Multilevel modeling framework. Modeling across multiple levels connects biological level phenomena to population level outcomes. The lowest level describes the effects of trial interventions on metabolic and signaling pathways. Models at this scale determine the parameters of the tissue level cancer onset models, which describe malignant transformation. Finally, cancer onset models provide input to natural history models, which describe tumor progression, symptoms, and diagnosis. A full description of the biochemical and cancer onset model used here is given in Figure 2.