The OncoSim-Breast Cancer Microsimulation Model.

BACKGROUND: OncoSim-Breast is a Canadian breast cancer simulation model to evaluate breast cancer interventions. This paper aims to describe the OncoSim-Breast model and how well it reproduces observed breast cancer trends. METHODS: The OncoSim-Breast model simulates the onset, growth, and spread of invasive and ductal carcinoma in situ tumours. It combines Canadian cancer incidence, mortality, screening program, and cost data to project population-level outcomes. Users can change the model input to answer specific questions. Here, we compared its projections with observed data. First, we compared the model's projected breast cancer trends with the observed data in the Canadian Cancer Registry and from Vital Statistics. Next, we replicated a screening trial to compare the model's projections with the trial's observed screening effects. RESULTS: OncoSim-Breast's projected incidence, mortality, and stage distribution of breast cancer were close to the observed data in the Canadian Cancer Registry and from Vital Statistics. OncoSim-Breast also reproduced the breast cancer screening effects observed in the UK Age trial. CONCLUSIONS: OncoSim-Breast's ability to reproduce the observed population-level breast cancer trends and the screening effects in a randomized trial increases the confidence of using its results to inform policy decisions related to early detection of breast cancer.

Clinical impact and cost-effectiveness of integrating smoking cessation into lung cancer screening: a microsimulation model.

BACKGROUND: Low-dose computed tomography (CT) screening can reduce lung cancer mortality in people at high risk; adding a smoking cessation intervention to screening could further improve screening program outcomes. This study aimed to assess the impact of adding a smoking cessation intervention to lung cancer screening on clinical outcomes, costs and cost-effectiveness. METHODS: Using the OncoSim-Lung mathematical microsimulation model, we compared the projected lifetime impact of a smoking cessation intervention (nicotine replacement therapy, varenicline and 12 wk of counselling) in the context of annual low-dose CT screening for lung cancer in people at high risk to lung cancer screening without a cessation intervention in Canada. The simulated population consisted of Canadians born in 1940-1974; lung cancer screening was offered to eligible people in 2020. In the base-case scenario, we assumed that the intervention would be offered to smokers up to 10 times; each intervention would achieve a 2.5% permanent quit rate. Sensitivity analyses varied key model inputs. We calculated incremental cost-effectiveness ratios with a lifetime horizon from the health system's perspective, discounted at 1.5% per year. Costs are in 2019 Canadian dollars. RESULTS: Offering a smoking cessation intervention in the context of lung cancer screening could lead to an additional 13% of smokers quitting smoking. It could potentially prevent 12 more lung cancers and save 200 more life-years for every 1000 smokers screened, at a cost of $22 000 per quality-adjusted life-year (QALY) gained. The results were most sensitive to quit rate. The intervention would cost over $50 000 per QALY gained with a permanent quit rate of less than 1.25% per attempt. INTERPRETATION: Adding a smoking cessation intervention to lung cancer screening is likely cost-effective. To optimize the benefits of lung cancer screening, health care providers should encourage participants who still smoke to quit smoking.

A Phase I Study of DLYE5953A, an Anti-LY6E Antibody Covalently Linked to Monomethyl Auristatin E, in Patients with Refractory Solid Tumors.

PURPOSE: DLYE5953A is an antibody-drug conjugate consisting of an anti-LY6E antibody covalently linked to the cytotoxic agent monomethyl auristatin E. This study characterized the safety, pharmacokinetics, immunogenicity, potential biomarkers, and antitumor activity of DLYE5953A in patients with metastatic solid tumors. PATIENTS AND METHODS: This was a phase I, open-label, 3+3 dose-escalation, and dose-expansion study of DLYE5953A administered intravenously every 21 days (Q3W) in patients with locally advanced or metastatic solid malignancies. RESULTS: Sixty-eight patients received DLYE5953A (median, four cycles; range, 1-27). No dose-limiting toxicities were identified during dose escalation (0.2-2.4 mg/kg; n = 20). The recommended phase II dose (RP2D) of 2.4 mg/kg Q3W was based on overall safety and tolerability. Dose-expansion cohorts for HER2-negative metastatic breast cancer (HER2-negative MBC; n = 23) and non-small cell lung cancer (NSCLC; n = 25) patients were enrolled at the RP2D. Among patients receiving DLYE5953A 2.4 mg/kg (n = 55), the most common (≥30%) related adverse events (AEs) included alopecia, fatigue, nausea, and peripheral neuropathy. Grade ≥3 related AEs occurred in 14 of 55 (26%) patients, with neutropenia being the most common (13%). DLYE5953A demonstrated linear total antibody pharmacokinetics at doses of ≥0.8 mg/kg with low unconjugated monomethyl auristatin E levels in blood. Partial response was confirmed in eight of 68 (12%) patients, including three of 29 patients with MBC (10%) and five of 25 patients with NSCLC (20%) at the RP2D. Stable disease was the best response for 37 of 68 (54%) patients. CONCLUSIONS: DLYE5953A administered at 2.4 mg/kg has acceptable safety. Preliminary evidence of antitumor activity in patients with HER2-negative MBC and NSCLC supports further investigation of LY6E as a therapeutic target.

