Authors: Ittai Dayan Holger R. Roth Aoxiao Zhong Ahmed Harouni Amilcare Gentili Anas Z. Abidin Andrew Liu Anthony Beardsworth Costa Bradford J. Wood Chien-Sung Tsai Chih-Hung Wang Chun-Nan Hsu C. K. Lee Peiying Ruan Daguang Xu Dufan Wu Eddie Huang Felipe Campos Kitamura Griffin Lacey Gustavo César de Antônio Corradi Gustavo Nino Hao-Hsin Shin Hirofumi Obinata Hui Ren Jason C. Crane Jesse Tetreault Jiahui Guan John W. Garrett Joshua D. Kaggie Jung Gil Park Keith Dreyer Krishna Juluru Kristopher Kersten Marcio Aloisio Bezerra Cavalcanti Rockenbach Marius George Linguraru Masoom A. Haider Meena AbdelMaseeh Nicola Rieke Pablo F. Damasceno Pedro Mario Cruz e Silva Pochuan Wang Sheng Xu Shuichi Kawano Sira Sriswasdi Soo Young Park Thomas M. Grist Varun Buch Watsamon Jantarabenjakul Weichung Wang Won Young Tak Xiang Li Xihong Lin Young Joon Kwon Abood Quraini Andrew Feng Andrew N. Priest Baris Turkbey Benjamin Glicksberg Bernardo Bizzo Byung Seok Kim Carlos Tor-Díez Chia-Cheng Lee Chia-Jung Hsu Chin Lin Chiu-Ling Lai Christopher P. Hess Colin Compas Deepeksha Bhatia Eric K. Oermann Evan Leibovitz Hisashi Sasaki Hitoshi Mori Isaac Yang Jae Ho Sohn Krishna Nand Keshava Murthy Li-Chen Fu Matheus Ribeiro Furtado de Mendonça Mike Fralick Min Kyu Kang Mohammad Adil Natalie Gangai Peerapon Vateekul Pierre Elnajjar Sarah Hickman Sharmila Majumdar Shelley L. McLeod Sheridan Reed Stefan Gräf Stephanie Harmon Tatsuya Kodama Thanyawee Puthanakit Tony Mazzulli Vitor Lima de Lavor Yothin Rakvongthai Yu Rim Lee Yuhong Wen Fiona J. Gilbert Mona G. Flores Quanzheng Li Authors: Ittai Dayan Holger R. Roth Aoxiao Zhong Hakkında Ahmed Harun Amilcare Gentili Anas Z. Abidin Andrew Liu Anthony Beardsworth Costa Bradford J. Wood Chien-Sung Tsai Chih-Hung Wang Chun-Nan Hsu C. K. Lee Hakkında Peiying Ruan Daguang Xu Dufan Wu Eddie Huang Felipe Campos Kitamura Griffin Lacey Hakkında Gustavo César de Antônio Corradi Gustavo Nino Şanlıurfa Shin Hirofumi Obinata Hakkında Yüce Ren Jason C. Crane Hakkında Jesse Tetreault Jiahui Guan Hakkında John W. Garrett Hakkında Joshua D. Kaggie Jung Gil Park Keith Dreyer Hakkında Kılıçdaroğlu Kristof Karadeniz Marcio Aloisio Bezerra Cavalcanti Rockenbach Marius George Linguraru Masoom A. Haider Meena AbdelMaseeh Nicola Rieke Pablo F. Damasceno Pedro Mario Cruz ve Silva Pochuan Wang Sheng Xu Hakkında Shuichi Kawano Hakkında Sira Sriswasdi Soo Young Park Thomas M. Grist Varun Buch Watsamon Jantarabenjakul Weichung Wang Genç Tak Xiang Li Xihong Lin Young Joon Kwon Abood Quraini Andrew Feng Andrew N. Priest Baris Turkbey Benjamin Glicksberg Bernardo Bizzo Byung Seok Kim Carlos Tor-Díez Hakkında Chia-Cheng Lee Hakkında Chia-Jung Hsu Çin Lin Chiu-Ling Lai Christopher P. Hess Colin Compas Deepeksha Bhatia Eric K. Oermann Evan Leibovitz Hisashi Sasaki Hitoshi Mori Hakkında Isaac Yang Jae Ho Sohn Krishna Nand Keshava Murthy Li-Chen Fu Matheus Ribeiro Furtado de Mendonça Mike Fralick Min Kyu Kang Mohammad Adil Natalie Gangai Çanakkale Vatandaşlık Pierre Elnajjar Sarah Hickman Sharmila Majumdar Shelley L. McLeod Sheridan Reed Stefan Gräf Hakkında Stephanie Harmon Tatsuya Kodama Hakkında Thanyawee Puthanakit Tony Mazzulli Vitor Lima İşçi Yothin Rakvongthai Yu Rim Lee Yuhong Wen Fiona J. Gilbert Mona G. Flores Quanzheng Li Abstract Federated learning (FL) is a method used for training artificial intelligence models with data from multiple sources while maintaining data anonymity, thus removing many barriers to data sharing. Here we used data from 20 institutes across the globe to train a FL model, called EXAM (electronic medical record (EMR) chest X-ray AI model), that predicts the future oxygen requirements of symptomatic patients with COVID-19 using inputs of vital signs, laboratory data and chest X-rays. EXAM achieved an average area under the curve (AUC) >0.92 for predicting outcomes at 24 and 72 h from the time of initial presentation to the emergency room, and it provided 16% improvement in average AUC measured across all participating sites and an average increase in generalizability of 38% when compared with models trained at a single site using that site’s data. For prediction of mechanical ventilation treatment or death at 24 h at the largest independent test site, EXAM achieved a sensitivity of 0.950 and specificity of 0.882. In this study, FL facilitated rapid data science collaboration without data exchange and generated a model that generalized across heterogeneous, unharmonized datasets for prediction of clinical outcomes in patients with COVID-19, setting the stage for the broader use of FL in healthcare. Main The scientific, academic, medical and data science communities have come together in the face of the COVID-19 pandemic crisis to rapidly assess novel paradigms in artificial intelligence (AI) that are rapid and secure, and potentially incentivize data sharing and model training and testing without the usual privacy and data ownership hurdles of conventional collaborations , Sağlık hizmetleri sağlayıcıları, araştırmacılar ve endüstri, kriz tarafından yaratılan karşılamayan ve kritik klinik ihtiyaçları karşılamak için odaklandılar, olağanüstü sonuçlarla. , , , , , , . Clinical trial recruitment has been expedited and facilitated by national regulatory bodies and an international cooperative spirit , , Veri analizi ve AI disiplinleri her zaman açık ve işbirliği yaklaşımları teşvik etmiştir, açık kaynaklı yazılım, tekrarlanabilir araştırma, veri depoları ve anonim veri kümelerini halka açık hale getirmek gibi kavramları kapsıyor. , . The pandemic has emphasized the need to expeditiously conduct data collaborations that empower the clinical and scientific communities when responding to rapidly evolving and widespread global challenges. Data sharing has ethical, regulatory and legal complexities that are underscored, and perhaps somewhat complicated, by the recent entrance of large technology companies into the healthcare data world , , . 