FlowLOT: Linearized Optimal Transport for Flow Cytometry Analysis.

Multiparameter flow cytometry generates high-dimensional, unordered single-cell mea- surement data for disease diagnosis and monitoring, yet analysis often remains dependent on manual gating, limiting scalability and reproducibility. Existing machine-learning ap- proaches can reduce annotation burden but frequently require large training cohorts and offer limited interpretability. To address these challenges, we introduce FlowLOT , an optimal-transport-based framework that models the single-cell measurement data of a pa- tient sample as an empirical cellular distribution and maps it directly into a fixed-length feature vector. Within a single transparent architecture, FlowLOT unifies high-dimensional classification, interpretable visualization, and continuous quantitative inference. In few-shot regimes, using as few as 16 patients per class on FlowCAP-II and 8 patients per class on BLAST110, it accurately distinguishes healthy from acute myeloid leukemia (AML) sam- ples, reaching 94.3% and 98.0% balanced accuracy, respectively. The underlying embedding exposes marker-level variation driving disease-associated population shifts and enables quantitative measurable residual disease (MRD) estimation, achieving a Pearson correlation of 0.82 on held-out samples and 0.79 under cross-dataset transfer. Furthermore, at the clinically relevant 0.1% threshold for leukemia-associated immunophenotype (LAIP) residual disease, FlowLOT detects positivity with 72% sensitivity at 100% specificity. By replacing subjective manual gating and black-box deep learning with a distribution-aware framework, FlowLOT offers a sample-efficient, scalable, and interpretable solution for high- dimensional cytometry under realistic clinical and experimental constraints.