Figure 2

Relation of mechanistic axes to measured population-level therapeutic responses. The MAPEL algorithm for developing VPops links the mechanistic axes underlying biosimulation to clinical statistics through VPs. In the bottom panel, MAPEL assigns probability distributions directly to the mechanistic axes. A simple case of two axes is shown for clarity. In the middle panel, prevalence weights for VPs in the cohort are calculated. The prevalence weight is essentially a measure of the fraction of the total VPop that a given VP statistically represents. The prevalence weight of each VP is calculated from the axes weights assigned by MAPEL. VPs assigned a higher weight are depicted as darker colors. In the top panel, the VPop’s clinical response distribution is calculated. As described in the text, the Entelos RA Physiolab^® platform was re-run for each individual VP in the population for each therapy. Therefore, biosimulation results provide the response to therapies for each VP. These simulated responses to therapy were used in combination with the prevalence weights to calculate population-level responses to therapy. The calculation of a binned response distribution is shown, e.g. ACR20, 50, 70. In addition, weighted means and weighted standard deviations are also calculated, as detailed in the methods. In practice, MAPEL varies the axes weights until multiple clinical response distributions are in agreement with published trial statistics.