Yun Liu

M. Jorge Cardoso, Wenqi Li, Richard Brown et al.

Artificial Intelligence (AI) is having a tremendous impact across most areas of science. Applications of AI in healthcare have the potential to improve our ability to detect, diagnose, prognose, and intervene on human disease. For AI models to be used clinically, they need to be made safe, reproducible and robust, and the underlying software framework must be aware of the particularities (e.g. geometry, physiology, physics) of medical data being processed. This work introduces MONAI, a freely available, community-supported, and consortium-led PyTorch-based framework for deep learning in healthcare. MONAI extends PyTorch to support medical data, with a particular focus on imaging, and provide purpose-specific AI model architectures, transformations and utilities that streamline the development and deployment of medical AI models. MONAI follows best practices for software-development, providing an easy-to-use, robust, well-documented, and well-tested software framework. MONAI preserves the simple, additive, and compositional approach of its underlying PyTorch libraries. MONAI is being used by and receiving contributions from research, clinical and industrial teams from around the world, who are pursuing applications spanning nearly every aspect of healthcare.

David Stutz, Ali Taylan Cemgil, Abhijit Guha Roy et al. · deepmind

For safety, medical AI systems undergo thorough evaluations before deployment, validating their predictions against a ground truth which is assumed to be fixed and certain. However, this ground truth is often curated in the form of differential diagnoses. While a single differential diagnosis reflects the uncertainty in one expert assessment, multiple experts introduce another layer of uncertainty through disagreement. Both forms of uncertainty are ignored in standard evaluation which aggregates these differential diagnoses to a single label. In this paper, we show that ignoring uncertainty leads to overly optimistic estimates of model performance, therefore underestimating risk associated with particular diagnostic decisions. To this end, we propose a statistical aggregation approach, where we infer a distribution on probabilities of underlying medical condition candidates themselves, based on observed annotations. This formulation naturally accounts for the potential disagreements between different experts, as well as uncertainty stemming from individual differential diagnoses, capturing the entire ground truth uncertainty. Our approach boils down to generating multiple samples of medical condition probabilities, then evaluating and averaging performance metrics based on these sampled probabilities. In skin condition classification, we find that a large portion of the dataset exhibits significant ground truth uncertainty and standard evaluation severely over-estimates performance without providing uncertainty estimates. In contrast, our framework provides uncertainty estimates on common metrics of interest such as top-k accuracy and average overlap, showing that performance can change multiple percentage points. We conclude that, while assuming a crisp ground truth can be acceptable for many AI applications, a more nuanced evaluation protocol should be utilized in medical diagnosis.

Edoardo Mello Rella, Ajad Chhatkuli, Yun Liu et al.

Boundaries are among the primary visual cues used by human and computer vision systems. One of the key problems in boundary detection is the label representation, which typically leads to class imbalance and, as a consequence, to thick boundaries that require non-differential post-processing steps to be thinned. In this paper, we re-interpret boundaries as 1-D surfaces and formulate a one-to-one vector transform function that allows for training of boundary prediction completely avoiding the class imbalance issue. Specifically, we define the boundary representation at any point as the unit vector pointing to the closest boundary surface. Our problem formulation leads to the estimation of direction as well as richer contextual information of the boundary, and, if desired, the availability of zero-pixel thin boundaries also at training time. Our method uses no hyper-parameter in the training loss and a fixed stable hyper-parameter at inference. We provide theoretical justification/discussions of the vector transform representation. We evaluate the proposed loss method using a standard architecture and show the excellent performance over other losses and representations on several datasets. Code is available at https://github.com/edomel/BoundaryVT.

Karan Singhal, Shekoofeh Azizi, Tao Tu et al.

Large language models (LLMs) have demonstrated impressive capabilities in natural language understanding and generation, but the quality bar for medical and clinical applications is high. Today, attempts to assess models' clinical knowledge typically rely on automated evaluations on limited benchmarks. There is no standard to evaluate model predictions and reasoning across a breadth of tasks. To address this, we present MultiMedQA, a benchmark combining six existing open question answering datasets spanning professional medical exams, research, and consumer queries; and HealthSearchQA, a new free-response dataset of medical questions searched online. We propose a framework for human evaluation of model answers along multiple axes including factuality, precision, possible harm, and bias. In addition, we evaluate PaLM (a 540-billion parameter LLM) and its instruction-tuned variant, Flan-PaLM, on MultiMedQA. Using a combination of prompting strategies, Flan-PaLM achieves state-of-the-art accuracy on every MultiMedQA multiple-choice dataset (MedQA, MedMCQA, PubMedQA, MMLU clinical topics), including 67.6% accuracy on MedQA (US Medical License Exam questions), surpassing prior state-of-the-art by over 17%. However, human evaluation reveals key gaps in Flan-PaLM responses. To resolve this we introduce instruction prompt tuning, a parameter-efficient approach for aligning LLMs to new domains using a few exemplars. The resulting model, Med-PaLM, performs encouragingly, but remains inferior to clinicians. We show that comprehension, recall of knowledge, and medical reasoning improve with model scale and instruction prompt tuning, suggesting the potential utility of LLMs in medicine. Our human evaluations reveal important limitations of today's models, reinforcing the importance of both evaluation frameworks and method development in creating safe, helpful LLM models for clinical applications.

