The Association of Race, Ethnicity, and Insurance Status with the Visual Acuity of Retinoblastoma Survivors in the IRIS® Registry.

PURPOSE: To identify sociodemographic factors associated with the visual outcomes of retinoblastoma survivors. METHODS: Retrospective cohort study using a US-based clinical data registry. All individuals < 18 years of age with a history of retinoblastoma in the Intelligent Research in Sight (IRIS®) Registry (1/1/2013-12/31/2020). The primary outcome was visual acuity below the threshold for legal blindness (20/200 or worse) in at least one eye. Multivariable logistic regression was used to evaluate the association between visual outcomes and age, sex, laterality, race, ethnicity, type of insurance, and geographic location. RESULTS: This analysis included 1545 children with a history of retinoblastoma. The median length of follow-up was 4.1 years (IQR, 2.2-5.9 years) and the median age at most recent clinical visit was 12 years (IQR, 8-16 years). Retinoblastoma was unilateral in 54% of cases. Poor vision in at least one eye was identified in 78% of all children and poor vision in both eyes in 17% of those with bilateral disease. Poor visual outcomes were associated with unilateral diagnosis (OR, 1.55; 95% CI,1.13-2.12; p = .007), Black race (OR, 2.03; 95% CI, 1.19-3.47; p = .010), Hispanic ethnicity (OR, 1.65; 95% CI, 1.16-2.37; p = .006), and non-private insurance (OR, 1.47; 95% CI, 1.02-2.10; p = .037). CONCLUSIONS: Poor visual outcomes appear to be more common among Black, Hispanic, and publicly insured children with a history of retinoblastoma, raising concerns regarding healthcare inequities. Primary care physicians should ensure that young children receive red reflex testing during routine visits and consider retinoblastoma in the differential diagnosis of abnormal eye exams.

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

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

Racial Disparities in Glaucoma Vision Outcomes and Eye Care Utilization: An IRIS Registry Analysis.

PURPOSE: To evaluate racial disparities in vision outcomes and eye care utilization among glaucoma patients. DESIGN: Retrospective cohort study. METHODS: In this population-based IRIS Registry (Intelligent Research in Sight) study, we included patients with minimum one diagnosis code for glaucoma at least 6 months prior to January 1, 2015 and at least one eye exam, visual field (VF), optical coherence tomography (OCT), or eye-related inpatient or emergency department (ED) code in 2015. Multivariable logistic and negative binomial regression models were used to assess vision and utilization outcomes, respectively, across race and ethnicity from January 1, 2015 to January 1, 2020. Vision outcomes included cup-to-disc ratio (CDR) progression > 0.80, poor vision (visual acuity 20/200 or worse), low vision codes, and need for glaucoma filtering surgery. Utilization outcomes included outpatient eye exams, OCTs, VFs, inpatient/ED encounters, and lasers/surgeries. RESULTS: Among 996,297 patients, 73% were non-Hispanic White, 15% non-Hispanic Black, 9% Hispanic, 3% Asian/Pacific Islander, and 0.3% Native American/Alaska Native. Compared to White eyes, Black and Hispanic eyes had higher adjusted odds of CDR progression (odds ratio [OR] = 1.12, 95% confidence interval [CI] = 1.08-1.17; OR = 1.28, 95% CI = 1.22-1.34), poor vision (OR = 1.26, 95% CI = 1.22-1.29; OR = 1.26, 95% CI = 1.22-1.31), glaucoma filtering surgery (rate ratio (RR) = 1.47, 95% CI = 1.42-1.51; RR = 1.13, 95% CI = 1.09-1.18). Hispanic eyes also had increased odds of low vision diagnoses (Hispanic OR = 1.18, 95% CI = 1.07-1.30). Black and Hispanic patients were less likely to have eye exams (RR = 0.94, 95% CI = 0.94-0.95; RR = 0.99, 95% CI = 0.99-0.99) and OCTs (RR = 0.86, 95% CI = 0.85-0.86; RR = 0.97, 95% CI = 0.96-0.98), yet Black patients had higher odds of inpatient/ED encounters (RR = 1.64, 95% CI = 1.37-1.96) compared to White patients. Native American patients were more likely to have poor vision (OR = 1.17, 95% CI = 1.01-1.36) and less likely to have outpatient visits (RR = 0.89, 95% CI = 0.86-0.91), OCTs (RR = 0.85, 95% CI = 0.82-0.89), visual fields (RR = 0.91, 95% CI = 0.88-0.94) or lasers/surgeries (RR = 0.87, 95% CI = 0.79-0.96) compared to White patients. CONCLUSIONS: We found that significant disparities in US eye care exist with Black, Hispanic, and Native American patients having worse vision outcomes and less disease monitoring. Glaucoma may be undertreated in these racial and ethnic minority groups, increasing risk for glaucoma-related vision loss.

