A Deep Learning Model for Segmentation of Geographic Atrophy to Study Its Long-Term Natural History

__Purpose:__ To develop and validate a deep learning model for the automatic segmentation of geographic atrophy (GA) using color fundus images (CFIs) and its application to study the growth rate of GA. __Design:__ Prospective, multicenter, natural history study with up to 15 years of follow-up. __Participants:__ Four hundred nine CFIs of 238 eyes with GA from the Rotterdam Study (RS) and Blue Mountain Eye Study (BMES) for model development, and 3589 CFIs of 376 eyes from the Age-Related Eye Disease Study (AREDS) for analysis of GA growth rate. __Methods:__ A deep learning model based on an ensemble of encoder–decoder architectures was implemented and optimized for the segmentation of GA in CFIs. Four experienced graders delineated, in consensus, GA in CFIs from the RS and BMES. These manual delineations were used to evaluate the segmentation model using 5-fold cross-validation. The model was applied further to CFIs from the AREDS to study the growth rate of GA. Linear regression analysis was used to study associations between structural biomarkers at baseline and the GA growth rate. A general estimate of the progression of GA area over time was made by combining growth rates of all eyes with GA from the AREDS set. __Main Outcome Measures:__ Automatically segmented GA and GA growth rate. __Results:__ The model obtained an average Dice coefficient of 0.72±0.26 on the BMES and RS set while comparing the automatically segmented GA area with the graders’ manual delineations. An intraclass correlation coefficient of 0.83 was reached between the automatically estimated GA area and the graders’ consensus measures. Nine automatically calculated structural biomarkers (area, filled area, convex area, convex solidity, eccentricity, roundness, foveal involvement, perimeter, and circularity) were significantly associated with growth rate. Combining all growth rates indicated that GA area grows quadratically up to an area of approximately 12 mm2, after which growth rate stabilizes or decreases. __Conclusions:__ The deep learning model allowed for fully automatic and robust segmentation of GA on CFIs. These segmentations can be used to extract structural characteristics of GA that predict its growth rate

Detection of macular atrophy in age-related macular degeneration aided by artificial intelligence

INTRODUCTION: Age-related macular degeneration (AMD) is a leading cause of irreversible visual impairment worldwide. The endpoint of AMD, both in its dry or wet form, is macular atrophy (MA) which is characterized by the permanent loss of the RPE and overlying photoreceptors either in dry AMD or in wet AMD. A recognized unmet need in AMD is the early detection of MA development. AREAS COVERED: Artificial Intelligence (AI) has demonstrated great impact in detection of retinal diseases, especially with its robust ability to analyze big data afforded by ophthalmic imaging modalities, such as color fundus photography (CFP), fundus autofluorescence (FAF), near-infrared reflectance (NIR), and optical coherence tomography (OCT). Among these, OCT has been shown to have great promise in identifying early MA using the new criteria in 2018. EXPERT OPINION: There are few studies in which AI-OCT methods have been used to identify MA; however, results are very promising when compared to other imaging modalities. In this paper, we review the development and advances of ophthalmic imaging modalities and their combination with AI technology to detect MA in AMD. In addition, we emphasize the application of AI-OCT as an objective, cost-effective tool for the early detection and monitoring of the progression of MA in AMD

Detection of macular atrophy in age-related macular degeneration aided by artificial intelligence

INTRODUCTION: Age-related macular degeneration (AMD) is a leading cause of irreversible visual impairment worldwide. The endpoint of AMD, both in its dry or wet form, is macular atrophy (MA) which is characterized by the permanent loss of the RPE and overlying photoreceptors either in dry AMD or in wet AMD. A recognized unmet need in AMD is the early detection of MA development. AREAS COVERED: Artificial Intelligence (AI) has demonstrated great impact in detection of retinal diseases, especially with its robust ability to analyze big data afforded by ophthalmic imaging modalities, such as color fundus photography (CFP), fundus autofluorescence (FAF), near-infrared reflectance (NIR), and optical coherence tomography (OCT). Among these, OCT has been shown to have great promise in identifying early MA using the new criteria in 2018. EXPERT OPINION: There are few studies in which AI-OCT methods have been used to identify MA; however, results are very promising when compared to other imaging modalities. In this paper, we review the development and advances of ophthalmic imaging modalities and their combination with AI technology to detect MA in AMD. In addition, we emphasize the application of AI-OCT as an objective, cost-effective tool for the early detection and monitoring of the progression of MA in AMD

Learning Spatio-Temporal Model of Disease Progression with NeuralODEs from Longitudinal Volumetric Data

