Study protocol: optical coherence tomography angiography for the detection of neovascular age-related macular degeneration: a comprehensive multicentre diagnostic accuracy study in the UK-the ATHENA study.

INTRODUCTION: The diagnosis of neovascular age-related macular degeneration (nAMD), the leading cause of visual impairment in the developed world, relies on the interpretation of various imaging tests of the retina. These include invasive angiographic methods, such as Fundus Fluorescein Angiography (FFA) and, on occasion, Indocyanine-Green Angiography (ICGA). Newer, non-invasive imaging modalities, predominately Optical Coherence Tomography (OCT) and Optical Coherence Tomography Angiography (OCTA), have drastically transformed the diagnostic approach to nAMD. The aim of this study is to undertake a comprehensive diagnostic accuracy assessment of the various imaging modalities used in clinical practice for the diagnosis of nAMD (OCT, OCTA, FFA and, when a variant of nAMD called Polypoidal Choroidal Vasculopathy is suspected, ICGA) both alone and in various combinations. METHODS AND ANALYSIS: This is a non-inferiority, prospective, randomised diagnostic accuracy study of 1067 participants. Participants are patients with clinical features consistent with nAMD who present to a National Health Service secondary care ophthalmology unit in the UK. Patients will undergo OCT as per standard practice and those with suspicious features of nAMD on OCT will be approached for participation in the study. Patients who agree to take part will also undergo both OCTA and FFA (and ICGA if indicated). Interpretation of the imaging tests will be undertaken by clinicians at recruitment sites. A randomised design was selected to avoid bias from consecutive review of all imaging tests by the same clinician. The primary outcome of the study will be the difference in sensitivity and specificity between OCT+OCTA and OCT+FFA (±ICGA) for nAMD detection as interpreted by clinicians at recruitment sites. ETHICS AND DISSEMINATION: The study has been approved by the South Central-Oxford B Research Ethics Committee with reference number 21/SC/0412.Dissemination of study results will involve peer-review publications, presentations at major national and international scientific conferences. TRIAL REGISTRATION NUMBER: ISRCTN18313457.

What are the experiences of teleophthalmology in optometric referral pathways? A qualitative interview study with patients and clinicians.

OBJECTIVE: Implementing teleophthalmology into the optometric referral pathway may ease the current pressures on hospital eye services caused by over-referrals from some optometrists. This study aimed to understand the practical implications of implementing teleophthalmology by analysing lived experiences and perceptions of teleophthalmology in the optometric referral pathway for suspected retinal conditions. DESIGN: Qualitative in-depth interview study SETTING: Fourteen primary care optometry practices and four secondary care hospital eye services from four NHS Foundation Trusts across the UK. PARTICIPANTS: We interviewed 41 participants: patients (17), optometrists (18), and ophthalmologists (6) who were involved in the HERMES study. Through thematic analysis, we collated and present their experiences of implementing teleophthalmology. RESULTS: All participants interviewed were positive towards teleophthalmology as it could enable efficiencies in the referral pathway and improve feedback and communication between patients and healthcare professionals. Concerns included setup costs for optometrists and anxieties from patients about not seeing an ophthalmologist face to face. However, reducing unnecessary visits and increasing the availability of resources and capacity were seen as significant benefits. CONCLUSIONS: Overall, we report positive experiences of implementing teleophthalmology into the optometric referral pathway for suspected retinal conditions. Successful implementation will require appropriate investment to set up and integrate new technology and remunerate services, and continued evaluation to ensure timely feedback to patients and between healthcare professionals is received. TRIAL REGISTRATION NUMBER: ISRCTN18106677.

Periodontitis and Outer Retinal Thickness: a Cross-Sectional Analysis of the United Kingdom Biobank Cohort.

