Deep Learning-Based Detection of Reticular Pseudodrusen in Age-Related Macular Degeneration on Optical Coherence Tomography.

Reticular pseudodrusen (RPD) signify a critical phenotype driving vision loss in age-related macular degeneration (AMD). Their detection is paramount in the clinical management of those with AMD, yet they remain challenging to reliably identify. We thus developed a deep learning (DL) model to segment RPD from 9,800 optical coherence tomography B-scans, and this model produced RPD segmentations that had higher agreement with four retinal specialists (Dice similarity coefficient [DSC]=0·76 [95% confidence interval [CI] 0·71-0·81]) than the agreement amongst the specialists (DSC=0·68, 95% CI=0·63-0·73; p <0·001). In five external test datasets consisting of 1,017 eyes from 812 individuals, the DL model detected RPD with a similar level of performance as two retinal specialists (area-under-the-curve of 0·94 [95% CI=0·92-0·97], 0·95 [95% CI=0·92-0·97] and 0·96 [95% CI=0·94-0·98] respectively; p ≥0·32). This DL model enables the automatic detection and quantification of RPD with expert-level performance, which we have made publicly available.

Novel Outer Retinal Columnar Abnormalities (ORCA) and Non-Vasogenic Cystoid Macular Edema in Dense Deposit Disease.

PURPOSE: To describe the occurrence of bilateral outer retinal columnar abnormalities, non-vasogenic cystoid macular edema, and drusen in the context of dense deposit disease. METHODS: Case report. PATIENT: An 18-year-old female with dense deposit disease was referred to our specialist center for diagnosis and management with findings consistent with bilateral non-vasogenic cystoid macular edema and drusen. She was followed up in our clinic for forty months and treated with acetazolamide and ketorolac drops. RESULTS: Baseline examination revealed bilateral visual acuity (VA) reduction, and macular elevation with peripapillary drusen on fundus biomicroscopy. Optical coherence tomography revealed bilateral hyporeflective cystoid central macula changes, microcystoid changes with increased central subfield thickness (>450 microns), and outer retinal columnar abnormalities (ORCAs). Fluorescein angiography showed no evidence of macular leakage. Electrodiagnostic testing was within normal limits. Over the course of follow-up, she received treatment with acetazolamide 250mg BD PO and ketorolac 0.5% eye drops, with a partial reduction in her edema and improvement in VA. CONCLUSION: Dense deposit disease is a rare disease secondary to complement cascade dysregulation, associated with drusen. To the best of our knowledge, this is the first report of bilateral non-vasogenic cystoid macular edema and ORCA in a young female patient with dense deposit disease, confirmed with multimodal imaging.

Formal registration of visual impairment in people with diabetic retinopathy significantly underestimates the scale of the problem: a retrospective cohort study at a tertiary care eye hospital service in the UK.

AIMS: To analyse the prevalence of visual impairment (VI), compare it to certification of visual impairment (CVI) and analyse VI associations in patients with diabetic retinopathy (DR). METHODS: Retrospective cohort study, which included 8007 patients with DR referred from the English diabetic eye screening programme to a tertiary referral eye hospital. Main outcome measure was VI, defined as vision in the best eye of <6/24. We conducted a multivariable logistic regression for VI as primary outcome of interest, controlling for age, sex, type of diabetes, baseline DR grade, ethnicity and index of multiple deprivation (IMD). RESULTS: Mean age was 64.5 (SD 13.6) years; 61% of patients were men; and 31% of South Asian ethnicity. There were 68 patients with CVI during the study period, and 84% (272/325) of patients with VI did not have CVI after a mean follow-up of 1.87 (SD ±0.86) years. Older age showed a positive association with VI (OR per decade rise 1.88, 95% CI 1.70 to 2.08; p=1.8×10-34). Men had a lower risk of VI (OR 0.62, 95% CI 0.50 to 0.79, p=6.0×10-5), and less deprivation had a graded inverse association with VI (OR per IMD category increase 0.83, 95% CI 0.74 to 0.93, p value for linear trend 0.002). CONCLUSION: The majority of people with vision impairment are not registered at the point of care, which could translate to underestimation of diabetes-related VI and all-cause VI at a national level if replicated at other centres. Further work is needed to explore rates of VI and uptake of registration.

