MOSAIC: A Spectral Framework for Integrative Phenotypic Characterization Using Population-Level Single-Cell Multi-Omics.

Population-scale single-cell multi-omics offers unprecedented opportunities to link molecular variation to human health and disease. However, existing methods for single-cell multi-omics analysis are either cell-centric, prioritizing batch-corrected cell embeddings that neglect feature relationships, or feature-centric, imposing global feature representations that overlook inter-sample heterogeneity. To address these limitations, we present MOSAIC, a spectral framework that learns a high-resolution feature × sample joint embedding from population-scale single-cell multi-omics data. For each individual, MOSAIC constructs a sample-specific coupling matrix capturing complete intra- and cross-modality feature interactions, then projects these into a shared latent space via spectral decomposition. The joint feature × sample embedding defines each feature's connectivity profile per sample, enabling three downstream applications. Differential Connectivity analysis identifies features with regulatory network rewiring across conditions even when their abundance remains unchanged, revealing rewiring of proliferation programs in activated T cells from a vaccination cohort. Unsupervised subgroup detection isolates coherent feature modules to discover hidden patient subtypes, uncovering a stress-driven neuronal subtype within an HIV+ cohort. Clinical outcome prediction using connectivity-derived features complements abundance-based analysis, improving COVID-19 severity classification when integrated. MOSAIC provides a general-purpose framework for systems-level phenotypic characterization, bridging network-level discovery with clinical outcome prediction in population-scale single-cell studies.