Deep Learning of the Retina Enables Phenome- and Genome-Wide Analyses of the Microvasculature.

BACKGROUND: The microvasculature, the smallest blood vessels in the body, has key roles in maintenance of organ health and tumorigenesis. The retinal fundus is a window for human in vivo noninvasive assessment of the microvasculature. Large-scale complementary machine learning-based assessment of the retinal vasculature with phenome-wide and genome-wide analyses may yield new insights into human health and disease. METHODS: We used 97 895 retinal fundus images from 54 813 UK Biobank participants. Using convolutional neural networks to segment the retinal microvasculature, we calculated vascular density and fractal dimension as a measure of vascular branching complexity. We associated these indices with 1866 incident International Classification of Diseases-based conditions (median 10-year follow-up) and 88 quantitative traits, adjusting for age, sex, smoking status, and ethnicity. RESULTS: Low retinal vascular fractal dimension and density were significantly associated with higher risks for incident mortality, hypertension, congestive heart failure, renal failure, type 2 diabetes, sleep apnea, anemia, and multiple ocular conditions, as well as corresponding quantitative traits. Genome-wide association of vascular fractal dimension and density identified 7 and 13 novel loci, respectively, that were enriched for pathways linked to angiogenesis (eg, vascular endothelial growth factor, platelet-derived growth factor receptor, angiopoietin, and WNT signaling pathways) and inflammation (eg, interleukin, cytokine signaling). CONCLUSIONS: Our results indicate that the retinal vasculature may serve as a biomarker for future cardiometabolic and ocular disease and provide insights into genes and biological pathways influencing microvascular indices. Moreover, such a framework highlights how deep learning of images can quantify an interpretable phenotype for integration with electronic health record, biomarker, and genetic data to inform risk prediction and risk modification.

TIE1 and TEK signalling, intraocular pressure, and primary open-angle glaucoma: a Mendelian randomization study.

BACKGROUND: In primary open-angle glaucoma (POAG), lowering intraocular pressure (IOP) is the only proven way of slowing vision loss. Schlemm's canal (SC) is a hybrid vascular and lymphatic vessel that mediates aqueous humour drainage from the anterior ocular chamber. Animal studies support the importance of SC endothelial angiopoietin-TEK signalling, and more recently TIE1 signalling, in maintaining normal IOP. However, human genetic support for a causal role of TIE1 and TEK signalling in lowering IOP is currently lacking. METHODS: GWAS summary statistics were obtained for plasma soluble TIE1 (sTIE1) protein levels (N = 35,559), soluble TEK (sTEK) protein levels (N = 35,559), IOP (N = 139,555) and POAG (Ncases = 16,677, Ncontrols = 199,580). Mendelian randomization (MR) was performed to estimate the association of genetically proxied TIE1 and TEK protein levels with IOP and POAG liability. Where significant MR estimates were obtained, genetic colocalization was performed to assess the probability of a shared causal variant (PPshared) versus distinct (PPdistinct) causal variants underlying TIE1/TEK signalling and the outcome. Publicly available single-nucleus RNA-sequencing data were leveraged to investigate differential expression of TIE1 and TEK in the human ocular anterior segment. RESULTS: Increased genetically proxied TIE1 signalling and TEK signalling associated with a reduction in IOP (- 0.21 mmHg per SD increase in sTIE1, 95% CI = - 0.09 to - 0.33 mmHg, P = 6.57 × 10-4, and - 0.14 mmHg per SD decrease in sTEK, 95% CI = - 0.03 to - 0.25 mmHg, P = 0.011), but not with POAG liability. Colocalization analysis found that the probability of a shared causal variant was greater for TIE1 and IOP than for TEK and IOP (PPshared/(PPdistinct + PPshared) = 0.98 for TIE1 and 0.30 for TEK). In the anterior segment, TIE1 and TEK were preferentially expressed in SC, lymphatic, and vascular endothelium. CONCLUSIONS: This study provides novel human genetic support for a causal role of both TIE1 and TEK signalling in regulating IOP. Here, combined evidence from cis-MR and colocalization analyses provide stronger support for TIE1 than TEK as a potential IOP-lowering therapeutic target.

Relationship between Claims-Based Frailty Index and Eye Care Utilization among Medicare Beneficiaries with Glaucoma.

