A simple and flexible computational framework for inferring sources of heterogeneity from single-cell dynamics

The availability of high-resolution single-cell data makes data analysis and interpretation an important open problem, for example, to disentangle sources of cell-to-cell and intra-cellular variability. Nonlinear mixed effects models (NLMEs), well established in pharmacometrics, account for such multiple sources of variations, but their estimation is often difficult. Single-cell analysis is an even more challenging application with larger data sets and models that are more complicated. Here, we show how to leverage the quality of time-lapse microscopy data with a simple two-stage method to estimate realistic dynamic NLMEs accurately. We demonstrate accuracy by benchmarking with a published model and dataset, and scalability with a new mechanistic model and corresponding dataset for amino acid transporter endocytosis in budding yeast. We also propose variation-based sensitivity analysis to identify time-dependent causes of cell-to-cell variability, highlighting important sub-processes in endocytosis. Generality and simplicity of the approach will facilitate customized extensions for analyzing single-cell dynamics.