Biennial lung cancer screening in Canada with smoking cessation-outcomes and cost-effectiveness.

BACKGROUND: Guidelines recommend low-dose CT (LDCT) screening to detect lung cancer among eligible at-risk individuals. We used the OncoSim model (formerly Cancer Risk Management Model) to compare outcomes and costs between annual and biennial LDCT screening. METHODS: OncoSim incorporates vital statistics, cancer registry data, health survey and utility data, cost, and other data, and simulates individual lives, aggregating outcomes over millions of individuals. Using OncoSim and National Lung Screening Trial eligibility criteria (age 55-74, minimum 30 pack-year smoking history, smoking cessation less than 15 years from time of first screen) and data, we have modeled screening parameters, cancer stage distribution, and mortality shifts for screen diagnosed cancer. Costs (in 2008 Canadian dollars) and quality of life years gained are discounted at 3% annually. RESULTS: Compared with annual LDCT screening, biennial screening used fewer resources, gained fewer life-years (61,000 vs. 77,000), but resulted in very similar quality-adjusted life-years (QALYs) (24,000 vs. 23,000) over 20 years. The incremental cost-effectiveness ratio (ICER) of annual compared with biennial screening was $54,000-$4.8 million/QALY gained. Average incremental CT scan use in biennial screening was 52% of that in annual screening. A smoking cessation intervention decreased the average cost-effectiveness ratio in most scenarios by half. CONCLUSIONS: Over 20 years, biennial LDCT screening for lung cancer appears to provide similar benefit in terms of QALYs gained to annual screening and is more cost-effective. Further study of biennial screening should be undertaken in population screening programs. A smoking cessation program should be integrated into either screening strategy.

Risk of work loss due to illness or disability in patients with osteoarthritis: a population-based cohort study.

OBJECTIVES: To estimate the risk of work loss due to illness or disability in a cohort of employed persons with OA compared with matched non-OA individuals. METHODS: We performed a population-based cohort analysis using the last six cycles of the Canadian longitudinal National Population Health Survey from 2000 to 2010. OA cases and up to four age- and sex-matched non-OA individuals were selected. Discrete time hazard regression models were used to estimate the hazard of work loss due to illness or disability. To analyse the effect of a self-reported OA measure on the outcome, we performed a sensitivity analyses for case selection. RESULTS: From 7273 employed individuals between the ages of 20 and 70 years in the National Population Health Survey, 659 OA cases were selected and matched to 2144 non-OA individuals. The proportion of OA cases who experienced work loss due to illness or disability during the follow-up period was 12.6%, compared with 9.3% for non-OA individuals (P < 0.001). OA cases had a 90% [hazard ratio (HR) 1.90 (95% CI 1.36, 3.23)] higher hazard of work loss due to illness or disability compared with their matched non-OA individuals after adjusting for sociodemographic, health and work-related status. The adjusted HRs were 1.61 (95% CI 1.13, 2.30) and 2.04 (95% CI 1.74, 4.75) for females and males, respectively. CONCLUSION: OA is independently associated with an increased risk of work loss due to illness or disability. Given the high prevalence of OA in the population of working age, future research may wish to investigate ways to improve occupational participation among OA patients.

Effects of Reductions in Body Mass Index on the Future Osteoarthritis Burden in Canada: A Population-Based Microsimulation Study.

