Regulating cancer risk prediction: legal considerations and stakeholder perspectives on the Canadian context.

Risk prediction models hold great promise to reduce the impact of cancer in society through advanced warning of risk and improved preventative modalities. These models are evolving and becoming more complex, increasingly integrating genetic screening data and polygenic risk scores as well as calculating risk for multiple types of a disease. However, unclear regulatory compliance requirements applicable to these models raise significant legal uncertainty and new questions about the regulation of medical devices. This paper aims to address these novel regulatory questions by presenting an initial assessment of the legal status likely applicable to risk prediction models in Canada, using the CanRisk tool for breast and ovarian cancer as an exemplar. Legal analysis is supplemented with qualitative perspectives from expert stakeholders regarding the accessibility and compliance challenges of the Canadian regulatory framework. While the paper focuses on the Canadian context, it also refers to European and U.S. regulations in this domain to contrast them. Legal analysis and stakeholder perspectives highlight the need to clarify and update the Canadian regulatory framework for Software as a Medical Device as it applies to risk prediction models. Findings demonstrate how normative guidance perceived as convoluted, contradictory or overly burdensome can discourage innovation, compliance, and ultimately, implementation. This contribution aims to initiate discussion about a more optimal legal framework for risk prediction models as they continue to evolve and are increasingly integrated into landscape for public health.

Using Real-World Data to Determine Health System Costs of Ontario Women Screened for Breast Cancer.

Our study was to determine breast cancer screening costs in Ontario, Canada for screenings conducted through a formal (Ontario Breast Screening Program, OBSP) and informal (non-OBSP) screening program using administrative databases. Included women were 49-74 years of age when receiving screening mammograms between 1 January 2013 to 31 December 2019. Each woman was followed for a screening episode with screening and diagnostic components, and costs were calculated as an average cost per woman per month in 2021 Canadian dollars. The final cohort of 1,546,386 women screened had a mean age of 59.4 ± 7.1 years and ~87% were screened via OBSP. The average total cost per woman per month was $136 ± $103, $134 ± $103 and $155 ± $104 for the entire, OBSP and non-OBSP cohorts, respectively. This was further disaggregated into the average total screening cost per month, which was $103 ± $8, $100 ± $4 and $117 ± $9 per woman, and the average total diagnostic cost per woman per month at $219 ± $166, $228 ± $165 and $178 ± $159. for the entire, OBSP and non-OBSP cohorts, respectively. These results indicate similar screening costs across the different cohorts, but higher diagnostic costs for the OBSP cohort.

Income inequality and population health: a political-economic research agenda.

There is more than 30 years of research on relationships between income inequality and population health. In this article, we propose a research agenda with five recommendations for future research to refine existing knowledge and examine new questions. First, we recommend that future research prioritise analyses with broader time horizons, exploring multiple temporal aspects of the relationship. Second, we recommend expanding research on the effect of public expenditures on the inequality-health relationship. Third, we introduce a new area of inquiry focused on interactions between social mobility, income inequality and population health. Fourth, we argue the need to examine new perspectives on 21st century capitalism, specifically the population health impacts of inequality in income from capital (especially housing), in contrast to inequality in income from labour. Finally, we propose that this research broaden beyond all-cause mortality, to cause-specific mortality, avoidable mortality and subcategories thereof. We believe that such a research agenda is important for policy to respond to the changes following the COVID-19 pandemic.

Should Age-Dependent Absolute Risk Thresholds Be Used for Risk Stratification in Risk-Stratified Breast Cancer Screening?

In risk-stratified cancer screening, multiple risk factors are incorporated into the risk assessment. An individual's estimated absolute cancer risk is linked to risk categories with tailored screening recommendations for each risk category. Absolute risk, expressed as either remaining lifetime risk or shorter-term (five- or ten-year) risk, is estimated from the age at assessment. These risk estimates vary by age; however, some clinical guidelines (e.g., enhanced breast cancer surveillance guidelines) and ongoing personalised breast screening trials, stratify women based on absolute risk thresholds that do not vary by age. We examine an alternative approach in which the risk thresholds used for risk stratification vary by age and consider the implications of using age-independent risk thresholds on risk stratification. We demonstrate that using an age-independent remaining lifetime risk threshold approach could identify high-risk younger women but would miss high-risk older women, whereas an age-independent 5-year or 10-year absolute risk threshold could miss high-risk younger women and classify lower-risk older women as high risk. With risk misclassification, women with an equivalent risk level would be offered a different screening plan. To mitigate these problems, age-dependent absolute risk thresholds should be used to inform risk stratification.