Purpose: Periodontitis, a ubiquitous severe gum disease affecting the teeth and surrounding alveolar bone, can heighten systemic inflammation. We investigated the association between very severe periodontitis and early biomarkers of age-related macular degeneration (AMD), in individuals with no eye disease. Design: Cross-sectional analysis of the prospective community-based cohort United Kingdom (UK) Biobank. Participants: Sixty-seven thousand three hundred eleven UK residents aged 40 to 70 years recruited between 2006 and 2010 underwent retinal imaging. Methods: Macular-centered OCT images acquired at the baseline visit were segmented for retinal sublayer thicknesses. Very severe periodontitis was ascertained through a touchscreen questionnaire. Linear mixed effects regression modeled the association between very severe periodontitis and retinal sublayer thicknesses, adjusting for age, sex, ethnicity, socioeconomic status, alcohol consumption, smoking status, diabetes mellitus, hypertension, refractive error, and previous cataract surgery. Main Outcome Measures: Photoreceptor layer (PRL) and retinal pigment epithelium-Bruch's membrane (RPE-BM) thicknesses. Results: Among 36 897 participants included in the analysis, 1571 (4.3%) reported very severe periodontitis. Affected individuals were older, lived in areas of greater socioeconomic deprivation, and were more likely to be hypertensive, diabetic, and current smokers (all P < 0.001). On average, those with very severe periodontitis were hyperopic (0.05 ± 2.27 diopters) while those unaffected were myopic (-0.29 ± 2.40 diopters, P < 0.001). Following adjusted analysis, very severe periodontitis was associated with thinner PRL (-0.55 µm, 95% confidence interval [CI], -0.97 to -0.12; P = 0.022) but there was no difference in RPE-BM thickness (0.00 µm, 95% CI, -0.12 to 0.13; P = 0.97). The association between PRL thickness and very severe periodontitis was modified by age (P < 0.001). Stratifying individuals by age, thinner PRL was seen among those aged 60 to 69 years with disease (-1.19 µm, 95% CI, -1.85 to -0.53; P < 0.001) but not among those aged < 60 years. Conclusions: Among those with no known eye disease, very severe periodontitis is statistically associated with a thinner PRL, consistent with incipient AMD. Optimizing oral hygiene may hold additional relevance for people at risk of degenerative retinal disease. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Diagnostic decisions of specialist optometrists exposed to ambiguous deep-learning outputs.

Artificial intelligence (AI) has great potential in ophthalmology. We investigated how ambiguous outputs from an AI diagnostic support system (AI-DSS) affected diagnostic responses from optometrists when assessing cases of suspected retinal disease. Thirty optometrists (15 more experienced, 15 less) assessed 30 clinical cases. For ten, participants saw an optical coherence tomography (OCT) scan, basic clinical information and retinal photography ('no AI'). For another ten, they were also given AI-generated OCT-based probabilistic diagnoses ('AI diagnosis'); and for ten, both AI-diagnosis and AI-generated OCT segmentations ('AI diagnosis + segmentation') were provided. Cases were matched across the three types of presentation and were selected to include 40% ambiguous and 20% incorrect AI outputs. Optometrist diagnostic agreement with the predefined reference standard was lowest for 'AI diagnosis + segmentation' (204/300, 68%) compared to 'AI diagnosis' (224/300, 75% p = 0.010), and 'no Al' (242/300, 81%, p = < 0.001). Agreement with AI diagnosis consistent with the reference standard decreased (174/210 vs 199/210, p = 0.003), but participants trusted the AI more (p = 0.029) with segmentations. Practitioner experience did not affect diagnostic responses (p = 0.24). More experienced participants were more confident (p = 0.012) and trusted the AI less (p = 0.038). Our findings also highlight issues around reference standard definition.

Treatment of age-related macular degeneration with aflibercept using a treat, extend and fixed protocol; A 4-year study of treatment outcomes, durability, safety and quality of life (An extension to the MATE randomised controlled trial).

