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While holding great promise for improving and facilitating healthcare, large language models (LLMs) struggle to produce up-to-date responses on evolving topics due to outdated knowledge or hallucination. Retrieval-augmented generation (RAG) is a pivotal innovation that improves the accuracy and relevance of LLM responses by integrating LLMs with a search engine and external sources of knowledge. However, the quality of RAG responses can be largely impacted by the rank and density of key information in the retrieval results, such as the "lost-in-the-middle" problem. In this work, we aim to improve the robustness and reliability of the RAG workflow in the medical domain. Specifically, we propose a map-reduce strategy, BriefContext, to combat the "lost-in-the-middle" issue without modifying the model weights. We demonstrated the advantage of the workflow with various LLM backbones and on multiple QA datasets. This method promises to improve the safety and reliability of LLMs deployed in healthcare domains.

The remarkable capabilities of Large Language Models (LLMs) make them increasingly compelling for adoption in real-world healthcare applications. However, the risks associated with using LLMs in medical applications have not been systematically characterized. We propose using five key principles for safe and trustworthy medical AI: Truthfulness, Resilience, Fairness, Robustness, and Privacy, along with ten specific aspects. Under this comprehensive framework, we introduce a novel MedGuard benchmark with 1,000 expert-verified questions. Our evaluation of 11 commonly used LLMs shows that the current language models, regardless of their safety alignment mechanisms, generally perform poorly on most of our benchmarks, particularly when compared to the high performance of human physicians. Despite recent reports indicate that advanced LLMs like ChatGPT can match or even exceed human performance in various medical tasks, this study underscores a significant safety gap, highlighting the crucial need for human oversight and the implementation of AI safety guardrails.

Although large language models (LLMs) have been assessed for general medical knowledge using medical licensing exams, their ability to effectively support clinical decision-making tasks, such as selecting and using medical calculators, remains uncertain. Here, we evaluate the capability of both medical trainees and LLMs to recommend medical calculators in response to various multiple-choice clinical scenarios such as risk stratification, prognosis, and disease diagnosis. We assessed eight LLMs, including open-source, proprietary, and domain-specific models, with 1,009 question-answer pairs across 35 clinical calculators and measured human performance on a subset of 100 questions. While the highest-performing LLM, GPT-4o, provided an answer accuracy of 74.3% (CI: 71.5-76.9%), human annotators, on average, outperformed LLMs with an accuracy of 79.5% (CI: 73.5-85.0%). With error analysis showing that the highest-performing LLMs continue to make mistakes in comprehension (56.6%) and calculator knowledge (8.1%), our findings emphasize that humans continue to surpass LLMs on complex clinical tasks such as calculator recommendation.

Differential diagnosis is crucial for medicine as it helps healthcare providers systematically distinguish between conditions that share similar symptoms. This study assesses the impact of lab test results on differential diagnoses (DDx) made by large language models (LLMs). Clinical vignettes from 50 case reports from PubMed Central were created incorporating patient demographics, symptoms, and lab results. Five LLMs GPT-4, GPT-3.5, Llama-2-70b, Claude-2, and Mixtral-8x7B were tested to generate Top 10, Top 5, and Top 1 DDx with and without lab data. A comprehensive evaluation involving GPT-4, a knowledge graph, and clinicians was conducted. GPT-4 performed best, achieving 55% accuracy for Top 1 diagnoses and 60% for Top 10 with lab data, with lenient accuracy up to 80%. Lab results significantly improved accuracy, with GPT-4 and Mixtral excelling, though exact match rates were low. Lab tests, including liver function, metabolic/toxicology panels, and serology/immune tests, were generally interpreted correctly by LLMs for differential diagnosis.

Large Language Models (LLMs) have gained significant attention in the medical domain for their human-level capabilities, leading to increased efforts to explore their potential in various healthcare applications. However, despite such a promising future, there are multiple challenges and obstacles that remain for their real-world uses in practical settings. This work discusses key challenges for LLMs in medical applications from four unique aspects: operational vulnerabilities, ethical and social considerations, performance and assessment difficulties, and legal and regulatory compliance. Addressing these challenges is crucial for leveraging LLMs to their full potential and ensuring their responsible integration into healthcare.

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., Comment: Under review

This study reports a comprehensive environmental scan of the generative AI (GenAI) infrastructure in the national network for clinical and translational science across 36 institutions supported by the Clinical and Translational Science Award (CTSA) Program led by the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH) at the United States. With the rapid advancement of GenAI technologies, including large language models (LLMs), healthcare institutions face unprecedented opportunities and challenges. This research explores the current status of GenAI integration, focusing on stakeholder roles, governance structures, and ethical considerations by administering a survey among leaders of health institutions (i.e., representing academic medical centers and health systems) to assess the institutional readiness and approach towards GenAI adoption. Key findings indicate a diverse range of institutional strategies, with most organizations in the experimental phase of GenAI deployment. The study highlights significant variations in governance models, with a strong preference for centralized decision-making but notable gaps in workforce training and ethical oversight. Moreover, the results underscore the need for a more coordinated approach to GenAI governance, emphasizing collaboration among senior leaders, clinicians, information technology staff, and researchers. Our analysis also reveals concerns regarding GenAI bias, data security, and stakeholder trust, which must be addressed to ensure the ethical and effective implementation of GenAI technologies. This study offers valuable insights into the challenges and opportunities of GenAI integration in healthcare, providing a roadmap for institutions aiming to leverage GenAI for improved quality of care and operational efficiency.