OBJECTIVE: Osteoarthritis (OA) is the most common joint disease and a major cause of disability. Incidence and prevalence of OA are expected to increase due to population aging and increased levels of obesity. The purpose of this study was to project the effect of hypothetical interventions that change the distribution of body mass index (BMI) on OA burden in Canada. METHODS: We used a microsimulation computer model of OA based on the Population Health Model platform. The model used demographic predictions for Canada and population data from an administrative database in British Columbia and national Canadian surveys. RESULTS: Under the base-case scenario, between 2010 and 2030, OA prevalence is expected to increase from 11.5% to 15.6% in men and 16.3% to 21.1% in women. In scenarios assuming, on average, a 0.3-, 0.5-, or 1-unit drop in BMI per year, OA prevalence in 2030 would reach 14.9%, 14.6%, and 14.2% in men and 20.3%, 19.7%, and 18.5%, in women, respectively. Under these scenarios, the proportion of new cases prevented would be 9.5%, 13.2%, and 16.7%, respectively, in men, and 9.1%, 15.2%, and 25.0% in women. Targeting only those people ages ≥50 years for weight reduction would achieve approximately 70% of the impact of a full population strategy. Targeting only the obese (BMI ≥30) would likely result in a larger benefit for men than women. CONCLUSION: Due to the aging of the population, OA will remain a major and growing health issue in Canada over the next 2 decades, regardless of the course of the obesity epidemic.

The Population Health Model (POHEM): an overview of rationale, methods and applications.

The POpulation HEalth Model (POHEM) is a health microsimulation model that was developed at Statistics Canada in the early 1990s. POHEM draws together rich multivariate data from a wide range of sources to simulate the lifecycle of the Canadian population, specifically focusing on aspects of health. The model dynamically simulates individuals' disease states, risk factors, and health determinants, in order to describe and project health outcomes, including disease incidence, prevalence, life expectancy, health-adjusted life expectancy, quality of life, and healthcare costs. Additionally, POHEM was conceptualized and built with the ability to assess the impact of policy and program interventions, not limited to those taking place in the healthcare system, on the health status of Canadians. Internationally, POHEM and other microsimulation models have been used to inform clinical guidelines and health policies in relation to complex health and health system problems. This paper provides a high-level overview of the rationale, methodology, and applications of POHEM. Applications of POHEM to cardiovascular disease, physical activity, cancer, osteoarthritis, and neurological diseases are highlighted.

Cost-effectiveness of Lung Cancer Screening in Canada.

IMPORTANCE: The US National Lung Screening Trial supports screening for lung cancer among smokers using low-dose computed tomographic (LDCT) scans. The cost-effectiveness of screening in a publically funded health care system remains a concern. OBJECTIVE: To assess the cost-effectiveness of LDCT scan screening for lung cancer within the Canadian health care system. DESIGN, SETTING, AND PARTICIPANTS: The Cancer Risk Management Model (CRMM) simulated individual lives within the Canadian population from 2014 to 2034, incorporating cancer risk, disease management, outcome, and cost data. Smokers and former smokers eligible for lung cancer screening (30 pack-year smoking history, ages 55-74 years, for the reference scenario) were modeled, and performance parameters were calibrated to the National Lung Screening Trial (NLST). The reference screening scenario assumes annual scans to age 75 years, 60% participation by 10 years, 70% adherence to screening, and unchanged smoking rates. The CRMM outputs are aggregated, and costs (2008 Canadian dollars) and life-years are discounted 3% annually. MAIN OUTCOMES AND MEASURES: The incremental cost-effectiveness ratio. RESULTS: Compared with no screening, the reference scenario saved 51,000 quality-adjusted life-years (QALY) and had an incremental cost-effectiveness ratio of CaD $52,000/QALY. If smoking history is modeled for 20 or 40 pack-years, incremental cost-effectiveness ratios of CaD $62,000 and CaD $43,000/QALY, respectively, were generated. Changes in participation rates altered life years saved but not the incremental cost-effectiveness ratio, while the incremental cost-effectiveness ratio is sensitive to changes in adherence. An adjunct smoking cessation program improving the quit rate by 22.5% improves the incremental cost-effectiveness ratio to CaD $24,000/QALY. CONCLUSIONS AND RELEVANCE: Lung cancer screening with LDCT appears cost-effective in the publicly funded Canadian health care system. An adjunct smoking cessation program has the potential to improve outcomes.

