Replication of TCF4 through Association and Linkage Studies in Late-Onset Fuchs Endothelial Corneal Dystrophy

Fuchs endothelial corneal dystrophy (FECD) is a common, late-onset disorder of the corneal endothelium. Although progress has been made in understanding the genetic basis of FECD by studying large families in which the phenotype is transmitted in an autosomal dominant fashion, a recently reported genome-wide association study identified common alleles at a locus on chromosome 18 near TCF4 which confer susceptibility to FECD. Here, we report the findings of our independent validation study for TCF4 using the largest FECD dataset to date (450 FECD cases and 340 normal controls). Logistic regression with sex as a covariate was performed for three genetic models: dominant (DOM), additive (ADD), and recessive (REC). We found significant association with rs613872, the target marker reported by Baratz et al.(2010), for all three genetic models (DOM: P = 9.33×10−35; ADD: P = 7.48×10−30; REC: P = 5.27×10−6). To strengthen the association study, we also conducted a genome-wide linkage scan on 64 multiplex families, composed primarily of affected sibling pairs (ASPs), using both parametric and non-parametric two-point and multipoint analyses. The most significant linkage region localizes to chromosome 18 from 69.94cM to 85.29cM, with a peak multipoint HLOD = 2.5 at rs1145315 (75.58cM) under the DOM model, mapping 1.5 Mb proximal to rs613872. In summary, our study presents evidence to support the role of the intronic TCF4 single nucleotide polymorphism rs613872 in late-onset FECD through both association and linkage studies

Mobile-CellNet: Automatic Segmentation of Corneal Endothelium Using an Efficient Hybrid Deep Learning Model

Purpose: The corneal endothelium, the innermost layer of the human cornea, exhibits a morphology of predominantly hexagonal cells. These endothelial cells are believed to have limited regeneration capacity, and their density decreases over time. Endothelial cell density (ECD) can therefore be used to measure the health of the corneal endothelium and the overall cornea. In clinical settings, specular microscopes are used to image this layer. Owing to the unavailability of reliable automatic tools, technicians often manually mark the cell centers and borders to measure ECD for such images, a process that is time and resource-consuming. Methods: In this article, we propose Mobile-CellNet, a novel completely automatic, efficient deep learning-based cell segmentation algorithm to estimate ECD. This uses 2 similar image segmentation models working in parallel along with image postprocessing using classical image processing techniques. We also compare the proposed algorithm with widely used biomedical image segmentation networks U-Net and U-Net++. Results: The proposed technique achieved a mean absolute error of 4.06% for the ECD on the test set, comparable with the error for U-Net of 3.80% (P = 0.185 for difference), but requiring almost 31 times fewer floating-point operations (FLOPs) and 34 times fewer parameters. Conclusions: Mobile-CellNet accurately segments corneal endothelial cells and reports ECD and cell morphology efficiently. This can be used to develop tools to analyze specular corneal endothelial images in remote settings

Peripheral-to-central ratio of Guttae: validity and reliability of an objective method to characterize severity of Fuchs endothelial corneal dystrophy.

PURPOSE: Common methods of measuring severity of Fuchs endothelial corneal dystrophy (FECD) are limited in objectivity, reliability, or start with a variable baseline that prevents distinguishing healthy from affected eyes. The aim of this study was to describe a method of grading FECD that overcomes these limitations. METHODS: Fifteen patients with Fuchs endothelial corneal dystrophy were included in the study. Guttae were imaged with a slit lamp beam 8 mm tall; the bottom 4 mm half of each image was divided into two equally-sized sections. Guttae were counted by four independent graders blinded to disease severity scores. The peripheral:central guttae ratio was compared to modified Krachmer clinical severity scores. The peripheral:central guttae ratio was compared between mild (severity 0.5-3) versus moderate-to-severe (severity 4-5) disease. Receiver operating characteristics defined optimal ratio cutoffs for mild versus moderate-to-severe disease. RESULTS: Increased peripheral guttae and peripheral:central guttae ratio correlated with Krachmer severity (p = 0.021 and p = 0.009, respectively). The difference between mild and moderate-to-severe cases for the peripheral:central guttae ratio was significant (p \u3c 0.001). Inter-rater reliability of total guttae count was high (coefficient = 0.82, p \u3c 0.001). A peripheral:central guttae ratio of 0.16 was the ideal cut-off point (area under the curve = 0.79, sensitivity = 0.78, and specificity = 0.80). CONCLUSION: In this pilot study, the peripheral:central ratio of guttae correlates with subjective clinical severity of Fuchs dystrophy. It starts at a common baseline, has good inter-rater reliability, does not require dilation, and can be conducted with a smartphone and slit-lamp