PURPOSE: To determine differences in eye care utilization by frailty levels among Medicare beneficiaries with glaucoma. DESIGN: Retrospective cohort study. PARTICIPANTS: Medicare fee-for-service beneficiaries over 65 years of age with glaucoma, identified using International Classification of Diseases codes before July 1, 2014. METHODS: By using a validated claims-based frailty index (range, 0-1), beneficiaries were classified as nonfrail/prefrail (0-0.19), mildly frail (0.20-0.29), and moderate-to-severely frail (≥ 0.30). Negative binomial regression analyses were used to estimate incident rate ratios (IRRs) of eye care utilization by frailty levels between July 1, 2014, and December 31, 2016. MAIN OUTCOME MEASURES: Current Procedural Terminology codes for eye examinations and eye care-related office visits; eye care-related inpatient and emergency department (ED) encounters; eye care-related nursing facility and home-visit encounters; visual field (VF) and retinal nerve fiber layer (RNFL) OCT tests; and selective laser trabeculoplasties (SLTs) and glaucoma surgeries. RESULTS: Among 76 260 Medicare beneficiaries with glaucoma, the mean age was 78.9 years (standard deviation, 7.8), female beneficiaries constituted 60.5%, and 78.7% of beneficiaries self-identified as non-Hispanic White. According to a claims-based frailty index, 79.5% of beneficiaries were nonfrail/prefrail, 17.1% were mildly frail, and 3.4% were moderate-to-severely frail. Moderate-to-severely frail beneficiaries were less likely than nonfrail/prefrail beneficiaries to have outpatient encounters (IRR, 0.85, 95% confidence interval [CI], 0.83-0.88); VF tests (IRR, 0.64, 95% CI, 0.60-0.67); RNFL OCT tests (IRR, 0.77, 95% CI, 0.73-0.81); SLT (IRR, 0.74, 95% CI, 0.60-0.92); and glaucoma surgery (IRR, 0.74, 95% CI 0.55-0.99), after adjusting for age, gender, glaucoma severity, race, and socioeconomic status. Compared with nonfrail/prefrail beneficiaries, moderate-to-severely frail beneficiaries had higher rates of inpatient/ED encounters (IRR, 5.03, 95% CI, 2.36-10.71) and nursing facility/home-visit encounters (IRR, 34.89, 95% CI, 14.82-82.13). CONCLUSIONS: Compared with nonfrail/prefrail Medicare beneficiaries with glaucoma, beneficiaries with moderate-to-severe frailty had lower rates of eye care utilization in the outpatient setting and higher rates of utilization in acute care settings. This suggests that frail patients may receive less disease monitoring and fewer interventions for their glaucoma management. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Effectiveness of Microinvasive Glaucoma Surgery in the United States: Intelligent Research in Sight Registry Analysis 2013-2019.

PURPOSE: To evaluate the effectiveness of microinvasive glaucoma surgery (MIGS) with and without concurrent phacoemulsification. DESIGN: Multicenter, retrospective cohort study. PARTICIPANTS: Patients in the Intelligent Research in Sight (IRIS®) Registry who underwent Xen gel stent (ab interno) implantation, endoscopic cyclophotocoagulation (ECP), or goniotomy or canaloplasty from 2013 through 2019. METHODS: Kaplan-Meier survival analysis was used to assess reoperation rates. We defined reoperation as any subsequent glaucoma surgery occurring 1 month to 3 years after the initial procedure. Multivariable Cox proportional hazard models were used to determine factors predictive of reoperation. MAIN OUTCOME MEASURES: Reoperation rate, mean intraocular pressure (IOP) and visual acuity (VA), postoperative complications, predictors of reoperation, and reoperation procedure type. RESULTS: A total of 79 363 eyes from 57 561 patients were included, with 15 118 eyes (19%) receiving stand-alone MIGS and 64 245 eyes (81%) receiving MIGS concurrent with phacoemulsification. Overall, patients who underwent MIGS concurrently with phacoemulsification showed lower reoperation rates compared with stand-alone MIGS, most pronounced in ECP and goniotomy or canaloplasty. At postoperative year 2, the cumulative reoperation rate for stand-alone procedures was 15% for ECP, 24% for Xen implantation, and 24% for goniotomy or canaloplasty compared with 3% for ECP, 19% for Xen implantation, and 6% for goniotomy or canaloplasty concurrent with phacoemulsification (P < 0.001 for each stand-alone MIGS vs. MIGS with phacoemulsification). Black race, older age, moderate and severe glaucoma, higher baseline IOP, and glaucoma subtype were associated with higher reoperation risk. Although IOP decreased in all groups, stand-alone MIGS showed a more substantial decrease in mean IOP. Complication rates from MIGS were low overall: 1% for ECP, 1% for Xen implantation, and 2% for goniotomy or canaloplasty. CONCLUSIONS: In current United States clinical practice, MIGS has substantially lower reoperation rates when performed with phacoemulsification, especially for ECP and goniotomy or canaloplasty. Approximately one-sixth of patients undergoing stand-alone ECP and one-quarter of patients undergoing stand-alone Xen implantation or goniotomy or canaloplasty require reoperation by 2 years. Black race, diagnosis coding of moderate to severe glaucoma, and higher baseline IOP were associated with higher risk of reoperation after MIGS procedures. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Sex-Based Differences in Medicare Reimbursements among Ophthalmologists Persist across Time.

