Deep Learning and Glaucoma Specialists: The Relative Importance of Optic Disc Features to Predict Glaucoma Referral in Fundus Photos

Sonia Phene, R. Carter Dunn, Naama Hammel, Yun Liu, Jonathan Krause, Naho Kitade, Mike Schaekermann, Rory Sayres, Derek J. Wu, Ashish Bora, Christopher Semturs, Anita Misra, Abigail E. Huang, Arielle Spitze, Felipe A. Medeiros, April Y. Maa, Monica Gandhi, Greg S. Corrado, Lily Peng, Dale R. Webster

Glaucoma is the leading cause of preventable, irreversible blindness world-wide. The disease can remain asymptomatic until severe, and an estimated 50%-90% of people with glaucoma remain undiagnosed. Glaucoma screening is recommended for early detection and treatment. A cost-effective tool to detect glaucoma could expand screening access to a much larger patient population, but such a tool is currently unavailable. We trained a deep learning algorithm using a retrospective dataset of 86,618 images, assessed for glaucomatous optic nerve head features and referable glaucomatous optic neuropathy (GON). The algorithm was validated using 3 datasets. For referable GON, the algorithm had an AUC of 0.945 (95% CI, 0.929-0.960) in dataset A (1205 images, 1 image/patient; 18.1% referable), images adjudicated by panels of Glaucoma Specialists (GSs); 0.855 (95% CI, 0.841-0.870) in dataset B (9642 images, 1 image/patient; 9.2% referable), images from Atlanta Veterans Affairs Eye Clinic diabetic teleretinal screening program; and 0.881 (95% CI, 0.838-0.918) in dataset C (346 images, 1 image/patient; 81.7% referable), images from Dr. Shroff's Charity Eye Hospital's glaucoma clinic. The algorithm showed significantly higher sensitivity than 7 of 10 graders not involved in determining the reference standard, including 2 of 3 GSs, and showed higher specificity than 3 graders, while remaining comparable to others. For both GSs and the algorithm, the most crucial features related to referable GON were: presence of vertical cup-to-disc ratio of 0.7 or more, neuroretinal rim notching, retinal nerve fiber layer defect, and bared circumlinear vessels. An algorithm trained on fundus images alone can detect referable GON with higher sensitivity than and comparable specificity to eye care providers. The algorithm maintained good performance on an independent dataset with diagnoses based on a full glaucoma workup.

Improving Medical Annotation Quality to Decrease Labeling Burden Using Stratified Noisy Cross-Validation

Joy Hsu, Sonia Phene, Akinori Mitani, Jieying Luo, Naama Hammel, Jonathan Krause, Rory Sayres

As machine learning has become increasingly applied to medical imaging data, noise in training labels has emerged as an important challenge. Variability in diagnosis of medical images is well established; in addition, variability in training and attention to task among medical labelers may exacerbate this issue. Methods for identifying and mitigating the impact of low quality labels have been studied, but are not well characterized in medical imaging tasks. For instance, Noisy Cross-Validation splits the training data into halves, and has been shown to identify low-quality labels in computer vision tasks; but it has not been applied to medical imaging tasks specifically. In this work we introduce Stratified Noisy Cross-Validation (SNCV), an extension of noisy cross validation. SNCV can provide estimates of confidence in model predictions by assigning a quality score to each example; stratify labels to handle class imbalance; and identify likely low-quality labels to analyze the causes. We assess performance of SNCV on diagnosis of glaucoma suspect risk from retinal fundus photographs, a clinically important yet nuanced labeling task. Using training data from a previously-published deep learning model, we compute a continuous quality score (QS) for each training example. We relabel 1,277 low-QS examples using a trained glaucoma specialist; the new labels agree with the SNCV prediction over the initial label >85% of the time, indicating that low-QS examples mostly reflect labeler errors. We then quantify the impact of training with only high-QS labels, showing that strong model performance may be obtained with many fewer examples. By applying the method to randomly sub-sampled training dataset, we show that our method can reduce labelling burden by approximately 50% while achieving model performance non-inferior to using the full dataset on multiple held-out test sets.

