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.

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.

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.

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.

Structure-function association between contrast sensitivity and retinal thickness (total, regional, and individual retinal layer) in patients with idiopathic epiretinal membrane.

PURPOSE: To investigate structure-function associations between retinal thickness, visual acuity (VA), and contrast sensitivity (CS), using the quantitative contrast sensitivity function (qCSF) method in patients with idiopathic epiretinal membrane (ERM). METHODS: Retrospective, cross-sectional observational study. Patients with a diagnosis of idiopathic ERM were included. Patients underwent complete ophthalmic examination, spectral-domain optical coherence tomography imaging (SD-OCT) (SPECTRALIS® Heidelberg), and CS testing using the qCSF method. Outcomes included area under the log CSF (AULCSF), contrast acuity (CA), and CS thresholds at 1, 1.5, 3, 6, 12, and 18 cycles per degree (cpd). RESULTS: A total of 102 eyes of 79 patients were included. Comparing standardized regression coefficients, retinal thickness in most ETDRS sectors was associated with larger reductions in AULCSF, CA, and CS thresholds at 3 and 6 cpd than those in logMAR VA. These differences in effect on VA and CS metrics were more pronounced in the central subfield and inner ETDRS sectors. Among the retinal layers, increased INL thickness had the most detrimental effect on visual function, being significantly associated with reductions in logMAR VA, AULCSF, CA, and CS thresholds at 3 and 6 cpd (all p < .01), as well as at 1.5 and 12 cpd (p < .05). CONCLUSION: Retinal thickness seems to be associated with larger reductions in contrast sensitivity than VA in patients with ERM. Measured with the qCSF method, contrast sensitivity may serve as a valuable adjunct visual function metric for patients with ERM.

Structure-function associations between contrast sensitivity and widefield swept-source optical coherence tomography angiography in diabetic macular edema.

PURPOSE: To evaluate the relationship between contrast sensitivity (CS) and widefield swept-source optical coherence tomography angiography (WF SS-OCTA) vascular metrics in diabetic macular edema (DME) was the purpose. METHODS: This prospectively enrolled cross-sectional observational study included 61 eyes of 48 patients that were tested with the quantitative CS function (qCSF) test on the same day as imaging with WF SS-OCTA (PLEX® Elite 9000, Carl Zeiss Meditec) 3 × 3, 6 × 6, and 12 × 12 mm scans. Outcomes included visual acuity (VA) and multiple qCSF metrics. Vascular metrics included vessel density (VD) and vessel skeletonized density (VSD) in the superficial (SCP) and deep capillary plexus (DCP) and whole retina (WR) and foveal avascular zone (FAZ) parameters. Mixed effects multivariable linear regression models controlling for age, lens status, and diabetic retinopathy stage were performed. Standardized beta coefficients were calculated by refitting the standardized data. RESULTS: SS-OCTA metrics had a significant association with CS and VA. The effect size of OCTA metrics was larger on CS compared to VA. For example, the standardized beta coefficients for VSD and CS at 3 cpd (ßSCP = 0.76, ßDCP = 0.71, ßWR = 0.72, p < 0.001) were larger than those for VA (ßSCP = - 0.55, p < 0.001; ßDCP = - 0.43, p = 0.004; ßWR = - 0.50, p < 0.001). On 6 × 6 mm images, AULCSF, CS at 3 cpd, and CS at 6 cpd were significantly associated with VD and VSD in all three slab types (SCP, DCP, and WR), while VA was not. CONCLUSION: Structure-function associations in patients with DME leveraging the qCSF device suggest microvascular changes on WF SS-OCTA are associated with larger changes in contrast sensitivity than VA.

Adjustable Suture Technique Is Associated with Fewer Strabismus Reoperations in the Intelligent Research in Sight Registry.