Tao Tu, Shekoofeh Azizi, Danny Driess et al.

Medicine is inherently multimodal, with rich data modalities spanning text, imaging, genomics, and more. Generalist biomedical artificial intelligence (AI) systems that flexibly encode, integrate, and interpret this data at scale can potentially enable impactful applications ranging from scientific discovery to care delivery. To enable the development of these models, we first curate MultiMedBench, a new multimodal biomedical benchmark. MultiMedBench encompasses 14 diverse tasks such as medical question answering, mammography and dermatology image interpretation, radiology report generation and summarization, and genomic variant calling. We then introduce Med-PaLM Multimodal (Med-PaLM M), our proof of concept for a generalist biomedical AI system. Med-PaLM M is a large multimodal generative model that flexibly encodes and interprets biomedical data including clinical language, imaging, and genomics with the same set of model weights. Med-PaLM M reaches performance competitive with or exceeding the state of the art on all MultiMedBench tasks, often surpassing specialist models by a wide margin. We also report examples of zero-shot generalization to novel medical concepts and tasks, positive transfer learning across tasks, and emergent zero-shot medical reasoning. To further probe the capabilities and limitations of Med-PaLM M, we conduct a radiologist evaluation of model-generated (and human) chest X-ray reports and observe encouraging performance across model scales. In a side-by-side ranking on 246 retrospective chest X-rays, clinicians express a pairwise preference for Med-PaLM M reports over those produced by radiologists in up to 40.50% of cases, suggesting potential clinical utility. While considerable work is needed to validate these models in real-world use cases, our results represent a milestone towards the development of generalist biomedical AI systems.

Shawn Xu, Lin Yang, Christopher Kelly et al.

In this work, we present an approach, which we call Embeddings for Language/Image-aligned X-Rays, or ELIXR, that leverages a language-aligned image encoder combined or grafted onto a fixed LLM, PaLM 2, to perform a broad range of chest X-ray tasks. We train this lightweight adapter architecture using images paired with corresponding free-text radiology reports from the MIMIC-CXR dataset. ELIXR achieved state-of-the-art performance on zero-shot chest X-ray (CXR) classification (mean AUC of 0.850 across 13 findings), data-efficient CXR classification (mean AUCs of 0.893 and 0.898 across five findings (atelectasis, cardiomegaly, consolidation, pleural effusion, and pulmonary edema) for 1% (~2,200 images) and 10% (~22,000 images) training data), and semantic search (0.76 normalized discounted cumulative gain (NDCG) across nineteen queries, including perfect retrieval on twelve of them). Compared to existing data-efficient methods including supervised contrastive learning (SupCon), ELIXR required two orders of magnitude less data to reach similar performance. ELIXR also showed promise on CXR vision-language tasks, demonstrating overall accuracies of 58.7% and 62.5% on visual question answering and report quality assurance tasks, respectively. These results suggest that ELIXR is a robust and versatile approach to CXR AI.

Daniel McDuff, Mike Schaekermann, Tao Tu et al.

An accurate differential diagnosis (DDx) is a cornerstone of medical care, often reached through an iterative process of interpretation that combines clinical history, physical examination, investigations and procedures. Interactive interfaces powered by Large Language Models (LLMs) present new opportunities to both assist and automate aspects of this process. In this study, we introduce an LLM optimized for diagnostic reasoning, and evaluate its ability to generate a DDx alone or as an aid to clinicians. 20 clinicians evaluated 302 challenging, real-world medical cases sourced from the New England Journal of Medicine (NEJM) case reports. Each case report was read by two clinicians, who were randomized to one of two assistive conditions: either assistance from search engines and standard medical resources, or LLM assistance in addition to these tools. All clinicians provided a baseline, unassisted DDx prior to using the respective assistive tools. Our LLM for DDx exhibited standalone performance that exceeded that of unassisted clinicians (top-10 accuracy 59.1% vs 33.6%, [p = 0.04]). Comparing the two assisted study arms, the DDx quality score was higher for clinicians assisted by our LLM (top-10 accuracy 51.7%) compared to clinicians without its assistance (36.1%) (McNemar's Test: 45.7, p < 0.01) and clinicians with search (44.4%) (4.75, p = 0.03). Further, clinicians assisted by our LLM arrived at more comprehensive differential lists than those without its assistance. Our study suggests that our LLM for DDx has potential to improve clinicians' diagnostic reasoning and accuracy in challenging cases, meriting further real-world evaluation for its ability to empower physicians and widen patients' access to specialist-level expertise.

Jeremy Lai, Faruk Ahmed, Supriya Vijay et al.

