Postoperative Endothelial Cell Density Is Associated with Late Endothelial Graft Failure after Descemet Stripping Automated Endothelial Keratoplasty.

PURPOSE: To determine whether preoperative endothelial cell density (ECD) and postoperative ECD after Descemet stripping automated endothelial keratoplasty (DSAEK) are associated with late endothelial graft failure (LEGF) in the Cornea Preservation Time Study (CPTS). DESIGN: Cohort study within a multicenter, randomized clinical trial. PARTICIPANTS: A total of 1007 individuals (1223 study eyes), mean age 70 years, undergoing DSAEK for Fuchs' dystrophy (94% of eyes) or pseudophakic or aphakic corneal edema (PACE) (6% of eyes) and followed for up to 5 years. METHODS: Central ECD was determined by a central image analysis reading center. Preoperative ECD was determined for 1209 eyes that did not fail and 14 eyes that experienced LEGF. The ECD at 6 and 12 months after DSAEK, the change in ECD from preoperative to 6 and 12 months, surgeon-reported operative complications, and postoperative graft dislocation were investigated for an association with LEGFs unrelated to other postoperative events. Univariable and multivariable Cox proportional hazards regression models were used to assess associations. MAIN OUTCOME MEASURES: Late endothelial graft failure and its associations with pre- and postoperative ECD and operative complications. RESULTS: The cumulative probability of LEGF was 1.3% (95% confidence interval [CI], 0.8%-2.4%). Median (interquartile range [IQR]) preoperative ECDs were similar for eyes with LEGF (2523; 2367-3161) cells/mm2) and eyes without failure (2727; 2508-2973) cells/mm2) (P = 0.34). The ECD at 6 months was associated with LEGF (P < 0.001) in time-to-event analyses, whereas preoperative ECD was not (P = 0.55). The cumulative incidence (95% CI) of LEGF was 6.5% (3.0%, 14.0%) for 97 grafts with a 6-month ECD less than 1200 cells/mm2, 0.3% (0.0%, 2.4%) for 310 grafts with a 6-month ECD between 1200 and 2000 cells/mm2, and 0.6% (0.1%, 2.7%) for 589 grafts with a 6-month ECD greater than 2000 cells/mm2. In multivariable analyses, ECD at 6 months and operative complications were both associated with LEGF (P = 0.002 and P = 0.01, respectively), whereas graft dislocation was not (P = 0.61). CONCLUSIONS: In eyes undergoing DSAEK, preoperative ECD is unrelated to LEGF, whereas lower ECD at 6 months is associated with LEGF. Early endothelial cell loss after DSAEK and intraoperative complications should be minimized to improve graft survival.

Donor, Recipient, and Operative Factors Associated with Graft Success in the Cornea Preservation Time Study.

PURPOSE: To associate donor, recipient, and operative factors with graft success 3 years after Descemet stripping automated endothelial keratoplasty (DSAEK) in the Cornea Preservation Time Study (CPTS). DESIGN: Cohort study within a multicenter, double-masked, randomized clinical trial. PARTICIPANTS: One thousand ninety individuals (1330 study eyes) with a median age of 70 years undergoing DSAEK for Fuchs endothelial corneal dystrophy (94% of eyes) or pseudophakic or aphakic corneal edema (PACE; 6% of eyes). METHODS: Eyes undergoing DSAEK were randomized to receive a donor cornea with preservation time (PT) of 0 to 7 days (n = 675) or 8 to 14 days (n = 655). Donor, recipient, and operative parameters were recorded prospectively. Graft failure was defined as regraft for any reason, a graft that failed to clear by 8 weeks after surgery, or an initially clear graft that became and remained cloudy for 90 days. Failure in the first 8 weeks was classified further as primary donor failure or early failure, in the absence or presence of operative complications, respectively. Proportional hazards and logistic regression models were used to estimate risk ratios (RR) and 99% confidence intervals (CIs) for graft failure. MAIN OUTCOME MEASURES: Graft success at 3 years. RESULTS: One thousand two hundred fifty-one of 1330 grafts (94%) remained clear at 3 years and were considered successful. After adjusting for PT, tissue from donors with diabetes (RR, 2.35; 99% CI, 1.03-5.33) and operative complications (RR, 4.21; 99% CI, 1.42-12.47) were associated with increased risk for primary or early failure. Preoperative diagnosis of PACE (RR, 3.59; 99% CI, 1.05-12.24) was associated with increased risk for late failure by 3 years after surgery compared with Fuchs dystrophy. Graft success showed little variation among other factors evaluated, including donor age (RR, 1.19 per decade; 99% CI, 0.91-1.56 per decade), preoperative donor endothelial cell density (RR, 1.10 per 500 cells; 99% CI, 0.74-1.63 per 500 cells), graft diameter (RR, 1.22 per 1 mm; 99% CI, 0.39-3.76 per 1 mm), and injector use for graft insertion (RR, 0.92; 99% CI, 0.40-2.10). CONCLUSIONS: Descemet stripping automated endothelial keratoplasty success in the early and entire postoperative period is more likely when the donor did not have diabetes and was without operative complications and in the long-term postoperative period in recipients with Fuchs dystrophy compared with those with PACE. Mechanisms whereby diabetic donors and PACE recipients reduce the rate of graft success after DSAEK warrant further study.