Effectiveness of Angle-Based Minimally Invasive Glaucoma Surgery after Laser Trabeculoplasty: An Analysis of the IRIS® Registry (Intelligent Research in Sight).

OBJECTIVE: Angle-based minimally invasive glaucoma surgery (ab-MIGS) has grown substantially, although long-term efficacy is poorly understood. We analyze ab-MIGS effectiveness with and without preceding laser trabeculoplasty (LTP). DESIGN: Retrospective cohort study. SUBJECTS: Eyes undergoing ab-MIGS (Canaloplasty, Goniotomy, Trabectome, and iStent) with and without prior laser trabeculoplasty (< 2 years preceding MIGS) were identified in the IRIS® Registry (Intelligent Research in Sight) 2013 to 2018. METHODS: Propensity score matching (PSM) was undertaken to define the following 4 cohorts: (1) standalone ab-MIGS, no prior LTP vs. (2) standalone ab-MIGS, with prior LTP; and (3) ab-MIGS + phacoemulsification, no prior LTP vs. (4) ab-MIGS + phacoemulsification, with prior LTP. MAIN OUTCOME MEASURES: Failure was defined as subsequent glaucoma reoperation after ab-MIGS (either MIGS or traditional glaucoma surgery). Time-to-event outcome and incidence rates were calculated using survival analysis, and adjusted hazard ratios (aHRs) were generated using multivariate Cox proportional hazards models. Medication data were not available for analysis. RESULTS: A total of 164 965 unique MIGS procedures were performed, from 2013 to 2018. After PSM, we identified 954 eyes undergoing standalone ab-MIGS and 7522 undergoing ab-MIGS + phacoemulsification. For eyes undergoing standalone ab-MIGS, those with prior LTP (n = 477) were more likely to undergo reoperation vs. those without LTP (n = 477) at 6 and 12 months. In multivariable models, those with prior LTP were more likely to undergo reoperation over the 36-month period vs. those without prior LTP (aHR, 1.53; CI, 1.15-2.04; P = 0.004). For eyes undergoing ab-MIGS + phacoemulsification, those with prior LTP (n = 3761) were more likely to undergo reoperation vs. those without LTP (n = 3761) at 12, 24, and 36 months. In multivariable models, those with prior LTP were more likely to undergo reoperation over the 36-month period vs. those without prior LTP (aHR, 1.53 CI, 1.15-2.04; P = 0.004). CONCLUSIONS: Prior LTP may be associated with a higher chance of subsequent glaucoma surgery following ab-MIGS, either with or without concurrent phacoemulsification. These findings have important implications for understanding who may benefit most from ab-MIGS, and for guiding patient and surgeon treatment expectations. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

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

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

Glucose tolerance and insulin resistance/sensitivity associate with retinal layer characteristics: the LIFE-Adult-Study.

