FuseLinker: Leveraging LLM's pre-trained text embeddings and domain knowledge to enhance GNN-based link prediction on biomedical knowledge graphs.

OBJECTIVE: To develop the FuseLinker, a novel link prediction framework for biomedical knowledge graphs (BKGs), which fully exploits the graph's structural, textual and domain knowledge information. We evaluated the utility of FuseLinker in the graph-based drug repurposing task through detailed case studies. METHODS: FuseLinker leverages fused pre-trained text embedding and domain knowledge embedding to enhance the graph neural network (GNN)-based link prediction model tailored for BKGs. This framework includes three parts: a) obtain text embeddings for BKGs using embedding-visible large language models (LLMs), b) learn the representations of medical ontology as domain knowledge information by employing the Poincaré graph embedding method, and c) fuse these embeddings and further learn the graph structure representations of BKGs by applying a GNN-based link prediction model. We evaluated FuseLinker against traditional knowledge graph embedding models and a conventional GNN-based link prediction model across four public BKG datasets. Additionally, we examined the impact of using different embedding-visible LLMs on FuseLinker's performance. Finally, we investigated FuseLinker's ability to generate medical hypotheses through two drug repurposing case studies for Sorafenib and Parkinson's disease. RESULTS: By comparing FuseLinker with baseline models on four BKGs, our method demonstrates superior performance. The Mean Reciprocal Rank (MRR) and Area Under receiver operating characteristic Curve (AUROC) for KEGG50k, Hetionet, SuppKG and ADInt are 0.969 and 0.987, 0.548 and 0.903, 0.739 and 0.928, and 0.831 and 0.890, respectively. CONCLUSION: Our study demonstrates that FuseLinker is an effective novel link prediction framework that integrates multiple graph information and shows significant potential for practical applications in biomedical and clinical tasks. Source code and data are available at https://github.com/YKXia0/FuseLinker.

A review of reinforcement learning for natural language processing and applications in healthcare.

IMPORTANCE: Reinforcement learning (RL) represents a pivotal avenue within natural language processing (NLP), offering a potent mechanism for acquiring optimal strategies in task completion. This literature review studies various NLP applications where RL has demonstrated efficacy, with notable applications in healthcare settings. OBJECTIVES: To systematically explore the applications of RL in NLP, focusing on its effectiveness in acquiring optimal strategies, particularly in healthcare settings, and provide a comprehensive understanding of RL's potential in NLP tasks. MATERIALS AND METHODS: Adhering to the PRISMA guidelines, an exhaustive literature review was conducted to identify instances where RL has exhibited success in NLP applications, encompassing dialogue systems, machine translation, question-answering, text summarization, and information extraction. Our methodological approach involves closely examining the technical aspects of RL methodologies employed in these applications, analyzing algorithms, states, rewards, actions, datasets, and encoder-decoder architectures. RESULTS: The review of 93 papers yields insights into RL algorithms, prevalent techniques, emergent trends, and the fusion of RL methods in NLP healthcare applications. It clarifies the strategic approaches employed, datasets utilized, and the dynamic terrain of RL-NLP systems, thereby offering a roadmap for research and development in RL and machine learning techniques in healthcare. The review also addresses ethical concerns to ensure equity, transparency, and accountability in the evolution and application of RL-based NLP technologies, particularly within sensitive domains such as healthcare. DISCUSSION: The findings underscore the promising role of RL in advancing NLP applications, particularly in healthcare, where its potential to optimize decision-making and enhance patient outcomes is significant. However, the ethical challenges and technical complexities associated with RL demand careful consideration and ongoing research to ensure responsible and effective implementation. CONCLUSIONS: By systematically exploring RL's applications in NLP and providing insights into technical analysis, ethical implications, and potential advancements, this review contributes to a deeper understanding of RL's role for language processing.

LEAP: LLM instruction-example adaptive prompting framework for biomedical relation extraction.

OBJECTIVE: To investigate the demonstration in large language models (LLMs) for biomedical relation extraction. This study introduces a framework comprising three types of adaptive tuning methods to assess their impacts and effectiveness. MATERIALS AND METHODS: Our study was conducted in two phases. Initially, we analyzed a range of demonstration components vital for LLMs' biomedical data capabilities, including task descriptions and examples, experimenting with various combinations. Subsequently, we introduced the LLM instruction-example adaptive prompting (LEAP) framework, including instruction adaptive tuning, example adaptive tuning, and instruction-example adaptive tuning methods. This framework aims to systematically investigate both adaptive task descriptions and adaptive examples within the demonstration. We assessed the performance of the LEAP framework on the DDI, ChemProt, and BioRED datasets, employing LLMs such as Llama2-7b, Llama2-13b, and MedLLaMA_13B. RESULTS: Our findings indicated that Instruction + Options + Example and its expanded form substantially improved F1 scores over the standard Instruction + Options mode for zero-shot LLMs. The LEAP framework, particularly through its example adaptive prompting, demonstrated superior performance over conventional instruction tuning across all models. Notably, the MedLLAMA_13B model achieved an exceptional F1 score of 95.13 on the ChemProt dataset using this method. Significant improvements were also observed in the DDI 2013 and BioRED datasets, confirming the method's robustness in sophisticated data extraction scenarios. CONCLUSION: The LEAP framework offers a compelling strategy for enhancing LLM training strategies, steering away from extensive fine-tuning towards more dynamic and contextually enriched prompting methodologies, showcasing in biomedical relation extraction.