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Bu tür işbirliğinin belirgin bir örneği, AI tabanlı bir SARS-COV-2 klinik karar desteği (CDS) modeli üzerinde yaptığımız önceki çalışmamızdır.Bu CDS modeli Mass General Brigham (MGB)'de geliştirildi ve çok sayıda sağlık sisteminin verilerinde doğrulanmıştır. CDS modeli içeriği, göğüs X-ray (CXR) görüntüleri, hayati belirtiler, demografik veriler ve önceki yayınlarda COVID-19 ile hastaların sonuçlarını tahmin eden laboratuvar değerleri olarak gösterildi. , , , . CXR was selected as the imaging input because it is widely available and commonly indicated by guidelines such as those provided by ACR , the Fleischner Society , the WHO , national thoracic societies , national health ministry COVID handbooks and radiology societies across the world . The output of the CDS model was a score, termed CORISK , that corresponds to oxygen support requirements and that could aid in triaging patients by frontline clinicians , , . Healthcare providers have been known to prefer models that were validated on their own data . To date most AI models, including the aforementioned CDS model, have been trained and validated on ‘narrow’ data that often lack diversity , , potentially resulting in overfitting and lower generalizability. This can be mitigated by training with diverse data from multiple sites without centralization of data using methods such as transfer learning , or FL. FL is a method used to train AI models on disparate data sources, without the data being transported or exposed outside their original location. While applicable to many industries, FL has recently been proposed for cross-institutional healthcare research . 18 19 20 21 22 23 24 25 26 27 28 29 30 27 31 32 33 34 35 36 Federated learning supports the rapid launch of centrally orchestrated experiments with improved traceability of data and assessment of algorithmic changes and impact . One approach to FL, called client-server, sends an ‘untrained’ model to other servers (‘nodes’) that conduct partial training tasks, in turn sending the results back to be merged in the central (‘federated’) server. This is conducted as an iterative process until training is complete . 37 36 Governance of data for FL is maintained locally, alleviating privacy concerns, with only model weights or gradients communicated between client sites and the federated server , . FL has already shown promise in recent medical imaging applications , , , , including in COVID-19 analysis , , . A notable example is a mortality prediction model in patients infected with SARS-COV-2 that uses clinical features, albeit limited in terms of number of modalities and scale . 38 39 40 41 42 43 8 44 45 46 Hedefimiz, hastaların test edilmesinde yardımcı olabilecek sağlam, genelleşebilir bir model geliştirmekti. CDS modeli, klinik pratikte nispeten yaygın olan ve hastanın durumunun operatör bağımlı değerlendirmelerine (klinik izlenimler veya bildirilen semptomlar gibi) büyük ölçüde bağlı olmayan veri girişlerinin kullanılması nedeniyle başarılı bir şekilde federalize edilebileceğini teoride bulduk. Bunun yerine, laboratuvar sonuçları, hayati belirtiler, bir görüntüleme çalışması ve yaygın olarak ele alınan bir demografik (yani yaş) kullanıldı. Dolayısıyla, katılımcı kurumların bir merkezi depolara verileri aktarmak için CXR ve EMR özelliklerini kullanarak yeni bir küresel FL modelini geliştirmek için bir müşteri-server FL yaklaşımını kullanarak çeşitli verilerle CDS modeli yeniden eğittik. Our hypothesis was that EXAM would perform better than local models and would generalize better across healthcare systems. Results The EXAM model architecture The EXAM model is based on the CDS model mentioned above Toplam 20 özellik (19 EMR ve bir CXR) modeline giriş olarak kullanılmıştır. Sonuç etiketi (yani “toprak gerçeği”) 24 saat ve 72 saat süren tedavinin ardından hastanın oksijen tedavisine dayanarak başlangıçta acil durum departmanına (ED) kabul edildi. talep edilen özelliklerin ve sonuçların ayrıntılı bir listesi Tablo'da bulunabilir. . 27 1 The outcome labels of patients were set to 0, 0.25, 0.50 and 0.75 depending on the most intensive oxygen therapy the patient received in the prediction window. The oxygen therapy categories were, respectively, room air (RA), low-flow oxygen (LFO), high-flow oxygen (HFO)/noninvasive ventilation (NIV) or mechanical ventilation (MV). If the patient died within the prediction window, the outcome label was set to 1. This resulted in each case being assigned two labels in the range 0–1, corresponding to each of the prediction windows (that is, 24 and 72 h). For EMR features, only the first values captured in the ED were used and data preprocessing included deidentification, missing value imputation and normalization to zero-mean and unit variance. For CXR images, only the first obtained in the ED was used. Bu nedenle, model hem EMR hem de CXR özelliklerinden bilgi birleştirir, bir CXR ve bir Deep & Cross ağından özellikleri çıkarmak için bir 34 katmanlı konvolisyonel nöral ağı (ResNet34) kullanarak özellikleri EMR özellikleriyle birlikte birleştirir (daha genişletilmiş ayrıntılar için, bkz. ). The model output is a risk score, termed the EXAM score, which is a continuous value in the range 0–1 for each of the 24- and 72-hour predictions corresponding to the labels described above. Methods Federating the model The EXAM model was trained using a cohort of 16,148 cases, making it not only among the first FL models for COVID-19 but also a very large and multicontinent development project in clinically relevant AI (Fig. ). Data between sites were not harmonized before extraction and, in light of real-life clinical informatics circumstances, a meticulous harmonization of the data input was not conducted by the authors (Fig. ). 