Daily Papers

Patient recruitment is challenging for clinical trials. We introduce TrialGPT, an end-to-end framework for zero-shot patient-to-trial matching with large language models. TrialGPT comprises three modules: it first performs large-scale filtering to retrieve candidate trials (TrialGPT-Retrieval); then predicts criterion-level patient eligibility (TrialGPT-Matching); and finally generates trial-level scores (TrialGPT-Ranking). We evaluate TrialGPT on three cohorts of 183 synthetic patients with over 75,000 trial annotations. TrialGPT-Retrieval can recall over 90% of relevant trials using less than 6% of the initial collection. Manual evaluations on 1,015 patient-criterion pairs show that TrialGPT-Matching achieves an accuracy of 87.3% with faithful explanations, close to the expert performance. The TrialGPT-Ranking scores are highly correlated with human judgments and outperform the best-competing models by 43.8% in ranking and excluding trials. Furthermore, our user study reveals that TrialGPT can reduce the screening time by 42.6% in patient recruitment. Overall, these results have demonstrated promising opportunities for patient-to-trial matching with TrialGPT.

We study the problem of adaptively identifying patient subpopulations that benefit from a given treatment during a confirmatory clinical trial. This type of adaptive clinical trial has been thoroughly studied in biostatistics, but has been allowed only limited adaptivity so far. Here, we aim to relax classical restrictions on such designs and investigate how to incorporate ideas from the recent machine learning literature on adaptive and online experimentation to make trials more flexible and efficient. We find that the unique characteristics of the subpopulation selection problem -- most importantly that (i) one is usually interested in finding subpopulations with any treatment benefit (and not necessarily the single subgroup with largest effect) given a limited budget and that (ii) effectiveness only has to be demonstrated across the subpopulation on average -- give rise to interesting challenges and new desiderata when designing algorithmic solutions. Building on these findings, we propose AdaGGI and AdaGCPI, two meta-algorithms for subpopulation construction. We empirically investigate their performance across a range of simulation scenarios and derive insights into their (dis)advantages across different settings.

Clinical trials are fundamental in developing new drugs, medical devices, and treatments. However, they are often time-consuming and have low success rates. Although there have been initial attempts to create large language models (LLMs) for clinical trial design and patient-trial matching, these models remain task-specific and not adaptable to diverse clinical trial tasks. To address this challenge, we propose a clinical trial foundation model named Panacea, designed to handle multiple tasks, including trial search, trial summarization, trial design, and patient-trial matching. We also assemble a large-scale dataset, named TrialAlign, of 793,279 trial documents and 1,113,207 trial-related scientific papers, to infuse clinical knowledge into the model by pre-training. We further curate TrialInstruct, which has 200,866 of instruction data for fine-tuning. These resources enable Panacea to be widely applicable for a range of clinical trial tasks based on user requirements. We evaluated Panacea on a new benchmark, named TrialPanorama, which covers eight clinical trial tasks. Our method performed the best on seven of the eight tasks compared to six cutting-edge generic or medicine-specific LLMs. Specifically, Panacea showed great potential to collaborate with human experts in crafting the design of eligibility criteria, study arms, and outcome measures, in multi-round conversations. In addition, Panacea achieved 14.42% improvement in patient-trial matching, 41.78% to 52.02% improvement in trial search, and consistently ranked at the top for five aspects of trial summarization. Our approach demonstrates the effectiveness of Panacea in clinical trials and establishes a comprehensive resource, including training data, model, and benchmark, for developing clinical trial foundation models, paving the path for AI-based clinical trial development.

Synthesizing clinical evidence largely relies on systematic reviews of clinical trials and retrospective analyses from medical literature. However, the rapid expansion of publications presents challenges in efficiently identifying, summarizing, and updating clinical evidence. Here, we introduce TrialMind, a generative artificial intelligence (AI) pipeline for facilitating human-AI collaboration in three crucial tasks for evidence synthesis: study search, screening, and data extraction. To assess its performance, we chose published systematic reviews to build the benchmark dataset, named TrialReviewBench, which contains 100 systematic reviews and the associated 2,220 clinical studies. Our results show that TrialMind excels across all three tasks. In study search, it generates diverse and comprehensive search queries to achieve high recall rates (Ours 0.711-0.834 v.s. Human baseline 0.138-0.232). For study screening, TrialMind surpasses traditional embedding-based methods by 30% to 160%. In data extraction, it outperforms a GPT-4 baseline by 29.6% to 61.5%. We further conducted user studies to confirm its practical utility. Compared to manual efforts, human-AI collaboration using TrialMind yielded a 71.4% recall lift and 44.2% time savings in study screening and a 23.5% accuracy lift and 63.4% time savings in data extraction. Additionally, when comparing synthesized clinical evidence presented in forest plots, medical experts favored TrialMind's outputs over GPT-4's outputs in 62.5% to 100% of cases. These findings show the promise of LLM-based approaches like TrialMind to accelerate clinical evidence synthesis via streamlining study search, screening, and data extraction from medical literature, with exceptional performance improvement when working with human experts.

Clinical trial matching is a key process in health delivery and discovery. In practice, it is plagued by overwhelming unstructured data and unscalable manual processing. In this paper, we conduct a systematic study on scaling clinical trial matching using large language models (LLMs), with oncology as the focus area. Our study is grounded in a clinical trial matching system currently in test deployment at a large U.S. health network. Initial findings are promising: out of box, cutting-edge LLMs, such as GPT-4, can already structure elaborate eligibility criteria of clinical trials and extract complex matching logic (e.g., nested AND/OR/NOT). While still far from perfect, LLMs substantially outperform prior strong baselines and may serve as a preliminary solution to help triage patient-trial candidates with humans in the loop. Our study also reveals a few significant growth areas for applying LLMs to end-to-end clinical trial matching, such as context limitation and accuracy, especially in structuring patient information from longitudinal medical records.

Clinical trial matching is the task of identifying trials for which patients may be potentially eligible. Typically, this task is labor-intensive and requires detailed verification of patient electronic health records (EHRs) against the stringent inclusion and exclusion criteria of clinical trials. This process is manual, time-intensive, and challenging to scale up, resulting in many patients missing out on potential therapeutic options. Recent advancements in Large Language Models (LLMs) have made automating patient-trial matching possible, as shown in multiple concurrent research studies. However, the current approaches are confined to constrained, often synthetic datasets that do not adequately mirror the complexities encountered in real-world medical data. In this study, we present the first, end-to-end large-scale empirical evaluation of clinical trial matching using real-world EHRs. Our study showcases the capability of LLMs to accurately match patients with appropriate clinical trials. We perform experiments with proprietary LLMs, including GPT-4 and GPT-3.5, as well as our custom fine-tuned model called OncoLLM and show that OncoLLM, despite its significantly smaller size, not only outperforms GPT-3.5 but also matches the performance of qualified medical doctors. All experiments were carried out on real-world EHRs that include clinical notes and available clinical trials from a single cancer center in the United States.

The global cost of drug discovery and development exceeds $200 billion annually. The main results of drug discovery and development are the outcomes of clinical trials, which directly influence the regulatory approval of new drug candidates and ultimately affect patient outcomes. Despite their significance, large-scale, high-quality clinical trial outcome data are not readily available to the public. Suppose a large clinical trial outcome dataset is provided; machine learning researchers can potentially develop accurate prediction models using past trials and outcome labels, which could help prioritize and optimize therapeutic programs, ultimately benefiting patients. This paper introduces Clinical Trial Outcome (CTO) dataset, the largest trial outcome dataset with around 479K clinical trials, aggregating outcomes from multiple sources of weakly supervised labels, minimizing the noise from individual sources, and eliminating the need for human annotation. These sources include large language model (LLM) decisions on trial-related documents, news headline sentiments, stock prices of trial sponsors, trial linkages across phases, and other signals such as patient dropout rates and adverse events. CTO's labels show unprecedented agreement with supervised clinical trial outcome labels from test split of the supervised TOP dataset, with a 91 F1.

Adverse drug events (ADEs) significantly impact clinical research, causing many clinical trial failures. ADE prediction is key for developing safer medications and enhancing patient outcomes. To support this effort, we introduce CT-ADE, a dataset for multilabel predictive modeling of ADEs in monopharmacy treatments. CT-ADE integrates data from 2,497 unique drugs, encompassing 168,984 drug-ADE pairs extracted from clinical trials, annotated with patient and contextual information, and comprehensive ADE concepts standardized across multiple levels of the MedDRA ontology. Preliminary analyses with large language models (LLMs) achieved F1-scores up to 55.90%. Models using patient and contextual information showed F1-score improvements of 21%-38% over models using only chemical structure data. Our results highlight the importance of target population and treatment regimens in the predictive modeling of ADEs, offering greater performance gains than LLM domain specialization and scaling. CT-ADE provides an essential tool for researchers aiming to leverage artificial intelligence and machine learning to enhance patient safety and minimize the impact of ADEs on pharmaceutical research and development. The dataset is publicly accessible at https://github.com/ds4dh/CT-ADE.

How do we most effectively treat a disease or condition? Ideally, we could consult a database of evidence gleaned from clinical trials to answer such questions. Unfortunately, no such database exists; clinical trial results are instead disseminated primarily via lengthy natural language articles. Perusing all such articles would be prohibitively time-consuming for healthcare practitioners; they instead tend to depend on manually compiled systematic reviews of medical literature to inform care. NLP may speed this process up, and eventually facilitate immediate consult of published evidence. The Evidence Inference dataset was recently released to facilitate research toward this end. This task entails inferring the comparative performance of two treatments, with respect to a given outcome, from a particular article (describing a clinical trial) and identifying supporting evidence. For instance: Does this article report that chemotherapy performed better than surgery for five-year survival rates of operable cancers? In this paper, we collect additional annotations to expand the Evidence Inference dataset by 25\%, provide stronger baseline models, systematically inspect the errors that these make, and probe dataset quality. We also release an abstract only (as opposed to full-texts) version of the task for rapid model prototyping. The updated corpus, documentation, and code for new baselines and evaluations are available at http://evidence-inference.ebm-nlp.com/.

Accurate prediction of knee osteoarthritis (KOA) progression from structural MRI has a potential to enhance disease understanding and support clinical trials. Prior art focused on manually designed imaging biomarkers, which may not fully exploit all disease-related information present in MRI scan. In contrast, our method learns relevant representations from raw data end-to-end using Deep Learning, and uses them for progression prediction. The method employs a 2D CNN to process the data slice-wise and aggregate the extracted features using a Transformer. Evaluated on a large cohort (n=4,866), the proposed method outperforms conventional 2D and 3D CNN-based models and achieves average precision of 0.58pm0.03 and ROC AUC of 0.78pm0.01. This paper sets a baseline on end-to-end KOA progression prediction from structural MRI. Our code is publicly available at https://github.com/MIPT-Oulu/OAProgressionMR.

Large language models (LLMs) represent a transformative class of AI tools capable of revolutionizing various aspects of healthcare by generating human-like responses across diverse contexts and adapting to novel tasks following human instructions. Their potential application spans a broad range of medical tasks, such as clinical documentation, matching patients to clinical trials, and answering medical questions. In this primer paper, we propose an actionable guideline to help healthcare professionals more efficiently utilize LLMs in their work, along with a set of best practices. This approach consists of several main phases, including formulating the task, choosing LLMs, prompt engineering, fine-tuning, and deployment. We start with the discussion of critical considerations in identifying healthcare tasks that align with the core capabilities of LLMs and selecting models based on the selected task and data, performance requirements, and model interface. We then review the strategies, such as prompt engineering and fine-tuning, to adapt standard LLMs to specialized medical tasks. Deployment considerations, including regulatory compliance, ethical guidelines, and continuous monitoring for fairness and bias, are also discussed. By providing a structured step-by-step methodology, this tutorial aims to equip healthcare professionals with the tools necessary to effectively integrate LLMs into clinical practice, ensuring that these powerful technologies are applied in a safe, reliable, and impactful manner.

We present the findings of "The Alzheimer's Disease Prediction Of Longitudinal Evolution" (TADPOLE) Challenge, which compared the performance of 92 algorithms from 33 international teams at predicting the future trajectory of 219 individuals at risk of Alzheimer's disease. Challenge participants were required to make a prediction, for each month of a 5-year future time period, of three key outcomes: clinical diagnosis, Alzheimer's Disease Assessment Scale Cognitive Subdomain (ADAS-Cog13), and total volume of the ventricles. The methods used by challenge participants included multivariate linear regression, machine learning methods such as support vector machines and deep neural networks, as well as disease progression models. No single submission was best at predicting all three outcomes. For clinical diagnosis and ventricle volume prediction, the best algorithms strongly outperform simple baselines in predictive ability. However, for ADAS-Cog13 no single submitted prediction method was significantly better than random guesswork. Two ensemble methods based on taking the mean and median over all predictions, obtained top scores on almost all tasks. Better than average performance at diagnosis prediction was generally associated with the additional inclusion of features from cerebrospinal fluid (CSF) samples and diffusion tensor imaging (DTI). On the other hand, better performance at ventricle volume prediction was associated with inclusion of summary statistics, such as the slope or maxima/minima of biomarkers. TADPOLE's unique results suggest that current prediction algorithms provide sufficient accuracy to exploit biomarkers related to clinical diagnosis and ventricle volume, for cohort refinement in clinical trials for Alzheimer's disease. However, results call into question the usage of cognitive test scores for patient selection and as a primary endpoint in clinical trials.

Osteoarthritis (OA) is the most common musculoskeletal disease, which has no cure. Knee OA (KOA) is one of the highest causes of disability worldwide, and it costs billions of United States dollars to the global community. Prediction of KOA progression has been of high interest to the community for years, as it can advance treatment development through more efficient clinical trials and improve patient outcomes through more efficient healthcare utilization. Existing approaches for predicting KOA, however, are predominantly static, i.e. consider data from a single time point to predict progression many years into the future, and knee level, i.e. consider progression in a single joint only. Due to these and related reasons, these methods fail to deliver the level of predictive performance, which is sufficient to result in cost savings and better patient outcomes. Collecting extensive data from all patients on a regular basis could address the issue, but it is limited by the high cost at a population level. In this work, we propose to go beyond static prediction models in OA, and bring a novel Active Sensing (AS) approach, designed to dynamically follow up patients with the objective of maximizing the number of informative data acquisitions, while minimizing their total cost over a period of time. Our approach is based on Reinforcement Learning (RL), and it leverages a novel reward function designed specifically for AS of disease progression in more than one part of a human body. Our method is end-to-end, relies on multi-modal Deep Learning, and requires no human input at inference time. Throughout an exhaustive experimental evaluation, we show that using RL can provide a higher monetary benefit when compared to state-of-the-art baselines.

Despite the recent success of representation learning in sequential decision making, the study of the pure exploration scenario (i.e., identify the best option and minimize the sample complexity) is still limited. In this paper, we study multi-task representation learning for best arm identification in linear bandits (RepBAI-LB) and best policy identification in contextual linear bandits (RepBPI-CLB), two popular pure exploration settings with wide applications, e.g., clinical trials and web content optimization. In these two problems, all tasks share a common low-dimensional linear representation, and our goal is to leverage this feature to accelerate the best arm (policy) identification process for all tasks. For these problems, we design computationally and sample efficient algorithms DouExpDes and C-DouExpDes, which perform double experimental designs to plan optimal sample allocations for learning the global representation. We show that by learning the common representation among tasks, our sample complexity is significantly better than that of the native approach which solves tasks independently. To the best of our knowledge, this is the first work to demonstrate the benefits of representation learning for multi-task pure exploration.

Black box optimisation of an unknown function from expensive and noisy evaluations is a ubiquitous problem in machine learning, academic research and industrial production. An abstraction of the problem can be formulated as a kernel based bandit problem (also known as Bayesian optimisation), where a learner aims at optimising a kernelized function through sequential noisy observations. The existing work predominantly assumes feedback is immediately available; an assumption which fails in many real world situations, including recommendation systems, clinical trials and hyperparameter tuning. We consider a kernel bandit problem under stochastically delayed feedback, and propose an algorithm with mathcal{O}(Gamma_k(T)T+E[tau]) regret, where T is the number of time steps, Gamma_k(T) is the maximum information gain of the kernel with T observations, and tau is the delay random variable. This represents a significant improvement over the state of the art regret bound of mathcal{O}(Gamma_k(T)T+E[tau]Gamma_k(T)) reported in Verma et al. (2022). In particular, for very non-smooth kernels, the information gain grows almost linearly in time, trivializing the existing results. We also validate our theoretical results with simulations.

Traditional drug design faces significant challenges due to inherent chemical and biological complexities, often resulting in high failure rates in clinical trials. Deep learning advancements, particularly generative models, offer potential solutions to these challenges. One promising algorithm is DrugGPT, a transformer-based model, that generates small molecules for input protein sequences. Although promising, it generates both chemically valid and invalid structures and does not incorporate the features of approved drugs, resulting in time-consuming and inefficient drug discovery. To address these issues, we introduce DrugGen, an enhanced model based on the DrugGPT structure. DrugGen is fine-tuned on approved drug-target interactions and optimized with proximal policy optimization. By giving reward feedback from protein-ligand binding affinity prediction using pre-trained transformers (PLAPT) and a customized invalid structure assessor, DrugGen significantly improves performance. Evaluation across multiple targets demonstrated that DrugGen achieves 100% valid structure generation compared to 95.5% with DrugGPT and produced molecules with higher predicted binding affinities (7.22 [6.30-8.07]) compared to DrugGPT (5.81 [4.97-6.63]) while maintaining diversity and novelty. Docking simulations further validate its ability to generate molecules targeting binding sites effectively. For example, in the case of fatty acid-binding protein 5 (FABP5), DrugGen generated molecules with superior docking scores (FABP5/11, -9.537 and FABP5/5, -8.399) compared to the reference molecule (Palmitic acid, -6.177). Beyond lead compound generation, DrugGen also shows potential for drug repositioning and creating novel pharmacophores for existing targets. By producing high-quality small molecules, DrugGen provides a high-performance medium for advancing pharmaceutical research and drug discovery.

A digital twin is a virtual replica of a real-world physical phenomena that uses mathematical modeling to characterize and simulate its defining features. By constructing digital twins for disease processes, we can perform in-silico simulations that mimic patients' health conditions and counterfactual outcomes under hypothetical interventions in a virtual setting. This eliminates the need for invasive procedures or uncertain treatment decisions. In this paper, we propose a method to identify digital twin model parameters using only noninvasive patient health data. We approach the digital twin modeling as a composite inverse problem, and observe that its structure resembles pretraining and finetuning in self-supervised learning (SSL). Leveraging this, we introduce a physics-informed SSL algorithm that initially pretrains a neural network on the pretext task of solving the physical model equations. Subsequently, the model is trained to reconstruct low-dimensional health measurements from noninvasive modalities while being constrained by the physical equations learned in pretraining. We apply our method to identify digital twins of cardiac hemodynamics using noninvasive echocardiogram videos, and demonstrate its utility in unsupervised disease detection and in-silico clinical trials.

Knee Osteoarthritis (KOA) is a highly prevalent chronic musculoskeletal condition with no currently available treatment. The manifestation of KOA is heterogeneous and prediction of its progression is challenging. Current literature suggests that the use of multi-modal data and advanced modeling methods, such as the ones based on Deep Learning, has promise in tackling this challenge. To date, however, the evidence on the efficacy of this approach is limited. In this study, we leveraged recent advances in Deep Learning and, using a Transformer approach, developed a unified framework for the multi-modal fusion of knee imaging data. Subsequently, we analyzed its performance across a range of scenarios by investigating multiple progression horizons -- from short-term to long-term. We report our findings using a large cohort (n=2421-3967) derived from the Osteoarthritis Initiative dataset. We show that structural knee MRI allows identifying radiographic KOA progressors on par with multi-modal fusion approaches, achieving an area under the ROC curve (ROC AUC) of 0.70-0.76 and Average Precision (AP) of 0.15-0.54 in 2-8 year horizons. Progression within 1 year was better predicted with a multi-modal method using X-ray, structural, and compositional MR images -- ROC AUC of 0.76(0.04), AP of 0.13(0.04) -- or via clinical data. Our follow-up analysis generally shows that prediction from the imaging data is more accurate for post-traumatic subjects, and we further investigate which subject subgroups may benefit the most. The present study provides novel insights into multi-modal imaging of KOA and brings a unified data-driven framework for studying its progression in an end-to-end manner, providing new tools for the design of more efficient clinical trials. The source code of our framework and the pre-trained models are made publicly available.