Robust forecasting of the future anatomical changes inflicted by an ongoing disease is an extremely challenging task that is out of grasp even for experienced healthcare professionals. Such a capability, however, is of great importance since it can improve patient management by providing information on the speed of disease progression already at the admission stage, or it can enrich the clinical trials with fast progressors and avoid the need for control arms by the means of digital twins. In this work, we develop a deep learning method that models the evolution of age-related disease by processing a single medical scan and providing a segmentation of the target anatomy at a requested future point in time. Our method represents a time-invariant physical process and solves a large-scale problem of modeling temporal pixel-level changes utilizing NeuralODEs. In addition, we demonstrate the approaches to incorporate the prior domain-specific constraints into our method and define temporal Dice loss for learning temporal objectives. To evaluate the applicability of our approach across different age-related diseases and imaging modalities, we developed and tested the proposed method on the datasets with 967 retinal OCT volumes of 100 patients with Geographic Atrophy, and 2823 brain MRI volumes of 633 patients with Alzheimer's Disease. For Geographic Atrophy, the proposed method outperformed the related baseline models in the atrophy growth prediction. For Alzheimer's Disease, the proposed method demonstrated remarkable performance in predicting the brain ventricle changes induced by the disease, achieving the state-of-the-art result on TADPOLE challenge

Deep learning in ophthalmology: The technical and clinical considerations

The advent of computer graphic processing units, improvement in mathematical models and availability of big data has allowed artificial intelligence (AI) using machine learning (ML) and deep learning (DL) techniques to achieve robust performance for broad applications in social-media, the internet of things, the automotive industry and healthcare. DL systems in particular provide improved capability in image, speech and motion recognition as well as in natural language processing. In medicine, significant progress of AI and DL systems has been demonstrated in image-centric specialties such as radiology, dermatology, pathology and ophthalmology. New studies, including pre-registered prospective clinical trials, have shown DL systems are accurate and effective in detecting diabetic retinopathy (DR), glaucoma, age-related macular degeneration (AMD), retinopathy of prematurity, refractive error and in identifying cardiovascular risk factors and diseases, from digital fundus photographs. There is also increasing attention on the use of AI and DL systems in identifying disease features, progression and treatment response for retinal diseases such as neovascular AMD and diabetic macular edema using optical coherence tomography (OCT). Additionally, the application of ML to visual fields may be useful in detecting glaucoma progression. There are limited studies that incorporate clinical data including electronic health records, in AL and DL algorithms, and no prospective studies to demonstrate that AI and DL algorithms can predict the development of clinical eye disease. This article describes global eye disease burden, unmet needs and common conditions of public health importance for which AI and DL systems may be applicable. Technical and clinical aspects to build a DL system to address those needs, and the potential challenges for clinical adoption are discussed. AI, ML and DL will likely play a crucial role in clinical ophthalmology practice, with implications for screening, diagnosis and follow up of the major causes of vision impairment in the setting of ageing populations globally

Identification of Surrogate Anatomic Identifiers of Disease Progression in Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is the leading cause of vision loss in patients over 50 in the developed world. The visual impairment is due to either choroidal neovascularisation (wet AMD) or geographic atrophy (GA). Drusen is the hallmark of AMD but the presence of drusen does not inform progression to wet AMD. Although the disease is mostly bilateral, the rate of progression of disease in both eyes may not be simultaneous. If one eye is affected by wet AMD, the risk of progression of the fellow eye to wet AMD increases by 10% every year. However, there are no markers that inform the time of conversion to wet AMD. For this reason, there is an unmet need to identify biomarkers that can fully predict the progression to wet AMD in order to allow early intervention before permanent damage. My thesis aimed to assess whether changes in imaging characteristics can more precisely explain conversion. I studied various cohorts including (a) normal aging eyes (b) eyes with early/ intermediate AMD and (c) fellow eyes of unilateral wet AMD to study the conversion to wet AMD. Firstly, I evaluated longitudinally volume changes in inner and outer retinal layers of 71 eyes with early/intermediate AMD using optical coherence tomography (OCT). Our results showed that inner and outer retina layer volumes may differentiate AMD eyes from healthy eyes. When comparing those who progressed to wet AMD at year 2 to those who did not, we found that baseline volume of GCIPL may differentiate between the 2 groups. As it is an inner retinal change, I hypothesized that heritability of the retinal layers may influence the rate of retinal layer changes and that may in turn help understand the changes seen in aging and AMD. I worked with the TWIN Study database, in which OCT was done in eyes of twins of different age groups and OCT data were available on 364 eyes of 184 (92 pair) twins. I evaluated whether heritability was responsible for ageing changes of the retinal layers. I found that total retinal volume and inner retinal layer volumes may be affected by genetic factors

Evaluating the Effects of C3 Inhibition on Geographic Atrophy Progression from Deep-Learning OCT Quantification:A Split-Person Study

