Figure 1. Microsimulation of HPV infection and cervical carcinogenesis: Translating the molecular pathogenesis of HPV to health decision modeling.

Cervical cancer incidence and mortality in a theoretical cohort is the summation of individual women's lifetime experiences with each of the carcinogenic or “high-risk” (hr) HPV types. Over time, a woman's cervix is exposed (or not) to each of the hrHPV types. She reacts to each type independently. The worst viral outcome measured at a given moment defines the woman's health state. She might have cleared 10 types previously but if one is present at the time of measurement, she is "infected". If any type persists and a precancer develops, she has "precancer". If any precancer invades, the woman has incident cancer. Outcomes are aggregated over the entire cohort (a “bottom-up” approach) over time to estimate the long-term population impact and cost-effectiveness of different scenarios. The proposed microsimulation model represents the summation of an individual woman’s experience with each HPV type (or group of types) in the cervix at any given month. The model begins tracking a theoretical cohort of girls prior to sexual initiation (e.g., age 9 years) on a monthly basis. Upon entering the model, all females in the cohort have a normal cervix (blue) (left). While HPV exposures do not necessarily happen concurrently, they are likely to happen soon after the woman becomes sexually active. Women who are infected with HPV are depicted in orange. Outcomes for individual women are then aggregated over the entire theoretical cohort to project population-level outcomes. With time, most infections clear but some persist, increasing the risk of progression to precancer (green) which, if untreated, may invade. The health decision modeling framework categorizes a woman by the status of her worst clone or lesion associated with each HPV type at a given time. In the example at right, the woman would be classified as having HPV-16 associated squamous precancer and an HPV-31 associated squamous precancer, but the model would not keep track of the multiple clones associated with each type. By tracking the worst clone or lesion for a given HPV type, the model aggregates information at the level of the infection, then the level of the woman, and then the level of the population. Women in the theoretical cohort can die of cervical cancer or of other causes (gray). Photograph from van der Marel MD, Quint WGV, Schiffman M, et al. Molecular mapping of high-grade cervical intraepithelial neoplasia shows etiological dominance of HPV16. International Journal of Cancer 2012;131:E946-E953. Used with permission from John Wiley & Sons, Inc.