PURPOSE: Data are limited pertaining to the long-term benefits of aflibercept treatment for neovascular age-related macular degeneration (nAMD). The aim of this study was to provide outcomes, safety, durability and quality-of-life data with aflibercept using a modified treat, extend and fixed regime over 4 years. METHODS: Prospective, multicentre, single cohort observational study of treatment-naïve nAMD participants treated with aflibercept as 2-year extension of the MATE-trial that compared early and late Treat-and-Extend for 2 years. Refracted ETDRS best corrected visual acuity (BCVA), central retinal thickness (CRT), treatment interval and adverse events were assessed. Quality-of-life was measured using the Macular Disease Dependent Quality of Life (MacDQoL) and Macular Disease Treatment Satisfaction Questionnaires (MacTSQ). RESULTS: Twenty-six of 40 participants completing the MATE-trial were enrolled with 20 completing the total 4-year study. Mean BCVA was 60.7 at Month 0 and 64.8 ETDRS letters at Month 48 while CRT decreased from 423.7 µm to 292.2 µm. Five participants discontinued treatment due to inactivity. The mean number of treatments and visits for the remaining participants was 27 and 30.0, respectively, with treatment intervals extended to 12 weeks in four participants at Month 48. Both AMD-specific QoL and treatment satisfaction remained stable between Months 0 and 48 and mean BCVA significantly correlated with AMD-specific QoL scores at Months 12, 24 and 48. CONCLUSIONS: Results suggest that BCVA can be maintained over 48 months when following a treat-extend-and-fix regimen of aflibercept with intervals out to 12 weeks, while maintaining AMD-specific QoL and treatment satisfaction.

The effectiveness of interventions for optometric referrals into the hospital eye service: A review.

PURPOSE: Ophthalmic services are currently under considerable stress; in the UK, ophthalmology departments have the highest number of outpatient appointments of any department within the National Health Service. Recognising the need for intervention, several approaches have been trialled to tackle the high numbers of false-positive referrals initiated in primary care and seen face to face within the hospital eye service (HES). In this mixed-methods narrative synthesis, we explored interventions based on their clinical impact, cost and acceptability to determine whether they are clinically effective, safe and sustainable. A systematic literature search of PubMed, MEDLINE and CINAHL, guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), was used to identify appropriate studies published between December 2001 and December 2022. RECENT FINDINGS: A total of 55 studies were reviewed. Four main interventions were assessed, where two studies covered more than one type: training and guidelines (n = 8), referral filtering schemes (n = 32), asynchronous teleophthalmology (n = 13) and synchronous teleophthalmology (n = 5). All four approaches demonstrated effectiveness for reducing false-positive referrals to the HES. There was sufficient evidence for stakeholder acceptance and cost-effectiveness of referral filtering schemes; however, cost comparisons involved assumptions. Referral filtering and asynchronous teleophthalmology reported moderate levels of false-negative cases (2%-20%), defined as discharged patients requiring HES monitoring. SUMMARY: The effectiveness of interventions varied depending on which outcome and stakeholder was considered. More studies are required to explore stakeholder opinions around all interventions. In order to maximise clinical safety, it may be appropriate to combine more than one approach, such as referral filtering schemes with virtual review of discharged patients to assess the rate of false-negative cases. The implementation of a successful intervention is more complex than a 'one-size-fits-all' approach and there is potential space for newer types of interventions, such as artificial intelligence clinical support systems within the referral pathway.

Home vision monitoring in patients with maculopathy: current and future options for digital technologies.

Patients with macular pathology, including that caused by age-related macular degeneration and diabetic macular oedema, must attend frequent in-clinic monitoring appointments to detect onset of disease activity requiring treatment and to monitor progression of existing disease. In-person clinical monitoring places a significant burden on patients, caregivers and healthcare systems and is limited in that it only provides clinicians with a snapshot of the patient's disease status. The advent of remote monitoring technologies offers the potential for patients to test their own retinal health at home in collaboration with clinicians, reducing the need for in-clinic appointments. In this review we discuss visual function tests, both existing and novel, that have the potential for remote use and consider their suitability for discriminating the presence of disease and progression of disease. We then review the clinical evidence supporting the use of mobile applications for monitoring of visual function from clinical development through to validation studies and real-world implementation. This review identified seven app-based visual function tests: four that have already received some form of regulatory clearance and three under development. The evidence included in this review shows that remote monitoring offers great potential for patients with macular pathology to monitor their condition from home, reducing the need for burdensome clinic visits and expanding clinicians' understanding of patients' retinal health beyond traditional clinical monitoring. In order to instil confidence in the use of remote monitoring in both patients and clinicians further longitudinal real-world studies are now warranted.

Safety and efficacy of an artificial intelligence-enabled decision tool for treatment decisions in neovascular age-related macular degeneration and an exploration of clinical pathway integration and implementation: protocol for a multi-methods validation study.

