Medication Recommendation Framework

Large language model (LLM) agents can support medication review between clinical visits, but safe choices for older adults with multimorbidity depend on conditions, medications, and geriatric risks that users may omit. We introduce ATLAS, a coupled graph--policy distillation framework for patient-adaptive medication safety. ATLAS structures guideline evidence as a medication-safety graph. Targeted questions update the patient state and distill relevant relations into a patient-specific medication conflict graph (PMCG). A risk-first multi-agent policy uses the PMCG to screen contraindications, assess cautions and monitoring needs, identify safer alternatives, and verify the final medication plan. We also introduce GeriMedBench, an interactive benchmark that tests safety-critical information acquisition and evidence-based decision revision. Across a European non-interactive multimorbidity benchmark, an Asian interactive multimorbidity benchmark, and an Asian non-interactive cross-guideline benchmark, ATLAS achieves the strongest complete-decision performance among the compared systems. On the European non-interactive multimorbidity benchmark, it exceeds the strongest proprietary LLM baseline by 53.73 points in Strict Success Rate and 14.63 points in overall safety reasoning score (OSRS), with no unsafe recommendations under the automated evaluator. A blinded clinician evaluation gives ATLAS higher mean ratings across all five criteria and flags potentially unsafe recommendations in one ATLAS case and two Gemini cases.

Applying a valid medication-safety rule when its patient-specific conditions are not met can produce an incorrect decision. Existing medical evaluations largely use isolated and fixed scenarios. A model may therefore answer correctly by recalling a drug-risk association without showing that it used patient information to decide whether the rule applies. To address this gap, we introduce MedPIC-Bench, a benchmark of source-verifiable recommendations and expert-validated questions for patient-specific medication-safety reasoning. It combines guideline-following questions with paired counterfactual questions in which a controlled change in patient information changes whether a rule applies. The benchmark contains 467 questions annotated along six clinical and reasoning dimensions. Across 28 medical-specific, general, and proprietary LLMs, every model performs worse on counterfactual questions, with mean accuracy falling from 63.6% to 45.1%. Models perform well when an explicit patient attribute directly signals a familiar contraindication, but struggle when patient information must narrow or withdraw a safety warning. Model rationales often acknowledge the changed patient information, yet the final answers retain the previous safety judgment. This vulnerability persists among medical-specific LLMs, whose average CF performance trails that of general LLMs. MedPIC-Bench therefore makes conditional rule application measurable and highlights the limitations of static medication-safety accuracy for assessing patient-specific reliability.

Clinic notes and structured electronic health record (EHR) medication history often contain different medication information. Same-visit disagreement between these sources may result from note-side normalization errors, differences in terminology or timing, or actual differences in documentation. We developed a note-grounded approach that uses large language model (LLM) assisted reference construction, targeted and random human review, deterministic medication normalization, and semantic and temporal comparisons with structured medication history. We evaluated all normalization results on a patient-level held-out test set to limit adaptation to the study cohort. On 5,403 held-out mention rows, exact canonical agreement improved from 0.7226 with surface-exact matching to 0.8429 after lexical cleanup and curated alias mapping. In a random audit of previously unaudited rows, canonical-label agreement was 0.9210 among evaluable valid medication mentions, whereas treatment-action attribution was lower at 0.5326. In the full-cohort characterization analysis, only 16.44% of note-derived rows had same-visit exact overlap with structured medication history, but 55.17% had same-visit semantic overlap, 90.34% had same-visit or +/-30-day overlap, and only 3.97% remained in the strict no-structured-overlap bucket under broad project-level mapping. An ontology-backed sensitivity analysis further showed that held-out strict Observational Medical Outcomes Partnership (OMOP)-backed no-overlap fell from 43.99% to 36.68% after a development-derived alias supplement. These results show that note-to-structured-medication mismatch can arise from normalization errors, differences in terminology, and differences in documentation timing.