A Study of Biomedical Relation Extraction Using GPT Models.

Relation Extraction (RE) is a natural language processing (NLP) task for extracting semantic relations between biomedical entities. Recent developments in pre-trained large language models (LLM) motivated NLP researchers to use them for various NLP tasks. We investigated GPT-3.5-turbo and GPT-4 on extracting the relations from three standard datasets, EU-ADR, Gene Associations Database (GAD), and ChemProt. Unlike the existing approaches using datasets with masked entities, we used three versions for each dataset for our experiment: a version with masked entities, a second version with the original entities (unmasked), and a third version with abbreviations replaced with the original terms. We developed the prompts for various versions and used the chat completion model from GPT API. Our approach achieved a F1-score of 0.498 to 0.809 for GPT-3.5-turbo, and a highest F1-score of 0.84 for GPT-4. For certain experiments, the performance of GPT, BioBERT, and PubMedBERT are almost the same.

RT: a Retrieving and Chain-of-Thought framework for few-shot medical named entity recognition.

OBJECTIVES: This article aims to enhance the performance of larger language models (LLMs) on the few-shot biomedical named entity recognition (NER) task by developing a simple and effective method called Retrieving and Chain-of-Thought (RT) framework and to evaluate the improvement after applying RT framework. MATERIALS AND METHODS: Given the remarkable advancements in retrieval-based language model and Chain-of-Thought across various natural language processing tasks, we propose a pioneering RT framework designed to amalgamate both approaches. The RT approach encompasses dedicated modules for information retrieval and Chain-of-Thought processes. In the retrieval module, RT discerns pertinent examples from demonstrations during instructional tuning for each input sentence. Subsequently, the Chain-of-Thought module employs a systematic reasoning process to identify entities. We conducted a comprehensive comparative analysis of our RT framework against 16 other models for few-shot NER tasks on BC5CDR and NCBI corpora. Additionally, we explored the impacts of negative samples, output formats, and missing data on performance. RESULTS: Our proposed RT framework outperforms other LMs for few-shot NER tasks with micro-F1 scores of 93.50 and 91.76 on BC5CDR and NCBI corpora, respectively. We found that using both positive and negative samples, Chain-of-Thought (vs Tree-of-Thought) performed better. Additionally, utilization of a partially annotated dataset has a marginal effect of the model performance. DISCUSSION: This is the first investigation to combine a retrieval-based LLM and Chain-of-Thought methodology to enhance the performance in biomedical few-shot NER. The retrieval-based LLM aids in retrieving the most relevant examples of the input sentence, offering crucial knowledge to predict the entity in the sentence. We also conducted a meticulous examination of our methodology, incorporating an ablation study. CONCLUSION: The RT framework with LLM has demonstrated state-of-the-art performance on few-shot NER tasks.

Repurposing non-pharmacological interventions for Alzheimer's disease through link prediction on biomedical literature.

Non-pharmaceutical interventions (NPI) have great potential to improve cognitive function but limited investigation to discover NPI repurposing for Alzheimer's Disease (AD). This is the first study to develop an innovative framework to extract and represent NPI information from biomedical literature in a knowledge graph (KG), and train link prediction models to repurpose novel NPIs for AD prevention. We constructed a comprehensive KG, called ADInt, by extracting NPI information from biomedical literature. We used the previously-created SuppKG and NPI lexicon to identify NPI entities. Four KG embedding models (i.e., TransE, RotatE, DistMult and ComplEX) and two novel graph convolutional network models (i.e., R-GCN and CompGCN) were trained and compared to learn the representation of ADInt. Models were evaluated and compared on two test sets (time slice and clinical trial ground truth) and the best performing model was used to predict novel NPIs for AD. Discovery patterns were applied to generate mechanistic pathways for high scoring candidates. The ADInt has 162,212 nodes and 1,017,284 edges. R-GCN performed best in time slice (MR = 5.2054, Hits@10 = 0.8496) and clinical trial ground truth (MR = 3.4996, Hits@10 = 0.9192) test sets. After evaluation by domain experts, 10 novel dietary supplements and 10 complementary and integrative health were proposed from the score table calculated by R-GCN. Among proposed novel NPIs, we found plausible mechanistic pathways for photodynamic therapy and Choerospondias axillaris to prevent AD, and validated psychotherapy and manual therapy techniques using real-world data analysis. The proposed framework shows potential for discovering new NPIs for AD prevention and understanding their mechanistic pathways.