1a,b 1c,d Dünya haritası, EXAM çalışmasına katkıda bulunan 20 farklı müşteri sitesini göstermektedir. , Number of cases contributed by each institution or site (client 1 represents the site contributing the largest number of cases). , Chest X-ray intensity distribution at each client site. , Her bir müşteri sitesinde hastaların yaşı, minimum ve maksimum yaş (asterisks), ortalama yaş (üçgenler) ve standart sapma (horizontal çubuklar) gösterir. . a b c d 1 We compared locally trained models with the global FL model on each client’s test data. Training the model through FL resulted in a significant performance improvement ( « 1 × 10–3, Wilcoxon signed-rank test) of 16% (as defined by average AUC when running the model on respective local test sets: from 0.795 to 0.920, or 12.5 percentage points) (Fig. ). It also resulted in 38% generalizability improvement (as defined by average AUC when running the model on all test sets: from 0.667 to 0.920, or 25.3 percentage points) of the best global model for prediction of 24-h oxygen treatment compared with models trained only on a site’s own data (Fig. ). For the prediction results of 72-h oxygen treatment, the best global model training resulted in an average performance improvement of 18% compared to locally trained models, while generalizability of the global model improved on average by 34% (Extended Data Fig. Sonuçlarımızın istikrarı, farklı rastgele veri bölünmelerinde yerel ve FL eğitiminin üç çalışmasını tekrarlayarak doğrulanmıştır. P 2a 2b 1 , Performance on each client’s test set in prediction of 24-h oxygen treatment for models trained on local data only (Local) versus that of the best global model available on the server (FL (gl. best)). Av., average test performance across all sites. , Genişletilebilirlik (orta AUC olarak temsil edilen diğer sitelerin test verilerindeki ortalama performans) bir müşteri veritabanının büyüklüğünün bir işlevi olarak (hiçbir durumda). yeşil yatay çizgi, en iyi küresel modelin genelleştirilebilirlik performansını gösterir. 20 müşteri için 18 için performans gösterilir, çünkü müşteri 12'nin sadece 72 saat oksijen için sonuçları vardı (Genişletilmiş veri figürü). ) ve 14 müşterinin sadece RA tedavisi olan vakaları vardı, bu nedenle değerlendirme metrikleri (AUC) bu durumların hiçbirinde geçerli değildi ( ). Data for client 14 were also excluded from computation of average generalizability in local models. a b 1 Methods Local models that were trained using unbalanced cohorts (for example, mostly mild cases of COVID-19) markedly benefited from the FL approach, with a substantial improvement in prediction average AUC performance for categories with only a few cases. This was evident at client site 16 (an unbalanced dataset), with most patients experiencing mild disease severity and with only a few severe cases. The FL model achieved a higher true-positive rate for the two positive (severe) cases and a markedly lower false-positive rate compared to the local model, both shown in the receiver operating characteristic (ROC) plots and confusion matrices (Fig. and Extended Data Fig. ). More important, the generalizability of the FL model was considerably increased over the locally trained model. 3a 2 , ROC at client site 16, with unbalanced data and mostly mild cases. , ROC of the local model at client site 12 (a small dataset), mean ROC of models trained on larger datasets corresponding to the five client sites in the Boston area (1, 4, 5, 6, 8) and ROC of the best global model in prediction of 72-h oxygen treatment for different thresholds of EXAM score (left, middle, right). The mean ROC is calculated based on five locally trained models while the gray area denotes the ROC standard deviation. ROCs for three different cutoff values ( Pos ve neg, bu sınav puanı aralığında tanımlanan pozitif ve negatif vakaların sayısını ifade eder. a b t In the case of client sites with relatively small datasets, the best FL model markedly outperformed not only the local model but also those trained on larger datasets from five client sites in the Boston area of the USA (Fig. ). 3b The global model performed well in predicting oxygen needs at 24/72 h in patients both COVID positive and negative (Extended Data Fig. ). 3 Validation at independent sites Following initial training, EXAM was subsequently tested at three independent validation sites: Cooley Dickinson Hospital (CDH), Martha’s Vineyard Hospital (MVH) and Nantucket Cottage Hospital (NCH), all in Massachusetts, USA. The model was not retrained at these sites and it was used only for validation purposes. The cohort size and model inference results are summarized in Table , and the ROC curves and confusion matrices for the largest dataset (from CDH) are shown in Fig. . The operating point was set to discriminate between nonmechanical ventilation and mechanical ventilation (MV) treatment (or death). The FL global trained model, EXAM, achieved an average AUC of 0.944 and 0.924 for 24- and 72-h prediction tasks, respectively (Table 24 saatte MV tedavisi (veya ölüm) tahmin etmek için, EXAM CDH'de 0.950 h hassasiyet ve 0.882 hassasiyet ve 1.000 hassasiyet MVH'de 0.934 hassasiyet elde etti. NCH 24 saatte MV/ölüm ile ilgili herhangi bir vakaya sahip değildi. 72 saat MV tahminine ilişkin olarak, EXAM CDH'de 0.929 hassasiyet ve 0.880 hassasiyet, 1000 hassasiyet ve 0.976 hassasiyet ve 1000 hassasiyet ve 0.929 hassasiyet elde etti. 2 4 2 , , Performance (ROC) (top) and confusion matrices (bottom) of the EXAM FL model on the CDH dataset for prediction of oxygen requirement at 24 h ( ) and 72 h ( ). ROCs for three different cutoff values ( ) of the EXAM risk score are shown. a b a b t For MV at CDH at 72 h, EXAM had a low false-negative rate of 7.1%. Representative failure cases are presented in Extended Data Fig. , showing two false-negative cases from CDH where one case had many missing EMR data features and the other had a CXR with a motion artifact and some missing EMR features. 