Nine loci for ocular axial length identified through genome-wide association studies, including shared loci with refractive error.

Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways.

Descemet Stripping Endothelial Keratoplasty: Ten-Year Endothelial Cell Loss Compared with Penetrating Keratoplasty.

PURPOSE: To assess endothelial cell density (ECD) and model 10-year cell loss after Descemet stripping endothelial keratoplasty (DSEK), and to compare with results after penetrating keratoplasty (PK) performed for the same indications in the Cornea Donor Study (CDS). DESIGN: Retrospective, longitudinal study. PARTICIPANTS: Five hundred ninety DSEK recipients, 21 to 96 years of age, treated for Fuchs' dystrophy (n = 498; 84%), pseudophakic or aphakic corneal edema (n = 89; 15%), or other endothelial dysfunction (n = 3; <1%). METHODS: Review of 1005 consecutive primary DSEK procedures by 6 surgeons identified 752 grafts (75%) in 590 recipients with ECD measurements at 1 or more postoperative examinations between 6 months and 10 years. Four statistical models applied previously to the CDS PK data were considered. The preferred model (Bayesian Markov chain Monte Carlo) accounted for missing data, selective dropout from graft failure, correlations between fellow eyes, and correlations between longitudinal repeated measures. MAIN OUTCOME MEASURES: Central corneal ECD. RESULTS: The median donor corneal ECD (25th-75th percentiles) was 3005 cells/mm(2) (2852-3203 cells/mm(2)) at baseline, 2077 cells/mm(2) (1660-2411 cells/mm(2)) at 6 months, and 926 cells/mm(2) (617-1433 cells/mm(2)), with a range from 408 to 2538 cells/mm(2) at 10 years. After median cell loss of 32% in the perioperative period, ECD declined at a linear rate of approximately 110 cells/mm(2) per year between 6 months and 10 years after DSEK. At 10 years, the median cell loss was 71% (53%-80%) relative to the baseline donor ECD, comparable with the 76% (70%-82%) median cell loss after PK by 68 surgeons in the CDS. The 10-year ECD correlated with the 6-month postoperative ECD (r = 0.56; P < 0.001), but not with the baseline donor ECD (r = -0.04; P = 0.78). Selective dropout from graft failure did not affect the cell loss model significantly. CONCLUSIONS: The linear decline in ECD after DSEK was consistent with shorter-term endothelial keratoplasty studies and was distinct from the biexponential cell loss trend characteristic of PK. By 10 years, cell loss was comparable in surviving clear grafts for both DSEK and PK.

The effect of donor diabetes history on graft failure and endothelial cell density 10 years after penetrating keratoplasty.

OBJECTIVE: To examine the long-term effect of donor diabetes history on graft failure and endothelial cell density (ECD) after penetrating keratoplasty (PK) in the Cornea Donor Study. DESIGN: Multicenter, prospective, double-masked, controlled clinical trial. PARTICIPANTS: One thousand ninety subjects undergoing PK for a moderate risk condition, principally Fuchs' dystrophy or pseudophakic or aphakic corneal edema, were enrolled by 105 surgeons from 80 clinical sites in the United States. METHODS: Corneas from donors 12 to 75 years of age were assigned by 43 eye banks to participants without respect to recipient factors. Donor and recipient diabetes status was determined from existing medical records. Images of the central endothelium were obtained before surgery (baseline) and at intervals for 10 years after surgery and were analyzed by a central image analysis reading center to determine ECD. MAIN OUTCOME MEASURES: Time to graft failure (regraft or cloudy cornea for 3 consecutive months) and ECD. RESULTS: There was no statistically significant association of donor diabetes history with 10-year graft failure, baseline ECD, 10-year ECD, or ECD values longitudinally over time in unadjusted analyses, nor after adjusting for donor age and other significant covariates. The 10-year graft failure rate was 23% in the 199 patients receiving a cornea from a donor with diabetes versus 26% in the 891 patients receiving a cornea from a donor without diabetes (95% confidence interval for the difference, -10% to 6%; unadjusted P=0.60). Baseline ECD (P=0.71), 10-year ECD (P>0.99), and changes in ECD over 10 years (P=0.86) were similar comparing donor groups with and without diabetes. CONCLUSIONS: The study results do not suggest an association between donor diabetes and PK outcome. However, the assessment of donor diabetes was imprecise and based on historical data only. The increasing frequency of diabetes in the aging population in the United States affects the donor pool. Thus, the impact of donor diabetes on long-term endothelial health after PK or endothelial keratoplasty, or both, warrants further study with more precise measures of diabetes and its complications.

