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Skin conditions affect an estimated 1.9 billion people worldwide. A shortage of dermatologists causes long wait times and leads patients to seek dermatologic care from general practitioners. However, the diagnostic accuracy of general practitioners has been reported to be only 0.24-0.70 (compared to 0.77-0.96 for dermatologists), resulting in referral errors, delays in care, and errors in diagnosis and treatment. In this paper, we developed a deep learning system (DLS) to provide a differential diagnosis of skin conditions for clinical cases (skin photographs and associated medical histories). The DLS distinguishes between 26 skin conditions that represent roughly 80% of the volume of skin conditions seen in primary care. The DLS was developed and validated using de-identified cases from a teledermatology practice serving 17 clinical sites via a temporal split: the first 14,021 cases for development and the last 3,756 cases for validation. On the validation set, where a panel of three board-certified dermatologists defined the reference standard for every case, the DLS achieved 0.71 and 0.93 top-1 and top-3 accuracies respectively. For a random subset of the validation set (n=963 cases), 18 clinicians reviewed the cases for comparison. On this subset, the DLS achieved a 0.67 top-1 accuracy, non-inferior to board-certified dermatologists (0.63, p

Chest radiography (CXR) is the most widely-used thoracic clinical imaging modality and is crucial for guiding the management of cardiothoracic conditions. The detection of specific CXR findings has been the main focus of several artificial intelligence (AI) systems. However, the wide range of possible CXR abnormalities makes it impractical to detect every possible condition by building multiple separate systems, each of which detects one or more pre-specified conditions. In this work, we developed and evaluated an AI system to classify CXRs as normal or abnormal. For training and tuning the system, we used a de-identified dataset of 248,445 patients from a multi-city hospital network in India. To assess generalizability, we evaluated our system using 6 international datasets from India, China, and the United States. Of these datasets, 4 focused on diseases that the AI was not trained to detect: 2 datasets with tuberculosis and 2 datasets with coronavirus disease 2019. Our results suggest that the AI system trained using a large dataset containing a diverse array of CXR abnormalities generalizes to new patient populations and unseen diseases. In a simulated workflow where the AI system prioritized abnormal cases, the turnaround time for abnormal cases reduced by 7–28%. These results represent an important step towards evaluating whether AI can be safely used to flag cases in a general setting where previously unseen abnormalities exist. Lastly, to facilitate the continued development of AI models for CXR, we release our collected labels for the publicly available dataset.

Background Automated machine-learning systems are able to de-identify electronic medical records, including free-text clinical notes. Use of such systems would greatly boost the amount of data available to researchers, yet their deployment has been limited due to uncertainty about their performance when applied to new datasets. Objective We present practical options for clinical note de-identification, assessing performance of machine learning systems ranging from off-the-shelf to fully customized. Methods We implement a state-of-the-art machine learning de-identification system, training and testing on pairs of datasets that match the deployment scenarios. We use clinical notes from two i2b2 competition corpora, the Physionet Gold Standard corpus, and parts of the MIMIC-III dataset. Results Fully customized systems remove 97–99% of personally identifying information. Performance of off-the-shelf systems varies by dataset, with performance mostly above 90%. Providing a small labeled dataset or large unlabeled dataset allows for fine-tuning that improves performance over off-the-shelf systems. Conclusion Health organizations should be aware of the levels of customization available when selecting a de-identification deployment solution, in order to choose the one that best matches their resources and target performance level.