AIMS/HYPOTHESIS: As the prevalence of insulin resistance and glucose intolerance is increasing throughout the world, diabetes-induced eye diseases are a global health burden. We aim to identify distinct optical bands which are closely related to insulin and glucose metabolism, using non-invasive, high-resolution spectral domain optical coherence tomography (SD-OCT) in a large, population-based dataset. METHODS: The LIFE-Adult-Study randomly selected 10,000 participants from the population registry of Leipzig, Germany. Cross-sectional, standardised phenotyping included the assessment of various metabolic risk markers and ocular imaging, such as SD-OCT-derived thicknesses of ten optical bands of the retina. Global and Early Treatment Diabetic Retinopathy Study (ETDRS) subfield-specific optical retinal layer thicknesses were investigated in 7384 healthy eyes of 7384 participants from the LIFE-Adult-Study stratified by normal glucose tolerance, prediabetes (impaired fasting glucose and/or impaired glucose tolerance and/or HbA1c 5.7-6.4% [39-47 mmol/mol]) and diabetes. The association of optical retinal band characteristics with different indices of glucose tolerance (e.g. fasting glucose, area under the glucose curve), insulin resistance (e.g. HOMA2-IR, triglyceride glucose index), or insulin sensitivity (e.g. estimated glucose disposal rate [eGDR], Stumvoll metabolic clearance rate) was determined using multivariable linear regression analyses for the individual markers adjusted for age, sex and refraction. Various sensitivity analyses were performed to validate the observed findings. RESULTS: In the study cohort, nine out of ten optical bands of the retina showed significant sex- and glucose tolerance-dependent differences in band thicknesses. Multivariable linear regression analyses revealed a significant, independent, and inverse association between markers of glucose intolerance and insulin resistance (e.g. HOMA2-IR) with the thickness of the optical bands representing the anatomical retinal outer nuclear layer (ONL, standardised ß=-0.096; p<0.001 for HOMA2-IR) and myoid zone (MZ; ß=-0.096; p<0.001 for HOMA2-IR) of the photoreceptors. Conversely, markers of insulin sensitivity (e.g. eGDR) positively and independently associated with ONL (ß=0.090; p<0.001 for eGDR) and MZ (ß=0.133; p<0.001 for eGDR) band thicknesses. These global associations were confirmed in ETDRS subfield-specific analyses. Sensitivity analyses further validated our findings when physical activity, neuroanatomical cell/tissue types and ETDRS subfield categories were investigated after stratifying the cohort by glucose homeostasis. CONCLUSIONS/INTERPRETATION: An impaired glucose homeostasis associates with a thinning of the optical bands of retinal ONL and photoreceptor MZ. Changes in ONL and MZ thicknesses might predict early metabolic retinal alterations in diabetes.

RNFLT2Vec: Artifact-corrected representation learning for retinal nerve fiber layer thickness maps.

Optical coherence tomography imaging provides a crucial clinical measurement for diagnosing and monitoring glaucoma through the two-dimensional retinal nerve fiber layer (RNFL) thickness (RNFLT) map. Researchers have been increasingly using neural models to extract meaningful features from the RNFLT map, aiming to identify biomarkers for glaucoma and its progression. However, accurately representing the RNFLT map features relevant to glaucoma is challenging due to significant variations in retinal anatomy among individuals, which confound the pathological thinning of the RNFL. Moreover, the presence of artifacts in the RNFLT map, caused by segmentation errors in the context of degraded image quality and defective imaging procedures, further complicates the task. In this paper, we propose a general framework called RNFLT2Vec for unsupervised learning of vectorized feature representations from RNFLT maps. Our method includes an artifact correction component that learns to rectify RNFLT values at artifact locations, producing a representation reflecting the RNFLT map without artifacts. Additionally, we incorporate two regularization techniques to encourage discriminative representation learning. Firstly, we introduce a contrastive learning-based regularization to capture the similarities and dissimilarities between RNFLT maps. Secondly, we employ a consistency learning-based regularization to align pairwise distances of RNFLT maps with their corresponding thickness distributions. Through extensive experiments on a large-scale real-world dataset, we demonstrate the superiority of RNFLT2Vec in three different clinical tasks: RNFLT pattern discovery, glaucoma detection, and visual field prediction. Our results validate the effectiveness of our framework and its potential to contribute to a better understanding and diagnosis of glaucoma.

The Incidence of Strabismus After Upper and Lower Blepharoplasty in the United States.