Task-specific deep learning models in histopathology offer promising opportunities for improving diagnosis, clinical research, and precision medicine. However, development of such models is often limited by availability of high-quality data. Foundation models in histopathology that learn general representations across a wide range of tissue types, diagnoses, and magnifications offer the potential to reduce the data, compute, and technical expertise necessary to develop task-specific deep learning models with the required level of model performance. In this work, we describe the development and evaluation of foundation models for histopathology via self-supervised learning (SSL). We first establish a diverse set of benchmark tasks involving 17 unique tissue types and 12 unique cancer types and spanning different optimal magnifications and task types. Next, we use this benchmark to explore and evaluate histopathology-specific SSL methods followed by further evaluation on held out patch-level and weakly supervised tasks. We found that standard SSL methods thoughtfully applied to histopathology images are performant across our benchmark tasks and that domain-specific methodological improvements can further increase performance. Our findings reinforce the value of using domain-specific SSL methods in pathology, and establish a set of high quality foundation models to enable further research across diverse applications.

Fen Fang, Yun Liu, Ali Koksal et al.

A key challenge with procedure planning in instructional videos lies in how to handle a large decision space consisting of a multitude of action types that belong to various tasks. To understand real-world video content, an AI agent must proficiently discern these action types (e.g., pour milk, pour water, open lid, close lid, etc.) based on brief visual observation. Moreover, it must adeptly capture the intricate semantic relation of the action types and task goals, along with the variable action sequences. Recently, notable progress has been made via the integration of diffusion models and visual representation learning to address the challenge. However, existing models employ rudimentary mechanisms to utilize task information to manage the decision space. To overcome this limitation, we introduce a simple yet effective enhancement - a masked diffusion model. The introduced mask acts akin to a task-oriented attention filter, enabling the diffusion/denoising process to concentrate on a subset of action types. Furthermore, to bolster the accuracy of task classification, we harness more potent visual representation learning techniques. In particular, we learn a joint visual-text embedding, where a text embedding is generated by prompting a pre-trained vision-language model to focus on human actions. We evaluate the method on three public datasets and achieve state-of-the-art performance on multiple metrics. Code is available at https://github.com/ffzzy840304/Masked-PDPP.

Boris Babenko, Ilana Traynis, Christina Chen et al.

External eye photos were recently shown to reveal signs of diabetic retinal disease and elevated HbA1c. In this paper, we evaluate if external eye photos contain information about additional systemic medical conditions. We developed a deep learning system (DLS) that takes external eye photos as input and predicts multiple systemic parameters, such as those related to the liver (albumin, AST); kidney (eGFR estimated using the race-free 2021 CKD-EPI creatinine equation, the urine ACR); bone & mineral (calcium); thyroid (TSH); and blood count (Hgb, WBC, platelets). Development leveraged 151,237 images from 49,015 patients with diabetes undergoing diabetic eye screening in 11 sites across Los Angeles county, CA. Evaluation focused on 9 pre-specified systemic parameters and leveraged 3 validation sets (A, B, C) spanning 28,869 patients with and without diabetes undergoing eye screening in 3 independent sites in Los Angeles County, CA, and the greater Atlanta area, GA. We compared against baseline models incorporating available clinicodemographic variables (e.g. age, sex, race/ethnicity, years with diabetes). Relative to the baseline, the DLS achieved statistically significant superior performance at detecting AST>36, calcium<8.6, eGFR<60, Hgb<11, platelets<150, ACR>=300, and WBC<4 on validation set A (a patient population similar to the development sets), where the AUC of DLS exceeded that of the baseline by 5.2-19.4%. On validation sets B and C, with substantial patient population differences compared to the development sets, the DLS outperformed the baseline for ACR>=300 and Hgb<11 by 7.3-13.2%. Our findings provide further evidence that external eye photos contain important biomarkers of systemic health spanning multiple organ systems. Further work is needed to investigate whether and how these biomarkers can be translated into clinical impact.

Stephen R. Pfohl, Heather Cole-Lewis, Rory Sayres et al.

Large language models (LLMs) hold promise to serve complex health information needs but also have the potential to introduce harm and exacerbate health disparities. Reliably evaluating equity-related model failures is a critical step toward developing systems that promote health equity. We present resources and methodologies for surfacing biases with potential to precipitate equity-related harms in long-form, LLM-generated answers to medical questions and conduct a large-scale empirical case study with the Med-PaLM 2 LLM. Our contributions include a multifactorial framework for human assessment of LLM-generated answers for biases, and EquityMedQA, a collection of seven datasets enriched for adversarial queries. Both our human assessment framework and dataset design process are grounded in an iterative participatory approach and review of Med-PaLM 2 answers. Through our empirical study, we find that our approach surfaces biases that may be missed via narrower evaluation approaches. Our experience underscores the importance of using diverse assessment methodologies and involving raters of varying backgrounds and expertise. While our approach is not sufficient to holistically assess whether the deployment of an AI system promotes equitable health outcomes, we hope that it can be leveraged and built upon towards a shared goal of LLMs that promote accessible and equitable healthcare.

