Benchmarking Next-Generation Reasoning-Focused Large Language Models in Ophthalmology: A Head-to-Head Evaluation on 5,888 Items

Recent advances in reasoning-focused large language models (LLMs) mark a shift from general LLMs toward models designed for complex decision-making, a crucial aspect in medicine. However, their performance in specialized domains like ophthalmology remains underexplored. This study comprehensively evaluated and compared the accuracy and reasoning capabilities of four newly developed reasoning-focused LLMs, namely DeepSeek-R1, OpenAI o1, o3-mini, and Gemini 2.0 Flash-Thinking. Each model was assessed using 5,888 multiple-choice ophthalmology exam questions from the MedMCQA dataset in zero-shot setting. Quantitative evaluation included accuracy, Macro-F1, and five text-generation metrics (ROUGE-L, METEOR, BERTScore, BARTScore, and AlignScore), computed against ground-truth reasonings. Average inference time was recorded for a subset of 100 randomly selected questions. Additionally, two board-certified ophthalmologists qualitatively assessed clarity, completeness, and reasoning structure of responses to differential diagnosis questions.O1 (0.902) and DeepSeek-R1 (0.888) achieved the highest accuracy, with o1 also leading in Macro-F1 (0.900). The performance of models across the text-generation metrics varied: O3-mini excelled in ROUGE-L (0.151), o1 in METEOR (0.232), DeepSeek-R1 and o3-mini tied for BERTScore (0.673), DeepSeek-R1 (-4.105) and Gemini 2.0 Flash-Thinking (-4.127) performed best in BARTScore, while o3-mini (0.181) and o1 (0.176) led AlignScore. Inference time across the models varied, with DeepSeek-R1 being slowest (40.4 seconds) and Gemini 2.0 Flash-Thinking fastest (6.7 seconds). Qualitative evaluation revealed that DeepSeek-R1 and Gemini 2.0 Flash-Thinking tended to provide detailed and comprehensive intermediate reasoning, whereas o1 and o3-mini displayed concise and summarized justifications.

A Benchmark for End-to-End Zero-Shot Biomedical Relation Extraction with LLMs: Experiments with OpenAI Models

Objective: Zero-shot methodology promises to cut down on costs of dataset annotation and domain expertise needed to make use of NLP. Generative large language models trained to align with human goals have achieved high zero-shot performance across a wide variety of tasks. As of yet, it is unclear how well these models perform on biomedical relation extraction (RE). To address this knowledge gap, we explore patterns in the performance of OpenAI LLMs across a diverse sampling of RE tasks. Methods: We use OpenAI GPT-4-turbo and their reasoning model o1 to conduct end-to-end RE experiments on seven datasets. We use the JSON generation capabilities of GPT models to generate structured output in two ways: (1) by defining an explicit schema describing the structure of relations, and (2) using a setting that infers the structure from the prompt language. Results: Our work is the first to study and compare the performance of the GPT-4 and o1 for the end-to-end zero-shot biomedical RE task across a broad array of datasets. We found the zero-shot performances to be proximal to that of fine-tuned methods. The limitations of this approach are that it performs poorly on instances containing many relations and errs on the boundaries of textual mentions. Conclusion: Recent large language models exhibit promising zero-shot capabilities in complex biomedical RE tasks, offering competitive performance with reduced dataset curation and NLP modeling needs at the cost of increased computing, potentially increasing medical community accessibility. Addressing the limitations we identify could further boost reliability. The code, data, and prompts for all our experiments are publicly available: https://github.com/bionlproc/ZeroShotRE

Enhancing Large Language Models with Domain-specific Retrieval Augment Generation: A Case Study on Long-form Consumer Health Question Answering in Ophthalmology

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.

Comparison of pipeline, sequence-to-sequence, and GPT models for end-to-end relation extraction: experiments with the rare disease use-case

End-to-end relation extraction (E2ERE) is an important and realistic application of natural language processing (NLP) in biomedicine. In this paper, we aim to compare three prevailing paradigms for E2ERE using a complex dataset focused on rare diseases involving discontinuous and nested entities. We use the RareDis information extraction dataset to evaluate three competing approaches (for E2ERE): NER $\rightarrow$ RE pipelines, joint sequence to sequence models, and generative pre-trained transformer (GPT) models. We use comparable state-of-the-art models and best practices for each of these approaches and conduct error analyses to assess their failure modes. Our findings reveal that pipeline models are still the best, while sequence-to-sequence models are not far behind; GPT models with eight times as many parameters are worse than even sequence-to-sequence models and lose to pipeline models by over 10 F1 points. Partial matches and discontinuous entities caused many NER errors contributing to lower overall E2E performances. We also verify these findings on a second E2ERE dataset for chemical-protein interactions. Although generative LM-based methods are more suitable for zero-shot settings, when training data is available, our results show that it is better to work with more conventional models trained and tailored for E2ERE. More innovative methods are needed to marry the best of the both worlds from smaller encoder-decoder pipeline models and the larger GPT models to improve E2ERE. As of now, we see that well designed pipeline models offer substantial performance gains at a lower cost and carbon footprint for E2ERE. Our contribution is also the first to conduct E2ERE for the RareDis dataset.

End-to-End Models for Chemical-Protein Interaction Extraction: Better Tokenization and Span-Based Pipeline Strategies

End-to-end relation extraction (E2ERE) is an important task in information extraction, more so for biomedicine as scientific literature continues to grow exponentially. E2ERE typically involves identifying entities (or named entity recognition (NER)) and associated relations, while most RE tasks simply assume that the entities are provided upfront and end up performing relation classification. E2ERE is inherently more difficult than RE alone given the potential snowball effect of errors from NER leading to more errors in RE. A complex dataset in biomedical E2ERE is the ChemProt dataset (BioCreative VI, 2017) that identifies relations between chemical compounds and genes/proteins in scientific literature. ChemProt is included in all recent biomedical natural language processing benchmarks including BLUE, BLURB, and BigBio. However, its treatment in these benchmarks and in other separate efforts is typically not end-to-end, with few exceptions. In this effort, we employ a span-based pipeline approach to produce a new state-of-the-art E2ERE performance on the ChemProt dataset, resulting in $> 4\%$ improvement in F1-score over the prior best effort. Our results indicate that a straightforward fine-grained tokenization scheme helps span-based approaches excel in E2ERE, especially with regards to handling complex named entities. Our error analysis also identifies a few key failure modes in E2ERE for ChemProt.