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ConceptM$^3$oE: Concept-Guided Multimodal Mixture of Experts for Interpretable Computational Pathology

arXiv:2605.24399v1 Announce Type: new Abstract: Healthcare models are transitioning from unimodal prediction toward multimodal reasoning over heterogeneous diagnostic inputs. In computational pathology, for complex tumor subtypes where morphology alone can be challenging to distinguish, pathology reports and molecular measurements may provide additional diagnostic evidence alongside whole-slide images, yet existing models often fail to clarify how diverse signals assemble into recognizable diagnostic concepts. We propose ConceptM$^3$oE (Concept Multimodal MoE), which embeds concept formation directly within interaction-aware mixture-of-experts (MoE) pathways. The architecture decomposes evidence into modality-specific, redundant, and synergistic experts, which are then projected into structured concept bottlenecks mapping latent features to a hierarchy of morphology and biomarker concepts. To prevent the information loss typical of interpretable bottlenecks, we utilize residual pathways within each expert to allow task-relevant signals to flow both through the concepts and directly to the final task prediction, so that high performance is maintained alongside interpretability. Across an institutional pediatric brain tumor cohort and a public glioma cohort, the framework delivers competitive performance to unconstrained models while producing reasoning traces validated by an independent neuropathologist. In data-limited regimes, ConceptM$^3$oE improves limited-data performance, increasing macro-F1 from 56.41% to 66.70% at small training sizes compared to non-concept-informed baselines, while also showing faster training convergence consistent with the regularizing effect of concept learning. This work offers a scalable path toward high-performance medical AI that is inherently verifiable and better aligned with the complex decision-making of clinical practice.

SeqRoute: Global Budget-Aware Sequential LLM Routing via Offline Reinforcement Learning

arXiv:2605.25424v1 Announce Type: cross Abstract: Existing LLM routing frameworks treat queries as independent events, neglecting the sequential nature of real-world user sessions constrained by global computational budgets. This mismatch inevitably leads to budget bankruptcy: myopic routing policies exhaust resources on early interactions, forcing subsequent and often more complex queries onto inadequate models. We introduce SeqRoute, a framework that formulates multi-turn routing as a finite-horizon Markov Decision Process and solves it via offline reinforcement learning. By incorporating the remaining budget into the state space and training with Conservative Q-Learning (CQL), SeqRoute learns delayed gratification to strategically preserve resources for high-stakes turns later in the session. To overcome data starvation, we propose Hindsight Budget Relabeling (HBR). This technique retrospectively simulates historical trajectories under diverse hypothetical budgets, expanding 10,000 raw sessions into 2.38 million transitions enriched with critical bankruptcy signals. At deployment, a dynamic $\lambda$-sweep mechanism enables zero-shot navigation of the cost-quality Pareto frontier without retraining. Extensive evaluations demonstrate that SeqRoute reduces operational costs by 6.0-73.5% while maintaining or improving quality, and suppresses bankruptcy rates to under 1%, strictly dominating behavior cloning, budget-aware heuristics, and static baselines across the entire Pareto frontier.

Deciphering lung adenocarcinoma heterogeneity: a multi-omics approach reveals nuclear division fibroblasts as prognosticators and therapeutic targets

J Transl Med. 2026 Mar 20. doi: 10.1186/s12967-026-08022-3. Online ahead of print.

ABSTRACT

BACKGROUND: Lung adenocarcinoma (LUAD) is a predominant contributor to cancer‑related mortality globally. Lung‑associated fibroblasts (LAFs) are intricately linked to tumorigenesis and the tumor microenvironment (TME), but their heterogeneity and prognostic relevance in LUAD remain incompletely understood. This study aimed to systematically characterize LAF subsets across the spectrum of pulmonary disease, identify LAF subpopulations associated with LUAD prognosis, and construct a robust LAF‑based prognostic signature.

METHODS: We employed a multi-omics approach, leveraging bulk RNA data of 2719 patients from 19 LUAD cohorts, single-cell RNA (scRNA) sequencing data of 368,904 cells from 93 samples, and spatial transcriptomics data of 15,673 spots from 6 samples to characterize the landscape of LAFs across various stages of pulmonary disease. We employed multiple advanced machine learning algorithms to construct and validate a robust nuclear division LAFs (nLAFs) risk score (nLRS) prediction model.

RESULTS: We observed a dynamic and gradual increase in the proportion of LAFs during the progression of LUAD. Throughout this process, we identified nine LAFs subtypes and found nLAFs are significantly associated with the prognosis of LUAD. Utilizing 100 machine learning algorithm combinations and integrating nLAFs marker genes, we developed a five gene based nLRS model, which demonstrated superior performance than other 49 published models in predicting clinical outcomes for LUAD. Additionally, we observed distinct biological functions and immune cell infiltration in the TME between high and low nLRS groups. Exploratory analysis of pan-cancer immunotherapy cohorts suggested that patients with high nLRS scores may exhibit resistance to immunotherapy in some cancer types, but prospective validation in LUAD-specific cohorts is required. Conversely, high nLRS patients displayed increased sensitivity to chemotherapeutic and targeted therapies in preclinical models.

CONCLUSION: Our study introduces a candidate five-gene signature derived from nLAFs that may serve as a robust prognostic biomarker pending prospective validation, offering insights into personalized therapeutic strategies for LUAD patients.

PMID:41862916 | DOI:10.1186/s12967-026-08022-3

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