Khaled Saab, Jan Freyberg, Chunjong Park et al.

Large Language Models (LLMs) have demonstrated great potential for conducting diagnostic conversations but evaluation has been largely limited to language-only interactions, deviating from the real-world requirements of remote care delivery. Instant messaging platforms permit clinicians and patients to upload and discuss multimodal medical artifacts seamlessly in medical consultation, but the ability of LLMs to reason over such data while preserving other attributes of competent diagnostic conversation remains unknown. Here we advance the conversational diagnosis and management performance of the Articulate Medical Intelligence Explorer (AMIE) through a new capability to gather and interpret multimodal data, and reason about this precisely during consultations. Leveraging Gemini 2.0 Flash, our system implements a state-aware dialogue framework, where conversation flow is dynamically controlled by intermediate model outputs reflecting patient states and evolving diagnoses. Follow-up questions are strategically directed by uncertainty in such patient states, leading to a more structured multimodal history-taking process that emulates experienced clinicians. We compared AMIE to primary care physicians (PCPs) in a randomized, blinded, OSCE-style study of chat-based consultations with patient actors. We constructed 105 evaluation scenarios using artifacts like smartphone skin photos, ECGs, and PDFs of clinical documents across diverse conditions and demographics. Our rubric assessed multimodal capabilities and other clinically meaningful axes like history-taking, diagnostic accuracy, management reasoning, communication, and empathy. Specialist evaluation showed AMIE to be superior to PCPs on 7/9 multimodal and 29/32 non-multimodal axes (including diagnostic accuracy). The results show clear progress in multimodal conversational diagnostic AI, but real-world translation needs further research.

Theo Guidroz, Diego Ardila, Jimmy Li et al.

Information on the web, such as scientific publications and Wikipedia, often surpasses users' reading level. To help address this, we used a self-refinement approach to develop a LLM capability for minimally lossy text simplification. To validate our approach, we conducted a randomized study involving 4563 participants and 31 texts spanning 6 broad subject areas: PubMed (biomedical scientific articles), biology, law, finance, literature/philosophy, and aerospace/computer science. Participants were randomized to viewing original or simplified texts in a subject area, and answered multiple-choice questions (MCQs) that tested their comprehension of the text. The participants were also asked to provide qualitative feedback such as task difficulty. Our results indicate that participants who read the simplified text answered more MCQs correctly than their counterparts who read the original text (3.9% absolute increase, p<0.05). This gain was most striking with PubMed (14.6%), while more moderate gains were observed for finance (5.5%), aerospace/computer science (3.8%) domains, and legal (3.5%). Notably, the results were robust to whether participants could refer back to the text while answering MCQs. The absolute accuracy decreased by up to ~9% for both original and simplified setups where participants could not refer back to the text, but the ~4% overall improvement persisted. Finally, participants' self-reported perceived ease based on a simplified NASA Task Load Index was greater for those who read the simplified text (absolute change on a 5-point scale 0.33, p<0.05). This randomized study, involving an order of magnitude more participants than prior works, demonstrates the potential of LLMs to make complex information easier to understand. Our work aims to enable a broader audience to better learn and make use of expert knowledge available on the web, improving information accessibility.

Shun Liao, Paolo Di Achille, Jiang Wu et al.

Resting heart rate (RHR) is an important biomarker of cardiovascular health and mortality, but tracking it longitudinally generally requires a wearable device, limiting its availability. We present PHRM, a deep learning system for passive heart rate (HR) and RHR measurements during everyday smartphone use, using facial video-based photoplethysmography. Our system was developed using 225,773 videos from 495 participants and validated on 185,970 videos from 205 participants in laboratory and free-living conditions, representing the largest validation study of its kind. Compared to reference electrocardiogram, PHRM achieved a mean absolute percentage error (MAPE) < 10% for HR measurements across three skin tone groups of light, medium and dark pigmentation; MAPE for each skin tone group was non-inferior versus the others. Daily RHR measured by PHRM had a mean absolute error < 5 bpm compared to a wearable HR tracker, and was associated with known risk factors. These results highlight the potential of smartphones to enable passive and equitable heart health monitoring.

Rajeev V. Rikhye, Aaron Loh, Grace Eunhae Hong et al.

Recently, there has been great progress in the ability of artificial intelligence (AI) algorithms to classify dermatological conditions from clinical photographs. However, little is known about the robustness of these algorithms in real-world settings where several factors can lead to a loss of generalizability. Understanding and overcoming these limitations will permit the development of generalizable AI that can aid in the diagnosis of skin conditions across a variety of clinical settings. In this retrospective study, we demonstrate that differences in skin condition distribution, rather than in demographics or image capture mode are the main source of errors when an AI algorithm is evaluated on data from a previously unseen source. We demonstrate a series of steps to close this generalization gap, requiring progressively more information about the new source, ranging from the condition distribution to training data enriched for data less frequently seen during training. Our results also suggest comparable performance from end-to-end fine tuning versus fine tuning solely the classification layer on top of a frozen embedding model. Our approach can inform the adaptation of AI algorithms to new settings, based on the information and resources available.