PURPOSE: To evaluate differences in Medicare reimbursements between male and female ophthalmologists between 2013 and 2019. DESIGN: Retrospective cohort study. PARTICIPANTS: Ophthalmologists receiving Medicare reimbursements between 2013 and 2019. METHODS: The Centers for Medicare and Medicaid Services Physician and Other Supplier Public Use File was used to determine total reimbursements and number of services submitted by ophthalmologists between 2013 and 2019. Reimbursements were standardized to account for geographic differences in Medicare reimbursement per service. Data from the American Community Survey (ACS) were used to determine socioeconomic characteristics (unemployment, poverty, income, and education) by zip code for the location of each physician's practice. A multivariate linear regression model was used to evaluate differences in annual reimbursements by sex, accounting for calendar year, years of experience, total number of services, ACS zip code data, and proportion of procedural services. MAIN OUTCOME MEASURES: Annual Medicare reimbursement and use of billing codes (e.g., outpatient office visits and eye examinations, diagnostic testing, laser treatment, and surgery). RESULTS: Among 20 281 ophthalmologists who received Medicare reimbursements between 2013 and 2019, 15 451 (76%) were men. The most common billing codes submitted were for outpatient visits and eye examinations (13.8 million charges/year), diagnostic imaging of the retina (5.6 million charges/year), intravitreal injections (2.9 million charges/year), and removal of cataract with insertion of lens (2.4 million charges/year). Compared with men, female ophthalmologists received less in median annual reimbursements (median, $94 734.21 [interquartile range (IQR), $30 944.52-$195 701.70] for women vs. $194 176.90 [IQR, $76 380.76-$355 790.80] for men; P < 0.001) and billed for fewer annual median services (median, 1228 [IQR, 454-2433] vs. 2259 [IQR, 996-4075, respectively]; P < 0.001). After adjustment for covariates, female ophthalmologists billed for 1015 fewer services (95% confidence interval [CI], 1001-1029; P < 0.001) and received $20 209.12 less in reimbursements than men (95% CI, -$21 717.57 to -$18 700.66; P < 0.001). CONCLUSIONS: Female ophthalmologists billed for fewer services and received less in reimbursement from Medicare than men over time and across all categories of billing codes. Disparities persisted after controlling for physician and practice characteristics.

Racial and Socioeconomic Differences in Eye Care Utilization among Medicare Beneficiaries with Glaucoma.

PURPOSE: Evaluate differences in eye care utilization among patients with glaucoma by race and socioeconomic status (SES). DESIGN: Retrospective cohort study. PARTICIPANTS: Representative 5% sample of Medicare beneficiaries aged > 65 years with continuous part A/B enrollment between January 1, 2014, and July 1, 2014, at least 1 diagnosis code for glaucoma within that period, and a glaucoma diagnosis in the Chronic Conditions Warehouse before January 1, 2014. METHODS: The following race/ethnicity categories were defined in our cohort: non-Hispanic White, Black/African American, Hispanic, and Asian/Pacific Islander. Low SES was defined as having 2 or more enrollment-based low-income indicators (dual eligibility for Medicare/Medicaid, Part D limited income subsidies, and eligibility for Part A and B State buy-in). Negative binomial regression analyses were carried out to compare relative rate ratios (RRs) of eye care utilization among racial groups stratified by low and non-low SES. MAIN OUTCOME MEASURES: Measured from July 1, 2014, to December 31, 2016: eye examinations and eye care-related office visits; eye care-related inpatient and emergency department (ED) encounters; eye care-related nursing home and home-visit encounters; visual field and retinal nerve fiber OCT tests; glaucoma lasers and surgeries. RESULTS: Among 78 526 participants with glaucoma, mean age was 79.1 years (standard deviation, 7.9 years), 60.9% were female, 78.4% were non-Hispanic White, and 13.8% met enrollment-based criteria for low-SES. Compared with White beneficiaries, Blacks had lower counts of outpatient visits (RR, 0.92; 95% confidence interval [CI], 0.90-0.93), visual field (VF) tests (RR, 0.92; 95% CI, 0.90-0.94), but more inpatient/ED encounters (RR, 2.42; 95% CI, 1.55-3.78) and surgeries (RR, 1.14; 95% CI, 1.03-1.27). Hispanics had fewer outpatient visits (RR, 0.97; 95% CI, 0.95-0.98) and retinal nerve fiber layer (RNFL) OCT tests (RR, 0.89; 95% CI, 0.86-0.93), but more inpatient/ED encounters (RR, 2.32; 95% CI, 1.18-4.57) and selective laser trabeculoplasty (SLT) (RR, 1.25; 95% CI, 1.11-1.42) versus non-Hispanic Whites. In the non-low SES group, Black versus White disparities persisted in outpatient visits (RR, 0.93; 95% CI, 0.92-0.95), VF (RR, 0.96; 95% CI, 0.94-0.98), RNFL OCT (RR, 0.81; 95% CI, 0.78-0.83), and inpatient/ED encounters (RR, 2.57; 95% CI, 1.55-4.26). CONCLUSIONS: Disparities were found in eye care utilization among Black and Hispanic patients with glaucoma. These differences persisted among Blacks after stratification by SES, suggesting that systemic racism may be an independent driver in this population.

