Qiao Jin

Zheng Yuan, Qiao Jin, Chuanqi Tan et al. · tsinghua

Vision-and-language multi-modal pretraining and fine-tuning have shown great success in visual question answering (VQA). Compared to general domain VQA, the performance of biomedical VQA suffers from limited data. In this paper, we propose a retrieval-augmented pretrain-and-finetune paradigm named RAMM for biomedical VQA to overcome the data limitation issue. Specifically, we collect a new biomedical dataset named PMCPM which offers patient-based image-text pairs containing diverse patient situations from PubMed. Then, we pretrain the biomedical multi-modal model to learn visual and textual representation for image-text pairs and align these representations with image-text contrastive objective (ITC). Finally, we propose a retrieval-augmented method to better use the limited data. We propose to retrieve similar image-text pairs based on ITC from pretraining datasets and introduce a novel retrieval-attention module to fuse the representation of the image and the question with the retrieved images and texts. Experiments demonstrate that our retrieval-augmented pretrain-and-finetune paradigm obtains state-of-the-art performance on Med-VQA2019, Med-VQA2021, VQARAD, and SLAKE datasets. Further analysis shows that the proposed RAMM and PMCPM can enhance biomedical VQA performance compared with previous resources and methods. We will open-source our dataset, codes, and pretrained model.

Qiao Jin, Zifeng Wang, Charalampos S. Floudas et al. · tsinghua

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.

Shubo Tian, Qiao Jin, Lana Yeganova et al. · tsinghua

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.

Qiao Jin, Yifan Yang, Qingyu Chen et al. · tsinghua

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.

Qiao Jin, Won Kim, Qingyu Chen et al. · tsinghua

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.

Guangzhi Xiong, Qiao Jin, Xiao Wang et al.

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.

Qiao Jin, Ashley Shin, Zhiyong Lu · tsinghua

Queries with similar information needs tend to have similar document clicks, especially in biomedical literature search engines where queries are generally short and top documents account for most of the total clicks. Motivated by this, we present a novel architecture for biomedical literature search, namely Log-Augmented DEnse Retrieval (LADER), which is a simple plug-in module that augments a dense retriever with the click logs retrieved from similar training queries. Specifically, LADER finds both similar documents and queries to the given query by a dense retriever. Then, LADER scores relevant (clicked) documents of similar queries weighted by their similarity to the input query. The final document scores by LADER are the average of (1) the document similarity scores from the dense retriever and (2) the aggregated document scores from the click logs of similar queries. Despite its simplicity, LADER achieves new state-of-the-art (SOTA) performance on TripClick, a recently released benchmark for biomedical literature retrieval. On the frequent (HEAD) queries, LADER largely outperforms the best retrieval model by 39% relative NDCG@10 (0.338 v.s. 0.243). LADER also achieves better performance on the less frequent (TORSO) queries with 11% relative NDCG@10 improvement over the previous SOTA (0.303 v.s. 0.272). On the rare (TAIL) queries where similar queries are scarce, LADER still compares favorably to the previous SOTA method (NDCG@10: 0.310 v.s. 0.295). On all queries, LADER can improve the performance of a dense retriever by 24%-37% relative NDCG@10 while not requiring additional training, and further performance improvement is expected from more logs. Our regression analysis has shown that queries that are more frequent, have higher entropy of query similarity and lower entropy of document similarity, tend to benefit more from log augmentation.

Qiao Jin, Robert Leaman, Zhiyong Lu · tsinghua

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.

Gongbo Zhang, Qiao Jin, Denis Jered McInerney et al. · amazon-science, salesforce

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.

Aidan Gilson, Xuguang Ai, Thilaka Arunachalam et al.

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.

Yunfei Xie, Juncheng Wu, Haoqin Tu et al.

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.

Qingqing Zhu, Qiao Jin, Tejas S. Mathai et al.