Jan Freyberg, Abhijit Guha Roy, Terry Spitz et al.

During the diagnostic process, doctors incorporate multimodal information including imaging and the medical history - and similarly medical AI development has increasingly become multimodal. In this paper we tackle a more subtle challenge: doctors take a targeted medical history to obtain only the most pertinent pieces of information; how do we enable AI to do the same? We develop a wrapper method named MINT (Make your model INTeractive) that automatically determines what pieces of information are most valuable at each step, and ask for only the most useful information. We demonstrate the efficacy of MINT wrapping a skin disease prediction model, where multiple images and a set of optional answers to $25$ standard metadata questions (i.e., structured medical history) are used by a multi-modal deep network to provide a differential diagnosis. We show that MINT can identify whether metadata inputs are needed and if so, which question to ask next. We also demonstrate that when collecting multiple images, MINT can identify if an additional image would be beneficial, and if so, which type of image to capture. We showed that MINT reduces the number of metadata and image inputs needed by 82% and 36.2% respectively, while maintaining predictive performance. Using real-world AI dermatology system data, we show that needing fewer inputs can retain users that may otherwise fail to complete the system submission and drop off without a diagnosis. Qualitative examples show MINT can closely mimic the step-by-step decision making process of a clinical workflow and how this is different for straight forward cases versus more difficult, ambiguous cases. Finally we demonstrate how MINT is robust to different underlying multi-model classifiers and can be easily adapted to user requirements without significant model re-training.

Yida Cai, Ranjuexiao Hu, Huiyuan Xie et al.

Legal relations form a highly consequential analytical framework of civil law system, serving as a crucial foundation for resolving disputes and realizing values of the rule of law in judicial practice. However, legal relations in Chinese civil cases remain underexplored in the field of legal artificial intelligence (legal AI), largely due to the absence of comprehensive schemas. In this work, we firstly introduce a comprehensive schema, which contains a hierarchical taxonomy and definitions of arguments, for AI systems to capture legal relations in Chinese civil cases. Based on this schema, we then formulate legal relation extraction task and present LexRel, an expert-annotated benchmark for legal relation extraction in Chinese civil law. We use LexRel to evaluate state-of-the-art large language models (LLMs) on legal relation extractions, showing that current LLMs exhibit significant limitations in accurately identifying civil legal relations. Furthermore, we demonstrate that incorporating legal relations information leads to consistent performance gains on other downstream legal AI tasks.

Elahe Vedadi, David Barrett, Natalie Harris et al.

Recent work has demonstrated the promise of conversational AI systems for diagnostic dialogue. However, real-world assurance of patient safety means that providing individual diagnoses and treatment plans is considered a regulated activity by licensed professionals. Furthermore, physicians commonly oversee other team members in such activities, including nurse practitioners (NPs) or physician assistants/associates (PAs). Inspired by this, we propose a framework for effective, asynchronous oversight of the Articulate Medical Intelligence Explorer (AMIE) AI system. We propose guardrailed-AMIE (g-AMIE), a multi-agent system that performs history taking within guardrails, abstaining from individualized medical advice. Afterwards, g-AMIE conveys assessments to an overseeing primary care physician (PCP) in a clinician cockpit interface. The PCP provides oversight and retains accountability of the clinical decision. This effectively decouples oversight from intake and can thus happen asynchronously. In a randomized, blinded virtual Objective Structured Clinical Examination (OSCE) of text consultations with asynchronous oversight, we compared g-AMIE to NPs/PAs or a group of PCPs under the same guardrails. Across 60 scenarios, g-AMIE outperformed both groups in performing high-quality intake, summarizing cases, and proposing diagnoses and management plans for the overseeing PCP to review. This resulted in higher quality composite decisions. PCP oversight of g-AMIE was also more time-efficient than standalone PCP consultations in prior work. While our study does not replicate existing clinical practices and likely underestimates clinicians' capabilities, our results demonstrate the promise of asynchronous oversight as a feasible paradigm for diagnostic AI systems to operate under expert human oversight for enhancing real-world care.

Faruk Ahmed, Andrew Sellergren, Lin Yang et al.

Microscopic interpretation of histopathology images underlies many important diagnostic and treatment decisions. While advances in vision-language modeling raise new opportunities for analysis of such images, the gigapixel-scale size of whole slide images (WSIs) introduces unique challenges. Additionally, pathology reports simultaneously highlight key findings from small regions while also aggregating interpretation across multiple slides, often making it difficult to create robust image-text pairs. As such, pathology reports remain a largely untapped source of supervision in computational pathology, with most efforts relying on region-of-interest annotations or self-supervision at the patch-level. In this work, we develop a vision-language model based on the BLIP-2 framework using WSIs paired with curated text from pathology reports. This enables applications utilizing a shared image-text embedding space, such as text or image retrieval for finding cases of interest, as well as integration of the WSI encoder with a frozen large language model (LLM) for WSI-based generative text capabilities such as report generation or AI-in-the-loop interactions. We utilize a de-identified dataset of over 350,000 WSIs and diagnostic text pairs, spanning a wide range of diagnoses, procedure types, and tissue types. We present pathologist evaluation of text generation and text retrieval using WSI embeddings, as well as results for WSI classification and workflow prioritization (slide-level triaging). Model-generated text for WSIs was rated by pathologists as accurate, without clinically significant error or omission, for 78% of WSIs on average. This work demonstrates exciting potential capabilities for language-aligned WSI embeddings.