Effect of Simultaneous Endothelial Keratoplasty and Cataract Surgery: A Secondary Analysis of the Descemet Endothelial Thickness Comparison Trial.

PURPOSE: Combining cataract surgery with endothelial keratoplasty (triple EK) is a common practice and may be safer because it commits the patient to only one surgery. This study aimed to determine whether outcomes of pseudophakic endothelial keratoplasty and triple EK have similar outcomes. METHODS: This was a non-prespecified secondary analysis of a multicenter, double-masked, randomized, controlled clinical trial. Enrollment centers included the Casey Eye Institute at Oregon Health and Sciences University and the Byers Eye Institute at Stanford University. Patients with damaged or diseased endothelium and were considered good candidates for either Descemet membrane endothelial keratoplasty or ultrathin Descemet stripping automated endothelial keratoplasty were randomized to one of the two surgeries 1-2 days prior to surgery. If the patient had a cataract, they underwent simultaneous cataract surgery. The primary outcome was visual acuity at 6 months. Visual acuity at 3, 12, and 24 months, 3, 6, 12, and 24 month endothelial cell density and intraoperative and postoperative complications were also recorded. RESULTS: Those who had pseudophakic EK generally were older, more likely to be male, and more likely to have worse baseline vision with higher corneal densitometry values. After controlling for baseline visual acuity and type of keratoplasty, those that underwent Triple-EK had 0.09 better LogMAR lines better visual acuity at 6 (95% CI -0.17 to -0.10; P = 0.02) and 12 months (95% CI -0.21 to -0.07; P = 0.03). Although those receiving Triple- EK had nearly one-half LogMAR line better visual acuity at 24 months, it was no longer statistically significant (95% CI -0.20 to -0.05; P = 0.36). There was no statistically significant difference in ECD between groups at any timepoint. Those undergoing triple EK were more likely to have at least one adverse event (P = 0.02). CONCLUSIONS: Earlier intervention with Triple-EK may improve visual acuity outcomes after endothelial keratoplasty compared with staged procedures, but may also increase the risks of adverse events including the need for re-bubble.

Deep learning segmentation of endothelial cell images using an active learning paradigm with guided label corrections.

Purpose: To create Guided Correction Software for informed manual editing of automatically generated corneal endothelial cell (EC) segmentations and apply it to an active learning paradigm to analyze a diverse set of post-keratoplasty EC images. Approach: An original U-Net model trained on 130 manually labeled post-Descemet stripping automated endothelial keratoplasty (EK) images was applied to 841 post-Descemet membrane EK images generating "uncorrected" cell border segmentations. Segmentations were then manually edited using the Guided Correction Software to create corrected labels. This dataset was split into 741 training and 100 testing EC images. U-Net and DeepLabV3+ were trained on the EC images and the corresponding uncorrected and corrected labels. Model performance was evaluated in a cell-by-cell analysis. Evaluation metrics included the number of over-segmentations, under-segmentations, correctly identified new cells, and endothelial cell density (ECD). Results: Utilizing corrected segmentations for training U-Net and DeepLabV3+ improved their performance. The average number of over- and under-segmentations per image was reduced from 23 to 11 with the corrected training set. Predicted ECD values generated by networks trained on the corrected labels were not significantly different than the ground truth counterparts (p=0.02, paired t-test). These models also correctly segmented a larger percentage of newly identified cells. The proposed Guided Correction Software and semi-automated approach reduced the time to accurately segment EC images from 15 to 30 to 5 min, an ∼80% decrease compared to manual editing. Conclusions: Guided Correction Software can efficiently label new training data for improved deep learning performance and generalization between EC datasets.

