MINGL Quantifies Borders, Gradients, and Heterogeneity in Multicellular Tissue Organization.

Tissues are organized with interacting multicellular organizational units whose interfaces and transitions shape function in health and disease. Current spatial-omics analyses typically assign cells to a single cellular neighborhood-ignoring natural gradients, heterogeneity, and borders. Here we present MINGL (Mixture-based Identification of Neighborhood Gradients with Likelihood estimates), a probabilistic framework that converts existing neighborhood annotations into continuous measures of tissue architecture. MINGL models each cell by multi-membership probabilities across hierarchical organizational units and uses these probabilities to identify enriched cells at interfaces between units, constructs interaction networks across hierarchical scales, quantifies compositional gradient transitions, measures context-specific composition heterogeneity, and provides a starting point for neighborhood resolution. Across multiple spatial-omic datasets spanning melanoma, healthy intestine, and Barrett's Esophagus progression, MINGL detected innate immune-enriched interfaces at tumor and anatomical interfaces, plasma cell niches linking cellular neighborhoods, distinct regimes of sharp and gradual transitions between organizational states, and disease-associated neighborhood remodeling. By treating neighborhood assignment uncertainty as a biological signal rather than noise, MINGL unifies discrete and continuous representations of tissue organization and makes tissue architecture measurable, comparable, and scalable across biological scales and spatial-omics platforms.