Konstantin Hemker

Konstantin Hemker, Nikola Simidjievski, Mateja Jamnik

Technological advances in medical data collection, such as high-throughput genomic sequencing and digital high-resolution histopathology, have contributed to the rising requirement for multimodal biomedical modelling, specifically for image, tabular and graph data. Most multimodal deep learning approaches use modality-specific architectures that are often trained separately and cannot capture the crucial cross-modal information that motivates the integration of different data sources. This paper presents the Hybrid Early-fusion Attention Learning Network (HEALNet): a flexible multimodal fusion architecture, which a) preserves modality-specific structural information, b) captures the cross-modal interactions and structural information in a shared latent space, c) can effectively handle missing modalities during training and inference, and d) enables intuitive model inspection by learning on the raw data input instead of opaque embeddings. We conduct multimodal survival analysis on Whole Slide Images and Multi-omic data on four cancer datasets from The Cancer Genome Atlas (TCGA). HEALNet achieves state-of-the-art performance compared to other end-to-end trained fusion models, substantially improving over unimodal and multimodal baselines whilst being robust in scenarios with missing modalities.

Konstantin Hemker, Zohreh Shams, Mateja Jamnik

Rule-based surrogate models are an effective and interpretable way to approximate a Deep Neural Network's (DNN) decision boundaries, allowing humans to easily understand deep learning models. Current state-of-the-art decompositional methods, which are those that consider the DNN's latent space to extract more exact rule sets, manage to derive rule sets at high accuracy. However, they a) do not guarantee that the surrogate model has learned from the same variables as the DNN (alignment), b) only allow to optimise for a single objective, such as accuracy, which can result in excessively large rule sets (complexity), and c) use decision tree algorithms as intermediate models, which can result in different explanations for the same DNN (stability). This paper introduces the CGX (Column Generation eXplainer) to address these limitations - a decompositional method using dual linear programming to extract rules from the hidden representations of the DNN. This approach allows to optimise for any number of objectives and empowers users to tweak the explanation model to their needs. We evaluate our results on a wide variety of tasks and show that CGX meets all three criteria, by having exact reproducibility of the explanation model that guarantees stability and reduces the rule set size by >80% (complexity) at equivalent or improved accuracy and fidelity across tasks (alignment).

Laura Wenderoth, Konstantin Hemker, Nikola Simidjievski et al.

Integrating AI in healthcare can greatly improve patient care and system efficiency. However, the lack of explainability in AI systems (XAI) hinders their clinical adoption, especially in multimodal settings that use increasingly complex model architectures. Most existing XAI methods focus on unimodal models, which fail to capture cross-modal interactions crucial for understanding the combined impact of multiple data sources. Existing methods for quantifying cross-modal interactions are limited to two modalities, rely on labelled data, and depend on model performance. This is problematic in healthcare, where XAI must handle multiple data sources and provide individualised explanations. This paper introduces InterSHAP, a cross-modal interaction score that addresses the limitations of existing approaches. InterSHAP uses the Shapley interaction index to precisely separate and quantify the contributions of the individual modalities and their interactions without approximations. By integrating an open-source implementation with the SHAP package, we enhance reproducibility and ease of use. We show that InterSHAP accurately measures the presence of cross-modal interactions, can handle multiple modalities, and provides detailed explanations at a local level for individual samples. Furthermore, we apply InterSHAP to multimodal medical datasets and demonstrate its applicability for individualised explanations.

Cristina Almagro-Pérez, Andrew H. Song, Luca Weishaupt et al.

