Trajectory inference for a branching SDE model of cell differentiation

TL;DR

This paper extends a trajectory inference method to account for cell proliferation and death using lineage trees, enabling more accurate reconstruction of cell differentiation pathways from high-dimensional gene expression data.

Contribution

It introduces a novel extension of gWOT that incorporates proliferation and death, leveraging lineage tracing data without prior knowledge of rates, with theoretical guarantees.

Findings

Successfully reconstructs differentiation landscapes from simulated data.

Outperforms benchmarks that require true branching rates.

Handles cases with and without cell death/subsampling.

Abstract

A core challenge for modern biology is how to infer the trajectories of individual cells from population-level time courses of high-dimensional gene expression data. Birth and death of cells present a particular difficulty: existing trajectory inference methods cannot distinguish variability in net proliferation from cell differentiation dynamics, and hence require accurate prior knowledge of the proliferation rate. Building on Global Waddington-OT (gWOT), which performs trajectory inference with rigorous theoretical guarantees when birth and death can be neglected, we show how to use lineage trees available with recently developed CRISPR-based measurement technologies to disentangle proliferation and differentiation. In particular, when there is neither death nor subsampling of cells, we show that we extend gWOT to the case with proliferation with similar theoretical guarantees and computational cost, without requiring any prior information. In the case of death and/or subsampling, our method introduces a bias, that we describe explicitly and argue to be inherent to these lineage tracing data. We demonstrate in both cases the ability of this method to reliably reconstruct the landscape of a branching SDE from time-courses of simulated datasets with lineage tracing, outperforming even a benchmark using the experimentally unavailable true branching rates.