Adaptive-CaRe: Adaptive Causal Regularization for Robust Outcome Prediction

Accurate prediction of outcomes is crucial for clinical decision-making and personalized patient care. Supervised machine learning algorithms, which are commonly used for outcome prediction in the medical domain, optimize for predictive accuracy, which can result in models latching onto spurious correlations instead of robust predictors. Causal structure learning methods on the other hand have the potential to provide robust predictors for the target, but can be too conservative because of algorithmic and data assumptions, resulting in loss of diagnostic precision. Therefore, we propose a novel model-agnostic regularization strategy, Adaptive-CaRe, for generalized outcome prediction in the medical domain. Adaptive-CaRe strikes a balance between both predictive value and causal robustness by incorporating a penalty that is proportional to the difference between the estimated statistical contribution and estimated causal contribution of the input features for model predictions. Our experiments on synthetic data establish the efficacy of the proposed Adaptive-CaRe regularizer in finding robust predictors for the target while maintaining competitive predictive accuracy. With experiments on a standard causal benchmark, we provide a blueprint for navigating the trade-off between predictive accuracy and causal robustness by tweaking the regularization strength, $λ$. Validation using real-world dataset confirms that the results translate to practical, real-domain settings. Therefore, Adaptive-CaRe provides a simple yet effective solution to the long-standing trade-off between predictive accuracy and causal robustness in the medical domain. Future work would involve studying alternate causal structure learning frameworks and complex classification models to provide deeper insights at a larger scale.

MoLF: Mixture-of-Latent-Flow for Pan-Cancer Spatial Gene Expression Prediction from Histology

Inferring spatial transcriptomics (ST) from histology enables scalable histogenomic profiling, yet current methods are largely restricted to single-tissue models. This fragmentation fails to leverage biological principles shared across cancer types and hinders application to data-scarce scenarios. While pan-cancer training offers a solution, the resulting heterogeneity challenges monolithic architectures. To bridge this gap, we introduce MoLF (Mixture-of-Latent-Flow), a generative model for pan-cancer histogenomic prediction. MoLF leverages a conditional Flow Matching objective to map noise to the gene latent manifold, parameterized by a Mixture-of-Experts (MoE) velocity field. By dynamically routing inputs to specialized sub-networks, this architecture effectively decouples the optimization of diverse tissue patterns. Our experiments demonstrate that MoLF establishes a new state-of-the-art, consistently outperforming both specialized and foundation model baselines on pan-cancer benchmarks. Furthermore, MoLF exhibits zero-shot generalization to cross-species data, suggesting it captures fundamental, conserved histo-molecular mechanisms.

HistoPrism: Unlocking Functional Pathway Analysis from Pan-Cancer Histology via Gene Expression Prediction

Predicting spatial gene expression from H&E histology offers a scalable and clinically accessible alternative to sequencing, but realizing clinical impact requires models that generalize across cancer types and capture biologically coherent signals. Prior work is often limited to per-cancer settings and variance-based evaluation, leaving functional relevance underexplored. We introduce HistoPrism, an efficient transformer-based architecture for pan-cancer prediction of gene expression from histology. To evaluate biological meaning, we introduce a pathway-level benchmark, shifting assessment from isolated gene-level variance to coherent functional pathways. HistoPrism not only surpasses prior state-of-the-art models on highly variable genes , but also more importantly, achieves substantial gains on pathway-level prediction, demonstrating its ability to recover biologically coherent transcriptomic patterns. With strong pan-cancer generalization and improved efficiency, HistoPrism establishes a new standard for clinically relevant transcriptomic modeling from routinely available histology.