Efficient Bayesian inference for mechanistic modelling with high-throughput data

Author summaryDuring wound healing, cells work together to close a wound to restore tissue integrity. Thousands of different genes play a role in wound healing, and scratch assay experiments are routinely used to investigate the role of these genes by analysing how a wound closes when each of these is not expressed, i.e. knocked down. So far, the impact of knocking down genes on wound healing has been determined by comparing the size of the wound before and after a given time period, but these measurements do not elucidate the fine-scale mechanisms that determine how cells behave in the presence of their neighbours. By combining a detailed mathematical model with experimental imaging of wound healing, we identify how cells respond to and work together with their neighbours during wound healing. Applying this method to a large number of gene knockdowns, we identify three well-defined functional subgroups of knockdowns, each displaying its own typical behaviours of movement and proliferation to close the wound. These observations explain the role of each of the knockdowns on wound healing and further our understanding of cell-cell interactions in wound healing. Bayesian methods are routinely used to combine experimental data with detailed mathematical models to obtain insights into physical phenomena. However, the computational cost of Bayesian computation with detailed models has been a notorious problem. Moreover, while high-throughput data presents opportunities to calibrate sophisticated models, comparing large amounts of data with model simulations quickly becomes computationally prohibitive. Inspired by the method of Stochastic Gradient Descent, we propose a minibatch approach to approximate Bayesian computation. Through a case study of a high-throughput imaging scratch assay experiment, we show that reliable inference can be performed at a fraction of the computational cost of a traditional Bayesian inference scheme. By applying a detailed mathematical model of single cell motility, proliferation and death to a data set of 118 gene knockdowns, we characterise functional subgroups of gene knockdowns, each displaying its own typical combination of local cell density-dependent and -independent motility and proliferation patterns. By comparing these patterns to experimental measurements of cell counts and wound closure, we find that density-dependent interactions play a crucial role in the process of wound healing.

Automated summary

Researchers identified three distinct types of gene knockdowns during wound healing, each displaying unique cell behaviors through a combination of mathematical modeling and experimental imaging. By applying detailed models to a large dataset of gene knockdowns, they revealed the importance of density-dependent interactions in the process of wound healing.