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Background: We are developing 10 de novo population-level mathematical models in 4 malignancies (multiple myeloma and bladder, gastric, and uterine cancers). Each of these sites has documented disparities in outcome that are believed to be downstream effects of systemic racism., Methods: Ten models are being independently developed as part of the Cancer Intervention and Surveillance Modeling Network incubator program. These models simulate trends in cancer incidence, early diagnosis, treatment, and mortality for the general population and are stratified by racial subgroup. Model inputs are based on large population datasets, clinical trials, and observational studies. Some core parameters are shared, and other parameters are model specific. All models are microsimulation models that use self-reported race to stratify model inputs. They can simulate the distribution of relevant risk factors (eg, smoking, obesity) and insurance status (for multiple myeloma and uterine cancer) in US birth cohorts and population., Discussion: The models aim to refine approaches in prevention, detection, and management of 4 cancers given uncertainties and constraints. They will help explore whether the observed racial disparities are explainable by inequities, assess the effects of existing and potential cancer prevention and control policies on health equity and disparities, and identify policies that balance efficiency and fairness in decreasing cancer mortality., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Since 2000, the National Cancer Institute's Cancer Intervention and Surveillance Modeling Network (CISNET) modeling teams have developed and applied microsimulation and statistical models of breast cancer. Here, we illustrate the use of collaborative breast cancer multilevel systems modeling in CISNET to demonstrate the flexibility of systems modeling to address important clinical and policy-relevant questions. Challenges and opportunities of future systems modeling are also summarized. The 6 CISNET breast cancer models embody the key features of systems modeling by incorporating numerous data sources and reflecting tumor, person, and health system factors that change over time and interact to affect the burden of breast cancer. Multidisciplinary modeling teams have explored alternative representations of breast cancer to reveal insights into breast cancer natural history, including the role of overdiagnosis and race differences in tumor characteristics. The models have been used to compare strategies for improving the balance of benefits and harms of breast cancer screening based on personal risk factors, including age, breast density, polygenic risk, and history of Down syndrome or a history of childhood cancer. The models have also provided evidence to support the delivery of care by simulating outcomes following clinical decisions about breast cancer treatment and estimating the relative impact of screening and treatment on the United States population. The insights provided by the CISNET breast cancer multilevel modeling efforts have informed policy and clinical guidelines. The 20 years of CISNET modeling experience has highlighted opportunities and challenges to expanding the impact of systems modeling. Moving forward, CISNET research will continue to use systems modeling to address cancer control issues, including modeling structural inequities affecting racial disparities in the burden of breast cancer. Future work will also leverage the lessons from team science, expand resource sharing, and foster the careers of early stage modeling scientists to ensure the sustainability of these efforts., Competing Interests: The authors have declared that no competing interests exist.

Objective: To estimate the cost-effectiveness of noncardia gastric adenocarcinoma (NCGA) screening strategies based on new biomarker and endoscopic technologies., Design: Using an intestinal-type NCGA microsimulation model, we evaluated the following one-time screening strategies for US men: (1) serum pepsinogen to detect gastric atrophy (with endoscopic follow-up of positive screen results), (2) endoscopic screening to detect dysplasia and asymptomatic cancer (with endoscopic mucosal resection (EMR) treatment for detected lesions) and (3) Helicobacter pylori screening and treatment. Screening performance, treatment effectiveness, cancer and cost data were based on published literature and databases. Subgroups included current, former and never smokers. Outcomes included lifetime cancer risk and incremental cost-effectiveness ratios (ICERs), expressed as cost per quality-adjusted-life-year (QALY) gained., Results: Screening the general population at age 50 years reduced the lifetime intestinal-type NCGA risk (0.24%) by 26.4% with serum pepsinogen screening, 21.2% with endoscopy and EMR and 0.2% with H. pylori screening/treatment. Targeting current smokers reduced the lifetime risk (0.35%) by 30.8%, 25.5%, and 0.1%, respectively. For all subgroups, serum pepsinogen screening was more effective and more cost-effective than all other strategies, although its ICER varied from $76,000/QALY (current smokers) to $105,400/QALY (general population). Results were sensitive to H. pylori prevalence, screen age and serum pepsinogen test sensitivity. Probabilistic sensitivity analysis found that at a $100,000/QALY willingness-to-pay threshold, the probability that serum pepsinogen screening was preferred was 0.97 for current smokers., Conclusions: Although not warranted for the general population, targeting high-risk smokers for serum pepsinogen screening may be a cost-effective strategy to reduce intestinal-type NCGA mortality., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Although gastric cancer has declined dramatically in the US, the disease remains the second leading cause of cancer mortality worldwide. A better understanding of reasons for the decline can provide important insights into effective preventive strategies. We sought to estimate the contribution of risk factor trends on past and future intestinal-type noncardia gastric adenocarcinoma (NCGA) incidence., Methods and Findings: We developed a population-based microsimulation model of intestinal-type NCGA and calibrated it to US epidemiologic data on precancerous lesions and cancer. The model explicitly incorporated the impact of Helicobacter pylori and smoking on disease natural history, for which birth cohort-specific trends were derived from the National Health and Nutrition Examination Survey (NHANES) and National Health Interview Survey (NHIS). Between 1978 and 2008, the model estimated that intestinal-type NCGA incidence declined 60% from 11.0 to 4.4 per 100,000 men, <3% discrepancy from national statistics. H. pylori and smoking trends combined accounted for 47% (range = 30%-58%) of the observed decline. With no tobacco control, incidence would have declined only 56%, suggesting that lower smoking initiation and higher cessation rates observed after the 1960s accelerated the relative decline in cancer incidence by 7% (range = 0%-21%). With continued risk factor trends, incidence is projected to decline an additional 47% between 2008 and 2040, the majority of which will be attributable to H. pylori and smoking (81%; range = 61%-100%). Limitations include assuming all other risk factors influenced gastric carcinogenesis as one factor and restricting the analysis to men., Conclusions: Trends in modifiable risk factors explain a significant proportion of the decline of intestinal-type NCGA incidence in the US, and are projected to continue. Although past tobacco control efforts have hastened the decline, full benefits will take decades to be realized, and further discouragement of smoking and reduction of H. pylori should be priorities for gastric cancer control efforts.