Timely disease diagnosis is challenging due to increasing disease burdens and limited clinician availability. AI shows promise in diagnosis accuracy but faces real-world application issues due to insufficient validation in clinical workflows and diverse populations. This study addresses gaps in medical AI downstream accountability through a case study on age-related macular degeneration (AMD) diagnosis and severity classification. We designed and implemented an AI-assisted diagnostic workflow for AMD, comparing diagnostic performance with and without AI assistance among 24 clinicians from 12 institutions with real patient data sampled from the Age-Related Eye Disease Study (AREDS). Additionally, we demonstrated continual enhancement of an existing AI model by incorporating approximately 40,000 additional medical images (named AREDS2 dataset). The improved model was then systematically evaluated using both AREDS and AREDS2 test sets, as well as an external test set from Singapore. AI assistance markedly enhanced diagnostic accuracy and classification for 23 out of 24 clinicians, with the average F1-score increasing by 20% from 37.71 (Manual) to 45.52 (Manual + AI) (P-value < 0.0001), achieving an improvement of over 50% in some cases. In terms of efficiency, AI assistance reduced diagnostic times for 17 out of the 19 clinicians tracked, with time savings of up to 40%. Furthermore, a model equipped with continual learning showed robust performance across three independent datasets, recording a 29% increase in accuracy, and elevating the F1-score from 42 to 54 in the Singapore population.

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.

The emergent abilities of large language models (LLMs) have demonstrated great potential in solving medical questions. They can possess considerable medical knowledge, but may still hallucinate and are inflexible in the knowledge updates. While Retrieval-Augmented Generation (RAG) has been proposed to enhance the medical question-answering capabilities of LLMs with external knowledge bases, it may still fail in complex cases where multiple rounds of information-seeking are required. To address such an issue, we propose iterative RAG for medicine (i-MedRAG), where LLMs can iteratively ask follow-up queries based on previous information-seeking attempts. In each iteration of i-MedRAG, the follow-up queries will be answered by a conventional RAG system and they will be further used to guide the query generation in the next iteration. Our experiments show the improved performance of various LLMs brought by i-MedRAG compared with conventional RAG on complex questions from clinical vignettes in the United States Medical Licensing Examination (USMLE), as well as various knowledge tests in the Massive Multitask Language Understanding (MMLU) dataset. Notably, our zero-shot i-MedRAG outperforms all existing prompt engineering and fine-tuning methods on GPT-3.5, achieving an accuracy of 69.68% on the MedQA dataset. In addition, we characterize the scaling properties of i-MedRAG with different iterations of follow-up queries and different numbers of queries per iteration. Our case studies show that i-MedRAG can flexibly ask follow-up queries to form reasoning chains, providing an in-depth analysis of medical questions. To the best of our knowledge, this is the first-of-its-kind study on incorporating follow-up queries into medical RAG. The implementation of i-MedRAG is available at https://github.com/Teddy-XiongGZ/MedRAG., Comment: Accepted to PSB 2025

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.

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.

The integration of Large Language Models (LLMs) into healthcare applications offers promising advancements in medical diagnostics, treatment recommendations, and patient care. However, the susceptibility of LLMs to adversarial attacks poses a significant threat, potentially leading to harmful outcomes in delicate medical contexts. This study investigates the vulnerability of LLMs to two types of adversarial attacks in three medical tasks. Utilizing real-world patient data, we demonstrate that both open-source and proprietary LLMs are susceptible to manipulation across multiple tasks. This research further reveals that domain-specific tasks demand more adversarial data in model fine-tuning than general domain tasks for effective attack execution, especially for more capable models. We discover that while integrating adversarial data does not markedly degrade overall model performance on medical benchmarks, it does lead to noticeable shifts in fine-tuned model weights, suggesting a potential pathway for detecting and countering model attacks. This research highlights the urgent need for robust security measures and the development of defensive mechanisms to safeguard LLMs in medical applications, to ensure their safe and effective deployment in healthcare settings.

As opposed to evaluating computation and logic-based reasoning, current benchmarks for evaluating large language models (LLMs) in medicine are primarily focused on question-answering involving domain knowledge and descriptive reasoning. While such qualitative capabilities are vital to medical diagnosis, in real-world scenarios, doctors frequently use clinical calculators that follow quantitative equations and rule-based reasoning paradigms for evidence-based decision support. To this end, we propose MedCalc-Bench, a first-of-its-kind dataset focused on evaluating the medical calculation capability of LLMs. MedCalc-Bench contains an evaluation set of over 1000 manually reviewed instances from 55 different medical calculation tasks. Each instance in MedCalc-Bench consists of a patient note, a question requesting to compute a specific medical value, a ground truth answer, and a step-by-step explanation showing how the answer is obtained. While our evaluation results show the potential of LLMs in this area, none of them are effective enough for clinical settings. Common issues include extracting the incorrect entities, not using the correct equation or rules for a calculation task, or incorrectly performing the arithmetic for the computation. We hope our study highlights the quantitative knowledge and reasoning gaps in LLMs within medical settings, encouraging future improvements of LLMs for various clinical calculation tasks., Comment: Github link: https://github.com/ncbi-nlp/MedCalc-Bench HuggingFace link: https://huggingface.co/datasets/nsk7153/MedCalc-Bench