Medication recommendation from electronic health records must balance predictive accuracy against the risk of adverse drug-drug interactions (DDIs) under polypharmacy. Existing safety-aware recommenders operate at one of two granularities: the drug code, which treats each medication as an indivisible token, or the molecular substructure, which is finer than pharmacological interaction knowledge is actually organized. We argue that the active ingredient is the missing granularity, and introduce GRAIN, a medication recommendation framework built around it. GRAIN encodes longitudinal patient trajectories (diagnoses, procedures, past medications) with a selective state space backbone that handles long, irregular visit sequences in linear time. On top of it we introduce a joint objective unifying three knowledge sources aligned to a common medication vocabulary: a drug-level DDI graph, an ingredient-level DDI graph obtained by normalizing medication codes to active ingredients via RxNorm, and an EHR-derived co-prescription graph. A proportional controller adapts the accuracy-safety trade-off to the observed validation DDI rate rather than fixing it a priori. Under strictly matched settings -- identical preprocessing, cohort, vocabulary, split, and evaluation code -- GRAIN improves over a re-implemented MambaHealth baseline on MIMIC-IV across all standard multi-label metrics (Jaccard 0.4488 to 0.4983, PRAUC 0.6911 to 0.7485, F1 0.5989 to 0.6453) while reducing the drug-level DDI rate from 0.1875 to 0.0948. We further define an ingredient-level DDI rate, a safety measure invisible to drug-code-level evaluation. The results indicate that ingredient-level normalization recovers predictive signal erased by code-level aggregation, and that it is complementary to, rather than in competition with, accurate sequence modeling.

AI-based medication recommendation systems have attracted substantial attention due to their potential to enhance patient safety and therapeutic outcomes. Despite the clinical importance of accurately recommending rarely prescribed medications (rare-meds), we observe that most existing methods show significantly lower predictive performance for rare-meds. We attribute this issue to two intrinsic limitations: (a) the inherent scarcity of data for rare-meds and (b) limited consideration of co-recommended medications. To address these limitations, we propose GenRxR, a novel framework based on large language models (LLMs). GenRxR leverages the medical knowledge and clinical reasoning capability of LLMs to generate counterfactual medical data, mitigating the data scarcity issue for rare-meds. It also integrates an LLM into the medication recommendation process to model relationships among co-recommended medications. To further enhance the clinical reasoning, we introduce an instruction tuning step that aligns the LLM's capability with the recommendation task, enabling better handling of clinical context, including rare-meds cases. In our experiments, we show that GenRxR outperforms 14 (including 5 LLM-based) baselines in most cases. Specifically, it achieves up to 30.9% higher predictive performance for rare-meds than the strongest baseline.

Translating complex biomedical data into patient-friendly narratives is central to modern biomedical informatics. This study presents a comparative analysis of training small language models (SLMs) in specialized biomedical datato-text generation tasks. We explore widely adopted post-training methods including supervised fine-tuning (SFT), direct preference optimization (DPO), odds ratio preference optimization (ORPO), and group relative policy optimization (GRPO) with Qwen-based SLMs on a medicine package leaflets dataset. To assess cross-dataset generalizability, we also curated drug label data from openFDA. We evaluate models using both standard lexical overlap metrics like ROUGE as well as semantic similarity measures. Across our experiments, the results show that (1) the aligned SLMs outperform proprietary models like GPT-5; (2) ORPO outperforms the SFTbaselines; (3) GRPO yields the most robust cross-dataset performance among the alignment methods tested as well as GPT-5.