A multi-ancestry GWAS of Fuchs corneal dystrophy highlights the contributions of laminins, collagen, and endothelial cell regulation.

Fuchs endothelial corneal dystrophy (FECD) is a leading indication for corneal transplantation, but its molecular etiology remains poorly understood. We performed genome-wide association studies (GWAS) of FECD in the Million Veteran Program followed by multi-ancestry meta-analysis with the previous largest FECD GWAS, for a total of 3970 cases and 333,794 controls. We confirm the previous four loci, and identify eight novel loci: SSBP3, THSD7A, LAMB1, PIDD1, RORA, HS3ST3B1, LAMA5, and COL18A1. We further confirm the TCF4 locus in GWAS for admixed African and Hispanic/Latino ancestries and show an enrichment of European-ancestry haplotypes at TCF4 in FECD cases. Among the novel associations are low frequency missense variants in laminin genes LAMA5 and LAMB1 which, together with previously reported LAMC1, form laminin-511 (LM511). AlphaFold 2 protein modeling, validated through homology, suggests that mutations at LAMA5 and LAMB1 may destabilize LM511 by altering inter-domain interactions or extracellular matrix binding. Finally, phenome-wide association scans and colocalization analyses suggest that the TCF4 CTG18.1 trinucleotide repeat expansion leads to dysregulation of ion transport in the corneal endothelium and has pleiotropic effects on renal function.

Descemet's stripping automated endothelial keratoplasty: three-year graft and endothelial cell survival compared with penetrating keratoplasty.

PURPOSE: To assess 3-year outcomes of Descemet's stripping automated endothelial keratoplasty (DSAEK) in comparison with penetrating keratoplasty (PKP) from the Cornea Donor Study (CDS). DESIGN: Prospective, multicenter, nonrandomized clinical trial. PARTICIPANTS: A total of 173 subjects undergoing DSAEK for a moderate risk condition (principally Fuchs' dystrophy or pseudophakic corneal edema) compared with 1101 subjects undergoing PKP from the CDS. METHODS: The DSAEK procedures were performed by 2 experienced surgeons using the same donor and similar recipient criteria as for the CDS PKP procedures, performed by 68 surgeons. Graft success was assessed by Kaplan-Meier survival analysis. Central endothelial cell density (ECD) was determined from baseline donor and postoperative central endothelial images by the reading center used in the CDS Specular Microscopy Ancillary Study. MAIN OUTCOME MEASURES: Graft clarity and ECD. RESULTS: The donor and recipient demographics were comparable in the DSAEK and PKP groups, except that the proportion of Fuchs' dystrophy cases was higher in the DSAEK cohort. The 3-year survival rate did not differ significantly between DSAEK and PKP procedures performed for either Fuchs' dystrophy (96% for both; P = 0.81) or non-Fuchs' cases (86% vs. 84%, respectively; P = 0.41). Principal causes of graft failure or regraft within 3 years after DSAEK and PKP were immunologic graft rejection (0.6% vs. 3.1%), endothelial decompensation in the absence of documented rejection (1.7% vs 2.1%), unsatisfactory visual or refractive outcome (1.7% vs. 0.5%), and infection (0% vs. 1.1%), respectively. The 3-year predicted probability of a rejection episode was 9% with DSAEK versus 20% with PKP (P = 0.0005). The median 3-year cell loss for DSAEK and PKP was 46% and 51%, respectively (P = 0.33), in Fuchs' dystrophy cases and 59% and 61%, respectively (P = 0.70), in the non-Fuchs' cases. At 3 years, use of a smaller DSAEK insertion incision was associated with significantly higher cell loss (60% vs. 33% for 3.2- and 5.0-mm incisions, respectively; P = 0.0007), but not with a significant difference in graft survival (P = 0.45). CONCLUSIONS: The graft success rate and endothelial cell loss were comparable at 3 years for DSAEK and PKP procedures. A 5-mm DSAEK incision width was associated with significantly less cell loss than a 3.2-mm incision.

Donor age and factors related to endothelial cell loss 10 years after penetrating keratoplasty: Specular Microscopy Ancillary Study.