PURPOSE: To compare the incidence of strabismus after upper and lower blepharoplasty in the United States. METHODS: Retrospective cohort study of adults (age ≥18 years) in the IRIS Registry (Intelligent Research in Sight) who underwent blepharoplasty between January 1, 2013 and December 31, 2020. The primary outcome was the Kaplan-Meier estimated cumulative incidence of strabismus diagnosis and surgery within 3 years of blepharoplasty. Multivariable Cox regression was used to determine the association of blepharoplasty type with strabismus diagnosis and surgery, adjusting for patient age, sex, and geographic region. RESULTS: Blepharoplasty was performed in 368,623 patients (median [interquartile range] age, 69 [63-75] years, and 69% female). Compared with those undergoing upper eyelid blepharoplasty, patients treated with lower eyelid blepharoplasty were slightly younger (median age, 66 vs. 69 years; p < 0.001) and more likely to be female (71% vs. 69%; p < 0.001). There was a greater 3-year incidence of strabismus diagnosis (2.0% vs. 1.5%; p < 0.001) and a greater 3-year incidence of strabismus surgery (0.15% vs. 0.06%; p = 0.003) for individuals undergoing lower vs. upper blepharoplasty. After adjusting for age, sex, and geographic region, lower blepharoplasty was associated with a higher 3-year risk of strabismus diagnosis (HR, 1.49; 95% CI, 1.23-1.81; p < 0.001) and surgery (HR, 2.53; 95% CI, 1.27-5.03; p = 0.008). CONCLUSIONS: This registry-based analysis found that individuals undergoing lower eyelid blepharoplasty were at higher risk of strabismus compared with those undergoing upper eyelid blepharoplasty. Using large databases to understand the incidence of complications of frequently performed procedures may improve ophthalmologists' ability to provide data-driven counseling on surgical risks prior to intervention.

Machine Learning-Derived Baseline Visual Field Patterns Predict Future Glaucoma Onset in the Ocular Hypertension Treatment Study.

Purpose: The Ocular Hypertension Treatment Study (OHTS) identified risk factors for primary open-angle glaucoma (POAG) in patients with ocular hypertension, including pattern standard deviation (PSD). Archetypal analysis, an unsupervised machine learning method, may offer a more interpretable approach to risk stratification by identifying patterns in baseline visual fields (VFs). Methods: There were 3272 eyes available in the OHTS. Archetypal analysis was applied using 24-2 baseline VFs, and model selection was performed with cross-validation. Decomposition coefficients for archetypes (ATs) were calculated. A penalized Cox proportional hazards model was implemented to select discriminative ATs. The AT model was compared to the OHTS model. Associations were identified between ATs with both POAG onset and VF progression, defined by mean deviation change per year. Results: We selected 8494 baseline VFs. Optimal AT count was 19. The highest prevalence ATs were AT9, AT11, and AT7. The AT-based prediction model had a C-index of 0.75 for POAG onset. Multivariable models demonstrated that a one-interquartile range increase in the AT5 (hazard ratio [HR] = 1.14; 95% confidence interval [CI], 1.04-1.25), AT8 (HR = 1.22; 95% CI, 1.09-1.37), AT15 (HR = 1.26; 95% CI, 1.12-1.41), and AT17 (HR = 1.17; 95% CI, 1.03-1.31) coefficients conferred increased risk of POAG onset. AT5, AT10, and AT14 were significantly associated with rapid VF progression. In a subgroup analysis by high-risk ATs (>95th percentile or <75th percentile coefficients), PSD lost significance as a predictor of POAG in the low-risk group. Conclusions: Baseline VFs, prior to detectable glaucomatous damage, contain occult patterns representing early changes that may increase the risk of POAG onset and VF progression in patients with ocular hypertension. The relationship between PSD and POAG is modified by the presence of high-risk patterns at baseline. An AT-based prediction model for POAG may provide more interpretable glaucoma-specific information in a clinical setting.

Fellow Eyes Conversion Rates in Patients With Unilateral Exudative Age-Related Macular Degeneration: An Academy IRIS® Registry Analysis.