Specialist epilepsy expertise is scarce in resource-constrained settings, making LLM-based decision support attractive for frontline clinicians managing longitudinal treatment. Such systems must adapt to local prescribing practice and know when to defer. We study this problem in Ugandan pediatric epilepsy care, predicting anti-seizure medication regimens from longitudinal unstructured clinic notes. Standard prompting achieves non-trivial agreement with physician prescriptions, but neurologist review shows that many errors reflect distribution-miscalibrated prescribing defaults rather than failures to parse the local record. We introduce MANANA, a non-parametric prompt-learning framework that learns local prescribing guidance from a small patient-level training set. MANANA converts observed prescription errors into auditable prompt memories, instantiated in single-agent and multi-agent variants, and improves over classical ML models, direct LLM prompting, and prompt-optimization baselines across two independently collected Ugandan cohorts. We further propose Bayesian prompt averaging, which converts the learned prompt trajectory into prescription likelihoods and an uncertainty-based deferral signal. On the independently collected held-out cohort, this improves visit-level top-3 prescription accuracy by 4-8 percentage points over prompt-optimization baselines and enables selective prediction: the system can auto-handle the most confident half of cases at 95% precision, or the most confident quarter at 99% precision, while deferring lower-confidence cases for specialist review.

Patients increasingly seek medication information online, yet safety knowledge for psychiatric drugs is split between regulatory adverse-event records, which are authoritative but abstract, and patient narratives, which are experience-near but unvalidated. Integrating them without conflating evidence and anecdote is especially consequential in psychiatry, where poorly contextualised information can amplify fear, nocebo responses, and non-adherence. Here we develop a provenance-aware, knowledge-graph-based multi-agent framework unifying 466,525 Reddit posts, 60,782 WebMD reviews, and twenty years of U.S. FDA Adverse Event Reporting System records for nine antidepressants. A large-language-model entity-recognition pipeline benchmarked against physician annotations reached highest F1 scores of 0.969 for medications and 0.973 for conditions. The two community platforms were far more concordant with each other (overlap up to a Jaccard similarity of 0.905) than with regulatory reports, indicating that patient-generated data form a partly independent safety signal. For sertraline, many adverse events appeared in community sources hundreds of days before the corresponding FDA date. A Neo4j knowledge graph grounded in ATC-N, ICD-10, and MedDRA vocabularies preserves provenance, keeping every claim traceable and regulatory facts distinct from patient experience. These results establish source-aware integration as a route to more auditable psychiatric medication information, with usefulness and patient benefit to be tested prospectively.

Autonomous AI systems are transitioning from advisory to autonomous roles for medication prescriptions. Recent United States bill H.R. 238 and Utah's prescription-renewal pilot both authorize AI to prescribe medications in an agentic capacity. While some regulatory guidelines suggest aggregate model performance metrics for clearance, they do not require i) calibrated per-prediction confidence for action-gated thresholds, ii) differentiated communication of uncertainty arising from model ignorance (epistemic) versus genuine clinical ambiguity (aleatoric), and iii) inferential transparency at the moment of decision that allows for liability allocation. Here, we present a regulatory and technical argument (tested with a survey of 136 U.S. prescribing clinicians) positioning these as minimum architectural requirements for safe autonomous prescribing. Our results suggest prescribing clinicians i) would not permit autonomous prescribing without a calibrated confidence-based escalation mechanism, ii) preferred a competing-options summary when uncertainty was aleatoric but shifted to abstention when uncertainty was epistemic, and iii) were only willing to accept additional liability when inferential transparency enabled a substantive judgment under acknowledged uncertainty. These findings indicate our recommended architectural features would encourage higher rates of clinician adoption, largely through collapsing much of what "autonomy" conventionally means. A system meeting these requirements would function less as an autonomous agent and more as a heavily supervised decision-support tool. As legislation and state pilots proceed, our technical argument backed by clinician perspectives provides opportunities for regulation to constrain the degree of autonomy ethically granted to AI in prescribing while aligning liability with the institutional actors who control system design and deployment.