Enhancing Diversity in the Ophthalmology Workforce.

Health care teams are most effective at addressing complex problems and improving health outcomes for underserved populations when team members bring diverse life experiences and perspectives to the effort. With rates of visual impairment expected to increase in the United States by 2050, especially among minority populations, diversification of the ophthalmology workforce will be critical in reducing disparities in access to and quality of vision health care. Currently, ophthalmology is less diverse with respect to race, ethnicity, and gender than graduating medical classes and other medical specialties, as well as the general US population. In addition, data on diversity in sexual orientation and gender identity, socioeconomic status, and disability are lacking in ophthalmology. The Minority Ophthalmology Mentoring and Rabb-Venable Excellence in Ophthalmology Programs are examples of initiatives to increase racial and ethnic diversity in the workforce and can serve as models for increasing other aspects of inclusiveness. Other strategies for improving vision health care for all Americans include continuing to support existing diversity programs and creating new ones; addressing unconscious and implicit bias in medical school, residency, and faculty selections; conducting holistic reviews of medical school and residency applications; diversifying selection committees and leadership; and encouraging faculty development of underrepresented groups.

Photoreceptor Layer Thinning Is an Early Biomarker for Age-Related Macular Degeneration: Epidemiologic and Genetic Evidence from UK Biobank OCT Data.

PURPOSE: Despite widespread use of OCT, an early-stage imaging biomarker for age-related macular degeneration (AMD) has not been identified. Pathophysiologically, the timing of drusen accumulation in relationship to photoreceptor degeneration in AMD remains unclear, as are the inherited genetic variants contributing to these processes. Herein, we jointly analyzed OCT, electronic health record data, and genomic data to characterize the time sequence of changes in retinal layer thicknesses in AMD, as well as epidemiologic and genetic associations between retinal layer thicknesses and AMD. DESIGN: Cohort study. PARTICIPANTS: Forty-four thousand eight hundred twenty-three individuals from the UK Biobank (enrollment age range, 40-70 years; 54% women; median follow-up, 10 years). METHODS: The Topcon Advanced Boundary Segmentation algorithm was used for retinal layer segmentation. We associated 9 retinal layer thicknesses with prevalent AMD (present at enrollment) in a logistic regression model and with incident AMD (diagnosed after enrollment) in a Cox proportional hazards model. Next, we associated AMD-associated genetic alleles, individually and as a polygenic risk score (PRS), with retinal layer thicknesses. All analyses were adjusted for age, age-squared (age2), sex, smoking status, and principal components of ancestry. MAIN OUTCOME MEASURES: Prevalent and incident AMD. RESULTS: Photoreceptor segment (PS) thinning was observed throughout the lifespan of individuals analyzed, whereas retinal pigment epithelium (RPE) and Bruch's membrane (BM) complex thickening started after 57 years of age. Each standard deviation (SD) of PS thinning and RPE-BM complex thickening was associated with incident AMD (PS: hazard ratio [HR], 1.35; 95% confidence interval [CI], 1.23-1.47; P = 3.7 × 10-11; RPE-BM complex: HR, 1.14; 95% CI, 1.06-1.22; P = 0.00024). The AMD PRS was associated with PS thinning (ß, -0.21 SD per twofold genetically increased risk of AMD; 95% CI, -0.23 to -0.19; P = 2.8 × 10-74), and its association with RPE-BM complex was U-shaped (thinning with AMD PRS less than the 92nd percentile and thickening with AMD PRS more than the 92nd percentile). The loci with strongest support for genetic correlation were AMD risk-raising variants Complement Factor H (CFH):rs570618-T, CFH:rs10922109-C, and Age-Related Maculopathy Susceptibility 2 (ARMS2)/High-Temperature Requirement Serine Protease 1 (HTRA1):rs3750846-C on PS thinning and SYN3/Tissue Inhibitor of Metalloprotease 3 (TIMP3):rs5754227-T on RPE-BM complex thickening. CONCLUSIONS: Epidemiologically, PS thinning precedes RPE-BM complex thickening by decades and is the retinal layer most strongly predictive of future AMD risk. Genetically, AMD risk variants are associated with decreased PS thickness. Overall, these findings support PS thinning as an early-stage biomarker for future AMD development.