Training a neural network-based biomedical named entity recognition (BioNER) model usually requires extensive and costly human annotations. While several studies have employed multi-task learning with multiple BioNER datasets to reduce human effort, this approach does not consistently yield performance improvements and may introduce label ambiguity in different biomedical corpora. We aim to tackle those challenges through transfer learning from easily accessible resources with fewer concept overlaps with biomedical datasets. In this paper, we proposed GERBERA, a simple-yet-effective method that utilized a general-domain NER dataset for training. Specifically, we performed multi-task learning to train a pre-trained biomedical language model with both the target BioNER dataset and the general-domain dataset. Subsequently, we fine-tuned the models specifically for the BioNER dataset. We systematically evaluated GERBERA on five datasets of eight entity types, collectively consisting of 81,410 instances. Despite using fewer biomedical resources, our models demonstrated superior performance compared to baseline models trained with multiple additional BioNER datasets. Specifically, our models consistently outperformed the baselines in six out of eight entity types, achieving an average improvement of 0.9% over the best baseline performance across eight biomedical entity types sourced from five different corpora. Our method was especially effective in amplifying performance on BioNER datasets characterized by limited data, with a 4.7% improvement in F1 scores on the JNLPBA-RNA dataset., Comment: Published in JBI 2024. We make data, codes, and models publicly available via https://github.com/qingyu-qc/bioner_gerbera

In this paper, we introduce DRR-RATE, a large-scale synthetic chest X-ray dataset derived from the recently released CT-RATE dataset. DRR-RATE comprises of 50,188 frontal Digitally Reconstructed Radiographs (DRRs) from 21,304 unique patients. Each image is paired with a corresponding radiology text report and binary labels for 18 pathology classes. Given the controllable nature of DRR generation, it facilitates the inclusion of lateral view images and images from any desired viewing position. This opens up avenues for research into new and novel multimodal applications involving paired CT, X-ray images from various views, text, and binary labels. We demonstrate the applicability of DRR-RATE alongside existing large-scale chest X-ray resources, notably the CheXpert dataset and CheXnet model. Experiments demonstrate that CheXnet, when trained and tested on the DRR-RATE dataset, achieves sufficient to high AUC scores for the six common pathologies cited in common literature: Atelectasis, Cardiomegaly, Consolidation, Lung Lesion, Lung Opacity, and Pleural Effusion. Additionally, CheXnet trained on the CheXpert dataset can accurately identify several pathologies, even when operating out of distribution. This confirms that the generated DRR images effectively capture the essential pathology features from CT images. The dataset and labels are publicly accessible at https://huggingface.co/datasets/farrell236/DRR-RATE.

Gene set knowledge discovery is essential for advancing human functional genomics. Recent studies have shown promising performance by harnessing the power of Large Language Models (LLMs) on this task. Nonetheless, their results are subject to several limitations common in LLMs such as hallucinations. In response, we present GeneAgent, a first-of-its-kind language agent featuring self-verification capability. It autonomously interacts with various biological databases and leverages relevant domain knowledge to improve accuracy and reduce hallucination occurrences. Benchmarking on 1,106 gene sets from different sources, GeneAgent consistently outperforms standard GPT-4 by a significant margin. Moreover, a detailed manual review confirms the effectiveness of the self-verification module in minimizing hallucinations and generating more reliable analytical narratives. To demonstrate its practical utility, we apply GeneAgent to seven novel gene sets derived from mouse B2905 melanoma cell lines, with expert evaluations showing that GeneAgent offers novel insights into gene functions and subsequently expedites knowledge discovery., Comment: 30 pages with 10 figures and/or tables

Deep learning has enabled breakthroughs in automated diagnosis from medical imaging, with many successful applications in ophthalmology. However, standard medical image classification approaches only assess disease presence at the time of acquisition, neglecting the common clinical setting of longitudinal imaging. For slow, progressive eye diseases like age-related macular degeneration (AMD) and primary open-angle glaucoma (POAG), patients undergo repeated imaging over time to track disease progression and forecasting the future risk of developing disease is critical to properly plan treatment. Our proposed Longitudinal Transformer for Survival Analysis (LTSA) enables dynamic disease prognosis from longitudinal medical imaging, modeling the time to disease from sequences of fundus photography images captured over long, irregular time periods. Using longitudinal imaging data from the Age-Related Eye Disease Study (AREDS) and Ocular Hypertension Treatment Study (OHTS), LTSA significantly outperformed a single-image baseline in 19/20 head-to-head comparisons on late AMD prognosis and 18/20 comparisons on POAG prognosis. A temporal attention analysis also suggested that, while the most recent image is typically the most influential, prior imaging still provides additional prognostic value., Comment: Accepted to npj Digital Medicine

Expert curation is essential to capture knowledge of enzyme functions from the scientific literature in FAIR open knowledgebases but cannot keep pace with the rate of new discoveries and new publications. In this work we present EnzChemRED, for Enzyme Chemistry Relation Extraction Dataset, a new training and benchmarking dataset to support the development of Natural Language Processing (NLP) methods such as (large) language models that can assist enzyme curation. EnzChemRED consists of 1,210 expert curated PubMed abstracts in which enzymes and the chemical reactions they catalyze are annotated using identifiers from the UniProt Knowledgebase (UniProtKB) and the ontology of Chemical Entities of Biological Interest (ChEBI). We show that fine-tuning pre-trained language models with EnzChemRED can significantly boost their ability to identify mentions of proteins and chemicals in text (Named Entity Recognition, or NER) and to extract the chemical conversions in which they participate (Relation Extraction, or RE), with average F1 score of 86.30% for NER, 86.66% for RE for chemical conversion pairs, and 83.79% for RE for chemical conversion pairs and linked enzymes. We combine the best performing methods after fine-tuning using EnzChemRED to create an end-to-end pipeline for knowledge extraction from text and apply this to abstracts at PubMed scale to create a draft map of enzyme functions in literature to guide curation efforts in UniProtKB and the reaction knowledgebase Rhea. The EnzChemRED corpus is freely available at https://ftp.expasy.org/databases/rhea/nlp/.