The brightfield microscope is instrumental in the visual examination of both biological and physical samples at sub-millimeter scales. One key clinical application has been in cancer histopathology, where the microscopic assessment of the tissue samples is used for the diagnosis and staging of cancer and thus guides clinical therapy. However, the interpretation of these samples is inherently subjective, resulting in significant diagnostic variability. Moreover, in many regions of the world, access to pathologists is severely limited due to lack of trained personnel. In this regard, Artificial Intelligence (AI) based tools promise to improve the access and quality of healthcare. However, despite significant advances in AI research, integration of these tools into real-world cancer diagnosis workflows remains challenging because of the costs of image digitization and difficulties in deploying AI solutions. Here we propose a cost-effective solution to the integration of AI: the Augmented Reality Microscope (ARM). The ARM overlays AI-based information onto the current view of the sample through the optical pathway in real-time, enabling seamless integration of AI into the regular microscopy workflow. We demonstrate the utility of ARM in the detection of lymph node metastases in breast cancer and the identification of prostate cancer with a latency that supports real-time workflows. We anticipate that ARM will remove barriers towards the use of AI in microscopic analysis and thus improve the accuracy and efficiency of cancer diagnosis. This approach is applicable to other microscopy tasks and AI algorithms in the life sciences and beyond.

For prostate cancer patients, the Gleason score is one of the most important prognostic factors, potentially determining treatment independent of the stage. However, Gleason scoring is based on subjective microscopic examination of tumor morphology and suffers from poor reproducibility. Here we present a deep learning system (DLS) for Gleason scoring whole-slide images of prostatectomies. Our system was developed using 112 million pathologist-annotated image patches from 1226 slides, and evaluated on an independent validation dataset of 331 slides. Compared to a reference standard provided by genitourinary pathology experts, the mean accuracy among 29 general pathologists was 0.61 on the validation set. The DLS achieved a significantly higher diagnostic accuracy of 0.70 (p = 0.002) and trended towards better patient risk stratification in correlations to clinical follow-up data. Our approach could improve the accuracy of Gleason scoring and subsequent therapy decisions, particularly where specialist expertise is unavailable. The DLS also goes beyond the current Gleason system to more finely characterize and quantitate tumor morphology, providing opportunities for refinement of the Gleason system itself.

We develop and rigorously evaluate a deep learning based system that can accurately classify skin conditions while detecting rare conditions for which there is not enough data available for training a confident classifier. We frame this task as an out-of-distribution (OOD) detection problem. Our novel approach, hierarchical outlier detection (HOD) assigns multiple abstention classes for each training outlier class and jointly performs a coarse classification of inliers vs. outliers, along with fine-grained classification of the individual classes. We demonstrate the effectiveness of the HOD loss in conjunction with modern representation learning approaches (BiT, SimCLR, MICLe) and explore different ensembling strategies for further improving the results. We perform an extensive subgroup analysis over conditions of varying risk levels and different skin types to investigate how the OOD detection performance changes over each subgroup and demonstrate the gains of our framework in comparison to baselines. Finally, we introduce a cost metric to approximate downstream clinical impact. We use this cost metric to compare the proposed method against a baseline system, thereby making a stronger case for the overall system effectiveness in a real-world deployment scenario., Comment: Under Review, 19 Pages

Deriving interpretable prognostic features from deep-learning-based prognostic histopathology models remains a challenge. In this study, we developed a deep learning system (DLS) for predicting disease-specific survival for stage II and III colorectal cancer using 3652 cases (27,300 slides). When evaluated on two validation datasets containing 1239 cases (9340 slides) and 738 cases (7140 slides), respectively, the DLS achieved a 5-year disease-specific survival AUC of 0.70 (95% CI: 0.66–0.73) and 0.69 (95% CI: 0.64–0.72), and added significant predictive value to a set of nine clinicopathologic features. To interpret the DLS, we explored the ability of different human-interpretable features to explain the variance in DLS scores. We observed that clinicopathologic features such as T-category, N-category, and grade explained a small fraction of the variance in DLS scores (R2 = 18% in both validation sets). Next, we generated human-interpretable histologic features by clustering embeddings from a deep-learning-based image-similarity model and showed that they explained the majority of the variance (R2 of 73–80%). Furthermore, the clustering-derived feature most strongly associated with high DLS scores was also highly prognostic in isolation. With a distinct visual appearance (poorly differentiated tumor cell clusters adjacent to adipose tissue), this feature was identified by annotators with 87.0–95.5% accuracy. Our approach can be used to explain predictions from a prognostic deep learning model and uncover potentially-novel prognostic features that can be reliably identified by people for future validation studies.