4 Use of differential privacy A primary motivation for healthcare institutes to use FL is to preserve the security and privacy of their data, as well as adherence to data compliance measures. For FL, there remains the potential risk of model ‘inversion’ or even the reconstruction of training images from the model gradients themselves . To counter these risks, security-enhancing measures were used to mitigate risk in the event of data ‘interception’ during site-server communication . We experimented with techniques to avoid interception of FL data, and added a security feature that we believe could encourage more institutions to use FL. We thus validated previous findings showing that partial weight sharing, and other differential privacy techniques, can successfully be applied in FL Bir kısmi ağırlık paylaşım sisteminin araştırılmasıyla , , , modellerin yalnızca ağırlık güncellemelerinin% 25'ini paylaşıldığında bile karşılaştırılabilir bir performans elde edebildiğini gösterdik (Extended Data Fig. ) için 47 48 49 50 50 51 52 5 Discussion Bu çalışmada, kullanılan sitelerin sayısı ve veri noktalarının sayısı bakımından geniş, gerçek dünya FL çalışması bulunur. Bu çalışmada, sağlık sektöründe gerekli AI modellerinin hızlı ve işbirliği içinde geliştirilmesi için FL'yi kullanmanın uygulanabilirliğinin güçlü bir kanıtı olduğunu düşünüyoruz. Çalışmamız dört kıtada ve farklı düzenleyici organların denetimi altındaki çok sayıda siteyi içeriyor ve böylece farklı düzenlenmiş pazarlara hızlı bir şekilde sunulma vaatini yerine getiriyor. Küresel FL modeli, EXAM, bireysel sitelerde daha sağlam ve yalnızca yerel veriler üzerine eğitilmiş herhangi bir modelden daha iyi sonuçlar elde ettiğini kanıtladı. Bu faktörler, bu FL yaklaşımının faydalarını artırmada ve performans, genelleşme ve nihai olarak, modelleri kullanımı üzerindeki etkilerini artırmada önemli bir rol For a client site with a relatively small dataset, two typical approaches could be used for fitting a useful model: one is to train locally with its own data, the other is to apply a model trained on a larger dataset. For sites with small datasets, it would have been virtually impossible to build a performant deep learning model using only their local data. The finding, that these two approaches were outperformed on all three prediction tasks by the global FL model, indicates that the benefit for client sites with small datasets arising from participation in FL collaborations is substantial. This is probaby a reflection of FL’s ability to capture more diversity than local training, and to mitigate the bias present in models trained on a homogenous population. An under-represented population or age group in one hospital/region might be highly represented in another region—such as children who might be differentially affected by COVID-19, including disease manifestations in lung imaging . 46 Validasyon sonuçları küresel modelin dayanıklı olduğunu doğruladı, FL eğitilmiş modellerin sağlık sistemlerinde yaygınlaşabileceği varsayımımızı destekledi. COVID-19 hastane bakımında öngörülen algoritmaların kullanımı ve model oluşturulmasında ve testlerde FL'nin kullanımı için ikna edici bir durum sağlar. Bu çalışmaya katılarak, müşteri siteleri, herhangi bir düzenleyici onay veya klinik bakımda gelecekteki tanıtım öncesinde daha da doğrulanması için EXAM'a erişim sağladı. Aynı zamanda sınavın bir parçası değildi. 53 Over 200 prediction models to support decision-making in patients with COVID-19 have been published . Unlike the majority of publications focused on diagnosis of COVID-19 or prediction of mortality, we predicted oxygen requirements that have implications for patient management. We also used cases with unknown SARS-COV-2 status, and so the model could provide input to the physician ahead of receiving a result for PCR with reverse transcription (RT–PCR), making it useful for a real-life clinical setting. The model’s imaging input is used in common practice, in contrast with models that use chest computed tomography, a nonconsensual diagnostic modality. The model’s design was constrained to objective predictors, unlike many published studies that leveraged subjective clinical impressions. The data collected reflect varied incidence rates, and thus the ‘population momentum’ we encountered is more diverse. This implies that the algorithm can be useful in populations with different incidence rates. 19 Patient cohort identification and data harmonization are not novel issues in research and data science , but are further complicated, when using FL, given the lack of visibility on other sites’ datasets. Improvements to clinical information systems are needed to streamline data preparation, leading to better leverage of a network of sites participating in FL. This, in conjunction with hyperparameter engineering, can allow algorithms to ‘learn’ more effectively from larger data batches and adapt model parameters to a particular site for further personalization—for example, through further fine-tuning on that site . A system that would allow seamless, close-to real-time model inference and results processing would also be of benefit and would ‘close the loop’ from training to model deployment. 54 39 Because data were not centralized they are not readily accessible. Given that, any future analysis of the results, beyond what was derived and collected, is limited. Similar to other machine learning models, EXAM is limited by the quality of the training data. Institutions interested in deploying this algorithm for clinical care need to understand potential biases in the training. For example, the labels used as ground truth in the training of the EXAM model were derived from 24- and 72-h oxygen consumption in the patient; it is assumed that oxygen delivered to the patient equates the oxygen need. However, in the early phase of the COVID-19 pandemic, many patients were provided high-flow oxygen prophylactically regardless of their oxygen need. Such clinical practice could skew the predictions made by this model. Since our data access was limited, we did not have sufficient available information for the generation of detailed statistics regarding failure causes, post hoc, at most sites. However, we did study failure cases from the largest independent test site, CDH, and were able to generate hypotheses that we can test in the future. For high-performing