Complementary and Integrative Health Information in the literature: its lexicon and named entity recognition.

OBJECTIVE: To construct an exhaustive Complementary and Integrative Health (CIH) Lexicon (CIHLex) to help better represent the often underrepresented physical and psychological CIH approaches in standard terminologies, and to also apply state-of-the-art natural language processing (NLP) techniques to help recognize them in the biomedical literature. MATERIALS AND METHODS: We constructed the CIHLex by integrating various resources, compiling and integrating data from biomedical literature and relevant sources of knowledge. The Lexicon encompasses 724 unique concepts with 885 corresponding unique terms. We matched these concepts to the Unified Medical Language System (UMLS), and we developed and utilized BERT models comparing their efficiency in CIH named entity recognition to well-established models including MetaMap and CLAMP, as well as the large language model GPT3.5-turbo. RESULTS: Of the 724 unique concepts in CIHLex, 27.2% could be matched to at least one term in the UMLS. About 74.9% of the mapped UMLS Concept Unique Identifiers were categorized as "Therapeutic or Preventive Procedure." Among the models applied to CIH named entity recognition, BLUEBERT delivered the highest macro-average F1-score of 0.91, surpassing other models. CONCLUSION: Our CIHLex significantly augments representation of CIH approaches in biomedical literature. Demonstrating the utility of advanced NLP models, BERT notably excelled in CIH entity recognition. These results highlight promising strategies for enhancing standardization and recognition of CIH terminology in biomedical contexts.

Extracting Complementary and Integrative Health Approaches in Electronic Health Records.

Complementary and Integrative Health (CIH) has gained increasing popularity in the past decades. While the evidence bases to support them are growing, there is still a gap in understanding their effects and potential adverse events using real-world data. The overall goal of this study is to represent information pertinent to both psychological and physical CIH approaches (specifically, using examples of music therapy, chiropractic, and aquatic exercise in this study) in an electronic health record (EHR) system. We also aim to evaluate the ability of existing natural language processing (NLP) systems to identify CIH approaches. A total of 300 notes were randomly selected and manually annotated. Annotations were made for status, symptom, and frequency of each approach. This set of annotations was used as a gold standard to evaluate the performance of NLP systems used in this study (specifically BioMedICUS, MetaMap, and cTAKES) for extracting CIH concepts. Venn diagram was used to investigate the consistency of medical records searching by Current Procedural Terminology (CPT) codes and CIH approaches keywords in SQL. Since CPT codes usually do not have specific mentions of CIH approaches, the Venn diagram had less overlap with those found in clinical notes for all three CIH therapies. The three NLP systems achieved 0.41 in average lenient match F1-score in all three CIH approaches, respectively. BioMedICUS achieved the best performance in aquatic exercise with an F1-score of 0.66. This study contributes to the overall representation of CIH in clinical note and lays a foundation for using EHR for clinical research for CIH approaches.

Repurposing Non-pharmacological Interventions for Alzheimer's Diseases through Link Prediction on Biomedical Literature.

Recently, computational drug repurposing has emerged as a promising method for identifying new pharmaceutical interventions (PI) for Alzheimer's Disease (AD). Non-pharmaceutical interventions (NPI), such as Vitamin E and Music therapy, have great potential to improve cognitive function and slow the progression of AD, but have largely been unexplored. This study predicts novel NPIs for AD through link prediction on our developed biomedical knowledge graph. We constructed a comprehensive knowledge graph containing AD concepts and various potential interventions, called ADInt, by integrating a dietary supplement domain knowledge graph, SuppKG, with semantic relations from SemMedDB database. Four knowledge graph embedding models (TransE, RotatE, DistMult and ComplEX) and two graph convolutional network models (R-GCN and CompGCN) were compared to learn the representation of ADInt. R-GCN outperformed other models by evaluating on the time slice test set and the clinical trial test set and was used to generate the score tables of the link prediction task. Discovery patterns were applied to generate mechanism pathways for high scoring triples. Our ADInt had 162,213 nodes and 1,017,319 edges. The graph convolutional network model, R-GCN, performed best in both the Time Slicing test set (MR = 7.099, MRR = 0.5007, Hits@1 = 0.4112, Hits@3 = 0.5058, Hits@10 = 0.6804) and the Clinical Trials test set (MR = 1.731, MRR = 0.8582, Hits@1 = 0.7906, Hits@3 = 0.9033, Hits@10 = 0.9848). Among high scoring triples in the link prediction results, we found the plausible mechanism pathways of (Photodynamic therapy, PREVENTS, Alzheimer's Disease) and (Choerospondias axillaris, PREVENTS, Alzheimer's Disease) by discovery patterns and discussed them further. In conclusion, we presented a novel methodology to extend an existing knowledge graph and discover NPIs (dietary supplements (DS) and complementary and integrative health (CIH)) for AD. We used discovery patterns to find mechanisms for predicted triples to solve the poor interpretability of artificial neural networks. Our method can potentially be applied to other clinical problems, such as discovering drug adverse reactions and drug-drug interactions.