A ChatGPT-like system for drug compounds could be a game-changer in pharmaceutical research, accelerating drug discovery, enhancing our understanding of structure-activity relationships, guiding lead optimization, aiding drug repurposing, reducing the failure rate, and streamlining clinical trials. In this work, we make an initial attempt towards enabling ChatGPT-like capabilities on drug molecule graphs, by developing a prototype system DrugChat. DrugChat works in a similar way as ChatGPT. Users upload a compound molecule graph and ask various questions about this compound. DrugChat will answer these questions in a multi-turn, interactive manner. The DrugChat system consists of a graph neural network (GNN), a large language model (LLM), and an adaptor. The GNN takes a compound molecule graph as input and learns a representation for this graph. The adaptor transforms the graph representation produced by the GNN into another representation that is acceptable to the LLM. The LLM takes the compound representation transformed by the adaptor and users' questions about this compound as inputs and generates answers. All these components are trained end-to-end. To train DrugChat, we collected instruction tuning datasets which contain 10,834 drug compounds and 143,517 question-answer pairs. The code and data is available at https://github.com/UCSD-AI4H/drugchat

We present a corpus of 5,000 richly annotated abstracts of medical articles describing clinical randomized controlled trials. Annotations include demarcations of text spans that describe the Patient population enrolled, the Interventions studied and to what they were Compared, and the Outcomes measured (the `PICO' elements). These spans are further annotated at a more granular level, e.g., individual interventions within them are marked and mapped onto a structured medical vocabulary. We acquired annotations from a diverse set of workers with varying levels of expertise and cost. We describe our data collection process and the corpus itself in detail. We then outline a set of challenging NLP tasks that would aid searching of the medical literature and the practice of evidence-based medicine.

The increasing threat of emerging infectious diseases and antimicrobial resistance requires more efficient, high-quality research. Perpetual Observational Studies (POS) nested within a clinical research network can improve planning, quality and efficiency of interventional and observational studies, although real-life benefits and challenges need to be assessed. Ecraid (European Clinical Research Alliance on Infectious Diseases) has initiated POS and will monitor the impact for five specific infectious syndromes.

Large Language Models (LLMs) and multi-agent systems have shown impressive capabilities in natural language tasks but face challenges in clinical trial applications, primarily due to limited access to external knowledge. Recognizing the potential of advanced clinical trial tools that aggregate and predict based on the latest medical data, we propose an integrated solution to enhance their accessibility and utility. We introduce Clinical Agent System (ClinicalAgent), a clinical multi-agent system designed for clinical trial tasks, leveraging GPT-4, multi-agent architectures, LEAST-TO-MOST, and ReAct reasoning technology. This integration not only boosts LLM performance in clinical contexts but also introduces novel functionalities. The proposed method achieves competitive predictive performance in clinical trial outcome prediction (0.7908 PR-AUC), obtaining a 0.3326 improvement over the standard prompt Method. Publicly available code can be found at https://anonymous.4open.science/r/ClinicalAgent-6671.

Natural language processing (NLP) of clinical trial documents can be useful in new trial design. Here we identify entity types relevant to clinical trial design and propose a framework called CT-BERT for information extraction from clinical trial text. We trained named entity recognition (NER) models to extract eligibility criteria entities by fine-tuning a set of pre-trained BERT models. We then compared the performance of CT-BERT with recent baseline methods including attention-based BiLSTM and Criteria2Query. The results demonstrate the superiority of CT-BERT in clinical trial NLP.

Systematic literature review is essential for evidence-based medicine, requiring comprehensive analysis of clinical trial publications. However, the application of artificial intelligence (AI) models for medical literature mining has been limited by insufficient training and evaluation across broad therapeutic areas and diverse tasks. Here, we present LEADS, an AI foundation model for study search, screening, and data extraction from medical literature. The model is trained on 633,759 instruction data points in LEADSInstruct, curated from 21,335 systematic reviews, 453,625 clinical trial publications, and 27,015 clinical trial registries. We showed that LEADS demonstrates consistent improvements over four cutting-edge generic large language models (LLMs) on six tasks. Furthermore, LEADS enhances expert workflows by providing supportive references following expert requests, streamlining processes while maintaining high-quality results. A study with 16 clinicians and medical researchers from 14 different institutions revealed that experts collaborating with LEADS achieved a recall of 0.81 compared to 0.77 experts working alone in study selection, with a time savings of 22.6%. In data extraction tasks, experts using LEADS achieved an accuracy of 0.85 versus 0.80 without using LEADS, alongside a 26.9% time savings. These findings highlight the potential of specialized medical literature foundation models to outperform generic models, delivering significant quality and efficiency benefits when integrated into expert workflows for medical literature mining.

Randomized controlled trials (RCTs) are considered the gold standard for estimating the average treatment effect (ATE) of interventions. One use of RCTs is to study the causes of global poverty -- a subject explicitly cited in the 2019 Nobel Memorial Prize awarded to Duflo, Banerjee, and Kremer "for their experimental approach to alleviating global poverty." Because the ATE is a population summary, anti-poverty experiments often seek to unpack the effect variation around the ATE by conditioning (CATE) on tabular variables such as age and ethnicity that were measured during the RCT data collection. Although such variables are key to unpacking CATE, using only such variables may fail to capture historical, geographical, or neighborhood-specific contributors to effect variation, as tabular RCT data are often only observed near the time of the experiment. In global poverty research, when the location of the experiment units is approximately known, satellite imagery can provide a window into such factors important for understanding heterogeneity. However, there is no method that specifically enables applied researchers to analyze CATE from images. In this paper, using a deep probabilistic modeling framework, we develop such a method that estimates latent clusters of images by identifying images with similar treatment effects distributions. Our interpretable image CATE model also includes a sensitivity factor that quantifies the importance of image segments contributing to the effect cluster prediction. We compare the proposed methods against alternatives in simulation; also, we show how the model works in an actual RCT, estimating the effects of an anti-poverty intervention in northern Uganda and obtaining a posterior predictive distribution over effects for the rest of the country where no experimental data was collected. We make all models available in open-source software.

Dynamic treatment regimes (DTRs) are personalized, adaptive, multi-stage treatment plans that adapt treatment decisions both to an individual's initial features and to intermediate outcomes and features at each subsequent stage, which are affected by decisions in prior stages. Examples include personalized first- and second-line treatments of chronic conditions like diabetes, cancer, and depression, which adapt to patient response to first-line treatment, disease progression, and individual characteristics. While existing literature mostly focuses on estimating the optimal DTR from offline data such as from sequentially randomized trials, we study the problem of developing the optimal DTR in an online manner, where the interaction with each individual affect both our cumulative reward and our data collection for future learning. We term this the DTR bandit problem. We propose a novel algorithm that, by carefully balancing exploration and exploitation, is guaranteed to achieve rate-optimal regret when the transition and reward models are linear. We demonstrate our algorithm and its benefits both in synthetic experiments and in a case study of adaptive treatment of major depressive disorder using real-world data.

The drug development pipeline for a new compound can last 10-20 years and cost over 10 billion. Drug repurposing offers a more time- and cost-effective alternative. Computational approaches based on biomedical knowledge graph representations have recently yielded new drug repurposing hypotheses. In this study, we present a novel, disease-specific hypergraph representation learning technique to derive contextual embeddings of biological pathways of various lengths but that all start at any given drug and all end at the disease of interest. Further, we extend this method to multi-disease hypergraphs. To determine the repurposing potential of each of the 1,522 drugs, we derive drug-specific distributions of cosine similarity values and ultimately consider the median for ranking. Cosine similarity values are computed between (1) all biological pathways starting at the considered drug and ending at the disease of interest and (2) all biological pathways starting at drugs currently prescribed against that disease and ending at the disease of interest. We illustrate our approach with Alzheimer's disease (AD) and two of its risk factors: hypertension (HTN) and type 2 diabetes (T2D). We compare each drug's rank across four hypergraph settings (single- or multi-disease): AD only, AD + HTN, AD + T2D, and AD + HTN + T2D. Notably, our framework led to the identification of two promising drugs whose repurposing potential was significantly higher in hypergraphs combining two diseases: dapagliflozin (antidiabetic; moved up, from top 32% to top 7%, across all considered drugs) and debrisoquine (antihypertensive; moved up, from top 76% to top 23%). Our approach serves as a hypothesis generation tool, to be paired with a validation pipeline relying on laboratory experiments and semi-automated parsing of the biomedical literature.

Large-language models have recently demonstrated impressive zero-shot capabilities in a variety of natural language tasks such as summarization, dialogue generation, and question-answering. Despite many promising applications in clinical medicine, adoption of these models in real-world settings has been largely limited by their tendency to generate incorrect and sometimes even toxic statements. In this study, we develop Almanac, a large language model framework augmented with retrieval capabilities for medical guideline and treatment recommendations. Performance on a novel dataset of clinical scenarios (n = 130) evaluated by a panel of 5 board-certified and resident physicians demonstrates significant increases in factuality (mean of 18% at p-value < 0.05) across all specialties, with improvements in completeness and safety. Our results demonstrate the potential for large language models to be effective tools in the clinical decision-making process, while also emphasizing the importance of careful testing and deployment to mitigate their shortcomings.

This technical report introduces a Named Clinical Entity Recognition Benchmark for evaluating language models in healthcare, addressing the crucial natural language processing (NLP) task of extracting structured information from clinical narratives to support applications like automated coding, clinical trial cohort identification, and clinical decision support. The leaderboard provides a standardized platform for assessing diverse language models, including encoder and decoder architectures, on their ability to identify and classify clinical entities across multiple medical domains. A curated collection of openly available clinical datasets is utilized, encompassing entities such as diseases, symptoms, medications, procedures, and laboratory measurements. Importantly, these entities are standardized according to the Observational Medical Outcomes Partnership (OMOP) Common Data Model, ensuring consistency and interoperability across different healthcare systems and datasets, and a comprehensive evaluation of model performance. Performance of models is primarily assessed using the F1-score, and it is complemented by various assessment modes to provide comprehensive insights into model performance. The report also includes a brief analysis of models evaluated to date, highlighting observed trends and limitations. By establishing this benchmarking framework, the leaderboard aims to promote transparency, facilitate comparative analyses, and drive innovation in clinical entity recognition tasks, addressing the need for robust evaluation methods in healthcare NLP.

Alzheimer's disease (AD) is a degenerative brain disease impairing a person's ability to perform day to day activities. The clinical manifestations of Alzheimer's disease are characterized by heterogeneity in age, disease span, progression rate, impairment of memory and cognitive abilities. Due to these variabilities, personalized care and treatment planning, as well as patient counseling about their individual progression is limited. Recent developments in machine learning to detect hidden patterns in complex, multi-dimensional datasets provides significant opportunities to address this critical need. In this work, we use unsupervised and supervised machine learning approaches for subtype identification and prediction. We apply machine learning methods to the extensive clinical observations available at the Alzheimer's Disease Neuroimaging Initiative (ADNI) data set to identify patient subtypes and to predict disease progression. Our analysis depicts the progression space for the Alzheimer's disease into low, moderate and high disease progression zones. The proposed work will enable early detection and characterization of distinct disease subtypes based on clinical heterogeneity. We anticipate that our models will enable patient counseling, clinical trial design, and ultimately individualized clinical care.

Clinical diagnosis is critical in medical practice, typically requiring a continuous and evolving process that includes primary diagnosis, differential diagnosis, and final diagnosis. However, most existing clinical diagnostic tasks are single-step processes, which does not align with the complex multi-step diagnostic procedures found in real-world clinical settings. In this paper, we propose a multi-step diagnostic task and annotate a clinical diagnostic dataset (MSDiagnosis). This dataset includes primary diagnosis, differential diagnosis, and final diagnosis questions. Additionally, we propose a novel and effective framework. This framework combines forward inference, backward inference, reflection, and refinement, enabling the LLM to self-evaluate and adjust its diagnostic results. To assess the effectiveness of our proposed method, we design and conduct extensive experiments. The experimental results demonstrate the effectiveness of the proposed method. We also provide a comprehensive experimental analysis and suggest future research directions for this task.

Understanding causality should be a core requirement of any attempt to build real impact through AI. Due to the inherent unobservability of counterfactuals, large randomised trials (RCTs) are the standard for causal inference. But large experiments are generically expensive, and randomisation carries its own costs, e.g. when suboptimal decisions are trialed. Recent work has proposed more sample-efficient alternatives to RCTs, but these are not adaptable to the downstream application for which the causal effect is sought. In this work, we develop a task-specific approach to experimental design and derive sampling strategies customised to particular downstream applications. Across a range of important tasks, real-world datasets, and sample sizes, our method outperforms other benchmarks, e.g. requiring an order-of-magnitude less data to match RCT performance on targeted marketing tasks.

The approval success rate of drug candidates is very low with the majority of failure due to safety and efficacy. Increasingly available high dimensional information on targets, drug molecules and indications provides an opportunity for ML methods to integrate multiple data modalities and better predict clinically promising drug targets. Notably, drug targets with human genetics evidence are shown to have better odds to succeed. However, a recent tensor factorization-based approach found that additional information on targets and indications might not necessarily improve the predictive accuracy. Here we revisit this approach by integrating different types of human genetics evidence collated from publicly available sources to support each target-indication pair. We use Bayesian tensor factorization to show that models incorporating all available human genetics evidence (rare disease, gene burden, common disease) modestly improves the clinical outcome prediction over models using single line of genetics evidence. We provide additional insight into the relative predictive power of different types of human genetics evidence for predicting the success of clinical outcomes.

To generate evidence regarding the safety and efficacy of artificial intelligence (AI) enabled medical devices, AI models need to be evaluated on a diverse population of patient cases, some of which may not be readily available. We propose an evaluation approach for testing medical imaging AI models that relies on in silico imaging pipelines in which stochastic digital models of human anatomy (in object space) with and without pathology are imaged using a digital replica imaging acquisition system to generate realistic synthetic image datasets. Here, we release M-SYNTH, a dataset of cohorts with four breast fibroglandular density distributions imaged at different exposure levels using Monte Carlo x-ray simulations with the publicly available Virtual Imaging Clinical Trial for Regulatory Evaluation (VICTRE) toolkit. We utilize the synthetic dataset to analyze AI model performance and find that model performance decreases with increasing breast density and increases with higher mass density, as expected. As exposure levels decrease, AI model performance drops with the highest performance achieved at exposure levels lower than the nominal recommended dose for the breast type.

Combination therapies have become the standard of care for diseases such as cancer, tuberculosis, malaria and HIV. However, the combinatorial set of available multi-drug treatments creates a challenge in identifying effective combination therapies available in a situation. To assist medical professionals in identifying beneficial drug-combinations, we construct an expert-annotated dataset for extracting information about the efficacy of drug combinations from the scientific literature. Beyond its practical utility, the dataset also presents a unique NLP challenge, as the first relation extraction dataset consisting of variable-length relations. Furthermore, the relations in this dataset predominantly require language understanding beyond the sentence level, adding to the challenge of this task. We provide a promising baseline model and identify clear areas for further improvement. We release our dataset, code, and baseline models publicly to encourage the NLP community to participate in this task.

We introduce a general, flexible, parametric survival modelling framework which encompasses key shapes of hazard function (constant, increasing, decreasing, up-then-down, down-then-up), various common survival distributions (log-logistic, Burr type XII, Weibull, Gompertz), and includes defective distributions (i.e., cure models). This generality is achieved using four basic distributional parameters: two scale-type parameters and two shape parameters. Generalising to covariate dependence, the scale-type regression components correspond to accelerated failure time (AFT) and proportional hazards (PH) models. Therefore, this general formulation unifies the most popular survival models which allows us to consider the practical value of possible modelling choices for survival data. Furthermore, in line with our proposed flexible baseline distribution, we advocate the use of multi-parameter regression in which more than one distributional parameter depends on covariates - rather than the usual convention of having a single covariate-dependent (scale) parameter. While many choices are available, we suggest introducing covariates through just one or other of the two scale parameters, which covers AFT and PH models, in combination with a `power' shape parameter, which allows for more complex non-AFT/non-PH effects, while the other shape parameter remains covariate-independent, and handles automatic selection of the baseline distribution. We explore inferential issues in simulations, both with and without a covariate, with particular focus on evidence concerning the need, or otherwise, to include both AFT and PH parameters. We illustrate the efficacy of our modelling framework by investigating differences between treatment groups using data from a lung cancer study and a melanoma study. Censoring is accommodated throughout.

Given the dominance of dense retrievers that do not generalize well beyond their training dataset distributions, domain-specific test sets are essential in evaluating retrieval. There are few test datasets for retrieval systems intended for use by healthcare providers in a point-of-care setting. To fill this gap we have collaborated with medical professionals to create CURE, an ad-hoc retrieval test dataset for passage ranking with 2000 queries spanning 10 medical domains with a monolingual (English) and two cross-lingual (French/Spanish -> English) conditions. In this paper, we describe how CURE was constructed and provide baseline results to showcase its effectiveness as an evaluation tool. CURE is published with a Creative Commons Attribution Non Commercial 4.0 license and can be accessed on Hugging Face.

Scientific discovery relies on scientists generating novel hypotheses that undergo rigorous experimental validation. To augment this process, we introduce an AI co-scientist, a multi-agent system built on Gemini 2.0. The AI co-scientist is intended to help uncover new, original knowledge and to formulate demonstrably novel research hypotheses and proposals, building upon prior evidence and aligned to scientist-provided research objectives and guidance. The system's design incorporates a generate, debate, and evolve approach to hypothesis generation, inspired by the scientific method and accelerated by scaling test-time compute. Key contributions include: (1) a multi-agent architecture with an asynchronous task execution framework for flexible compute scaling; (2) a tournament evolution process for self-improving hypotheses generation. Automated evaluations show continued benefits of test-time compute, improving hypothesis quality. While general purpose, we focus development and validation in three biomedical areas: drug repurposing, novel target discovery, and explaining mechanisms of bacterial evolution and anti-microbial resistance. For drug repurposing, the system proposes candidates with promising validation findings, including candidates for acute myeloid leukemia that show tumor inhibition in vitro at clinically applicable concentrations. For novel target discovery, the AI co-scientist proposed new epigenetic targets for liver fibrosis, validated by anti-fibrotic activity and liver cell regeneration in human hepatic organoids. Finally, the AI co-scientist recapitulated unpublished experimental results via a parallel in silico discovery of a novel gene transfer mechanism in bacterial evolution. These results, detailed in separate, co-timed reports, demonstrate the potential to augment biomedical and scientific discovery and usher an era of AI empowered scientists.

Large participatory biomedical studies, studies that recruit individuals to join a dataset, are gaining popularity and investment, especially for analysis by modern AI methods. Because they purposively recruit participants, these studies are uniquely able to address a lack of historical representation, an issue that has affected many biomedical datasets. In this work, we define representativeness as the similarity to a target population distribution of a set of attributes and our goal is to mirror the U.S. population across distributions of age, gender, race, and ethnicity. Many participatory studies recruit at several institutions, so we introduce a computational approach to adaptively allocate recruitment resources among sites to improve representativeness. In simulated recruitment of 10,000-participant cohorts from medical centers in the STAR Clinical Research Network, we show that our approach yields a more representative cohort than existing baselines. Thus, we highlight the value of computational modeling in guiding recruitment efforts.

The increased capabilities of generative AI have dramatically expanded its possible use cases in medicine. We provide a comprehensive overview of generative AI use cases for clinicians, patients, clinical trial organizers, researchers, and trainees. We then discuss the many challenges -- including maintaining privacy and security, improving transparency and interpretability, upholding equity, and rigorously evaluating models -- which must be overcome to realize this potential, and the open research directions they give rise to.

In the pharmaceutical industry, the use of artificial intelligence (AI) has seen consistent growth over the past decade. This rise is attributed to major advancements in statistical machine learning methodologies, computational capabilities and the increased availability of large datasets. AI techniques are applied throughout different stages of drug development, ranging from drug discovery to post-marketing benefit-risk assessment. Kolluri et al. provided a review of several case studies that span these stages, featuring key applications such as protein structure prediction, success probability estimation, subgroup identification, and AI-assisted clinical trial monitoring. From a regulatory standpoint, there was a notable uptick in submissions incorporating AI components in 2021. The most prevalent therapeutic areas leveraging AI were oncology (27%), psychiatry (15%), gastroenterology (12%), and neurology (11%). The paradigm of personalized or precision medicine has gained significant traction in recent research, partly due to advancements in AI techniques hamburg2010path. This shift has had a transformative impact on the pharmaceutical industry. Departing from the traditional "one-size-fits-all" model, personalized medicine incorporates various individual factors, such as environmental conditions, lifestyle choices, and health histories, to formulate customized treatment plans. By utilizing sophisticated machine learning algorithms, clinicians and researchers are better equipped to make informed decisions in areas such as disease prevention, diagnosis, and treatment selection, thereby optimizing health outcomes for each individual.