GPT-4o System Card

OpenAI, :, Aaron Hurst, Adam Lerer, Adam P. Goucher, Adam Perelman, Aditya Ramesh, Aidan Clark, AJ Ostrow, Akila Welihinda, Alan Hayes, Alec Radford, Aleksander Mądry, Alex Baker-Whitcomb, Alex Beutel, Alex Borzunov, Alex Carney, Alex Chow, Alex Kirillov, Alex Nichol, Alex Paino, Alex Renzin, Alex Tachard Passos, Alexander Kirillov, Alexi Christakis, Alexis Conneau, Ali Kamali, Allan Jabri, Allison Moyer, Allison Tam, Amadou Crookes, Amin Tootoochian, Amin Tootoonchian, Ananya Kumar, Andrea Vallone, Andrej Karpathy, Andrew Braunstein, Andrew Cann, Andrew Codispoti, Andrew Galu, Andrew Kondrich, Andrew Tulloch, Andrey Mishchenko, Angela Baek, Angela Jiang, Antoine Pelisse, Antonia Woodford, Anuj Gosalia, Arka Dhar, Ashley Pantuliano, Avi Nayak, Avital Oliver, Barret Zoph, Behrooz Ghorbani, Ben Leimberger, Ben Rossen, Ben Sokolowsky, Ben Wang, Benjamin Zweig, Beth Hoover, Blake Samic, Bob McGrew, Bobby Spero, Bogo Giertler, Bowen Cheng, Brad Lightcap, Brandon Walkin, Brendan Quinn, Brian Guarraci, Brian Hsu, Bright Kellogg, Brydon Eastman, Camillo Lugaresi, Carroll Wainwright, Cary Bassin, Cary Hudson, Casey Chu, Chad Nelson, Chak Li, Chan Jun Shern, Channing Conger, Charlotte Barette, Chelsea Voss, Chen Ding, Cheng Lu, Chong Zhang, Chris Beaumont, Chris Hallacy, Chris Koch, Christian Gibson, Christina Kim, Christine Choi, Christine McLeavey, Christopher Hesse, Claudia Fischer, Clemens Winter, Coley Czarnecki, Colin Jarvis, Colin Wei, Constantin Koumouzelis, Dane Sherburn, Daniel Kappler, Daniel Levin, Daniel Levy, David Carr, David Farhi, David Mely, David Robinson, David Sasaki, Denny Jin, Dev Valladares, Dimitris Tsipras, Doug Li, Duc Phong Nguyen, Duncan Findlay, Edede Oiwoh, Edmund Wong, Ehsan Asdar, Elizabeth Proehl, Elizabeth Yang, Eric Antonow, Eric Kramer, Eric Peterson, Eric Sigler, Eric Wallace, Eugene Brevdo, Evan Mays, Farzad Khorasani, Felipe Petroski Such, Filippo Raso, Francis Zhang, Fred von Lohmann, Freddie Sulit, Gabriel Goh, Gene Oden, Geoff Salmon, Giulio Starace, Greg Brockman, Hadi Salman, Haiming Bao, Haitang Hu, Hannah Wong, Haoyu Wang, Heather Schmidt, Heather Whitney, Heewoo Jun, Hendrik Kirchner, Henrique Ponde de Oliveira Pinto, Hongyu Ren, Huiwen Chang, Hyung Won Chung, Ian Kivlichan, Ian O'Connell, Ian O'Connell, Ian Osband, Ian Silber, Ian Sohl, Ibrahim Okuyucu, Ikai Lan, Ilya Kostrikov, Ilya Sutskever, Ingmar Kanitscheider, Ishaan Gulrajani, Jacob Coxon, Jacob Menick, Jakub Pachocki, James Aung, James Betker, James Crooks, James Lennon, Jamie Kiros, Jan Leike, Jane Park, Jason Kwon, Jason Phang, Jason Teplitz, Jason Wei, Jason Wolfe, Jay Chen, Jeff Harris, Jenia Varavva, Jessica Gan Lee, Jessica Shieh, Ji Lin, Jiahui Yu, Jiayi Weng, Jie Tang, Jieqi Yu, Joanne Jang, Joaquin Quinonero Candela, Joe Beutler, Joe Landers, Joel Parish, Johannes Heidecke, John Schulman, Jonathan Lachman, Jonathan McKay, Jonathan Uesato, Jonathan Ward, Jong Wook Kim, Joost Huizinga, Jordan Sitkin, Jos Kraaijeveld, Josh Gross, Josh Kaplan, Josh