Automatically interpreting CT scans can ease the workload of radiologists. However, this is challenging mainly due to the scarcity of adequate datasets and reference standards for evaluation. This study aims to bridge this gap by introducing a novel evaluation framework, named ``GPTRadScore''. This framework assesses the capabilities of multi-modal LLMs, such as GPT-4 with Vision (GPT-4V), Gemini Pro Vision, LLaVA-Med, and RadFM, in generating descriptions for prospectively-identified findings. By employing a decomposition technique based on GPT-4, GPTRadScore compares these generated descriptions with gold-standard report sentences, analyzing their accuracy in terms of body part, location, and type of finding. Evaluations demonstrated a high correlation with clinician assessments and highlighted its potential over traditional metrics, such as BLEU, METEOR, and ROUGE. Furthermore, to contribute to future studies, we plan to release a benchmark dataset annotated by clinicians. Using GPTRadScore, we found that while GPT-4V and Gemini Pro Vision fare better, their performance revealed significant areas for improvement, primarily due to limitations in the dataset used for training these models. To demonstrate this potential, RadFM was fine-tuned and it resulted in significant accuracy improvements: location accuracy rose from 3.41\% to 12.8\%, body part accuracy from 29.12\% to 53\%, and type accuracy from 9.24\% to 30\%, thereby validating our hypothesis.

The summarization capabilities of pretrained and large language models (LLMs) have been widely validated in general areas, but their use in scientific corpus, which involves complex sentences and specialized knowledge, has been less assessed. This paper presents conceptual and experimental analyses of scientific summarization, highlighting the inadequacies of traditional evaluation methods, such as $n$-gram, embedding comparison, and QA, particularly in providing explanations, grasping scientific concepts, or identifying key content. Subsequently, we introduce the Facet-aware Metric (FM), employing LLMs for advanced semantic matching to evaluate summaries based on different aspects. This facet-aware approach offers a thorough evaluation of abstracts by decomposing the evaluation task into simpler subtasks.Recognizing the absence of an evaluation benchmark in this domain, we curate a Facet-based scientific summarization Dataset (FD) with facet-level annotations. Our findings confirm that FM offers a more logical approach to evaluating scientific summaries. In addition, fine-tuned smaller models can compete with LLMs in scientific contexts, while LLMs have limitations in learning from in-context information in scientific domains. This suggests an area for future enhancement of LLMs., Comment: 14pages

Clinical calculators play a vital role in healthcare by offering accurate evidence-based predictions for various purposes such as prognosis. Nevertheless, their widespread utilization is frequently hindered by usability challenges, poor dissemination, and restricted functionality. Augmenting large language models with extensive collections of clinical calculators presents an opportunity to overcome these obstacles and improve workflow efficiency, but the scalability of the manual curation process poses a significant challenge. In response, we introduce AgentMD, a novel language agent capable of curating and applying clinical calculators across various clinical contexts. Using the published literature, AgentMD has automatically curated a collection of 2,164 diverse clinical calculators with executable functions and structured documentation, collectively named RiskCalcs. Manual evaluations show that RiskCalcs tools achieve an accuracy of over 80% on three quality metrics. At inference time, AgentMD can automatically select and apply the relevant RiskCalcs tools given any patient description. On the newly established RiskQA benchmark, AgentMD significantly outperforms chain-of-thought prompting with GPT-4 (87.7% vs. 40.9% in accuracy). Additionally, we also applied AgentMD to real-world clinical notes for analyzing both population-level and risk-level patient characteristics. In summary, our study illustrates the utility of language agents augmented with clinical calculators for healthcare analytics and patient care., Comment: Work in progress

While large language models (LLMs) have achieved state-of-the-art performance on a wide range of medical question answering (QA) tasks, they still face challenges with hallucinations and outdated knowledge. Retrieval-augmented generation (RAG) is a promising solution and has been widely adopted. However, a RAG system can involve multiple flexible components, and there is a lack of best practices regarding the optimal RAG setting for various medical purposes. To systematically evaluate such systems, we propose the Medical Information Retrieval-Augmented Generation Evaluation (MIRAGE), a first-of-its-kind benchmark including 7,663 questions from five medical QA datasets. Using MIRAGE, we conducted large-scale experiments with over 1.8 trillion prompt tokens on 41 combinations of different corpora, retrievers, and backbone LLMs through the MedRAG toolkit introduced in this work. Overall, MedRAG improves the accuracy of six different LLMs by up to 18% over chain-of-thought prompting, elevating the performance of GPT-3.5 and Mixtral to GPT-4-level. Our results show that the combination of various medical corpora and retrievers achieves the best performance. In addition, we discovered a log-linear scaling property and the "lost-in-the-middle" effects in medical RAG. We believe our comprehensive evaluations can serve as practical guidelines for implementing RAG systems for medicine., Comment: Homepage: https://teddy-xionggz.github.io/benchmark-medical-rag/

