Predicting conversion to wet age-related macular degeneration using deep learning

Progression to exudative ‘wet’ age-related macular degeneration (exAMD) is a major cause of visual deterioration. In patients diagnosed with exAMD in one eye, we introduce an artificial intelligence (AI) system to predict progression to exAMD in the second eye. By combining models based on three-dimensional (3D) optical coherence tomography images and corresponding automatic tissue maps, our system predicts conversion to exAMD within a clinically actionable 6-month time window, achieving a per-volumetric-scan sensitivity of 80% at 55% specificity, and 34% sensitivity at 90% specificity. This level of performance corresponds to true positives in 78% and 41% of individual eyes, and false positives in 56% and 17% of individual eyes at the high sensitivity and high specificity points, respectively. Moreover, we show that automatic tissue segmentation can identify anatomical changes before conversion and high-risk subgroups. This AI system overcomes substantial interobserver variability in expert predictions, performing better than five out of six experts, and demonstrates the potential of using AI to predict disease progression. In individuals diagnosed with age-related macular degeneration in one eye, a deep learning model can predict progression to the ‘wet’, sight-threatening form of the disease in the second eye within a 6-month time frame.

[1]  N. Bressler,et al.  Relationship of drusen and abnormalities of the retinal pigment epithelium to the prognosis of neovascular macular degeneration. The Macular Photocoagulation Study Group. , 1990, Archives of ophthalmology.

[2]  R. Klein,et al.  The five-year incidence and progression of age-related maculopathy: the Beaver Dam Eye Study. , 1997, Ophthalmology.

[3]  R. Klein,et al.  Risk Factors Associated with Age-Related Macular Degeneration: A Case-control Study in the Age-Related Eye Disease Study: Age-Related Eye Disease Study , 2000 .

[4]  Risk factors associated with age-related macular degeneration. A case-control study in the age-related eye disease study: Age-Related Eye Disease Study Report Number 3. , 2000, Ophthalmology.

[5]  The Age-Related Eye Disease Study system for classifying age-related macular degeneration from stereoscopic color fundus photographs: the Age-Related Eye Disease Study Report Number 6. , 2001, American journal of ophthalmology.

[6]  Leslie Hyman,et al.  A Simplified Severity Scale for Age-Related Macular Degeneration , 2005 .

[7]  Ronald Klein,et al.  A simplified severity scale for age-related macular degeneration: AREDS Report No. 18. , 2005, Archives of ophthalmology.

[8]  Johanna M Seddon,et al.  Risk factors for the incidence of Advanced Age-Related Macular Degeneration in the Age-Related Eye Disease Study (AREDS) AREDS report no. 19. , 2003, Ophthalmology.

[9]  G Quentel,et al.  Prevalence of reticular pseudodrusen in age-related macular degeneration with newly diagnosed choroidal neovascularisation , 2006, British Journal of Ophthalmology.

[10]  A. Ramé [Age-related macular degeneration]. , 2006, Revue de l'infirmiere.

[11]  Joan W. Miller,et al.  Age-related macular degeneration. , 2008, The New England journal of medicine.

[12]  Emily Y Chew,et al.  Summary results and recommendations from the age-related eye disease study. , 2009, Archives of ophthalmology.

[13]  J. Saaddine,et al.  Forecasting age-related macular degeneration through the year 2050: the potential impact of new treatments. , 2009, Archives of ophthalmology.

[14]  Richard F Spaide,et al.  Prevalence and significance of subretinal drusenoid deposits (reticular pseudodrusen) in age-related macular degeneration. , 2010, Ophthalmology.

[15]  Sascha Fauser,et al.  Delay between medical indication to anti-VEGF treatment in age-related macular degeneration can result in a loss of visual acuity , 2011, Graefe's Archive for Clinical and Experimental Ophthalmology.

[16]  B. Nan,et al.  Racial differences in age-related macular degeneration rates in the United States: a longitudinal analysis of a managed care network. , 2011, American journal of ophthalmology.

[17]  R. Gale,et al.  Action on AMD. Optimising patient management: act now to ensure current and continual delivery of best possible patient care , 2012, Eye.

[18]  Action on AMD. Optimising patient management: act now to ensure current and continual delivery of best possible patient care , 2012, Eye.

[19]  R. Guymer,et al.  Delay to treatment and visual outcomes in patients treated with anti-vascular endothelial growth factor for age-related macular degeneration. , 2012, American journal of ophthalmology.

