Closing the AI generalization gap by adjusting for dermatology condition distribution differences across clinical settings

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.

Towards Conversational Diagnostic AI

At the heart of medicine lies the physician-patient dialogue, where skillful history-taking paves the way for accurate diagnosis, effective management, and enduring trust. Artificial Intelligence (AI) systems capable of diagnostic dialogue could increase accessibility, consistency, and quality of care. However, approximating clinicians' expertise is an outstanding grand challenge. Here, we introduce AMIE (Articulate Medical Intelligence Explorer), a Large Language Model (LLM) based AI system optimized for diagnostic dialogue. AMIE uses a novel self-play based simulated environment with automated feedback mechanisms for scaling learning across diverse disease conditions, specialties, and contexts. We designed a framework for evaluating clinically-meaningful axes of performance including history-taking, diagnostic accuracy, management reasoning, communication skills, and empathy. We compared AMIE's performance to that of primary care physicians (PCPs) in a randomized, double-blind crossover study of text-based consultations with validated patient actors in the style of an Objective Structured Clinical Examination (OSCE). The study included 149 case scenarios from clinical providers in Canada, the UK, and India, 20 PCPs for comparison with AMIE, and evaluations by specialist physicians and patient actors. AMIE demonstrated greater diagnostic accuracy and superior performance on 28 of 32 axes according to specialist physicians and 24 of 26 axes according to patient actors. Our research has several limitations and should be interpreted with appropriate caution. Clinicians were limited to unfamiliar synchronous text-chat which permits large-scale LLM-patient interactions but is not representative of usual clinical practice. While further research is required before AMIE could be translated to real-world settings, the results represent a milestone towards conversational diagnostic AI.

Towards Accurate Differential Diagnosis with Large Language Models

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.

ELIXR: Towards a general purpose X-ray artificial intelligence system through alignment of large language models and radiology vision encoders

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.

Large Language Models Encode Clinical Knowledge

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.

Enabling faster and more reliable sonographic assessment of gestational age through machine learning

Fetal ultrasounds are an essential part of prenatal care and can be used to estimate gestational age (GA). Accurate GA assessment is important for providing appropriate prenatal care throughout pregnancy and identifying complications such as fetal growth disorders. Since derivation of GA from manual fetal biometry measurements (head, abdomen, femur) are operator-dependent and time-consuming, there have been a number of research efforts focused on using artificial intelligence (AI) models to estimate GA using standard biometry images, but there is still room to improve the accuracy and reliability of these AI systems for widescale adoption. To improve GA estimates, without significant change to provider workflows, we leverage AI to interpret standard plane ultrasound images as well as 'fly-to' ultrasound videos, which are 5-10s videos automatically recorded as part of the standard of care before the still image is captured. We developed and validated three AI models: an image model using standard plane images, a video model using fly-to videos, and an ensemble model (combining both image and video). All three were statistically superior to standard fetal biometry-based GA estimates derived by expert sonographers, the ensemble model has the lowest mean absolute error (MAE) compared to the clinical standard fetal biometry (mean difference: -1.51 $\pm$ 3.96 days, 95% CI [-1.9, -1.1]) on a test set that consisted of 404 participants. We showed that our models outperform standard biometry by a more substantial margin on fetuses that were small for GA. Our AI models have the potential to empower trained operators to estimate GA with higher accuracy while reducing the amount of time required and user variability in measurement acquisition.

AI system for fetal ultrasound in low-resource settings

Despite considerable progress in maternal healthcare, maternal and perinatal deaths remain high in low-to-middle income countries. Fetal ultrasound is an important component of antenatal care, but shortage of adequately trained healthcare workers has limited its adoption. We developed and validated an artificial intelligence (AI) system that uses novice-acquired "blind sweep" ultrasound videos to estimate gestational age (GA) and fetal malpresentation. We further addressed obstacles that may be encountered in low-resourced settings. Using a simplified sweep protocol with real-time AI feedback on sweep quality, we have demonstrated the generalization of model performance to minimally trained novice ultrasound operators using low cost ultrasound devices with on-device AI integration. The GA model was non-inferior to standard fetal biometry estimates with as few as two sweeps, and the fetal malpresentation model had high AUC-ROCs across operators and devices. Our AI models have the potential to assist in upleveling the capabilities of lightly trained ultrasound operators in low resource settings.

Deep learning for detecting pulmonary tuberculosis via chest radiography: an international study across 10 countries

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.

Speech recognition for medical conversations

In this work we explored building automatic speech recognition models for transcribing doctor patient conversation. We collected a large scale dataset of clinical conversations ($14,000$ hr), designed the task to represent the real word scenario, and explored several alignment approaches to iteratively improve data quality. We explored both CTC and LAS systems for building speech recognition models. The LAS was more resilient to noisy data and CTC required more data clean up. A detailed analysis is provided for understanding the performance for clinical tasks. Our analysis showed the speech recognition models performed well on important medical utterances, while errors occurred in causal conversations. Overall we believe the resulting models can provide reasonable quality in practice.

Scalable and accurate deep learning for electronic health records

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.