Dataset Information

Modeling human papillomavirus and cervical cancer in the United States for analyses of screening and vaccination.

ABSTRACT:

Background

To provide quantitative insight into current U.S. policy choices for cervical cancer prevention, we developed a model of human papillomavirus (HPV) and cervical cancer, explicitly incorporating uncertainty about the natural history of disease.

Methods

We developed a stochastic microsimulation of cervical cancer that distinguishes different HPV types by their incidence, clearance, persistence, and progression. Input parameter sets were sampled randomly from uniform distributions, and simulations undertaken with each set. Through systematic reviews and formal data synthesis, we established multiple epidemiologic targets for model calibration, including age-specific prevalence of HPV by type, age-specific prevalence of cervical intraepithelial neoplasia (CIN), HPV type distribution within CIN and cancer, and age-specific cancer incidence. For each set of sampled input parameters, likelihood-based goodness-of-fit (GOF) scores were computed based on comparisons between model-predicted outcomes and calibration targets. Using 50 randomly resampled, good-fitting parameter sets, we assessed the external consistency and face validity of the model, comparing predicted screening outcomes to independent data. To illustrate the advantage of this approach in reflecting parameter uncertainty, we used the 50 sets to project the distribution of health outcomes in U.S. women under different cervical cancer prevention strategies.

Results

Approximately 200 good-fitting parameter sets were identified from 1,000,000 simulated sets. Modeled screening outcomes were externally consistent with results from multiple independent data sources. Based on 50 good-fitting parameter sets, the expected reductions in lifetime risk of cancer with annual or biennial screening were 76% (range across 50 sets: 69-82%) and 69% (60-77%), respectively. The reduction from vaccination alone was 75%, although it ranged from 60% to 88%, reflecting considerable parameter uncertainty about the natural history of type-specific HPV infection. The uncertainty surrounding the model-predicted reduction in cervical cancer incidence narrowed substantially when vaccination was combined with every-5-year screening, with a mean reduction of 89% and range of 83% to 95%.

Conclusion

We demonstrate an approach to parameterization, calibration and performance evaluation for a U.S. cervical cancer microsimulation model intended to provide qualitative and quantitative inputs into decisions that must be taken before long-term data on vaccination outcomes become available. This approach allows for a rigorous and comprehensive description of policy-relevant uncertainty about health outcomes under alternative cancer prevention strategies. The model provides a tool that can accommodate new information, and can be modified as needed, to iteratively assess the expected benefits, costs, and cost-effectiveness of different policies in the U.S.

SUBMITTER: Goldhaber-Fiebert JD

PROVIDER: S-EPMC2213637 | biostudies-literature | 2007 Oct

REPOSITORIES: biostudies-literature

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Publications

Modeling human papillomavirus and cervical cancer in the United States for analyses of screening and vaccination.

Goldhaber-Fiebert Jeremy D JD Stout Natasha K NK Ortendahl Jesse J Kuntz Karen M KM Goldie Sue J SJ Salomon Joshua A JA

Population health metrics 20071029

<h4>Background</h4>To provide quantitative insight into current U.S. policy choices for cervical cancer prevention, we developed a model of human papillomavirus (HPV) and cervical cancer, explicitly incorporating uncertainty about the natural history of disease.<h4>Methods</h4>We developed a stochastic microsimulation of cervical cancer that distinguishes different HPV types by their incidence, clearance, persistence, and progression. Input parameter sets were sampled randomly from uniform distr ...[more]

PMID: 17967185

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Project description:ImportanceCervical cancer screening is a lifesaving intervention, with an array of approaches, including liquid-based cytology (LBC), molecular testing for human papillomavirus (HPV) infection, and combinations via parallel cotesting or sequential triage. Maximizing screening efficacy while minimizing overtreatment is vital, especially when considering how the HPV vaccine will affect the interpretation of results.ObjectivesTo estimate the likely outcomes of different screening modalities and to model how the increasing uptake of the HPV vaccine could affect the interpretation of screening results.Design, setting, and participantsThis decision analytic model established a simple Markov model to compare the outcomes of different cervical cancer screening modalities on a simulated population of women (aged ≥25 years), considering different levels of HPV vaccination.Main outcomes and measuresThe number of cases of cervical intraepithelial neoplasia (CIN) grade 2 and 3 detected and missed, the number of false positives, and the number of tests required to achieve a given level of accuracy. Positive and negative predictive values of different modalities were simulated under varying levels of HPV vaccination and therefore HPV prevalence.ResultsIn a simulated population of 1000 women aged 25 years and older with an HPV prevalence of 2%, HPV-based modalities outperformed LBC-based approaches, detecting 19% more true positives (HPV test sensitivity, 89.9% [95% CI, 88.6%-91.1%]; LBC test sensitivity, 75.5% [95% CI, 66.6%-82.7%]). While cotesting markedly reduced missed cases, detecting 29% more true positives than LBC alone (19.5 [95% CI, 19.3-19.7] per 1000 women screened vs 15.1 [95% CI, 13.3-16.5] per 1000 women screened), it unacceptably increased excess colposcopy referral by 94% (184.4 [95% CI, 181.8-188.0] false positives per 1000 women screened vs 95.1 [95% CI, 93.1-97.0] false positives per 1000 women screened). By contrast, triage testing with reflex screening substantially reduced false positives by a factor of approximately 10 (eg, HPV with LBC triage, 9.6 [95% CI, 9.3-10.0] per 1000 women screened). Over a lifetime of screening, reflex approaches with appropriate test intervals maximized therapeutic efficacy; as HPV vaccination rates increased, HPV-based screening approaches resulted in fewer unnecessary colposcopies than LBC approaches (HPV testing, 80% vaccine coverage: 44.1 [95% CI, 40-45.9] excess colposcopies; LBC testing, 80% vaccine coverage: 96.9 [95% CI, 96.8-97.0] excess colposcopies).Conclusions and relevanceIn this decision analytic model, the effectiveness of cervical cancer screening was dependent on the prevalence of cervical dysplasia and/or HPV infection or vaccination in a population as well as the sensitivity and specificity of various modalities. Although screening is lifesaving, overtesting or modalities inappropriate to the target population may cause significant harm, including overtreatment.