INTRODUCTION: Neovascular age-related macular degeneration (nAMD) management is one of the largest single-disease contributors to hospital outpatient appointments. Partial automation of nAMD treatment decisions could reduce demands on clinician time. Established artificial intelligence (AI)-enabled retinal imaging analysis tools, could be applied to this use-case, but are not yet validated for it. A primary qualitative investigation of stakeholder perceptions of such an AI-enabled decision tool is also absent. This multi-methods study aims to establish the safety and efficacy of an AI-enabled decision tool for nAMD treatment decisions and understand where on the clinical pathway it could sit and what factors are likely to influence its implementation. METHODS AND ANALYSIS: Single-centre retrospective imaging and clinical data will be collected from nAMD clinic visits at a National Health Service (NHS) teaching hospital ophthalmology service, including judgements of nAMD disease stability or activity made in real-world consultant-led-care. Dataset size will be set by a power calculation using the first 127 randomly sampled eligible clinic visits. An AI-enabled retinal segmentation tool and a rule-based decision tree will independently analyse imaging data to report nAMD stability or activity for each of these clinic visits. Independently, an external reading centre will receive both clinical and imaging data to generate an enhanced reference standard for each clinic visit. The non-inferiority of the relative negative predictive value of AI-enabled reports on disease activity relative to consultant-led-care judgements will then be tested. In parallel, approximately 40 semi-structured interviews will be conducted with key nAMD service stakeholders, including patients. Transcripts will be coded using a theoretical framework and thematic analysis will follow. ETHICS AND DISSEMINATION: NHS Research Ethics Committee and UK Health Research Authority approvals are in place (21/NW/0138). Informed consent is planned for interview participants only. Written and oral dissemination is planned to public, clinical, academic and commercial stakeholders.

Biomarkers of macular neovascularisation activity using optical coherence tomography angiography in treated stable neovascular age related macular degeneration.

BACKGROUND: The aim of this study was to describe features of disease activity in patients with treated stable macular neovascularisation (MNV) in neovascular age related macular degeneration (nAMD) using optical coherence tomography angiography (OCTA). METHODS: Thirty-two eyes of 32 patients with nAMD were included in this prospective, observational study. These patients were undergoing treatment with aflibercept on a treat-and-extend regimen attending an extension to a 12-week treatment interval. RESULTS: All subjects had no macular haemorrhage and no structural OCT markers of active MNV activity at the index 12-week treatment extension visit. 31/32 OCTA images were gradeable without significant imaging artefact. The mean MNV size was 3.6mm2 ± 4.6mm2 and 27 (87.1%) had detectable MNV blood flow. 29/31 (93.5%) subjects had MNV with mature phenotypes including 10 non-specific, 10 tangle and 3 deadtree phenotypes. MNV halo and MNV central feeder vessel were noted in 18 (58.1%) and 19 (61.3%) of subjects respectively; only 1 (3.2%) subject was noted to have a MNV capillary fringe. CONCLUSIONS: MNV blood flow is still detectable using OCTA in the majority of subjects in this study with treated stable MNV. OCTA features associated included MNV mature phenotype, MNV feeder vessel, MNV halo and absence of capillary fringe.

Protocol for a qualitative study to explore acceptability, barriers and facilitators of the implementation of new teleophthalmology technologies between community optometry practices and hospital eye services.

INTRODUCTION: Novel teleophthalmology technologies have the potential to reduce unnecessary and inaccurate referrals between community optometry practices and hospital eye services and as a result improve patients' access to appropriate and timely eye care. However, little is known about the acceptability and facilitators and barriers to the implementations of these technologies in real life. METHODS AND ANALYSIS: A theoretically informed, qualitative study will explore patients' and healthcare professionals' perspectives on teleophthalmology and Artificial Intelligence Decision Support System models of care. A combination of situated observations in community optometry practices and hospital eye services, semistructured qualitative interviews with patients and healthcare professionals and self-audiorecordings of healthcare professionals will be conducted. Participants will be purposively selected from 4 to 5 hospital eye services and 6-8 affiliated community optometry practices. The aim will be to recruit 30-36 patients and 30 healthcare professionals from hospital eye services and community optometry practices. All interviews will be audiorecorded, with participants' permission, and transcribed verbatim. Data from interviews, observations and self-audiorecordings will be analysed thematically and will be informed by normalisation process theory and an inductive approach. ETHICS AND DISSEMINATION: Ethical approval has been received from London-Bromley research ethics committee. Findings will be reported through academic journals and conferences in ophthalmology, health services research, management studies and human-computer interaction.