Introduction: To evaluate the effect pegcetacoplan, a C3 and C3b inhibitor, on the rate of progression of geographic atrophy (GA) as assessed by spectral domain optical coherence tomography (SD-OCT) using a split-person study design and deep-learning quantification. Methods: A post hoc analysis of phase 2 FILLY trial data comparing study (treated monthly, treated every other month and sham-treated) and fellow (untreated) eyes in a split-person study design was performed. This analysis included 288 eyes from 144 patients with bilateral GA from the FILLY phase 2 trial (Clinical Trials identifier: NCT02503332). Only patients with bilateral GA and without evidence of choroidal neovascularisation in either eye were included. Patient study eyes were treated with sham injections or with pegcetacoplan monthly (PM) or every other month (PEOM) for 12 months. SD-OCT scans of study and fellow eyes taken at baseline and 12 months were used for the analysis. The main outcomes were the annual change in the area of retinal pigment epithelial and outer retinal atrophy (RORA), its constituent features (photoreceptor degeneration [PRD], retinal pigment epithelium [RPE] loss, hypertransmission) and intact macula as compared to the untreated fellow eye. Results: Annual GA growth was reduced in eyes treated with PM versus untreated fellow eyes for OCT features, including RORA (study eye 0.792 vs. fellow eye 1.13 mm2; P = 0.003), PRD (0.739 vs. 1.23 mm2; P = 0.015), RPE-loss (0.789 vs. 1.17 mm2; P = 0.007) and intact macula (− 0.735 vs. − 1.29 mm2; P = 0.011). Similar (but not statistically significant) trends were observed with the PEOM treatment or when GA was quantified with fundus autofluorescence (FAF). The sham treatment demonstrated no effect. Pearson correlation coefficients showed concordance in the enlargement rate of GA between the study and fellow eyes in the sham (R = 0.64) and PEOM (R = 0.68) groups, but not in the PM group (R = 0.21). Conclusions: Pegcetacoplan-treated eyes demonstrated a reduction in spatial GA progression compared to their untreated counterparts. This effect was more evident on OCT than with FAF. Trial Registration: Clinical Trials identifier: NCT02503332.</p

Evaluating the Effects of C3 Inhibition on Geographic Atrophy Progression from Deep-Learning OCT Quantification: A Split-Person Study

INTRODUCTION: To evaluate the effect pegcetacoplan, a C3 and C3b inhibitor, on the rate of progression of geographic atrophy (GA) as assessed by spectral domain optical coherence tomography (SD-OCT) using a split-person study design and deep-learning quantification. METHODS: A post hoc analysis of phase 2 FILLY trial data comparing study (treated monthly, treated every other month and sham-treated) and fellow (untreated) eyes in a split-person study design was performed. This analysis included 288 eyes from 144 patients with bilateral GA from the FILLY phase 2 trial (Clinical Trials identifier: NCT02503332). Only patients with bilateral GA and without evidence of choroidal neovascularisation in either eye were included. Patient study eyes were treated with sham injections or with pegcetacoplan monthly (PM) or every other month (PEOM) for 12 months. SD-OCT scans of study and fellow eyes taken at baseline and 12 months were used for the analysis. The main outcomes were the annual change in the area of retinal pigment epithelial and outer retinal atrophy (RORA), its constituent features (photoreceptor degeneration [PRD], retinal pigment epithelium [RPE] loss, hypertransmission) and intact macula as compared to the untreated fellow eye. RESULTS: Annual GA growth was reduced in eyes treated with PM versus untreated fellow eyes for OCT features, including RORA (study eye 0.792 vs. fellow eye 1.13 mm2; P = 0.003), PRD (0.739 vs. 1.23 mm2; P = 0.015), RPE-loss (0.789 vs. 1.17 mm2; P = 0.007) and intact macula (- 0.735 vs. - 1.29 mm2; P = 0.011). Similar (but not statistically significant) trends were observed with the PEOM treatment or when GA was quantified with fundus autofluorescence (FAF). The sham treatment demonstrated no effect. Pearson correlation coefficients showed concordance in the enlargement rate of GA between the study and fellow eyes in the sham (R = 0.64) and PEOM (R = 0.68) groups, but not in the PM group (R = 0.21). CONCLUSIONS: Pegcetacoplan-treated eyes demonstrated a reduction in spatial GA progression compared to their untreated counterparts. This effect was more evident on OCT than with FAF. TRIAL REGISTRATION: Clinical Trials identifier: NCT02503332

The upcoming role of Artificial Intelligence (AI) for retinal and glaucomatous diseases

: In recent years, the role of artificial intelligence (AI) and deep learning (DL) models is attracting increasing global interest in the field of ophthalmology. DL models are considered the current state-of-art among the AI technologies. In fact, DL systems have the capability to recognize, quantify and describe pathological clinical features. Their role is currently being investigated for the early diagnosis and management of several retinal diseases and glaucoma. The application of DL models to fundus photographs, visual fields and optical coherence tomography (OCT) imaging has provided promising results in the early detection of diabetic retinopathy (DR), wet age-related macular degeneration (w-AMD), retinopathy of prematurity (ROP) and glaucoma. In this review we analyze the current evidence of AI applied to these ocular diseases, as well as discuss the possible future developments and potential clinical implications, without neglecting the present limitations and challenges in order to adopt AI and DL models as powerful tools in the everyday routine clinical practice