BACKGROUND AND OBJECTIVE: This study aimed to examine conversion rates from non-exudative to exudative age-related macular degeneration (AMD) in the fellow eye of patients with unilateral exudative AMD using the Academy IRIS® Registry. PATIENTS AND METHODS: This study was a retrospective, cohort analysis from 2016 to 2019. Patient and disease characteristics including initial AMD stage were collected. Cox proportional-hazard (PH) and logistic regression modeling were performed. RESULTS: The risk of conversion was lower for men relative to women and for Asians and Blacks relative to Whites. Compared to never-smokers, active smokers were at increased risk of conversion, and compared to initially early non-exudative AMD eyes, intermediate and advanced non-exudative AMD eyes had higher rates of conversion. Compared to active choroidal neovascularization eyes, eyes with inactive choroidal neovascularization and inactive scars had lower rates of fellow eye conversion. CONCLUSIONS: In this cohort analysis of unilateral exudative AMD patients, women, Whites, and active smokers had higher rates of non-exudative to exudative AMD conversion in the fellow eye. [Ophthalmic Surg Lasers Imaging Retina 2024;55:220-226.].

The epidemiology of pediatric dry eye disease in the United States: An IRIS® registry (Intelligent Research in Sight) analysis.

PURPOSE: Dry-eye disease (DED) is a chronic progressive ocular surface disorder with limited studies in the pediatric population. The Academy of Ophthalmology's IRIS® Registry was leveraged to investigate the prevalence of DED in the pediatric population (PDED, patients <18 years old) and the demographic differences of DED between pediatric and adult patients (ADED). METHODS: Retrospective cohort study. Patients with DED between January 1st, 2013 and December 31st, 2019 (N = 4,795,979) were included. Descriptive statistics, Pearson's chi-squared tests and two-sample proportions tests were conducted to compare key demographic distributions between the ADED and PDED cohorts. RESULTS: The average age at onset for ADED patients was 61.06 (±14.75) years and for PDED patients was 12.51 (±3.86). The overall tests for independence and the individual tests of proportions of each category were statistically significant for all demographic characteristics (p < 0.001). Characteristics with the largest discrepancies between patients of PDED and the IRIS Registry pediatric patient pool (PIRIS) included female sex (58.08 % vs. 50.60 %), male sex (41.58 % vs. 48.78 %) and Asian race (6.02 % vs. 3.11 %) respectively. Within the PDED cohort, females were at higher risk of PDED (58 % vs. 42 %). PDED was more prevalent in children with refractive errors (76 %) and eyelid/conjunctival disorders (41 %). Characteristics with the largest discrepancies between PDED and ADED patients included female sex (58.08 % vs. 68.12 %), male sex (41.58 % vs. 31.55 %) and Caucasian race (50.24 % vs. 67.06 %) respectively. CONCLUSIONS: Significant differences in the PDED cohort are demonstrated in this study. PDED was more prevalent in the female sex and Caucasian race compared to PIRIS and was more commonly associated with refractive errors and eyelid/conjunctival disorders.

Factors associated with the use of botulinum toxin injections for adult strabismus in the IRIS Registry.

This cross-sectional study used data from a large nationwide registry to describe the factors associated with use of botulinum toxin injections for adults with strabismus in the United States. Botulinum toxin injections were performed on 3.1% of adults undergoing an intervention for strabismus between 2013 and 2020. Adults treated with botulinum toxin injections were more likely to be older and female. Compared to non-Hispanic White patients, non-Hispanic Black patients were three times less likely to receive treatment with botulinum toxin after adjusting for age, sex, geographic region, and type of insurance. Efforts to understand the factors contributing to disparities in the use of botulinum toxin for strabismus may lead to opportunities for more equitable access to this intervention.

Phenome- and genome-wide analyses of retinal optical coherence tomography images identify links between ocular and systemic health.