sites, it seems that most failure cases fall into one of two categories: (1) low quality of input data—for example, missing data or motion artifact in CXR; or (2) out-of-distribution data—for example a very young patient. Gelecekte, hastalık ilerlemesinin farklı aşamaları nedeniyle “popülasyon kayması” potansiyelini de araştırmayı planlıyoruz. A feature that would enhance these kinds of large-scale collaboration is the ability to predict the contribution of each client site towards improving the global FL model. This will help in client site selection, and in prioritization of data acquisition and annotation efforts. The latter is especially important given the high costs and difficult logistics of these large-consortia endeavors, and it will enable these endeavors to capture diversity rather than the sheer quantity of data samples. Future approaches may incorporate automated hyperparameter searching , neural architecture search Diğer Otomatik Makine Öğrenimi Her bir müşteri sitesi için en iyi eğitim parametrelerini daha verimli bir şekilde bulmak için yaklaşımlar. 55 56 57 Known issues of batch normalization (BN) in FL Görüntü Özellikleri Ekstraksiyonu için temel modelimizi düzeltmek için bizi motive etti to reduce the divergence between unbalanced client sites. Future work might explore different types of normalization techniques to allow the training of AI models in FL more effectively when client data are nonindependent and identically distributed. 58 49 Recent works on privacy attacks within the FL setting have raised concerns on data leakage during model training . Meanwhile, protection algorithms remain underexplored and constrained by multiple factors. While differential privacy algorithms , , show good protection, they may weaken the model’s performance. Encryption algorithms, such as homomorphic encryption , maintain performance but may substantially increase message size and training time. A quantifiable way to measure privacy would allow better choices for deciding the minimal privacy parameters necessary while maintaining clinically acceptable performance , , . 59 36 48 49 60 36 48 49 Following further validation, we envision deployment of the EXAM model in the ED setting as a way to evaluate risk at both the per-patient and population level, and to provide clinicians with an additional reference point when making the frequently difficult task of triaging patients. We also envision using the model as a more sensitive population-level metric to help balance resources between regions, hospitals and departments. Our hope is that similar FL efforts can break the data silos and allow for faster development of much-needed AI models in the near future. Methods Ethics approval Bilinçli Hastalık Merkezi’nin tüm prosedürleri, Helsinkiler Deklarasyonu ve Uluslararası Sağlık Uygulama Kılavuzları’nda tanımlanan İnsan Deneyimi İlkelerine uygun olarak yürütüldü ve ilgili kurumsal inceleme kurulları tarafından aşağıdaki doğrulama sitelerinde onaylanmıştır: CDH, MVH, NCH ve aşağıdaki eğitim sitelerinde: MGB, Mass Genel Hastanesi (MGH), Brigham ve Kadın Hastanesi, Newton-Wellesley Hastanesi, North Shore Halk Tıp Merkezi ve New Faulkner Hastanesi (bu hastalardan sekiz tanesi, MGB’nin etik danışmanlık kurulu referansı, No. 2020P002673, ve bilgilendirilmiş onay, kurumsal inceleme kurulu (IRBH) tarafından reddedildi). Benzer şekilde, Klinik AI modellerinin raporlanması için MI-CLAIM kılavuzları uygulanmıştır (Devamını Oku ) 2 Study setting The study included data from 20 institutions (Fig. ): MGB, MGH, Brigham and Women’s Hospital, Newton-Wellesley Hospital, North Shore Medical Center and Faulkner Hospital; Children’s National Hospital in Washington, DC; NIHR Cambridge Biomedical Research Centre; The Self-Defense Forces Central Hospital in Tokyo; National Taiwan University MeDA Lab and MAHC and Taiwan National Health Insurance Administration; Tri-Service General Hospital in Taiwan; Kyungpook National University Hospital in South Korea; Faculty of Medicine, Chulalongkorn University in Thailand; Diagnosticos da America SA in Brazil; University of California, San Francisco; VA San Diego; University of Toronto; National Institutes of Health in Bethesda, Maryland; University of Wisconsin-Madison School of Medicine and Public Health; Memorial Sloan Kettering Cancer Center in New York; and Mount Sinai Health System in New York. Institutions were recruited between March and May 2020. Dataset curation started in June 2020 and the final data cohort was added in September 2020. Between August and October 2020, 140 independent FL runs were conducted to develop the EXAM model and, by the end of October 2020, EXAM was made public on NVIDIA NGC , , Bağımsız doğrulama için üç bağımsız siteden gelen veriler kullanılmıştır: CDH, MVH ve NCH, Massachusetts, ABD. Bu üç hastane, eğitim sitelerinden farklı hastalık nüfus özelliklerine sahipti. Algoritma doğrulaması için kullanılan veriler, Mart 2020 ve Şubat 2021 tarihleri arasında bu sitelerde ED'ye kabul edilen hastalardan oluşmuştur ve FL modelini eğitmek için kullanılan verilerle aynı kapsama kriterlerini karşılamıştır. 1a 61 62 63 Data collection The 20 client sites prepared a total of 16,148 cases (both positive and negative) for the purposes of training, validation and testing of the model (Fig. ). Medical data were accessed in relation to patients who satisfied the study inclusion criteria. Client sites strived to include all COVID-positive cases from the beginning of the pandemic in December 2019 and up to the time they started local training for the EXAM study. All local training had started by 30 September 2020. The sites also included other patients in the same period with negative RT–PCR test results. Since most of the sites had more SARS-COV-2-negative than -positive patients, we limited the number of negative patients included to, at most, 95% of the total cases at each client site. 1b A ‘case’ included a CXR and the requisite data inputs taken from the patient’s medical record. A breakdown of the cohort size of the dataset for each client site is shown in Fig. . The distribution and patterns of CXR image intensity (pixel values) varied greatly among sites owing to a multitude of patient- and site-specific factors, such as different device manufacturers and imaging protocols, as shown in Fig. . Patient age and EMR feature distribution varied greatly among sites, as expected owing to the differing demographics between globally distributed hospitals (Extended Data Fig. ). 