OBJECTIVE: To examine the effect of donor age and other perioperative factors on long-term endothelial cell loss after penetrating keratoplasty (PKP). DESIGN: Multicenter, prospective, double-masked clinical trial. PARTICIPANTS: We included 176 participants from the Cornea Donor Study cohort who had not experienced graft failure ≥ 10 years after PKP for a moderate risk condition (principally Fuchs' dystrophy or pseudophakic/aphakic corneal edema). METHODS: Corneas from donors 12 to 75 years old were assigned to participants using a randomized approach, without respect to recipient factors. Surgery and postoperative care were performed according to the surgeons' usual routines. Images of the central endothelium were obtained preoperatively and at intervals for 10 years postoperatively. Images were analyzed by a central image analysis reading center to determine endothelial cell density (ECD). MAIN OUTCOME MEASURES: Endothelial cell density at 10 years. RESULTS: Among study participants with a clear graft at 10 years, the 125 who received a cornea from a donor 12 to 65 years old experienced a median cell loss of 76%, resulting in a 10-year median ECD of 628 cells/mm(2) (interquartile range [IQR], 522-850 cells/mm(2)), whereas the 51 who received a cornea from a donor 66 to 75 years old experienced a cell loss of 79%, resulting in a median 10-year ECD of 550 cells/mm(2) (IQR, 483-694 cells/mm(2); P adjusted for baseline ECD = 0.03). In addition to younger donor age, higher ECD values were significantly associated with higher baseline ECD (P<0.001) and larger donor tissue size (P<0.001). Forty-two of the 176 participants (24%) had an ECD of <500 cells/mm(2) at 10 years and only 24 (14%) had an ECD of >1000 cells/mm(2). CONCLUSIONS: Substantial cell loss occurs in eyes with a clear graft 10 years after PKP, with the rate of cell loss being slightly greater with older donor age. Greater preoperative ECD and larger donor tissue size are associated with higher ECD at 10 years.

The effect of donor age on penetrating keratoplasty for endothelial disease: graft survival after 10 years in the Cornea Donor Study.

OBJECTIVE: To determine whether the 10-year success rate of penetrating keratoplasty for corneal endothelial disorders is associated with donor age. DESIGN: Multicenter, prospective, double-masked clinical trial. PARTICIPANTS: A total of 1090 participants undergoing penetrating keratoplasty at 80 sites for Fuchs' dystrophy (62%), pseudophakic/aphakic corneal edema (34%), or another corneal endothelial disorder (4%) and followed for up to 12 years. METHODS: Forty-three eye banks provided corneas from donors aged 12 to 75 years, using a randomized approach to assign donor corneas to study participants without respect to recipient factors. Surgery and postoperative care were performed according to the surgeons' usual routines. MAIN OUTCOME MEASURES: Graft failure defined as a regraft or, in the absence of a regraft, a cloudy cornea that was sufficiently opaque to compromise vision for 3 consecutive months. RESULTS: In the primary analysis, the 10-year success rate was 77% for 707 corneas from donors aged 12 to 65 years compared with 71% for 383 donors aged 66 to 75 years (difference, +6%; 95% confidence interval, -1 to +12; P = 0.11). When analyzed as a continuous variable, higher donor age was associated with lower graft success beyond the first 5 years (P<0.001). Exploring this association further, we observed that the 10-year success rate was relatively constant for donors aged 34 to 71 years (75%). The success rate was higher for 80 donors aged 12 to 33 years (96%) and lower for 130 donors aged 72 to 75 years (62%). The relative decrease in the success rate with donor ages 72 to 75 years was not observed until after year 6. CONCLUSIONS: Although the primary analysis did not show a significant difference in 10-year success rates comparing donor ages 12 to 65 years and 66 to 75 years, there was evidence of a donor age effect at the extremes of the age range. Because we observed a fairly constant 10-year success rate for donors aged 34 to 71 years, which account for approximately 75% of corneas in the United States available for transplant, the Cornea Donor Study results indicate that donor age is not an important factor in most penetrating keratoplasties for endothelial disease.

Trends in Ophthalmological Patents, 2005-2020.

Purpose: Technological development drives the optimization of therapeutics in ophthalmology, but quantifiable and systematic review of such innovation is lacking. To fill this gap, we characterize trends in ophthalmology-related patents in the United States from 2005 to 2020. Methods: Publicly available patent data from the US Patent and Trademark Office was analyzed with the R programming language. Ophthalmology-related patents were identified with a keyword search of their titles and claims text. Temporal trends were assessed with the Mann-Kendall trend test (α = 0.05, two-sided). Results: Of 4.5 million collected patents, some 21,000 (0.5%) were ophthalmology related. The number of annually granted ophthalmology patents increased over time (Mann-Kendall test: z = 4.91; P < 0.001), from 619 patents released in 2005 to 2,019 patents in 2020. Patent counts also increased over time for all ophthalmic subspecialties except oculoplastics, with steepest rises in retina (z = 4.91; P < 0.001) and cornea (z = 4.64; P < 0.001). The most cited patents were in biocompatible intraocular implants and implantable controlled-release drug delivery systems, which underscores particular advancement in therapeutic efficacy and safety in devices used in the treatment and management of common yet debilitating eye conditions. Conclusion: This exploratory analysis reveals hotspots for ophthalmology-related innovation in the United States that may predict current and future growth trends in device development and pharmacologic advancement in ophthalmology, paving the way for more diverse and effective treatment options for preserving vision.

