Scott J. Rodig

Muhammad Shaban, Yuzhou Chang, Huaying Qiu et al.

Foundation models have begun to transform image analysis by acting as pretrained generalist backbones that can be adapted to many tasks even when post-training data are limited, yet their impact on spatial proteomics, imaging that maps proteins at single-cell resolution, remains limited. Here, we introduce KRONOS, a foundation model built for spatial proteomics. KRONOS was trained in a self-supervised manner on over 47 million image patches covering 175 protein markers, 16 tissue types, and 8 fluorescence-based imaging platforms. We introduce key architectural adaptations to address the high-dimensional, multi-channel, and heterogeneous nature of multiplex imaging. We demonstrate that KRONOS learns biologically meaningful representations across multiple scales, ranging from cellular and microenvironment to tissue levels, enabling it to address diverse downstream tasks, including cell phenotyping, region classification, and patient stratification. Evaluated across 11 independent cohorts, KRONOS achieves state-of-the-art performance across cell phenotyping, treatment response prediction, and retrieval tasks, and is highly data-efficient. KRONOS also introduces the paradigm of segmentation-free patch-level processing for efficient and scalable spatial proteomics analysis, allowing cross-institutional comparisons, and as an image reverse search engine for spatial patterns. Together, these results position KRONOS as a flexible and scalable tool for spatial proteomics. The model is publicly accessible at https://github.com/mahmoodlab/KRONOS.

Stella Su, Marc Harary, Scott J. Rodig et al.

Self-supervised learning (SSL) has emerged as a powerful approach for learning visual representations without manual annotations. However, the robustness of standard SSL methods to domain shift -- systematic differences across data sources -- remains uncertain, posing an especially critical challenge in biomedical imaging where batch effects can obscure true biological signals. We present AdvDINO, a domain-adversarial self-supervised learning framework that integrates a gradient reversal layer into the DINOv2 architecture to promote domain-invariant feature learning. Applied to a real-world cohort of six-channel multiplex immunofluorescence (mIF) whole slide images from non-small cell lung cancer patients, AdvDINO mitigates slide-specific biases to learn more robust and biologically meaningful representations than non-adversarial baselines. Across $>5.46$ million mIF image tiles, the model uncovers phenotype clusters with distinct proteomic profiles and prognostic significance, and improves survival prediction in attention-based multiple instance learning. While demonstrated on mIF data, AdvDINO is broadly applicable to other imaging domains -- including radiology, remote sensing, and autonomous driving -- where domain shift and limited annotated data hinder model generalization and interpretability.

Richard J. Chen, Ming Y. Lu, Jingwen Wang et al.

Cancer diagnosis, prognosis, and therapeutic response predictions are based on morphological information from histology slides and molecular profiles from genomic data. However, most deep learning-based objective outcome prediction and grading paradigms are based on histology or genomics alone and do not make use of the complementary information in an intuitive manner. In this work, we propose Pathomic Fusion, an interpretable strategy for end-to-end multimodal fusion of histology image and genomic (mutations, CNV, RNA-Seq) features for survival outcome prediction. Our approach models pairwise feature interactions across modalities by taking the Kronecker product of unimodal feature representations and controls the expressiveness of each representation via a gating-based attention mechanism. Following supervised learning, we are able to interpret and saliently localize features across each modality, and understand how feature importance shifts when conditioning on multimodal input. We validate our approach using glioma and clear cell renal cell carcinoma datasets from the Cancer Genome Atlas (TCGA), which contains paired whole-slide image, genotype, and transcriptome data with ground truth survival and histologic grade labels. In a 15-fold cross-validation, our results demonstrate that the proposed multimodal fusion paradigm improves prognostic determinations from ground truth grading and molecular subtyping, as well as unimodal deep networks trained on histology and genomic data alone. The proposed method establishes insight and theory on how to train deep networks on multimodal biomedical data in an intuitive manner, which will be useful for other problems in medicine that seek to combine heterogeneous data streams for understanding diseases and predicting response and resistance to treatment.