Performance of the cancer risk management model lung cancer screening module.

BACKGROUND: The National Lung Screening Trial (NLST) demonstrated that low-dose computed tomography (LDCT) screening reduces lung cancer mortality in a high-risk U.S. population. A microsimulation model of LDCT screening was developed to estimate the impact of introducing population-based screening in Canada. DATA AND METHODS: LDCT screening was simulated using the lung cancer module of the Cancer Risk Management Model (CRMM-LC), which generates large, representative samples of the Canadian population from which a cohort with characteristics similar to NLST participants was selected. Screening parameters were estimated for stage shift, LDCT sensitivity and specificity, lead time, and survival to fit to NLST incidence and mortality results. The estimation process was a step-wise directed search. RESULTS: Simulated mortality reduction from LDCT screening was 23% in the CRMM-LC, compared with 20% in the NLST. The difference in the number of lung cancer cases over six years varied by, at most, 2.3% in the screen arm. The difference in cumulative incidence at six years was less than 2% in both screen and control arms. The estimated percentage over-diagnosed was 24.8%, which was 6% higher than NLST results. INTERPRETATION: Simulated screening reproduces NLST results. The CRMM-LC can evaluate a variety of population-based screening strategies. Sensitivity analyses are recommended to provide a range of projections to reflect model uncertainty.

Eligibility for low-dose computerized tomography screening among asbestos-exposed individuals.

OBJECTIVES: The study aimed to incorporate an estimate of risk for asbestos exposure in the Canadian Cancer Risk Management Lung Cancer (CRMM-LC) microsimulation model. METHODS: In CRMM-LC, a 3-year probability of developing lung cancer can be derived from different risk profiles. An asbestos-exposed cohort was simulated and different scenarios of low-dose computerized tomography (LDCT) screening were simulated. RESULTS: As annual LDCT screening among non-asbestos-exposed individuals is less cost-effective than biennial screening, all the scenarios modeled for an asbestos-exposed cohort were biennial. For individuals with a two-fold risk of asbestos-induced lung cancer to be eligible for biennial LDCT screening, a smoking history of ≥15 pack-years would be necessary. For non-smokers with asbestos exposure resulting in a relative risk (RR) for lung cancer, it is not cost-effective to screen those with a RR of 5, but it is cost-effective to screen those with a RR of 10 (the heavily exposed). CONCLUSION: Asbestos-exposed individuals with an estimated two-fold or more risk of lung cancer from asbestos-exposure are eligible for LDCT screening at all ages from 55-74 years if they have a cigarette smoking history of ≥15 pack-years. Asbestos-exposed individuals who are lifelong non-smokers are eligible for LDCT screening at all ages from 55-74 years if they have accumulated a degree of asbestos exposure resulting in an estimated risk of lung cancer of ≥10.

Development of a population-based microsimulation mode of physical activity in Canada.

BACKGROUND: Computer simulation modeling makes it possible to project physical activity levels and the prevalence of related health outcomes. Such projections can help to inform programs that aim to increase physical activity levels and improve population health. DATA AND METHODS: The Population Health Model (POHEM) platform was used to develop a dynamic microsimulation model of physical activity among Canadian adults. Key parameters were derived from the National Population Health Survey (1994/1995 to 2006/2007) and the 2000/2001 Canadian Community Health Survey. To assess the validity of the physical activity module (POHEM-PA), estimates from the simulation projections were compared with results from nationally representative surveys. RESULTS: Trends over time in physical activity levels, chronic disease prevalence, and Health Utilities Index based on POHEM-PA projections were similar to those based on data from subsequent cycles of the Canadian Community Health Survey. INTERPRETATION: The addition of a physical activity module to POHEM provides a tool that can improve understanding of the complex dynamics underlying the relationship between physical activity and health outcomes as a population ages.

Canadian Cancer Risk Management Model: evaluation of cancer control.