Project description:BackgroundLimited data are available describing human papillomavirus (HPV) genotype distributions in cervical cancer in the United States. Such studies are needed to predict how HPV vaccination and HPV-based screening will influence cervical cancer prevention.MethodsWe used the New Mexico Surveillance, Epidemiology, and End Results Registry to ascertain cases of in situ (n = 1213) and invasive (n = 808) cervical cancer diagnosed during 1985-1999 and 1980-1999, respectively, in the state of New Mexico. HPV genotyping was performed using two polymerase chain reaction-based methods on paraffin-embedded tissues from in situ and invasive cancers and on cervical Papanicolaou test specimen from control subjects (ie, women aged 18-40 years attending clinics for routine cervical screening [n = 4007]). Relative risks for cervical cancer were estimated, and factors associated with age at cancer diagnosis and the prevalence of HPV genotypes in cancers were examined.ResultsThe most common HPV genotypes detected in invasive cancers were HPV type 16 (HPV16, 53.2%), HPV18 (13.1%), and HPV45 (6.1%) and those in in situ cancers were HPV16 (56.3%), HPV31 (12.6%), and HPV33 (8.0%). Invasive cancer case subjects who were positive for HPV16 or 18 were diagnosed at younger ages than those who were positive for other carcinogenic HPV genotypes (mean age at diagnosis: 48.1 [95% confidence interval {CI} = 46.6 to 49.6 years], 45.9 [95% CI = 42.9 to 49.0 years], and 52.3 years [95% CI = 50.0 to 54.6 years], respectively). The proportion of HPV16-positive in situ and invasive cancers, but not of HPV18-positive cancers, declined with more recent calendar year of diagnosis, whereas the proportion positive for carcinogenic HPV genotypes other than HPV18 increased.ConclusionsHPV16 and 18 caused the majority of invasive cervical cancer in this population sample of US women, but the proportion attributable to HPV16 declined over the last 20 years. The age at diagnosis of HPV16- and HPV18-related cancers was 5 years earlier than that of cancers caused by carcinogenic HPV genotypes other than HPV16 and 18, suggesting that the age at initiation of cervical screening could be delayed in HPV-vaccinated populations.

Project description:The availability of human papillomavirus (HPV) DNA testing and vaccination against HPV types 16 and 18 (HPV-16,18) motivates questions about the cost-effectiveness of cervical cancer prevention in the United States for unvaccinated older women and for girls eligible for vaccination.An empirically calibrated model was used to assess the quality-adjusted life years (QALYs), lifetime costs, and incremental cost-effectiveness ratios (2004 US dollars per QALY) of screening, vaccination of preadolescent girls, and vaccination combined with screening. Screening varied by initiation age (18, 21, or 25 years), interval (every 1, 2, 3, or 5 years), and test (HPV DNA testing of cervical specimens or cytologic evaluation of cervical cells with a Pap test). Testing strategies included: 1) cytology followed by HPV DNA testing for equivocal cytologic results (cytology with HPV test triage); 2) HPV DNA testing followed by cytology for positive HPV DNA results (HPV test with cytology triage); and 3) combined HPV DNA testing and cytology. Strategies were permitted to switch once at age 25, 30, or 35 years.For unvaccinated women, triennial cytology with HPV test triage, beginning by age 21 years and switching to HPV testing with cytology triage at age 30 years, cost $78,000 per QALY compared with the next best strategy. For girls vaccinated before age 12 years, this same strategy, beginning at age 25 years and switching at age 35 years, cost $41,000 per QALY with screening every 5 years and $188,000 per QALY screening triennially, each compared with the next best strategy. These strategies were more effective and cost-effective than screening women of all ages with cytology alone or cytology with HPV triage annually or biennially.For both vaccinated and unvaccinated women, age-based screening by use of HPV DNA testing as a triage test for equivocal results in younger women and as a primary screening test in older women is expected to be more cost-effective than current screening recommendations.

Dataset Information

Modeling human papillomavirus and cervical cancer in the United States for analyses of screening and vaccination.

Background

Methods

Results

Conclusion

Publications

Modeling human papillomavirus and cervical cancer in the United States for analyses of screening and vaccination.

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