Characteristics of p.Gln368Ter Myocilin Variant and Influence of Polygenic Risk on Glaucoma Penetrance in the UK Biobank.

PURPOSE: MYOC (myocilin) mutations account for 3% to 5% of primary open-angle glaucoma (POAG) cases. We aimed to understand the true population-wide penetrance and characteristics of glaucoma among individuals with the most common MYOC variant (p.Gln368Ter) and the impact of a POAG polygenic risk score (PRS) in this population. DESIGN: Cross-sectional population-based study. PARTICIPANTS: Individuals with the p.Gln368Ter variant among 77 959 UK Biobank participants with fundus photographs (FPs). METHODS: A genome-wide POAG PRS was computed, and 2 masked graders reviewed FPs for disc-defined glaucoma (DDG). MAIN OUTCOME MEASURES: Penetrance of glaucoma. RESULTS: Two hundred individuals carried the p.Gln368Ter heterozygous genotype, and 177 had gradable FPs. One hundred thirty-two showed no evidence of glaucoma, 45 (25.4%) had probable/definite glaucoma in at least 1 eye, and 19 (10.7%) had bilateral glaucoma. No differences were found in age, race/ethnicity, or gender among groups (P > 0.05). Of those with DDG, 31% self-reported or had International Classification of Diseases codes for glaucoma, whereas 69% were undiagnosed. Those with DDG had higher medication-adjusted cornea-corrected intraocular pressure (IOPcc) (P < 0.001) vs. those without glaucoma. This difference in IOPcc was larger in those with DDG with a prior glaucoma diagnosis versus those not diagnosed (P < 0.001). Most p.Gln368Ter carriers showed IOP in the normal range (≤21 mmHg), although this proportion was lower in those with DDG (P < 0.02) and those with prior glaucoma diagnosis (P < 0.03). Prevalence of DDG increased with each decile of POAG PRS. Individuals with DDG demonstrated significantly higher PRS compared with those without glaucoma (0.37 ± 0.97 vs. 0.01 ± 0.90; P = 0.03). Of those with DDG, individuals with a prior diagnosis of glaucoma had higher PRS compared with undiagnosed individuals (1.31 ± 0.64 vs. 0.00 ± 0.81; P < 0.001) and 27.5 times (95% confidence interval, 2.5-306.6) adjusted odds of being in the top decile of PRS for POAG. CONCLUSIONS: One in 4 individuals with the MYOC p.Gln368Ter mutation demonstrated evidence of glaucoma, a substantially higher penetrance than previously estimated, with 69% of cases undetected. A large portion of p.Gln368Ter carriers, including those with DDG, have IOP in the normal range, despite similar age. Polygenic risk score increases disease penetrance and severity, supporting the usefulness of PRS in risk stratification among MYOC p.Gln368Ter carriers.

Association Between Diabetes, Diabetic Retinopathy, and Glaucoma.

PURPOSE OF REVIEW: The strength of the relationship between diabetes, diabetic retinopathy (DR), and glaucoma remains controversial. We review evidence supporting and refuting this association and explore mechanistic pathological and treatment relationships linking these diseases. RECENT FINDINGS: While studies have shown diabetes/DR may increase the risk for glaucoma, this remains inconsistently demonstrated. Diabetes/DR may contribute toward glaucomatous optic neuropathy indirectly (either by increasing intraocular pressure or vasculopathy) or through direct damage to the optic nerve. However, certain elements of diabetes may slow glaucoma progression, and diabetic treatment may concurrently be beneficial in glaucoma management. Diabetes plays a significant role in poor outcomes after glaucoma surgery. While the relationship between diabetes/DR and glaucoma remains controversial, multiple mechanistic links connecting pathophysiology and management of diabetes, DR, and glaucoma have been made. However, a deeper understanding of the causes of disease association is needed.