Much work aims to explain a model's prediction on a static input. We consider explanations in a temporal setting where a stateful dynamical model produces a sequence of risk estimates given an input at each time step. When the estimated risk increases, the goal of the explanation is to attribute the increase to a few relevant inputs from the past. While our formal setup and techniques are general, we carry out an in-depth case study in a clinical setting. The goal here is to alert a clinician when a patient's risk of deterioration rises. The clinician then has to decide whether to intervene and adjust the treatment. Given a potentially long sequence of new events since she last saw the patient, a concise explanation helps her to quickly triage the alert. We develop methods to lift static attribution techniques to the dynamical setting, where we identify and address challenges specific to dynamics. We then experimentally assess the utility of different explanations of clinical alerts through expert evaluation.

Traditionally, medical discoveries are made by observing associations, making hypotheses from them and then designing and running experiments to test the hypotheses. However, with medical images, observing and quantifying associations can often be difficult because of the wide variety of features, patterns, colours, values and shapes that are present in real data. Here, we show that deep learning can extract new knowledge from retinal fundus images. Using deep-learning models trained on data from 284,335 patients and validated on two independent datasets of 12,026 and 999 patients, we predicted cardiovascular risk factors not previously thought to be present or quantifiable in retinal images, such as age (mean absolute error within 3.26 years), gender (area under the receiver operating characteristic curve (AUC) = 0.97), smoking status (AUC = 0.71), systolic blood pressure (mean absolute error within 11.23 mmHg) and major adverse cardiac events (AUC = 0.70). We also show that the trained deep-learning models used anatomical features, such as the optic disc or blood vessels, to generate each prediction.

We propose a simple solution to use a single Neural Machine Translation (NMT) model to translate between multiple languages. Our solution requires no changes to the model architecture from a standard NMT system but instead introduces an artificial token at the beginning of the input sentence to specify the required target language. Using a shared wordpiece vocabulary, our approach enables Multilingual NMT systems using a single model. On the WMT’14 benchmarks, a single multilingual model achieves comparable performance for English→French and surpasses state-of-theart results for English→German. Similarly, a single multilingual model surpasses state-of-the-art results for French→English and German→English on WMT’14 and WMT’15 benchmarks, respectively. On production corpora, multilingual models of up to twelve language pairs allow for better translation of many individual pairs. Our models can also learn to perform implicit bridging between language pairs never seen explicitly during training, showing that transfer learning and zero-shot translation is possible for neural translation. Finally, we show analyses that hints at a universal interlingua representation in our models and also show some interesting examples when mixing languages.

Model explanation techniques play a critical role in understanding the source of a model’s performance and making its decisions transparent. Here we investigate if explanation techniques can also be used as a mechanism for scientific discovery. We make three contributions: first, we propose a framework to convert predictions from explanation techniques to a mechanism of discovery. Second, we show how generative models in combination with black-box predictors can be used to generate hypotheses (without human priors) that can be critically examined. Third, with these techniques we study classification models for retinal images predicting Diabetic Macular Edema (DME), where recent work [30] showed that a CNN trained on these images is likely learning novel features in the image. We demonstrate that the proposed framework is able to explain the underlying scientific mechanism, thus bridging the gap between the model’s performance and human understanding.

