Towards a Physiological Scale of Vocal Fold Agent-Based Models of Surgical Injury and Repair: Sensitivity Analysis, Calibration and Verification.

Agent based models (ABM) were developed to numerically simulate the biological response to surgical vocal fold injury and repair at the physiological level. This study aimed to improve the representation of existing ABM through a combination of empirical and computational experiments. Empirical data of vocal fold cell populations including neutrophils, macrophages and fibroblasts were obtained using flow cytometry up to four weeks following surgical injury. Random Forests were used as a sensitivity analysis method to identify model parameters that were most influential to ABM outputs. Statistical Parameter Optimization Tool for Python was used to calibrate those parameter values to match the ABM-simulation data with the corresponding empirical data from Day 1 to Day 5 following surgery. Model performance was evaluated by verifying if the empirical data fell within the 95% confidence intervals of ABM outputs of cell quantities at Day 7, Week 2 and Week 4. For Day 7, all empirical data were within the ABM output ranges. The trends of ABM-simulated cell populations were also qualitatively comparable to those of the empirical data beyond Day 7. Exact values, however, fell outside of the 95% statistical confidence intervals. Parameters related to fibroblast proliferation were indicative to the ABM-simulation of fibroblast dynamics in final stages of wound healing.