IMPORTANCE Age-related macular degeneration (AMD) affects millions of people throughout the world. The intermediate stage may go undetected, as it typically is asymptomatic. However, the preferred practice patterns for AMD recommend identifying individuals with this stage of the disease to educate how to monitor for the early detection of the choroidal neovascular stage before substantial vision loss has occurred and to consider dietary supplements that might reduce the risk of the disease progressing from the intermediate to the advanced stage. Identification, though, can be time-intensive and requires expertly trained individuals. OBJECTIVE To develop methods for automatically detecting AMD from fundus images using a novel application of deep learning methods to the automated assessment of these images and to leverage artificial intelligence advances. DESIGN, SETTING, AND PARTICIPANTSDeep convolutional neural networks that are explicitly trained for performing automated AMD grading were compared with an alternate deep learning method that used transfer learning and universal features and with a trained clinical grader. Age-related macular degeneration automated detection was applied to a 2-class classification problem in which the task was to distinguish the disease-free/early stages from the referable intermediate/advanced stages. Using several experiments that entailed different data partitioning, the performance of the machine algorithms and human graders in evaluating more than 130 000 images that were deidentified with respect to age, sex, and race/ethnicity from 4613 patients against a gold standard included in the National Institutes of Health Age-Related Eye Disease Study data set was evaluated.MAIN OUTCOMES AND MEASURES Accuracy, receiver operating characteristics and area under the curve, and κ score. RESULTSThe deep convolutional neural network method yielded accuracy that ranged between 88.4% (SD, 0.5%) and 91.6% (SD, 0.1%), the area under the receiver operating characteristic curve was between 0.94 and 0.96, and κ (SD) between 0.764 (0.010) and 0.829 (0.003), which indicated a substantial agreement with the gold standard Age-Related Eye Disease Study data set.CONCLUSIONS AND RELEVANCE Applying a deep learning-based automated assessment of AMD from fundus images can produce results that are similar to human performance levels. This study demonstrates that automated algorithms could play a role that is independent of expert human graders in the current management of AMD and could address the costs of screening or monitoring, access to health care, and the assessment of novel treatments that address the development or progression of AMD.

Background When left untreated, age-related macular degeneration (AMD) is the leading cause of vision loss in people over fifty in the US. Currently it is estimated that about eight million US individuals have the intermediate stage of AMD that is often asymptomatic with regard to visual deficit. These individuals are at high risk for progressing to the advanced stage where the often treatable choroidal neovascular form of AMD can occur. Careful monitoring to detect the onset and prompt treatment of the neovascular form as well as dietary supplementation can reduce the risk of vision loss from AMD, therefore, preferred practice patterns recommend identifying individuals with the intermediate stage in a timely manner. Methods Past automated retinal image analysis (ARIA) methods applied on fundus imagery have relied on engineered and hand-designed visual features. We instead detail the novel application of a machine learning approach using deep learning for the problem of ARIA and AMD analysis. We use transfer learning and universal features derived from deep convolutional neural networks (DCNN). We address clinically relevant 4-class, 3-class, and 2-class AMD severity classification problems. Results Using 5664 color fundus images from the NIH AREDS dataset and DCNN universal features, we obtain values for accuracy for the (4-,3-,2-) class classification problem of (79.4%, 81.5%, 93.4%) for machine vs. (75.8%, 85.0%, 95.2%) for physician grading. Discussion This study demonstrates the efficacy of machine grading based on deep universal features/transfer learning when applied to ARIA and is a promising step in providing a pre-screener to identify individuals with intermediate AMD and also as a tool that can facilitate identifying such individuals for clinical studies aimed at developing improved therapies. It also demonstrates comparable performance between computer and physician grading.

IMPORTANCE Although deep learning (DL) can identify the intermediate or advanced stages of age-related macular degeneration (AMD) as a binary yes or no, stratified gradings using the more granular Age-Related Eye Disease Study (AREDS) 9-step detailed severity scale for AMD provide more precise estimation of 5-year progression to advanced stages. The AREDS 9-step detailed scale's complexity and implementation solely with highly trained fundus photograph graders potentially hampered its clinical use, warranting development and use of an alternate AREDS simple scale, which although valuable, has less predictive ability. OBJECTIVE To describe DL techniques for the AREDS 9-step detailed severity scale for AMD to estimate 5-year risk probability with reasonable accuracy. DESIGN, SETTING, AND PARTICIPANTS This study used data collected from November 13, 1992, to November 30, 2005, from 4613 study participants of the AREDS data set to develop deep convolutional neural networks that were trained to provide detailed automated AMD grading on several AMD severity classification scales, using a multiclass classification setting. Two AMD severity classification problems using criteria based on 4-step (AMD-1, AMD-2, AMD-3, and AMD-4 from classifications developed for AREDS eligibility criteria) and 9-step (from AREDS detailed severity scale) AMD severity scales were investigated. The performance of these algorithms was compared with a contemporary human grader and against a criterion standard (fundus photograph reading center graders) used at the time of AREDS enrollment and follow-up. Three methods for estimating 5-year risk were developed, including one based on DL regression. Data were analyzed from December 1, 2017, through April 15, 2018. MAIN OUTCOMES AND MEASURES Weighted κ scores and mean unsigned errors for estimating 5-year risk probability of progression to advanced AMD. RESULTS This study used 67 401 color fundus images from the 4613 study participants. The weighted κ scores were 0.77 for the 4-step and 0.74 for the 9-step AMD severity scales. The overall mean estimation error for the 5-year risk ranged from 3.5% to 5.3%. CONCLUSIONS AND RELEVANCE These findings suggest that DL AMD grading has, for the 4-step classification evaluation, performance comparable with that of humans and achieves promising results for providing AMD detailed severity grading (9-step classification), which normally requires highly trained graders, and for estimating 5-year risk of progression to advanced AMD. Use of DL has the potential to assist physicians in longitudinal care for individualized, detailed risk assessment as well as clinical studies of disease progression during treatment or as public screening or monitoring worldwide.