The primary goal of drug safety researchers and regulators is to promptly identify adverse drug reactions. Doing so may in turn prevent or reduce the harm to patients and ultimately improve public health. Evaluating and monitoring drug safety (i.e., pharmacovigilance) involves analyzing an ever growing collection of spontaneous reports from health professionals, physicians, and pharmacists, and information voluntarily submitted by patients. In this scenario, facilitating analysis of such reports via automation has the potential to rapidly identify safety signals. Unfortunately, public resources for developing natural language models for this task are scant. We present PHEE, a novel dataset for pharmacovigilance comprising over 5000 annotated events from medical case reports and biomedical literature, making it the largest such public dataset to date. We describe the hierarchical event schema designed to provide coarse and fine-grained information about patients' demographics, treatments and (side) effects. Along with the discussion of the dataset, we present a thorough experimental evaluation of current state-of-the-art approaches for biomedical event extraction, point out their limitations, and highlight open challenges to foster future research in this area.

Keeping track of scientific challenges, advances and emerging directions is a fundamental part of research. However, researchers face a flood of papers that hinders discovery of important knowledge. In biomedicine, this directly impacts human lives. To address this problem, we present a novel task of extraction and search of scientific challenges and directions, to facilitate rapid knowledge discovery. We construct and release an expert-annotated corpus of texts sampled from full-length papers, labeled with novel semantic categories that generalize across many types of challenges and directions. We focus on a large corpus of interdisciplinary work relating to the COVID-19 pandemic, ranging from biomedicine to areas such as AI and economics. We apply a model trained on our data to identify challenges and directions across the corpus and build a dedicated search engine. In experiments with 19 researchers and clinicians using our system, we outperform a popular scientific search engine in assisting knowledge discovery. Finally, we show that models trained on our resource generalize to the wider biomedical domain and to AI papers, highlighting its broad utility. We make our data, model and search engine publicly available. https://challenges.apps.allenai.org/

Recent advances in generative models, including large language models (LLMs), vision language models (VLMs), and diffusion models, have accelerated the field of natural language and image processing in medicine and marked a significant paradigm shift in how biomedical models can be developed and deployed. While these models are highly adaptable to new tasks, scaling and evaluating their usage presents new challenges not addressed in previous frameworks. In particular, the ability of these models to produce useful outputs with little to no specialized training data ("zero-" or "few-shot" approaches), as well as the open-ended nature of their outputs, necessitate the development of new guidelines for robust reporting of clinical generative model research. In response to gaps in standards and best practices for the development of clinical AI tools identified by US Executive Order 141103 and several emerging national networks for clinical AI evaluation, we begin to formalize some of these guidelines by building on the original MI-CLAIM checklist. The new checklist, MI-CLAIM-GEN (Table 1), aims to address differences in training, evaluation, interpretability, and reproducibility of new generative models compared to non-generative ("predictive") AI models. This MI-CLAIM-GEN checklist also seeks to clarify cohort selection reporting with unstructured clinical data and adds additional items on alignment with ethical standards for clinical AI research.

Medical systematic reviews can be very costly and resource intensive. We explore how Large Language Models (LLMs) can support and be trained to perform literature screening when provided with a detailed set of selection criteria. Specifically, we instruction tune LLaMA and Guanaco models to perform abstract screening for medical systematic reviews. Our best model, Bio-SIEVE, outperforms both ChatGPT and trained traditional approaches, and generalises better across medical domains. However, there remains the challenge of adapting the model to safety-first scenarios. We also explore the impact of multi-task training with Bio-SIEVE-Multi, including tasks such as PICO extraction and exclusion reasoning, but find that it is unable to match single-task Bio-SIEVE's performance. We see Bio-SIEVE as an important step towards specialising LLMs for the biomedical systematic review process and explore its future developmental opportunities. We release our models, code and a list of DOIs to reconstruct our dataset for reproducibility.

Predicting how different interventions will causally affect a specific individual is important in a variety of domains such as personalized medicine, public policy, and online marketing. There are a large number of methods to predict the effect of an existing intervention based on historical data from individuals who received it. However, in many settings it is important to predict the effects of novel interventions (e.g., a newly invented drug), which these methods do not address. Here, we consider zero-shot causal learning: predicting the personalized effects of a novel intervention. We propose CaML, a causal meta-learning framework which formulates the personalized prediction of each intervention's effect as a task. CaML trains a single meta-model across thousands of tasks, each constructed by sampling an intervention, along with its recipients and nonrecipients. By leveraging both intervention information (e.g., a drug's attributes) and individual features~(e.g., a patient's history), CaML is able to predict the personalized effects of novel interventions that do not exist at the time of training. Experimental results on real world datasets in large-scale medical claims and cell-line perturbations demonstrate the effectiveness of our approach. Most strikingly, CaML's zero-shot predictions outperform even strong baselines trained directly on data from the test interventions.

User-generated data sources have gained significance in uncovering Adverse Drug Reactions (ADRs), with an increasing number of discussions occurring in the digital world. However, the existing clinical corpora predominantly revolve around scientific articles in English. This work presents a multilingual corpus of texts concerning ADRs gathered from diverse sources, including patient fora, social media, and clinical reports in German, French, and Japanese. Our corpus contains annotations covering 12 entity types, four attribute types, and 13 relation types. It contributes to the development of real-world multilingual language models for healthcare. We provide statistics to highlight certain challenges associated with the corpus and conduct preliminary experiments resulting in strong baselines for extracting entities and relations between these entities, both within and across languages.

Motivation: The development of novel compounds targeting proteins of interest is one of the most important tasks in the pharmaceutical industry. Deep generative models have been applied to targeted molecular design and have shown promising results. Recently, target-specific molecule generation has been viewed as a translation between the protein language and the chemical language. However, such a model is limited by the availability of interacting protein-ligand pairs. On the other hand, large amounts of unlabeled protein sequences and chemical compounds are available and have been used to train language models that learn useful representations. In this study, we propose exploiting pretrained biochemical language models to initialize (i.e. warm start) targeted molecule generation models. We investigate two warm start strategies: (i) a one-stage strategy where the initialized model is trained on targeted molecule generation (ii) a two-stage strategy containing a pre-finetuning on molecular generation followed by target specific training. We also compare two decoding strategies to generate compounds: beam search and sampling. Results: The results show that the warm-started models perform better than a baseline model trained from scratch. The two proposed warm-start strategies achieve similar results to each other with respect to widely used metrics from benchmarks. However, docking evaluation of the generated compounds for a number of novel proteins suggests that the one-stage strategy generalizes better than the two-stage strategy. Additionally, we observe that beam search outperforms sampling in both docking evaluation and benchmark metrics for assessing compound quality. Availability and implementation: The source code is available at https://github.com/boun-tabi/biochemical-lms-for-drug-design and the materials are archived in Zenodo at https://doi.org/10.5281/zenodo.6832145

To assess the effectiveness of any medical intervention, researchers must conduct a time-intensive and highly manual literature review. NLP systems can help to automate or assist in parts of this expensive process. In support of this goal, we release MS^2 (Multi-Document Summarization of Medical Studies), a dataset of over 470k documents and 20k summaries derived from the scientific literature. This dataset facilitates the development of systems that can assess and aggregate contradictory evidence across multiple studies, and is the first large-scale, publicly available multi-document summarization dataset in the biomedical domain. We experiment with a summarization system based on BART, with promising early results. We formulate our summarization inputs and targets in both free text and structured forms and modify a recently proposed metric to assess the quality of our system's generated summaries. Data and models are available at https://github.com/allenai/ms2

With the introduction of ChatGPT, Large Language Models (LLMs) have received enormous attention in healthcare. Despite their potential benefits, researchers have underscored various ethical implications. While individual instances have drawn much attention, the debate lacks a systematic overview of practical applications currently researched and ethical issues connected to them. Against this background, this work aims to map the ethical landscape surrounding the current stage of deployment of LLMs in medicine and healthcare. Electronic databases and preprint servers were queried using a comprehensive search strategy. Studies were screened and extracted following a modified rapid review approach. Methodological quality was assessed using a hybrid approach. For 53 records, a meta-aggregative synthesis was performed. Four fields of applications emerged and testify to a vivid exploration phase. Advantages of using LLMs are attributed to their capacity in data analysis, personalized information provisioning, support in decision-making, mitigating information loss and enhancing information accessibility. However, we also identifies recurrent ethical concerns connected to fairness, bias, non-maleficence, transparency, and privacy. A distinctive concern is the tendency to produce harmful misinformation or convincingly but inaccurate content. A recurrent plea for ethical guidance and human oversight is evident. Given the variety of use cases, it is suggested that the ethical guidance debate be reframed to focus on defining what constitutes acceptable human oversight across the spectrum of applications. This involves considering diverse settings, varying potentials for harm, and different acceptable thresholds for performance and certainty in healthcare. In addition, a critical inquiry is necessary to determine the extent to which the current experimental use of LLMs is necessary and justified.

Accumulated clinical studies show that microbes living in humans interact closely with human hosts, and get involved in modulating drug efficacy and drug toxicity. Microbes have become novel targets for the development of antibacterial agents. Therefore, screening of microbe-drug associations can benefit greatly drug research and development. With the increase of microbial genomic and pharmacological datasets, we are greatly motivated to develop an effective computational method to identify new microbe-drug associations. In this paper, we proposed a novel method, Graph2MDA, to predict microbe-drug associations by using variational graph autoencoder (VGAE). We constructed multi-modal attributed graphs based on multiple features of microbes and drugs, such as molecular structures, microbe genetic sequences, and function annotations. Taking as input the multi-modal attribute graphs, VGAE was trained to learn the informative and interpretable latent representations of each node and the whole graph, and then a deep neural network classifier was used to predict microbe-drug associations. The hyperparameter analysis and model ablation studies showed the sensitivity and robustness of our model. We evaluated our method on three independent datasets and the experimental results showed that our proposed method outperformed six existing state-of-the-art methods. We also explored the meaningness of the learned latent representations of drugs and found that the drugs show obvious clustering patterns that are significantly consistent with drug ATC classification. Moreover, we conducted case studies on two microbes and two drugs and found 75\%-95\% predicted associations have been reported in PubMed literature. Our extensive performance evaluations validated the effectiveness of our proposed method.\

Clinical Natural Language Processing (NLP) has become an emerging technology in healthcare that leverages a large amount of free-text data in electronic health records (EHRs) to improve patient care, support clinical decisions, and facilitate clinical and translational science research. Recently, deep learning has achieved state-of-the-art performance in many clinical NLP tasks. However, training deep learning models usually requires large annotated datasets, which are normally not publicly available and can be time-consuming to build in clinical domains. Working with smaller annotated datasets is typical in clinical NLP and therefore, ensuring that deep learning models perform well is crucial for the models to be used in real-world applications. A widely adopted approach is fine-tuning existing Pre-trained Language Models (PLMs), but these attempts fall short when the training dataset contains only a few annotated samples. Few-Shot Learning (FSL) has recently been investigated to tackle this problem. Siamese Neural Network (SNN) has been widely utilized as an FSL approach in computer vision, but has not been studied well in NLP. Furthermore, the literature on its applications in clinical domains is scarce. In this paper, we propose two SNN-based FSL approaches for clinical NLP, including Pre-Trained SNN (PT-SNN) and SNN with Second-Order Embeddings (SOE-SNN). We evaluated the proposed approaches on two clinical tasks, namely clinical text classification and clinical named entity recognition. We tested three few-shot settings including 4-shot, 8-shot, and 16-shot learning. Both clinical NLP tasks were benchmarked using three PLMs, including BERT,BioBERT, and BioClinicalBERT. The experimental results verified the effectiveness of the proposed SNN-based FSL approaches in both NLP tasks.

Temporally dense single-person "small data" have become widely available thanks to mobile apps and wearable sensors. Many caregivers and self-trackers want to use these data to help a specific person change their behavior to achieve desired health outcomes. Ideally, this involves discerning possible causes from correlations using that person's own observational time series data. In this paper, we estimate within-individual average treatment effects of physical activity on sleep duration, and vice-versa. We introduce the model twin randomization (MoTR; "motor") method for analyzing an individual's intensive longitudinal data. Formally, MoTR is an application of the g-formula (i.e., standardization, back-door adjustment) under serial interference. It estimates stable recurring effects, as is done in n-of-1 trials and single case experimental designs. We compare our approach to standard methods (with possible confounding) to show how to use causal inference to make better personalized recommendations for health behavior change, and analyze 222 days of Fitbit sleep and steps data for one of the authors.

With the development of computer-assisted techniques, research communities including biochemistry and deep learning have been devoted into the drug discovery field for over a decade. Various applications of deep learning have drawn great attention in drug discovery, such as molecule generation, molecular property prediction, retrosynthesis prediction, and reaction prediction. While most existing surveys only focus on one of the applications, limiting the view of researchers in the community. In this paper, we present a comprehensive review on the aforementioned four aspects, and discuss the relationships among different applications. The latest literature and classical benchmarks are presented for better understanding the development of variety of approaches. We commence by summarizing the molecule representation format in these works, followed by an introduction of recent proposed approaches for each of the four tasks. Furthermore, we review a variety of commonly used datasets and evaluation metrics and compare the performance of deep learning-based models. Finally, we conclude by identifying remaining challenges and discussing the future trend for deep learning methods in drug discovery.

Inspire therapy is an FDA-approved internal neurostimulation treatment for obstructive sleep apnea. However, not all patients respond to this therapy, posing a challenge even for experienced otolaryngologists to determine candidacy. This paper makes the first attempt to leverage both machine learning and deep learning techniques in discerning patient responsiveness to Inspire therapy using medical data and videos captured through Drug-Induced Sleep Endoscopy (DISE), an essential procedure for Inspire therapy. To achieve this, we gathered and annotated three datasets from 127 patients. Two of these datasets comprise endoscopic videos focused on the Base of the Tongue and Velopharynx. The third dataset composes the patient's clinical information. By utilizing these datasets, we benchmarked and compared the performance of six deep learning models and five classical machine learning algorithms. The results demonstrate the potential of employing machine learning and deep learning techniques to determine a patient's eligibility for Inspire therapy, paving the way for future advancements in this field.

Predicting clinical outcomes from preclinical data is essential for identifying safe and effective drug combinations. Current models rely on structural or target-based features to identify high-efficacy, low-toxicity drug combinations. However, these approaches fail to incorporate the multimodal data necessary for accurate, clinically-relevant predictions. Here, we introduce MADRIGAL, a multimodal AI model that learns from structural, pathway, cell viability, and transcriptomic data to predict drug combination effects across 953 clinical outcomes and 21842 compounds, including combinations of approved drugs and novel compounds in development. MADRIGAL uses a transformer bottleneck module to unify preclinical drug data modalities while handling missing data during training and inference--a major challenge in multimodal learning. It outperforms single-modality methods and state-of-the-art models in predicting adverse drug interactions. MADRIGAL performs virtual screening of anticancer drug combinations and supports polypharmacy management for type II diabetes and metabolic dysfunction-associated steatohepatitis (MASH). It identifies transporter-mediated drug interactions. MADRIGAL predicts resmetirom, the first and only FDA-approved drug for MASH, among therapies with the most favorable safety profile. It supports personalized cancer therapy by integrating genomic profiles from cancer patients. Using primary acute myeloid leukemia samples and patient-derived xenograft models, it predicts the efficacy of personalized drug combinations. Integrating MADRIGAL with a large language model allows users to describe clinical outcomes in natural language, improving safety assessment by identifying potential adverse interactions and toxicity risks. MADRIGAL provides a multimodal approach for designing combination therapies with improved predictive accuracy and clinical relevance.

Objective: To transform heterogeneous clinical data from electronic health records into clinically meaningful constructed features using data driven method that rely, in part, on temporal relations among data. Materials and Methods: The clinically meaningful representations of medical concepts and patients are the key for health analytic applications. Most of existing approaches directly construct features mapped to raw data (e.g., ICD or CPT codes), or utilize some ontology mapping such as SNOMED codes. However, none of the existing approaches leverage EHR data directly for learning such concept representation. We propose a new way to represent heterogeneous medical concepts (e.g., diagnoses, medications and procedures) based on co-occurrence patterns in longitudinal electronic health records. The intuition behind the method is to map medical concepts that are co-occuring closely in time to similar concept vectors so that their distance will be small. We also derive a simple method to construct patient vectors from the related medical concept vectors. Results: For qualitative evaluation, we study similar medical concepts across diagnosis, medication and procedure. In quantitative evaluation, our proposed representation significantly improves the predictive modeling performance for onset of heart failure (HF), where classification methods (e.g. logistic regression, neural network, support vector machine and K-nearest neighbors) achieve up to 23% improvement in area under the ROC curve (AUC) using this proposed representation. Conclusion: We proposed an effective method for patient and medical concept representation learning. The resulting representation can map relevant concepts together and also improves predictive modeling performance.

Background: Rapid advancements in natural language processing have led to the development of large language models with the potential to revolutionize mental health care. These models have shown promise in assisting clinicians and providing support to individuals experiencing various psychological challenges. Objective: This study aims to compare the performance of two large language models, GPT-4 and Chat-GPT, in responding to a set of 18 psychological prompts, to assess their potential applicability in mental health care settings. Methods: A blind methodology was employed, with a clinical psychologist evaluating the models' responses without knowledge of their origins. The prompts encompassed a diverse range of mental health topics, including depression, anxiety, and trauma, to ensure a comprehensive assessment. Results: The results demonstrated a significant difference in performance between the two models (p > 0.05). GPT-4 achieved an average rating of 8.29 out of 10, while Chat-GPT received an average rating of 6.52. The clinical psychologist's evaluation suggested that GPT-4 was more effective at generating clinically relevant and empathetic responses, thereby providing better support and guidance to potential users. Conclusions: This study contributes to the growing body of literature on the applicability of large language models in mental health care settings. The findings underscore the importance of continued research and development in the field to optimize these models for clinical use. Further investigation is necessary to understand the specific factors underlying the performance differences between the two models and to explore their generalizability across various populations and mental health conditions.

In response to the pressing need for advanced clinical problem-solving tools in healthcare, we introduce BooksMed, a novel framework based on a Large Language Model (LLM). BooksMed uniquely emulates human cognitive processes to deliver evidence-based and reliable responses, utilizing the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) framework to effectively quantify evidence strength. For clinical decision-making to be appropriately assessed, an evaluation metric that is clinically aligned and validated is required. As a solution, we present ExpertMedQA, a multispecialty clinical benchmark comprised of open-ended, expert-level clinical questions, and validated by a diverse group of medical professionals. By demanding an in-depth understanding and critical appraisal of up-to-date clinical literature, ExpertMedQA rigorously evaluates LLM performance. BooksMed outperforms existing state-of-the-art models Med-PaLM 2, Almanac, and ChatGPT in a variety of medical scenarios. Therefore, a framework that mimics human cognitive stages could be a useful tool for providing reliable and evidence-based responses to clinical inquiries.

The COVID-19 pandemic has posed a heavy burden to the healthcare system worldwide and caused huge social disruption and economic loss. Many deep learning models have been proposed to conduct clinical predictive tasks such as mortality prediction for COVID-19 patients in intensive care units using Electronic Health Record (EHR) data. Despite their initial success in certain clinical applications, there is currently a lack of benchmarking results to achieve a fair comparison so that we can select the optimal model for clinical use. Furthermore, there is a discrepancy between the formulation of traditional prediction tasks and real-world clinical practice in intensive care. To fill these gaps, we propose two clinical prediction tasks, Outcome-specific length-of-stay prediction and Early mortality prediction for COVID-19 patients in intensive care units. The two tasks are adapted from the naive length-of-stay and mortality prediction tasks to accommodate the clinical practice for COVID-19 patients. We propose fair, detailed, open-source data-preprocessing pipelines and evaluate 17 state-of-the-art predictive models on two tasks, including 5 machine learning models, 6 basic deep learning models and 6 deep learning predictive models specifically designed for EHR data. We provide benchmarking results using data from two real-world COVID-19 EHR datasets. One dataset is publicly available without needing any inquiry and another dataset can be accessed on request. We provide fair, reproducible benchmarking results for two tasks. We deploy all experiment results and models on an online platform. We also allow clinicians and researchers to upload their data to the platform and get quick prediction results using our trained models. We hope our efforts can further facilitate deep learning and machine learning research for COVID-19 predictive modeling.

