and thinner corneas (all P < 0.001). Family history of glaucoma did not differ between AD and ED POAG patients.ConclusionsWith its large sample size, extensive specimen collection, and deep phenotyping of AD and ED glaucoma patients and control participants from different regions in the United States, the ADAGES III genomics study will address gaps in our knowledge of the genetics of POAG in this high-risk population.