1b 1c,d 6 Patient inclusion criteria Patient inclusion criteria were: (1) patient presented to the hospital’s ED or equivalent; (2) patient had a RT–PCR test performed at any time between presentation to the ED and discharge from the hospital; (3) patient had a CXR in the ED; and (4) patient’s record had at least five of the EMR values detailed in Table , all obtained in the ED, and the relevant outcomes captured during hospitalization. Of note, The CXR, laboratory results and vitals used were the first available for capture during the visit to the ED. The model did not incorporate any CXR, laboratory results or vitals acquired after leaving the ED. 1 Model input In total, 21 EMR features were used as input to the model. The outcome (that is, ground truth) labels were assigned based on patient requirements after 24- and 72-h periods from initial admission to the ED. A detailed list of the requested EMR features and outcomes can be seen in Table . 1 The distribution of oxygen treatment using different devices at different client sites is shown in Extended Data Fig. , which details the device usage at admission to the ED and after 24- and 72-h periods. The difference in dataset distribution between the largest and smallest client sites can be seen in Extended Data Fig. . 7 8 The number of positive COVID-19 cases, as confirmed by a single RT–PCR test obtained at any time between presentation to the ED and discharge from the hospital, is listed in Supplementary Table . Each client site was asked to randomly split its dataset into three parts: 70% for training, 10% for validation and 20% for testing. For both 24- and 72-h outcome prediction models, random splits for each of the three repeated local and FL training and evaluation experiments were independently generated. 1 EXAM model development There is wide variation in the clinical course of patients who present to hospital with symptoms of COVID-19, with some experiencing rapid deterioration in respiratory function requiring different interventions to prevent or mitigate hypoxemia , . A critical decision made during the evaluation of a patient at the initial point of care, or in the ED, is whether the patient is likely to require more invasive or resource-limited countermeasures or interventions (such as MV or monoclonal antibodies), and should therefore receive a scarce but effective therapy, a therapy with a narrow risk–benefit ratio due to side effects or a higher level of care, such as admittance to the intensive care unit . In contrast, a patient who is at lower risk of requiring invasive oxygen therapy may be placed in a less intensive care setting such as a regular ward, or even released from the ED for continuing self-monitoring at home . EXAM was developed to help triage such patients. 62 63 64 65 Of note, the model is not approved by any regulatory agency at this time and it should be used only for research purposes. EXAM score EXAM was trained using FL; it outputs a risk score (termed EXAM score) similar to CORISK (Extended Data Fig. ) and can be used in the same way to triage patients. It corresponds to a patient’s oxygen support requirements within two windows—24 and 72 h—after initial presentation to the ED. Extended Data Fig. illustrates how CORISK and the EXAM score can be used for patient triage. 27 9a 9b Göğüs X-ray görüntüleri, ön konum görüntüsünü seçmek ve yan görüntü görüntüleri dışlamak için önceden işlenmiş ve daha sonra 224 × 224 çözünürlüğe ölçülmüştür. , the model fuses information from both EMR and CXR features (based on a modified ResNet34 with spatial attention pretrained on the CheXpert dataset) and the Deep & Cross network . To converge these different data types, a 512-dimensional feature vector was extracted from each CXR image using a pretrained ResNet34, with spatial attention, then concatenated with the EMR features as the input for the Deep & Cross network. The final output was a continuous value in the range 0–1 for both 24- and 72-h predictions, corresponding to the labels described above, as shown in Extended Data Fig. . We used cross-entropy as the loss function and ‘Adam’ as the optimizer. The model was implemented in Tensorflow using the NVIDIA Clara Train SDK . The average AUC for the classification tasks (≥LFO, ≥HFO/NIV or ≥MV) was calculated and used as the final evaluation metric, with normalization to zero-mean and unit variance. CXR images were preprocessed to select the correct series and exclude lateral view images, then scaled to a resolution of 224 × 224 (ref. ). 9a 66 67 68 9b 69 70 27 Feature imputation and normalization A MissForest algorithm was used to impute EMR features, based on the local training dataset. If an EMR feature was completely missing from a client site dataset, the mean value of that feature, calculated exclusively on data from MGB client sites, was used. Then, EMR features were rescaled to zero-mean and unit variance based on statistics calculated on data from the MGB client sites. 71 Details of EMR–CXR data fusion using the Deep & Cross network EMR ve CXR verilerindeki özelliklerin etkileşimlerini örneklemek için, Deep & Cross ağ mimarisine dayanan derin özellik şeması kullanılmıştır. . Binary and categorical features for the EMR inputs, as well as 512-dimensional image features in the CXR, were transformed into fused dense vectors of real values by embedding and stacking layers. The transformed dense vectors served as input to the fusion framework, which specifically employed a crossing network to enforce fusion among input from different sources. The crossing network performed explicit feature crossing within its layers, by conducting inner products between the original input feature and output from the previous layer, thus increasing the degree of interaction across features. At the same time, two individual classic deep neural networks with several stacked, fully connected feed-forward layers were trained. The final output of our framework was then derived from the concatenation of both classic and crossing networks. 