In this study, we present MedS-Bench, a comprehensive benchmark designed to evaluate the performance of large language models (LLMs) in clinical contexts. Unlike existing benchmarks that focus on multiple-choice question answering, MedS-Bench spans 11 high-level clinical tasks, including clinical report summarization, treatment recommendations, diagnosis, named entity recognition, and medical concept explanation, among others. We evaluated six leading LLMs, e.g., MEDITRON, Mistral, InternLM 2, Llama 3, GPT-4, and Claude-3.5 using few-shot prompting, and found that even the most sophisticated models struggle with these complex tasks. To address these limitations, we developed MedS-Ins, a large-scale instruction tuning dataset for medicine. MedS-Ins comprises 58 medically oriented language corpora, totaling 13.5 million samples across 122 tasks. To demonstrate the dataset's utility, we conducted a proof-of-concept experiment by performing instruction tuning on a lightweight, open-source medical language model. The resulting model, MMedIns-Llama 3, significantly outperformed existing models across nearly all clinical tasks. To promote further advancements in the application of LLMs to clinical challenges, we have made the MedS-Ins dataset fully accessible and invite the research community to contribute to its expansion.Additionally, we have launched a dynamic leaderboard for MedS-Bench, which we plan to regularly update the test set to track progress and enhance the adaptation of general LLMs to the medical domain. Leaderboard: https://henrychur.github.io/MedS-Bench/. Github: https://github.com/MAGIC-AI4Med/MedS-Ins.

In recent years, medical information technology has made it possible for electronic health record (EHR) to store fairly complete clinical data. This has brought health care into the era of "big data". However, medical data are often sparse and strongly correlated, which means that medical problems cannot be solved effectively. With the rapid development of deep learning in recent years, it has provided opportunities for the use of big data in healthcare. In this paper, we propose a temporal-saptial correlation attention network (TSCAN) to handle some clinical characteristic prediction problems, such as predicting death, predicting length of stay, detecting physiologic decline, and classifying phenotypes. Based on the design of the attention mechanism model, our approach can effectively remove irrelevant items in clinical data and irrelevant nodes in time according to different tasks, so as to obtain more accurate prediction results. Our method can also find key clinical indicators of important outcomes that can be used to improve treatment options. Our experiments use information from the Medical Information Mart for Intensive Care (MIMIC-IV) database, which is open to the public. Finally, we have achieved significant performance benefits of 2.0\% (metric) compared to other SOTA prediction methods. We achieved a staggering 90.7\% on mortality rate, 45.1\% on length of stay. The source code can be find: https://github.com/yuyuheintju/TSCAN.

Stroke remains a leading cause of global morbidity and mortality, placing a heavy socioeconomic burden. Over the past decade, advances in endovascular reperfusion therapy and the use of CT and MRI imaging for treatment guidance have significantly improved patient outcomes and are now standard in clinical practice. To develop machine learning algorithms that can extract meaningful and reproducible models of brain function for both clinical and research purposes from stroke images - particularly for lesion identification, brain health quantification, and prognosis - large, diverse, and well-annotated public datasets are essential. While only a few datasets with (sub-)acute stroke data were previously available, several large, high-quality datasets have recently been made publicly accessible. However, these existing datasets include only MRI data. In contrast, our dataset is the first to offer comprehensive longitudinal stroke data, including acute CT imaging with angiography and perfusion, follow-up MRI at 2-9 days, as well as acute and longitudinal clinical data up to a three-month outcome. The dataset includes a training dataset of n = 150 and a test dataset of n = 100 scans. Training data is publicly available, while test data will be used exclusively for model validation. We are making this dataset available as part of the 2024 edition of the Ischemic Stroke Lesion Segmentation (ISLES) challenge (https://www.isles-challenge.org/), which continuously aims to establish benchmark methods for acute and sub-acute ischemic stroke lesion segmentation, aiding in creating open stroke imaging datasets and evaluating cutting-edge image processing algorithms.

Literature-Based Discovery (LBD) aims to discover new scientific knowledge by mining papers and generating hypotheses. Standard LBD is limited to predicting pairwise relations between discrete concepts (e.g., drug-disease links), and ignores critical contexts like experimental settings (e.g., a specific patient population where a drug is evaluated) and background motivations (e.g., to find drugs without specific side effects). We address these limitations with a novel formulation of contextualized-LBD (C-LBD): generating scientific hypotheses in natural language, while grounding them in a context that controls the hypothesis search space. We present a modeling framework using retrieval of ``inspirations'' from past scientific papers. Our evaluations reveal that GPT-4 tends to generate ideas with overall low technical depth and novelty, while our inspiration prompting approaches partially mitigate this issue. Our work represents a first step toward building language models that generate new ideas derived from scientific literature.

Objective: We develop a deep learning framework based on the pre-trained Bidirectional Encoder Representations from Transformers (BERT) model using unstructured clinical notes from electronic health records (EHRs) to predict the risk of disease progression from Mild Cognitive Impairment (MCI) to Alzheimer's Disease (AD). Materials and Methods: We identified 3657 patients diagnosed with MCI together with their progress notes from Northwestern Medicine Enterprise Data Warehouse (NMEDW) between 2000-2020. The progress notes no later than the first MCI diagnosis were used for the prediction. We first preprocessed the notes by deidentification, cleaning and splitting, and then pretrained a BERT model for AD (AD-BERT) based on the publicly available Bio+Clinical BERT on the preprocessed notes. The embeddings of all the sections of a patient's notes processed by AD-BERT were combined by MaxPooling to compute the probability of MCI-to-AD progression. For replication, we conducted a similar set of experiments on 2563 MCI patients identified at Weill Cornell Medicine (WCM) during the same timeframe. Results: Compared with the 7 baseline models, the AD-BERT model achieved the best performance on both datasets, with Area Under receiver operating characteristic Curve (AUC) of 0.8170 and F1 score of 0.4178 on NMEDW dataset and AUC of 0.8830 and F1 score of 0.6836 on WCM dataset. Conclusion: We developed a deep learning framework using BERT models which provide an effective solution for prediction of MCI-to-AD progression using clinical note analysis.

Diabetes is a chronic disease that poses a significant global health burden, and optimizing diabetes management requires multi-stakeholder collaboration. Large language models (LLMs) have shown promise in various healthcare scenarios, but their effectiveness across a diverse range of diabetes tasks remains unproven. In this study, we introduced a framework to train and validate diabetes-specific LLMs. We first developed a comprehensive data processing pipeline that includes data collection, filtering, augmentation and refinement. This approach contributes to creating a high-quality, diabetes-specific dataset, and several evaluation benchmarks entirely from scratch. Utilizing the collected training dataset, we fine-tuned a diabetes-specific LLM family that demonstrated state-of-the-art proficiency in understanding and processing various diabetes tasks compared to other LLMs. Furthermore, clinical studies showed the potential applications of our models in diabetes care, including providing personalized healthcare, assisting medical education, and streamlining clinical tasks. In conclusion, our study introduced a framework to develop and evaluate a diabetes-specific LLM family, and highlighted its potential to enhance clinical practice and provide personalized, data-driven support for diabetes support when facing different end users. The code is provided via GitHub at https://github.com/waltonfuture/Diabetica.

Large language models (LLMs) have shown remarkable progress in encoding clinical knowledge and responding to complex medical queries with appropriate clinical reasoning. However, their applicability in subspecialist or complex medical settings remains underexplored. In this work, we probe the performance of AMIE, a research conversational diagnostic AI system, in the subspecialist domain of breast oncology care without specific fine-tuning to this challenging domain. To perform this evaluation, we curated a set of 50 synthetic breast cancer vignettes representing a range of treatment-naive and treatment-refractory cases and mirroring the key information available to a multidisciplinary tumor board for decision-making (openly released with this work). We developed a detailed clinical rubric for evaluating management plans, including axes such as the quality of case summarization, safety of the proposed care plan, and recommendations for chemotherapy, radiotherapy, surgery and hormonal therapy. To improve performance, we enhanced AMIE with the inference-time ability to perform web search retrieval to gather relevant and up-to-date clinical knowledge and refine its responses with a multi-stage self-critique pipeline. We compare response quality of AMIE with internal medicine trainees, oncology fellows, and general oncology attendings under both automated and specialist clinician evaluations. In our evaluations, AMIE outperformed trainees and fellows demonstrating the potential of the system in this challenging and important domain. We further demonstrate through qualitative examples, how systems such as AMIE might facilitate conversational interactions to assist clinicians in their decision making. However, AMIE's performance was overall inferior to attending oncologists suggesting that further research is needed prior to consideration of prospective uses.

We consider the task of evaluating policies of algorithmic resource allocation through randomized controlled trials (RCTs). Such policies are tasked with optimizing the utilization of limited intervention resources, with the goal of maximizing the benefits derived. Evaluation of such allocation policies through RCTs proves difficult, notwithstanding the scale of the trial, because the individuals' outcomes are inextricably interlinked through resource constraints controlling the policy decisions. Our key contribution is to present a new estimator leveraging our proposed novel concept, that involves retrospective reshuffling of participants across experimental arms at the end of an RCT. We identify conditions under which such reassignments are permissible and can be leveraged to construct counterfactual trials, whose outcomes can be accurately ascertained, for free. We prove theoretically that such an estimator is more accurate than common estimators based on sample means -- we show that it returns an unbiased estimate and simultaneously reduces variance. We demonstrate the value of our approach through empirical experiments on synthetic, semi-synthetic as well as real case study data and show improved estimation accuracy across the board.

Randomized controlled trials are susceptible to imbalance on covariates predictive of the outcome. Rerandomization and deterministic treatment assignment are two proposed solutions. This paper explores the relationship between rerandomization and deterministic assignment, showing how deterministic assignment is an extreme case of rerandomization. The paper argues that in small experiments, both fully randomized and fully deterministic assignment have limitations. Instead, the researcher should consider setting the rerandomization acceptance probability based on an analysis of covariates and assumptions about the data structure to achieve an optimal alignment between randomness and balance. This allows for the calculation of minimum p-values along with valid permutation tests and fiducial intervals. The paper also introduces tools, including a new, open-source R package named fastrerandomize, to implement rerandomization and explore options for optimal rerandomization acceptance thresholds.

To effectively optimize and personalize treatments, it is necessary to investigate the heterogeneity of treatment effects. With the wide range of users being treated over many online controlled experiments, the typical approach of manually investigating each dimension of heterogeneity becomes overly cumbersome and prone to subjective human biases. We need an efficient way to search through thousands of experiments with hundreds of target covariates and hundreds of breakdown dimensions. In this paper, we propose a systematic paradigm for detecting, surfacing and characterizing heterogeneous treatment effects. First, we detect if treatment effect variation is present in an experiment, prior to specifying any breakdowns. Second, we surface the most relevant dimensions for heterogeneity. Finally, we characterize the heterogeneity beyond just the conditional average treatment effects (CATE) by studying the conditional distributions of the estimated individual treatment effects. We show the effectiveness of our methods using simulated data and empirical studies.

Objective: Using natural language processing (NLP) to find sentences that state treatment plans in a clinical note, would automate plan extraction and would further enable their use in tools that help providers and care managers. However, as in the most NLP tasks on clinical text, creating gold standard to train and test NLP models is tedious and expensive. Fortuitously, sometimes but not always clinical notes contain sections with a heading that identifies the section as a plan. Leveraging contents of such labeled sections as a noisy training data, we assessed accuracy of NLP models trained with the data. Methods: We used common variations of plan headings and rule-based heuristics to find plan sections with headings in clinical notes, and we extracted sentences from them and formed a noisy training data of plan sentences. We trained Support Vector Machine (SVM) and Convolutional Neural Network (CNN) models with the data. We measured accuracy of the trained models on the noisy dataset using ten-fold cross validation and separately on a set-aside manually annotated dataset. Results: About 13% of 117,730 clinical notes contained treatment plans sections with recognizable headings in the 1001 longitudinal patient records that were obtained from Cleveland Clinic under an IRB approval. We were able to extract and create a noisy training data of 13,492 plan sentences from the clinical notes. CNN achieved best F measures, 0.91 and 0.97 in the cross-validation and set-aside evaluation experiments respectively. SVM slightly underperformed with F measures of 0.89 and 0.96 in the same experiments. Conclusion: Our study showed that the training supervised learning models using noisy plan sentences was effective in identifying them in all clinical notes. More broadly, sections with informal headings in clinical notes can be a good source for generating effective training data.

Adverse Drug Reactions (ADRs) from psychiatric medications are the leading cause of hospitalizations among mental health patients. With healthcare systems and online communities facing limitations in resolving ADR-related issues, Large Language Models (LLMs) have the potential to fill this gap. Despite the increasing capabilities of LLMs, past research has not explored their capabilities in detecting ADRs related to psychiatric medications or in providing effective harm reduction strategies. To address this, we introduce the Psych-ADR benchmark and the Adverse Drug Reaction Response Assessment (ADRA) framework to systematically evaluate LLM performance in detecting ADR expressions and delivering expert-aligned mitigation strategies. Our analyses show that LLMs struggle with understanding the nuances of ADRs and differentiating between types of ADRs. While LLMs align with experts in terms of expressed emotions and tone of the text, their responses are more complex, harder to read, and only 70.86% aligned with expert strategies. Furthermore, they provide less actionable advice by a margin of 12.32% on average. Our work provides a comprehensive benchmark and evaluation framework for assessing LLMs in strategy-driven tasks within high-risk domains.

Chemical similarity searches are widely used in-silico methods for identifying new drug-like molecules. These methods have historically relied on structure-based comparisons to compute molecular similarity. Here, we use a chemical language model to create a vector-based chemical search. We extend implementations by creating a prompt engineering strategy that utilizes two different chemical string representation algorithms: one for the query and the other for the database. We explore this method by reviewing the search results from five drug-like query molecules (penicillin G, nirmatrelvir, zidovudine, lysergic acid diethylamide, and fentanyl) and three dye-like query molecules (acid blue 25, avobenzone, and 2-diphenylaminocarbazole). We find that this novel method identifies molecules that are functionally similar to the query, indicated by the associated patent literature, and that many of these molecules are structurally distinct from the query, making them unlikely to be found with traditional chemical similarity search methods. This method may aid in the discovery of novel structural classes of molecules that achieve target functionality.

Objective: Data unavailability has been one of the biggest barriers in clinical natural language processing. This paper is aimed at providing a large-scale and publicly available patient note dataset, named PMC-Patients, with relevant articles and similar patients annotations. The ultimate goal of PMC-Patients is to facilitate the development of retrieval-based clinical decision support systems. Materials and Methods: To collect PMC-Patients, we extract patient notes from case reports in PubMed Central by recognizing certain section patterns. Patient-article relevance and patient-patient similarity are annotated by citation relationships in PubMed. In addition, we perform three tasks with PMC-Patients to demonstrate its utility in providing clinical decision support for a given patient, including (1) classifying whether another patient is similar, (2) retrieving similar patients in PMC-Patients, and (3) retrieving relevant articles in PubMed. Results: We collect and release PMC-Patients under the CC BY-NC-SA license, which becomes the largest publicly available patient note dataset so far. PMC-Patients contains 167k patient notes that are annotated with 3.1M relevant articles and 293k similar patients. Qualitative and quantitative analyses reveal the high quality and richness of our dataset. Experiments show that classifying the similarity of patient pairs is relatively easy, but it is hard to retrieve similar patients or relevant articles for a given patient from a large set of candidates. Conclusion: We present PMC-Patients, a large-scale dataset of patient notes with high quality, easy access, diverse conditions, and rich annotations. The proposed dataset can also serve as a hard benchmark for evaluating retrieval-based clinical decision support systems.

Nowadays the medical domain is receiving more and more attention in applications involving Artificial Intelligence. Clinicians have to deal with an enormous amount of unstructured textual data to make a conclusion about patients' health in their everyday life. Argument mining helps to provide a structure to such data by detecting argumentative components in the text and classifying the relations between them. However, as it is the case for many tasks in Natural Language Processing in general and in medical text processing in particular, the large majority of the work on computational argumentation has been done only for English. This is also the case with the only dataset available for argumentation in the medical domain, namely, the annotated medical data of abstracts of Randomized Controlled Trials (RCT) from the MEDLINE database. In order to mitigate the lack of annotated data for other languages, we empirically investigate several strategies to perform argument mining and classification in medical texts for a language for which no annotated data is available. This project shows that automatically translating and project annotations from English to a target language (Spanish) is an effective way to generate annotated data without manual intervention. Furthermore, our experiments demonstrate that the translation and projection approach outperforms zero-shot cross-lingual approaches using a large masked multilingual language model. Finally, we show how the automatically generated data in Spanish can also be used to improve results in the original English evaluation setting.

Large Language Models (LLMs) hold great promise to revolutionize current clinical systems for their superior capacities on medical text processing tasks and medical licensing exams. Meanwhile, traditional ML models such as SVM and XGBoost have still been mainly adopted in clinical prediction tasks. An emerging question is Can LLMs beat traditional ML models in clinical prediction? Thus, we build a new benchmark ClinicalBench to comprehensively study the clinical predictive modeling capacities of both general-purpose and medical LLMs, and compare them with traditional ML models. ClinicalBench embraces three common clinical prediction tasks, two databases, 14 general-purpose LLMs, 8 medical LLMs, and 11 traditional ML models. Through extensive empirical investigation, we discover that both general-purpose and medical LLMs, even with different model scales, diverse prompting or fine-tuning strategies, still cannot beat traditional ML models in clinical prediction yet, shedding light on their potential deficiency in clinical reasoning and decision-making. We call for caution when practitioners adopt LLMs in clinical applications. ClinicalBench can be utilized to bridge the gap between LLMs' development for healthcare and real-world clinical practice.

Medical language models (MLMs) have become pivotal in advancing medical natural language processing. However, prior models that rely on pre-training or supervised fine-tuning often exhibit low data efficiency and limited practicality in real-world clinical applications. While OpenAIs O1 highlights test-time scaling in mathematics, attempts to replicate this approach in medicine typically distill responses from GPT-series models to open-source models, focusing primarily on multiple-choice tasks. This strategy, though straightforward, neglects critical concerns like data privacy and realistic deployment in clinical settings. In this work, we present a deployable, small-scale medical language model, \mone, designed for long-chain reasoning in clinical tasks using a self-evolution paradigm. Starting with a seed dataset of around 8,000 instances spanning five domains and 16 datasets, we prompt a base policy model to perform Monte Carlo Tree Search (MCTS) to construct verifiable reasoning chains. Each reasoning step is assigned an evolution rollout value, allowing verified trajectories to train the policy model and the reward model. During inference, the policy model generates multiple responses, and the reward model selects the one with the highest reward score. Experiments on eleven evaluation datasets demonstrate that \mone outperforms prior open-source models by 2 points, with the addition of the reward model further boosting performance (sim13 points), surpassing GPT-4o-mini. Code and data are available at https://github.com/pixas/MedSSS.

Accurate prediction of Drug-Target Affinity (DTA) is of vital importance in early-stage drug discovery, facilitating the identification of drugs that can effectively interact with specific targets and regulate their activities. While wet experiments remain the most reliable method, they are time-consuming and resource-intensive, resulting in limited data availability that poses challenges for deep learning approaches. Existing methods have primarily focused on developing techniques based on the available DTA data, without adequately addressing the data scarcity issue. To overcome this challenge, we present the SSM-DTA framework, which incorporates three simple yet highly effective strategies: (1) A multi-task training approach that combines DTA prediction with masked language modeling (MLM) using paired drug-target data. (2) A semi-supervised training method that leverages large-scale unpaired molecules and proteins to enhance drug and target representations. This approach differs from previous methods that only employed molecules or proteins in pre-training. (3) The integration of a lightweight cross-attention module to improve the interaction between drugs and targets, further enhancing prediction accuracy. Through extensive experiments on benchmark datasets such as BindingDB, DAVIS, and KIBA, we demonstrate the superior performance of our framework. Additionally, we conduct case studies on specific drug-target binding activities, virtual screening experiments, drug feature visualizations, and real-world applications, all of which showcase the significant potential of our work. In conclusion, our proposed SSM-DTA framework addresses the data limitation challenge in DTA prediction and yields promising results, paving the way for more efficient and accurate drug discovery processes. Our code is available at https://github.com/QizhiPei/SSM-DTA{Github}.

With worldwide concerns surrounding the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), there is a rapidly growing body of scientific literature on the virus. Clinicians, researchers, and policy-makers need to be able to search these articles effectively. In this work, we present a zero-shot ranking algorithm that adapts to COVID-related scientific literature. Our approach filters training data from another collection down to medical-related queries, uses a neural re-ranking model pre-trained on scientific text (SciBERT), and filters the target document collection. This approach ranks top among zero-shot methods on the TREC COVID Round 1 leaderboard, and exhibits a P@5 of 0.80 and an nDCG@10 of 0.68 when evaluated on both Round 1 and 2 judgments. Despite not relying on TREC-COVID data, our method outperforms models that do. As one of the first search methods to thoroughly evaluate COVID-19 search, we hope that this serves as a strong baseline and helps in the global crisis.