Purpose To present and evaluate a remote, tool-based system and structured grading rubric for adjudicating image-based diabetic retinopathy (DR) grades. Methods We compared three different procedures for adjudicating DR severity assessments among retina specialist panels, including (1) in-person adjudication based on a previously described procedure (Baseline), (2) remote, tool-based adjudication for assessing DR severity alone (TA), and (3) remote, tool-based adjudication using a feature-based rubric (TA-F). We developed a system allowing graders to review images remotely and asynchronously. For both TA and TA-F approaches, images with disagreement were reviewed by all graders in a round-robin fashion until disagreements were resolved. Five panels of three retina specialists each adjudicated a set of 499 retinal fundus images (1 panel using Baseline, 2 using TA, and 2 using TA-F adjudication). Reliability was measured as grade agreement among the panels using Cohen's quadratically weighted kappa. Efficiency was measured as the number of rounds needed to reach a consensus for tool-based adjudication. Results The grades from remote, tool-based adjudication showed high agreement with the Baseline procedure, with Cohen's kappa scores of 0.948 and 0.943 for the two TA panels, and 0.921 and 0.963 for the two TA-F panels. Cases adjudicated using TA-F were resolved in fewer rounds compared with TA (P < 0.001; standard permutation test). Conclusions Remote, tool-based adjudication presents a flexible and reliable alternative to in-person adjudication for DR diagnosis. Feature-based rubrics can help accelerate consensus for tool-based adjudication of DR without compromising label quality. Translational Relevance This approach can generate reference standards to validate automated methods, and resolve ambiguous diagnoses by integrating into existing telemedical workflows.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Behavior deviating from our normative expectations often appears irrational. For example, even though behavior following the so-called matching law can maximize reward in a stationary foraging task, actual behavior commonly deviates from matching. Such behavioral deviations are interpreted as a failure of the subject; however, here we instead suggest that they reflect an adaptive strategy, suitable for uncertain, non-stationary environments. To prove it, we analyzed the behavior of primates that perform a dynamic foraging task. In such nonstationary environment, learning on both fast and slow timescales is beneficial: fast learning allows the animal to react to sudden changes, at the price of large fluctuations (variance) in the estimates of task relevant variables. Slow learning reduces the fluctuations but costs a bias that causes systematic behavioral deviations. Our behavioral analysis shows that the animals solved this bias-variance tradeoff by combining learning on both fast and slow timescales, suggesting that learning on multiple timescales can be a biologically plausible mechanism for optimizing decisions under uncertainty., Recent experience can only provide limited information to guide decisions in a volatile environment. Here, the authors report that the choices made by a monkey in a dynamic foraging task can be better explained by a model that combines learning on both fast and slow timescales.

The increasing availability of large institutional and public histopathology image datasets is enabling the searching of these datasets for diagnosis, research, and education. Though these datasets typically have associated metadata such as diagnosis or clinical notes, even carefully curated datasets rarely contain annotations of the location of regions of interest on each image. Because pathology images are extremely large (up to 100,000 pixels in each dimension), further laborious visual search of each image may be needed to find the feature of interest. In this paper, we introduce a deep learning based reverse image search tool for histopathology images: Similar Medical Images Like Yours (SMILY). We assessed SMILY's ability to retrieve search results in two ways: using pathologist-provided annotations, and via prospective studies where pathologists evaluated the quality of SMILY search results. As a negative control in the second evaluation, pathologists were blinded to whether search results were retrieved by SMILY or randomly. In both types of assessments, SMILY was able to retrieve search results with similar histologic features, organ site, and prostate cancer Gleason grade compared with the original query. SMILY may be a useful general-purpose tool in the pathologist's arsenal, to improve the efficiency of searching large archives of histopathology images, without the need to develop and implement specific tools for each application., 23 Pages with 6 figures and 3 tables. The file also has 6 pages of supplemental material. Improved figure resolution, edited metadata

Machine learning (ML) is increasingly being used in image retrieval systems for medical decision making. One application of ML is to retrieve visually similar medical images from past patients (e.g. tissue from biopsies) to reference when making a medical decision with a new patient. However, no algorithm can perfectly capture an expert's ideal notion of similarity for every case: an image that is algorithmically determined to be similar may not be medically relevant to a doctor's specific diagnostic needs. In this paper, we identified the needs of pathologists when searching for similar images retrieved using a deep learning algorithm, and developed tools that empower users to cope with the search algorithm on-the-fly, communicating what types of similarity are most important at different moments in time. In two evaluations with pathologists, we found that these refinement tools increased the diagnostic utility of images found and increased user trust in the algorithm. The tools were preferred over a traditional interface, without a loss in diagnostic accuracy. We also observed that users adopted new strategies when using refinement tools, re-purposing them to test and understand the underlying algorithm and to disambiguate ML errors from their own errors. Taken together, these findings inform future human-ML collaborative systems for expert decision-making.