Personalized Model to Predict Keratoconus Progression From Demographic, Topographic, and Genetic Data.

PURPOSE: To generate a prognostic model to predict keratoconus progression to corneal crosslinking (CXL). DESIGN: Retrospective cohort study. METHODS: We recruited 5025 patients (9341 eyes) with early keratoconus between January 2011 and November 2020. Genetic data from 926 patients were available. We investigated both keratometry or CXL as end points for progression and used the Royston-Parmar method on the proportional hazards scale to generate a prognostic model. We calculated hazard ratios (HRs) for each significant covariate, with explained variation and discrimination, and performed internal-external cross validation by geographic regions. RESULTS: After exclusions, model fitting comprised 8701 eyes, of which 3232 underwent CXL. For early keratoconus, CXL provided a more robust prognostic model than keratometric progression. The final model explained 33% of the variation in time to event: age HR (95% CI) 0.9 (0.90-0.91), maximum anterior keratometry 1.08 (1.07-1.09), and minimum corneal thickness 0.95 (0.93-0.96) as significant covariates. Single-nucleotide polymorphisms (SNPs) associated with keratoconus (n=28) did not significantly contribute to the model. The predicted time-to-event curves closely followed the observed curves during internal-external validation. Differences in discrimination between geographic regions was low, suggesting the model maintained its predictive ability. CONCLUSIONS: A prognostic model to predict keratoconus progression could aid patient empowerment, triage, and service provision. Age at presentation is the most significant predictor of progression risk. Candidate SNPs associated with keratoconus do not contribute to progression risk.

Long-term Retinal Morphology and Functional Associations in Treated Neovascular Age-Related Macular Degeneration: Findings from the Inhibition of VEGF in Age-Related Choroidal Neovascularisation Trial.

PURPOSE: To describe the frequency of long-term morphologic features and their relationships with visual function in participants who exited the Inhibition of VEGF in Age-Related Choroidal Neovascularisation (IVAN; ISRCTN92166560) trial. DESIGN: Multicenter cohort study up to 7 years after enrollment. PARTICIPANTS: Patients enrolled in the IVAN trial, excluding participants who died or withdrew during the trial. METHODS: Multimodal fundus images, best-corrected visual acuity (BCVA), and low-luminance visual acuity (LLVA) were obtained for a subset of 199 participants who attended a research visit. Clinical sites (n = 20) also provided all visual acuity and clinical information from usual care records for 532 participants and submitted the most recent color, OCT, and other fundus images for 468 participants to a reading center. MAIN OUTCOME MEASURES: Assessed the following from the most recent images: intralesional macular atrophy (ILMA) within the footprint of the neovascular lesion; hyperreflective material (HRM); intraretinal fluid (IRF); subretinal fluid (SRF); pigment epithelial detachment (PED); and disorganized retinal outer layers (DROLs). Cross-sectional relationships between morphologic features and BCVA/LLVA were estimated. RESULTS: Intralesional macular atrophy was present in 31.8% of the study eyes at IVAN exit (mean follow-up, 1.96 years) and 89.5% at the most recent imaging visit (mean follow-up, 6.18 years). Hyperreflective material, IRF, SRF, PED, and DROLs were present in 78.8%, 47.7%, 7.6%, 94.5%, and 55% of the study eyes, respectively. In the subset with complete imaging data, in eyes without DROL, the BCVA was worst in the thinnest outer fovea tertile (thinnest minus middle and thickest tertiles, -19.7 and -19.5 letters, respectively), whereas in eyes with DROL, the BCVA was worst in the thickest (thinnest and middle tertiles minus thickest, 12.5 and 12.2, respectively). Regression models showed that the presence of ILMA and HRM was independently associated with BCVA (22 letters worse [95% confidence interval {CI}, -11.2 to -32.8; P < 0.001] and 9.8 letters worse [95% CI, -0.1 to -19.4; P = 0.047], respectively). Subretinal fluid and foveal PED were associated with better BCVA (5.9 letters [95% CI, -7.9 to 19.7; P = 0.399] and 6.4 letters [95% CI, -1.1 to 14.0; P = 0.094], respectively). The model with LLVA was similar. A sensitivity analysis involving the entire eligible cohort yielded similar estimates. CONCLUSIONS: Macular atrophy and HRM were common after 7 years of follow-up and strongly associated with visual outcomes.

