Multi-Agent Retrieval-Augmented Causality Assessment (MARCA) of Individual Case Safety Reports in Pharmacovigilance

Background: Growing individual case safety report (ICSR) volumes have intensified demand for scalable automated causality assessment. Large Language Models (LLMs) show promise, yet performance on clinically demanding tasks remains suboptimal and inference-time hyperparameter optimization has not been investigated. Objective: To develop a Gaussian Process (GP)-compatible optimization objective and investigate whether temperature optimization improves LLM-expert agreement on Naranjo causality assessment of FAERS ICSRs. Methods: Expert causality assessments were performed on 723 stratified FAERS cases. OpenAI's GPT-5.2 was evaluated using chain-of-thought (CoT) prompting. Four composite metrics were developed: Weighted Cosine Similarity (WCS), Information-Weighted Agreement Score (IWAS), Entropy-Weighted Agreement and Cosine Similarity Score (EWACS), and Consensus-Weighted Cosine Similarity (CWCS) and Bayesian optimization using a GP surrogate with Probability of Improvement (PoI) acquisition was applied across temperature [0, 2]. Results: GPT-5.2 outperformed prior biomedical LLMs at baseline (T = 0), achieving 74.1% agreement on question 5 and 65.4% on question 10 of Naranjo algorithm. Entropy analysis identified these as the sole informative optimization targets. Temperature showed no systematic population-level effect (\b{eta} = 0.002, p = 0.959). EWACS-guided Bayesian optimization improved causality classification agreement from 45.0% to 72.0% (+27 pp), with the largest gain in Doubtful cases (+42.9 pp). Conclusion: EWACS was identified as the optimal GP-compatible metric. The absence of a universal temperature optimum indicates LLM performance is driven primarily by ICSR content, yet case-specific temperature selection produced meaningful improvements, supporting temperature optimization for LLM-assisted pharmacovigilance.

Two clinical AI systems can score nearly identically on coverage-based rubrics yet behave radically differently when their patient inputs change: one updates its recommendations to match the new clinical signal, while the other produces the same output regardless. We introduce the Causal Sensitivity Score (CSS), a pre-registered interventional metric that mutates oncology tumor-board cases along five clinically meaningful dimensions - biomarker flips, prior-treatment failures, biomarker removals, surgery-status changes, and stage perturbations - and scores whether each model updates its recommendations in the pre-registered correct direction using a {0, 0.5, 1.0} scale. Benchmarked against the Consensus Match Score (CMS), a coverage-based weighted recall metric, six frontier models from three labs evaluated in single-shot inference across 224 cases rank in nearly opposite orders: all six models change rank, the CMS-worst model becomes CSS-best, and one upper-mid CMS model ranks last on CSS. We further surface a universal safety blind spot: every frontier model fails on surgery-status interventions (at most 17.2% CSS on Family D), a finding CMS does not expose. The metric also transfers to tool-using agents: in a ReAct-style experiment, tool use improves CSS for five of six models (+2.5 to +20.3 percentage points), yet the lowest-CSS model retrieves the same chart sections and still fails to update its recommendations - revealing a structural responsiveness deficit visible only under counterfactual evaluation. Cross-judge replication and three-rater medical-professional validation confirm the aggregate findings. Interventional pre-registered metrics like CSS complement coverage-based evaluation for clinical AI agents: they capture responsiveness that coverage metrics miss and offer a candidate dense reward signal for future agentic RL systems.

Agentic retrieval-augmented generation (RAG) interleaves retrieval, reasoning, and answer generation across multiple hops. A retrieval error at hop 1 can surface only as a wrong answer at hop 3, while later retrieval can also repair the trajectory. This paper introduces AgenticRAG-FP, an interventional benchmark for causal failure attribution in agentic RAG. The benchmark injects a certified fault at a specified hop, re-executes the downstream trajectory, and evaluates diagnosers against the known intervention. Its central question is whether a post-hoc trace still identifies the injected hop after the suffix changes. In the completed strict dense Claude Haiku 4.5 sweep on 80 three-hop MuSiQue questions, coverage-based diagnosis is 0.91 at hop 1 and 0.00 at hops 2 and 3 (n=43,36,21 failed trajectories). A smaller content-corruption study changes an answer-bearing or bridge fact in topically intact evidence. At depth 2, where 18 failed cases remain after filtering, coverage-based diagnosis is 0.00 and a frozen-hop counterfactual probe is 0.67 in an exploratory pooled comparison. Depth-3 content estimates are descriptive only because they contain three failed cases. These results make propagation depth an explicit evaluation axis for diagnosing agentic RAG failures while distinguishing broad evidence of post-hoc signal loss from small-sample method comparisons.