Descemet Membrane Endothelial Keratoplasty: 10-Year Cell Loss and Failure Rate Compared With Descemet Stripping Endothelial Keratoplasty and Penetrating Keratoplasty.

PURPOSE: The aim of this study was to assess long-term endothelial cell loss (ECL) and graft failure with Descemet membrane endothelial keratoplasty (DMEK) and Descemet stripping endothelial keratoplasty (DSEK) versus penetrating keratoplasty (PK) performed for the same indications (primarily Fuchs dystrophy and pseudophakic corneal edema) in the Cornea Donor Study. METHODS: This retrospective study included consecutive primary DMEK (529 recipients, 739 eyes) and DSEK cases (585 recipients, 748 eyes) with 1 or more endothelial cell density (ECD) measurements at 6 months to 16 years. Main outcomes were ECD, longitudinal ECL, and graft failure. RESULTS: Between 6 months and 8 years the ECD declined linearly by approximately 118 cells/mm2/yr after DMEK and 112 cells/mm2/yr after DSEK. Beyond 8 years postoperatively the rate of decline slowed substantially. Selective dropout from graft failure did not significantly affect the ECD trend. At 10 years, median ECL (interquartile range) was 63% (45, 73) with DMEK, 68% (48, 78) with DSEK, and 76% (70, 82) with PK (P = 0.01 DMEK vs. DSEK, P <0.001 DMEK vs. PK, and P < 0.001 DSEK vs. PK). The proportion of surviving grafts with 10-year ECD <500 cells/mm2 was 1.4% with DMEK, 7.3% with DSEK, and 23.9% with PK. The cumulative risk of graft failure between 6 months and 10 years was 5% with DMEK, 11% with DSEK, and 19% with PK (P < 0.001). CONCLUSIONS: Compared with PK and DSEK, DMEK had significantly lower ECL and significantly lower risk of secondary graft failure through 10 years.

Long-Term Endothelial Safety Profile With iStent Inject in Patients With Open-Angle Glaucoma.

PURPOSE: To report 5-year postoperative safety data of iStent inject, including overall stability, endothelial cell density (ECD), and endothelial cell loss (ECL) in patients with mild-to-moderate primary open-angle glaucoma (POAG). DESIGN: 5-year follow-up safety study of the prospective, randomized, single-masked, concurrently controlled, multicenter iStent inject pivotal trial. METHODS: In this 5-year follow-up safety study of the 2-year iStent inject pivotal randomized controlled trial, patients receiving iStent inject placement and phacoemulsification or phacoemulsification alone were studied for the incidence of clinically relevant complications associated with iStent inject placement and stability. Corneal endothelial endpoints were mean change in ECD from screening and proportion of patients with >30% ECL from screening, from analysis of central specular endothelial images by a central image analysis reading center at several time points through 60 months postoperatively. RESULTS: Of the 505 original randomized patients, 227 elected to participate (iStent inject and phacoemulsification group, n = 178; phacoemulsification-alone control group, n = 49). No specific device-related adverse events or complications were reported through month 60. No significant differences were observed in mean ECD, mean percentage change in ECD, or proportion of eyes with >30% ECL between the iStent inject and control groups at any time point; mean percentage decrease in ECD at 60 months was 14.3% ± 13.4% in the iStent inject group and 14.8% ± 10.3% in the control group (P = .8112). The annualized rate of ECD change from 3 to 60 months was neither clinically nor statistically significant between groups. CONCLUSIONS: Implantation of iStent inject during phacoemulsification in patients with mild-to-moderate POAG did not produce any device-related complications or ECD safety concerns compared to phacoemulsification alone through 60 months.

Machine Learning Analysis of Postkeratoplasty Endothelial Cell Images for the Prediction of Future Graft Rejection.