[20]  Stefanie G. Schuman,et al.  Spatial correlation between hyperpigmentary changes on color fundus photography and hyperreflective foci on SDOCT in intermediate AMD. , 2012, Investigative ophthalmology & visual science.

[21]  Richard Wormald,et al.  The estimated prevalence and incidence of late stage age related macular degeneration in the UK , 2012, British Journal of Ophthalmology.

[22]  R. Avery,et al.  Incidence of choroidal neovascularization in the fellow eye in the comparison of age-related macular degeneration treatments trials. , 2013, Ophthalmology.

[23]  Sina Farsiu,et al.  Progression of intermediate age-related macular degeneration with proliferation and inner retinal migration of hyperreflective foci. , 2013, Ophthalmology.

[24]  R. Klein,et al.  Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. , 2014, The Lancet. Global health.

[25]  C. Bunce,et al.  The neovascular age-related macular degeneration database: report 2: incidence, management, and visual outcomes of second treated eyes. , 2014, Ophthalmology.

[26]  Geoffrey E. Hinton,et al.  Distilling the Knowledge in a Neural Network , 2015, ArXiv.

[27]  Jimmy Ba,et al.  Adam: A Method for Stochastic Optimization , 2014, ICLR.

[28]  D. Cook,et al.  Incidence of Late-Stage Age-Related Macular Degeneration in American Whites: Systematic Review and Meta-analysis. , 2015, American journal of ophthalmology.

[29]  C. Curcio,et al.  Clinical Characteristics, Choroidal Neovascularization, and Predictors of Visual Outcomes in Acquired Vitelliform Lesions. , 2016, American journal of ophthalmology.

[30]  Jesse J. Jung,et al.  Associations Between Retinal Pigment Epithelium and Drusen Volume Changes During the Lifecycle of Large Drusenoid Pigment Epithelial Detachments , 2016, Investigative ophthalmology & visual science.

[31]  G. Ying,et al.  Pseudodrusen and Incidence of Late Age-Related Macular Degeneration in Fellow Eyes in the Comparison of Age-Related Macular Degeneration Treatments Trials. , 2016, Ophthalmology.

[32]  Geraint Rees,et al.  Automated analysis of retinal imaging using machine learning techniques for computer vision , 2016, F1000Research.

[33]  Sandra S Stinnett,et al.  Optical Coherence Tomography Reflective Drusen Substructures Predict Progression to Geographic Atrophy in Age-related Macular Degeneration. , 2016, Ophthalmology.

[34]  Thomas Brox,et al.  3D U-Net: Learning Dense Volumetric Segmentation from Sparse Annotation , 2016, MICCAI.

[35]  Geraint Rees,et al.  Automated analysis of retinal imaging using machine learning techniques for computer vision , 2016, F1000Research.

[36]  Martín Abadi,et al.  TensorFlow: Large-Scale Machine Learning on Heterogeneous Distributed Systems , 2016, ArXiv.

[37]  Sina Farsiu,et al.  Drusen Volume and Retinal Pigment Epithelium Abnormal Thinning Volume Predict 2-Year Progression of Age-Related Macular Degeneration. , 2016, Ophthalmology.

[38]  Ruikang K. Wang,et al.  Original articleOptical Coherence Tomography Angiography of Asymptomatic Neovascularization in Intermediate Age-Related Macular Degeneration , 2016 .

[39]  P. Rosenfeld,et al.  Drusen Volume as a Predictor of Disease Progression in Patients With Late Age-Related Macular Degeneration in the Fellow Eye. , 2016, Investigative ophthalmology & visual science.

[40]  M. Mandai,et al.  Evaluation of the Surgical Device and Procedure for Extracellular Matrix-Scaffold-Supported Human iPSC-Derived Retinal Pigment Epithelium Cell Sheet Transplantation. , 2017, Investigative ophthalmology & visual science.

[41]  De Fauw Automated analysis of retinal imaging using machine learning techniques for computer vision , 2017 .

[42]  Kilian Q. Weinberger,et al.  Densely Connected Convolutional Networks , 2016, 2017 IEEE Conference on Computer Vision and Pattern Recognition (CVPR).

[43]  Thomas Ach,et al.  Activated Retinal Pigment Epithelium, an Optical Coherence Tomography Biomarker for Progression in Age-Related Macular Degeneration , 2017, Investigative ophthalmology & visual science.