Several studies showed that Large Language Models (LLMs) can answer medical questions correctly, even outperforming the average human score in some medical exams. However, to our knowledge, no study has been conducted to assess the ability of language models to validate existing or generated medical text for correctness and consistency. In this paper, we introduce MEDEC (https://github.com/abachaa/MEDEC), the first publicly available benchmark for medical error detection and correction in clinical notes, covering five types of errors (Diagnosis, Management, Treatment, Pharmacotherapy, and Causal Organism). MEDEC consists of 3,848 clinical texts, including 488 clinical notes from three US hospital systems that were not previously seen by any LLM. The dataset has been used for the MEDIQA-CORR shared task to evaluate seventeen participating systems [Ben Abacha et al., 2024]. In this paper, we describe the data creation methods and we evaluate recent LLMs (e.g., o1-preview, GPT-4, Claude 3.5 Sonnet, and Gemini 2.0 Flash) for the tasks of detecting and correcting medical errors requiring both medical knowledge and reasoning capabilities. We also conducted a comparative study where two medical doctors performed the same task on the MEDEC test set. The results showed that MEDEC is a sufficiently challenging benchmark to assess the ability of models to validate existing or generated notes and to correct medical errors. We also found that although recent LLMs have a good performance in error detection and correction, they are still outperformed by medical doctors in these tasks. We discuss the potential factors behind this gap, the insights from our experiments, the limitations of current evaluation metrics, and share potential pointers for future research.

The recommendation of medication is a vital aspect of intelligent healthcare systems, as it involves prescribing the most suitable drugs based on a patient's specific health needs. Unfortunately, many sophisticated models currently in use tend to overlook the nuanced semantics of medical data, while only relying heavily on identities. Furthermore, these models face significant challenges in handling cases involving patients who are visiting the hospital for the first time, as they lack prior prescription histories to draw upon. To tackle these issues, we harness the powerful semantic comprehension and input-agnostic characteristics of Large Language Models (LLMs). Our research aims to transform existing medication recommendation methodologies using LLMs. In this paper, we introduce a novel approach called Large Language Model Distilling Medication Recommendation (LEADER). We begin by creating appropriate prompt templates that enable LLMs to suggest medications effectively. However, the straightforward integration of LLMs into recommender systems leads to an out-of-corpus issue specific to drugs. We handle it by adapting the LLMs with a novel output layer and a refined tuning loss function. Although LLM-based models exhibit remarkable capabilities, they are plagued by high computational costs during inference, which is impractical for the healthcare sector. To mitigate this, we have developed a feature-level knowledge distillation technique, which transfers the LLM's proficiency to a more compact model. Extensive experiments conducted on two real-world datasets, MIMIC-III and MIMIC-IV, demonstrate that our proposed model not only delivers effective results but also is efficient. To ease the reproducibility of our experiments, we release the implementation code online.

The utilization of clinical reports for various secondary purposes, including health research and treatment monitoring, is crucial for enhancing patient care. Natural Language Processing (NLP) tools have emerged as valuable assets for extracting and processing relevant information from these reports. However, the availability of specialized language models for the clinical domain in Spanish has been limited. In this paper, we introduce EriBERTa, a bilingual domain-specific language model pre-trained on extensive medical and clinical corpora. We demonstrate that EriBERTa outperforms previous Spanish language models in the clinical domain, showcasing its superior capabilities in understanding medical texts and extracting meaningful information. Moreover, EriBERTa exhibits promising transfer learning abilities, allowing for knowledge transfer from one language to another. This aspect is particularly beneficial given the scarcity of Spanish clinical data.

The burgeoning integration of 3D medical imaging into healthcare has led to a substantial increase in the workload of medical professionals. To assist clinicians in their diagnostic processes and alleviate their workload, the development of a robust system for retrieving similar case studies presents a viable solution. While the concept holds great promise, the field of 3D medical text-image retrieval is currently limited by the absence of robust evaluation benchmarks and curated datasets. To remedy this, our study presents a groundbreaking dataset, BIMCV-R (This dataset will be released upon acceptance.), which includes an extensive collection of 8,069 3D CT volumes, encompassing over 2 million slices, paired with their respective radiological reports. Expanding upon the foundational work of our dataset, we craft a retrieval strategy, MedFinder. This approach employs a dual-stream network architecture, harnessing the potential of large language models to advance the field of medical image retrieval beyond existing text-image retrieval solutions. It marks our preliminary step towards developing a system capable of facilitating text-to-image, image-to-text, and keyword-based retrieval tasks.

Predicting drug-target interactions (DTI) is an essential part of the drug discovery process, which is an expensive process in terms of time and cost. Therefore, reducing DTI cost could lead to reduced healthcare costs for a patient. In addition, a precisely learned molecule representation in a DTI model could contribute to developing personalized medicine, which will help many patient cohorts. In this paper, we propose a new molecule representation based on the self-attention mechanism, and a new DTI model using our molecule representation. The experiments show that our DTI model outperforms the state of the art by up to 4.9% points in terms of area under the precision-recall curve. Moreover, a study using the DrugBank database proves that our model effectively lists all known drugs targeting a specific cancer biomarker in the top-30 candidate list.

Plain language summarization with LLMs can be useful for improving textual accessibility of technical content. But how factual are these summaries in a high-stakes domain like medicine? This paper presents FactPICO, a factuality benchmark for plain language summarization of medical texts describing randomized controlled trials (RCTs), which are the basis of evidence-based medicine and can directly inform patient treatment. FactPICO consists of 345 plain language summaries of RCT abstracts generated from three LLMs (i.e., GPT-4, Llama-2, and Alpaca), with fine-grained evaluation and natural language rationales from experts. We assess the factuality of critical elements of RCTs in those summaries: Populations, Interventions, Comparators, Outcomes (PICO), as well as the reported findings concerning these. We also evaluate the correctness of the extra information (e.g., explanations) added by LLMs. Using FactPICO, we benchmark a range of existing factuality metrics, including the newly devised ones based on LLMs. We find that plain language summarization of medical evidence is still challenging, especially when balancing between simplicity and factuality, and that existing metrics correlate poorly with expert judgments on the instance level.

We present PubMed 200k RCT, a new dataset based on PubMed for sequential sentence classification. The dataset consists of approximately 200,000 abstracts of randomized controlled trials, totaling 2.3 million sentences. Each sentence of each abstract is labeled with their role in the abstract using one of the following classes: background, objective, method, result, or conclusion. The purpose of releasing this dataset is twofold. First, the majority of datasets for sequential short-text classification (i.e., classification of short texts that appear in sequences) are small: we hope that releasing a new large dataset will help develop more accurate algorithms for this task. Second, from an application perspective, researchers need better tools to efficiently skim through the literature. Automatically classifying each sentence in an abstract would help researchers read abstracts more efficiently, especially in fields where abstracts may be long, such as the medical field.

Systematic literature reviews (SLRs) play an essential role in summarising, synthesising and validating scientific evidence. In recent years, there has been a growing interest in using machine learning techniques to automate the identification of relevant studies for SLRs. However, the lack of standardised evaluation datasets makes comparing the performance of such automated literature screening systems difficult. In this paper, we analyse the citation screening evaluation datasets, revealing that many of the available datasets are either too small, suffer from data leakage or have limited applicability to systems treating automated literature screening as a classification task, as opposed to, for example, a retrieval or question-answering task. To address these challenges, we introduce CSMeD, a meta-dataset consolidating nine publicly released collections, providing unified access to 325 SLRs from the fields of medicine and computer science. CSMeD serves as a comprehensive resource for training and evaluating the performance of automated citation screening models. Additionally, we introduce CSMeD-FT, a new dataset designed explicitly for evaluating the full text publication screening task. To demonstrate the utility of CSMeD, we conduct experiments and establish baselines on new datasets.

Drug discovery typically consists of multiple steps, including identifying a target protein key to a disease's etiology, validating that interacting with this target could prevent symptoms or cure the disease, discovering a small molecule or biologic therapeutic to interact with it, and optimizing the candidate molecule through a complex landscape of required properties. Drug discovery related tasks often involve prediction and generation while considering multiple entities that potentially interact, which poses a challenge for typical AI models. For this purpose we present MAMMAL - Molecular Aligned Multi-Modal Architecture and Language - a method that we applied to create a versatile multi-task foundation model ibm/biomed.omics.bl.sm.ma-ted-458m that learns from large-scale biological datasets (2 billion samples) across diverse modalities, including proteins, small molecules, and genes. We introduce a prompt syntax that supports a wide range of classification, regression, and generation tasks. It allows combining different modalities and entity types as inputs and/or outputs. Our model handles combinations of tokens and scalars and enables the generation of small molecules and proteins, property prediction, and transcriptomic lab test predictions. We evaluated the model on 11 diverse downstream tasks spanning different steps within a typical drug discovery pipeline, where it reaches new SOTA in 9 tasks and is comparable to SOTA in 2 tasks. This performance is achieved while using a unified architecture serving all tasks, in contrast to the original SOTA performance achieved using tailored architectures. The model code and pretrained weights are publicly available at https://github.com/BiomedSciAI/biomed-multi-alignment and https://huggingface.co/ibm/biomed.omics.bl.sm.ma-ted-458m.

Radiation therapy plays a crucial role in cancer treatment, necessitating precise delivery of radiation to tumors while sparing healthy tissues over multiple days. Computed tomography (CT) is integral for treatment planning, offering electron density data crucial for accurate dose calculations. However, accurately representing patient anatomy is challenging, especially in adaptive radiotherapy, where CT is not acquired daily. Magnetic resonance imaging (MRI) provides superior soft-tissue contrast. Still, it lacks electron density information while cone beam CT (CBCT) lacks direct electron density calibration and is mainly used for patient positioning. Adopting MRI-only or CBCT-based adaptive radiotherapy eliminates the need for CT planning but presents challenges. Synthetic CT (sCT) generation techniques aim to address these challenges by using image synthesis to bridge the gap between MRI, CBCT, and CT. The SynthRAD2023 challenge was organized to compare synthetic CT generation methods using multi-center ground truth data from 1080 patients, divided into two tasks: 1) MRI-to-CT and 2) CBCT-to-CT. The evaluation included image similarity and dose-based metrics from proton and photon plans. The challenge attracted significant participation, with 617 registrations and 22/17 valid submissions for tasks 1/2. Top-performing teams achieved high structural similarity indices (>0.87/0.90) and gamma pass rates for photon (>98.1%/99.0%) and proton (>99.0%/97.3%) plans. However, no significant correlation was found between image similarity metrics and dose accuracy, emphasizing the need for dose evaluation when assessing the clinical applicability of sCT. SynthRAD2023 facilitated the investigation and benchmarking of sCT generation techniques, providing insights for developing MRI-only and CBCT-based adaptive radiotherapy.

Large language models (LLMs) hold great promise in summarizing medical evidence. Most recent studies focus on the application of proprietary LLMs. Using proprietary LLMs introduces multiple risk factors, including a lack of transparency and vendor dependency. While open-source LLMs allow better transparency and customization, their performance falls short compared to proprietary ones. In this study, we investigated to what extent fine-tuning open-source LLMs can further improve their performance in summarizing medical evidence. Utilizing a benchmark dataset, MedReview, consisting of 8,161 pairs of systematic reviews and summaries, we fine-tuned three broadly-used, open-sourced LLMs, namely PRIMERA, LongT5, and Llama-2. Overall, the fine-tuned LLMs obtained an increase of 9.89 in ROUGE-L (95% confidence interval: 8.94-10.81), 13.21 in METEOR score (95% confidence interval: 12.05-14.37), and 15.82 in CHRF score (95% confidence interval: 13.89-16.44). The performance of fine-tuned LongT5 is close to GPT-3.5 with zero-shot settings. Furthermore, smaller fine-tuned models sometimes even demonstrated superior performance compared to larger zero-shot models. The above trends of improvement were also manifested in both human and GPT4-simulated evaluations. Our results can be applied to guide model selection for tasks demanding particular domain knowledge, such as medical evidence summarization.

Medical knowledge is context-dependent and requires consistent reasoning across various natural language expressions of semantically equivalent phrases. This is particularly crucial for drug names, where patients often use brand names like Advil or Tylenol instead of their generic equivalents. To study this, we create a new robustness dataset, RABBITS, to evaluate performance differences on medical benchmarks after swapping brand and generic drug names using physician expert annotations. We assess both open-source and API-based LLMs on MedQA and MedMCQA, revealing a consistent performance drop ranging from 1-10\%. Furthermore, we identify a potential source of this fragility as the contamination of test data in widely used pre-training datasets. All code is accessible at https://github.com/BittermanLab/RABBITS, and a HuggingFace leaderboard is available at https://huggingface.co/spaces/AIM-Harvard/rabbits-leaderboard.

Large Language Models (LLMs) have rapidly become important tools in Biomedical and Health Informatics (BHI), enabling new ways to analyze data, treat patients, and conduct research. This bibliometric review aims to provide a panoramic view of how LLMs have been used in BHI by examining research articles and collaboration networks from 2022 to 2023. It further explores how LLMs can improve Natural Language Processing (NLP) applications in various BHI areas like medical diagnosis, patient engagement, electronic health record management, and personalized medicine. To do this, our bibliometric review identifies key trends, maps out research networks, and highlights major developments in this fast-moving field. Lastly, it discusses the ethical concerns and practical challenges of using LLMs in BHI, such as data privacy and reliable medical recommendations. Looking ahead, we consider how LLMs could further transform biomedical research as well as healthcare delivery and patient outcomes. This bibliometric review serves as a resource for stakeholders in healthcare, including researchers, clinicians, and policymakers, to understand the current state and future potential of LLMs in BHI.

The integration of Artificial Intelligence (AI), especially Large Language Models (LLMs), into the clinical diagnosis process offers significant potential to improve the efficiency and accessibility of medical care. While LLMs have shown some promise in the medical domain, their application in clinical diagnosis remains underexplored, especially in real-world clinical practice, where highly sophisticated, patient-specific decisions need to be made. Current evaluations of LLMs in this field are often narrow in scope, focusing on specific diseases or specialties and employing simplified diagnostic tasks. To bridge this gap, we introduce CliBench, a novel benchmark developed from the MIMIC IV dataset, offering a comprehensive and realistic assessment of LLMs' capabilities in clinical diagnosis. This benchmark not only covers diagnoses from a diverse range of medical cases across various specialties but also incorporates tasks of clinical significance: treatment procedure identification, lab test ordering and medication prescriptions. Supported by structured output ontologies, CliBench enables a precise and multi-granular evaluation, offering an in-depth understanding of LLM's capability on diverse clinical tasks of desired granularity. We conduct a zero-shot evaluation of leading LLMs to assess their proficiency in clinical decision-making. Our preliminary results shed light on the potential and limitations of current LLMs in clinical settings, providing valuable insights for future advancements in LLM-powered healthcare.

Large language models, particularly GPT-3, are able to produce high quality summaries of general domain news articles in few- and zero-shot settings. However, it is unclear if such models are similarly capable in more specialized, high-stakes domains such as biomedicine. In this paper, we enlist domain experts (individuals with medical training) to evaluate summaries of biomedical articles generated by GPT-3, given zero supervision. We consider both single- and multi-document settings. In the former, GPT-3 is tasked with generating regular and plain-language summaries of articles describing randomized controlled trials; in the latter, we assess the degree to which GPT-3 is able to synthesize evidence reported across a collection of articles. We design an annotation scheme for evaluating model outputs, with an emphasis on assessing the factual accuracy of generated summaries. We find that while GPT-3 is able to summarize and simplify single biomedical articles faithfully, it struggles to provide accurate aggregations of findings over multiple documents. We release all data and annotations used in this work.

Given a stationary state-space model that relates a sequence of hidden states and corresponding measurements or observations, Bayesian filtering provides a principled statistical framework for inferring the posterior distribution of the current state given all measurements up to the present time. For example, the Apollo lunar module implemented a Kalman filter to infer its location from a sequence of earth-based radar measurements and land safely on the moon. To perform Bayesian filtering, we require a measurement model that describes the conditional distribution of each observation given state. The Kalman filter takes this measurement model to be linear, Gaussian. Here we show how a nonlinear, Gaussian approximation to the distribution of state given observation can be used in conjunction with Bayes' rule to build a nonlinear, non-Gaussian measurement model. The resulting approach, called the Discriminative Kalman Filter (DKF), retains fast closed-form updates for the posterior. We argue there are many cases where the distribution of state given measurement is better-approximated as Gaussian, especially when the dimensionality of measurements far exceeds that of states and the Bernstein-von Mises theorem applies. Online neural decoding for brain-computer interfaces provides a motivating example, where filtering incorporates increasingly detailed measurements of neural activity to provide users control over external devices. Within the BrainGate2 clinical trial, the DKF successfully enabled three volunteers with quadriplegia to control an on-screen cursor in real-time using mental imagery alone. Participant "T9" used the DKF to type out messages on a tablet PC.

Large language models (LLMs) have exhibited remarkable capabilities across various domains and tasks, pushing the boundaries of our knowledge in learning and cognition. The latest model, OpenAI's o1, stands out as the first LLM with an internalized chain-of-thought technique using reinforcement learning strategies. While it has demonstrated surprisingly strong capabilities on various general language tasks, its performance in specialized fields such as medicine remains unknown. To this end, this report provides a comprehensive exploration of o1 on different medical scenarios, examining 3 key aspects: understanding, reasoning, and multilinguality. Specifically, our evaluation encompasses 6 tasks using data from 37 medical datasets, including two newly constructed and more challenging question-answering (QA) tasks based on professional medical quizzes from the New England Journal of Medicine (NEJM) and The Lancet. These datasets offer greater clinical relevance compared to standard medical QA benchmarks such as MedQA, translating more effectively into real-world clinical utility. Our analysis of o1 suggests that the enhanced reasoning ability of LLMs may (significantly) benefit their capability to understand various medical instructions and reason through complex clinical scenarios. Notably, o1 surpasses the previous GPT-4 in accuracy by an average of 6.2% and 6.6% across 19 datasets and two newly created complex QA scenarios. But meanwhile, we identify several weaknesses in both the model capability and the existing evaluation protocols, including hallucination, inconsistent multilingual ability, and discrepant metrics for evaluation. We release our raw data and model outputs at https://ucsc-vlaa.github.io/o1_medicine/ for future research.

Machine learning (ML) holds great potential for accurately forecasting treatment outcomes over time, which could ultimately enable the adoption of more individualized treatment strategies in many practical applications. However, a significant challenge that has been largely overlooked by the ML literature on this topic is the presence of informative sampling in observational data. When instances are observed irregularly over time, sampling times are typically not random, but rather informative -- depending on the instance's characteristics, past outcomes, and administered treatments. In this work, we formalize informative sampling as a covariate shift problem and show that it can prohibit accurate estimation of treatment outcomes if not properly accounted for. To overcome this challenge, we present a general framework for learning treatment outcomes in the presence of informative sampling using inverse intensity-weighting, and propose a novel method, TESAR-CDE, that instantiates this framework using Neural CDEs. Using a simulation environment based on a clinical use case, we demonstrate the effectiveness of our approach in learning under informative sampling.

We survey clinical document corpora, with focus on German textual data. Due to rigid data privacy legislation in Germany these resources, with only few exceptions, are stored in safe clinical data spaces and locked against clinic-external researchers. This situation stands in stark contrast with established workflows in the field of natural language processing where easy accessibility and reuse of data collections are common practice. Hence, alternative corpus designs have been examined to escape from this data poverty. Besides machine translation of English clinical datasets and the generation of synthetic corpora with fictitious clinical contents, several other types of domain proxies have come up as substitutes for authentic clinical documents. Common instances of close proxies are medical journal publications, clinical therapy guidelines, drug labels, etc., more distant proxies include online encyclopedic medical articles or medical contents from social media channels. After PRISM-conformant screening of 359 hits from four bibliographic systems, 75 relevant documents were finally selected for this review and 59 distinct corpora were determined. We identified 24 real clinical corpora (from 40 publications) out of which only 5 are publicly distributable. 2 translations of real corpora and 3 synthetic ones complement the set of clinical corpora. 14 corpora were categorized as close domain proxies, 16 as distant ones. There is a clear divide between the large number of non-accessible authentic clinical German-language corpora and their publicly accessible substitutes: translated or synthetic, close or more distant proxies. So on first sight, the data bottleneck seems broken. Intuitively yet, differences in genre-specific writing style, wording and medical domain expertise in this typological space are also obvious. This raises the question how valid alternative corpus designs really are.

