Accelerating Clinical Evidence Synthesis with Large Language Models

Automatic medical discovery by AI is a dream of many. One step toward that goal is to create an AI model to understand clinical studies and synthesize clinical evidence from the literature. Clinical evidence synthesis currently 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 evidence. We introduce TrialMind, a generative AI-based pipeline for conducting medical systematic reviews, encompassing study search, screening, and data extraction phases. We utilize large language models (LLMs) to drive each pipeline component while incorporating human expert oversight to minimize errors. To facilitate evaluation, we also create a benchmark dataset TrialReviewBench, a custom dataset with 870 annotated clinical studies from 25 meta-analysis papers across various medical treatments. Our results demonstrate that TrialMind significantly improves the literature review process, achieving high recall rates (0.897-1.000) in study searching from over 20 million PubMed studies and outperforming traditional language model embeddings-based methods in screening (Recall@20 of 0.227-0.246 vs. 0.000-0.102). Furthermore, our approach surpasses direct GPT-4 performance in result extraction, with accuracy ranging from 0.65 to 0.84. We also support clinical evidence synthesis in forest plots, as validated by eight human annotators who preferred TrialMind over the GPT-4 baseline with a winning rate of 62.5%-100% across the involved reviews. Our findings suggest that an LLM-based clinical evidence synthesis approach, such as TrialMind, can enable reliable and high-quality clinical evidence synthesis to improve clinical research efficiency.

Adversarial Attacks on Large Language Models in Medicine

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.

MedCalc-Bench: Evaluating Large Language Models for Medical Calculations

As opposed to evaluating computation and logic-based reasoning, current bench2 marks for evaluating large language models (LLMs) in medicine are primarily focused on question-answering involving domain knowledge and descriptive rea4 soning. While such qualitative capabilities are vital to medical diagnosis, in real5 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.

Augmenting Biomedical Named Entity Recognition with General-domain Resources

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.

Shadow and Light: Digitally Reconstructed Radiographs for Disease Classification

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.

GeneAgent: Self-verification Language Agent for Gene Set Knowledge Discovery using Domain Databases

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.

Harnessing the power of longitudinal medical imaging for eye disease prognosis using Transformer-based sequence modeling

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.

EnzChemRED, a rich enzyme chemistry relation extraction dataset

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/.

Decomposing Vision-based LLM Predictions for Auto-Evaluation with GPT-4

The volume of CT exams being done in the world has been rising every year, which has led to radiologist burn-out. Large Language Models (LLMs) have the potential to reduce their burden, but their adoption in the clinic depends on radiologist trust, and easy evaluation of generated content. Presently, many automated methods are available to evaluate the reports generated for chest radiographs, but such an approach is not available for CT presently. In this paper, we propose a novel evaluation framework to judge the capabilities of vision-language LLMs in generating accurate summaries of CT-based abnormalities. CT slices containing an abnormality (e.g., lesion) were input to a vision-based LLM (GPT-4V, LLaVA-Med, and RadFM), and it generated a free-text summary of the predicted characteristics of the abnormality. Next, a GPT-4 model decomposed the summary into specific aspects (body part, location, type, and attributes), automatically evaluated the characteristics against the ground-truth, and generated a score for each aspect based on its clinical relevance and factual accuracy. These scores were then contrasted against those obtained from a clinician, and a high correlation ( 85%, p < .001) was observed. Although GPT-4V outperformed other models in our evaluation, it still requires overall improvement. Our evaluation method offers valuable insights into the specific areas that need the most enhancement, guiding future development in this field.

Benchmarking Retrieval-Augmented Generation for Medicine

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.