Information-seeking failures of large language models in agentic clinical reasoning

Large language models achieve high scores on medical knowledge assessments, yet clinical reasoning requires actively deciding what to investigate under uncertainty. We developed an agentic evaluation framework in hematologic oncology in which models must proactively request clinical data across three sequential rounds before committing to a diagnosis and treatment plan. Across 32 frontier models, the best achieved only 68% overall accuracy. Information utilization, the fraction of available data actually requested, was the strongest predictor of diagnostic accuracy (R = 0.69, P < 0.001), yet utilization collapsed from 57% to 26% in the final round, leaving molecular and cytogenetic data critical for treatment selection unexamined. Reasoning traces scored high on a clinical reasoning rubric (91% above threshold) but decorrelated from accuracy, revealing a gap between locally coherent rationales and globally correct conclusions. Error analysis identified search satisficing, anchoring and premature closure as the dominant failure modes, the same cognitive biases that characterize novice clinicians under dual-process models of diagnostic reasoning. These findings demonstrate that the primary limitation of current models in clinical oncology is not insufficient medical knowledge but a systematic failure of information-seeking under uncertainty.

Routine laboratory trajectories encode the onset of organ-level complications in cancer

Routine laboratory panels drawn during cancer treatment constitute longitudinal physiological recordings of organ function, yet their temporal structure is discarded by single-timepoint prognostic tools. A transformer trained on 2,777,595 laboratory measurements from 3,905 patients with multiple myeloma or ovarian cancer predicted the two-year onset of 162 treatment-associated complications, including therapy-related myelodysplastic syndromes, spanning eight clinical categories, achieving 1.5- to 6.1-fold enrichment above prevalence at the group level. It matched or outperformed non-sequential baselines across grouped endpoints (AUROC gains up to +0.11), demonstrating that longitudinal laboratory trajectories capture evolving complication-specific physiology inaccessible from isolated measurements. Predictions generalised across both cancers, divergence concentrating in disease-specific complications, and biomarker masking recovered signatures consistent with established pathophysiology. External validation on MIMIC-IV and MMRF CoMMpass confirmed transferability across independent healthcare systems (AUROC up to 0.85). Routine oncological laboratory data encode organ deterioration weeks to months before clinical onset, enabling complication-specific surveillance without additional testing infrastructure.

Agentic clinical reasoning over longitudinal myeloma records: a retrospective evaluation against expert consensus

Multiple myeloma is managed through sequential lines of therapy over years to decades, with each decision depending on cumulative disease history distributed across dozens to hundreds of heterogeneous clinical documents. Whether LLM-based systems can synthesise this evidence at a level approaching expert agreement has not been established. A retrospective evaluation was conducted on longitudinal clinical records of 811 myeloma patients treated at a tertiary centre (2001-2026), covering 44,962 documents and 1,334,677 laboratory values, with external validation on MIMIC-IV. An agentic reasoning system was compared against single-pass retrieval-augmented generation (RAG), iterative RAG, and full-context input on 469 patient-question pairs from 48 templates at three complexity levels. Reference labels came from double annotation by four oncologists with senior haematologist adjudication. Iterative RAG and full-context input converged on a shared ceiling (75.4% vs 75.8%, p = 1.00). The agentic system reached 79.6% concordance (95% CI 76.4-82.8), exceeding both baselines (+3.8 and +4.2 pp; p = 0.006 and 0.007). Gains rose with question complexity, reaching +9.4 pp on criteria-based synthesis (p = 0.032), and with record length, reaching +13.5 pp in the top decile (n = 10). The system error rate (12.2%) was comparable to expert disagreement (13.6%), but severity was inverted: 57.8% of system errors were clinically significant versus 18.8% of expert disagreements. Agentic reasoning was the only approach to exceed the shared ceiling, with gains concentrated on the most complex questions and longest records. The greater clinical consequence of residual system errors indicates that prospective evaluation in routine care is required before these findings translate into patient benefit.