In this paper, we release a largest ever medical Question Answering (QA) dataset with 26 million QA pairs. We benchmark many existing approaches in our dataset in terms of both retrieval and generation. Experimental results show that the existing models perform far lower than expected and the released dataset is still challenging in the pre-trained language model era. Moreover, we also experimentally show the benefit of the proposed dataset in many aspects: (i) trained models for other QA datasets in a zero-shot fashion; and (ii) as external knowledge for retrieval-augmented generation (RAG); and (iii) improving existing pre-trained language models by using the QA pairs as a pre-training corpus in continued training manner. We believe that this dataset will not only contribute to medical research but also facilitate both the patients and clinical doctors. See https://github.com/FreedomIntelligence/Huatuo-26M.

Recent research in representation learning utilizes large databases of proteins or molecules to acquire knowledge of drug and protein structures through unsupervised learning techniques. These pre-trained representations have proven to significantly enhance the accuracy of subsequent tasks, such as predicting the affinity between drugs and target proteins. In this study, we demonstrate that by incorporating knowledge graphs from diverse sources and modalities into the sequences or SMILES representation, we can further enrich the representation and achieve state-of-the-art results on established benchmark datasets. We provide preprocessed and integrated data obtained from 7 public sources, which encompass over 30M triples. Additionally, we make available the pre-trained models based on this data, along with the reported outcomes of their performance on three widely-used benchmark datasets for drug-target binding affinity prediction found in the Therapeutic Data Commons (TDC) benchmarks. Additionally, we make the source code for training models on benchmark datasets publicly available. Our objective in releasing these pre-trained models, accompanied by clean data for model pretraining and benchmark results, is to encourage research in knowledge-enhanced representation learning.

We present OCTCube-M, a 3D OCT-based multi-modal foundation model for jointly analyzing OCT and en face images. OCTCube-M first developed OCTCube, a 3D foundation model pre-trained on 26,685 3D OCT volumes encompassing 1.62 million 2D OCT images. It then exploits a novel multi-modal contrastive learning framework COEP to integrate other retinal imaging modalities, such as fundus autofluorescence and infrared retinal imaging, into OCTCube, efficiently extending it into multi-modal foundation models. OCTCube achieves best performance on predicting 8 retinal diseases, demonstrating strong generalizability on cross-cohort, cross-device and cross-modality prediction. OCTCube can also predict cross-organ nodule malignancy (CT) and low cardiac ejection fraction as well as systemic diseases, such as diabetes and hypertension, revealing its wide applicability beyond retinal diseases. We further develop OCTCube-IR using COEP with 26,685 OCT and IR image pairs. OCTCube-IR can accurately retrieve between OCT and IR images, allowing joint analysis between 3D and 2D retinal imaging modalities. Finally, we trained a tri-modal foundation model OCTCube-EF from 4 million 2D OCT images and 400K en face retinal images. OCTCube-EF attains the best performance on predicting the growth rate of geographic atrophy (GA) across datasets collected from 6 multi-center global trials conducted in 23 countries. This improvement is statistically equivalent to running a clinical trial with more than double the size of the original study. Our analysis based on another retrospective case study reveals OCTCube-EF's ability to avoid false positive Phase-III results according to its accurate treatment effect estimation on the Phase-II results. In sum, OCTCube-M is a 3D multi-modal foundation model framework that integrates OCT and other retinal imaging modalities revealing substantial diagnostic and prognostic benefits.

This paper introduces the Pandemic PACT Advanced Categorisation Engine (PPACE) along with its associated dataset. PPACE is a fine-tuned model developed to automatically classify research abstracts from funded biomedical projects according to WHO-aligned research priorities. This task is crucial for monitoring research trends and identifying gaps in global health preparedness and response. Our approach builds on human-annotated projects, which are allocated one or more categories from a predefined list. A large language model is then used to generate `rationales' explaining the reasoning behind these annotations. This augmented data, comprising expert annotations and rationales, is subsequently used to fine-tune a smaller, more efficient model. Developed as part of the Pandemic PACT project, which aims to track and analyse research funding and clinical evidence for a wide range of diseases with outbreak potential, PPACE supports informed decision-making by research funders, policymakers, and independent researchers. We introduce and release both the trained model and the instruction-based dataset used for its training. Our evaluation shows that PPACE significantly outperforms its baselines. The release of PPACE and its associated dataset offers valuable resources for researchers in multilabel biomedical document classification and supports advancements in aligning biomedical research with key global health priorities.

Large language models have exhibited exceptional performance on various Natural Language Processing (NLP) tasks, leveraging techniques such as the pre-training, and instruction fine-tuning. Despite these advances, their effectiveness in medical applications is limited, due to challenges such as factual inaccuracies, reasoning abilities, and lack grounding in real-world experience. In this study, we present ClinicalGPT, a language model explicitly designed and optimized for clinical scenarios. By incorporating extensive and diverse real-world data, such as medical records, domain-specific knowledge, and multi-round dialogue consultations in the training process, ClinicalGPT is better prepared to handle multiple clinical task. Furthermore, we introduce a comprehensive evaluation framework that includes medical knowledge question-answering, medical exams, patient consultations, and diagnostic analysis of medical records. Our results demonstrate that ClinicalGPT significantly outperforms other models in these tasks, highlighting the effectiveness of our approach in adapting large language models to the critical domain of healthcare.

Observational studies require adjustment for confounding factors that are correlated with both the treatment and outcome. In the setting where the observed variables are tabular quantities such as average income in a neighborhood, tools have been developed for addressing such confounding. However, in many parts of the developing world, features about local communities may be scarce. In this context, satellite imagery can play an important role, serving as a proxy for the confounding variables otherwise unobserved. In this paper, we study confounder adjustment in this non-tabular setting, where patterns or objects found in satellite images contribute to the confounder bias. Using the evaluation of anti-poverty aid programs in Africa as our running example, we formalize the challenge of performing causal adjustment with such unstructured data -- what conditions are sufficient to identify causal effects, how to perform estimation, and how to quantify the ways in which certain aspects of the unstructured image object are most predictive of the treatment decision. Via simulation, we also explore the sensitivity of satellite image-based observational inference to image resolution and to misspecification of the image-associated confounder. Finally, we apply these tools in estimating the effect of anti-poverty interventions in African communities from satellite imagery.

A comprehensive bibliographic review with R statistical methods of the COVID pandemic in PubMed literature and Web of Science Core Collection, supported with Google Scholar search. In addition, a case study review of emerging new approaches in different regions, using medical literature, academic literature, news articles and other reliable data sources. Public responses of mistrust about privacy data misuse differ across countries, depending on the chosen public communication strategy.

We present Eir Thai Medical LLM, a large language model with 8 billion parameters, specifically designed to enhance the accuracy of handling medical tasks in the Thai language. This model focuses on providing clear and easy-to-understand answers for both healthcare professionals and patients, thereby improving the efficiency of diagnosis and treatment processes. Human evaluation was conducted to ensure that the model adheres to care standards and provides unbiased answers. To prioritize data security, the model is deployed within the hospital's internal network, ensuring both high security and faster processing speeds. The internal API connection is secured with encryption and strict authentication measures to prevent data leaks and unauthorized access. We evaluated several open-source large language models with 8 billion parameters on four medical benchmarks: MedQA, MedMCQA, PubMedQA, and the medical subset of MMLU. The best-performing baselines were used to develop Eir Thai Medical LLM. Our evaluation employed multiple questioning strategies, including zero-shot, few-shot, chain-of-thought reasoning, and ensemble/self-consistency voting methods. Our model outperformed commercially available Thai-language large language models by more than 10%. In addition, we developed enhanced model testing tailored for clinical use in Thai across 18 clinical tasks, where our model exceeded GPT-4o performance by more than 11%

Tabular data (or tables) are the most widely used data format in machine learning (ML). However, ML models often assume the table structure keeps fixed in training and testing. Before ML modeling, heavy data cleaning is required to merge disparate tables with different columns. This preprocessing often incurs significant data waste (e.g., removing unmatched columns and samples). How to learn ML models from multiple tables with partially overlapping columns? How to incrementally update ML models as more columns become available over time? Can we leverage model pretraining on multiple distinct tables? How to train an ML model which can predict on an unseen table? To answer all those questions, we propose to relax fixed table structures by introducing a Transferable Tabular Transformer (TransTab) for tables. The goal of TransTab is to convert each sample (a row in the table) to a generalizable embedding vector, and then apply stacked transformers for feature encoding. One methodology insight is combining column description and table cells as the raw input to a gated transformer model. The other insight is to introduce supervised and self-supervised pretraining to improve model performance. We compare TransTab with multiple baseline methods on diverse benchmark datasets and five oncology clinical trial datasets. Overall, TransTab ranks 1.00, 1.00, 1.78 out of 12 methods in supervised learning, feature incremental learning, and transfer learning scenarios, respectively; and the proposed pretraining leads to 2.3% AUC lift on average over the supervised learning.

This paper introduces a new testbed CLIFT (Clinical Shift) for the clinical domain Question-answering task. The testbed includes 7.5k high-quality question answering samples to provide a diverse and reliable benchmark. We performed a comprehensive experimental study and evaluated several QA deep-learning models under the proposed testbed. Despite impressive results on the original test set, the performance degrades when applied to new test sets, which shows the distribution shift. Our findings emphasize the need for and the potential for increasing the robustness of clinical domain models under distributional shifts. The testbed offers one way to track progress in that direction. It also highlights the necessity of adopting evaluation metrics that consider robustness to natural distribution shifts. We plan to expand the corpus by adding more samples and model results. The full paper and the updated benchmark are available at github.com/openlifescience-ai/clift

The Russian Drug Reaction Corpus (RuDReC) is a new partially annotated corpus of consumer reviews in Russian about pharmaceutical products for the detection of health-related named entities and the effectiveness of pharmaceutical products. The corpus itself consists of two parts, the raw one and the labelled one. The raw part includes 1.4 million health-related user-generated texts collected from various Internet sources, including social media. The labelled part contains 500 consumer reviews about drug therapy with drug- and disease-related information. Labels for sentences include health-related issues or their absence. The sentences with one are additionally labelled at the expression level for identification of fine-grained subtypes such as drug classes and drug forms, drug indications, and drug reactions. Further, we present a baseline model for named entity recognition (NER) and multi-label sentence classification tasks on this corpus. The macro F1 score of 74.85% in the NER task was achieved by our RuDR-BERT model. For the sentence classification task, our model achieves the macro F1 score of 68.82% gaining 7.47% over the score of BERT model trained on Russian data. We make the RuDReC corpus and pretrained weights of domain-specific BERT models freely available at https://github.com/cimm-kzn/RuDReC

The increasing use of tools and solutions based on Large Language Models (LLMs) for various tasks in the medical domain has become a prominent trend. Their use in this highly critical and sensitive domain has thus raised important questions about their robustness, especially in response to variations in input, and the reliability of the generated outputs. This study addresses these questions by constructing a textual dataset based on the ICD-10-CM code descriptions, widely used in US hospitals and containing many clinical terms, and their easily reproducible rephrasing. We then benchmarked existing embedding models, either generalist or specialized in the clinical domain, in a semantic search task where the goal was to correctly match the rephrased text to the original description. Our results showed that generalist models performed better than clinical models, suggesting that existing clinical specialized models are more sensitive to small changes in input that confuse them. The highlighted problem of specialized models may be due to the fact that they have not been trained on sufficient data, and in particular on datasets that are not diverse enough to have a reliable global language understanding, which is still necessary for accurate handling of medical documents.

Discovering novel drug candidate molecules is one of the most fundamental and critical steps in drug development. Generative deep learning models, which create synthetic data given a probability distribution, have been developed with the purpose of picking completely new samples from a partially known space. Generative models offer high potential for designing de novo molecules; however, in order for them to be useful in real-life drug development pipelines, these models should be able to design target-specific molecules, which is the next step in this field. In this study, we propose DrugGEN, for the de novo design of drug candidate molecules that interact with selected target proteins. The proposed system represents compounds and protein structures as graphs and processes them via serially connected two generative adversarial networks comprising graph transformers. DrugGEN is trained using a large dataset of compounds from ChEMBL and target-specific bioactive molecules, to design effective and specific inhibitory molecules against the AKT1 protein, which has critical importance for developing treatments against various types of cancer. On fundamental benchmarks, DrugGEN models have either competitive or better performance against other methods. To assess the target-specific generation performance, we conducted further in silico analysis with molecular docking and deep learning-based bioactivity prediction. Results indicate that de novo molecules have high potential for interacting with the AKT1 protein structure in the level of its native ligand. DrugGEN can be used to design completely novel and effective target-specific drug candidate molecules for any druggable protein, given target features and a dataset of experimental bioactivities. Code base, datasets, results and trained models of DrugGEN are available at https://github.com/HUBioDataLab/DrugGEN

This study investigates GPT-4's assessment of its performance in healthcare applications. A simple prompting technique was used to prompt the LLM with questions taken from the United States Medical Licensing Examination (USMLE) questionnaire and it was tasked to evaluate its confidence score before posing the question and after asking the question. The questionnaire was categorized into two groups-questions with feedback (WF) and questions with no feedback(NF) post-question. The model was asked to provide absolute and relative confidence scores before and after each question. The experimental findings were analyzed using statistical tools to study the variability of confidence in WF and NF groups. Additionally, a sequential analysis was conducted to observe the performance variation for the WF and NF groups. Results indicate that feedback influences relative confidence but doesn't consistently increase or decrease it. Understanding the performance of LLM is paramount in exploring its utility in sensitive areas like healthcare. This study contributes to the ongoing discourse on the reliability of AI, particularly of LLMs like GPT-4, within healthcare, offering insights into how feedback mechanisms might be optimized to enhance AI-assisted medical education and decision support.

This paper presents the challenge report for the 2021 Kidney and Kidney Tumor Segmentation Challenge (KiTS21) held in conjunction with the 2021 international conference on Medical Image Computing and Computer Assisted Interventions (MICCAI). KiTS21 is a sequel to its first edition in 2019, and it features a variety of innovations in how the challenge was designed, in addition to a larger dataset. A novel annotation method was used to collect three separate annotations for each region of interest, and these annotations were performed in a fully transparent setting using a web-based annotation tool. Further, the KiTS21 test set was collected from an outside institution, challenging participants to develop methods that generalize well to new populations. Nonetheless, the top-performing teams achieved a significant improvement over the state of the art set in 2019, and this performance is shown to inch ever closer to human-level performance. An in-depth meta-analysis is presented describing which methods were used and how they faired on the leaderboard, as well as the characteristics of which cases generally saw good performance, and which did not. Overall KiTS21 facilitated a significant advancement in the state of the art in kidney tumor segmentation, and provides useful insights that are applicable to the field of semantic segmentation as a whole.

The COVID-19 pandemic swept across the world rapidly, infecting millions of people. An efficient tool that can accurately recognize important clinical concepts of COVID-19 from free text in electronic health records (EHRs) will be valuable to accelerate COVID-19 clinical research. To this end, this study aims at adapting the existing CLAMP natural language processing tool to quickly build COVID-19 SignSym, which can extract COVID-19 signs/symptoms and their 8 attributes (body location, severity, temporal expression, subject, condition, uncertainty, negation, and course) from clinical text. The extracted information is also mapped to standard concepts in the Observational Medical Outcomes Partnership common data model. A hybrid approach of combining deep learning-based models, curated lexicons, and pattern-based rules was applied to quickly build the COVID-19 SignSym from CLAMP, with optimized performance. Our extensive evaluation using 3 external sites with clinical notes of COVID-19 patients, as well as the online medical dialogues of COVID-19, shows COVID-19 Sign-Sym can achieve high performance across data sources. The workflow used for this study can be generalized to other use cases, where existing clinical natural language processing tools need to be customized for specific information needs within a short time. COVID-19 SignSym is freely accessible to the research community as a downloadable package (https://clamp.uth.edu/covid/nlp.php) and has been used by 16 healthcare organizations to support clinical research of COVID-19.

In recent years, there is strong emphasis on mining medical data using machine learning techniques. A common problem is to obtain a noiseless set of textual documents, with a relevant content for the research question, and developing a Question Answering (QA) model for a specific medical field. The purpose of this paper is to present a new methodology for building a medical dataset and obtain a QA model for analysis of symptoms and impact on daily life for a specific disease domain. The ``Mental Health'' forum was used, a forum dedicated to people suffering from schizophrenia and different mental disorders. Relevant posts of active users, who regularly participate, were extrapolated providing a new method of obtaining low-bias content and without privacy issues. Furthermore, it is shown how to pre-process the dataset to convert it into a QA dataset. The Bidirectional Encoder Representations from Transformers (BERT), DistilBERT, RoBERTa, and BioBERT models were fine-tuned and evaluated via F1-Score, Exact Match, Precision and Recall. Accurate empirical experiments demonstrated the effectiveness of the proposed method for obtaining an accurate dataset for QA model implementation. By fine-tuning the BioBERT QA model, we achieved an F1 score of 0.885, showing a considerable improvement and outperforming the state-of-the-art model for mental disorders domain.

Purpose: To evaluate the performance of an automated deep learning method in detecting ascites and subsequently quantifying its volume in patients with liver cirrhosis and ovarian cancer. Materials and Methods: This retrospective study included contrast-enhanced and non-contrast abdominal-pelvic CT scans of patients with cirrhotic ascites and patients with ovarian cancer from two institutions, National Institutes of Health (NIH) and University of Wisconsin (UofW). The model, trained on The Cancer Genome Atlas Ovarian Cancer dataset (mean age, 60 years +/- 11 [s.d.]; 143 female), was tested on two internal (NIH-LC and NIH-OV) and one external dataset (UofW-LC). Its performance was measured by the Dice coefficient, standard deviations, and 95% confidence intervals, focusing on ascites volume in the peritoneal cavity. Results: On NIH-LC (25 patients; mean age, 59 years +/- 14 [s.d.]; 14 male) and NIH-OV (166 patients; mean age, 65 years +/- 9 [s.d.]; all female), the model achieved Dice scores of 0.855 +/- 0.061 (CI: 0.831-0.878) and 0.826 +/- 0.153 (CI: 0.764-0.887), with median volume estimation errors of 19.6% (IQR: 13.2-29.0) and 5.3% (IQR: 2.4-9.7) respectively. On UofW-LC (124 patients; mean age, 46 years +/- 12 [s.d.]; 73 female), the model had a Dice score of 0.830 +/- 0.107 (CI: 0.798-0.863) and median volume estimation error of 9.7% (IQR: 4.5-15.1). The model showed strong agreement with expert assessments, with r^2 values of 0.79, 0.98, and 0.97 across the test sets. Conclusion: The proposed deep learning method performed well in segmenting and quantifying the volume of ascites in concordance with expert radiologist assessments.

Brain tumor growth is unique to each glioma patient and extends beyond what is visible in imaging scans, infiltrating surrounding brain tissue. Understanding these hidden patient-specific progressions is essential for effective therapies. Current treatment plans for brain tumors, such as radiotherapy, typically involve delineating a uniform margin around the visible tumor on pre-treatment scans to target this invisible tumor growth. This "one size fits all" approach is derived from population studies and often fails to account for the nuances of individual patient conditions. We present the GliODIL framework, which infers the full spatial distribution of tumor cell concentration from available multi-modal imaging, leveraging a Fisher-Kolmogorov type physics model to describe tumor growth. This is achieved through the newly introduced method of Optimizing the Discrete Loss (ODIL), where both data and physics-based constraints are softly assimilated into the solution. Our test dataset comprises 152 glioblastoma patients with pre-treatment imaging and post-treatment follow-ups for tumor recurrence monitoring. By blending data-driven techniques with physics-based constraints, GliODIL enhances recurrence prediction in radiotherapy planning, challenging traditional uniform margins and strict adherence to the Fisher-Kolmogorov partial differential equation (PDE) model, which is adapted for complex cases.

With COVID-19 having emerged as the most widespread human pandemic disease in a century, the need to control its spread to avoid massive loss of life became more than necessary, and extremely fast. Several vaccines were developed and the task of policy makers was suddenly to convince the reluctant population to be vaccinated by various means. While some countries have chosen a policy of mandatory vaccination or punitive incentives, many states in the United States have adopted various incentives to try to increase vaccination coverage. A study we conducted in recent months quantified the effect of these measures on the proportion of the population vaccinated, using the synthetic control method, by simulating what would have happened without these measures. The aim now is to generalize this study to smaller scales, to improve the results of our previous study, to quantify their robustness and to provide a tool that can be used by policy makers to adapt their behavior in light of the results obtained.