Justin Cosentino, Anastasiya Belyaeva, Xin Liu et al.

In health, most large language model (LLM) research has focused on clinical tasks. However, mobile and wearable devices, which are rarely integrated into such tasks, provide rich, longitudinal data for personal health monitoring. Here we present Personal Health Large Language Model (PH-LLM), fine-tuned from Gemini for understanding and reasoning over numerical time-series personal health data. We created and curated three datasets that test 1) production of personalized insights and recommendations from sleep patterns, physical activity, and physiological responses, 2) expert domain knowledge, and 3) prediction of self-reported sleep outcomes. For the first task we designed 857 case studies in collaboration with domain experts to assess real-world scenarios in sleep and fitness. Through comprehensive evaluation of domain-specific rubrics, we observed that Gemini Ultra 1.0 and PH-LLM are not statistically different from expert performance in fitness and, while experts remain superior for sleep, fine-tuning PH-LLM provided significant improvements in using relevant domain knowledge and personalizing information for sleep insights. We evaluated PH-LLM domain knowledge using multiple choice sleep medicine and fitness examinations. PH-LLM achieved 79% on sleep and 88% on fitness, exceeding average scores from a sample of human experts. Finally, we trained PH-LLM to predict self-reported sleep quality outcomes from textual and multimodal encoding representations of wearable data, and demonstrate that multimodal encoding is required to match performance of specialized discriminative models. Although further development and evaluation are necessary in the safety-critical personal health domain, these results demonstrate both the broad knowledge and capabilities of Gemini models and the benefit of contextualizing physiological data for personal health applications as done with PH-LLM.

Karan Singhal, Tao Tu, Juraj Gottweis et al.

Recent artificial intelligence (AI) systems have reached milestones in "grand challenges" ranging from Go to protein-folding. The capability to retrieve medical knowledge, reason over it, and answer medical questions comparably to physicians has long been viewed as one such grand challenge. Large language models (LLMs) have catalyzed significant progress in medical question answering; Med-PaLM was the first model to exceed a "passing" score in US Medical Licensing Examination (USMLE) style questions with a score of 67.2% on the MedQA dataset. However, this and other prior work suggested significant room for improvement, especially when models' answers were compared to clinicians' answers. Here we present Med-PaLM 2, which bridges these gaps by leveraging a combination of base LLM improvements (PaLM 2), medical domain finetuning, and prompting strategies including a novel ensemble refinement approach. Med-PaLM 2 scored up to 86.5% on the MedQA dataset, improving upon Med-PaLM by over 19% and setting a new state-of-the-art. We also observed performance approaching or exceeding state-of-the-art across MedMCQA, PubMedQA, and MMLU clinical topics datasets. We performed detailed human evaluations on long-form questions along multiple axes relevant to clinical applications. In pairwise comparative ranking of 1066 consumer medical questions, physicians preferred Med-PaLM 2 answers to those produced by physicians on eight of nine axes pertaining to clinical utility (p < 0.001). We also observed significant improvements compared to Med-PaLM on every evaluation axis (p < 0.001) on newly introduced datasets of 240 long-form "adversarial" questions to probe LLM limitations. While further studies are necessary to validate the efficacy of these models in real-world settings, these results highlight rapid progress towards physician-level performance in medical question answering.

Wei-Hung Weng, Sebastien Baur, Mayank Daswani et al.

Cardiovascular diseases (CVDs) are responsible for a large proportion of premature deaths in low- and middle-income countries. Early CVD detection and intervention is critical in these populations, yet many existing CVD risk scores require a physical examination or lab measurements, which can be challenging in such health systems due to limited accessibility. Here we investigated the potential to use photoplethysmography (PPG), a sensing technology available on most smartphones that can potentially enable large-scale screening at low cost, for CVD risk prediction. We developed a deep learning PPG-based CVD risk score (DLS) to predict the probability of having major adverse cardiovascular events (MACE: non-fatal myocardial infarction, stroke, and cardiovascular death) within ten years, given only age, sex, smoking status and PPG as predictors. We compared the DLS with the office-based refit-WHO score, which adopts the shared predictors from WHO and Globorisk scores (age, sex, smoking status, height, weight and systolic blood pressure) but refitted on the UK Biobank (UKB) cohort. In UKB cohort, DLS's C-statistic (71.1%, 95% CI 69.9-72.4) was non-inferior to office-based refit-WHO score (70.9%, 95% CI 69.7-72.2; non-inferiority margin of 2.5%, p<0.01). The calibration of the DLS was satisfactory, with a 1.8% mean absolute calibration error. Adding DLS features to the office-based score increased the C-statistic by 1.0% (95% CI 0.6-1.4). DLS predicts ten-year MACE risk comparable with the office-based refit-WHO score. It provides a proof-of-concept and suggests the potential of a PPG-based approach strategies for community-based primary prevention in resource-limited regions.

