Datasets for PILOT Although clinical applications represent the next challenge in single-cell genomics and digital pathology, we are still lacking computational methods for the analysis of single-cell and pathomics data at a patient level for finding patient trajectories associated with diseases. This is challenging as a single-cell/pathomics data is represented by clusters of cells/structures, which cannot be compared with other samples. We propose here patient Level analysis with Optimal Transport (PILOT). PILOT uses optimal transport to compute the Wasserstein distance between two single single-cell experiments. This allows us to perform unsupervised analysis at the sample level and to uncover trajectories associated with disease progression. Moreover, PILOT provides a statistical approach to delineate non-linear changes in cell populations, gene expression and tissues structures related to the disease trajectories. We evaluate PILOT and competing approaches in disease single-cell genomics and pathomics studies with up to 1.000 patients/donors and millions of cells or structures. Results demonstrate that PILOT detects disease-associated samples, cells, and genes from large and complex single-cell and pathomics data.