PURPOSE: To compare the reoperation rates after strabismus surgery with and without the adjustable suture technique. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients 18 years of age or older in the Intelligent Research in Sight (IRIS®) Registry who underwent strabismus surgery between January 1, 2013, and December 31, 2018. METHODS: Data were collected from the electronic health records of practices participating in the IRIS Registry. The primary exposure of interest was use of the adjustable suture technique, identified by Current Procedural Terminology coding. MAIN OUTCOME MEASURES: The primary outcome was repeat strabismus surgery within 1 year of initial strabismus surgery. Odds ratios (ORs) were derived from a multivariable logistic regression model evaluating the association between the use of adjustable sutures and reoperation rate, adjusting for patient demographics and surgical factors. RESULTS: A total of 34 872 patients who underwent strabismus surgery during the study interval were identified: 72% underwent horizontal muscle surgery, 17% underwent vertical muscle surgery, and 11% underwent combined horizontal and vertical muscle surgery. Adjustable sutures were used in 18% of patients. The overall reoperation rate within 1 year of strabismus surgery was 7.7%. The 1-year reoperation rate was 6.0% for patients treated with adjustable sutures and 8.1% for patients treated without adjustable sutures (P < 0.001). The multivariable regression model revealed a statistically significant 30% decrease in the odds of reoperation within 1 year of surgery when adjustable sutures were used (OR, 0.70; 95% confidence interval [CI], 0.62-0.78), a 40% increase in those with a history of prior strabismus surgery (OR, 1.40; 95% CI, 1.28-1.53), and a 9% increase per decade of age at surgery (OR, 1.09; 95% CI, 1.06-1.11). CONCLUSIONS: In adults cared for in practices participating in the IRIS Registry, the adjustable suture technique was associated with a significantly lower reoperation rate within 1 year of undergoing horizontal or combined horizontal and vertical strabismus surgery. Adjustable suture use in vertical strabismus surgery alone did not reduce the 1-year reoperation rate significantly. A history of prior strabismus surgery was associated with increased odds of reoperation.

Unsupervised Machine Learning Shows Change in Visual Field Loss in the Idiopathic Intracranial Hypertension Treatment Trial.

PURPOSE: We previously reported that archetypal analysis (AA), a type of unsupervised machine learning, identified and quantified patterns of visual field (VF) loss in idiopathic intracranial hypertension (IIH), referred to as archetypes (ATs). We assessed whether AT weight changes over time are consistent with changes in conventional global indices, whether visual outcome or treatment effects are associated with select AT, and whether AA reveals residual VF defects in eyes deemed normal after treatment. DESIGN: Analysis of data collected from a randomized controlled trial. PARTICIPANTS: Two thousand eight hundred sixty-two VFs obtained from 165 participants during the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). METHODS: We applied a 14-AT model derived from IIHTT VFs. We examined changes in individual AT weights over time for all study eyes and evaluated differences between treatment groups. We created an AT change score to assess overall VF change from baseline. We tested threshold baseline AT weights for association with VF outcome and treatment effect at 6 months. We determined the abnormal ATs with meaningful weight at outcome for VFs with a mean deviation (MD) of -2.00 dB or more. MAIN OUTCOME MEASURES: Individual AT weighting coefficients and MD. RESULTS: Archetype 1 (a normal VF pattern) showed the greatest weight change for all study eyes, increasing from 11.9% (interquartile range [IQR], 0.44%-24.1%) at baseline to 31.2% (IQR, 16.0%-45.5%) at outcome (P < 0.001). Archetype 1 weight change (r = 0.795; P < 0.001) and a global score of AT change (r = 0.988; P < 0.001) correlated strongly with MD change. Study eyes with baseline AT2 (a mild diffuse VF loss pattern) weight of 44% or more (≥ 1 standard deviation more than the mean) showed higher AT2 weights at outcome than those with AT2 weight of < 44% at baseline (P < 0.001). Only the latter group showed a significant acetazolamide treatment effect. Archetypal analysis revealed residual VF loss patterns, most frequently representing mild diffuse loss and an enlarged blind spot in 64 of 66 study eyes with MD of -2.00 dB or more at outcome. CONCLUSIONS: Archetypal analysis provides a quantitative approach to monitoring VF changes in IIH. Baseline AT features may be associated with treatment response and VF outcome. Archetypal analysis uncovers residual VF defects not otherwise revealed by MD.

Neurotrophic Keratopathy in the United States: An Intelligent Research in Sight Registry Analysis.

