Counterfactual Bidirectional Co-Attention Transformer for Integrative Histology-Genomic Cancer Risk Stratification

Applying deep learning to predict patient prognostic survival outcomes using histological whole-slide images (WSIs) and genomic data is challenging due to the morphological and transcriptomic heterogeneity present in the tumor microenvironment. Existing deep learning-enabled methods often exhibit learning biases, primarily because the genomic knowledge used to guide directional feature extraction from WSIs may be irrelevant or incomplete. This results in a suboptimal and sometimes myopic understanding of the overall pathological landscape, potentially overlooking crucial histological insights. To tackle these challenges, we propose the CounterFactual Bidirectional Co-Attention Transformer framework. By integrating a bidirectional co-attention layer, our framework fosters effective feature interactions between the genomic and histology modalities and ensures consistent identification of prognostic features from WSIs. Using counterfactual reasoning, our model utilizes causality to model unimodal and multimodal knowledge for cancer risk stratification. This approach directly addresses and reduces bias, enables the exploration of ’what-if' scenarios, and offers a deeper understanding of how different features influence survival outcomes. Our framework, validated across eight diverse cancer benchmark datasets from The Cancer Genome Atlas (TCGA), represents a major improvement over current histology-genomic model learning methods. It shows an average 2.5% improvement in c-index performance over 18 state-of-the-art models in predicting patient prognoses across eight cancer types.