Here we present deep-learning techniques for healthcare, centering our discussion on deep learning in computer vision, natural language processing, reinforcement learning, and generalized methods. We describe how these computational techniques can impact a few key areas of medicine and explore how to build end-to-end systems. Our discussion of computer vision focuses largely on medical imaging, and we describe the application of natural language processing to domains such as electronic health record data. Similarly, reinforcement learning is discussed in the context of robotic-assisted surgery, and generalized deep-learning methods for genomics are reviewed.

Predictive modeling with electronic health record (EHR) data is anticipated to drive personalized medicine and improve healthcare quality. Constructing predictive statistical models typically requires extraction of curated predictor variables from normalized EHR data, a labor-intensive process that discards the vast majority of information in each patient's record. We propose a representation of patients' entire, raw EHR records based on the Fast Healthcare Interoperability Resources (FHIR) format. We demonstrate that deep learning methods using this representation are capable of accurately predicting multiple medical events from multiple centers without site-specific data harmonization. We validated our approach using de-identified EHR data from two U.S. academic medical centers with 216,221 adult patients hospitalized for at least 24 hours. In the sequential format we propose, this volume of EHR data unrolled into a total of 46,864,534,945 data points, including clinical notes. Deep learning models achieved high accuracy for tasks such as predicting in-hospital mortality (AUROC across sites 0.93-0.94), 30-day unplanned readmission (AUROC 0.75-0.76), prolonged length of stay (AUROC 0.85-0.86), and all of a patient's final discharge diagnoses (frequency-weighted AUROC 0.90). These models outperformed state-of-the-art traditional predictive models in all cases. We also present a case-study of a neural-network attribution system, which illustrates how clinicians can gain some transparency into the predictions. We believe that this approach can be used to create accurate and scalable predictions for a variety of clinical scenarios, complete with explanations that directly highlight evidence in the patient's chart., Comment: Published version from https://www.nature.com/articles/s41746-018-0029-1

Behavior which deviates from our normative expectations often appears irrational. A classic example concerns the question of how choice should be distributed among multiple alternatives. The so-called matching law predicts that the fraction of choices made to any option should match the fraction of total rewards earned from the option. This choice strategy can maximize reward in a stationary reward schedule. Empirically, however, behavior often deviates from this ideal. While such deviations have often been interpreted as reflecting ‘noisy’, suboptimal, decision-making, here we instead suggest that they reflect a strategy which is adaptive in nonstationary and uncertain environments. We analyze the results of a dynamic foraging task. Animals exhibited significant deviations from matching, and animals turned out to be able to collect more rewards when deviation was larger. We show that this behavior can be understood if one considers that animals had incomplete information about the environments dynamics. In particular, using computational models, we show that in such nonstationary environments, learning on both fast and slow timescales is beneficial. Learning on fast timescales means that an animal can react to sudden changes in the environment, though this inevitably introduces large fluctuations (variance) in value estimates. Concurrently, learning on slow timescales reduces the amplitude of these fluctuations at the price of introducing a bias that causes systematic deviations. We confirm this prediction in data – monkeys indeed solved the bias-variance tradeoff by combining learning on both fast and slow timescales. Our work suggests that multi-timescale learning could be a biologically plausible mechanism for optimizing decisions under uncertainty.