Sahar Kazemzadeh, Jin Yu, Shahar Jamshy et al.

Tuberculosis (TB) is a top-10 cause of death worldwide. Though the WHO recommends chest radiographs (CXRs) for TB screening, the limited availability of CXR interpretation is a barrier. We trained a deep learning system (DLS) to detect active pulmonary TB using CXRs from 9 countries across Africa, Asia, and Europe, and utilized large-scale CXR pretraining, attention pooling, and noisy student semi-supervised learning. Evaluation was on (1) a combined test set spanning China, India, US, and Zambia, and (2) an independent mining population in South Africa. Given WHO targets of 90% sensitivity and 70% specificity, the DLS's operating point was prespecified to favor sensitivity over specificity. On the combined test set, the DLS's ROC curve was above all 9 India-based radiologists, with an AUC of 0.90 (95%CI 0.87-0.92). The DLS's sensitivity (88%) was higher than the India-based radiologists (75% mean sensitivity), p<0.001 for superiority; and its specificity (79%) was non-inferior to the radiologists (84% mean specificity), p=0.004. Similar trends were observed within HIV positive and sputum smear positive sub-groups, and in the South Africa test set. We found that 5 US-based radiologists (where TB isn't endemic) were more sensitive and less specific than the India-based radiologists (where TB is endemic). The DLS also remained non-inferior to the US-based radiologists. In simulations, using the DLS as a prioritization tool for confirmatory testing reduced the cost per positive case detected by 40-80% compared to using confirmatory testing alone. To conclude, our DLS generalized to 5 countries, and merits prospective evaluation to assist cost-effective screening efforts in radiologist-limited settings. Operating point flexibility may permit customization of the DLS to account for site-specific factors such as TB prevalence, demographics, clinical resources, and customary practice patterns.

Abhijit Guha Roy, Jie Ren, Shekoofeh Azizi et al.

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.

Ellery Wulczyn, David F. Steiner, Zhaoyang Xu et al.

Prognostic information at diagnosis has important implications for cancer treatment and monitoring. Although cancer staging, histopathological assessment, molecular features, and clinical variables can provide useful prognostic insights, improving risk stratification remains an active research area. We developed a deep learning system (DLS) to predict disease specific survival across 10 cancer types from The Cancer Genome Atlas (TCGA). We used a weakly-supervised approach without pixel-level annotations, and tested three different survival loss functions. The DLS was developed using 9,086 slides from 3,664 cases and evaluated using 3,009 slides from 1,216 cases. In multivariable Cox regression analysis of the combined cohort including all 10 cancers, the DLS was significantly associated with disease specific survival (hazard ratio of 1.58, 95% CI 1.28-1.70, p<0.0001) after adjusting for cancer type, stage, age, and sex. In a per-cancer adjusted subanalysis, the DLS remained a significant predictor of survival in 5 of 10 cancer types. Compared to a baseline model including stage, age, and sex, the c-index of the model demonstrated an absolute 3.7% improvement (95% CI 1.0-6.5) in the combined cohort. Additionally, our models stratified patients within individual cancer stages, particularly stage II (p=0.025) and stage III (p<0.001). By developing and evaluating prognostic models across multiple cancer types, this work represents one of the most comprehensive studies exploring the direct prediction of clinical outcomes using deep learning and histopathology images. Our analysis demonstrates the potential for this approach to provide prognostic information in multiple cancer types, and even within specific pathologic stages. However, given the relatively small number of clinical events, we observed wide confidence intervals, suggesting that future work will benefit from larger datasets.

Akinori Mitani, Yun Liu, Abigail Huang et al.

Despite its high prevalence, anemia is often undetected due to the invasiveness and cost of screening and diagnostic tests. Though some non-invasive approaches have been developed, they are less accurate than invasive methods, resulting in an unmet need for more accurate non-invasive methods. Here, we show that deep learning-based algorithms can detect anemia and quantify several related blood measurements using retinal fundus images both in isolation and in combination with basic metadata such as patient demographics. On a validation dataset of 11,388 patients from the UK Biobank, our algorithms achieved a mean absolute error of 0.63 g/dL (95% confidence interval (CI) 0.62-0.64) in quantifying hemoglobin concentration and an area under receiver operating characteristic curve (AUC) of 0.88 (95% CI 0.86-0.89) in detecting anemia. This work shows the potential of automated non-invasive anemia screening based on fundus images, particularly in diabetic patients, who may have regular retinal imaging and are at increased risk of further morbidity and mortality from anemia.