As pediatric Hodgkin lymphoma (HL) survival rates approach > 95%, treatment decisions are increasingly based on minimizing late effects. Using a model-based approach, we explored whether the addition of radiotherapy contributes to improved overall long-term survival. We developed a state-transition model to simulate the lifetime HL clinical course, and we compared 2 treatment strategies: chemotherapy alone (CT) and chemoradiotherapy (CRT). Data on HL relapse, late recurrence, and excess second cancer and cardiac late-effects mortality were estimated from the published literature and databases. Outcomes included conditional life expectancy, cause-specific mortality, and proportion alive at age 50. For a hypothetical cohort of HL patients (diagnosis age 15), conditional life expectancy was 57.2 years with CT compared with 56.4 years with CRT. Estimated lifetime HL mortality risk was 3.6% with CT versus 2.2% with CRT. In contrast, combined risk of excess late-effects mortality was lower for CT (1.8% vs 7.4% with CRT). Among those alive at age 50, only 9.2% of those initially treated with CT were at risk for radiation-related late effects (100% for CRT). Initial treatment with CT may be associated with longer average per-person life expectancy. These results support the need for careful consideration of the risk-benefit profile of radiation as frontline therapy in pediatric patients.

Background: The incidence of esophageal adenocarcinoma (EAC) has risen rapidly in the U.S. and western world. The aim of the study was to begin the investigation of this rapid rise by developing, calibrating, and validating a mathematical disease simulation model of EAC using available epidemiologic data., Methods: The model represents the natural history of EAC, including the essential biologic health states from normal mucosa to detected cancer. Progression rates between health states were estimated via calibration, which identified distinct parameter sets producing model outputs that fit epidemiologic data; specifically, the prevalence of pre-cancerous lesions and EAC cancer incidence from the published literature and Surveillance, Epidemiology, and End Results (SEER) data. As an illustrative example of a clinical and policy application, the calibrated and validated model retrospectively analyzed the potential benefit of an aspirin chemoprevention program., Results: Model outcomes approximated calibration targets; results of the model's fit and validation are presented. Approximately 7,000 cases of EAC could have been prevented over a 30-year period if all white males started aspirin chemoprevention at age 40 in 1965., Conclusions: The model serves as the foundation for future analyses to determine a cost-effective screening and management strategy to prevent EAC morbidity and mortality.

Background: The major complications of pelvic inflammatory disease (infertility, ectopic pregnancy, and chronic pelvic pain) are the leading cause of non-HIV sexually transmitted disease morbidity in the United States., Goal: The goal of the study was to estimate a plausible range for the average lifetime cost of pelvic inflammatory disease (PID) and its major complications in a cohort of U.S. women of reproductive age., Study Design: We developed a state-transition computer-based model to simulate the natural history of PID, incorporating the severity of infection, number of recurrent episodes, treatment setting, and the risk over time of major complications. Clinical and cost data were from the published literature. Model outcomes included life expectancy, quality-adjusted life expectancy, and lifetime costs., Results: In a cohort of 100,000 females acquiring PID between 20 and 24 years of age, 8550 ectopic pregnancies, 16,800 cases of infertility, and 18,600 cases of chronic pelvic pain were projected to occur. Assuming a 3% annual discount rate, we found the average per-person lifetime cost to be $2150. Average lifetime costs for women who developed major complications were $6350 for chronic pelvic pain, $6840 for ectopic pregnancy, and $1270 for infertility. The majority of costs (79%) were accrued within 5 years of upper genital tract infection. Results were most sensitive to assumptions about the timing of major complications and the discount rate., Conclusion: The average per-person lifetime cost of PID ranges between $1060 and $3180. Future cost-effectiveness analyses of STD screening programs can include this range as a reasonable upper and lower bound. These findings suggest successful PID prevention efforts may avert substantial costs for care providers such as managed care organizations while providing well documented clinical benefits for women in the United States.

This paper is the first of its kind to study the impact of Fabry disease (FD) in affected males, and shows that FD is associated with a significant decline in several domains. Using the medical outcomes study (MOS) SF-36 and a FD-specific questionnaire, we compared the observations found among these patients with that obtained for the general US population and other chronic disease states, including Gaucher disease (GD) (another lysosomal storage disorder), end-stage renal disease, stoke and AIDS. Patients with FD have a score profile most similar to patients with AIDS. In comparison with patients with GD, Fabry patients score substantially lower across all domains. Using simple linear regression, potential predictors of health-related quality of life (HRQOL) for Fabry patients were also determined. As in the general population, stroke, cardiac problems and renal disease lead to substantial decrement in HRQOL. In addition, two disease specific symptoms (acroparesthesia and anhidrosis) and pain are also predictors of decreased quality of life. Currently, no specific therapy for FD exists. As enzyme therapy for FD becomes increasingly available, it will be interesting to evaluate the therapy's impact on the quality of life of patients.