Dynamic distribution decomposition for single-cell snapshot time series identifies subpopulations and trajectories during iPSC reprogramming

Recent high-dimensional single-cell technologies such as mass cytometry are enabling time series experiments to monitor the temporal evolution of cell state distributions and to identify dynamically important cell states, such as fate decision states in differentiation. However, these technologies are destructive, and require analysis approaches that temporally map between cell state distributions across time points. Current approaches to approximate the single-cell time series as a dynamical system suffer from too restrictive assumptions about the type of kinetics, or link together pairs of sequential measurements in a discontinuous fashion. We propose Dynamic Distribution Decomposition (DDD), an operator approximation approach to infer a continuous distribution map between time points. On the basis of single-cell snapshot time series data, DDD approximates the continuous time Perron-Frobenius operator by means of a finite set of basis functions. This procedure can be interpreted as a continuous time Markov chain over a continuum of states. By only assuming a memoryless Markov (autonomous) process, the types of dynamics represented are more general than those represented by other common models, e.g., chemical reaction networks, stochastic differential equations. Furthermore, we can a posteriori check whether the autonomy assumptions are valid by calculation of prediction error—which we show gives a measure of autonomy within the studied system. The continuity and autonomy assumptions ensure that the same dynamical system maps between all time points, not arbitrarily changing at each time point. We demonstrate the ability of DDD to reconstruct dynamically important cell states and their transitions both on synthetic data, as well as on mass cytometry time series of iPSC reprogramming of a fibroblast system. We use DDD to find previously identified subpopulations of cells and to visualise differentiation trajectories. Dynamic Distribution Decomposition allows interpretation of high-dimensional snapshot time series data as a low-dimensional Markov process, thereby enabling an interpretable dynamics analysis for a variety of biological processes by means of identifying their dynamically important cell states.Author summary: High-dimensional single-cell snapshot measurements are now increasingly utilized to study dynamic processes. Such measurements enable us to evaluate cell population distributions and their evolution over time. However, it is not trivial to map these distribution across time and to identify dynamically important cell states, i.e. bottleneck regions of state space exhibiting a high degree of change. We present Dynamic Distribution Decomposition (DDD) achieving this task by encoding single-cell measurements as linear combination of basis function distributions and evolving these as a linear system. We demonstrate reconstruction of dynamically important states for synthetic data of a bifurcated diffusion process and mass cytometry data for iPSC reprogramming.