A Deep Learning Framework for the Detection and Quantification of Reticular Pseudodrusen and Drusen on Optical Coherence Tomography.

Purpose: The purpose of this study was to develop and validate a deep learning (DL) framework for the detection and quantification of reticular pseudodrusen (RPD) and drusen on optical coherence tomography (OCT) scans. Methods: A DL framework was developed consisting of a classification model and an out-of-distribution (OOD) detection model for the identification of ungradable scans; a classification model to identify scans with drusen or RPD; and an image segmentation model to independently segment lesions as RPD or drusen. Data were obtained from 1284 participants in the UK Biobank (UKBB) with a self-reported diagnosis of age-related macular degeneration (AMD) and 250 UKBB controls. Drusen and RPD were manually delineated by five retina specialists. The main outcome measures were sensitivity, specificity, area under the receiver operating characteristic (ROC) curve (AUC), kappa, accuracy, intraclass correlation coefficient (ICC), and free-response receiver operating characteristic (FROC) curves. Results: The classification models performed strongly at their respective tasks (0.95, 0.93, and 0.99 AUC, respectively, for the ungradable scans classifier, the OOD model, and the drusen and RPD classification models). The mean ICC for the drusen and RPD area versus graders was 0.74 and 0.61, respectively, compared with 0.69 and 0.68 for intergrader agreement. FROC curves showed that the model's sensitivity was close to human performance. Conclusions: The models achieved high classification and segmentation performance, similar to human performance. Translational Relevance: Application of this robust framework will further our understanding of RPD as a separate entity from drusen in both research and clinical settings.

The Effect of CMS's Comprehensive Care for Joint Replacement Bundled Payment Model on Trajectories of Post-acute Rehabilitation Care After Total Hip Arthroplasty.

OBJECTIVE: To evaluate the effect of the Comprehensive Care for Joint Replacement (CJR) policy on the 90-day trajectory of post-acute care after a total hip arthroplasty (THA). DESIGN: Multivariable difference-in-difference models applied to Medicare beneficiaries undergoing a THA prior to (2014-2015) and post-CJR implementation (2017) in areas subjected to or exempt from the policy. SETTING: Hospitals in standard metropolitan statistical areas. PARTICIPANTS: 357,844 elderly Medicare patients nationwide undergoing THA (N=357,844). INTERVENTIONS: None. MAIN OUTCOME MEASURES: Escalation in care to institutionalization (ie, admission to an inpatient rehabilitation or skilled nursing facility during 90-days postdischarge for those initially discharged to the community and return to the community at the end of the episode of care among those initially discharged to an institutional setting). RESULTS: Of the 357,844 elderly Medicare patients nationwide undergoing THA during the study period, 47.6% were discharged directly to the community and 52.4% received post-acute care in an institution. Patients discharged to an institution post-policy in a CJR area were about 10% less likely to return to the community (odds ratio=0.91; 95% confidence interval, 0.84-0.98; P=.02) at the end of the 90-day episode of care than those treated in policy-exempt areas. Despite the large magnitude, estimates of escalation in care among patients treated in bundling areas post-CJR implementation were not statistically significant. CONCLUSIONS: Our findings support further exploration of unanticipated effects of mandatory bundled payment policies on outcomes, as well as further examination of outcomes among policy-relevant subgroups of patients undergoing hip replacement in the United States.

Estimating excess visual loss from neovascular age-related macular degeneration in the UK during the COVID-19 pandemic: a retrospective clinical audit and simulation model.