IMPORTANCEDeep learning (DL) used for discriminative tasks in ophthalmology, such as diagnosing diabetic retinopathy or age-related macular degeneration (AMD), requires large image data sets graded by human experts to train deep convolutional neural networks (DCNNs). In contrast, generative DL techniques could synthesize large new data sets of artificial retina images with different stages of AMD. Such images could enhance existing data sets of common and rare ophthalmic diseases without concern for personally identifying information to assist medical education of students, residents, and retinal specialists, as well as for training new DL diagnostic models for which extensive data sets from large clinical trials of expertly graded images may not exist. OBJECTIVE To develop DL techniques for synthesizing high-resolution realistic fundus images serving as proxy data sets for use by retinal specialists and DL machines. DESIGN, SETTING, AND PARTICIPANTSGenerative adversarial networks were trained on 133 821 color fundus images from 4613 study participants from the Age-Related Eye Disease Study (AREDS), generating synthetic fundus images with and without AMD. We compared retinal specialists' ability to diagnose AMD on both real and synthetic images, asking them to assess image gradability and testing their ability to discern real from synthetic images. The performance of AMD diagnostic DCNNs (referable vs not referable AMD) trained on either all-real vs all-synthetic data sets was compared.MAIN OUTCOMES AND MEASURES Accuracy of 2 retinal specialists (T.Y.A.L. and K.D.P.) for diagnosing and distinguishing AMD on real vs synthetic images and diagnostic performance (area under the curve) of DL algorithms trained on synthetic vs real images. RESULTSThe diagnostic accuracy of 2 retinal specialists on real vs synthetic images was similar. The accuracy of diagnosis as referable vs nonreferable AMD compared with certified human graders for retinal specialist 1 was 84.54% (error margin, 4.06%) on real images vs 84.12% (error margin, 4.16%) on synthetic images and for retinal specialist 2 was 89.47% (error margin, 3.45%) on real images vs 89.19% (error margin, 3.54%) on synthetic images. Retinal specialists could not distinguish real from synthetic images, with an accuracy of 59.50% (error margin, 3.93%) for retinal specialist 1 and 53.67% (error margin, 3.99%) for retinal specialist 2. The DCNNs trained on real data showed an area under the curve of 0.9706 (error margin, 0.0029), and those trained on synthetic data showed an area under the curve of 0.9235 (error margin, 0.0045).CONCLUSIONS AND RELEVANCE Deep learning-synthesized images appeared to be realistic to retinal specialists, and DCNNs achieved diagnostic performance on synthetic data close to that for real images, suggesting that DL generative techniques hold promise for training humans and machines.

Purpose This study evaluated generative methods to potentially mitigate artificial intelligence (AI) bias when diagnosing diabetic retinopathy (DR) resulting from training data imbalance or domain generalization, which occurs when deep learning systems (DLSs) face concepts at test/inference time they were not initially trained on. Methods The public domain Kaggle EyePACS dataset (88,692 fundi and 44,346 individuals, originally diverse for ethnicity) was modified by adding clinician-annotated labels and constructing an artificial scenario of data imbalance and domain generalization by disallowing training (but not testing) exemplars for images of retinas with DR warranting referral (DR-referable) from darker-skin individuals, who presumably have greater concentration of melanin within uveal melanocytes, on average, contributing to retinal image pigmentation. A traditional/baseline diagnostic DLS was compared against new DLSs that would use training data augmented via generative models for debiasing. Results Accuracy (95% confidence intervals [CIs]) of the baseline diagnostics DLS for fundus images of lighter-skin individuals was 73.0% (66.9% to 79.2%) versus darker-skin of 60.5% (53.5% to 67.3%), demonstrating bias/disparity (delta = 12.5%; Welch t -test t = 2.670, P = 0.008) in AI performance across protected subpopulations. Using novel generative methods for addressing missing subpopulation training data (DR-referable darker-skin) achieved instead accuracy, for lighter-skin, of 72.0% (65.8% to 78.2%), and for darker-skin, of 71.5% (65.2% to 77.8%), demonstrating closer parity (delta = 0.5%) in accuracy across subpopulations (Welch t -test t = 0.111, P = 0.912). Conclusions Findings illustrate how data imbalance and domain generalization can lead to disparity of accuracy across subpopulations, and show that novel generative methods of synthetic fundus images may play a role for debiasing AI. Translational Relevance New AI methods have possible applications to address potential AI bias in DR diagnostics from fundus pigmentation, and potentially other ophthalmic DLSs too.