The memory capacity, computational power, communication bandwidth, energy consumption, and physical size of the brain all tend to scale with the number of synapses, which outnumber neurons by a factor of 10,000. Although progress in cortical simulations using modern digital computers has been rapid, the essential disparity between the classical von Neumann computer architecture and the computational fabric of the nervous system makes large-scale simulations expensive, power hungry, and time consuming. Over the last three decades, CMOS-based neuromorphic implementations of “electronic cortex” have emerged as an energy efficient alternative for modeling neuronal behavior. However, the key ingredient for electronic implementation of any self-learning system—programmable, plastic Hebbian synapses scalable to biological densities—has remained elusive. We demonstrate the viability of implementing such electronic synapses using nanoscale phase change devices. We introduce novel programming schemes for modulation of device conductance to closely mimic the phenomenon of Spike Timing Dependent Plasticity (STDP) observed biologically, and verify through simulations that such plastic phase change devices should support simple correlative learning in networks of spiking neurons. Our devices, when arranged in a crossbar array architecture, could enable the development of synaptronic systems that approach the density (∼10 11 synapses per sq cm) and energy efficiency (consuming ∼1pJ per synaptic programming event) of the human brain.

Generalized linear models with nonlinear feature transformations are widely used for large-scale regression and classification problems with sparse inputs. Memorization of feature interactions through a wide set of cross-product feature transformations are effective and interpretable, while generalization requires more feature engineering effort. With less feature engineering, deep neural networks can generalize better to unseen feature combinations through low-dimensional dense embeddings learned for the sparse features. However, deep neural networks with embeddings can over-generalize and recommend less relevant items when the user-item interactions are sparse and high-rank. In this paper, we present Wide & Deep learning---jointly trained wide linear models and deep neural networks---to combine the benefits of memorization and generalization for recommender systems. We productionized and evaluated the system on Google Play, a commercial mobile app store with over one billion active users and over one million apps. Online experiment results show that Wide & Deep significantly increased app acquisitions compared with wide-only and deep-only models. We have also open-sourced our implementation in TensorFlow.

In this paper we propose and investigate a novel end-to-end method for automatically generating short email responses, called Smart Reply. It generates semantically diverse suggestions that can be used as complete email responses with just one tap on mobile. The system is currently used in Inbox by Gmail and is responsible for assisting with 10% of all mobile responses. It is designed to work at very high throughput and process hundreds of millions of messages daily. The system exploits state-of-the-art, large-scale deep learning. We describe the architecture of the system as well as the challenges that we faced while building it, like response diversity and scalability. We also introduce a new method for semantic clustering of user-generated content that requires only a modest amount of explicitly labeled data., Comment: Accepted to KDD 2016

We present a new approach to learning sparse, spatiotemporal codes in which the number of basis vectors, their orientations, velocities and the size of their receptive fields change over the duration of unsupervised training. The algorithm starts with a relatively small, initial basis with minimal temporal extent. This initial basis is obtained through conventional sparse coding techniques and is expanded over time by recursively constructing a new basis consisting of basis vectors with larger temporal extent that proportionally conserve regions of previously trained weights. These proportionally conserved weights are combined with the result of adjusting newly added weights to represent a greater range of primitive motion features. The size of the current basis is determined probabilistically by sampling from existing basis vectors according to their activation on the training set. The resulting algorithm produces bases consisting of filters that are bandpass, spatially oriented and temporally diverse in terms of their transformations and velocities. The basic methodology borrows inspiration from the layer-by-layer learning of multiple-layer restricted Boltzmann machines developed by Geoff Hinton and his students. Indeed, we can learn multiple-layer sparse codes by training a stack of denoising autoencoders, but we have had greater success using L1 regularized regression in a variation on Olshausen and Field’s original SPARSENET. To accelerate learning and focus attention, we apply a space-time interest-point operator that selects for periodic motion. This attentional mechanism enables us to efficiently compute and compactly represent a broad range of interesting motion. We demonstrate the utility of our approach by using it to recognize human activity in video. Our algorithm meets or exceeds the performance of state-of-the-art activity-recognition methods.