Beyond Continuity: Simulation-free Reconstruction of Discrete Branching Dynamics from Single-cell Snapshots

TL;DR

This paper introduces USB, a novel simulation-free framework that accurately reconstructs cellular trajectories by modeling discrete birth-death events at single-cell resolution, surpassing traditional continuous methods.

Contribution

USB provides a rigorous, scalable solution to the Branching Schrödinger Bridge problem, capturing stochastic and unbalanced effects in cellular dynamics without simulation.

Findings

USB outperforms existing methods in trajectory reconstruction accuracy.

USB enables realistic discrete simulation of birth-death processes.

Theoretical solution to the Branching Schrödinger Bridge problem.

Abstract

Inferring cellular trajectories from destructive snapshots is complicated by the challenges of stochasticity and non-conservative mass dynamics such as cell proliferation and apoptosis. Existing unbalanced Optimal Transport (OT) methods treat mass as a continuous fluid, performing inference at the population level. However, this macroscopic view often fails to capture the discrete, jump-like nature of birth-death events at single-cell resolution, which is essential for understanding lineage branching and fate decisions. We present Unbalanced Schr\"odinger Bridge (USB), a simulation-free framework for learning underlying dynamics that effectively integrates both stochastic and unbalanced effects which also models the discrete, jump-like birth-death dynamics at single-cell resolution. Theoretically, USB provides a tractable solution to the Branching Schr\"odinger Bridge (BSB) problem, offering a rigorous microscopic interpretation where individual cells undergo both Brownian motion and discrete birth-death jumps. Technically, the method implements an efficient solver by introducing a simulation-free training objective that effectively scales to high-dimensional omics data. Empirically, we demonstrate on both simulated and real-world datasets that USB not only achieves trajectory reconstruction performance better than or comparable to deterministic baselines but also uniquely enables realistic discrete simulation of birth-death dynamics at single-cell resolution.