Artificial intelligence (AI) can automatically delineate lesions on computed tomography (CT) and generate radiology report content, yet progress is limited by the scarcity of publicly available CT datasets with lesion-level annotations. To bridge this gap, we introduce CT-Bench, a first-of-its-kind benchmark dataset comprising two components: a Lesion Image and Metadata Set containing 20,335 lesions from 7,795 CT studies with bounding boxes, descriptions, and size information, and a multitask visual question answering benchmark with 2,850 QA pairs covering lesion localization, description, size estimation, and attribute categorization. Hard negative examples are included to reflect real-world diagnostic challenges. We evaluate multiple state-of-the-art multimodal models, including vision-language and medical CLIP variants, by comparing their performance to radiologist assessments, demonstrating the value of CT-Bench as a comprehensive benchmark for lesion analysis. Moreover, fine-tuning models on the Lesion Image and Metadata Set yields significant performance gains across both components, underscoring the clinical utility of CT-Bench.

Yin Fang, Qiao Jin, Guangzhi Xiong et al.

Cell type annotation is a key task in analyzing the heterogeneity of single-cell RNA sequencing data. Although recent foundation models automate this process, they typically annotate cells independently, without considering batch-level cellular context or providing explanatory reasoning. In contrast, human experts often annotate distinct cell types for different cell clusters based on their domain knowledge. To mimic this workflow, we introduce the CellPuzzles task, where the objective is to assign unique cell types to a batch of cells. This benchmark spans diverse tissues, diseases, and donor conditions, and requires reasoning across the batch-level cellular context to ensure label uniqueness. We find that off-the-shelf large language models (LLMs) struggle on CellPuzzles, with the best baseline (OpenAI's o1) achieving only 19.0% batch-level accuracy. To fill this gap, we propose Cell-o1, a 7B LLM trained via supervised fine-tuning on distilled reasoning traces, followed by reinforcement learning with batch-level rewards. Cell-o1 achieves state-of-the-art performance, outperforming o1 by over 73% and generalizing well across contexts. Further analysis of training dynamics and reasoning behaviors provides insights into batch-level annotation performance and emergent expert-like reasoning. Code and data are available at https://github.com/ncbi-nlp/cell-o1.

Guangzhi Xiong, Qiao Jin, Zhiyong Lu et al.

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.

Qiao Jin, Yin Fang, Lauren He et al.

Assessing whether an article supports an assertion is essential for hallucination detection and claim verification. While large language models (LLMs) have the potential to automate this task, achieving strong performance requires frontier models such as GPT-5 that are prohibitively expensive to deploy at scale. To efficiently perform biomedical evidence attribution, we present Med-V1, a family of small language models with only three billion parameters. Trained on high-quality synthetic data newly developed in this study, Med-V1 substantially outperforms (+27.0% to +71.3%) its base models on five biomedical benchmarks unified into a verification format. Despite its smaller size, Med-V1 performs comparably to frontier LLMs such as GPT-5, along with high-quality explanations for its predictions. We use Med-V1 to conduct a first-of-its-kind use case study that quantifies hallucinations in LLM-generated answers under different citation instructions. Results show that the format instruction strongly affects citation validity and hallucination, with GPT-5 generating more claims but exhibiting hallucination rates similar to GPT-4o. Additionally, we present a second use case showing that Med-V1 can automatically identify high-stakes evidence misattributions in clinical practice guidelines, revealing potentially negative public health impacts that are otherwise challenging to identify at scale. Overall, Med-V1 provides an efficient and accurate lightweight alternative to frontier LLMs for practical and real-world applications in biomedical evidence attribution and verification tasks. Med-V1 is available at https://github.com/ncbi-nlp/Med-V1.

Lexiang Tang, Weihao Gao, Bingchen Zhao et al.

Recent work on test-time scaling for large language model (LLM) reasoning typically assumes that allocating more inference-time computation uniformly improves correctness. However, prior studies show that reasoning uncertainty is highly localized: a small subset of low-confidence tokens disproportionately contributes to reasoning errors and unnecessary output expansion. Motivated by this observation, we propose Thinking by Subtraction, a confidence-driven contrastive decoding approach that improves reasoning reliability through targeted token-level intervention. Our method, Confidence-Driven Contrastive Decoding, detects low-confidence tokens during decoding and intervenes selectively at these positions. It constructs a contrastive reference by replacing high-confidence tokens with minimal placeholders, and refines predictions by subtracting this reference distribution at low-confidence locations. Experiments show that CCD significantly improves accuracy across mathematical reasoning benchmarks while substantially reducing output length, with minimal KV-cache overhead. As a training-free method, CCD enhances reasoning reliability through targeted low-confidence intervention without computational redundancy. Our code will be made available at: https://github.com/bolo-web/CCD.

