SORBET: Automated cell-neighborhood analysis of spatial transcriptomics or proteomics for interpretable sample...

Spatial cellular profiling technologies have revolutionized our understanding of complex biological processes, from development and disease progression to immunity and aging. Despite their promise, integrating spatial information with multiplexed molecular data to accurately predict phenotypes poses significant challenges, especially in clinical settings. Here, we present SORBET, a geometric deep learning framework that directly analyzes complete spatial profiling data, eliminating the need to compress complete cell profiles into a limited set of annotations, such as cell types. SORBET models tissues as graphs of adjacent cells and applies graph convolutional networks to infer emergent phenotypes, such as responses to immunotherapy. The model leverages a novel data augmentation technique to ensure robust predictions, complemented by tailored interpretability analyses to identify the molecular and spatial patterns underlying the model's phenotype inferences. We apply our method to a CosMx spatial transcriptomics dataset of pre-treatment metastatic melanoma samples annotated with response to immunotherapy; we show that spatial information significantly improves clinical endpoint, or phenotype, prediction and identifies important biological patterns. To our knowledge, SORBET is the first example of phenotype prediction on spatial transcriptomics data. We further validated our method using two spatial proteomics datasets, Imaging Mass Cytometry (IMC) and Co-detection by indexing (CODEX), obtained from Non-Small Cell Lung Cancer and Colorectal Cancer samples, respectively. SORBET demonstrates superior accuracy in phenotype prediction over leading spatial and non-spatial methods across various datasets of different observed phenotypes and technologies. SORBET sets a new benchmark for predictive analysis in spatial omics, promising to advance personalized medicine through refined patient treatment stratification, grounded in molecular and spatial tissue profiling.