Large Language Models have the potential to expand and improve the access to clinical information by enabling new ways of interacting with medical knowledge in natural language. However, their deployment in medical question-answering settings is safety-critical, since misaligned outputs can lead to severe patient harm. AI control is an emerging approach that introduces external safeguards to mitigate unsafe behaviours in misaligned systems and has been shown to be effective in domains such as code generation. However, its applicability and effectiveness in medical settings have not been systematically studied. In this work, we present a pipeline for evaluating AI control protocols to mitigate medication-related harm. To this end, we introduce DrugBench, an AI control evaluation benchmark which combines 3,671 multi-turn medical conversations from HealthBench with drug information from official FDA labels, covering four categories of medication-related harm: drug interactions, contraindications, dosing constraints, and patient action restrictions. Furthermore, inspired by the medical domain, we argue that safety should account for the severity of unsafe outputs, not just their probability. Under this revised definition, we show that existing control protocols can be subverted and propose severity-based monitoring to address this limitation.

Large language models (LLMs) are increasingly used for everyday health questions, including whether a user can safely take another dose of an over-the-counter (OTC) medication. Yet this common safety-relevant setting remains underexplored in existing medical QA evaluations, where correct answers require tracking dose timing, computing rolling 24-hour intake, following product-label constraints, and handling incomplete medication histories. We introduce DOSEBENCH, a focused benchmark of 81 curated OTC dosing scenarios focused on adult acetaminophen and ibuprofen use, with manually annotated gold references. We evaluate four LLMs across repeated runs using metrics for decision correctness, consistency, explanation verifiability, failure types, and confidence-related signals, resulting in 1,620 model responses. Our results show that models frequently struggle with rolling-window reasoning and ambiguity-sensitive cases and that stable or confident-looking responses can still violate dosing constraints. These findings suggest that OTC dosing QA provides a narrow yet practical testbed for evaluating temporal reasoning, constraint following, and safety-relevant uncertainty handling in medical QA.

Drug-information question answering is a high-stakes setting where hallucinated facts can mislead clinical decision-making and the provenance of each cited fact matters as much as the fact itself. We present DrugClaw, a multi-agent retrieval-augmented system that queries a registry of drug and pharmacovigilance skills via a reflection-driven state-machine workflow and returns answers grounded in primary regulatory or peer-reviewed records. We also contribute DrugAudit, a 3,772-item authority-aware benchmark with an evaluation panel that scores upstream-of-gold source match, token-level semantic snippet overlap, and citation faithfulness under a dual-judge LLM-as-judge protocol with inter-judge kappa = 0.88 (almost-perfect). Across DrugAudit plus drug-related subsets of MedQA (751) and PubMedQA (512), DrugClaw is top-1 on every column of the headline table: composite Evidence Index under both judges, judge-mediated answer correctness, primary-source rate (0.918, +10.1 pp over next-best), faithfulness (0.887, +5.9 pp), MedQA (0.920), and PubMedQA (0.693).

Financial exploitation is a growing concern for people with Alzheimer's disease, especially during periods of reduced cognitive stability. Conventional fraud detection systems usually rely on financial behavior alone and ignore clinically relevant factors that may alter vulnerability. This paper proposes a medication-aware framework that synchronizes medication adherence with transaction-level monitoring to improve detection of cognitively risky financial events. A hybrid simulation dataset was constructed for 180 patients across 45 days, producing 8,100 medication records and 30,855 transactions. The framework evaluates amount anomaly, vendor novelty, transaction frequency, time deviation, and medication adherence through financial-only, additive medication-aware, and interaction-aware logistic models. Results show that the financial-only baseline obtained the highest global F1-score of 0.5000, but the interaction-aware model improved recall during medication-induced vulnerability windows from 0.7442 to 0.9070 and achieved the highest average precision for ranked high-risk cases. The findings suggest that medication adherence is most useful as a contextual modifier of financial risk rather than as an isolated predictor.

Medication recommendation predicts medications for patient visits, but existing methods still face two key challenges. At the model level, traditional drug recommendation methods only predict structured drug codes with limited evidence grounding, while LLM agents can use richer clinical context but may lack safety verification and traceability. At the task level, existing benchmarks often use broad medication categories, which ignore subgroup-level safety differences and can lead to risk overestimation. We introduce the first fine-grained medication recommendation setting based on fourth-level ATC code generation. We propose Safe Prescription Agent (SafeRx-Agent), a knowledge-grounded multi-agent framework that uses patient context, external clinical knowledge, and safety verification to recommend traceable medication sets. Experimental results on MIMIC-III and MIMIC-IV datasets show that SafeRx-Agent improves fine-grained medication prediction accuracy while controlling drug interactions, contraindications, and medication set size.