Snyder, Joshua Achiam, Joy Jiao, Joyce Lee, Juntang Zhuang, Justyn Harriman, Kai Fricke, Kai Hayashi, Karan Singhal, Katy Shi, Kavin Karthik, Kayla Wood, Kendra Rimbach, Kenny Hsu, Kenny Nguyen, Keren Gu-Lemberg, Kevin Button, Kevin Liu, Kiel Howe, Krithika Muthukumar, Kyle Luther, Lama Ahmad, Larry Kai, Lauren Itow, Lauren Workman, Leher Pathak, Leo Chen, Li Jing, Lia Guy, Liam Fedus, Liang Zhou, Lien Mamitsuka, Lilian Weng, Lindsay McCallum, Lindsey Held, Long Ouyang, Louis Feuvrier, Lu Zhang, Lukas Kondraciuk, Lukasz Kaiser, Luke Hewitt, Luke Metz, Lyric Doshi, Mada Aflak, Maddie Simens, Madelaine Boyd, Madeleine Thompson, Marat Dukhan, Mark Chen, Mark Gray, Mark Hudnall, Marvin Zhang, Marwan Aljubeh, Mateusz Litwin, Matthew Zeng, Max Johnson, Maya Shetty, Mayank Gupta, Meghan Shah, Mehmet Yatbaz, Meng Jia Yang, Mengchao Zhong, Mia Glaese, Mianna Chen, Michael Janner, Michael Lampe, Michael Petrov, Michael Wu, Michele Wang, Michelle Fradin, Michelle Pokrass, Miguel Castro, Miguel Oom Temudo de Castro, Mikhail Pavlov, Miles Brundage, Miles Wang, Minal Khan, Mira Murati, Mo Bavarian, Molly Lin, Murat Yesildal, Nacho Soto, Natalia Gimelshein, Natalie Cone, Natalie Staudacher, Natalie Summers, Natan LaFontaine, Neil Chowdhury, Nick Ryder, Nick Stathas, Nick Turley, Nik Tezak, Niko Felix, Nithanth Kudige, Nitish Keskar, Noah Deutsch, Noel Bundick, Nora Puckett, Ofir Nachum, Ola Okelola, Oleg Boiko, Oleg Murk, Oliver Jaffe, Olivia Watkins, Olivier Godement, Owen Campbell-Moore, Patrick Chao, Paul McMillan, Pavel Belov, Peng Su, Peter Bak, Peter Bakkum, Peter Deng, Peter Dolan, Peter Hoeschele, Peter Welinder, Phil Tillet, Philip Pronin, Philippe Tillet, Prafulla Dhariwal, Qiming Yuan, Rachel Dias, Rachel Lim, Rahul Arora, Rajan Troll, Randall Lin, Rapha Gontijo Lopes, Raul Puri, Reah Miyara, Reimar Leike, Renaud Gaubert, Reza Zamani, Ricky Wang, Rob Donnelly, Rob Honsby, Rocky Smith, Rohan Sahai, Rohit Ramchandani, Romain Huet, Rory Carmichael, Rowan Zellers, Roy Chen, Ruby Chen, Ruslan Nigmatullin, Ryan Cheu, Saachi Jain, Sam Altman, Sam Schoenholz, Sam Toizer, Samuel Miserendino, Sandhini Agarwal, Sara Culver, Scott Ethersmith, Scott Gray, Sean Grove, Sean Metzger, Shamez Hermani, Shantanu Jain, Shengjia Zhao, Sherwin Wu, Shino Jomoto, Shirong Wu, Shuaiqi, Xia, Sonia Phene, Spencer Papay, Srinivas Narayanan, Steve Coffey, Steve Lee, Stewart Hall, Suchir Balaji, Tal Broda, Tal Stramer, Tao Xu, Tarun Gogineni, Taya Christianson, Ted Sanders, Tejal Patwardhan, Thomas Cunninghman, Thomas Degry, Thomas Dimson, Thomas Raoux, Thomas Shadwell, Tianhao Zheng, Todd Underwood, Todor Markov, Toki Sherbakov, Tom Rubin, Tom Stasi, Tomer Kaftan, Tristan Heywood, Troy Peterson, Tyce Walters, Tyna Eloundou, Valerie Qi, Veit Moeller, Vinnie Monaco, Vishal Kuo, Vlad Fomenko, Wayne Chang, Weiyi Zheng, Wenda Zhou, Wesam Manassra, Will Sheu, Wojciech Zaremba, Yash Patil, Yilei Qian, Yongjik Kim, Youlong Cheng, Yu Zhang, Yuchen He, Yuchen Zhang, Yujia Jin, Yunxing Dai, Yury Malkov

