QuadST: A Powerful and Robust Approach for Identifying Cell-Cell Interaction-Changed Genes on Spatially Resolved Transcriptomics.

Spatially resolved transcriptomics (SRT) have enabled profiling spatial organization of cells and their transcriptome in situ. Various analytical methods have been developed to uncover cell-cell interaction processes using SRT data. To improve upon existing efforts, we developed a novel statistical framework called QuadST for the robust and powerful identification of interaction-changed genes (ICGs) for cell-type-pair specific interactions on a single-cell SRT dataset. QuadST is motivated by the idea that in the presence of cell-cell interaction, gene expression level can vary with cell-cell distance between cell type pairs, which can be particularly pronounced within and in the vicinity of cell-cell interaction distance. Specifically, QuadST infers ICGs in a specific cell type pair's interaction based on a quantile regression model, which allows us to assess the strength of distance-expression association across entire distance quantiles conditioned on gene expression level. To identify ICGs, QuadST performs a hypothesis testing with an empirically estimated FDR, whose upper bound is determined by the ratio of cumulative associations at symmetrically smaller and larger distance quantiles simultaneously across all genes. Simulation studies illustrate that QuadST provides consistent FDR control and better power performance than other compared methods. Its application on SRT datasets profiled from mouse brains demonstrates that QuadST can identify ICGs presumed to play a role in specific cell type pair interactions (e.g., synaptic pathway genes among excitatory neuron cell interactions). These results suggest that QuadST can be a useful tool to discover genes and regulatory processes involved in specific cell type pair interactions.