Teleophthalmology-enabled and artificial intelligence-ready referral pathway for community optometry referrals of retinal disease (HERMES): a Cluster Randomised Superiority Trial with a linked Diagnostic Accuracy Study-HERMES study report 1-study protocol.

INTRODUCTION: Recent years have witnessed an upsurge of demand in eye care services in the UK. With a large proportion of patients referred to Hospital Eye Services (HES) for diagnostics and disease management, the referral process results in unnecessary referrals from erroneous diagnoses and delays in access to appropriate treatment. A potential solution is a teleophthalmology digital referral pathway linking community optometry and HES. METHODS AND ANALYSIS: The HERMES study (Teleophthalmology-enabled and artificial intelligence-ready referral pathway for community optometry referrals of retinal disease: a cluster randomised superiority trial with a linked diagnostic accuracy study) is a cluster randomised clinical trial for evaluating the effectiveness of a teleophthalmology referral pathway between community optometry and HES for retinal diseases. Nested within HERMES is a diagnostic accuracy study, which assesses the accuracy of an artificial intelligence (AI) decision support system (DSS) for automated diagnosis and referral recommendation. A postimplementation, observational substudy, a within-trial economic evaluation and discrete choice experiment will assess the feasibility of implementation of both digital technologies within a real-life setting. Patients with a suspicion of retinal disease, undergoing eye examination and optical coherence tomography (OCT) scans, will be recruited across 24 optometry practices in the UK. Optometry practices will be randomised to standard care or teleophthalmology. The primary outcome is the proportion of false-positive referrals (unnecessary HES visits) in the current referral pathway compared with the teleophthalmology referral pathway. OCT scans will be interpreted by the AI DSS, which provides a diagnosis and referral decision and the primary outcome for the AI diagnostic study is diagnostic accuracy of the referral decision made by the Moorfields-DeepMind AI system. Secondary outcomes relate to inappropriate referral rate, cost-effectiveness analyses and human-computer interaction (HCI) analyses. ETHICS AND DISSEMINATION: Ethical approval was obtained from the London-Bromley Research Ethics Committee (REC 20/LO/1299). Findings will be reported through academic journals in ophthalmology, health services research and HCI. TRIAL REGISTRATION NUMBER: ISRCTN18106677 (protocol V.1.1).

Evaluating an automated machine learning model that predicts visual acuity outcomes in patients with neovascular age-related macular degeneration.

PURPOSE: Neovascular age-related macular degeneration (nAMD) is a major global cause of blindness. Whilst anti-vascular endothelial growth factor (anti-VEGF) treatment is effective, response varies considerably between individuals. Thus, patients face substantial uncertainty regarding their future ability to perform daily tasks. In this study, we evaluate the performance of an automated machine learning (AutoML) model which predicts visual acuity (VA) outcomes in patients receiving treatment for nAMD, in comparison to a manually coded model built using the same dataset. Furthermore, we evaluate model performance across ethnic groups and analyse how the models reach their predictions. METHODS: Binary classification models were trained to predict whether patients' VA would be 'Above' or 'Below' a score of 70 one year after initiating treatment, measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. The AutoML model was built using the Google Cloud Platform, whilst the bespoke model was trained using an XGBoost framework. Models were compared and analysed using the What-if Tool (WIT), a novel model-agnostic interpretability tool. RESULTS: Our study included 1631 eyes from patients attending Moorfields Eye Hospital. The AutoML model (area under the curve [AUC], 0.849) achieved a highly similar performance to the XGBoost model (AUC, 0.847). Using the WIT, we found that the models over-predicted negative outcomes in Asian patients and performed worse in those with an ethnic category of Other. Baseline VA, age and ethnicity were the most important determinants of model predictions. Partial dependence plot analysis revealed a sigmoidal relationship between baseline VA and the probability of an outcome of 'Above'. CONCLUSION: We have described and validated an AutoML-WIT pipeline which enables clinicians with minimal coding skills to match the performance of a state-of-the-art algorithm and obtain explainable predictions.

