Decoding Phenotypes: A Framework for Fusing Genomic Language Models and Neuroimaging
Authors: Tianli Tao, Ziyang Wang, Emma Robinson, Rachel Sparks, Le Zhang
Organizations: School of Biomedical Engineering and Imaging Science, Faculty of Life Science and Medicine, King’s College London, UK · School of Computer Science and Digital Technologies, Aston University, UK · School of Engineering, College of Engineering and Physical Sciences, University of Birmingham, UK
Abstract
Neuroimaging and genetic testing are two important clinical references for nervous system diseases, offering complementary diagnostic information. However, integrating genomic and neuroimaging data for precise disease diagnosis is challenging due to cross-modality heterogeneity. Existing imaging-genetics approaches mainly encode genetic information as hard-coded labels, which lose the local sequence context around disease-associated variants. To address this limitation, we propose GeneFuse, a multimodal learning framework that aligns genetic representations from pre-trained Genomic Language Models (GLMs) with features extracted from images. GeneFuse integrates two components: (1) Genotype-Conditioned Feature Modulation (GCFM), a FiLM-inspired module that uses genomic embeddings to modulate image feature maps; and (2) Uncertainty-aware Genomic Residual Fusion (U-GRF), a fusion strategy that uses imaging-derived predictive uncertainty to gate the contribution of genotypic features. We evaluate GeneFuse on early cognitive decline identification (NC vs. MCI) and dementia screening (NC vs. AD). In the APOE-centered setting, GeneFuse achieves AUROCs of 0.77 and 0.83, outperforming existing imaging-genetics fusion methods. These results indicate that GLM-derived genomic embeddings provide additional information to imaging.
The interaction between brain structure and genetic influences is key to understanding neuropsychiatric disorders. However, most large-scale datasets are unimodal, providing either neuroimaging or genetics data. We propose CALM, a framework that learns interpretable associations between brain ROIs and genetic pathways from completely disjoint populations. CALM aligns the two modalities in a shared latent space via linear projections that simultaneously match the class-conditional latent distributions and ensure group separability. These projections provide interpretable pathway--ROI associations. When trained on unimodal imaging and genetics datasets, CALM generalizes to an unseen paired dataset, outperforming several state-of-the-art methods and ablation baselines. We also demonstrate stability of the learned associations against a paired baseline. Our experiments on autism spectrum disorder reveal immune and metabolic pathways linked to specific cortical regions and are consistent with established literature. Thus, CALM opens the door to leveraging large unimodal repositories for studying cross-modal interactions in brain disorders across disparate datasets.
Jueqi Wang, Zachary Jacokes, John Darrell Van Horn +3
Contemporary glioma diagnosis integrates molecular features with histopathology to guide clinical decision-making. However, in clinical settings, divergent imaging protocols result in incomplete MRI sequences, leading to two primary challenges: forcing existing frameworks to discard a large portion of clinical data during training and consequently limiting their clinical applicability. To address these limitations, we propose GMENet, a Generative Mixture of Experts Network for multi-center glioma diagnosis with incomplete imaging sequences. Firstly, we design a Cross-attention-based Gated Generation Module that synthesizes missing sequence features from available sequences via cross-attention and dynamic gating mechanisms, incorporating a cycle-consistency loss to preserve semantic integrity. Secondly, we introduce a Dynamically Weighted Experts Fusion Module that performs mixture-of-experts interaction and confidence-aware fusion over original and synthesized dual-sequence features for multi-task prediction. We evaluate GMENet on a multi-center cohort of 1,241 subjects from four in-house datasets and two public repositories. Experiments show that GMENet expands clinically usable training data by 97%, relative to complete-sequence-only data. Furthermore, it consistently outperforms state-of-the-art methods trained on complete data, demonstrating improved robustness under cross-center distribution shifts.
While generative models enable encoding of complex neuroimaging data for feature generation and reconstruction, developing optimal architectural frameworks with appropriate encoding and latent space processes is crucial for studying structural and functional properties of the brain. We design a multimodal generative framework for structural and functional magnetic resonance imaging (MRI) features through systematic evaluation of encoding strategies, latent multimodal fusion, and generative model selection. Using structural gray matter volume (GMV) and static functional network connectivity (sFNC) features from a large neuroimaging dataset, we analyze generative frameworks involving variational autoencoders (VAEs), transformers, generative adversarial networks (GANs), and diffusion models. Architectures that employ modality-aware graph encoding of functional connectivity into a lower-dimensional latent space outperform vectorized encoders or direct data space approaches. The proposed multimodal graph VAE (gMMVAE) surpasses alternative generative variants across multiple metrics for generation fidelity, reconstruction quality, efficiency, and latent space discriminability, highlighting its potential for robust multimodal neuroimaging analysis.