Psychometric validation techniques applied to the IND-VFQ-33 visual function questionnaire: the Hyderabad ocular morbidity in the elderly study (HOMES).

BACKGROUND: Over 2 billion people suffer from vision impairment or blindness globally, and access to validated visual measurement tools in imperative in accurately describing and managing the burden of eye disease. The present study applies contemporary psychometric validation techniques to the widely used 33-item Indian Visual Function Questionnaire (IND-VFQ-33). METHODS: We first estimated the polychoric correlation between each pair of items. Next, an unrotated and oblique Promax rotated factor analysis, item response theory (IRT, using a graded response model (GRM)), and differential item functioning (DIF) testing were applied to the IND-VFQ-33. We subsequently propose a validated IND-VFQ-33 questionnaire after psychometric testing, data reduction, and adjustment. RESULTS: Exploratory unrotated factor analysis identified two factors; one with a particularly high eigenvalue (18.1) and a second with a lower eigenvalue still above our threshold (1.1). A subsequent oblique Promax factor rotation was undertaken for a 2-factor solution, revealing two moderately correlated factors (+ 0.68) with clinically discrete item loadings onto either Factor 1 (21 items; collectively labelled "daily activities") or Factor 2 (5 items; collectively labelled "bright lights"). IRT confirmed high item discrimination for all remaining items with good separation between difficulty thresholds. We found significant DIF on depression for six items in Factor 1 (all uniform DIF, except item 21 (non-uniform DIF) with no substantive difference in beta thresholds for any item and no substantive difference in expected individual or sum score, by depression at baseline. For Factor 2, only one item demonstrated significant uniform DIF on gender, similarly without major differences in beta thresholds or expected total score between gender at baseline. Consequently, no further item recalibration or reduction was undertaken after IRT and DIF analysis. CONCLUSION: Applying IRT and DIF validation techniques to the IND-VFQ-33 identified 2 discrete factors with 26 uniquely-loading items, clinically representative of difficulty performing daily activities and experiencing difficulty due to bright lights/glare respectively. The proposed modified scale may be useful in evaluating symptomatic disease progression or response to treatment in an Indian population.

The functional burden of diabetic retinopathy in the United States.

OBJECTIVE: To study the association between diabetic retinopathy (DR) and physical functional difficulty using contemporary psychometric validation techniques, and to explore the predictors of physical difficulty among those with diabetes, non-proliferative DR (NPDR), or proliferative DR (PDR). METHODS: Cross-sectional study using the National Health and Nutrition Examination Survey (NHANES) database from 2005-2008. Participants were classified as either (i) no diabetes no DR, (ii) diabetes without DR, (iii) mild/moderate NPDR, or (iv) severe NPDR/PDR. The presence of DR was detected by retinal imaging and severity was graded using the Early Treatment Diabetic Retinopathy Study Protocol. The physical difficulty was assessed using a 13-question self-reported questionnaire, validated using factor analysis and item response theory (graded response model) psychometric techniques. Secondary analyses of diabetes and DR populations most at risk of reporting greater physical functional difficulty were undertaken. RESULTS: A total of 5321 participants over the age of 40 were included in our study. Of the 13 original physical difficulty questions, one latent trait was identified and 9 questions demonstrated good discrimination and were subsequently retained. In univariable analyses, participants with diabetes and any form of DR all reported significantly higher physical functional difficulty vs those with neither diabetes nor DR (p < 0.01 for all). In multivariable analyses, while those with diabetes or any form of DR remained more likely to report higher physical difficulty vs those with neither diabetes nor DR, only those with severe NPDR/PDR reported substantially higher scores (2.1 sum points higher, p = 0.002). Among participants with diabetes or any form of DR, those with 3 or more medical comorbidities and those with depression reported substantially higher sum physical difficulty scores (p < 0.05 for all). CONCLUSIONS: Those with diabetes or DR experience greater functional physical difficulty than those without, particularly profound among those with severe forms of DR. For those with DR, the presence of concurrent depression or medical comorbidities conferred a significantly higher risk of physical difficulty. Providers and healthcare systems should be aware of particularly vulnerable DR populations at increased risk of experiencing daily functioning deficits.

Effect of a Schlemm's Canal Microstent on Early Postoperative Intraocular Pressure after Cataract Surgery: An Analysis of the HORIZON Randomized Controlled Trial.

