Workflow for generating the ensemble of virtual populations. MAPEL can be applied iteratively to create an ensemble of acceptable axes weight solutions, or an ensemble of VPops. The general workflow is shown for clarity. First, valid VPs that meet the acceptance criteria detailed in the methods were developed. In total, a cohort of 1,206 VPs was created by introducing diversity along 51 mechanistic axes using a genetic algorithm and screening for VPs with realistic pathophysiology at baseline and feasible responses to therapy. The cohort of VPs was then used with the aggregated clinical trial data to inform the MAPEL algorithm. Valid axes weight solutions that defined VPops were randomized and used as starting points for additional iterations to create alternate virtual populations. Ultimately, 768 alternate VPops were developed for subsequent analyses.