Yifan Yang, Qiao Jin, Furong Huang et al.

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.

Benjamin Hou, Qingqing Zhu, Tejas Sudarshan Mathai et al.

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.

Xiangru Tang, Qiao Jin, Kunlun Zhu et al.

AI scientists powered by large language models have demonstrated substantial promise in autonomously conducting experiments and facilitating scientific discoveries across various disciplines. While their capabilities are promising, these agents also introduce novel vulnerabilities that require careful consideration for safety. However, there has been limited comprehensive exploration of these vulnerabilities. This perspective examines vulnerabilities in AI scientists, shedding light on potential risks associated with their misuse, and emphasizing the need for safety measures. We begin by providing an overview of the potential risks inherent to AI scientists, taking into account user intent, the specific scientific domain, and their potential impact on the external environment. Then, we explore the underlying causes 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 AI scientists and advocate for the development of improved models, robust benchmarks, and comprehensive regulations.

Qiao Jin, Zhizheng Wang, Yifan Yang et al.

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.

Zhe He, Balu Bhasuran, Qiao Jin et al.

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.

Qingqing Zhu, Xiuying Chen, Qiao Jin et al.

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.

Zifeng Wang, Lang Cao, Qiao Jin et al.

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.

Guangzhi Xiong, Qiao Jin, Xiao Wang et al.

Retrieval-augmented generation (RAG) has shown great promise for knowledge-intensive tasks and recently advanced with agentic RAG, where language agents engage in multi-round interactions with external knowledge sources for adaptive information retrieval. However, existing agentic RAG methods often depend on ad-hoc prompt engineering and lack a unified optimization framework. We introduce RAG-Gym, a comprehensive platform that systematically explores three optimization dimensions: (1) prompt engineering, (2) actor tuning, and (3) critic training. For prompt engineering, we propose Re$^2$Search, a novel agent incorporating reasoning reflection that significantly outperforms standard prompts. In actor tuning, we evaluate three popular post-training algorithms with fine-grained process supervision and identify direct preference optimization as the most effective. We further demonstrate that a trained critic can enhance inference by selecting higher-quality intermediate reasoning steps. Together, these findings lead to the optimized Re$^2$Search++ agent, which surpasses most recent methods like Search-R1 by a relative increase of 3.2% to 11.6% in average F1. Finally, we examine the impact of different reward sources and analyze scaling properties in training and inference, offering practical insights for agentic RAG optimization. The project homepage is available at https://rag-gym.github.io.

Yifan Yang, Qiao Jin, Robert Leaman et al.

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.

Yifan Yang, Qiao Jin, Qingqing Zhu et al.

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.

Qingqing Zhu, Benjamin Hou, Tejas S. Mathai et al.

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.

Gongbo Zhang, Zihan Xu, Qiao Jin et al.

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.

Zifeng Wang, Qiao Jin, Jiacheng Lin et al.

Developing artificial intelligence (AI) for vertical domains requires a solid data foundation for both training and evaluation. In this work, we introduce TrialPanorama, a large-scale, structured database comprising 1,657,476 clinical trial records aggregated from 15 global sources. The database captures key aspects of trial design and execution, including trial setups, interventions, conditions, biomarkers, and outcomes, and links them to standard biomedical ontologies such as DrugBank and MedDRA. This structured and ontology-grounded design enables TrialPanorama to serve as a unified, extensible resource for a wide range of clinical trial tasks, including trial planning, design, and summarization. To demonstrate its utility, we derive a suite of benchmark tasks directly from the TrialPanorama database. The benchmark spans eight tasks across two categories: three for systematic review (study search, study screening, and evidence summarization) and five for trial design (arm design, eligibility criteria, endpoint selection, sample size estimation, and trial completion assessment). The experiments using five state-of-the-art large language models (LLMs) show that while general-purpose LLMs exhibit some zero-shot capability, their performance is still inadequate for high-stakes clinical trial workflows. We release TrialPanorama database and the benchmark to facilitate further research on AI for clinical trials.

