When Large Language Models Fail in Healthcare: Evaluating Sensitivity to Prompt Variations

Large Language Models (LLMs) are increasingly used in healthcare for tasks such as clinical question answering, diagnosis support, and report summarization. Despite their promise, these models remain highly sensitive to subtle prompt perturbations, both lexical and syntactic, posing serious risks in safety-critical clinical applications. In this study, we conduct a systematic sensitivity analysis to evaluate the robustness of both general-purpose (e.g., GPT-3.5, Llama3) and medical-specific LLMs (e.g., ClinicalBERT, BioLlama3, BioBERT) using the MedMCQA benchmark. We categorize perturbations into natural and adversarial types and examine their effect on model consistency, accuracy, and reliability in clinical reasoning tasks. Our findings reveal that medical LLMs are not intrinsically safe. Even minor variations in phrasing can alter clinical advice, and targeted adversarial prompts can provoke harmful outputs. In high-stakes settings like healthcare, such unpredictability is unacceptable-models that change diagnoses due to reworded inputs or hallucinate medications when slightly rephrased cannot be reliably trusted by clinicians. While models tend to show resilience to simple lexical substitutions or paraphrasing, they often break down under syntactic reordering or misleading contextual cues. This fragility is evident across both general-purpose and domain-specific LLMs. Notably, adversarial manipulations can lead to clinically dangerous outputs, such as recommending incorrect dosages or omitting critical findings.

Same Patient, Different Words, Different Diagnosis? Evaluating Semantic Stability in Clinical LLMs

Large Language Models (LLMs) are increasingly used in clinical applications. However, their behavior remains highly sensitive to subtle linguistic variations, such as rephrasing or syntactic variation. This sensitivity poses risks in safety-critical healthcare settings, where semantically equivalent inputs should produce consistent predictions. However, a key challenge is to ensure that prompt variations truly preserve clinical meaning, as embedding-based similarity metrics often fail to capture distinctions involving negation, temporality, or severity. To address this limitation, we propose a semantic verification framework based on Natural Language Inference (NLI) to filter meaning-preserving prompt variations, which are further refined using an LLM-as-a-judge and audited by a clinical expert. In addition, we introduce three metrics to quantify model sensitivity: MeaningPreserving Variation Sensitivity (MVS), confidence variation (ΔC), and Worst-Case Instability (WCI). We evaluate 16 open-source general-purpose (GP) and medical LLMs within the same model families and parameter scales, using reformulated prompts derived from the DiagnosisQA and MedQA datasets. Our results demonstrate that robustness differences between domain-specific (DS) models are mixed and highly model-dependent, i.e., domain specialization does not consistently improve or reduce robustness to meaning-preserving prompt reformulations. Several DS models rank among the most robust (when compared with GP counterparts), and strong GP baselines remain competitive as well.

Open Foundation Models in Healthcare: Challenges, Paradoxes, and Opportunities with GenAI Driven Personalized Prescription

In response to the success of proprietary Large Language Models (LLMs) such as OpenAI's GPT-4, there is a growing interest in developing open, non-proprietary LLMs and AI foundation models (AIFMs) for transparent use in academic, scientific, and non-commercial applications. Despite their inability to match the refined functionalities of their proprietary counterparts, open models hold immense potential to revolutionize healthcare applications. In this paper, we examine the prospects of open-source LLMs and AIFMs for developing healthcare applications and make two key contributions. Firstly, we present a comprehensive survey of the current state-of-the-art open-source healthcare LLMs and AIFMs and introduce a taxonomy of these open AIFMs, categorizing their utility across various healthcare tasks. Secondly, to evaluate the general-purpose applications of open LLMs in healthcare, we present a case study on personalized prescriptions. This task is particularly significant due to its critical role in delivering tailored, patient-specific medications that can greatly improve treatment outcomes. In addition, we compare the performance of open-source models with proprietary models in settings with and without Retrieval-Augmented Generation (RAG). Our findings suggest that, although less refined, open LLMs can achieve performance comparable to proprietary models when paired with grounding techniques such as RAG. Furthermore, to highlight the clinical significance of LLMs-empowered personalized prescriptions, we perform subjective assessment through an expert clinician. We also elaborate on ethical considerations and potential risks associated with the misuse of powerful LLMs and AIFMs, highlighting the need for a cautious and responsible implementation in healthcare.