The human retina is a multilayered tissue that offers a unique window into systemic health. Optical coherence tomography (OCT) is widely used in eye care and allows the noninvasive, rapid capture of retinal anatomy in exquisite detail. We conducted genotypic and phenotypic analyses of retinal layer thicknesses using macular OCT images from 44,823 UK Biobank participants. We performed OCT layer cross-phenotype association analyses (OCT-XWAS), associating retinal thicknesses with 1866 incident conditions (median 10-year follow-up) and 88 quantitative traits and blood biomarkers. We performed genome-wide association studies (GWASs), identifying inherited genetic markers that influence retinal layer thicknesses and replicated our associations among the LIFE-Adult Study (N = 6313). Last, we performed a comparative analysis of phenome- and genome-wide associations to identify putative causal links between retinal layer thicknesses and both ocular and systemic conditions. Independent associations with incident mortality were detected for thinner photoreceptor segments (PSs) and, separately, ganglion cell complex layers. Phenotypic associations were detected between thinner retinal layers and ocular, neuropsychiatric, cardiometabolic, and pulmonary conditions. A GWAS of retinal layer thicknesses yielded 259 unique loci. Consistency between epidemiologic and genetic associations suggested links between a thinner retinal nerve fiber layer with glaucoma, thinner PS with age-related macular degeneration, and poor cardiometabolic and pulmonary function with a thinner PS. In conclusion, we identified multiple inherited genetic loci and acquired systemic cardio-metabolic-pulmonary conditions associated with thinner retinal layers and identify retinal layers wherein thinning is predictive of future ocular and systemic conditions.

Association of retinal optical coherence tomography metrics and polygenic risk scores with cognitive function and future cognitive decline.

PURPOSE: To evaluate the potential of retinal optical coherence tomography (OCT) measurements and polygenic risk scores (PRS) to identify people at risk of cognitive impairment. METHODS: Using OCT images from 50 342 UK Biobank participants, we examined associations between retinal layer thickness and genetic risk for neurodegenerative disease and combined these metrics with PRS to predict baseline cognitive function and future cognitive deterioration. Multivariate Cox proportional hazard models were used to predict cognitive performance. P values for retinal thickness analyses are false-discovery-rate-adjusted. RESULTS: Higher Alzheimer's disease PRS was associated with a thicker inner nuclear layer (INL), chorio-scleral interface (CSI) and inner plexiform layer (IPL) (all p<0.05). Higher Parkinson's disease PRS was associated with thinner outer plexiform layer (p<0.001). Worse baseline cognitive performance was associated with thinner retinal nerve fibre layer (RNFL) (aOR=1.038, 95% CI (1.029 to 1.047), p<0.001) and photoreceptor (PR) segment (aOR=1.035, 95% CI (1.019 to 1.051), p<0.001), ganglion cell complex (aOR=1.007, 95% CI (1.002 to 1.013), p=0.004) and thicker ganglion cell layer (aOR=0.981, 95% CI (0.967 to 0.995), p=0.009), IPL (aOR=0.976, 95% CI (0.961 to 0.992), p=0.003), INL (aOR=0.923, 95% CI (0.905 to 0.941), p<0.001) and CSI (aOR=0.998, 95% CI (0.997 to 0.999), p<0.001). Worse future cognitive performance was associated with thicker IPL (aOR=0.945, 95% CI (0.915 to 0.999), p=0.045) and CSI (aOR=0.996, 95% CI (0.993 to 0.999) 95% CI, p=0.014). Prediction of cognitive decline was significantly improved with the addition of PRS and retinal measurements. CONCLUSIONS AND RELEVANCE: Retinal OCT measurements are significantly associated with genetic risk of neurodegenerative disease and may serve as biomarkers predictive of future cognitive impairment.

Surgical Approach and Reoperation Risk in Intermittent Exotropia in the IRIS Registry.

