Structure of the modelling framework, with detail of cell progression and perturbation modules.

<p>(A) The model reproduces the flow of cell cohorts through the cell cycle phases and subsequent generations, each phase including specific quiescence (Q) and perturbation modules. A cohort of cells entering a phase is first processed by the quiescence module, committing a fraction of them to the G₁ quiescence compartment. Then untreated cells progress through the subsequent age compartments of each phase, exiting at different ages as shown in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003293#pcbi.1003293.s007" target="_blank">Figure S4</a> and detailed in supplementary <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003293#pcbi.1003293.s017" target="_blank">Text S3</a>. In treated samples this process is altered by perturbation modules, which can be applied to any phase, providing a flexible framework to build proliferation models with the desired complexity. (B) Cycling cell death module, exemplified for G₁ phase. It applies first-order death kinetics to all cycling cells in phase G₁ with a rate <i>DR_G1</i>. (C) The mitosis/polyploid module acts on dividing cells, doubling the number of cells exiting G₂M and assuming that a fraction (<i>pPol</i>) of newborn siblings re-fuse, collecting re-fused (polyploid) cells in a separate compartment, from which they die with a rate <i>DRPol</i>. (D) Checkpoint modules, exemplified for G₁ phase. A specific type of checkpoint module can be selected, as described in Computational Methods, with parameters <i>Del_G1</i> (producing a transit delay), <i>pBL_G1</i> (block probability), <i>DRBL_G1</i> (death rate of blocked cells), <i>Rec_G1</i> (recycling rate of blocked cells).