PURPOSE: To compare early postoperative intraocular pressure (IOP) in patients who underwent cataract surgery alone with those who underwent cataract surgery combined with implantation of a Hydrus Microstent (HMS) (Ivantis, Irvine, CA). DESIGN: Subanalysis of data from the randomized controlled HORIZON trial, a multicenter trial including 26 US and 12 international sites. PARTICIPANTS: Participants with mild/moderate primary open-angle glaucoma (POAG) and visually significant cataract with mean modified diurnal IOP between 22 and 34 mmHg after washout of IOP-lowering medications. METHODS: A total of 556 subjects were randomized in a 2:1 ratio to undergo cataract surgery with placement of the HMS versus cataract surgery alone (no microstent [NMS]). All eyes were washed out of IOP-lowering medications before surgery and remained unmedicated until surgery. No IOP-lowering prophylaxis was used postoperatively. Comprehensive eye examination including measurement of intraocular pressure was conducted on postoperative day (POD) 1, week 1, and month 1. MAIN OUTCOME MEASURES: Postoperative IOP >40 mmHg was analyzed as the primary outcome. Incidence of IOP increase >10 mmHg above baseline, unmedicated IOP, and mean IOP were analyzed as secondary outcomes. RESULTS: A total of 369 eyes were randomized to the HMS group, and 187 eyes were randomized to cataract surgery alone. The HMS and NMS groups did not differ with respect to baseline demographic or ocular characteristics. On POD1, the incidence of IOP spike >40 mmHg was significantly higher at 14.4% in the NMS group compared with 1.4% in the HMS group (P < 0.001). The incidence of IOP increase ≥10 mmHg relative to baseline on POD1 was also significantly higher in the NMS group than in the HMS group (22.5% vs. 3.0%, P < 0.001). IOP in the NMS group was significantly higher than in the HMS group (27.6 vs. 17.0 mmHg, P < 0.001). In multivariable logistic regression analysis, higher baseline IOP predicted higher odds of POD1 IOP spike >40 mmHg, whereas the presence of HMS was associated with a lower likelihood of postoperative IOP spike. CONCLUSIONS: The addition of an HMS at the time of cataract surgery lowered the risk of markedly elevated IOP in the early postoperative period in patients with glaucoma.

Comparison of New Visual Disturbances after Superior versus Nasal/Temporal Laser Peripheral Iridotomy: A Prospective Randomized Trial.

PURPOSE: To determine whether laser peripheral iridotomy (LPI) location affects postoperative dysphotopsia symptoms. DESIGN: Multicenter, randomized, prospective, single-masked trial. PARTICIPANTS: Five hundred fifty-nine South Indian patients 30 years of age or older diagnosed as primary angle-closure suspects (PACSs) or with primary angle closure (PAC) or primary angle-closure glaucoma (PACG) in both eyes. METHODS: Patients were randomized to either bilateral superior or bilateral nasal/temporal LPI. Occurrence of new visual disturbances was evaluated before and 2 weeks after LPI using a questionnaire based on the 7-item dysphotopsia symptoms described by Spaeth et al. MAIN OUTCOME MEASURES: New-onset dysphotopsia symptoms. RESULTS: Superior LPI (n = 285) and nasal/temporal LPI (n = 274) patients were matched for age (P = 0.6), gender (P = 0.7), and distribution of PACS versus PAC or PACG (P = 0.7). Similar initial laser energy settings were used in both groups (P = 0.3), although superior LPIs required more shots (P = 0.006) and greater total energy (P < 0.001) than nasal/temporal LPIs. No significant differences in postoperative anterior chamber reaction (P = 0.7) or LPI area (P = 0.9) were noted between the 2 groups. No group differences were noted regarding the proportion of patients demonstrating 1 or more dysphotopsia symptoms before LPI (15.8% for superior vs. 13.9% for nasal/temporal; P = 0.1) or any individual dysphotopsia symptom (P > 0.2 for all). After LPI, 8.9% of all patients reported 1 or more new symptoms, the most common consisting of linear dysphotopsias, glare, and blurring in 2.7%, 4.3%, and 4.3% of patients, respectively. Patients undergoing superior LPI were not more likely to describe the new onset of 1 or more dysphotopsia symptoms as compared with patients undergoing nasal/temporal LPI (8.4% vs. 9.5%; P = 0.7), nor did the frequency of any new individual symptoms differ by group (P ≥ 0.3 for all). In multivariate logistic regression analysis, neither LPI location nor LPI area nor total laser energy predicted higher odds of new postoperative dysphotopsias (P > 0.1 for all). CONCLUSIONS: Laser peripheral iridotomy likely is safe with respect to visual dysphotopsias regardless of location, LPI size, and amount of laser energy used.