Risk-Stratified Approach to Breast Cancer Screening in Canada: Women's Knowledge of the Legislative Context and Concerns about Discrimination from Genetic and Other Predictive Health Data.

The success of risk-stratified approaches in improving population-based breast cancer screening programs depends in no small part on women's buy-in. Fear of genetic discrimination (GD) could be a potential barrier to genetic testing uptake as part of risk assessment. Thus, the objective of this study was twofold. First, to evaluate Canadian women's knowledge of the legislative context governing GD. Second, to assess their concerns about the possible use of breast cancer risk levels by insurance companies or employers. We use a cross-sectional survey of 4293 (age: 30-69) women, conducted in four Canadian provinces (Alberta, British Colombia, Ontario and Québec). Canadian women's knowledge of the regulatory framework for GD is relatively limited, with some gaps and misconceptions noted. About a third (34.7%) of the participants had a lot of concerns about the use of their health information by employers or insurers; another third had some concerns (31.9%), while 20% had no concerns. There is a need to further educate and inform the Canadian public about GD and the legal protections that exist to prevent it. Enhanced knowledge could facilitate the implementation and uptake of risk prediction informed by genetic factors, such as the risk-stratified approach to breast cancer screening that includes risk levels.

Potential of polygenic risk scores for improving population estimates of women's breast cancer genetic risks.

PURPOSE: Breast cancer risk has conventionally been assessed using family history (FH) and rare high/moderate penetrance pathogenic variants (PVs), notably in BRCA1/2, and more recently PALB2, CHEK2, and ATM. In addition to these PVs, it is now possible to use increasingly predictive polygenic risk scores (PRS) as well. The comparative population-level predictive capability of these three different indicators of genetic risk for risk stratification is, however, unknown. METHODS: The Canadian heritable breast cancer risk distribution was estimated using a novel genetic mixing model (GMM). A realistically representative sample of women was synthesized based on empirically observed demographic patterns for appropriately correlated family history, inheritance of rare PVs, PRS, and residual risk from an unknown polygenotype. Risk assessment was simulated using the BOADICEA risk algorithm for 10-year absolute breast cancer incidence, and compared to heritable risks as if the overall polygene, including its measured PRS component, and PV risks were fully known. RESULTS: Generally, the PRS was most predictive for identifying women at high risk, while family history was the weakest. Only the PRS identified any women at low risk of breast cancer. CONCLUSION: PRS information would be the most important advance in enabling effective risk stratification for population-wide breast cancer screening.

Personalized Risk Assessment for Prevention and Early Detection of Breast Cancer: Integration and Implementation (PERSPECTIVE I&I).

Early detection of breast cancer through screening reduces breast cancer mortality. The benefits of screening must also be considered within the context of potential harms (e.g., false positives, overdiagnosis). Furthermore, while breast cancer risk is highly variable within the population, most screening programs use age to determine eligibility. A risk-based approach is expected to improve the benefit-harm ratio of breast cancer screening programs. The PERSPECTIVE I&I (Personalized Risk Assessment for Prevention and Early Detection of Breast Cancer: Integration and Implementation) project seeks to improve personalized risk assessment to allow for a cost-effective, population-based approach to risk-based screening and determine best practices for implementation in Canada. This commentary describes the four inter-related activities that comprise the PERSPECTIVE I&I project. 1: Identification and validation of novel moderate to high-risk susceptibility genes. 2: Improvement, validation, and adaptation of a risk prediction web-tool for the Canadian context. 3: Development and piloting of a socio-ethical framework to support implementation of risk-based breast cancer screening. 4: Economic analysis to optimize the implementation of risk-based screening. Risk-based screening and prevention is expected to benefit all women, empowering them to work with their healthcare provider to make informed decisions about screening and prevention.

Women's Views on Multifactorial Breast Cancer Risk Assessment and Risk-Stratified Screening: A Population-Based Survey from Four Provinces in Canada.