Artificial intelligence (AI) systems have the potential to revolutionize clinical practices, including improving diagnostic accuracy and surgical decision-making, while also reducing costs and manpower. However, it is important to recognize that these systems may perpetuate social inequities or demonstrate biases, such as those based on race or gender. Such biases can occur before, during, or after the development of AI models, making it critical to understand and address potential biases to enable the accurate and reliable application of AI models in clinical settings. To mitigate bias concerns during model development, we surveyed recent publications on different debiasing methods in the fields of biomedical natural language processing (NLP) or computer vision (CV). Then we discussed the methods that have been applied in the biomedical domain to address bias. We performed our literature search on PubMed, ACM digital library, and IEEE Xplore of relevant articles published between January 2018 and December 2023 using multiple combinations of keywords. We then filtered the result of 10,041 articles automatically with loose constraints, and manually inspected the abstracts of the remaining 890 articles to identify the 55 articles included in this review. Additional articles in the references are also included in this review. We discuss each method and compare its strengths and weaknesses. Finally, we review other potential methods from the general domain that could be applied to biomedicine to address bias and improve fairness.The bias of AIs in biomedicine can originate from multiple sources. Existing debiasing methods that focus on algorithms can be categorized into distributional or algorithmic.

Intelligent agents powered by large language models (LLMs) have demonstrated substantial promise in autonomously conducting experiments and facilitating scientific discoveries across various disciplines. While their capabilities are promising, these agents, called scientific LLM agents, also introduce novel vulnerabilities that demand careful consideration for safety. However, there exists a notable gap in the literature, as there has been no comprehensive exploration of these vulnerabilities. This perspective paper fills this gap by conducting a thorough examination of vulnerabilities in LLM-based agents within scientific domains, shedding light on potential risks associated with their misuse and emphasizing the need for safety measures. We begin by providing a comprehensive overview of the potential risks inherent to scientific LLM agents, taking into account user intent, the specific scientific domain, and their potential impact on the external environment. Then, we delve into the origins of these vulnerabilities and provide a scoping review of the limited existing works. Based on our analysis, we propose a triadic framework involving human regulation, agent alignment, and an understanding of environmental feedback (agent regulation) to mitigate these identified risks. Furthermore, we highlight the limitations and challenges associated with safeguarding scientific agents and advocate for the development of improved models, robust benchmarks, and comprehensive regulations to address these issues effectively.

Searching for a related article based on a reference article is an integral part of scientific research. PubMed, like many academic search engines, has a "similar articles" feature that recommends articles relevant to the current article viewed by a user. Explaining recommended items can be of great utility to users, particularly in the literature search process. With more than a million biomedical papers being published each year, explaining the recommended similar articles would facilitate researchers and clinicians in searching for related articles. Nonetheless, the majority of current literature recommendation systems lack explanations for their suggestions. We employ a post hoc approach to explaining recommendations by identifying relevant tokens in the titles of similar articles. Our major contribution is building PubCLogs by repurposing 5.6 million pairs of coclicked articles from PubMed's user query logs. Using our PubCLogs dataset, we train the Highlight Similar Article Title (HSAT), a transformer-based model designed to select the most relevant parts of the title of a similar article, based on the title and abstract of a seed article. HSAT demonstrates strong performance in our empirical evaluations, achieving an F1 score of 91.72 percent on the PubCLogs test set, considerably outperforming several baselines including BM25 (70.62), MPNet (67.11), MedCPT (62.22), GPT-3.5 (46.00), and GPT-4 (64.89). Additional evaluations on a separate, manually annotated test set further verifies HSAT's performance. Moreover, participants of our user study indicate a preference for HSAT, due to its superior balance between conciseness and comprehensiveness. Our study suggests that repurposing user query logs of academic search engines can be a promising way to train state-of-the-art models for explaining literature recommendation.

In radiology, Artificial Intelligence (AI) has significantly advanced report generation, but automatic evaluation of these AI-produced reports remains challenging. Current metrics, such as Conventional Natural Language Generation (NLG) and Clinical Efficacy (CE), often fall short in capturing the semantic intricacies of clinical contexts or overemphasize clinical details, undermining report clarity. To overcome these issues, our proposed method synergizes the expertise of professional radiologists with Large Language Models (LLMs), like GPT-3.5 and GPT-4 1. Utilizing In-Context Instruction Learning (ICIL) and Chain of Thought (CoT) reasoning, our approach aligns LLM evaluations with radiologist standards, enabling detailed comparisons between human and AI generated reports. This is further enhanced by a Regression model that aggregates sentence evaluation scores. Experimental results show that our "Detailed GPT-4 (5-shot)" model achieves a 0.48 score, outperforming the METEOR metric by 0.19, while our "Regressed GPT-4" model shows even greater alignment with expert evaluations, exceeding the best existing metric by a 0.35 margin. Moreover, the robustness of our explanations has been validated through a thorough iterative strategy. We plan to publicly release annotations from radiology experts, setting a new standard for accuracy in future assessments. This underscores the potential of our approach in enhancing the quality assessment of AI-driven medical reports.