Intravitreal injections: past trends and future projections within a UK tertiary hospital.

AIMS: To describe past trends and future projections for the number of intravitreal injections being administered at a large tertiary hospital in London, United Kingdom. METHODS: Retrospective data from Moorfields Eye Hospital were collected using the electronic medical record system. Descriptive statistics were used to visualise overall trends. Time series forecasting was used to predict the number of injections that will be administered up to and including the year 2029. RESULTS: The number of injections has increased nearly 11-fold from 2009 to 2019, with a total of 44,924 injections delivered in 2019. The majority of injections were given for the treatment of neovascular age-related macular degeneration. Aflibercept formed 87% of injections administered in 2019. The number of injections is predicted to continue to increase every year, with nearly 83,000 injections forecasted in the year 2029. CONCLUSION: The demand for intravitreal injections has increased substantially over the last decade and is predicted to further increase. Healthcare systems will need to adapt to accommodate the high demand. Other solutions may include longer-acting therapies to reduce the treatment burden.

Prospective validation of a virtual clinic pathway in the management of choroidal naevi: the NAEVUS study Report no. 1: safety assessment.

BACKGROUND: Choroidal naevi are a common incidental finding prompting specialist referrals to ocular oncology. Rarely, such lesions have sufficient suspicious features to diagnose a small melanoma. The aim of the study is to show that 'virtual' imaging-based pathways are a safe and efficient option to manage such referrals. METHODS: A prospective cohort study at the Manchester Royal Eye Hospital and Moorfields Eye Hospital between June 2016 and July 2017 of the management decision of 400 patients reviewed by an ophthalmologist in a face-to-face consultation (gold standard) supported by fundus photography, optical coherence tomography, autofluorescence (AF) and B-mode ultrasound. The images were also read independently by blinded graders (non-medical) and blinded ophthalmologists, and a management decision was made based on image review alone (virtual pathway). The two pathways were compared for safety. RESULTS: The agreement for management decisions between face-to-face and virtual pathways was 83.1% (non-medical) and 82.6% (medical). There were more over-referrals in the virtual pathway (non-medical 24.3%, medical 23.3% of gold standard discharge) and only two under-referrals (10.5% of gold standard referrals), both borderline cases with minimal clinical risk. The agreement for risk factors of growth (orange pigment, subretinal fluid, hyper-AF) ranged between 82.3% and 97.3%. CONCLUSIONS: We prospectively validated a virtual clinic model for the safe management of choroidal naevi. Such a model of care is feasible with low rate of under-referral. An over-referral rate of almost 24% from the vitrual pathway needs to be factored into designing such pathways in conjunction with evidence on their cost-effectiveness.

Validation and Clinical Applicability of Whole-Volume Automated Segmentation of Optical Coherence Tomography in Retinal Disease Using Deep Learning.