OBJECTIVES: To report the reduction in new neovascular age-related macular degeneration (nAMD) referrals during the COVID-19 pandemic and estimate the impact of delayed treatment on visual outcomes at 1 year. DESIGN: Retrospective clinical audit and simulation model. SETTING: Multiple UK National Health Service (NHS) ophthalmology centres. PARTICIPANTS: Data on the reduction in new nAMD referrals were obtained from four NHS Trusts comparing April 2020 with April 2019. To estimate the potential impact on 1-year visual outcomes, a stratified bootstrap simulation model was developed drawing on an electronic medical records dataset of 20 825 nAMD eyes from 27 NHS Trusts. MAIN OUTCOME MEASURES: Simulated mean visual acuity and proportions of eyes with vision ≤6/60, ≤6/24 and ≥6/12 at 1 year under four hypothetical scenarios: 0-month, 3-month, 6-month and 9-month treatment delays. Estimated additional number of eyes with vision ≤6/60 at 1 year nationally. RESULTS: The number of nAMD referrals dropped on average by 72% (range 65%-87%). Simulated 1-year visual outcomes for 1000 nAMD eyes with a 3-month treatment delay suggested an increase in the proportion of eyes with vision ≤6/60 from 15.5% (13.2%-17.9%) to 23.3% (20.7%-25.9%), and a decrease in the proportion of eyes with vision ≥6/12 (driving vision) from 35.1% (32.1%-38.1%) to 26.4% (23.8%-29.2%). Outcomes worsened incrementally with longer modelled delays. Assuming nAMD referrals are reduced to this level for 1 month nationally, these simulated results suggest an additional 186-365 eyes with vision ≤6/60 at 1 year. CONCLUSIONS: We report a large decrease in nAMD referrals during the COVID-19 lockdown and provide an important public health message regarding the risk of delayed treatment. As a conservative estimate, a treatment delay of 3 months could lead to a >50% relative increase in the number of eyes with vision ≤6/60 and 25% relative decrease in the number of eyes with driving vision at 1 year.

Evolving Treatment Patterns and Outcomes of Neovascular Age-Related Macular Degeneration Over a Decade.

PURPOSE: Management of neovascular age-related macular degeneration (nAMD) has evolved over the last decade with several treatment regimens and medications. This study describes the treatment patterns and visual outcomes over 10 years in a large cohort of patients. DESIGN: Retrospective analysis of electronic health records from 27 National Health Service secondary care healthcare providers in the UK. PARTICIPANTS: Treatment-naïve patients receiving at least 3 intravitreal anti-vascular endothelial growth factor (VEGF) injections for nAMD in their first 6 months of follow-up were included. Patients with missing data for age or gender and those aged less than 55 years were excluded. METHODS: Eyes with at least 3 years of follow-up were grouped by years of treatment initiation, and 3-year outcomes were compared between the groups. Data were generated during routine clinical care between September 2008 and December 2018. MAIN OUTCOME MEASURES: Visual acuity (VA), number of injections, and number of visits. RESULTS: A total of 15 810 eyes of 13 705 patients receiving 195 104 injections were included. Visual acuity improved from baseline during the first year, but decreased thereafter, resulting in loss of visual gains. This trend remained consistent throughout the past decade. Although an increasing proportion of eyes remained in the driving standard, this was driven by better presenting VA over the decade. The number of injections decreased substantially between the first and subsequent years, from a mean of 6.25 in year 1 to 3 in year 2 and 2.5 in year 3, without improvement over the decade. In a multivariable regression analysis, final VA improved by 0.24 letters for each year since 2008, and younger age and baseline VA were significantly associated with VA at 3 years. CONCLUSIONS: Our findings show that despite improvement in functional VA over the years, primarily driven by improving baseline VA, patients continue to lose vision after the first year of treatment, with only marginal change over the past decade. The data suggest these results may be related to suboptimal treatment patterns, which have not improved over the years. Rethinking treatment strategies may be warranted, possibly on a national level or through the introduction of longer-acting therapies.

Quantification of Key Retinal Features in Early and Late Age-Related Macular Degeneration Using Deep Learning.

PURPOSE: We sought to develop and validate a deep learning model for segmentation of 13 features associated with neovascular and atrophic age-related macular degeneration (AMD). DESIGN: Development and validation of a deep-learning model for feature segmentation. METHODS: Data for model development were obtained from 307 optical coherence tomography volumes. Eight experienced graders manually delineated all abnormalities in 2712 B-scans. A deep neural network was trained with these data to perform voxel-level segmentation of the 13 most common abnormalities (features). For evaluation, 112 B-scans from 112 patients with a diagnosis of neovascular AMD were annotated by 4 independent observers. The main outcome measures were Dice score, intraclass correlation coefficient, and free-response receiver operating characteristic curve. RESULTS: On 11 of 13 features, the model obtained a mean Dice score of 0.63 ± 0.15, compared with 0.61 ± 0.17 for the observers. The mean intraclass correlation coefficient for the model was 0.66 ± 0.22, compared with 0.62 ± 0.21 for the observers. Two features were not evaluated quantitatively because of a lack of data. Free-response receiver operating characteristic analysis demonstrated that the model scored similar or higher sensitivity per false positives compared with the observers. CONCLUSIONS: The quality of the automatic segmentation matches that of experienced graders for most features, exceeding human performance for some features. The quantified parameters provided by the model can be used in the current clinical routine and open possibilities for further research into treatment response outside clinical trials.