Testing a Popular Smartphone Application for Colour Vision Assessment in Healthy Volunteer Subjects.

We aimed to compare the Ishihara pseudoisochromatic colour vision test with a colour vision test from a popular smartphone application (EyeHandBook [EHB]) using digital image processing to simulate colour vision deficiencies. Three digital versions of the Ishihara and EHB slides were created: full colour; 32 bit- greyscale (removing all colour information); and blue channel (to simulate red-green colour vision deficiencies). Twenty healthy volunteers were shown each colour-edited plate. The answers they reported were compared with what would be expected for that colour-simulation scenario based on the answer key provided in the Ishihara booklet ( expected answer). There were nine plates that had comparable patterns between the EHB and Ishihara test. We found no significant difference in the overall proportion of expected answers for the full colour (p = .35), 32 bit-greyscale (p = .39) and blue channel (p = .22) conditions. There were significant differences between the proportion of expected answers among six individual colour- edited plates (p \u3c .05 for each). Colour vision assessment from the EHB is distinct from comparable Ishihara plates. Clinical scenarios that require serial assessment of colour vision may benefit from using the same modality consistently rather than exchanging between the two tests with the assumption of equivalence. Refinement of digital colour editing techniques beyond 32-bit greyscale and RGB channel splitting is necessary in order to accurately simulate colour vision deficiency

Alcohol Abuse Is Associated With Alterations in Corneal Endothelial Cell Morphology

PURPOSE: Alcohol consumption is highly prevalent throughout the world. We sought to detect, in a large sample of cornea donors, whether alcohol abuse is associated with changes in corneal endothelial morphology after accounting for other comorbidities including tobacco use. METHODS: At a single eye bank, 10,322 eyes from a total of 5624 unique donors underwent imaging with a Konan CellChek D specular microscope. Demographic information and medical history were associated with each tissue. Images were analyzed using a standardized protocol for assessment of endothelial cell density, hexagonality, and variation. In this retrospective analysis, a multivariable regression was conducted to assess for an association between alcohol abuse and corneal endothelial metrics. Measurements were averaged across eyes for each donor. Bonferroni corrections were applied to account for multiple comparisons. RESULTS: Among 5624 donors, the mean (standard deviation) endothelial cell density was 2785 (383.0) cells/mm2. Indicators of alcohol abuse were present in 1382 donors (24.5%). In a multivariable regression model that included age, sex, tobacco use, history of cataract surgery, and diabetes mellitus, alcohol abuse was associated with a decrease of 60.9 cells/mm2 [95% confidence interval (CI), -83.0 to -38.7 cells/mm2, P = 7.6 × 10-8], an increase in the coefficient of variation by 0.0048 (95% CI, 0.17-0.79, P = 0.002), and a decrease in percent hexagonality by 0.93% (95% CI, -1.3 to -0.6, P = 4.5 × 10-7). CONCLUSIONS: Alcohol abuse is associated with significant alterations to corneal endothelial density and morphology

Scheimpflug Corneal Densitometry Values and Severity of Guttae in Relation to Visual Acuity in Fuchs Endothelial Corneal Dystrophy