PURPOSE: To describe the characteristics of neurotrophic keratopathy (NK) in the United States. DESIGN: Retrospective database study. PARTICIPANTS: Thirty-one thousand nine hundred fifteen eyes of 27 483 patients with a diagnosis of NK. METHODS: Retrospective analysis of visits associated with a diagnosis of NK between 2013 and 2018 using the American Academy of Ophthalmology Intelligent Research in Sight (IRIS®) Registry. MAIN OUTCOME MEASURES: Demographic information, prevalence, visual acuity (VA), concomitant diagnosis and procedure codes, and risk factors impacting VA most closely after NK onset date. RESULTS: Mean ± standard deviation (SD) age at initial diagnosis of NK was 68.0 ± 16.0 years, and 58.91% of patients were women (P < 0.0001). Presentation was unilateral in 58.14%, bilateral in 16.13%, and unspecified in 25.73%. Average 6-year prevalence of NK in the IRIS Registry was 21.34 cases per 100 000 patients. Mean ± SD VA was 0.60 ± 0.79 logMAR before diagnosis and 0.88 ± 0.94 logMAR after diagnosis (P < 0.0001). Most common concomitant diagnoses included herpetic keratitis (33.70%), diabetes (31.59%), and corneal dystrophy (14.28%). Common procedures for NK management included the use of amniotic membrane (29.90%), punctal plugs (29.65%), and bandage contact lenses (22.67%). Age, male sex, Black race, Hispanic or Latino ethnicity, unilateral involvement, concomitant diagnoses of diabetes, corneal transplantation, and herpetic keratitis were associated significantly with worse VA. CONCLUSIONS: Based on the IRIS Registry, the prevalence of NK is 21.34 cases per 100 000 patients. Visual acuity was significantly worse after NK diagnosis compared with other time points. Neurotrophic keratopathy was associated most commonly with herpetic keratitis and diabetes. Worse VA in patients with NK was associated with several demographic characteristics, history of diabetes, corneal transplantation, and herpetic keratitis.

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.

Renal function and lipid metabolism are major predictors of circumpapillary retinal nerve fiber layer thickness-the LIFE-Adult Study.

BACKGROUND: Circumpapillary retinal nerve fiber layer thickness (cpRNFLT) as assessed by spectral domain optical coherence tomography (SD-OCT) is a new technique used for the detection and evaluation of glaucoma and other optic neuropathies. Before translating cpRNFLT into clinics, it is crucially important to investigate anthropometric, biochemical, and clinical parameters potentially affecting cpRNFLT in a large population-based dataset. METHODS: The population-based LIFE-Adult Study randomly selected 10,000 participants from the population registry of Leipzig, Germany. All participants underwent standardized systemic assessment of various cardiometabolic risk markers and ocular imaging, including cpRNFLT measurement using SD-OCT (Spectralis, Heidelberg Engineering). After employing strict SD-OCT quality criteria, 8952 individuals were analyzed. Multivariable linear regression analyses were used to evaluate the independent associations of various cardiometabolic risk markers with sector-specific cpRNFLT. For significant markers, the relative strength of the observed associations was compared to each other to identify the most relevant factors influencing cpRNFLT. In all analyses, the false discovery rate method for multiple comparisons was applied. RESULTS: In the entire cohort, female subjects had significantly thicker global and also sectoral cpRNFLT compared to male subjects (p < 0.05). Multivariable linear regression analyses revealed a significant and independent association between global and sectoral cpRNFLT with biomarkers of renal function and lipid profile. Thus, thinner cpRNFLT was associated with worse renal function as assessed by cystatin C and estimated glomerular filtration rate. Furthermore, an adverse lipid profile (i.e., low high-density lipoprotein (HDL) cholesterol, as well as high total, high non-HDL, high low-density lipoprotein cholesterol, and high apolipoprotein B) was independently and statistically significantly related to thicker cpRNFLT. In contrast, we do not observe a significant association between cpRNFLT and markers of inflammation, glucose homeostasis, liver function, blood pressure, or obesity in our sector-specific analysis and globally. CONCLUSIONS: Markers of renal function and lipid metabolism are predictors of sectoral cpRNFLT in a large and deeply phenotyped population-based study independently of previously established covariates. Future studies on cpRNFLT should include these biomarkers and need to investigate whether incorporation will improve the diagnosis of early eye diseases based on cpRNFLT.

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.

