MIcrosimulation SCreening Analysis (MISCAN) Sexually Transmitted Diseases Simulation (STDSIM) Model
Model overview. The MISCAN-STDSIM (Erasmus) modeling approach combines a microsimulation model (STDSIM) to simulate the transmission of human papillomavirus (HPV) and vaccination with the microsimulation model (MISCAN) to simulate the natural history of cervical carcinogenesis and screening.
HPV transmission. HPV-16 and -18 transmission is modeled in the well-established STDSIM dynamic microsimulation model for sexually transmitted diseases developed at the Department of Public Health in the Netherlands. (1-3) The model is parameterized using publicly available information on demography (4-5) and sexual behavior (currently for the Dutch population) (6-8); type-specific durations of infection are based on the literature (9-11). The model allows for natural immunity after HPV infection clearance, either full immunity for some time (Weibull distributed) or cumulatively reduced after each subsequent infection.
Cervical carcinogenesis. In the static MISCAN model, acquired HPV infection can progress to pre-invasive cervical intraepithelial neoplasia (CIN) lesions. The progression of cervical disease is subdivided into six sequential stages: three pre-invasive stages (CIN grade 1, 2 and 3), and three invasive stages (International Federation of Gynecology and Obstetrics [FIGO] stages IA, IB and II+). Cancer may be detected clinically (stages IB and II) or through screening (all stages). In the model, most HPV infections will clear without ever resulting in neoplasia, and lesions in pre-invasive stages can regress spontaneously. (12) CIN grades 1 and 2 can also develop in the absence of a high-risk HPV infection; these lesions will never progress to cancer. CIN grade 3 and cancer can only develop if a high-risk HPV infection is present.
Vaccination. The vaccination component of both the dynamic and static models allows variation by target groups, coverage rates, vaccine efficacy, and duration of protection. Vaccine efficacy is modeled as reduced susceptibility to vaccine-type infections, assumed to be lifelong in the base case. The dynamic model also captures the indirect (herd immunity) effects of vaccination. Herd immunity is a phenomenon where vaccination of a significant proportion of the population can reduce the prevalence of the vaccine-targeted HPV types in the population, thereby providing some protection for individuals who are not vaccinated. The resulting HPV incidence estimates in unvaccinated women are incorporated into the MISCAN model, to also account for herd immunity.
Screening, diagnosis, and treatment of pre-cancer. The MISCAN-STDSIM screening component enables a test to detect an HPV-infection (with or without neoplasia), CIN and preclinical cancers. Screening tests can be applied at certain ages. Per-lesion test sensitivity can vary by presence or absence of an HPV-infection, by the grade of CIN and the presence of a preclinical cancer. Based on the test result, a woman can be referred to undergo another test, or to colposcopy and eventual CIN treatment (and prevention of cancer). Screening can result in over-diagnosis, over-treatment (by the detection of CIN and cancers that would not have led to clinical disease without screening), and lead to complications.
Cancer treatment and survival. For invasive cancer, age- and stage-specific survival probabilities are determined by year since diagnosis based on recent data from the Netherlands Cancer Registry (NCR). Because the NCR data include all cases country-wide, and both adenocarcinoma and squamous cell carcinoma, the estimated survival is a weighted average of nationwide treatment practice of these two types of cervical cancer. Screen-detection of cancer allows for within-stage shift, consequently improving the probability of cure compared to the woman's situation without screening.
Calibration and validation. The HPV transmission probabilities per sexual contact, the Weibull shape parameter for the durations of infection, the mean duration of acquired immunity and its Weibull shape parameter (or the reduction in susceptibility after an infection in the MISCAN model) have been calibrated to the observed age- and type-specific HPV prevalence in the Netherlands. (13-15) The progression of HPV to CIN and from CIN to cervical cancer, and the cytology test characteristics, were simultaneously calibrated to Dutch pre-vaccination age-specific data on screening HPV-positivity in women with negative and positive cytology, CIN and cancer detection rates by HPV positivity, cancer incidence, stage distribution, and interval cancers. (13, 16-20) Prevalence of chlamydia provided a validation metric for sexual risk behavior. (21) To check the external validity of the MISCAN model, the predicted incidence without screening was compared to observed data in selected parts of the Netherlands (Rotterdam, the Hague, and Friesland) in the period 1965-1969 (22), before organized screening started. The projected interval carcinoma rates were also compared with those collected by the International Agency for Research on Cancer (IARC) in the early screening decades. (23-24)
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