OBJECTIVES: The aim of this study was to develop a decision support tool to assess the potential benefits and costs of new healthcare interventions. METHODS: The Canadian Partnership Against Cancer (CPAC) commissioned the development of a Cancer Risk Management Model (CRMM)--a computer microsimulation model that simulates individual lives one at a time, from birth to death, taking account of Canadian demographic and labor force characteristics, risk factor exposures, and health histories. Information from all the simulated lives is combined to produce aggregate measures of health outcomes for the population or for particular subpopulations. RESULTS: The CRMM can project the population health and economic impacts of cancer control programs in Canada and the impacts of major risk factors, cancer prevention, and screening programs and new cancer treatments on population health and costs to the healthcare system. It estimates both the direct costs of medical care, as well as lost earnings and impacts on tax revenues. The lung and colorectal modules are available through the CPAC Web site (www.cancerview.ca/cancerrriskmanagement) to registered users where structured scenarios can be explored for their projected impacts. Advanced users will be able to specify new scenarios or change existing modules by varying input parameters or by accessing open source code. Model development is now being extended to cervical and breast cancers.

Validation of population-based disease simulation models: a review of concepts and methods.

BACKGROUND: Computer simulation models are used increasingly to support public health research and policy, but questions about their quality persist. The purpose of this article is to review the principles and methods for validation of population-based disease simulation models. METHODS: We developed a comprehensive framework for validating population-based chronic disease simulation models and used this framework in a review of published model validation guidelines. Based on the review, we formulated a set of recommendations for gathering evidence of model credibility. RESULTS: Evidence of model credibility derives from examining: 1) the process of model development, 2) the performance of a model, and 3) the quality of decisions based on the model. Many important issues in model validation are insufficiently addressed by current guidelines. These issues include a detailed evaluation of different data sources, graphical representation of models, computer programming, model calibration, between-model comparisons, sensitivity analysis, and predictive validity. The role of external data in model validation depends on the purpose of the model (e.g., decision analysis versus prediction). More research is needed on the methods of comparing the quality of decisions based on different models. CONCLUSION: As the role of simulation modeling in population health is increasing and models are becoming more complex, there is a need for further improvements in model validation methodology and common standards for evaluating model credibility.

Trends in risk factors for cardiovascular disease in Canada: temporal, socio-demographic and geographic factors.

BACKGROUND: Temporal trends in risk factors for cardiovascular disease and the impact of socio-economic status on these risk factors remain unclear. METHODS: Using data from the National Population Health Survey and the Canadian Community Health Survey, we examined national trends in heart disease, hypertension, diabetes mellitus, obesity and smoking prevalence from 1994 to 2005, adjusting for age and sex. We stratified data by income adequacy category, body mass index and region of residence. RESULTS: An estimated 1.29 million Canadians reported having heart disease in 2005, representing increases of 19% for men and 2% for women, relative to 1994. Heart disease increased significantly in the lowest income category (by 27%), in the lower middle income category (by 37%) and in the upper middle income category (by 12%); however, it increased by only 6% in the highest income group. Diabetes increased in all but the highest income group: by 56% in the lowest income group, by 93% in the lower middle income group and by 59% in the upper middle income group. Hypertension increased in all income groups: by 85% in the lowest income group, by 80% in the lower middle income group, by 91% in the upper middle income group and by 117% in the highest income group. Obesity also increased in all income groups: by 20% in the lowest income group, by 25% in the lower middle income group, by 33% in the upper middle income group and by 37% in the highest income group. In addition to socio-economic status, obesity and overweight also modified the trends in risk factors. Diabetes increased to a greater extent among obese participants (61% increase) and overweight participants (25% increase), as did hypertension, which increased by 80% among obese individuals and by 74% among overweight individuals. Trends in diabetes, hypertension and obesity were consistent for all provinces. INTERPRETATION: During the study period, heart disease, hypertension, diabetes and obesity increased for all or most income groups in Canada. Further interventions supporting modification of lifestyle and risk factors are needed to prevent future cardiovascular disease.

Discovery of a potent and selective aurora kinase inhibitor.

This communication describes the discovery of a novel series of Aurora kinase inhibitors. Key SAR and critical binding elements are discussed. Some of the more advanced analogues potently inhibit cellular proliferation and induce phenotypes consistent with Aurora kinase inhibition. In particular, compound 21 (SNS-314) is a potent and selective Aurora kinase inhibitor that exhibits significant activity in pre-clinical in vivo tumor models.