Large language models like GPT-3.5-turbo and GPT-4 hold promise for healthcare professionals, but they may inadvertently inherit biases during their training, potentially affecting their utility in medical applications. Despite few attempts in the past, the precise impact and extent of these biases remain uncertain. Through both qualitative and quantitative analyses, we find that these models tend to project higher costs and longer hospitalizations for White populations and exhibit optimistic views in challenging medical scenarios with much higher survival rates. These biases, which mirror real-world healthcare disparities, are evident in the generation of patient backgrounds, the association of specific diseases with certain races, and disparities in treatment recommendations, etc. Our findings underscore the critical need for future research to address and mitigate biases in language models, especially in critical healthcare applications, to ensure fair and accurate outcomes for all patients.

Lab results are often confusing and hard to understand. Large language models (LLMs) such as ChatGPT have opened a promising avenue for patients to get their questions answered. We aim to assess the feasibility of using LLMs to generate relevant, accurate, helpful, and unharmful responses to lab test-related questions asked by patients and to identify potential issues that can be mitigated with augmentation approaches. We first collected lab test results related question and answer data from Yahoo! Answers and selected 53 QA pairs for this study. Using the LangChain framework and ChatGPT web portal, we generated responses to the 53 questions from four LLMs including GPT-4, Meta LLaMA 2, MedAlpaca, and ORCA_mini. We first assessed the similarity of their answers using standard QA similarity-based evaluation metrics including ROUGE, BLEU, METEOR, BERTScore. We also utilized an LLM-based evaluator to judge whether a target model has higher quality in terms of relevance, correctness, helpfulness, and safety than the baseline model. Finally, we performed a manual evaluation with medical experts for all the responses to seven selected questions on the same four aspects. The results of Win Rate and medical expert evaluation both showed that GPT-4's responses achieved better scores than all the other LLM responses and human responses on all four aspects (relevance, correctness, helpfulness, and safety). However, LLM responses occasionally also suffer from a lack of interpretation in one's medical context, incorrect statements, and lack of references. We find that compared to other three LLMs and human answer from the Q&A website, GPT-4's responses are more accurate, helpful, relevant, and safer. However, there are cases which GPT-4 responses are inaccurate and not individualized. We identified a number of ways to improve the quality of LLM responses.

PubTator 3.0 (https://www.ncbi.nlm.nih.gov/research/pubtator3/) is a biomedical literature resource using state-of-the-art AI techniques to offer semantic and relation searches for key concepts like proteins, genetic variants, diseases, and chemicals. It currently provides over one billion entity and relation annotations across approximately 36 million PubMed abstracts and 6 million full-text articles from the PMC open access subset, updated weekly. PubTator 3.0's online interface and API utilize these precomputed entity relations and synonyms to provide advanced search capabilities and enable large-scale analyses, streamlining many complex information needs. We showcase the retrieval quality of PubTator 3.0 using a series of entity pair queries, demonstrating that PubTator 3.0 retrieves a greater number of articles than either PubMed or Google Scholar, with higher precision in the top 20 results. We further show that integrating ChatGPT (GPT-4) with PubTator APIs dramatically improves the factuality and verifiability of its responses. In summary, PubTator 3.0 offers a comprehensive set of features and tools that allow researchers to navigate the ever-expanding wealth of biomedical literature, expediting research and unlocking valuable insights for scientific discovery.

This study introduces Ascle, a pioneering natural language processing (NLP) toolkit designed for medical text generation. Ascle is tailored for biomedical researchers and healthcare professionals with an easy-to-use, all-in-one solution that requires minimal programming expertise. For the first time, Ascle evaluates and provides interfaces for the latest pre-trained language models, encompassing four advanced and challenging generative functions: question-answering, text summarization, text simplification, and machine translation. In addition, Ascle integrates 12 essential NLP functions, along with query and search capabilities for clinical databases. The toolkit, its models, and associated data are publicly available via https://github.com/Yale-LILY/MedGen., Comment: 5 figures, 4 tables

Evidence-based medicine promises to improve the quality of healthcare by empowering medical decisions and practices with the best available evidence. The rapid growth of medical evidence, which can be obtained from various sources, poses a challenge in collecting, appraising, and synthesizing the evidential information. Recent advancements in generative AI, exemplified by large language models, hold promise in facilitating the arduous task. However, developing accountable, fair, and inclusive models remains a complicated undertaking. In this perspective, we discuss the trustworthiness of generative AI in the context of automated summarization of medical evidence.

Many real-world image recognition problems, such as diagnostic medical imaging exams, are "long-tailed" $\unicode{x2013}$ there are a few common findings followed by many more relatively rare conditions. In chest radiography, diagnosis is both a long-tailed and multi-label problem, as patients often present with multiple findings simultaneously. While researchers have begun to study the problem of long-tailed learning in medical image recognition, few have studied the interaction of label imbalance and label co-occurrence posed by long-tailed, multi-label disease classification. To engage with the research community on this emerging topic, we conducted an open challenge, CXR-LT, on long-tailed, multi-label thorax disease classification from chest X-rays (CXRs). We publicly release a large-scale benchmark dataset of over 350,000 CXRs, each labeled with at least one of 26 clinical findings following a long-tailed distribution. We synthesize common themes of top-performing solutions, providing practical recommendations for long-tailed, multi-label medical image classification. Finally, we use these insights to propose a path forward involving vision-language foundation models for few- and zero-shot disease classification., Comment: Update after major revision