Purpose: This study developed machine learning (ML) classifiers of postoperative corneal endothelial cell images to identify postkeratoplasty patients at risk for allograft rejection within 1 to 24 months of treatment. Methods: Central corneal endothelium specular microscopic images were obtained from 44 patients after Descemet membrane endothelial keratoplasty (DMEK), half of whom had experienced graft rejection. After deep learning segmentation of images from all patients' last and second-to-last imaging, time points prior to rejection were analyzed (175 and 168, respectively), and 432 quantitative features were extracted assessing cellular spatial arrangements and cell intensity values. Random forest (RF) and logistic regression (LR) models were trained on novel-to-this-application features from single time points, delta-radiomics, and traditional morphometrics (endothelial cell density, coefficient of variation, hexagonality) via 10 iterations of threefold cross-validation. Final assessments were evaluated on a held-out test set. Results: ML classifiers trained on novel-to-this-application features outperformed those trained on traditional morphometrics for predicting future graft rejection. RF and LR models predicted post-DMEK patients' allograft rejection in the held-out test set with >0.80 accuracy. RF models trained on novel features from second-to-last time points and delta-radiomics predicted post-DMEK patients' rejection with >0.70 accuracy. Cell-graph spatial arrangement, intensity, and shape features were most indicative of graft rejection. Conclusions: ML classifiers successfully predicted future graft rejections 1 to 24 months prior to clinically apparent rejection. This technology could aid clinicians to identify patients at risk for graft rejection and guide treatment plans accordingly. Translational Relevance: Our software applies ML techniques to clinical images and enhances patient care by detecting preclinical keratoplasty rejection.

Association Between Fuchs Endothelial Corneal Dystrophy, Diabetes Mellitus, and Multimorbidity.

PURPOSE: The aim of this study was to assess risk for demographic variables and other health conditions that are associated with Fuchs endothelial corneal dystrophy (FECD). METHODS: We developed a FECD case-control algorithm based on structured electronic health record data and confirmed accuracy by individual review of charts at 3 Veterans Affairs (VA) Medical Centers. This algorithm was applied to the Department of VA Million Veteran Program cohort from whom sex, genetic ancestry, comorbidities, diagnostic phecodes, and laboratory values were extracted. Single-variable and multiple variable logistic regression models were used to determine the association of these risk factors with FECD diagnosis. RESULTS: Being a FECD case was associated with female sex, European genetic ancestry, and a greater number of comorbidities. Of 1417 diagnostic phecodes evaluated, 213 had a significant association with FECD, falling in both ocular and nonocular conditions, including diabetes mellitus (DM). Five of 69 laboratory values were associated with FECD, with the direction of change for 4 being consistent with DM. Insulin dependency and type 1 DM raised risk to a greater degree than type 2 DM, like other microvascular diabetic complications. CONCLUSIONS: Female sex, European ancestry, and multimorbidity increased FECD risk. Endocrine/metabolic clinic encounter codes and altered patterns of laboratory values support DM increasing FECD risk. Our results evoke a threshold model in which the FECD phenotype is intensified by DM and potentially other health conditions that alter corneal physiology. Further studies to better understand the relationship between FECD and DM are indicated and may help identify opportunities for slowing FECD progression.

Comparison of Donor Corneal Endothelial Cell Density Determined by Eye Banks and by a Central Image Analysis Reading Center Using the Same Image Analysis Method.

PURPOSE: The purpose of this study was to evaluate agreement between eye banks (EBs) and an image analysis reading center on endothelial cell density (ECD) determinations using the same image analysis method. METHODS: The Cornea Image Analysis Reading Center (CIARC) determined ECD with a single experienced analyst on EB-obtained central endothelial images from donors intended for keratoplasty from 2 eye banks, Eversight and Lions VisionGift, using the Konan center analysis method. The EBs performed ECD determination on their respective sets of images using the same analysis method with experienced eye bank technicians. RESULTS: The mean age of the 200 donors was 54 years (range 30-75 years). Seventy (35%) of the 200 patients were women, and 57 (29%) were diabetic. The mean ECD was 10 cells/mm2 greater by the EBs than by CIARC (P = 0.39), with 95% limits of agreement of [-304 to 323 cells/mm2]. The mean difference was not substantially changed when the difference between EBs and CIARC ECD was adjusted for sex, donor age, donor diabetes, CV, HEX, number of cells analyzed, and EBs as a random effect (estimated mean difference of 20 cells/mm2 after adjustment in a linear mixed model; P = 0.73). The EB-determined preoperative ECD was within 10% of the CIARC-determined ECD for 178 (89%) image sets, with 15 (8%) higher by >10% and 7 (3%) lower by >10%. CONCLUSIONS: Well-trained eye bank technicians achieve comparable results for ECD determination with an experienced image analyst from an image analysis reading center when the same image analysis method is used.