Timo Kohlberger, Yun Liu, Melissa Moran et al.

Digital pathology enables remote access or consults and powerful image analysis algorithms. However, the slide digitization process can create artifacts such as out-of-focus (OOF). OOF is often only detected upon careful review, potentially causing rescanning and workflow delays. Although scan-time operator screening for whole-slide OOF is feasible, manual screening for OOF affecting only parts of a slide is impractical. We developed a convolutional neural network (ConvFocus) to exhaustively localize and quantify the severity of OOF regions on digitized slides. ConvFocus was developed using our refined semi-synthetic OOF data generation process, and evaluated using real whole-slide images spanning 3 different tissue types and 3 different stain types that were digitized by two different scanners. ConvFocus's predictions were compared with pathologist-annotated focus quality grades across 514 distinct regions representing 37,700 35x35 $μ$m image patches, and 21 digitized "z-stack" whole-slide images that contain known OOF patterns. When compared to pathologist-graded focus quality, ConvFocus achieved Spearman rank coefficients of 0.81 and 0.94 on two scanners, and reproduced the expected OOF patterns from z-stack scanning. We also evaluated the impact of OOF on the accuracy of a state-of-the-art metastatic breast cancer detector and saw a consistent decrease in performance with increasing OOF. Comprehensive whole-slide OOF categorization could enable rescans prior to pathologist review, potentially reducing the impact of digitization focus issues on the clinical workflow. We show that the algorithm trained on our semi-synthetic OOF data generalizes well to real OOF regions across tissue types, stains, and scanners. Finally, quantitative OOF maps can flag regions that might otherwise be misclassified by image analysis algorithms, preventing OOF-induced errors.

Sonia Phene, R. Carter Dunn, Naama Hammel et al.

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.

Po-Hsuan Cameron Chen, Krishna Gadepalli, Robert MacDonald et al.

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.

Kunal Nagpal, Davis Foote, Yun Liu et al.

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 1,226 slides, and evaluated on an independent validation dataset of 331 slides, where the reference standard was established by genitourinary specialist pathologists. On the validation dataset, the mean accuracy among 29 general pathologists was 0.61. 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.

Ryan Poplin, Avinash V. Varadarajan, Katy Blumer et al.

Traditionally, medical discoveries are made by observing associations and then designing experiments to test these hypotheses. However, observing and quantifying associations in images can be difficult because of the wide variety of features, patterns, colors, values, shapes in real data. In this paper, we use deep learning, a machine learning technique that learns its own features, to discover new knowledge from retinal fundus images. Using models trained on data from 284,335 patients, and validated on two independent datasets of 12,026 and 999 patients, we predict cardiovascular risk factors not previously thought to be present or quantifiable in retinal images, such as such as age (within 3.26 years), gender (0.97 AUC), smoking status (0.71 AUC), HbA1c (within 1.39%), systolic blood pressure (within 11.23mmHg) as well as major adverse cardiac events (0.70 AUC). We further show that our models used distinct aspects of the anatomy to generate each prediction, such as the optic disc or blood vessels, opening avenues of further research.

Yun Liu, Krishna Gadepalli, Mohammad Norouzi et al.

Each year, the treatment decisions for more than 230,000 breast cancer patients in the U.S. hinge on whether the cancer has metastasized away from the breast. Metastasis detection is currently performed by pathologists reviewing large expanses of biological tissues. This process is labor intensive and error-prone. We present a framework to automatically detect and localize tumors as small as 100 x 100 pixels in gigapixel microscopy images sized 100,000 x 100,000 pixels. Our method leverages a convolutional neural network (CNN) architecture and obtains state-of-the-art results on the Camelyon16 dataset in the challenging lesion-level tumor detection task. At 8 false positives per image, we detect 92.4% of the tumors, relative to 82.7% by the previous best automated approach. For comparison, a human pathologist attempting exhaustive search achieved 73.2% sensitivity. We achieve image-level AUC scores above 97% on both the Camelyon16 test set and an independent set of 110 slides. In addition, we discover that two slides in the Camelyon16 training set were erroneously labeled normal. Our approach could considerably reduce false negative rates in metastasis detection.

Yun Liu, Kun-Ta Chuang, Fu-Wen Liang et al.

In many domains such as medicine, training data is in short supply. In such cases, external knowledge is often helpful in building predictive models. We propose a novel method to incorporate publicly available domain expertise to build accurate models. Specifically, we use word2vec models trained on a domain-specific corpus to estimate the relevance of each feature's text description to the prediction problem. We use these relevance estimates to rescale the features, causing more important features to experience weaker regularization. We apply our method to predict the onset of five chronic diseases in the next five years in two genders and two age groups. Our rescaling approach improves the accuracy of the model, particularly when there are few positive examples. Furthermore, our method selects 60% fewer features, easing interpretation by physicians. Our method is applicable to other domains where feature and outcome descriptions are available.