Balu Bhasuran, Qiao Jin, Yuzhang Xie et al.

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.

Nikhil Khandekar, Qiao Jin, Guangzhi Xiong et al.

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.

Yifan Yang, Xiaoyu Liu, Qiao Jin et al.

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.

Chih-Hsuan Wei, Alexis Allot, Po-Ting Lai et al.

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.

Qiao Jin, Fangyuan Chen, Yiliang Zhou et al.

Recent studies indicate that Generative Pre-trained Transformer 4 with Vision (GPT-4V) outperforms human physicians in medical challenge tasks. However, these evaluations primarily focused on the accuracy of multi-choice questions alone. Our study extends the current scope by conducting a comprehensive analysis of GPT-4V's rationales of image comprehension, recall of medical knowledge, and step-by-step multimodal reasoning when solving New England Journal of Medicine (NEJM) Image Challenges - an imaging quiz designed to test the knowledge and diagnostic capabilities of medical professionals. Evaluation results confirmed that GPT-4V performs comparatively to human physicians regarding multi-choice accuracy (81.6% vs. 77.8%). GPT-4V also performs well in cases where physicians incorrectly answer, with over 78% accuracy. However, we discovered that GPT-4V frequently presents flawed rationales in cases where it makes the correct final choices (35.5%), most prominent in image comprehension (27.2%). Regardless of GPT-4V's high accuracy in multi-choice questions, our findings emphasize the necessity for further in-depth evaluations of its rationales before integrating such multimodal AI models into clinical workflows.

Zhengyun Zhao, Qiao Jin, Fangyuan Chen et al.

Objective: Retrieval-based Clinical Decision Support (ReCDS) can aid clinical workflow by providing relevant literature and similar patients for a given patient. However, the development of ReCDS systems has been severely obstructed by the lack of diverse patient collections and publicly available large-scale patient-level annotation datasets. In this paper, we aim to define and benchmark two ReCDS tasks: Patient-to-Article Retrieval (ReCDS-PAR) and Patient-to-Patient Retrieval (ReCDS-PPR) using a novel dataset called PMC-Patients. Methods: We extract patient summaries from PubMed Central articles using simple heuristics and utilize the PubMed citation graph to define patient-article relevance and patient-patient similarity. We also implement and evaluate several ReCDS systems on the PMC-Patients benchmarks, including sparse retrievers, dense retrievers, and nearest neighbor retrievers. We conduct several case studies to show the clinical utility of PMC-Patients. Results: PMC-Patients contains 167k patient summaries with 3.1M patient-article relevance annotations and 293k patient-patient similarity annotations, which is the largest-scale resource for ReCDS and also one of the largest patient collections. Human evaluation and analysis show that PMC-Patients is a diverse dataset with high-quality annotations. The evaluation of various ReCDS systems shows that the PMC-Patients benchmark is challenging and calls for further research. Conclusion: We present PMC-Patients, a large-scale, diverse, and publicly available patient summary dataset with the largest-scale patient-level relation annotations. Based on PMC-Patients, we formally define two benchmark tasks for ReCDS systems and evaluate various existing retrieval methods. PMC-Patients can largely facilitate methodology research on ReCDS systems and shows real-world clinical utility.

Dejie Chang, Mosha Chen, Chaozhen Liu et al.

Knowledge Graph has been proven effective in modeling structured information and conceptual knowledge, especially in the medical domain. However, the lack of high-quality annotated corpora remains a crucial problem for advancing the research and applications on this task. In order to accelerate the research for domain-specific knowledge graphs in the medical domain, we introduce DiaKG, a high-quality Chinese dataset for Diabetes knowledge graph, which contains 22,050 entities and 6,890 relations in total. We implement recent typical methods for Named Entity Recognition and Relation Extraction as a benchmark to evaluate the proposed dataset thoroughly. Empirical results show that the DiaKG is challenging for most existing methods and further analysis is conducted to discuss future research direction for improvements. We hope the release of this dataset can assist the construction of diabetes knowledge graphs and facilitate AI-based applications.

Qiao Jin, Zheng Yuan, Guangzhi Xiong et al.