A comprehensive three-dimensional (3D) map of tissue architecture and gene expression is crucial for illuminating the complexity and heterogeneity of tissues across diverse biomedical applications. However, most spatial transcriptomics (ST) approaches remain limited to two-dimensional (2D) sections of tissue. Although current 3D ST methods hold promise, they typically require extensive tissue sectioning, are complex, are not compatible with non-destructive 3D tissue imaging technologies, and often lack scalability. Here, we present VOlumetrically Resolved Transcriptomics EXpression (VORTEX), an AI framework that leverages 3D tissue morphology and minimal 2D ST to predict volumetric 3D ST. By pretraining on diverse 3D morphology-transcriptomic pairs from heterogeneous tissue samples and then fine-tuning on minimal 2D ST data from a specific volume of interest, VORTEX learns both generic tissue-related and sample-specific morphological correlates of gene expression. This approach enables dense, high-throughput, and fast 3D ST, scaling seamlessly to large tissue volumes far beyond the reach of existing 3D ST techniques. By offering a cost-effective and minimally destructive route to obtaining volumetric molecular insights, we anticipate that VORTEX will accelerate biomarker discovery and our understanding of morphomolecular associations and cell states in complex tissues. Interactive 3D ST volumes can be viewed at https://vortex-demo.github.io/

Zak Buzzard, Konstantin Hemker, Nikola Simidjievski et al.

Computational analysis of whole slide images (WSIs) has seen significant research progress in recent years, with applications ranging across important diagnostic and prognostic tasks such as survival or cancer subtype prediction. Many state-of-the-art models process the entire slide - which may be as large as $150,000 \times 150,000$ pixels - as a bag of many patches, the size of which necessitates computationally cheap feature aggregation methods. However, a large proportion of these patches are uninformative, such as those containing only healthy or adipose tissue, adding significant noise and size to the bag. We propose Pathology Transformer with Hierarchical Selection (PATHS), a novel top-down method for hierarchical weakly supervised representation learning on slide-level tasks in computational pathology. PATHS is inspired by the cross-magnification manner in which a human pathologist examines a slide, recursively filtering patches at each magnification level to a small subset relevant to the diagnosis. Our method overcomes the complications of processing the entire slide, enabling quadratic self-attention and providing a simple interpretable measure of region importance. We apply PATHS to five datasets of The Cancer Genome Atlas (TCGA), and achieve superior performance on slide-level prediction tasks when compared to previous methods, despite processing only a small proportion of the slide.

Konstantin Hemker, Andrew H. Song, Cristina Almagro-Pérez et al.

Spatial transcriptomics (ST) provides spatially resolved measurements of gene expression, enabling characterization of the molecular landscape of human tissue beyond histological assessment as well as localized readouts that can be aligned with morphology. Concurrently, the success of multimodal foundation models that integrate vision with complementary modalities suggests that morphomolecular coupling between local expression and morphology can be systematically used to improve histological representations themselves. We introduce Spatial Expression-Aligned Learning (SEAL), a vision-omics self-supervised learning framework that infuses localized molecular information into pathology vision encoders. Rather than training new encoders from scratch, SEAL is designed as a parameter-efficient vision-omics finetuning method that can be flexibly applied to widely used pathology foundation models. We instantiate SEAL by training on over 700,000 paired gene expression spot-tissue region examples spanning tumor and normal samples from 14 organs. Tested across 38 slide-level and 15 patch-level downstream tasks, SEAL provides a drop-in replacement for pathology foundation models that consistently improves performance over widely used vision-only and ST prediction baselines on slide-level molecular status, pathway activity, and treatment response prediction, as well as patch-level gene expression prediction tasks. Additionally, SEAL encoders exhibit robust domain generalization on out-of-distribution evaluations and enable new cross-modal capabilities such as gene-to-image retrieval. Our work proposes a general framework for ST-guided finetuning of pathology foundation models, showing that augmenting existing models with localized molecular supervision is an effective and practical step for improving visual representations and expanding their cross-modal utility.

Jan Ittner, Lukasz Bolikowski, Konstantin Hemker et al.

We offer a new formalism for global explanations of pairwise feature dependencies and interactions in supervised models. Building upon SHAP values and SHAP interaction values, our approach decomposes feature contributions into synergistic, redundant and independent components (S-R-I decomposition of SHAP vectors). We propose a geometric interpretation of the components and formally prove its basic properties. Finally, we demonstrate the utility of synergy, redundancy and independence by applying them to a constructed data set and model.