Importance: There is no consensus on the optimal surgical treatment for children with intermittent exotropia (IXT). Objective: To compare the 5-year reoperation rates for children with IXT treated with horizontal muscle strabismus surgery using bilateral lateral rectus recession (BLR) vs unilateral lateral rectus recession with medial rectus resection (RR). Design, Setting, and Participants: This cohort study examined data obtained from the Intelligent Research in Sight (IRIS) Registry on 7482 children (age, <18 years) with IXT who underwent horizontal eye muscle strabismus surgery between January 1, 2013, and December 31, 2017. Children undergoing initial surgeries involving 3 or more horizontal muscles, vertical muscles, or reoperations were excluded. Main Outcomes and Measures: The primary outcome was the adjusted cumulative incidence of repeat horizontal muscle surgery within 5 years after the initial surgery. Reoperation risk was analyzed using adjusted hazard ratios (AHRs) derived from multivariable Cox regression models, adjusting for individual demographic and surgical factors (age, sex, race and ethnicity, US Census region, and surgeon subspecialty). Data were analyzed between January 16 and September 20, 2023. Results: The study included 7482 children (median [IQR] age at initial surgery, 6 [4-9] years; 3945 females [53%]) with IXT treated with horizontal muscle strabismus surgery. Bilateral lateral rectus recession was performed more frequently than RR (85.3% vs 14.7%, P < .001), especially in younger children (rates of BLR vs RR by age: age 0 to ≤4 years, 88.4% vs 11.6%; age 5 to ≤11 years, 84.7% vs 15.3%; age 12 to ≤17 years, 78.1% vs 21.9%; P < 0.001). After data adjustment, the 5-year cumulative incidence of reoperation was 21.3% (95% CI, 20.1%-22.5%). The adjusted 5-year cumulative incidence of reoperation was higher for BLR than for RR (22.2% vs 17.2%; difference, 4.9%; 95% CI, 1.9%-8.0%). Unilateral lateral rectus recession with medial rectus resection was associated with a lower 5-year reoperation risk compared with BLR (AHR, 0.77; 95% CI, 0.64-0.93). Younger age at time of initial surgery was associated with a higher reoperation risk (AHR per 1-year decrease, 1.09; 95% CI, 1.07-1.11) after adjusting for all other covariates. Conclusions and Relevance: In this nationwide registry, approximately 1 in 5 children with IXT underwent reoperation within 5 years after the initial surgery. Children treated with RR were less likely to require a reoperation within 5 years compared with those treated with BLR. Further efforts to identify modifiable risk factors for reoperation are needed to reduce the surgical burden and improve outcomes for children with IXT.

The Epidemiology and Risk Factors for the Progression of Sympathetic Ophthalmia in the United States: An IRIS Registry Analysis.

PURPOSE: To investigate the demographic and clinical characteristics of patients with sympathetic ophthalmia (SO) and define the risk factors for its incidence following trauma and ophthalmic procedures. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients in the American Academy of Ophthalmology's (Academy) IRIS Registry (Intelligent Research in Sight) who were (n=1523) or were not diagnosed with SO following a documented procedure or trauma between January 1, 2013, and December 31, 2019. METHODS: Multiple demographic and clinical factors were collected, descriptive statistics and prevalence were calculated, and multivariate linear regression models were fit to the data. MAIN OUTCOME MEASURES: Prevalence of SO, demographic and clinical characteristics, and beta coefficient (ß) estimates of demographic and clinical characteristics impacting time to SO onset after procedure (Procedure Only cohort) or trauma (Trauma cohort). RESULTS: Of 65,348,409 distinct IRIS Registry patients, 1523 (0.0023%) were diagnosed with SO between 2013 and 2019, and also had a documented preceding trauma or procedure. Of these, 927 (60.87%) were female, 1336 (87.72%) belonged to the Procedure Only cohort, and 187 (12.28%) belonged to the Trauma cohort. The prevalence of SO after trauma was 0.0207%, whereas after procedures it was 0.0124%. The highest risk of procedure-related SO was seen in patients with history of "other anterior segment" (0.122%) followed by glaucoma (0.066%) procedures, whereas the lowest prevalence was noted with cataract surgeries (0.011%). The average time to onset of SO across both cohorts combined was 527.44 (±715.60) days, with statistically significant differences between the 2 cohorts (P < .001). On average, the time to onset from inciting event to SO was shorter with increasing age, by 9.02 (95% CI: -11.96, -6.08) days for every 1-year increase. CONCLUSIONS: SO following trauma and ophthalmic procedure is potentially rarer than previously reported, as measured in this large ophthalmic medical record database. Female sex may be a risk factor for SO. Older age may be a risk factor for quicker onset. These findings can guide clinical decision-making and management.

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

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

Risk Factors for Glaucoma Diagnosis and Surgical Intervention following Pediatric Cataract Surgery in the IRIS® Registry.