Automatic Question Answering (QA) has been successfully applied in various domains such as search engines and chatbots. Biomedical QA (BQA), as an emerging QA task, enables innovative applications to effectively perceive, access and understand complex biomedical knowledge. There have been tremendous developments of BQA in the past two decades, which we classify into 5 distinctive approaches: classic, information retrieval, machine reading comprehension, knowledge base and question entailment approaches. In this survey, we introduce available datasets and representative methods of each BQA approach in detail. Despite the developments, BQA systems are still immature and rarely used in real-life settings. We identify and characterize several key challenges in BQA that might lead to this issue, and discuss some potential future directions to explore.

Qiao Jin, Chuanqi Tan, Mosha Chen et al.

Clinical trials provide essential guidance for practicing Evidence-Based Medicine, though often accompanying with unendurable costs and risks. To optimize the design of clinical trials, we introduce a novel Clinical Trial Result Prediction (CTRP) task. In the CTRP framework, a model takes a PICO-formatted clinical trial proposal with its background as input and predicts the result, i.e. how the Intervention group compares with the Comparison group in terms of the measured Outcome in the studied Population. While structured clinical evidence is prohibitively expensive for manual collection, we exploit large-scale unstructured sentences from medical literature that implicitly contain PICOs and results as evidence. Specifically, we pre-train a model to predict the disentangled results from such implicit evidence and fine-tune the model with limited data on the downstream datasets. Experiments on the benchmark Evidence Integration dataset show that the proposed model outperforms the baselines by large margins, e.g., with a 10.7% relative gain over BioBERT in macro-F1. Moreover, the performance improvement is also validated on another dataset composed of clinical trials related to COVID-19.

Qiao Jin, Bhuwan Dhingra, Zhengping Liu et al.

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.

Qiao Jin, Jinling Liu, Xinghua Lu

Automatic identification and expansion of ambiguous abbreviations are essential for biomedical natural language processing applications, such as information retrieval and question answering systems. In this paper, we present DEep Contextualized Biomedical. Abbreviation Expansion (DECBAE) model. DECBAE automatically collects substantial and relatively clean annotated contexts for 950 ambiguous abbreviations from PubMed abstracts using a simple heuristic. Then it utilizes BioELMo to extract the contextualized features of words, and feed those features to abbreviation-specific bidirectional LSTMs, where the hidden states of the ambiguous abbreviations are used to assign the exact definitions. Our DECBAE model outperforms other baselines by large margins, achieving average accuracy of 0.961 and macro-F1 of 0.917 on the dataset. It also surpasses human performance for expanding a sample abbreviation, and remains robust in imbalanced, low-resources and clinical settings.

Qiao Jin, Bhuwan Dhingra, William W. Cohen et al.

Contextualized word embeddings derived from pre-trained language models (LMs) show significant improvements on downstream NLP tasks. Pre-training on domain-specific corpora, such as biomedical articles, further improves their performance. In this paper, we conduct probing experiments to determine what additional information is carried intrinsically by the in-domain trained contextualized embeddings. For this we use the pre-trained LMs as fixed feature extractors and restrict the downstream task models to not have additional sequence modeling layers. We compare BERT, ELMo, BioBERT and BioELMo, a biomedical version of ELMo trained on 10M PubMed abstracts. Surprisingly, while fine-tuned BioBERT is better than BioELMo in biomedical NER and NLI tasks, as a fixed feature extractor BioELMo outperforms BioBERT in our probing tasks. We use visualization and nearest neighbor analysis to show that better encoding of entity-type and relational information leads to this superiority.

Bhuwan Dhingra, Qiao Jin, Zhilin Yang et al.

Many problems in NLP require aggregating information from multiple mentions of the same entity which may be far apart in the text. Existing Recurrent Neural Network (RNN) layers are biased towards short-term dependencies and hence not suited to such tasks. We present a recurrent layer which is instead biased towards coreferent dependencies. The layer uses coreference annotations extracted from an external system to connect entity mentions belonging to the same cluster. Incorporating this layer into a state-of-the-art reading comprehension model improves performance on three datasets -- Wikihop, LAMBADA and the bAbi AI tasks -- with large gains when training data is scarce.