Large-scale machine learning-based phenotyping significantly improves genomic discovery for optic nerve head morphology

Babak Alipanahi, Farhad Hormozdiari, Babak Behsaz, Justin Cosentino, Zachary R. McCaw, Emanuel Schorsch, D. Sculley, Elizabeth H. Dorfman, Sonia Phene, Naama Hammel, Andrew Carroll, Anthony P. Khawaja, Cory Y. McLean

Genome-wide association studies (GWAS) require accurate cohort phenotyping, but expert labeling can be costly, time-intensive, and variable. Here we develop a machine learning (ML) model to predict glaucomatous optic nerve head features from color fundus photographs. We used the model to predict vertical cup-to-disc ratio (VCDR), a diagnostic parameter and cardinal endophenotype for glaucoma, in 65,680 Europeans in the UK Biobank (UKB). A GWAS of ML-based VCDR identified 299 independent genome-wide significant (GWS; $P\leq5\times10^{-8}$) hits in 156 loci. The ML-based GWAS replicated 62 of 65 GWS loci from a recent VCDR GWAS in the UKB for which two ophthalmologists manually labeled images for 67,040 Europeans. The ML-based GWAS also identified 92 novel loci, significantly expanding our understanding of the genetic etiologies of glaucoma and VCDR. Pathway analyses support the biological significance of the novel hits to VCDR, with select loci near genes involved in neuronal and synaptic biology or known to cause severe Mendelian ophthalmic disease. Finally, the ML-based GWAS results significantly improve polygenic prediction of VCDR and primary open-angle glaucoma in the independent EPIC-Norfolk cohort.

Deep Learning vs. Human Graders for Classifying Severity Levels of Diabetic Retinopathy in a Real-World Nationwide Screening Program

Paisan Raumviboonsuk, Jonathan Krause, Peranut Chotcomwongse, Rory Sayres, Rajiv Raman, Kasumi Widner, Bilson J L Campana, Sonia Phene, Kornwipa Hemarat, Mongkol Tadarati, Sukhum Silpa-Acha, Jirawut Limwattanayingyong, Chetan Rao, Oscar Kuruvilla, Jesse Jung, Jeffrey Tan, Surapong Orprayoon, Chawawat Kangwanwongpaisan, Ramase Sukulmalpaiboon, Chainarong Luengchaichawang, Jitumporn Fuangkaew, Pipat Kongsap, Lamyong Chualinpha, Sarawuth Saree, Srirat Kawinpanitan, Korntip Mitvongsa, Siriporn Lawanasakol, Chaiyasit Thepchatri, Lalita Wongpichedchai, Greg S Corrado, Lily Peng, Dale R Webster

Deep learning algorithms have been used to detect diabetic retinopathy (DR) with specialist-level accuracy. This study aims to validate one such algorithm on a large-scale clinical population, and compare the algorithm performance with that of human graders. 25,326 gradable retinal images of patients with diabetes from the community-based, nation-wide screening program of DR in Thailand were analyzed for DR severity and referable diabetic macular edema (DME). Grades adjudicated by a panel of international retinal specialists served as the reference standard. Across different severity levels of DR for determining referable disease, deep learning significantly reduced the false negative rate (by 23%) at the cost of slightly higher false positive rates (2%). Deep learning algorithms may serve as a valuable tool for DR screening.