Monitoring Glaucomatous Functional Loss Using an Artificial Intelligence-Enabled Dashboard.

PURPOSE: To develop an artificial intelligence (AI) dashboard for monitoring glaucomatous functional loss. DESIGN: Retrospective, cross-sectional, longitudinal cohort study. PARTICIPANTS: Of 31 591 visual fields (VFs) on 8077 subjects, 13 231 VFs from the most recent visit of each patient were included to develop the AI dashboard. Longitudinal VFs from 287 eyes with glaucoma were used to validate the models. METHOD: We entered VF data from the most recent visit of glaucomatous and nonglaucomatous patients into a "pipeline" that included principal component analysis (PCA), manifold learning, and unsupervised clustering to identify eyes with similar global, hemifield, and local patterns of VF loss. We visualized the results on a map, which we refer to as an "AI-enabled glaucoma dashboard." We used density-based clustering and the VF decomposition method called "archetypal analysis" to annotate the dashboard. Finally, we used 2 separate benchmark datasets-one representing "likely nonprogression" and the other representing "likely progression"-to validate the dashboard and assess its ability to portray functional change over time in glaucoma. MAIN OUTCOME MEASURES: The severity and extent of functional loss and characteristic patterns of VF loss in patients with glaucoma. RESULTS: After building the dashboard, we identified 32 nonoverlapping clusters. Each cluster on the dashboard corresponded to a particular global functional severity, an extent of VF loss into different hemifields, and characteristic local patterns of VF loss. By using 2 independent benchmark datasets and a definition of stability as trajectories not passing through over 2 clusters in a left or downward direction, the specificity for detecting "likely nonprogression" was 94% and the sensitivity for detecting "likely progression" was 77%. CONCLUSIONS: The AI-enabled glaucoma dashboard, developed using a large VF dataset containing a broad spectrum of visual deficit types, has the potential to provide clinicians with a user-friendly tool for determination of the severity of glaucomatous vision deficit, the spatial extent of the damage, and a means for monitoring the disease progression.

Sex-Specific Differences in Circumpapillary Retinal Nerve Fiber Layer Thickness.

PURPOSE: To investigate the role of sex on retinal nerve fiber layer (RNFL) thickness at 768 circumpapillary locations based on OCT findings. DESIGN: Population-based cross-sectional study. PARTICIPANTS: We investigated 5646 eyes of 5646 healthy participants from the Leipzig Research Centre for Civilization Diseases (LIFE)-Adult Study of a predominantly white population. METHODS: All participants underwent standardized systemic assessments and ocular imaging. Circumpapillary RNFL (cRNFL) thickness was measured at 768 points equidistant from the optic nerve head using spectral-domain OCT (Spectralis; Heidelberg Engineering, Heidelberg, Germany). To control ocular magnification effects, the true scanning radius was estimated by scanning focus. Student t test was used to evaluate sex differences in cRNFL thickness globally and at each of the 768 locations. Multivariable linear regression and analysis of variance were used to evaluate individual contributions of various factors to cRNFL thickness variance. MAIN OUTCOME MEASURES: Difference in cRNFL thickness between males and females. RESULTS: Our population consisted of 54.8% females. The global cRNFL thickness was 1 µm thicker in females (P < 0.001). However, detailed analysis at each of the 768 locations revealed substantial location specificity of the sex effects, with RNFL thickness difference ranging from -9.98 to +8.00 µm. Females showed significantly thicker RNFLs in the temporal, superotemporal, nasal, inferonasal, and inferotemporal regions (43.6% of 768 locations), whereas males showed significantly thicker RNFLs in the superior region (13.2%). The results were similar after adjusting for age, body height, and scanning radius. The superotemporal and inferotemporal RNFL peaks shifted temporally in females by 2.4° and 1.9°, respectively. On regions with significant sex effects, sex explained more RNFL thickness variance than age, whereas the major peak locations and interpeak angle explained most of the RNFL thickness variance unexplained by sex. CONCLUSIONS: Substantial sex effects on cRNFL thickness were found at 56.8% of all 768 circumpapillary locations, with specific patterns for different sectors. Over large regions, sex was at least as important in explaining the cRNFL thickness variance as was age, which is well established to have a substantial impact on cRNFL thickness. Including sex in the cRNFL thickness norm could therefore improve glaucoma diagnosis and monitoring.