Changes in Anterior Segment Morphology and Predictors of Angle Widening after Laser Iridotomy in South Indian Eyes.

PURPOSE: To compare anterior segment optical coherence tomography (ASOCT) angle morphology before and after laser peripheral iridotomy (LPI) in a cohort of South Indian subjects with primary angle-closure suspect (PACS) or primary angle-closure/primary angle-closure glaucoma (PAC/PACG) and to examine baseline parameters associated with angle widening. DESIGN: Prospective observational study. PARTICIPANTS: A total of 244 subjects aged ≥30 years with PACS or PAC/PACG in at least 1 eye. METHODS: The ASOCT images and angle gonioscopic grades were analyzed for all subjects at baseline and 2 weeks after LPI. Multivariable linear and logistic regression models were used to determine predictors of angle widening (change in mean angle opening distance [AOD750]) and angle opening (all 4 quadrants with trabecular meshwork [TM] visible on gonioscopy after LPI). MAIN OUTCOME MEASURES: Change in ASOCT parameters with LPI and baseline predictors of angle widening. RESULTS: Laser peripheral iridotomy resulted in angle widening on ASOCT with significant increases in AOD750, angle recess area, and trabecular iris surface area (P < 0.05 for all). Gonioscopically, 44.7% of all subjects had open angles in all 4 quadrants after LPI, with a greater percentage of angles open in the PACS group compared with the PAC/PACG group (52.4% vs. 36.4%; P = 0.01). In multivariable regression analyses, greater postoperative angle widening as defined by change in AOD750 was associated with shorter baseline AOD750 and axial length, and greater baseline anterior chamber depth, iris curvature, and lens vault (P ≤ 0.002 for all). Gonioscopic angle opening after LPI was more common with wider baseline angle width (modified Shaffer grade) and lower cup-to-disc ratio (P < 0.001 for both). CONCLUSIONS: In a South Indian population with PACS or PAC/PACG, LPI results in significant anterior chamber angle widening seen on both ASOCT and gonioscopy, although some degree of persistent iridotrabecular contact was present in approximately half of PACS eyes and approximately two thirds of PAC/PACG eyes on gonioscopy. The greatest widening by ASOCT was observed in eyes with features most consistent with greater baseline pupillary block.

Comparing the Impact of Refractive and Nonrefractive Vision Loss on Functioning and Disability: The Salisbury Eye Evaluation.

PURPOSE: To compare the effects of uncorrected refractive error (URE) and nonrefractive visual impairment (VI) on performance and disability measures. DESIGN: Cross-sectional, population-based study. PARTICIPANTS: A total of 2469 individuals with binocular presenting visual acuity (PVA) of ≥ 20/80 who participated in the first round of the Salisbury Eye Evaluation study. METHODS: The URE was defined as binocular PVA of ≤ 20/30, improving to >20/30 with subjective refraction. The VI was defined as post-refraction binocular best-corrected visual acuity (BCVA) of ≤ 20/30. The visual acuity decrement due to VI was calculated as the difference between BCVA and 20/30, whereas visual acuity due to URE was taken as the difference between PVA and BCVA. Multivariable regression analyses were used to assess the disability impact of (1) vision status (VI, URE, or normal vision) using the group with normal vision as reference and (2) a 1-line decrement in acuity due to VI or URE. MAIN OUTCOME MEASURES: Objective measures of visual function were obtained from timed performance of mobility and near vision tasks, self-reported driving cessation, and self-reported visual difficulty measured by the Activities of Daily Vision (ADV) scale. The ADV responses were analyzed using Rasch analysis to determine visual ability. RESULTS: Compared with individuals with normal vision, subjects with VI (n = 191) had significantly poorer objective and subjective visual functioning in all metrics examined (P < 0.05), whereas subjects with URE (n = 132) demonstrated slower walking speeds, slower near task performance, more frequent driving cessation, and lower ADV scores (P < 0.05), but did not demonstrate slower stair climbing or descent speed. For all functional metrics evaluated, the impact of VI was greater than the impact of URE. The impact of a 1-line VA decrement due to VI was associated with greater deficits in mobility measures and driving cessation when compared with a 1-line VA decrement due to URE. CONCLUSIONS: Visual impairment is associated with greater disability than URE across a wide variety of functional measures, even in analyses adjusting for the severity of vision loss. Refractive and nonrefractive vision loss should be distinguished in studies evaluating visual disability and be understood to have differing consequences.