scDiffEq: drift-diffusion modeling of single-cell dynamics with neural stochastic differential equations

Abstract

AbstractSingle-cell sequencing measurements facilitate the reconstruction of dynamic biology by capturing snapshots of the molecular profiles of individual cells. Cell fate decisions in development and disease are orchestrated through an intricate balance of deterministic and stochastic regulatory events. Drift-diffusion equations are effective in modeling single-cell dynamics from high-dimensional single-cell measurements. While existing solutions describe the deterministic dynamics associated with the drift term of these equations at the level of cell state, the diffusion is modeled as a constant across cell states. To fully understand the dynamic regulatory logic in development and disease, models explicitly attuned to the balance between deterministic and stochastic biology are required. Addressing these limitations, we introduce scDiffEq, a generative framework for learning neural stochastic differential equations that approximate the deterministic and stochastic dynamics in biology. Using lineage-traced single-cell data, we demonstrate that scDiffEq offers improved reconstruction of held-out cell states and prediction of cell fate from multipotent progenitors during hematopoiesis. By impartingin silicoperturbations to multipotent progenitor cells, we find that scDiffEq accurately recapitulates the dynamics of CRISPR-perturbed hematopoiesis. Using scDiffEq, we simulate high-resolution developmental cell trajectories, modeling their drift and diffusion, enabling us to study their time-dependent gene-level dynamics.