Artificial Intelligence Classification of Central Visual Field Patterns in Glaucoma.

PURPOSE: To quantify the central visual field (VF) loss patterns in glaucoma using artificial intelligence. DESIGN: Retrospective study. PARTICIPANTS: VFs of 8712 patients with 13 951 Humphrey 10-2 test results from 13 951 eyes for cross-sectional analyses, and 824 patients with at least 5 reliable 10-2 test results at 6-month intervals or more from 1191 eyes for longitudinal analyses. METHODS: Total deviation values were used to determine the central VF patterns using the most recent 10-2 test results. A 24-2 VF within a 3-month window of the 10-2 tests was used to stage eyes into mild, moderate, or severe functional loss using the Hodapp-Anderson-Parrish scale at baseline. Archetypal analysis was applied to determine the central VF patterns. Cross-validation was performed to determine the optimal number of patterns. Stepwise regression was applied to select the optimal feature combination of global indices, average baseline decomposition coefficients from central VFs archetypes, and other factors to predict central VF mean deviation (MD) slope based on the Bayesian information criterion (BIC). MAIN OUTCOME MEASURES: The central VF patterns stratified by severity stage based on 24-2 test results and a model to predict the central VF MD change over time using baseline test results. RESULTS: From cross-sectional analysis, 17 distinct central VF patterns were determined for the 13 951 eyes across the spectrum of disease severity. These central VF patterns could be divided into isolated superior loss, isolated inferior loss, diffuse loss, and other loss patterns. Notably, 4 of the 5 patterns of diffuse VF loss preserved the less vulnerable inferotemporal zone, whereas they lost most of the remaining more vulnerable zone described by the Hood model. Inclusion of coefficients from central VF archetypical patterns strongly improved the prediction of central VF MD slope (BIC decrease, 35; BIC decrease of >6 indicating strong prediction improvement) than using only the global indices of 2 baseline VF results. Eyes with baseline VF results with more superonasal and inferonasal loss were more likely to show worsening MD over time. CONCLUSIONS: We quantified central VF patterns in glaucoma, which were used to improve the prediction of central VF worsening compared with using only global indices.

Agreement and Predictors of Discordance of 6 Visual Field Progression Algorithms.

PURPOSE: To determine the agreement of 6 established visual field (VF) progression algorithms in a large dataset of VFs from multiple institutions and to determine predictors of discordance among these algorithms. DESIGN: Retrospective longitudinal cohort study. PARTICIPANTS: Visual fields from 5 major eye care institutions in the United States were analyzed, including a subset of eyes with at least 5 Swedish interactive threshold algorithm standard 24-2 VFs that met our reliability criteria. Of a total of 831 240 VFs, a subset of 90 713 VFs from 13 156 eyes of 8499 patients met the inclusion criteria. METHODS: Six commonly used VF progression algorithms (mean deviation [MD] slope, VF index slope, Advanced Glaucoma Intervention Study, Collaborative Initial Glaucoma Treatment Study, pointwise linear regression, and permutation of pointwise linear regression) were applied to this cohort, and each eye was determined to be stable or progressing using each measure. Agreement between individual algorithms was tested using Cohen's κ coefficient. Bivariate and multivariate analyses were used to determine predictors of discordance (3 algorithms progressing and 3 algorithms stable). MAIN OUTCOME MEASURES: Agreement and discordance between algorithms. RESULTS: Individual algorithms showed poor to moderate agreement with each other when compared directly (κ range, 0.12-0.52). Based on at least 4 algorithms, 11.7% of eyes progressed. Major predictors of discordance or lack of agreement among algorithms were more depressed initial MD (P < 0.01) and older age at first available VF (P < 0.01). A greater number of VFs (P < 0.01), more years of follow-up (P < 0.01), and eye care institution (P = 0.03) also were associated with discordance. CONCLUSIONS: This extremely large comparative series demonstrated that existing algorithms have limited agreement and that agreement varies with clinical parameters, including institution. These issues underscore the challenges to the clinical use and application of progression algorithms and of applying big-data results to individual practices.

Reversal of Glaucoma Hemifield Test Results and Visual Field Features in Glaucoma.