LLM Instruction-Example Adaptive Prompting (LEAP) Framework for Clinical Relation Extraction.

Objective: To investigate the demonstration in Large Language Models (LLMs) for clinical relation extraction. We focus on examining two types of adaptive demonstration: instruction adaptive prompting, and example adaptive prompting to understand their impacts and effectiveness. Materials and Methods: The study unfolds in two stages. Initially, we explored a range of demonstration components vital to LLMs' clinical data extraction, such as task descriptions and examples, and tested their combinations. Subsequently, we introduced the Instruction-Example Adaptive Prompting (LEAP) Framework, a system that integrates two types of adaptive prompts: one preceding instruction and another before examples. This framework is designed to systematically explore both adaptive task description and adaptive examples within the demonstration. We evaluated LEAP framework's performance on the DDI and BC5CDR chemical interaction datasets, applying it across LLMs such as Llama2-7b, Llama2-13b, and MedLLaMA_13B. Results: The study revealed that Instruction + Options + Examples and its expanded form substantially raised F1-scores over the standard Instruction + Options mode. LEAP framework excelled, especially with example adaptive prompting that outdid traditional instruction tuning across models. Notably, the MedLLAMA-13b model scored an impressive 95.13 F1 on the BC5CDR dataset with this method. Significant improvements were also seen in the DDI 2013 dataset, confirming the method's robustness in sophisticated data extraction. Conclusion: The LEAP framework presents a promising avenue for refining LLM training strategies, steering away from extensive finetuning towards more contextually rich and dynamic prompting methodologies.

One LLM is not Enough: Harnessing the Power of Ensemble Learning for Medical Question Answering.

Objective: To enhance the accuracy and reliability of diverse medical question-answering (QA) tasks and investigate efficient approaches deploying the Large Language Models (LLM) technologies, We developed a novel ensemble learning pipeline by utilizing state-of-the-art LLMs, focusing on improving performance on diverse medical QA datasets. Materials and Methods: Our study employs three medical QA datasets: PubMedQA, MedQA-USMLE, and MedMCQA, each presenting unique challenges in biomedical question-answering. The proposed LLM-Synergy framework, focusing exclusively on zero-shot cases using LLMs, incorporates two primary ensemble methods. The first is a Boosting-based weighted majority vote ensemble, where decision-making is expedited and refined by assigning variable weights to different LLMs through a boosting algorithm. The second method is Cluster-based Dynamic Model Selection, which dynamically selects the most suitable LLM votes for each query, based on the characteristics of question contexts, using a clustering approach. Results: The Majority Weighted Vote and Dynamic Model Selection methods demonstrate superior performance compared to individual LLMs across three medical QA datasets. Specifically, the accuracies are 35.84%, 96.21%, and 37.26% for MedMCQA, PubMedQA, and MedQA-USMLE, respectively, with the Majority Weighted Vote. Correspondingly, the Dynamic Model Selection yields slightly higher accuracies of 38.01%, 96.36%, and 38.13%. Conclusion: The LLM-Synergy framework with two ensemble methods, represents a significant advancement in leveraging LLMs for medical QA tasks and provides an innovative way of efficiently utilizing the development with LLM Technologies, customing for both existing and potentially future challenge tasks in biomedical and health informatics research.

Annotating Music Therapy, Chiropractic and Aquatic Exercise Using Electronic Health Record.

Complementary and Integrative Health (CIH) has gained increasing popularity in the past decades. The overall goal of this study is to represent information pertinent to music therapy, chiropractic and aquatic exercise in an EHR system. A total of 300 clinical notes were randomly selected and manually annotated. Annotations were made for status, symptom and frequency of each approach. This set of annotations was used as a gold standard to evaluate performance of NLP systems used in this study (specifically BioMedICUS, MetaMap and cTAKES) for extracting CIH concepts. Three NLP systems achieved an average lenient match F1-score of 0.50 in all three CIH approaches. BioMedICUS achieved the best performance in music therapy with an F1-score of 0.73. This study is a pilot to investigate CIH representation in clinical note and lays a foundation for using EHR for clinical research for CIH approaches.