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.
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.
* 4 main tables, 3 main figures, additional supplemental tables and
Our approach, which we call Embeddings for Language/Image-aligned X-Rays, or ELIXR, leverages a language-aligned image encoder combined or grafted onto a fixed LLM, PaLM 2, to perform a broad range of 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.
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.
For safety, AI systems in health undergo thorough evaluations before deployment, validating their predictions against a ground truth that is assumed certain. However, this is actually not the case and the ground truth may be uncertain. Unfortunately, this is largely ignored in standard evaluation of AI models but can have severe consequences such as overestimating the future performance. To avoid this, we measure the effects of ground truth uncertainty, which we assume decomposes into two main components: annotation uncertainty which stems from the lack of reliable annotations, and inherent uncertainty due to limited observational information. This ground truth uncertainty is ignored when estimating the ground truth by deterministically aggregating annotations, e.g., by majority voting or averaging. In contrast, we propose a framework where aggregation is done using a statistical model. Specifically, we frame aggregation of annotations as posterior inference of so-called plausibilities, representing distributions over classes in a classification setting, subject to a hyper-parameter encoding annotator reliability. Based on this model, we propose a metric for measuring annotation uncertainty and provide uncertainty-adjusted metrics for performance evaluation. We present a case study applying our framework to skin condition classification from images where annotations are provided in the form of differential diagnoses. The deterministic adjudication process called inverse rank normalization (IRN) from previous work ignores ground truth uncertainty in evaluation. Instead, we present two alternative statistical models: a probabilistic version of IRN and a Plackett-Luce-based model. We find that a large portion of the dataset exhibits significant ground truth uncertainty and standard IRN-based evaluation severely over-estimates performance without providing uncertainty estimates.
AI models have shown promise in many medical imaging tasks. However, our ability to explain what signals these models have learned is severely lacking. Explanations are needed in order to increase the trust in AI-based models, and could enable novel scientific discovery by uncovering signals in the data that are not yet known to experts. In this paper, we present a method for automatic visual explanations leveraging team-based expertise by generating hypotheses of what visual signals in the images are correlated with the task. We propose the following 4 steps: (i) Train a classifier to perform a given task (ii) Train a classifier guided StyleGAN-based image generator (StylEx) (iii) Automatically detect and visualize the top visual attributes that the classifier is sensitive towards (iv) Formulate hypotheses for the underlying mechanisms, to stimulate future research. Specifically, we present the discovered attributes to an interdisciplinary panel of experts so that hypotheses can account for social and structural determinants of health. We demonstrate results on eight prediction tasks across three medical imaging modalities: retinal fundus photographs, external eye photographs, and chest radiographs. We showcase examples of attributes that capture clinically known features, confounders that arise from factors beyond physiological mechanisms, and reveal a number of physiologically plausible novel attributes. Our approach has the potential to enable researchers to better understand, improve their assessment, and extract new knowledge from AI-based models. Importantly, we highlight that attributes generated by our framework can capture phenomena beyond physiology or pathophysiology, reflecting the real world nature of healthcare delivery and socio-cultural factors. Finally, we intend to release code to enable researchers to train their own StylEx models and analyze their predictive tasks.
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.
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.
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.
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.