Effects of Age on Optical Coherence Tomography Measurements of Healthy Retinal Nerve Fiber Layer, Macula, and Optic Nerve Head

Purpose—To determine the effects of age on global and sectoral peripapillary retinal nerve fiber layer (RNFL), macular thicknesses and optic nerve head (ONH) parameters in healthy subjects using optical coherence tomography (OCT). Design—Retrospective, cross-sectional observational study. Participants—226 eyes from 124 healthy subjects were included. Methods—Healthy subjects were scanned using the Fast RNFL, Fast Macula, and Fast ONH scan patterns on a Stratus OCT. All global and sectoral RNFL and macular parameters and global ONH parameters were modeled in terms of age using linear mixed effects models. Normalized slopes were also calculated by dividing the slopes by the mean value of the OCT parameter for inter-parameter comparison. Main Outcome Measures—Slope of each OCT parameter across age. Results—All global and sectoral RNFL thickness parameters statistically significantly decreased with increasing age, except for the temporal quadrant and clock hours 8-10, which were not statistically different from a slope of zero. Highest absolute slopes were in the inferior and superior quadrant RNFL and clock hour 1 (superior nasal). Normalized slopes showed similar rate in all sectors except for the temporal clock hours (8-10). All macular thickness parameters statistically significantly decreased with increasing age, except for the central fovea sector, which had a slight positive slope that was not statistically significant. The nasal outer sector had the greatest absolute slope. Normalized macular slope in the outer ring was similar to the normalized slopes in the RNFL. Normalized inner ring had shallower slope than the outer ring with similar rate in all quadrants. Disc area remained nearly constant across the ages, but cup area increased and rim area decreased with age, both of which were statistically significant. Conclusions—Global and regional changes due to the effects of age on RNFL, macula and ONH OCT measurements should be considered when assessing eyes over time.National Institutes of Health (U.S.) (R01-EY13178-09)National Institutes of Health (U.S.) (R01-EY11289-23)National Institutes of Health (U.S.) (P30-EY008098

Integration and fusion of standard automated perimetry and optical coherence tomography data for improved automated glaucoma diagnostics

<p>Abstract</p> <p>Background</p> <p>The performance of glaucoma diagnostic systems could be conceivably improved by the integration of functional and structural test measurements that provide relevant and complementary information for reaching a diagnosis. The purpose of this study was to investigate the performance of data fusion methods and techniques for simple combination of Standard Automated Perimetry (SAP) and Optical Coherence Tomography (OCT) data for the diagnosis of glaucoma using Artificial Neural Networks (ANNs).</p> <p>Methods</p> <p>Humphrey 24-2 SITA standard SAP and StratusOCT tests were prospectively collected from a randomly selected population of 125 healthy persons and 135 patients with glaucomatous optic nerve heads and used as input for the ANNs. We tested commercially available standard parameters as well as novel ones (fused OCT and SAP data) that exploit the spatial relationship between visual field areas and sectors of the OCT peripapillary scan circle. We evaluated the performance of these SAP and OCT derived parameters both separately and in combination.</p> <p>Results</p> <p>The diagnostic accuracy from a combination of fused SAP and OCT data (95.39%) was higher than that of the best conventional parameters of either instrument, i.e. SAP Glaucoma Hemifield Test (p < 0.001) and OCT Retinal Nerve Fiber Layer Thickness ≥ 1 quadrant (p = 0.031). Fused OCT and combined fused OCT and SAP data provided similar Area under the Receiver Operating Characteristic Curve (AROC) values of 0.978 that were significantly larger (p = 0.047) compared to ANNs using SAP parameters alone (AROC = 0.945). On the other hand, ANNs based on the OCT parameters (AROC = 0.970) did not perform significantly worse than the ANNs based on the fused or combined forms of input data. The use of fused input increased the number of tests that were correctly classified by both SAP and OCT based ANNs.</p> <p>Conclusions</p> <p>Compared to the use of SAP parameters, input from the combination of fused OCT and SAP parameters, and from fused OCT data, significantly increased the performance of ANNs. Integrating parameters by including a priori relevant information through data fusion may improve ANN classification accuracy compared to currently available methods.</p

GALC Deletions Increase the Risk of Primary Open-Angle Glaucoma: The Role of Mendelian Variants in Complex Disease

DNA copy number variants (CNVs) have been reported in many human diseases including autism and schizophrenia. Primary Open Angle Glaucoma (POAG) is a complex adult-onset disorder characterized by progressive optic neuropathy and vision loss. Previous studies have identified rare CNVs in POAG; however, their low frequencies prevented formal association testing. We present here the association between POAG risk and a heterozygous deletion in the galactosylceramidase gene (GALC). This CNV was initially identified in a dataset containing 71 Caucasian POAG cases and 478 ethnically matched controls obtained from dbGAP (study accession phs000126.v1.p1.) (p = 0.017, fisher's exact test). It was validated with array comparative genomic hybridization (arrayCGH) and realtime PCR, and replicated in an independent POAG dataset containing 959 cases and 1852 controls (p = 0.021, OR (odds ratio) = 3.5, 95% CI −1.1–12.0). Evidence for association was strengthened when the discovery and replication datasets were combined (p = 0.002; OR = 5.0, 95% CI 1.6–16.4). Several deletions with different endpoints were identified by array CGH of POAG patients. Homozygous deletions that eliminate GALC enzymatic activity cause Krabbe disease, a recessive Mendelian disorder of childhood displaying bilateral optic neuropathy and vision loss. Our findings suggest that heterozygous deletions that reduce GALC activity are a novel mechanism increasing risk of POAG. This is the first report of a statistically-significant association of a CNV with POAG risk, contributing to a growing body of evidence that CNVs play an important role in complex, inherited disorders. Our findings suggest an attractive biomarker and potential therapeutic target for patients with this form of POAG

Stereo Photo Measured ONH Shape Predicts Development of POAG in Subjects With Ocular Hypertension

To identify objective, quantitative optic nerve head (ONH) structural features and model the contributions of glaucoma

Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry.