PURPOSE: To compare demographic and clinical factors associated with glaucoma following cataract surgery (GFCS) and glaucoma surgery rates between infants, toddlers, and older children using a large, ophthalmic registry. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients in the IRIS® Registry (Intelligent Research in Sight) who underwent cataract surgery at ≤ 17 years old and between January 1, 2013 and December 31, 2020. METHODS: Glaucoma diagnosis and procedural codes were extracted from the electronic health records of practices participating in the IRIS Registry. Children with glaucoma diagnosis or surgery before cataract removal were excluded. The Kaplan-Meier estimator was used to determine the cumulative probability of GFCS diagnosis and glaucoma surgery after cataract surgery. Multivariable Cox regression was used to identify factors associated with GFCS and glaucoma surgery. MAIN OUTCOME MEASURES: Cumulative probability of glaucoma diagnosis and surgical intervention within 5 years after cataract surgery. RESULTS: The study included 6658 children (median age, 10.0 years; 46.2% female). The 5-year cumulative probability of GFCS was 7.1% (95% confidence interval [CI], 6.1%-8.1%) and glaucoma surgery was 2.6% (95% CI, 1.9%-3.2%). The 5-year cumulative probability of GFCS for children aged < 1 year was 22.3% (95% CI, 15.7%-28.4%). Risk factors for GFCS included aphakia (hazard ratio [HR], 2.63; 95% CI, 1.96-3.57), unilateral cataract (HR, 1.48; 95% CI, 1.12-1.96), and Black race (HR, 1.61; 95% CI, 1.12-2.32). The most common surgery was glaucoma drainage device insertion (32.6%), followed by angle surgery (23.3%), cyclophotocoagulation (15.1%), and trabeculectomy (5.8%). CONCLUSIONS: Glaucoma following cataract surgery diagnosis in children in the IRIS Registry was associated with young age, aphakia, unilateral cataract, and Black race. Glaucoma drainage device surgery was the preferred surgical treatment, consistent with the World Glaucoma Association 2013 consensus recommendations for GFCS management. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

An Artificial Intelligence Enabled System for Retinal Nerve Fiber Layer Thickness Damage Severity Staging.

Purpose: To develop an objective glaucoma damage severity classification system based on OCT-derived retinal nerve fiber layer (RNFL) thickness measurements. Design: Algorithm development for RNFL damage severity classification based on multicenter OCT data. Subjects and Participants: A total of 6561 circumpapillary RNFL profiles from 2269 eyes of 1171 subjects to develop models, and 2505 RNFL profiles from 1099 eyes of 900 subjects to validate models. Methods: We developed an unsupervised k-means model to identify clusters of eyes with similar RNFL thickness profiles. We annotated the clusters based on their respective global RNFL thickness. We computed the optimal global RNFL thickness thresholds that discriminated different severity levels based on Bayes' minimum error principle. We validated the proposed pipeline based on an independent validation dataset with 2505 RNFL profiles from 1099 eyes of 900 subjects. Main Outcome Measures: Accuracy, area under the receiver operating characteristic curve, and confusion matrix. Results: The k-means clustering discovered 4 clusters with 1382, 1613, 1727, and 1839 samples with mean (standard deviation) global RNFL thickness of 58.3 (8.9) µm, 78.9 (6.7) µm, 87.7 (8.2) µm, and 101.5 (7.9) µm. The Bayes' minimum error classifier identified optimal global RNFL values of > 95 µm, 86 to 95 µm, 70 to 85 µm, and < 70 µm for discriminating normal eyes and eyes at the early, moderate, and advanced stages of RNFL thickness loss, respectively. About 4% of normal eyes and 98% of eyes with advanced RNFL loss had either global, or ≥ 1 quadrant, RNFL thickness outside of normal limits provided by the OCT instrument. Conclusions: Unsupervised machine learning discovered that the optimal RNFL thresholds for separating normal eyes and eyes with early, moderate, and advanced RNFL loss were 95 µm, 85 µm, and 70 µm, respectively. This RNFL loss classification system is unbiased as there was no preassumption or human expert intervention in the development process. Additionally, it is objective, easy to use, and consistent, which may augment glaucoma research and day-to-day clinical practice. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.