68 FL details Arguably the most established form of FL is implemention of the federated averaging algorithm as proposed by McMahan et al. , or variations thereof. This algorithm can be realized using a client-server setup where each participating site acts as a client. One can think of FL as a method aiming to minimize a global loss function by reducing a set of local loss functions, which are estimated at each site. By minimizing each client site’s local loss while also synchronizing the learned client site weights on a centralized aggregation server, one can minimize global loss without needing to access the entire dataset in a centralized location. Each client site learns locally, and shares model weight updates with a central server that aggregates contributions using secure sockets layer encryption and communication protocols. The server then sends an updated set of weights to each client site after aggregation, and sites resume training locally. The server and client site iterate back and forth until the model converges (Extended Data Fig. ). 72 9c A pseudoalgorithm of FL is shown in Supplementary Note . In our experiments, we set the number of federated rounds at = 200, with one local training epoch per round at each client. The number of clients, , was up to 20 depending on the network connectivity of clients or available data for a specific targeted outcome period (24 or 72 h). The number of local training iterations, , depends on the dataset size at each client and is used to weigh each client’s contributions when aggregating the model weights in federated averaging. During the FL training task, each client site selects its best local model by tracking the model’s performance on its local validation set. At the same time, the server determines the best global model based on the average validation scores sent from each client site to the server after each FL round. After FL training finishes, the best local models and the best global model are automatically shared with all client sites and evaluated on their local test data. 1 T t K nk k When training on local data only (the baseline), we set the epoch number to 200. The Adam optimizer was used for both local training and FL with an initial learning rate of 5 × 10–5 and a stepwise learning rate decay with a factor 0.5 after every 40 epochs, which is important for the convergence of federated averaging . Random affine transformations, including rotation, translations, shear, scaling and random intensity noise and shifts, were applied to the images for data augmentation during training. 73 Owing to the sensitivity of BN layers when dealing with different clients in a nonindependent and identically distributed setting, we found the best model performance occurred when keeping the pretrained ResNet34 with spatial attention parameters fixed during FL training (that is, using a learning rate of zero for those layers). The Deep & Cross network that combines image features with EMR features does not contain BN layers and hence was not affected by BN instability issues. 58 47 In this study we investigated a privacy-preserving scheme that shares only partial model updates between server and client sites. The weight updates were ranked during each iteration by magnitude of contribution, and only a certain percentage of the largest weight updates was shared with the server. To be exact, weight updates (also known as gradients) were shared only if their absolute value was above a certain percentile threshold, f) Genişletilmiş veri tablosu. ), which was computed from all non-zero gradients, Δ , and could be different for each client Her turda FL . Variations of this scheme could include additional clipping of large gradients or differential privacy schemes that add random noise to the gradients, or even to the raw data, before feeding into the network . k 5 Wk(t) k t 49 51 Statistical analysis We conducted a Wilcoxon signed-rank test to confirm the significance of the observed improvement in performance between the locally trained model and the FL model for the 24- and 72-h time points (Fig. and Extended Data Fig. ). The null hypothesis was rejected with one-sided « 1 × 10–3 in both cases. 2 1 P Pearson’s correlation was used to assess the generalizability (robustness of the average AUC value to other client sites’ test data) of locally trained models in relation to respective local dataset size. Only a moderate correlation was observed ( 0 0 43 = 0.035, degrees of freedom (df) = 17 for the 24-h model and = 0.62, 72-h modeli için = 0,003, df = 16). Bu, yalnızca veri kümesi büyüklüğünün bir modelin görünmez verilere karşı sağlamlığını belirleyen tek faktör olmadığını göstermektedir. r P r P To compare ROC curves from the global FL model and local models trained at different sites (Extended Data Fig. ), we bootstrapped 1,000 samples from the data and computed the resulting AUCs. We then calculated the difference between the two series and standardized using the formula AUC1 – AUC2 – AUC2 – AUC2 , where is the standardized difference, is the standard deviation of the bootstrap differences and AUC1 and AUC2 are the corresponding bootstrapped AUC series. By comparing with normal distribution, we obtained the values illustrated in Supplementary Table . The results show that the null hypothesis was rejected with very low values, indicating the statistical significance of the superiority of FL outcomes. The computation of değerleri, pROC kütüphanesi ile R'de gerçekleştirildi . 