CALM: Interpretable Cross-Modal Alignment for Biomarker Discovery from Unpaired Data
Authors: Jueqi Wang, Zachary Jacokes, John Darrell Van Horn, Kevin A. Pelphrey, Michael C. Schatz, Archana Venkataraman
Abstract
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.
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.
Multimodal neuroimaging fusion of functional MRI (fMRI) and diffusion tensor imaging (DTI) provides complementary information for cognitive impairment analysis, but remains challenged by heterogeneous feature spaces and misaligned representations. We propose \textit{NeuroAlign}, a hierarchical framework for structured multimodal fusion. It introduces (1) \textit{Dual-Modal Hierarchical Alignment} (DMHA), which models multi-scale dynamic connectivity and aligns dynamic-static and functional-structural embeddings; and (2) \textit{Dual-Domain Hierarchical Interaction} (DDHI), which enables fine-grained modulation and global interaction between connectivity- and region-level features. To support feature-level inspection, we design \textit{Synergistic Activation Mapping} (SAM), a gradient-free, marker-oriented attribution method for DFC, SFC, ALFF, and FA. Evaluated on GUTCM, ADNI, and OASIS under five-fold validation, NeuroAlign achieves competitive MCI/SCD detection and preliminary cross-dataset transferability. Attribution analyses reveal modality-specific and partially consistent brain patterns, providing model-derived evidence for multimodal representation analysis.
Cross-modal alignment (CA) and cross-modal prediction (CP) are the dominant paradigms for multimodal representation learning, yet there is no systematic understanding of when each succeeds and when each fails --- a gap that leaves practitioners, especially in scientific domains with heterogeneous instruments and multiple levels of measurement, unable to diagnose why standard methods underperform the best single modality. We study both objectives under a spiked signal-plus-noise model with structured cross-modal nuisance correlation, the ingredient that breaks the classical recovery guarantees, and derive separation ratios that expose complementary failure modes: alignment whitens each modality and fails when nuisance is strongly correlated across views; prediction encodes whatever is cross-predictable through a one-sided whitening, with recovery governed by source-modality quality. The resulting phase diagram partitions multimodal problems into four regimes --- Both, CA only, CP only, and Neither --- refined by a recovery count that separates partial recovery from complete failure. We present a data-driven procedure to locate real-world datasets in this diagram using a small labeled subsample, identifying the preferred objective and prediction direction before any cross-modal training, and identifying when no objective in the CA/CP family can improve on the stronger modality alone. Experiments on synthetic data, stereo-vision benchmarks, image--caption pairs, and two real scientific domains --- astronomy and single-cell multi-omics --- validate the predictions in the nonlinear regime, including both faces of the Neither regime. Code to reproduce the results is available at https://github.com/IlayMalinyak/mm_align_vs_pred.