When a multi-module LLM agent fails, the module most responsible for the failure is not necessarily the best place to intervene. We demonstrate this Diagnostic Paradox empirically: causal analysis consistently identifies the routing module -- which selects which tool to call next -- as the primary bottleneck across three independent agent families. Yet injecting prompt-level correction examples into this module consistently degrades performance, sometimes severely. Patching an upstream query-rewriting module instead reliably improves outcomes. The effect holds with statistical significance on two agent families and directional consistency on a third; alternative repair strategies at the routing module (instruction rewriting, model upgrade) are neutral, confirming that the harm is specific to correction-injection patching. We explain this asymmetry through the Linguistic Contract hypothesis: each downstream module implicitly adapts to its upstream's characteristic error distribution, so correcting the bottleneck breaks this implicit alignment in a way that upstream corrections do not. We operationalize this via a per-agent co-adaptation measure, derived from diagnosis alone, and show it is consistently associated with patching harm across agent families: higher co-adaptation co-occurs with harm, lower with safety. This trend holds across all three agent families, providing preliminary support for the hypothesis beyond a single-agent observation.

Inpatient medication recommendation requires clinicians to repeatedly select specific medications, doses, and routes as a patient's condition evolves. Existing benchmarks formulate this task as admission-level prediction over coarse drug codes with multi-hot diagnostic and procedure code inputs, failing to capture the per-timepoint, information-rich nature of real prescribing. We propose RxEval, a prescription-level benchmark that evaluates LLM prescribing capability by multiple-choice questions: each question presents a detailed patient profile and time-ordered clinical trajectory, requiring selection of specific medication-dose-route triples from real prescriptions and patient-specific distractors generated via reasoning-chain perturbation. RxEval comprises 1,547 questions spanning 584 patients, 18 diagnostic categories, and 969 unique medications. Evaluation of 16 LLMs shows that RxEval is both challenging and discriminative: F1 ranges from 45.18 to 77.10 across models, and the best Exact Match is only 46.10%. Error analysis reveals that even frontier models may overlook stated patient information and fail to derive clinical conclusions.

Natural-language software requirements are often ambiguous, inconsistent, and underspecified; in safety-critical domains, these defects propagate into formal models that verify the wrong specification and into implementations that ship unsafe behavior. We show that large language models, equipped with an SMT solver, can audit such requirements: translating them into formal logic, detecting ambiguity through stochastic variation in the generated formalization, and exposing inconsistency, vacuousness, and safety violations through solver queries on the resulting specification. We present VERIMED, a neurosymbolic pipeline that operationalizes this idea for medical-device software requirements, and report two findings. First, stochastic variation across independent formalizations is a signal of ambiguity: requirements that admit multiple plausible interpretations produce SMT-inequivalent formalizations, and bidirectional SMT equivalence checking turns this disagreement into a solver-checkable test. Second, the usefulness of symbolic feedback depends on its granularity: in counterexample-guided repair on a hemodialysis question-answering benchmark, concrete SMT counterexamples raise verified accuracy from 55.4% to 98.5%. Over an extensive experimental evaluation on open-source hemodialysis safety requirements, we show that the LLM-based approach in VERIMED successfully reduces ambiguity-sensitive requirements and enables rigorous auditing of software requirements through SMT-based queries.

The objective of this paper is to understand what characteristics and features of clinical data influence physician's decision about ordering laboratory tests or prescribing medications the most. We conduct our analysis on data and decisions extracted from electronic health records of 4486 post-surgical cardiac patients. The summary statistics for 335 different lab order decisions and 407 medication decisions are reported. We show that in many cases, physician's lab-order and medication decisions can be well predicted from a small subset of all features.