Machine learning (ML) approaches have demonstrated promising results in a wide range of healthcare applications. Data plays a crucial role in developing ML-based healthcare systems that directly affect people's lives. Many of the ethical issues surrounding the use of ML in healthcare stem from structural inequalities underlying the way we collect, use, and handle data. Developing guidelines to improve documentation practices regarding the creation, use, and maintenance of ML healthcare datasets is therefore of critical importance. In this work, we introduce Healthsheet, a contextualized adaptation of the original datasheet questionnaire ~gebru2018datasheets for health-specific applications. Through a series of semi-structured interviews, we adapt the datasheets for healthcare data documentation. As part of the Healthsheet development process and to understand the obstacles researchers face in creating datasheets, we worked with three publicly-available healthcare datasets as our case studies, each with different types of structured data: Electronic health Records (EHR), clinical trial study data, and smartphone-based performance outcome measures. Our findings from the interviewee study and case studies show 1) that datasheets should be contextualized for healthcare, 2) that despite incentives to adopt accountability practices such as datasheets, there is a lack of consistency in the broader use of these practices 3) how the ML for health community views datasheets and particularly Healthsheets as diagnostic tool to surface the limitations and strength of datasets and 4) the relative importance of different fields in the datasheet to healthcare concerns.

For observational studies, we study the sensitivity of causal inference when treatment assignments may depend on unobserved confounders. We develop a loss minimization approach for estimating bounds on the conditional average treatment effect (CATE) when unobserved confounders have a bounded effect on the odds ratio of treatment selection. Our approach is scalable and allows flexible use of model classes in estimation, including nonparametric and black-box machine learning methods. Based on these bounds for the CATE, we propose a sensitivity analysis for the average treatment effect (ATE). Our semi-parametric estimator extends/bounds the augmented inverse propensity weighted (AIPW) estimator for the ATE under bounded unobserved confounding. By constructing a Neyman orthogonal score, our estimator of the bound for the ATE is a regular root-n estimator so long as the nuisance parameters are estimated at the o_p(n^{-1/4}) rate. We complement our methodology with optimality results showing that our proposed bounds are tight in certain cases. We demonstrate our method on simulated and real data examples, and show accurate coverage of our confidence intervals in practical finite sample regimes with rich covariate information.

Background: Natural Language Processing (NLP) is widely used to extract clinical insights from Electronic Health Records (EHRs). However, the lack of annotated data, automated tools, and other challenges hinder the full utilisation of NLP for EHRs. Various Machine Learning (ML), Deep Learning (DL) and NLP techniques are studied and compared to understand the limitations and opportunities in this space comprehensively. Methodology: After screening 261 articles from 11 databases, we included 127 papers for full-text review covering seven categories of articles: 1) medical note classification, 2) clinical entity recognition, 3) text summarisation, 4) deep learning (DL) and transfer learning architecture, 5) information extraction, 6) Medical language translation and 7) other NLP applications. This study follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Result and Discussion: EHR was the most commonly used data type among the selected articles, and the datasets were primarily unstructured. Various ML and DL methods were used, with prediction or classification being the most common application of ML or DL. The most common use cases were: the International Classification of Diseases, Ninth Revision (ICD-9) classification, clinical note analysis, and named entity recognition (NER) for clinical descriptions and research on psychiatric disorders. Conclusion: We find that the adopted ML models were not adequately assessed. In addition, the data imbalance problem is quite important, yet we must find techniques to address this underlining problem. Future studies should address key limitations in studies, primarily identifying Lupus Nephritis, Suicide Attempts, perinatal self-harmed and ICD-9 classification.

As mental health care systems worldwide struggle to meet demand, there is increasing focus on using language models to infer neuropsychiatric conditions or psychopathological traits from language production. Yet, so far, this research has only delivered solutions with limited clinical applicability, due to insufficient consideration of ethical questions crucial to ensuring the synergy between possible applications and model design. To accelerate progress towards clinically applicable models, our paper charts the ethical landscape of research on language-based inference of psychopathology and provides a practical tool for researchers to navigate it. We identify seven core ethical principles that should guide model development and deployment in this domain, translate them into ELLIPS, an ethical toolkit operationalizing these principles into questions that can guide researchers' choices with respect to data selection, architectures, evaluation, and model deployment, and provide a case study exemplifying its use. With this, we aim to facilitate the emergence of model technology with concrete potential for real-world applicability.

Personalized treatment effect estimates are often of interest in high-stakes applications -- thus, before deploying a model estimating such effects in practice, one needs to be sure that the best candidate from the ever-growing machine learning toolbox for this task was chosen. Unfortunately, due to the absence of counterfactual information in practice, it is usually not possible to rely on standard validation metrics for doing so, leading to a well-known model selection dilemma in the treatment effect estimation literature. While some solutions have recently been investigated, systematic understanding of the strengths and weaknesses of different model selection criteria is still lacking. In this paper, instead of attempting to declare a global `winner', we therefore empirically investigate success- and failure modes of different selection criteria. We highlight that there is a complex interplay between selection strategies, candidate estimators and the data used for comparing them, and provide interesting insights into the relative (dis)advantages of different criteria alongside desiderata for the design of further illuminating empirical studies in this context.

Artificial intelligence (AI)-driven methods can vastly improve the historically costly drug design process, with various generative models already in widespread use. Generative models for de novo drug design, in particular, focus on the creation of novel biological compounds entirely from scratch, representing a promising future direction. Rapid development in the field, combined with the inherent complexity of the drug design process, creates a difficult landscape for new researchers to enter. In this survey, we organize de novo drug design into two overarching themes: small molecule and protein generation. Within each theme, we identify a variety of subtasks and applications, highlighting important datasets, benchmarks, and model architectures and comparing the performance of top models. We take a broad approach to AI-driven drug design, allowing for both micro-level comparisons of various methods within each subtask and macro-level observations across different fields. We discuss parallel challenges and approaches between the two applications and highlight future directions for AI-driven de novo drug design as a whole. An organized repository of all covered sources is available at https://github.com/gersteinlab/GenAI4Drug.

Background: Recent advancements in large language models (LLMs) offer potential benefits in healthcare, particularly in processing extensive patient records. However, existing benchmarks do not fully assess LLMs' capability in handling real-world, lengthy clinical data. Methods: We present the LongHealth benchmark, comprising 20 detailed fictional patient cases across various diseases, with each case containing 5,090 to 6,754 words. The benchmark challenges LLMs with 400 multiple-choice questions in three categories: information extraction, negation, and sorting, challenging LLMs to extract and interpret information from large clinical documents. Results: We evaluated nine open-source LLMs with a minimum of 16,000 tokens and also included OpenAI's proprietary and cost-efficient GPT-3.5 Turbo for comparison. The highest accuracy was observed for Mixtral-8x7B-Instruct-v0.1, particularly in tasks focused on information retrieval from single and multiple patient documents. However, all models struggled significantly in tasks requiring the identification of missing information, highlighting a critical area for improvement in clinical data interpretation. Conclusion: While LLMs show considerable potential for processing long clinical documents, their current accuracy levels are insufficient for reliable clinical use, especially in scenarios requiring the identification of missing information. The LongHealth benchmark provides a more realistic assessment of LLMs in a healthcare setting and highlights the need for further model refinement for safe and effective clinical application. We make the benchmark and evaluation code publicly available.

With the advent of large multimodal language models, science is now at a threshold of an AI-based technological transformation. Recently, a plethora of new AI models and tools has been proposed, promising to empower researchers and academics worldwide to conduct their research more effectively and efficiently. This includes all aspects of the research cycle, especially (1) searching for relevant literature; (2) generating research ideas and conducting experimentation; generating (3) text-based and (4) multimodal content (e.g., scientific figures and diagrams); and (5) AI-based automatic peer review. In this survey, we provide an in-depth overview over these exciting recent developments, which promise to fundamentally alter the scientific research process for good. Our survey covers the five aspects outlined above, indicating relevant datasets, methods and results (including evaluation) as well as limitations and scope for future research. Ethical concerns regarding shortcomings of these tools and potential for misuse (fake science, plagiarism, harms to research integrity) take a particularly prominent place in our discussion. We hope that our survey will not only become a reference guide for newcomers to the field but also a catalyst for new AI-based initiatives in the area of "AI4Science".

Pathology text mining is a challenging task given the reporting variability and constant new findings in cancer sub-type definitions. However, successful text mining of a large pathology database can play a critical role to advance 'big data' cancer research like similarity-based treatment selection, case identification, prognostication, surveillance, clinical trial screening, risk stratification, and many others. While there is a growing interest in developing language models for more specific clinical domains, no pathology-specific language space exist to support the rapid data-mining development in pathology space. In literature, a few approaches fine-tuned general transformer models on specialized corpora while maintaining the original tokenizer, but in fields requiring specialized terminology, these models often fail to perform adequately. We propose PathologyBERT - a pre-trained masked language model which was trained on 347,173 histopathology specimen reports and publicly released in the Huggingface repository. Our comprehensive experiments demonstrate that pre-training of transformer model on pathology corpora yields performance improvements on Natural Language Understanding (NLU) and Breast Cancer Diagnose Classification when compared to nonspecific language models.

Large language models (LLMs) have demonstrated remarkable capabilities in natural language understanding and generation across various domains, including medicine. We present a comprehensive evaluation of GPT-4, a state-of-the-art LLM, on medical competency examinations and benchmark datasets. GPT-4 is a general-purpose model that is not specialized for medical problems through training or engineered to solve clinical tasks. Our analysis covers two sets of official practice materials for the USMLE, a three-step examination program used to assess clinical competency and grant licensure in the United States. We also evaluate performance on the MultiMedQA suite of benchmark datasets. Beyond measuring model performance, experiments were conducted to investigate the influence of test questions containing both text and images on model performance, probe for memorization of content during training, and study probability calibration, which is of critical importance in high-stakes applications like medicine. Our results show that GPT-4, without any specialized prompt crafting, exceeds the passing score on USMLE by over 20 points and outperforms earlier general-purpose models (GPT-3.5) as well as models specifically fine-tuned on medical knowledge (Med-PaLM, a prompt-tuned version of Flan-PaLM 540B). In addition, GPT-4 is significantly better calibrated than GPT-3.5, demonstrating a much-improved ability to predict the likelihood that its answers are correct. We also explore the behavior of the model qualitatively through a case study that shows the ability of GPT-4 to explain medical reasoning, personalize explanations to students, and interactively craft new counterfactual scenarios around a medical case. Implications of the findings are discussed for potential uses of GPT-4 in medical education, assessment, and clinical practice, with appropriate attention to challenges of accuracy and safety.

There is enormous enthusiasm and concerns in using large language models (LLMs) in healthcare, yet current assumptions are all based on general-purpose LLMs such as ChatGPT. This study develops a clinical generative LLM, GatorTronGPT, using 277 billion words of mixed clinical and English text with a GPT-3 architecture of 20 billion parameters. GatorTronGPT improves biomedical natural language processing for medical research. Synthetic NLP models trained using GatorTronGPT generated text outperform NLP models trained using real-world clinical text. Physicians Turing test using 1 (worst) to 9 (best) scale shows that there is no significant difference in linguistic readability (p = 0.22; 6.57 of GatorTronGPT compared with 6.93 of human) and clinical relevance (p = 0.91; 7.0 of GatorTronGPT compared with 6.97 of human) and that physicians cannot differentiate them (p < 0.001). This study provides insights on the opportunities and challenges of LLMs for medical research and healthcare.

Contextual word embedding models such as ELMo (Peters et al., 2018) and BERT (Devlin et al., 2018) have dramatically improved performance for many natural language processing (NLP) tasks in recent months. However, these models have been minimally explored on specialty corpora, such as clinical text; moreover, in the clinical domain, no publicly-available pre-trained BERT models yet exist. In this work, we address this need by exploring and releasing BERT models for clinical text: one for generic clinical text and another for discharge summaries specifically. We demonstrate that using a domain-specific model yields performance improvements on three common clinical NLP tasks as compared to nonspecific embeddings. These domain-specific models are not as performant on two clinical de-identification tasks, and argue that this is a natural consequence of the differences between de-identified source text and synthetically non de-identified task text.

The COVID-19 Open Research Dataset (CORD-19) is a growing resource of scientific papers on COVID-19 and related historical coronavirus research. CORD-19 is designed to facilitate the development of text mining and information retrieval systems over its rich collection of metadata and structured full text papers. Since its release, CORD-19 has been downloaded over 200K times and has served as the basis of many COVID-19 text mining and discovery systems. In this article, we describe the mechanics of dataset construction, highlighting challenges and key design decisions, provide an overview of how CORD-19 has been used, and describe several shared tasks built around the dataset. We hope this resource will continue to bring together the computing community, biomedical experts, and policy makers in the search for effective treatments and management policies for COVID-19.

We introduce MURA, a large dataset of musculoskeletal radiographs containing 40,561 images from 14,863 studies, where each study is manually labeled by radiologists as either normal or abnormal. To evaluate models robustly and to get an estimate of radiologist performance, we collect additional labels from six board-certified Stanford radiologists on the test set, consisting of 207 musculoskeletal studies. On this test set, the majority vote of a group of three radiologists serves as gold standard. We train a 169-layer DenseNet baseline model to detect and localize abnormalities. Our model achieves an AUROC of 0.929, with an operating point of 0.815 sensitivity and 0.887 specificity. We compare our model and radiologists on the Cohen's kappa statistic, which expresses the agreement of our model and of each radiologist with the gold standard. Model performance is comparable to the best radiologist performance in detecting abnormalities on finger and wrist studies. However, model performance is lower than best radiologist performance in detecting abnormalities on elbow, forearm, hand, humerus, and shoulder studies. We believe that the task is a good challenge for future research. To encourage advances, we have made our dataset freely available at https://stanfordmlgroup.github.io/competitions/mura .

In recent years, there have been significant breakthroughs in the field of natural language processing, particularly with the development of large language models (LLMs). These LLMs have showcased remarkable capabilities on various benchmarks. In the healthcare field, the exact role LLMs and other future AI models will play remains unclear. There is a potential for these models in the future to be used as part of adaptive physician training, medical co-pilot applications, and digital patient interaction scenarios. The ability of AI models to participate in medical training and patient care will depend in part on their mastery of the knowledge content of specific medical fields. This study investigated the medical knowledge capability of LLMs, specifically in the context of internal medicine subspecialty multiple-choice test-taking ability. We compared the performance of several open-source LLMs (Koala 7B, Falcon 7B, Stable-Vicuna 13B, and Orca Mini 13B), to GPT-4 and Claude 2 on multiple-choice questions in the field of Nephrology. Nephrology was chosen as an example of a particularly conceptually complex subspecialty field within internal medicine. The study was conducted to evaluate the ability of LLM models to provide correct answers to nephSAP (Nephrology Self-Assessment Program) multiple-choice questions. The overall success of open-sourced LLMs in answering the 858 nephSAP multiple-choice questions correctly was 17.1% - 25.5%. In contrast, Claude 2 answered 54.4% of the questions correctly, whereas GPT-4 achieved a score of 73.3%. We show that current widely used open-sourced LLMs do poorly in their ability for zero-shot reasoning when compared to GPT-4 and Claude 2. The findings of this study potentially have significant implications for the future of subspecialty medical training and patient care.

LLMs have demonstrated impressive performance in answering medical questions, such as passing scores on medical licensing examinations. However, medical board exam questions or general clinical questions do not capture the complexity of realistic clinical cases. Moreover, the lack of reference explanations means we cannot easily evaluate the reasoning of model decisions, a crucial component of supporting doctors in making complex medical decisions. To address these challenges, we construct two new datasets: JAMA Clinical Challenge and Medbullets. JAMA Clinical Challenge consists of questions based on challenging clinical cases, while Medbullets comprises USMLE Step 2&3 style clinical questions. Both datasets are structured as multiple-choice question-answering tasks, where each question is accompanied by an expert-written explanation. We evaluate four LLMs on the two datasets using various prompts. Experiments demonstrate that our datasets are harder than previous benchmarks. The inconsistency between automatic and human evaluations of model-generated explanations highlights the need to develop new metrics to support future research on explainable medical QA.

One essential task in information extraction from the medical corpus is drug name recognition. Compared with text sources come from other domains, the medical text is special and has unique characteristics. In addition, the medical text mining poses more challenges, e.g., more unstructured text, the fast growing of new terms addition, a wide range of name variation for the same drug. The mining is even more challenging due to the lack of labeled dataset sources and external knowledge, as well as multiple token representations for a single drug name that is more common in the real application setting. Although many approaches have been proposed to overwhelm the task, some problems remained with poor F-score performance (less than 0.75). This paper presents a new treatment in data representation techniques to overcome some of those challenges. We propose three data representation techniques based on the characteristics of word distribution and word similarities as a result of word embedding training. The first technique is evaluated with the standard NN model, i.e., MLP (Multi-Layer Perceptrons). The second technique involves two deep network classifiers, i.e., DBN (Deep Belief Networks), and SAE (Stacked Denoising Encoders). The third technique represents the sentence as a sequence that is evaluated with a recurrent NN model, i.e., LSTM (Long Short Term Memory). In extracting the drug name entities, the third technique gives the best F-score performance compared to the state of the art, with its average F-score being 0.8645.

Learning to represent free text is a core task in many clinical machine learning (ML) applications, as clinical text contains observations and plans not otherwise available for inference. State-of-the-art methods use large language models developed with immense computational resources and training data; however, applying these models is challenging because of the highly varying syntax and vocabulary in clinical free text. Structured information such as International Classification of Disease (ICD) codes often succinctly abstracts the most important facts of a clinical encounter and yields good performance, but is often not as available as clinical text in real-world scenarios. We propose a multi-view learning framework that jointly learns from codes and text to combine the availability and forward-looking nature of text and better performance of ICD codes. The learned text embeddings can be used as inputs to predictive algorithms independent of the ICD codes during inference. Our approach uses a Graph Neural Network (GNN) to process ICD codes, and Bi-LSTM to process text. We apply Deep Canonical Correlation Analysis (DCCA) to enforce the two views to learn a similar representation of each patient. In experiments using planned surgical procedure text, our model outperforms BERT models fine-tuned to clinical data, and in experiments using diverse text in MIMIC-III, our model is competitive to a fine-tuned BERT at a tiny fraction of its computational effort.

Specialised pre-trained language models are becoming more frequent in NLP since they can potentially outperform models trained on generic texts. BioBERT and BioClinicalBERT are two examples of such models that have shown promise in medical NLP tasks. Many of these models are overparametrised and resource-intensive, but thanks to techniques like Knowledge Distillation (KD), it is possible to create smaller versions that perform almost as well as their larger counterparts. In this work, we specifically focus on development of compact language models for processing clinical texts (i.e. progress notes, discharge summaries etc). We developed a number of efficient lightweight clinical transformers using knowledge distillation and continual learning, with the number of parameters ranging from 15 million to 65 million. These models performed comparably to larger models such as BioBERT and ClinicalBioBERT and significantly outperformed other compact models trained on general or biomedical data. Our extensive evaluation was done across several standard datasets and covered a wide range of clinical text-mining tasks, including Natural Language Inference, Relation Extraction, Named Entity Recognition, and Sequence Classification. To our knowledge, this is the first comprehensive study specifically focused on creating efficient and compact transformers for clinical NLP tasks. The models and code used in this study can be found on our Huggingface profile at https://huggingface.co/nlpie and Github page at https://github.com/nlpie-research/Lightweight-Clinical-Transformers, respectively, promoting reproducibility of our results.

In psychotherapy, therapeutic outcome assessment, or treatment outcome evaluation, is essential for enhancing mental health care by systematically evaluating therapeutic processes and outcomes. Existing large language model approaches often focus on therapist-centered, single-session evaluations, neglecting the client's subjective experience and longitudinal progress across multiple sessions. To address these limitations, we propose IPAEval, a client-Informed Psychological Assessment-based Evaluation framework that automates treatment outcome evaluations from the client's perspective using clinical interviews. IPAEval integrates cross-session client-contextual assessment and session-focused client-dynamics assessment to provide a comprehensive understanding of therapeutic progress. Experiments on our newly developed TheraPhase dataset demonstrate that IPAEval effectively tracks symptom severity and treatment outcomes over multiple sessions, outperforming previous single-session models and validating the benefits of items-aware reasoning mechanisms.