Contextualizing single-arm trials with real-world data: An emulated target trial comparing therapies for neovascular age-related macular degeneration.

One-in-four ophthalmology trials are single-armed, which poses challenges to their interpretation. We demonstrate how real-world cohorts used as external/synthetic control arms can contextualize such trials. We herein emulated a target trial on the intention-to-treat efficacy of off-label bevacizumab (q6w) pro re nata relative to fixed-interval aflibercept (q8w) for improving week 54 visual acuity of eyes affected by neovascular age-related macular degeneration. The bevacizumab arm (n = 65) was taken from the ABC randomized controlled trial. A total of 4,471 aflibercept-treated eyes aligning with the ABC trial eligibility were identified from electronic health records and synthetic control arms were created by emulating randomization conditional on age, sex, and baseline visual read via exact matching and propensity score methods. We undertook an inferiority analysis on mean difference at 54 weeks; outcomes regression on achieving a change in visual acuity of greater than or equal to 15, greater than or equal to 10, and less than or equal to -15 Early Treatment Diabetic Retinopathy (ETDRS) letters at week 54; and a time-to-event analysis on achieving a change in visual acuity of greater than or equal to 15, greater than or equal to 10, and less than or equal to -15 ETDRS letters by week 54. The findings suggest off-label bevacizumab to be neither inferior nor superior to licensed aflibercept. Our study highlights how real-world cohorts representing the counterfactual intervention could aid the interpretation of single-armed trials when analyzed in accord to the target trial framework. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? One-in-four randomized controlled trials in ophthalmology are single-armed, which poses challenges for interpreting their efficacy relative to standard of care. Recent conceptual advances in the methods of causal inference and in the emulation of target trials suggests that the standard-of-care arms representing the counterfactual intervention can be approximated with observational data. WHAT QUESTION DID THIS STUDY ADDRESS? How real-world cohorts representing the counterfactual intervention can aid the interpretation of single-armed ophthalmological trials. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Our study highlights how real-world cohorts representing the counterfactual intervention could aid the interpretation of single-armed ophthalmological trials when undertaken in accord with the target trial framework. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? External counterfactual arms could reduce the time and cost to reach potential regulatory approval.

Widefield optical coherence tomography angiography for early detection and objective evaluation of proliferative diabetic retinopathy.

PURPOSE: To evaluate the utility of widefield optical coherence tomography angiography (WF-OCTA) compared with clinical examination in grading diabetic retinopathy in patients diagnosed clinically with proliferative diabetic retinopathy (PDR) or severe non-proliferative diabetic retinopathy (NPDR). DESIGN: This retrospective observational case series included patients diagnosed clinically with PDR or severe NPDR. Patients underwent standard clinical examination and WF-OCTA imaging (PLEX Elite 9000, Carl Zeiss Meditec AG) using 12×12 montage scans between August 2018 and January 2019. Two trained graders identified neovascularisation at the disc (NVD) and neovascularisation elsewhere (NVE) on WF-OCTA which were compared with the clinical examination, and to ultra-widefield fluorescein angiography (UWFA) when available. RESULTS: Seventy-nine eyes of 46 patients were evaluated. Of those, 57 eyes were diagnosed clinically with PDR, and 22 with severe NPDR. NVD was detected on OCTA-B scan as preretinal hyperreflective material (PRHM) in 39 eyes (100%) with evident flow signals in 79.5% compared with 51.3% detected clinically. We further classified NVD on OCTA into four subtypes and found that subtypes 1 and 2 could not be seen on clinical examination alone. WF-OCTA detected NVE in 81% of the cases compared with 55.7% detected clinically. Using WF-OCTA resulted in a higher percentage of PDR grading (88.6%) than on clinical examination (72.2%). When available, UWFA confirmed the WF-OCTA diagnosis in the majority of cases. CONCLUSION: This study demonstrates that WF-OCTA has a higher detection rate of PDR than clinical examination. This suggests that this modality could be used non-invasively for the purpose of early detection and characterisation of neovascularisation.