Progression to dialysis or end-stage renal disease is a rare but clinically important outcome. Clinicians need evidence on how medication exposures influence downstream risk. We constructed a fixed-window EHR cohort (90-day observation, 730-day prediction; N=81401; dialysis/ESRD prevalence: 1.1%) and modeled sequences of diagnoses, procedures, and medications with kidney laboratory trends (creatinine, BUN, eGFR). A transformer-based causal multi-head model was trained to estimate drug- and ingredient-level average treatment effects (ATEs) using counterfactual exposure removal and insertion under a full medication history setup. On test set, predictive performance reached an AUC of 0.694 and PR-AUC of 0.094. At the selected decision threshold (0.883), the model achieved an F1 score of 0.201 with a Brier score of 0.018. Post-hoc causal analyses of lab changes (eGFR, creatinine, BUN) using IPTW, AIPW, naive, and covariate-adjusted OLS methods assessed clinical directionality. Results showed partial protective-direction support for ACE/ARB exposures and worsening-direction signals for loop diuretics.

Medication reconciliation at clinical handoffs is a high-stakes, error-prone process. Large language models are increasingly proposed to assist with this task using FHIR-structured patient records, but a fundamental and largely unstudied variable is how the FHIR data is serialised before being passed to the model. We present the first systematic comparison of four FHIR serialisation strategies (Raw JSON, Markdown Table, Clinical Narrative, and Chronological Timeline) across five open-weight models (Phi-3.5-mini, Mistral-7B, BioMistral-7B, Llama-3.1-8B, Llama-3.3-70B) on a controlled benchmark of 200 synthetic patients, totalling 4,000 inference runs. We find that serialisation strategy has a large, statistically significant effect on performance for models up to 8B parameters: Clinical Narrative outperforms Raw JSON by up to 19 F1 points for Mistral-7B (r = 0.617, p < 10^{-10}). This advantage reverses at 70B, where Raw JSON achieves the best mean F1 of 0.9956. In all 20 model and strategy combinations, mean precision exceeds mean recall: omission is the dominant failure mode, with models more often missing an active medication than fabricating one, which changes how clinical safety auditing priorities should be set. Smaller models plateau at roughly 7-10 concurrent active medications, leaving polypharmacy patients, the patients most at risk from reconciliation errors, systematically underserved. BioMistral-7B, a domain-pretrained model without instruction tuning, produces zero usable output in all conditions, showing that domain pretraining alone is not sufficient for structured extraction. These results offer practical, evidence-based format recommendations for clinical LLM deployment: Clinical Narrative for models up to 8B, Raw JSON for 70B and above. The complete pipeline is reproducible on open-source tools running on an AWS g6e.xlarge instance (NVIDIA L40S, 48 GB VRAM).

Drug recommendation requires a deep understanding of individual patient context, especially for complex conditions like Parkinson's disease. While LLMs possess broad medical knowledge, they fail to capture the subtle nuances of actual prescribing patterns. Existing RAG methods also struggle with these complexities because guideline-based retrieval remains too generic and similar-patient retrieval often replicates majority patterns without accounting for the unique clinical nuances of individual patients. To bridge this gap, we propose PACE-RAG (Patient-Aware Contextual and Evidence-Constrained RAG). Rather than directly copying frequent medications from retrieved patients, PACE-RAG personalizes recommendations by first extracting patient-specific clinical features, retrieving cases around these features, and then refining the final prescription using the patient's current symptoms, active medication history, and focus-specific prescribing tendencies. By analyzing treatment patterns tailored to specific clinical features, PACE-RAG generates patient-specific medication recommendations along with an explainable clinical summary. PACE-RAG achieved the strongest performance among the evaluated inference-only LLM-based methods, reaching F1 scores of 80.84% and 47.22% on the Parkinson's disease and MIMIC-IV cohorts, respectively. Our code is available at: https://github.com/ChaeYoungHuh/PACE-RAG.