Large Language Models (LLMs) have shown impressive performance on existing medical question-answering benchmarks. This high performance makes it increasingly difficult to meaningfully evaluate and differentiate advanced methods. We present MedAgentsBench, a benchmark that focuses on challenging medical questions requiring multi-step clinical reasoning, diagnosis formulation, and treatment planning-scenarios where current models still struggle despite their strong performance on standard tests. Drawing from seven established medical datasets, our benchmark addresses three key limitations in existing evaluations: (1) the prevalence of straightforward questions where even base models achieve high performance, (2) inconsistent sampling and evaluation protocols across studies, and (3) lack of systematic analysis of the interplay between performance, cost, and inference time. Through experiments with various base models and reasoning methods, we demonstrate that the latest thinking models, DeepSeek R1 and OpenAI o3, exhibit exceptional performance in complex medical reasoning tasks. Additionally, advanced search-based agent methods offer promising performance-to-cost ratios compared to traditional approaches. Our analysis reveals substantial performance gaps between model families on complex questions and identifies optimal model selections for different computational constraints. Our benchmark and evaluation framework are publicly available at https://github.com/gersteinlab/medagents-benchmark.

Large language models (LLMs) have shown potential in biomedical applications, leading to efforts to fine-tune them on domain-specific data. However, the effectiveness of this approach remains unclear. This study evaluates the performance of biomedically fine-tuned LLMs against their general-purpose counterparts on a variety of clinical tasks. We evaluated their performance on clinical case challenges from the New England Journal of Medicine (NEJM) and the Journal of the American Medical Association (JAMA) and on several clinical tasks (e.g., information extraction, document summarization, and clinical coding). Using benchmarks specifically chosen to be likely outside the fine-tuning datasets of biomedical models, we found that biomedical LLMs mostly perform inferior to their general-purpose counterparts, especially on tasks not focused on medical knowledge. While larger models showed similar performance on case tasks (e.g., OpenBioLLM-70B: 66.4% vs. Llama-3-70B-Instruct: 65% on JAMA cases), smaller biomedical models showed more pronounced underperformance (e.g., OpenBioLLM-8B: 30% vs. Llama-3-8B-Instruct: 64.3% on NEJM cases). Similar trends were observed across the CLUE (Clinical Language Understanding Evaluation) benchmark tasks, with general-purpose models often performing better on text generation, question answering, and coding tasks. Our results suggest that fine-tuning LLMs to biomedical data may not provide the expected benefits and may potentially lead to reduced performance, challenging prevailing assumptions about domain-specific adaptation of LLMs and highlighting the need for more rigorous evaluation frameworks in healthcare AI. Alternative approaches, such as retrieval-augmented generation, may be more effective in enhancing the biomedical capabilities of LLMs without compromising their general knowledge.

Concerns about hallucinations in Large Language Models (LLMs) have been raised by researchers, yet their potential in areas where creativity is vital, such as drug discovery, merits exploration. In this paper, we come up with the hypothesis that hallucinations can improve LLMs in drug discovery. To verify this hypothesis, we use LLMs to describe the SMILES string of molecules in natural language and then incorporate these descriptions as part of the prompt to address specific tasks in drug discovery. Evaluated on seven LLMs and five classification tasks, our findings confirm the hypothesis: LLMs can achieve better performance with text containing hallucinations. Notably, Llama-3.1-8B achieves an 18.35% gain in ROC-AUC compared to the baseline without hallucination. Furthermore, hallucinations generated by GPT-4o provide the most consistent improvements across models. Additionally, we conduct empirical analyses and a case study to investigate key factors affecting performance and the underlying reasons. Our research sheds light on the potential use of hallucinations for LLMs and offers new perspectives for future research leveraging LLMs in drug discovery.

Clinical question answering systems have the potential to provide clinicians with relevant and timely answers to their questions. Nonetheless, despite the advances that have been made, adoption of these systems in clinical settings has been slow. One issue is a lack of question-answering datasets which reflect the real-world needs of health professionals. In this work, we present RealMedQA, a dataset of realistic clinical questions generated by humans and an LLM. We describe the process for generating and verifying the QA pairs and assess several QA models on BioASQ and RealMedQA to assess the relative difficulty of matching answers to questions. We show that the LLM is more cost-efficient for generating "ideal" QA pairs. Additionally, we achieve a lower lexical similarity between questions and answers than BioASQ which provides an additional challenge to the top two QA models, as per the results. We release our code and our dataset publicly to encourage further research.

Large language models (LLMs) have received much attention and shown their potential in digital health, while their application in mental health is subject to ongoing debate. This systematic review aims to summarize and characterize the use of LLMs in mental health by investigating the strengths and limitations of the latest work in LLMs and discusses the challenges and opportunities for early screening, digital interventions, and other clinical applications in mental health. Following PRISMA guidelines, we examined English articles from PubMed, DBLP Computer Science Bibliography, and IEEE Xplore, published between 1 January 2017, and 1 September 2023, focusing on mental health and LLMs. The review analyzed 32 articles, including mental health analysis using social media datasets (n=13), mental health chatbots (n=10), and other mental health applications (n=9). Findings reveal LLMs' effectiveness in mental health issue detection and the enhancement of telepsychological services through personalised healthcare. Nonetheless, risks like text inconsistencies, hallucinatory content, and the lack of an ethical framework raise concerns about their clinical use. Despite these challenges, the advancement of LLMs underscores their potential as innovative clinical tools, necessitating further research and development. The review emphasizes that LLMs should complement, not replace, professional mental health services.

The successes of foundation models such as ChatGPT and AlphaFold have spurred significant interest in building similar models for electronic medical records (EMRs) to improve patient care and hospital operations. However, recent hype has obscured critical gaps in our understanding of these models' capabilities. We review over 80 foundation models trained on non-imaging EMR data (i.e. clinical text and/or structured data) and create a taxonomy delineating their architectures, training data, and potential use cases. We find that most models are trained on small, narrowly-scoped clinical datasets (e.g. MIMIC-III) or broad, public biomedical corpora (e.g. PubMed) and are evaluated on tasks that do not provide meaningful insights on their usefulness to health systems. In light of these findings, we propose an improved evaluation framework for measuring the benefits of clinical foundation models that is more closely grounded to metrics that matter in healthcare.

While the general machine learning (ML) community has benefited from public datasets, tasks, and models, the progress of ML in healthcare has been hampered by a lack of such shared assets. The success of foundation models creates new challenges for healthcare ML by requiring access to shared pretrained models to validate performance benefits. We help address these challenges through three contributions. First, we publish a new dataset, EHRSHOT, which contains deidentified structured data from the electronic health records (EHRs) of 6,739 patients from Stanford Medicine. Unlike MIMIC-III/IV and other popular EHR datasets, EHRSHOT is longitudinal and not restricted to ICU/ED patients. Second, we publish the weights of CLMBR-T-base, a 141M parameter clinical foundation model pretrained on the structured EHR data of 2.57M patients. We are one of the first to fully release such a model for coded EHR data; in contrast, most prior models released for clinical data (e.g. GatorTron, ClinicalBERT) only work with unstructured text and cannot process the rich, structured data within an EHR. We provide an end-to-end pipeline for the community to validate and build upon its performance. Third, we define 15 few-shot clinical prediction tasks, enabling evaluation of foundation models on benefits such as sample efficiency and task adaptation. Our model and dataset are available via a research data use agreement from the Stanford AIMI Center. Code to reproduce our results are available at our Github repo: https://github.com/som-shahlab/ehrshot-benchmark

When deploying machine learning models in high-stakes real-world environments such as health care, it is crucial to accurately assess the uncertainty concerning a model's prediction on abnormal inputs. However, there is a scarcity of literature analyzing this problem on medical data, especially on mixed-type tabular data such as Electronic Health Records. We close this gap by presenting a series of tests including a large variety of contemporary uncertainty estimation techniques, in order to determine whether they are able to identify out-of-distribution (OOD) patients. In contrast to previous work, we design tests on realistic and clinically relevant OOD groups, and run experiments on real-world medical data. We find that almost all techniques fail to achieve convincing results, partly disagreeing with earlier findings.

We introduce PubMedQA, a novel biomedical question answering (QA) dataset collected from PubMed abstracts. The task of PubMedQA is to answer research questions with yes/no/maybe (e.g.: Do preoperative statins reduce atrial fibrillation after coronary artery bypass grafting?) using the corresponding abstracts. PubMedQA has 1k expert-annotated, 61.2k unlabeled and 211.3k artificially generated QA instances. Each PubMedQA instance is composed of (1) a question which is either an existing research article title or derived from one, (2) a context which is the corresponding abstract without its conclusion, (3) a long answer, which is the conclusion of the abstract and, presumably, answers the research question, and (4) a yes/no/maybe answer which summarizes the conclusion. PubMedQA is the first QA dataset where reasoning over biomedical research texts, especially their quantitative contents, is required to answer the questions. Our best performing model, multi-phase fine-tuning of BioBERT with long answer bag-of-word statistics as additional supervision, achieves 68.1% accuracy, compared to single human performance of 78.0% accuracy and majority-baseline of 55.2% accuracy, leaving much room for improvement. PubMedQA is publicly available at https://pubmedqa.github.io.

Despite the potential of Large Language Models (LLMs) in medicine, they may generate responses lacking supporting evidence or based on hallucinated evidence. While Retrieval Augment Generation (RAG) is popular to address this issue, few studies implemented and evaluated RAG in downstream domain-specific applications. We developed a RAG pipeline with 70,000 ophthalmology-specific documents that retrieve relevant documents to augment LLMs during inference time. In a case study on long-form consumer health questions, we systematically evaluated the responses including over 500 references of LLMs with and without RAG on 100 questions with 10 healthcare professionals. The evaluation focuses on factuality of evidence, selection and ranking of evidence, attribution of evidence, and answer accuracy and completeness. LLMs without RAG provided 252 references in total. Of which, 45.3% hallucinated, 34.1% consisted of minor errors, and 20.6% were correct. In contrast, LLMs with RAG significantly improved accuracy (54.5% being correct) and reduced error rates (18.8% with minor hallucinations and 26.7% with errors). 62.5% of the top 10 documents retrieved by RAG were selected as the top references in the LLM response, with an average ranking of 4.9. The use of RAG also improved evidence attribution (increasing from 1.85 to 2.49 on a 5-point scale, P<0.001), albeit with slight decreases in accuracy (from 3.52 to 3.23, P=0.03) and completeness (from 3.47 to 3.27, P=0.17). The results demonstrate that LLMs frequently exhibited hallucinated and erroneous evidence in the responses, raising concerns for downstream applications in the medical domain. RAG substantially reduced the proportion of such evidence but encountered challenges.

Biomedical data is inherently multimodal, consisting of electronic health records, medical imaging, digital pathology, genome sequencing, wearable sensors, and more. The application of artificial intelligence tools to these multifaceted sensing technologies has the potential to revolutionize the prognosis, diagnosis, and management of human health and disease. However, current approaches to biomedical AI typically only train and evaluate with one or a small set of medical modalities and tasks. This limitation hampers the development of comprehensive tools that can leverage the rich interconnected information across many heterogeneous biomedical sensors. To address this challenge, we present MultiMed, a benchmark designed to evaluate and enable large-scale learning across a wide spectrum of medical modalities and tasks. MultiMed consists of 2.56 million samples across ten medical modalities such as medical reports, pathology, genomics, and protein data, and is structured into eleven challenging tasks, including disease prognosis, protein structure prediction, and medical question answering. Using MultiMed, we conduct comprehensive experiments benchmarking state-of-the-art unimodal, multimodal, and multitask models. Our analysis highlights the advantages of training large-scale medical models across many related modalities and tasks. Moreover, MultiMed enables studies of generalization across related medical concepts, robustness to real-world noisy data and distribution shifts, and novel modality combinations to improve prediction performance. MultiMed will be publicly available and regularly updated and welcomes inputs from the community.

The rapid growth of biomedical knowledge has outpaced our ability to efficiently extract insights and generate novel hypotheses. Large language models (LLMs) have emerged as a promising tool to revolutionize knowledge interaction and potentially accelerate biomedical discovery. In this paper, we present a comprehensive evaluation of LLMs as biomedical hypothesis generators. We construct a dataset of background-hypothesis pairs from biomedical literature, carefully partitioned into training, seen, and unseen test sets based on publication date to mitigate data contamination. Using this dataset, we assess the hypothesis generation capabilities of top-tier instructed models in zero-shot, few-shot, and fine-tuning settings. To enhance the exploration of uncertainty, a crucial aspect of scientific discovery, we incorporate tool use and multi-agent interactions in our evaluation framework. Furthermore, we propose four novel metrics grounded in extensive literature review to evaluate the quality of generated hypotheses, considering both LLM-based and human assessments. Our experiments yield two key findings: 1) LLMs can generate novel and validated hypotheses, even when tested on literature unseen during training, and 2) Increasing uncertainty through multi-agent interactions and tool use can facilitate diverse candidate generation and improve zero-shot hypothesis generation performance. However, we also observe that the integration of additional knowledge through few-shot learning and tool use may not always lead to performance gains, highlighting the need for careful consideration of the type and scope of external knowledge incorporated. These findings underscore the potential of LLMs as powerful aids in biomedical hypothesis generation and provide valuable insights to guide further research in this area.

Generating clinical reports from raw recordings such as X-rays and electroencephalogram (EEG) is an essential and routine task for doctors. However, it is often time-consuming to write accurate and detailed reports. Most existing methods try to generate the whole reports from the raw input with limited success because 1) generated reports often contain errors that need manual review and correction, 2) it does not save time when doctors want to write additional information into the report, and 3) the generated reports are not customized based on individual doctors' preference. We propose {\it CL}inic{\it A}l {\it R}eport {\it A}uto-completion (CLARA), an interactive method that generates reports in a sentence by sentence fashion based on doctors' anchor words and partially completed sentences. CLARA searches for most relevant sentences from existing reports as the template for the current report. The retrieved sentences are sequentially modified by combining with the input feature representations to create the final report. In our experimental evaluation, CLARA achieved 0.393 CIDEr and 0.248 BLEU-4 on X-ray reports and 0.482 CIDEr and 0.491 BLEU-4 for EEG reports for sentence-level generation, which is up to 35% improvement over the best baseline. Also via our qualitative evaluation, CLARA is shown to produce reports which have a significantly higher level of approval by doctors in a user study (3.74 out of 5 for CLARA vs 2.52 out of 5 for the baseline).

The rapid advancement of large-scale vision-language models has showcased remarkable capabilities across various tasks. However, the lack of extensive and high-quality image-text data in medicine has greatly hindered the development of large-scale medical vision-language models. In this work, we present a diagnosis-guided bootstrapping strategy that exploits both image and label information to construct vision-language datasets. Based on the constructed dataset, we developed MedDr, a generalist foundation model for healthcare capable of handling diverse medical data modalities, including radiology, pathology, dermatology, retinography, and endoscopy. Moreover, during inference, we propose a simple but effective retrieval-augmented medical diagnosis strategy, which enhances the model's generalization ability. Extensive experiments on visual question answering, medical report generation, and medical image diagnosis demonstrate the superiority of our method.

This research tests the role of Large Language Models (LLMs) as formal second opinion tools in professional decision-making, particularly focusing on complex medical cases where even experienced physicians seek peer consultation. The work analyzed 183 challenging medical cases from Medscape over a 20-month period, testing multiple LLMs' performance against crowd-sourced physician responses. A key finding was the high overall score possible in the latest foundational models (>80% accuracy compared to consensus opinion), which exceeds most human metrics reported on the same clinical cases (450 pages of patient profiles, test results). The study rates the LLMs' performance disparity between straightforward cases (>81% accuracy) and complex scenarios (43% accuracy), particularly in these cases generating substantial debate among human physicians. The research demonstrates that LLMs may be valuable as generators of comprehensive differential diagnoses rather than as primary diagnostic tools, potentially helping to counter cognitive biases in clinical decision-making, reduce cognitive loads, and thus remove some sources of medical error. The inclusion of a second comparative legal dataset (Supreme Court cases, N=21) provides added empirical context to the AI use to foster second opinions, though these legal challenges proved considerably easier for LLMs to analyze. In addition to the original contributions of empirical evidence for LLM accuracy, the research aggregated a novel benchmark for others to score highly contested question and answer reliability between both LLMs and disagreeing human practitioners. These results suggest that the optimal deployment of LLMs in professional settings may differ substantially from current approaches that emphasize automation of routine tasks.

The mining of adverse drug events (ADEs) is pivotal in pharmacovigilance, enhancing patient safety by identifying potential risks associated with medications, facilitating early detection of adverse events, and guiding regulatory decision-making. Traditional ADE detection methods are reliable but slow, not easily adaptable to large-scale operations, and offer limited information. With the exponential increase in data sources like social media content, biomedical literature, and Electronic Medical Records (EMR), extracting relevant ADE-related information from these unstructured texts is imperative. Previous ADE mining studies have focused on text-based methodologies, overlooking visual cues, limiting contextual comprehension, and hindering accurate interpretation. To address this gap, we present a MultiModal Adverse Drug Event (MMADE) detection dataset, merging ADE-related textual information with visual aids. Additionally, we introduce a framework that leverages the capabilities of LLMs and VLMs for ADE detection by generating detailed descriptions of medical images depicting ADEs, aiding healthcare professionals in visually identifying adverse events. Using our MMADE dataset, we showcase the significance of integrating visual cues from images to enhance overall performance. This approach holds promise for patient safety, ADE awareness, and healthcare accessibility, paving the way for further exploration in personalized healthcare.

High-throughput drug screening -- using cell imaging or gene expression measurements as readouts of drug effect -- is a critical tool in biotechnology to assess and understand the relationship between the chemical structure and biological activity of a drug. Since large-scale screens have to be divided into multiple experiments, a key difficulty is dealing with batch effects, which can introduce systematic errors and non-biological associations in the data. We propose InfoCORE, an Information maximization approach for COnfounder REmoval, to effectively deal with batch effects and obtain refined molecular representations. InfoCORE establishes a variational lower bound on the conditional mutual information of the latent representations given a batch identifier. It adaptively reweighs samples to equalize their implied batch distribution. Extensive experiments on drug screening data reveal InfoCORE's superior performance in a multitude of tasks including molecular property prediction and molecule-phenotype retrieval. Additionally, we show results for how InfoCORE offers a versatile framework and resolves general distribution shifts and issues of data fairness by minimizing correlation with spurious features or removing sensitive attributes. The code is available at https://github.com/uhlerlab/InfoCORE.

Accelerating MRI scans is one of the principal outstanding problems in the MRI research community. Towards this goal, we hosted the second fastMRI competition targeted towards reconstructing MR images with subsampled k-space data. We provided participants with data from 7,299 clinical brain scans (de-identified via a HIPAA-compliant procedure by NYU Langone Health), holding back the fully-sampled data from 894 of these scans for challenge evaluation purposes. In contrast to the 2019 challenge, we focused our radiologist evaluations on pathological assessment in brain images. We also debuted a new Transfer track that required participants to submit models evaluated on MRI scanners from outside the training set. We received 19 submissions from eight different groups. Results showed one team scoring best in both SSIM scores and qualitative radiologist evaluations. We also performed analysis on alternative metrics to mitigate the effects of background noise and collected feedback from the participants to inform future challenges. Lastly, we identify common failure modes across the submissions, highlighting areas of need for future research in the MRI reconstruction community.

Instrumental variable (IV) methods are used to estimate causal effects in settings with unobserved confounding, where we cannot directly experiment on the treatment variable. Instruments are variables which only affect the outcome indirectly via the treatment variable(s). Most IV applications focus on low-dimensional treatments and crucially require at least as many instruments as treatments. This assumption is restrictive: in the natural sciences we often seek to infer causal effects of high-dimensional treatments (e.g., the effect of gene expressions or microbiota on health and disease), but can only run few experiments with a limited number of instruments (e.g., drugs or antibiotics). In such underspecified problems, the full treatment effect is not identifiable in a single experiment even in the linear case. We show that one can still reliably recover the projection of the treatment effect onto the instrumented subspace and develop techniques to consistently combine such partial estimates from different sets of instruments. We then leverage our combined estimators in an algorithm that iteratively proposes the most informative instruments at each round of experimentation to maximize the overall information about the full causal effect.

Recent advances in machine learning have made significant contributions to drug discovery. Deep neural networks in particular have been demonstrated to provide significant boosts in predictive power when inferring the properties and activities of small-molecule compounds. However, the applicability of these techniques has been limited by the requirement for large amounts of training data. In this work, we demonstrate how one-shot learning can be used to significantly lower the amounts of data required to make meaningful predictions in drug discovery applications. We introduce a new architecture, the residual LSTM embedding, that, when combined with graph convolutional neural networks, significantly improves the ability to learn meaningful distance metrics over small-molecules. We open source all models introduced in this work as part of DeepChem, an open-source framework for deep-learning in drug discovery.