Abstract The surge in single-cell datasets and reference atlases has enabled the comparison of cell states across conditions, yet a gap persists in quantifying pathological shifts from healthy cell states. To address this gap, we introduce single-cell Pathological Shift Scoring (scPSS) which provides a statistical measure for how much a “query” cell from a diseased sample has been shifted away from a reference group of healthy cells. In scPSS, The distance of a query cell to its k -th nearest reference cell is con…