Learning predictive models for combinations of heterogeneous proteomic data sources

Predicting immune biomarkers associated with the tumor immune microenvironment (TIME) is critical for advancing precision oncology, yet existing approaches are largely limited to single image modalities and suffer from insufficient resolution and incomplete utilization of complementary clinical and biological information. Here we introduce MixTIME, a multimodal foundation model that leverages a mixture-of-experts (MoE) architecture to integrate pathology foundation models trained across distinct modalities: image only (UNIv2), image text (CONCHv1.5), and image transcriptomic (STPath) representations for pixel-level and slide-level prediction of multiplex immunofluorescence (mIF) protein expression from hematoxylin and eosin (HE) whole-slide images. MixTIME employs a learnable router to dynamically weight expert contributions and is trained with a distribution- and tendency-aware loss function. Benchmarked on two datasets of different scales, MixTIME achieves state-of-the-art performance across 17 protein markers as measured by correlation metrics. The predicted mIF profiles substantially enhance downstream tasks, including spatial domain identification, survival prediction, and AI-assisted pathology report generation validated by expert pathologists from multiple institutes across the world. Furthermore, MixTIME enables longitudinal tracking of protein expression dynamics across clinical time points and reveals protein gene interaction patterns linked to drug resistance and immune suppression in tumor microenvironments. Collectively, MixTIME provides a scalable framework for multimodal biomarker discovery and clinical translation in computational pathology.

Foundation models (FMs) have emerged as powerful representation extractors for medical data, yet their generalizability to datasets under distribution shift remains underexplored. This work systematically evaluates FM-based representations on a suite of computational pathology tasks across two real-world commercial cohorts, IH-BC and IH-NSCLC, drawn from the licensed in-house (IH) oncology dataset. The analysis focuses on two modalities, whole-slide images and transcriptomic profiles, drawn from the IH multimodal data. We first benchmark unimodal probing performance across five FMs on eight downstream classification tasks, and find that image and omics representations carry complementary predictive signals. Then we investigate whether multimodal fusion can yield additional gains over unimodal baselines by comparing three image-omics fusion strategies built on paired representations. The trustworthiness of selected unimodal and multimodal pipelines is further assessed through conformal prediction. Our results show that FM representations achieve competitive performance on out-of-distribution data and that multimodal fusion helps mainly when no single modality dominates the signal. Conformal prediction reveals that in the majority of cases where a point prediction fails, the true diagnosis remains recoverable within the prediction set, reinforcing the value of uncertainty-aware inference for clinical support.

This article presents a complementary approach for integrating multimodal medical data in cancer classification, based on state space models represented by the Mamba architecture. To this end, a mixed multimodal fusion architecture, called Mixed Fusion, was employed and developed to enhance the interpretability of the decision-making process. The proposed approach explores two variants of Mamba: one dedicated to visual processing, responsible for classifying the lesion image and generating probabilities associated with the target classes, and another focused on tabular processing, which uses these probabilities together with clinical and/or sociodemographic data to produce the final diagnosis. The experiments were conducted on two medical datasets: PAD-UFES-20, composed of clinical images and information associated with skin lesions, and NDB-UFES, consisting of histopathological images and sociodemographic data related to oral cancer. The results indicate slightly lower performance in balanced accuracy, compared with Transformer-based approaches, on PAD-UFES-20, and superior performance on NDB-UFES. Additionally, substantial gains were observed in the recall metric. Furthermore, the adoption of the Mixed Fusion architecture enables the application of the Shapley Additive Explanations (SHAP) method, increasing the interpretability of the results. These findings indicate that Mamba-based models constitute a suitable alternative for multimodal classification in medical data, especially in scenarios in which sensitivity is a relevant requirement.