The purpose of this study was to investigate the association between corneal densitometry (CD) values from Scheimpflug tomography imaging, severity of guttae, and visual acuity in eyes with Fuchs endothelial corneal dystrophy (FECD). This was a retrospective, cross-sectional study. Patients with FECD were examined at the Bascom Palmer Eye Institute from January 2015 to September 2019. We extracted CD values at central annuli of 0-2, 2-6, 6-10 and 10-12 mm from Scheimpflug tomography images. We investigated the association of corrected distance visual acuity (CDVA) with CD values, severity of guttae, central corneal thickness (CCT), cataract grade, refractive error, corneal edema grade, age, and gender using multivariate generalized estimating equation regression models. One hundred ninety-two eyes from 110 patients were included in this study. Increase in central CD values at the 0 to 2 mm zone (P 0.05) in the final multivariate regression model. Our study demonstrates that central CD values at 0 to 2 mm and severity of guttae are each associated with decreased CDVA in FECD. These findings carry implications for patients with FECD considering surgical intervention for phacoemulsification alone, Descemet stripping only, or endothelial cell transplantation and provide a multifactorial perspective on vision loss in FECD

Outcomes of Femtosecond Laser-Assisted Cataract Surgery Compared to Conventional Phacoemulsification in Eyes with Pseudoexfoliation Syndrome

To compare the outcomes including complications, in a large cohort of eyes with pseudoexfoliation syndrome that underwent Femtosecond Laser-Assisted Cataract Surgery (FLACS) versus conventional phacoemulsification. Retrospective cohort study. A total of 513 eyes from 366 patients with pseudoexfoliation syndrome that underwent cataract surgery between April 1, 2014, and December 31, 2018. Charts were reviewed for preoperative examination findings, intraoperative complications, and post-operative outcomes. Best-corrected visual acuity (BCVA) was measured by logMAR and compared between groups at one month and the final follow-up visit. Of 513 eyes, 71 (13.8%) underwent FLACS, and 442 (86.2%) eyes underwent conventional cataract surgery. Between the two groups, there was no difference in the incidence of vitreous prolapse, capsular tear, pupillary expansion device usage, capsular tension support device usage, or postoperative cystoid macular edema (p > .05 for all). At the final visit, there was no significant difference in BCVA between FLACS and conventional phacoemulsification groups (mean logMAR 0.26 vs. 0.25, p = .87). When comparing FLACS and conventional phacoemulsification in eyes with pseudoexfoliation syndrome, no difference was seen in the incidence of complications. BCVA was comparable between the two groups. Zonular weakness significantly increased the risk of complications in both groups

Comparison of Corneal Endothelial Cell Density and Morphology With Optisol-GS and Life4C Storage Media in the Eye Bank: A 5-Year Retrospective Analysis

Purpose: Optisol-GS and Life4C are corneal storage media used by eye banks worldwide. We sought to determine whether either solution was associated with superior corneal endothelial cell density (ECD) or morphology in a large cohort of donor corneas. Methods: From January 2016 to December 2020, 10,316 corneas from 5624 unique donors were acquired and analyzed at Rocky Mountain Lions Eye Bank. In April 2019, Life4C replaced Optisol-GS as the sole storage medium. We compared ECD and morphology before and after April 2019 and excluded corneas processed within the transition period. Univariable and multivariable regression analyses accounted for age, sex, tobacco use, heavy alcohol use, and diabetes. Only right corneas were analyzed to account for the correlation between eyes. Results: Of 5042 right corneas analyzed, 3486 were stored in Optisol-GS and 1556 in Life4C. There was no significant difference in ECD across groups (2794 vs. 2793 cells/mm 2 in Optisol-GS and Life4C, P = 0.88). In multivariate analyses, there was no significant difference in corneal ECD (0.6 cells/mm 2 higher with Life4C, P = 0.96) or hexagonality (0.22% higher with Life4C, P = 0.31). However, the coefficient of variation was significantly lower in the Life4C group (−0.0039, P = 0.03). After adjustment for above factors, corneas in Life4C demonstrated a 3.1% decreased likelihood of exhibiting coefficient of variation (CV) values greater than 0.40 ( P = 0.009). Conclusions: This study demonstrates comparable and favorable outcomes using both storage media and confirms their overall efficacy. The decreased CV in Life4C is not of clinically significant magnitude but merits further research in clinical and long-term settings