3 D s D s D P 2 P P 74 Model, 0’dan 1’e kadar sürekli bir puanlama ile ayrıntılı bir sonuç tahmin ettiği için, qqplot gibi basit bir kalibrasyon değerlendirmesi mümkün değildir. ). We conducted one-way analysis of variation (ANOVA) tests to compare local and FL model scores among four ground truth categories (RA, LFO, HFO, MV). The -statistic, calculated as the variation between the sample means divided by variation within the samples and representing the degree of dispersion among different groups, was used to quantify the models. Our results show that the -values of five different local sites are 245.7, 253.4, 342.3, 389.8 and 634.8, while that of the FL model is 843.5. Given that larger -values mean that groups are more separable, the scores from our FL model clearly show a greater dispersion among the four ground truth categories. Furthermore, the value of the ANOVA test on the FL model is <2 × 10–16, indicating that the FL prediction scores are statistically significantly different among the different prediction classes. 10 F F F P Reporting Summary Further information on research design is available in the linked to this article. Nature Research Reporting Summary Data availability The dataset from the 20 institutes that participated in this study remains under their custody. These data were used for training at each of the local sites and were not shared with any of the other participating institutions or with the federated server, and they are not publicly available. Data from the independent validation sites are maintained by CAMCA, and access can be requested by contacting Q.L. Based on determination by CAMCA, a data-sharing review and amendment of IRB for research purposes can be conducted by MGB research administration and in accordance with MGB IRB and policy. Code availability All code and software used in this study are publicly available at NGC. To access, log in as a guest or create a profile then enter one of the URLs below. The trained models, data preparation guidelines, code for training, validating testing of the model, readme file, installation guideline and license files are publicly available at NVIDIA NGC : Hakkında Federated Learning yazılımı Clara Train SDK'nın bir parçası olarak mevcuttur: . Alternatively, use this command to download the model “wget --content-disposition -O clara_train_covid19_exam_ehr_xray_1.zip”. 61 https://ngc.nvidia.com/catalog/models/nvidia:med:clara_train_covid19_exam_ehr_xray https://ngc.nvidia.com/catalog/containers/nvidia:clara-train-sdk https://api.ngc.nvidia.com/v2/models/nvidia/med/clara_train_covid19_exam_ehr_xray/versions/1/zip References Budd, J. et al. Digital technologies in the public-health response to COVID-19. , 1183–1192 (2020). Nat. Med. 26 Moorthy, V., Henao Restrepo, A. M., Preziosi, M.-P. & Swaminathan, S. Data sharing for novel coronavirus (COVID-19). , 150 (2020). Bull. World Health Organ. 98 Chen, Q., Allot, A. & Lu, Z. Keep up with the latest coronavirus research. , 193 (2020). Nature 579 Fabbri, F., Bhatia, A., Mayer, A., Schlotter, B. & Kaiser, J. BCG IT spend pulse: how COVID-19 is shifting tech priorities. 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Machine Learning Robin, X. et al. pROC: an open-source package for R and S+ to analyze and compare ROC curves. , 77 (2011). BMC Bioinformatics 12 Acknowledgements The views expressed in this study are those of the authors and not necessarily those of the NHS, the NIHR, the Department of Health and Social Care or any of the organizations associated with the authors. MGB thank the following individuals for their support: J. Brink, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA; M. Kalra, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA; N. Neumark, Center for Clinical Data Science, Massachusetts General Brigham, Boston, MA; T. Schultz, Department of Radiology, Massachusetts General Hospital, Boston, MA; N. Guo, Center for Advanced Medical Computing and Analysis, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA; J. K. Cramer, Director, QTIM lab at the Athinoula A. Martinos Center for Biomedical Imaging at MGH; S. Pomerantz, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA; G. Boland, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; W. Mayo-Smith, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA. UCSF thank P. B. Storey, J. Chan and J. Block for implementing the UCSF FL client infrastructure, and W. Tellis for providing the source imaging repository for this work. The UCSF EMR and clinical notes for this study were accessed via the COVID-19 Research Data Mart, . The Faculty of Medicine, Chulalongkorn University thank the Ratchadapisek Sompoch Endowment Fund RA (PO) (no. 001/63) for the collection and management of COVID‐19-related clinical data and biological specimens for the Research Task Force, Faculty of Medicine, Chulalongkorn University. NIHR Cambridge Biomedical Research Centre thank A. Priest, who is supported by the NIHR (Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust). National Taiwan University MeDA Lab and the MAHC and Taiwan National Health Insurance Administration thank the MOST Joint Research Center for AI technology, the All Vista Healthcare National Health Insurance Administration, Taiwan, the Ministry of Science and Technology, Taiwan and the National Center for Theoretical Sciences Mathematics Division. National Institutes of Health (NIH) acknowledge that the NIH Medical Research Scholars Program is a public–private partnership supported jointly by the NIH and by generous contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation, the American Association for Dental Research, the Colgate-Palmolive Company, Genentech, alumni of student research programs and other individual supporters via contributions to the Foundation for the NIH. https://data.ucsf.edu/covid19 This paper is under CC by 4.0 Deed (Attribution 4.0 International) license. available on nature This paper is under CC by 4.0 Deed (Attribution 4.0 International) license. available on nature