Risk-stratified screening for breast cancer (BC) is increasingly considered as a promising approach. However, its implementation is challenging and needs to be acceptable to women. We examined Canadian women's attitudes towards, comfort level about, and willingness to take part in BC risk-stratified screening. We conducted an online survey in women aged 30 to 69 years in four Canadian provinces. In total, 4293 women completed the questionnaire (response rate of 63%). The majority of women (63.5% to 72.8%) expressed favorable attitudes towards BC risk-stratified screening. Most women reported that they would be comfortable providing personal and genetic information for BC risk assessment (61.5% to 67.4%) and showed a willingness to have their BC risk assessed if offered (74.8%). Most women (85.9%) would also accept an increase in screening frequency if they were at higher risk, but fewer (49.3%) would accept a reduction in screening frequency if they were at lower risk. There were few differences by province; however, outcomes varied by age, education level, marital status, income, perceived risk, history of BC, prior mammography, and history of genetic test for BC (all p ≤ 0.01). Risk-based BC screening using multifactorial risk assessment appears to be acceptable to most women. This suggests that the implementation of this approach is likely to be well-supported by Canadian women.

Personalizing Breast Cancer Screening Based on Polygenic Risk and Family History.

BACKGROUND: We assessed the clinical utility of a first-degree breast cancer family history and polygenic risk score (PRS) to inform screening decisions among women aged 30-50 years. METHODS: Two established breast cancer models evaluated digital mammography screening strategies in the 1985 US birth cohort by risk groups defined by family history and PRS based on 313 single nucleotide polymorphisms. Strategies varied in initiation age (30, 35, 40, 45, and 50 years) and interval (annual, hybrid, biennial, triennial). The benefits (breast cancer deaths averted, life-years gained) and harms (false-positive mammograms, overdiagnoses) were compared with those seen with 3 established screening guidelines. RESULTS: Women with a breast cancer family history who initiated biennial screening at age 40 years (vs 50 years) had a 36% (model range = 29%-40%) increase in life-years gained and 20% (model range = 16%-24%) more breast cancer deaths averted, but 21% (model range = 17%-23%) more overdiagnoses and 63% (model range = 62%-64%) more false positives. Screening tailored to PRS vs biennial screening from 50 to 74 years had smaller positive effects on life-years gained (20%) and breast cancer deaths averted (11%) but also smaller increases in overdiagnoses (10%) and false positives (26%). Combined use of family history and PRS vs biennial screening from 50 to 74 years had the greatest increase in life-years gained (29%) and breast cancer deaths averted (18%). CONCLUSIONS: Our results suggest that breast cancer family history and PRS could guide screening decisions before age 50 years among women at increased risk for breast cancer but expected increases in overdiagnoses and false positives should be expected.

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.

Real-world direct healthcare costs of treating recurrent high-grade serous ovarian cancer with cytotoxic chemotherapy.

Aim: To describe the direct healthcare costs associated with repeated cytotoxic chemotherapy treatments for recurrent high-grade serous cancer (HGSC) of the ovaries. Patients & methods: Retrospective review of 66 women with recurrent stage III/IV HGSC ovarian cancer treated with repeated lines of cytotoxic chemotherapy in a Canadian University Tertiary Center. Results: Mean cost of treatment of first relapse was CAD$52,227 increasing by 38% for two, and 86% for three or more relapses with median overall survival of 36.0, 50.7 and 42.8 months, respectively. In-hospital care accounted for 71% and chemotherapy drugs accounted for 17% of the total costs. Conclusion: After the third relapse of HGSC, cytotoxic chemotherapy did not prolong survival but was associated with substantially increased healthcare costs.

Advanced technologies for intuitive control and sensation of prosthetics.

The Department of Defense, Department of Veterans Affairs and National Institutes of Health have invested significantly in advancing prosthetic technologies over the past 25 years, with the overall intent to improve the function, participation and quality of life of Service Members, Veterans, and all United States Citizens living with limb loss. These investments have contributed to substantial advancements in the control and sensory perception of prosthetic devices over the past decade. While control of motorized prosthetic devices through the use of electromyography has been widely available since the 1980s, this technology is not intuitive. Additionally, these systems do not provide stimulation for sensory perception. Recent research has made significant advancement not only in the intuitive use of electromyography for control but also in the ability to provide relevant meaningful perceptions through various stimulation approaches. While much of this previous work has traditionally focused on those with upper extremity amputation, new developments include advanced bidirectional neuroprostheses that are applicable to both the upper and lower limb amputation. The goal of this review is to examine the state-of-the-science in the areas of intuitive control and sensation of prosthetic devices and to discuss areas of exploration for the future. Current research and development efforts in external systems, implanted systems, surgical approaches, and regenerative approaches will be explored.

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.

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.