Importance:Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders. Objectives:To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma. Design, Settings, and Participants:A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma. Exposures:Genetic variants associated with primary open-angle glaucoma. Main Outcomes and Measures:Presence of primary open-angle glaucoma. Genome-wide significance was defined as P &lt; 5 × 10-8 in the discovery stage and in the meta-analysis of combined discovery and validation data. Results:A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-β A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T&gt;C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P &lt; .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10-13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry. Conclusions and Relevance:In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies

Estrogen pathway polymorphisms in relation to primary open angle glaucoma: An analysis accounting for gender from the United States

Purpose Circulating estrogen levels are relevant in glaucoma phenotypic traits. We assessed the association between an estrogen metabolism single nucleotide polymorphism (SNP) panel in relation to primary open angle glaucoma (POAG), accounting for gender. Methods: We included 3,108 POAG cases and 3,430 controls of both genders from the Glaucoma Genes and Environment (GLAUGEN) study and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) consortium genotyped on the Illumina 660W-Quad platform. We assessed the relation between the SNP panels representative of estrogen metabolism and POAG using pathway- and gene-based approaches with the Pathway Analysis by Randomization Incorporating Structure (PARIS) software. PARIS executes a permutation algorithm to assess statistical significance relative to the pathways and genes of comparable genetic architecture. These analyses were performed using the meta-analyzed results from the GLAUGEN and NEIGHBOR data sets. We evaluated POAG overall as well as two subtypes of POAG defined as intraocular pressure (IOP) ≥22 mmHg (high-pressure glaucoma [HPG]) or IOP 0.99). Among women, gene-based analyses revealed that the catechol-O-methyltransferase gene showed strong associations with HTG (permuted gene p≤0.001) and NPG (permuted gene p=0.01). Conclusions: The estrogen SNP pathway was associated with POAG among women

Risk Factors for Tube Shunt Exposure: A Matched Case-Control Study

Purpose. To evaluate potential risk factors for developing tube shunt exposure in glaucoma patients. Patients and Methods. Forty-one cases from 41 patients that had tube shunt exposure from 1996 to 2005 were identified from the Robert Cizik Eye Clinic and Bascom Palmer Eye Institute. Each case was matched with 2 controls of the same gender and with tube shunts implanted within 6 months of the index case. Conditional logistic regression was used to determine risk factors. Results. The study cohort includes a total of 121 eyes from 121 patients. The mean age was 63.6 ± 19.7 years, ranging from 1 to 96 years. The average time to exposure was 19.29 ± 23.75 months (range 0.36–85.74 months). Risk factors associated with tube exposure were Hispanic ethnicity (; OR = 3.6; 95% CI, 1.3–9.7), neovascular glaucoma (; OR = 28.5; 95% CI, 2.6–316.9), previous trabeculectomy (; OR = 5.3; 95% CI, 1.6–17.7), and combined surgery (; OR = 3.7; 95% CI, 1.1–12.7). Conclusions. Hispanic ethnicity, neovascular glaucoma, previous trabeculectomy, and combined surgery were identified as potential risk factors for tube shunt exposure. These potential risk factors should be considered when determining the indication for performing tube shunt implantation and the frequency of long-term followup

Specification of progression in glaucomatous visual field loss, applying locally condensed stimulus arrangements

The goal of this work was to (i) determine patterns of progression in glaucomatous visual field loss, (ii) compare the detection rate of progression between locally condensed stimulus arrangements and conventional 6° × 6° grid, and (iii) assess the individual frequency distribution of test locations exhibiting a local event (i.e., an abrupt local deterioration of differential luminance sensitivity (DLS) by more than -10dB between any two examinations). The visual function of 41 glaucomatous eyes of 41 patients (16 females, 25 males, 37 to 75 years old) was examined with automated static perimetry (Tuebingen Computer Campimeter or Octopus 101-Perimeter). Stimuli were added to locally enhance the spatial resolution in suspicious regions of the visual field. The minimum follow-up was four subsequent sessions with a minimum of 2-month (median 6-month) intervals between each session. Progression was identified using a modified pointwise linear regression (PLR) method and a modified Katz criterion. The presence of events was assessed in all progressive visual fields. Eleven eyes (27%) showed progression over the study period (median 2.5 years, range 1.3–8.6 years). Six (55%) of these had combined progression in depth and size and five eyes (45%) progressed in depth only. Progression in size conformed always to the nerve fiber course. Seven out of 11 (64%) of the progressive scotomata detected by spatially condensed grids would have been missed by the conventional 6° × 6° grid. At least one event occurred in 64% of all progressive eyes. Five of 11 (46%) progressive eyes showed a cluster of events. The most common pattern of progression in glaucomatous visual fields is combined progression in depth and size of an existing scotoma. Applying individually condensed test grids remarkably enhances the detection rate of glaucomatous visual field deterioration (at the expense of an increased examination time) compared to conventional stimulus arrangements