[44]  Sebastian Thrun,et al.  Dermatologist-level classification of skin cancer with deep neural networks , 2017, Nature.

[45]  U. Schmidt-Erfurth,et al.  Machine Learning of the Progression of Intermediate Age-Related Macular Degeneration Based on OCT Imaging. , 2017, Investigative ophthalmology & visual science.

[46]  Michael V. McConnell,et al.  Prediction of cardiovascular risk factors from retinal fundus photographs via deep learning , 2017, Nature Biomedical Engineering.

[47]  E. Souied,et al.  Natural History of Treatment-Naïve Quiescent Choroidal Neovascularization in Age-Related Macular Degeneration Using OCT Angiography. , 2018, Ophthalmology. Retina.

[48]  P. Rosenfeld,et al.  Interpretation of Subretinal Fluid Using OCT in Intermediate Age-Related Macular Degeneration. , 2018, Ophthalmology. Retina.

[49]  Tommaso Rossi,et al.  PREDICTIVE FACTORS FOR DEVELOPMENT OF NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: A Spectral-Domain Optical Coherence Tomography Study , 2017, Retina.

[50]  T. Bek,et al.  Incidence and risk factors for neovascular age-related macular degeneration in the fellow eye , 2018, Graefe's Archive for Clinical and Experimental Ophthalmology.

[51]  Bianca S. Gerendas,et al.  Prediction of Individual Disease Conversion in Early AMD Using Artificial Intelligence. , 2018, Investigative ophthalmology & visual science.

[52]  Glenn J Jaffe,et al.  Consensus Definition for Atrophy Associated with Age-Related Macular Degeneration on OCT: Classification of Atrophy Report 3. , 2017, Ophthalmology.

[53]  Chen Sun,et al.  Rethinking Spatiotemporal Feature Learning: Speed-Accuracy Trade-offs in Video Classification , 2017, ECCV.

[54]  Jonathan Krause,et al.  Grader variability and the importance of reference standards for evaluating machine learning models for diabetic retinopathy , 2017, Ophthalmology.

[55]  Geraint Rees,et al.  Clinically applicable deep learning for diagnosis and referral in retinal disease , 2018, Nature Medicine.

[56]  Sophie Kubach,et al.  Natural History of Subclinical Neovascularization in Nonexudative Age-Related Macular Degeneration Using Swept-Source OCT Angiography. , 2017, Ophthalmology.

[57]  Min Kim,et al.  Neovascularization in Fellow Eye of Unilateral Neovascular Age-Related Macular Degeneration According to Different Drusen Types. , 2019, American journal of ophthalmology.

[58]  G. Corrado,et al.  End-to-end lung cancer screening with three-dimensional deep learning on low-dose chest computed tomography , 2019, Nature Medicine.

[59]  C. Wykoff,et al.  Simultaneous Inhibition of Angiopoietin-2 and Vascular Endothelial Growth Factor-A with Faricimab in Diabetic Macular Edema: BOULEVARD Phase 2 Randomized Trial. , 2019, Ophthalmology.

[60]  Aaron Y. Lee,et al.  The Moorfields AMD Database Report 2 - Fellow Eye Involvement with Neovascular Age-related Macular Degeneration , 2019, bioRxiv.

[61]  Suman V. Ravuri,et al.  A Clinically Applicable Approach to Continuous Prediction of Future Acute Kidney Injury , 2019, Nature.

[62]  Anna Goldenberg,et al.  What Clinicians Want: Contextualizing Explainable Machine Learning for Clinical End Use , 2019, MLHC.

[63]  Daniel B. Russakoff,et al.  Deep Learning for Prediction of AMD Progression: A Pilot Study. , 2019, Investigative ophthalmology & visual science.

[64]  P. Campochiaro,et al.  The Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration: Results from the Randomized Phase 2 Ladder Clinical Trial. , 2019, Ophthalmology.

[65]  U. Schmidt-Erfurth,et al.  HAWK and HARRIER: Phase 3, Multicenter, Randomized, Double-Masked Trials of Brolucizumab for Neovascular Age-Related Macular Degeneration. , 2019, Ophthalmology.

[66]  Sergio Gomez Colmenarejo,et al.  TF-Replicator: Distributed Machine Learning for Researchers , 2019, ArXiv.

[67]  Daniel L. Rubin,et al.  A Deep-learning Approach for Prognosis of Age-Related Macular Degeneration Disease using SD-OCT Imaging Biomarkers , 2019, ArXiv.