Comparison of Graft Outcomes Reusing Original Intermediate-Term Cold Storage Solution for Entire Corneal Donor Storage Period With Exchanged Fresh Storage Solution After Donor Preparation in the Cornea Preservation Time Study.

PURPOSE: The purpose of this study was to evaluate outcomes of Descemet stripping automated endothelial keratoplasty comparing exchange with fresh intermediate-term cold storage solution after lenticule preparation versus reuse of the original solution in the Cornea Preservation Time Study. METHODS: In the Cornea Preservation Time Study, 508 donor corneas had lenticules prepared by the eye bank with fresh solution exchange (Fresh group) and 283 with reuse of the original solution (Original group). Storage time for all donors was ≤11 days. Graft success rates, central endothelial cell loss at 3 years, and frequency of positive donor rim cultures were compared between the 2 groups. RESULTS: The 3-year graft success rate (95% confidence interval) was 93.4% (90.7%-95.3%) in the Fresh group and 95.2% (91.8%-97.2%) in the Original group (adjusted hazard ratio for graft failure = 0.64, 95% confidence interval, 0.33-1.24, P = 0.19). The mean percentage endothelial cell loss was significantly greater in the Fresh group versus Original group (45% ± 22% vs. 38% ± 20%, respectively, P = 0.004). Cultures were positive in 4 (1.5%) of 267 donor rims (3 fungal and 1 bacterial) in the Fresh group and in 4 (2.5%) of 158 in the Original group ( P = 0.57). There were 2 postoperative infections in the Original group and none in the Fresh group. CONCLUSIONS: The use of the original intermediate-term cold storage solution did not reduce the 3-year graft success rate compared with exchanging with fresh solution after lenticule preparation for Descemet stripping automated endothelial keratoplasty, while the frequency of positive donor rim cultures did not significantly differ between groups.

Random Survival Forests Analysis of Intraoperative Complications as Predictors of Descemet Stripping Automated Endothelial Keratoplasty Graft Failure in the Cornea Preservation Time Study.

Importance: A new analytic method can evaluate factors of interest associated with graft failure after Descemet stripping automated endothelial keratoplasty (DSAEK) or more generally in any ophthalmic surgical setting with a time-to-event outcome. Objective: To reanalyze types of intraoperative complications associated with DSAEK graft failure in the Cornea Preservation Time Study using random survival forests. Design, Setting, and Participants: This cohort study, initially conceived in April 2019, used a prediction model to conduct a post hoc secondary analysis of data collected in a multicenter, double-masked, randomized clinical trial. Forty US clinical sites with 70 surgeons participated, with donor corneas provided by 23 US eye banks. The study included 1090 participants, representing 1330 eyes, undergoing DSAEK for Fuchs dystrophy (1255 eyes [94.4%]) or pseudophakic or aphakic corneal edema (75 eyes [5.6%]). Enrollment occurred between April 16, 2012, and February 20, 2014, and follow-up ended June 5, 2017. Statistical analysis was performed from July 10, 2019, to May 29, 2020. Intervention: Descemet stripping automated endothelial keratoplasty with random assignment of a donor cornea with preservation time of 7 days or less or 8 to 14 days. Main Outcomes and Measures: Ranked variable importance for intraoperative complications among 50 donor, recipient, and eye bank variables and restricted mean survival time through 47 months (1434 days) after DSAEK were examined. Random survival forests, a nonparametric method (with less restrictive model assumptions) that is far more flexible in its ability to model nonlinear effects and interactions, was used to analyze the data. Results: This study included 1090 participants (663 women [60.8%]; median age, 70 years [range, 42-90 years]), representing 1330 eyes. Random survival forests ranked a DSAEK intraoperative complication as the third most predictive factor of graft failure, after surgeon and eye bank, in the final model with 5 predictors. In the first 47 months after DSAEK, the estimated mean difference in restricted mean survival time for grafts that experienced a DSAEK intraoperative complication vs those that did not was -227 days (99% CI, -352 to -70 days) based on the final RSF model. Conclusions and Relevance: These findings, while post hoc, support the hypothesis that random survival forests allow for an improved analytic approach for identifying factors predictive of graft failure and for obtaining adjusted graft survival estimates. Random survival forests offer the opportunity to guide the development of future population-based cohort ophthalmic surgical studies, establishing definitive factors for procedural success.