Recent studies have shown that the shape and radial profile of the colliding nuclei have strong influences on the initial condition of the heavy ion collisions and the subsequent development of the anisotropic flow. Using A Multi-Phase Transport model (AMPT) model, we investigated the impact of nuclear quadrupole deformation $\beta_2$ and nuclear diffuseness $a_0$ of $^{129}$Xe on various of flow observables in Xe--Xe collisions at $\sqrtnn =$ 5.44 TeV. We found that $\beta_2$ has a strong influence on central collisions while $a_0$ mostly influences the mid-central collisions. The relative change of flow observables induced by a change in $\beta_2$ and $a_0$ are also found to be insensitive to the values of parameters controlling the strength of the interaction among final state particles. Our study demonstrates the potential for constraining the initial condition of heavy ion collisions using future system scans at the LHC., Comment: 25 pages, for the EPJA Topical Issues

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., Comment: Nature Communications

Biomedical research yields a wealth of information, much of which is only accessible through the literature. Consequently, literature search is an essential tool for building on prior knowledge in clinical and biomedical research. Although recent improvements in artificial intelligence have expanded functionality beyond keyword-based search, these advances may be unfamiliar to clinicians and researchers. In response, we present a survey of literature search tools tailored to both general and specific information needs in biomedicine, with the objective of helping readers efficiently fulfill their information needs. We first examine the widely used PubMed search engine, discussing recent improvements and continued challenges. We then describe literature search tools catering to five specific information needs: 1. Identifying high-quality clinical research for evidence-based medicine. 2. Retrieving gene-related information for precision medicine and genomics. 3. Searching by meaning, including natural language questions. 4. Locating related articles with literature recommendation. 5. Mining literature to discover associations between concepts such as diseases and genetic variants. Additionally, we cover practical considerations and best practices for choosing and using these tools. Finally, we provide a perspective on the future of literature search engines, considering recent breakthroughs in large language models such as ChatGPT. In summary, our survey provides a comprehensive view of biomedical literature search functionalities with 36 publicly available tools., Comment: 27 pages, 6 figures, 36 tools

Computer-assisted diagnostic and prognostic systems of the future should be capable of simultaneously processing multimodal data. Multimodal deep learning (MDL), which involves the integration of multiple sources of data, such as images and text, has the potential to revolutionize the analysis and interpretation of biomedical data. However, it only caught researchers' attention recently. To this end, there is a critical need to conduct a systematic review on this topic, identify the limitations of current work, and explore future directions. In this scoping review, we aim to provide a comprehensive overview of the current state of the field and identify key concepts, types of studies, and research gaps with a focus on biomedical images and texts joint learning, mainly because these two were the most commonly available data types in MDL research. This study reviewed the current uses of multimodal deep learning on five tasks: (1) Report generation, (2) Visual question answering, (3) Cross-modal retrieval, (4) Computer-aided diagnosis, and (5) Semantic segmentation. Our results highlight the diverse applications and potential of MDL and suggest directions for future research in the field. We hope our review will facilitate the collaboration of natural language processing (NLP) and medical imaging communities and support the next generation of decision-making and computer-assisted diagnostic system development., Comment: This paper has been accepted by the Journal of Biomedical Informatics

Information retrieval (IR) is essential in biomedical knowledge acquisition and clinical decision support. While recent progress has shown that language model encoders perform better semantic retrieval, training such models requires abundant query-article annotations that are difficult to obtain in biomedicine. As a result, most biomedical IR systems only conduct lexical matching. In response, we introduce MedCPT, a first-of-its-kind Contrastively Pre-trained Transformer model for zero-shot semantic IR in biomedicine. To train MedCPT, we collected an unprecedented scale of 255 million user click logs from PubMed. With such data, we use contrastive learning to train a pair of closely-integrated retriever and re-ranker. Experimental results show that MedCPT sets new state-of-the-art performance on six biomedical IR tasks, outperforming various baselines including much larger models such as GPT-3-sized cpt-text-XL. In addition, MedCPT also generates better biomedical article and sentence representations for semantic evaluations. As such, MedCPT can be readily applied to various real-world biomedical IR tasks., Comment: The MedCPT code and API are available at https://github.com/ncbi/MedCPT

Biomedical relation extraction (RE) is the task of automatically identifying and characterizing relations between biomedical concepts from free text. RE is a central task in biomedical natural language processing (NLP) research and plays a critical role in many downstream applications, such as literature-based discovery and knowledge graph construction. State-of-the-art methods were used primarily to train machine learning models on individual RE datasets, such as protein-protein interaction and chemical-induced disease relation. Manual dataset annotation, however, is highly expensive and time-consuming, as it requires domain knowledge. Existing RE datasets are usually domain-specific or small, which limits the development of generalized and high-performing RE models. In this work, we present a novel framework for systematically addressing the data heterogeneity of individual datasets and combining them into a large dataset. Based on the framework and dataset, we report on BioREx, a data-centric approach for extracting relations. Our evaluation shows that BioREx achieves significantly higher performance than the benchmark system trained on the individual dataset, setting a new SOTA from 74.4% to 79.6% in F-1 measure on the recently released BioRED corpus. We further demonstrate that the combined dataset can improve performance for five different RE tasks. In addition, we show that on average BioREx compares favorably to current best-performing methods such as transfer learning and multi-task learning. Finally, we demonstrate BioREx's robustness and generalizability in two independent RE tasks not previously seen in training data: drug-drug N-ary combination and document-level gene-disease RE. The integrated dataset and optimized method have been packaged as a stand-alone tool available at https://github.com/ncbi/BioREx.