IMPORTANCE: Quantitative volumetric measures of retinal disease in optical coherence tomography (OCT) scans are infeasible to perform owing to the time required for manual grading. Expert-level deep learning systems for automatic OCT segmentation have recently been developed. However, the potential clinical applicability of these systems is largely unknown. OBJECTIVE: To evaluate a deep learning model for whole-volume segmentation of 4 clinically important pathological features and assess clinical applicability. DESIGN, SETTING, PARTICIPANTS: This diagnostic study used OCT data from 173 patients with a total of 15 558 B-scans, treated at Moorfields Eye Hospital. The data set included 2 common OCT devices and 2 macular conditions: wet age-related macular degeneration (107 scans) and diabetic macular edema (66 scans), covering the full range of severity, and from 3 points during treatment. Two expert graders performed pixel-level segmentations of intraretinal fluid, subretinal fluid, subretinal hyperreflective material, and pigment epithelial detachment, including all B-scans in each OCT volume, taking as long as 50 hours per scan. Quantitative evaluation of whole-volume model segmentations was performed. Qualitative evaluation of clinical applicability by 3 retinal experts was also conducted. Data were collected from June 1, 2012, to January 31, 2017, for set 1 and from January 1 to December 31, 2017, for set 2; graded between November 2018 and January 2020; and analyzed from February 2020 to November 2020. MAIN OUTCOMES AND MEASURES: Rating and stack ranking for clinical applicability by retinal specialists, model-grader agreement for voxelwise segmentations, and total volume evaluated using Dice similarity coefficients, Bland-Altman plots, and intraclass correlation coefficients. RESULTS: Among the 173 patients included in the analysis (92 [53%] women), qualitative assessment found that automated whole-volume segmentation ranked better than or comparable to at least 1 expert grader in 127 scans (73%; 95% CI, 66%-79%). A neutral or positive rating was given to 135 model segmentations (78%; 95% CI, 71%-84%) and 309 expert gradings (2 per scan) (89%; 95% CI, 86%-92%). The model was rated neutrally or positively in 86% to 92% of diabetic macular edema scans and 53% to 87% of age-related macular degeneration scans. Intraclass correlations ranged from 0.33 (95% CI, 0.08-0.96) to 0.96 (95% CI, 0.90-0.99). Dice similarity coefficients ranged from 0.43 (95% CI, 0.29-0.66) to 0.78 (95% CI, 0.57-0.85). CONCLUSIONS AND RELEVANCE: This deep learning-based segmentation tool provided clinically useful measures of retinal disease that would otherwise be infeasible to obtain. Qualitative evaluation was additionally important to reveal clinical applicability for both care management and research.

FENETRE study: quality-assured follow-up of quiescent neovascular age-related macular degeneration by non-medical practitioners: study protocol and statistical analysis plan for a randomised controlled trial.

OBJECTIVE: Management of age-related macular degeneration (AMD) places a high demand on already constrained hospital-based eye services. This study aims to assess the safety and quality of follow-up within the community led by suitably trained non-medical practitioners for the management of quiescent neovascular AMD (QnAMD). METHODS/DESIGN: This is a prospective, multisite, randomised clinical trial. 742 participants with QnAMD will be recruited and randomised to either continue hospital-based secondary care or to receive follow-up within a community setting. Participants in both groups will be monitored for disease reactivation over the course of 12 months and referred for treatment as necessary. Outcomes measures will assess the non-inferiority of primary care follow-up accounting for accuracy of the identification of disease reactivation, patient loss to follow-up and accrued costs and the budget impact to the National Health Service. ETHICS AND DISSEMINATION: Research ethics approval was obtained from the London Bloomsbury Ethics Committee. The results of this study will be disseminated through academic peer-reviewed publications, conferences and collaborations with eye charities to insure the findings reach the appropriate patient populations. TRIAL REGISTRATION NUMBER: NCT03893474.

Fundus Autofluorescence Imaging in Macular Telangiectasia Type 2: MacTel Study Report Number 9.

PURPOSE: To investigate the role of fundus autofluorescence (FAF) imaging in the diagnosis of macular telangiectasia type 2 (MacTel) and to describe disease-associated FAF patterns and their origin. DESIGN: Cross-sectional multicenter study METHODS: FAF images were collected from the multicenter MacTel Natural History Observation and Registry Study. In a first qualitative approach, common FAF phenotypes were defined and correlated with multimodal imaging. We then evaluated how many eyes showed FAF changes, and temporal vs nasal asymmetry of FAF changes was graded. Finally, 100 eyes of MacTel patients and 100 control eyes (50 normal eyes and 50 eyes with other macular diseases) were combined and 2 masked graders assessed the presence of MacTel based on FAF images alone. RESULTS: The study included 807 eyes of 420 patients (33 eyes were excluded owing to poor image quality). Loss of macular pigment, cystoid spaces, pigment plaques, neovascular membranes, and ectatic vascular changes commonly caused characteristic changes on FAF images. All MacTel patients had macular FAF changes in at least 1 eye. In 95% of eyes, these changes were more pronounced temporally than nasally. Common FAF patterns were increased (60%) and mixed/decreased FAF (38%) and/or visibility of vascular changes such as blunted vessels or ectatic capillaries (79%). Based on those features, high diagnostic performance was achieved for detection of the disease based on FAF alone (Youden index up to 0.91). CONCLUSIONS: The study demonstrates that MacTel is consistently associated with disease-specific changes on FAF imaging. Those changes are typically more pronounced in the temporal parafovea.

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.