PURPOSE: To develop a visual field (VF) feature model to predict the reversal of glaucoma hemifield test (GHT) results to within normal limits (WNL) after 2 consecutive outside normal limits (ONL) results. DESIGN: Retrospective cohort study. PARTICIPANTS: Visual fields of 44 503 eyes from 26 130 participants. METHODS: Eyes with 3 or more consecutive reliable VFs measured with the Humphrey Field Analyzer (Swedish interactive threshold algorithm standard 24-2) were included. Eyes with ONL GHT results for the 2 baseline VFs were selected. We extracted 3 categories of VF features from the baseline tests: (1) VF global indices (mean deviation [MD] and pattern standard deviation), (2) mismatch between baseline VFs, and (3) VF loss patterns (archetypes). Logistic regression was applied to predict the GHT results reversal. Cross-validation was applied to evaluate the model on testing data by the area under the receiver operating characteristic curve (AUC). We ascertained clinical glaucoma status on a patient subset (n = 97) to determine the usefulness of our model. MAIN OUTCOME MEASURES: Predictive models for GHT results reversal using VF features. RESULTS: For the 16 604 eyes with 2 initial ONL results, the prevalence of a subsequent WNL result increased from 0.1% for MD < -12 dB to 13.8% for MD ≥-3 dB. Compared with models with VF global indices, the AUC of predictive models increased from 0.669 (MD ≥-3 dB) and 0.697 (-6 dB ≤ MD < -3 dB) to 0.770 and 0.820, respectively, by adding VF mismatch features and computationally derived VF archetypes (P < 0.001 for both). The GHT results reversal was associated with a large mismatch between baseline VFs. Moreover, the GHT results reversal was associated more with VF archetypes of nonglaucomatous loss, severe widespread loss, and lens rim artifacts. For a subset of 97 eyes, using our model to predict absence of glaucoma based on clinical evidence after 2 ONL results yielded significantly better prediction accuracy (87.7%; P < 0.001) than predicting GHT results reversal (68.8%) with a prescribed specificity 67.7%. CONCLUSIONS: Using VF features may predict the GHT results reversal to WNL after 2 consecutive ONL results.

Systemic and Ocular Determinants of Peripapillary Retinal Nerve Fiber Layer Thickness Measurements in the European Eye Epidemiology (E3) Population.

PURPOSE: To investigate systemic and ocular determinants of peripapillary retinal nerve fiber layer thickness (pRNFLT) in the European population. DESIGN: Cross-sectional meta-analysis. PARTICIPANTS: A total of 16 084 European adults from 8 cohort studies (mean age range, 56.9±12.3-82.1±4.2 years) of the European Eye Epidemiology (E3) consortium. METHODS: We examined associations with pRNFLT measured by spectral-domain OCT in each study using multivariable linear regression and pooled results using random effects meta-analysis. MAIN OUTCOME MEASURES: Determinants of pRNFLT. RESULTS: Mean pRNFLT ranged from 86.8±21.4 µm in the Rotterdam Study I to 104.7±12.5 µm in the Rotterdam Study III. We found the following factors to be associated with reduced pRNFLT: Older age (ß = -0.38 µm/year; 95% confidence interval [CI], -0.57 to -0.18), higher intraocular pressure (IOP) (ß = -0.36 µm/mmHg; 95% CI, -0.56 to -0.15), visual impairment (ß = -5.50 µm; 95% CI, -9.37 to -1.64), and history of systemic hypertension (ß = -0.54 µm; 95% CI, -1.01 to -0.07) and stroke (ß = -1.94 µm; 95% CI, -3.17 to -0.72). A suggestive, albeit nonsignificant, association was observed for dementia (ß = -3.11 µm; 95% CI, -6.22 to 0.01). Higher pRNFLT was associated with more hyperopic spherical equivalent (ß = 1.39 µm/diopter; 95% CI, 1.19-1.59) and smoking (ß = 1.53 µm; 95% CI, 1.00-2.06 for current smokers compared with never-smokers). CONCLUSIONS: In addition to previously described determinants such as age and refraction, we found that systemic vascular and neurovascular diseases were associated with reduced pRNFLT. These may be of clinical relevance, especially in glaucoma monitoring of patients with newly occurring vascular comorbidities.