ChatGPT has drawn considerable attention from both the general public and domain experts with its remarkable text generation capabilities. This has subsequently led to the emergence of diverse applications in the field of biomedicine and health. In this work, we examine the diverse applications of large language models (LLMs), such as ChatGPT, in biomedicine and health. Specifically we explore the areas of biomedical information retrieval, question answering, medical text summarization, information extraction, and medical education, and investigate whether LLMs possess the transformative power to revolutionize these tasks or whether the distinct complexities of biomedical domain presents unique challenges. Following an extensive literature survey, we find that significant advances have been made in the field of text generation tasks, surpassing the previous state-of-the-art methods. For other applications, the advances have been modest. Overall, LLMs have not yet revolutionized biomedicine, but recent rapid progress indicates that such methods hold great potential to provide valuable means for accelerating discovery and improving health. We also find that the use of LLMs, like ChatGPT, in the fields of biomedicine and health entails various risks and challenges, including fabricated information in its generated responses, as well as legal and privacy concerns associated with sensitive patient data. We believe this survey can provide a comprehensive and timely overview to biomedical researchers and healthcare practitioners on the opportunities and challenges associated with using ChatGPT and other LLMs for transforming biomedicine and health.

Despite the reduction in turn-around times in radiology reports with the use of speech recognition software, persistent communication errors can significantly impact the interpretation of the radiology report. Pre-filling a radiology report holds promise in mitigating reporting errors, and despite efforts in the literature to generate medical reports, there exists a lack of approaches that exploit the longitudinal nature of patient visit records in the MIMIC-CXR dataset. To address this gap, we propose to use longitudinal multi-modal data, i.e., previous patient visit CXR, current visit CXR, and previous visit report, to pre-fill the 'findings' section of a current patient visit report. We first gathered the longitudinal visit information for 26,625 patients from the MIMIC-CXR dataset and created a new dataset called Longitudinal-MIMIC. With this new dataset, a transformer-based model was trained to capture the information from longitudinal patient visit records containing multi-modal data (CXR images + reports) via a cross-attention-based multi-modal fusion module and a hierarchical memory-driven decoder. In contrast to previous work that only uses current visit data as input to train a model, our work exploits the longitudinal information available to pre-fill the 'findings' section of radiology reports. Experiments show that our approach outperforms several recent approaches. Code will be published at https://github.com/CelestialShine/Longitudinal-Chest-X-Ray.

The biomedical literature is rapidly expanding, posing a significant challenge for manual curation and knowledge discovery. Biomedical Natural Language Processing (BioNLP) has emerged as a powerful solution, enabling the automated extraction of information and knowledge from this extensive literature. Recent attention has been directed towards Large Language Models (LLMs) due to their impressive performance. However, there remains a critical gap in understanding the effectiveness of LLMs in BioNLP tasks and their broader implications for method development and downstream users. Currently, there is a lack of baseline performance data, benchmarks, and practical recommendations for using LLMs in the biomedical domain. To address this gap, we present a systematic evaluation of four representative LLMs: GPT-3.5 and GPT-4 (closed-source), LLaMA 2 (open-sourced), and PMC LLaMA (domain-specific) across 12 BioNLP datasets covering six applications (named entity recognition, relation extraction, multi-label document classification, question answering, text summarization, and text simplification). The evaluation is conducted under four settings: zero-shot, static few-shot, dynamic K-nearest few-shot, and fine-tuning. We compare these models against state-of-the-art (SOTA) approaches that fine-tune (domain-specific) BERT or BART models, which are well-established methods in BioNLP tasks. The evaluation covers both quantitative and qualitative evaluations, where the latter involves manually reviewing collectively hundreds of thousands of LLM outputs for inconsistencies, missing information, and hallucinations in extractive and classification tasks. The qualitative review also examines accuracy, 1 completeness, and readability in text summarization tasks. Additionally, a cost analysis of closed-source GPT models is conducted.

While large language models (LLMs) have been successfully applied to various tasks, they still face challenges with hallucinations. Augmenting LLMs with domain-specific tools such as database utilities can facilitate easier and more precise access to specialized knowledge. In this paper, we present GeneGPT, a novel method for teaching LLMs to use the Web APIs of the National Center for Biotechnology Information (NCBI) for answering genomics questions. Specifically, we prompt Codex to solve the GeneTuring tests with NCBI Web APIs by in-context learning and an augmented decoding algorithm that can detect and execute API calls. Experimental results show that GeneGPT achieves state-of-the-art performance on eight tasks in the GeneTuring benchmark with an average score of 0.83, largely surpassing retrieval-augmented LLMs such as the new Bing (0.44), biomedical LLMs such as BioMedLM (0.08) and BioGPT (0.04), as well as GPT-3 (0.16) and ChatGPT (0.12). Our further analyses suggest that: (1) API demonstrations have good cross-task generalizability and are more useful than documentations for in-context learning; (2) GeneGPT can generalize to longer chains of API calls and answer multi-hop questions in GeneHop, a novel dataset introduced in this work; (3) Different types of errors are enriched in different tasks, providing valuable insights for future improvements.