Trends in physician-diagnosed osteoarthritis incidence in an administrative database in British Columbia, Canada, 1996-1997 through 2003-2004.

OBJECTIVE: Prevalence of osteoarthritis (OA) is expected to increase due to population aging. However, there is little information on the trends in the incidence of OA over time. The purpose of this study was to describe changes in physician-diagnosed OA incidence rates between 1996-1997 and 2003-2004 in British Columbia (BC), Canada. METHODS: We used data on all visits to health professionals and hospital admissions covered by the Medical Services Plan of BC (population approximately 4 million) for the fiscal years 1991-1992 through 2003-2004. Rates were standardized to the BC population in 2000. We used 2 definitions of OA: 1) at least 1 visit or hospitalization with a diagnostic code for OA, and 2) at least 2 visits or 1 hospitalization with a code for OA. Incidence rates were calculated with a 5-year run-in period to exclude prevalent cases. RESULTS: Between 1996-1997 and 2003-2004, crude incidence rates of OA based on definition 1 increased from 10.5 to 12.2 per 1,000 in men and from 13.9 to 17.4 per 1,000 in women. The age-standardized rates did not change in men and increased from 14.7 to 16.7 per 1,000 in women. Incidence rates based on definition 2 were almost 50% lower, but the trends were similar. CONCLUSION: We observed an increase in the incidence of OA in both men and women due to population aging and an additional increase in women beyond the effect of aging. These trends have important implications for public health and provision of health services to this very large group of patients.

Population health impact of cancer in Canada, 2001.

Summary measures of population health that incorporate morbidity provide a new perspective for health policy and priority setting. Health-adjusted life years (HALYs) lost to a disease combine the impact of years of life lost to premature mortality and morbidity, measured as year-equivalents lost to reduced functioning. HALYs for 25 cancers were estimated from mortality and incidence in 2001 in Canada; population-attributable fractions were estimated for major risk factors contributing to these cancers. Results from this analysis indicate that Canadians would lose an estimated 905,000 health-adjusted years of life to cancer for 2001, including 771,000 to premature mortality and 134,000 to morbidity from incident cases (years discounted at 3 percent). Most of the estimated premature mortality was due to lung cancer; morbidity was largely due to breast, prostate and colorectal cancers. An estimated one quarter of HALYs lost to cancer were attributable to smoking and almost one quarter were attributable to alcohol consumption, lack of fruit and vegetables, obesity and physical inactivity combined. These results are a significant advance in measuring the population health impact of cancer in Canada because they incorporate morbidity as well as mortality.

Small-molecule inhibition of TNF-alpha.

We have identified a small-molecule inhibitor of tumor necrosis factor alpha (TNF-alpha) that promotes subunit disassembly of this trimeric cytokine family member. The compound inhibits TNF-alpha activity in biochemical and cell-based assays with median inhibitory concentrations of 22 and 4.6 micromolar, respectively. Formation of an intermediate complex between the compound and the intact trimer results in a 600-fold accelerated subunit dissociation rate that leads to trimer dissociation. A structure solved by x-ray crystallography reveals that a single compound molecule displaces a subunit of the trimer to form a complex with a dimer of TNF-alpha subunits.

Potential impact of population-based colorectal cancer screening in Canada.

Randomized controlled trials (RCT) have shown the efficacy of screening for colorectal cancer (CRC) using the faecal occult blood test (FOBT) with follow-up by colonoscopy. We evaluated the potential impact of population-based screening by FOBT followed by colonoscopy in Canada: mortality reduction, cost-effectiveness, and resource requirements. The microsimulation model POHEM was adapted to simulate CRC screening using Canadian data and RCT results about test sensitivity and specificity, participation, incidence, staging, progression, mortality and direct health care costs. In Canada, biennial screening of 67% of individuals aged 50-74 in the year 2000 resulted in an estimated 10-year CRC mortality reduction of 16.7%. The life expectancy of the cohort increased by 15 days on average and the demand for colonoscopy rose by 15% in the first year. The estimated cost of screening was $112 million per year or $11,907 per life-year gained (discounted at 5%). Potential effectiveness would depend on reaching target participation rates and finding resources to meet the demand for FOBT and colonoscopy. This work was conducted in support of the National Committee on Colorectal Cancer Screening.