A Practical ANOVA Approach for Uncertainty Analysis in Population-Based Disease Microsimulation Models.

OBJECTIVES: To provide a practical approach for calculating uncertainty intervals and variance components associated with initial-condition and dynamic-equation parameters in computationally expensive population-based disease microsimulation models. METHODS: In the proposed uncertainty analysis approach, we calculated the required computational time and the number of runs given a user-defined error bound on the variance of the grand mean. The equations for optimal sample sizes were derived by minimizing the variance of the grand mean using initial estimates for variance components. Finally, analysis of variance estimators were used to calculate unbiased variance estimates. RESULTS: To illustrate the proposed approach, we performed uncertainty analysis to estimate the uncertainty associated with total direct cost of osteoarthritis in Canada from 2010 to 2031 according to a previously published population health microsimulation model of osteoarthritis. We first calculated crude estimates for initial-population sampling and dynamic-equation parameters uncertainty by performing a small number of runs. We then calculated the optimal sample sizes and finally derived 95% uncertainty intervals of the total cost and unbiased estimates for variance components. According to our results, the contribution of dynamic-equation parameter uncertainty to the overall variance was higher than that of initial parameter sampling uncertainty throughout the study period. CONCLUSIONS: The proposed analysis of variance approach provides the uncertainty intervals for the mean outcome in addition to unbiased estimates for each source of uncertainty. The contributions of each source of uncertainty can then be compared with each other for validation purposes so as to improve the model accuracy.

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.

Population health outcomes of blood-based screening for colorectal cancer in comparison to current screening modalities: insights from a discrete-event simulation model incorporating longitudinal adherence.

AIM: Insufficient adherence to colorectal cancer (CRC) screening impedes individual and population health benefits, with about one-third of individuals non-adherent to available screening options. The impact of poor adherence is inadequately considered in most health economics models, limiting the evaluation of real-world population-level screening outcomes. This study introduces the CAN-SCREEN (Colorectal cANcer SCReening Economics and adherENce) model, utilizing real-world adherence scenarios to assess the effectiveness of a blood-based test (BBT) compared to existing strategies. MATERIALS AND METHODS: The CAN-SCREEN model evaluates various CRC screening strategies per 1,000 screened individuals for ages 45-75. Adherence is modeled in two ways: (1) full adherence and (2) longitudinally declining adherence. BBT performance is based on recent pivotal trial data while existing strategies are informed using literature. The full adherence model is calibrated using previously published Cancer Intervention and Surveillance Modeling Network (CISNET) models. Outcomes, including life-years gained (LYG), CRC cases averted, CRC deaths averted, and colonoscopies, are compared to no screening. RESULTS: Longitudinal adherence modeling reveals differences in the relative ordering of health outcomes and resource utilization, as measured by the number of colonoscopies performed per 1,000, between screening modalities. BBT outperforms the fecal immunochemical test (FIT) and the multitarget stool DNA (mtsDNA) test with more CRC deaths averted (13) compared to FIT and mtsDNA (7, 11), more CRC cases averted (27 vs. 16, 22) and higher LYG (214 vs. 157, 199). BBT yields fewer CRC deaths averted compared to colonoscopy (13, 15) but requires fewer colonoscopies (1,053 vs. 1,928). LIMITATIONS: Due to limited data, the CAN-SCREEN model with longitudinal adherence leverages evidence-informed assumptions for the natural history and real-world longitudinal adherence to screening. CONCLUSIONS: The CAN-SCREEN model demonstrates that amongst non-invasive CRC screening strategies, those with higher adherence yield more favorable health outcomes as measured by CRC deaths averted, CRC cases averted, and LYG.

This study explored the impact of poor adherence to colorectal cancer (CRC) screening, where about one-third of people face barriers to screening. Common models don't consider real-world adherence, so we introduced the CAN-SCREEN model. It uses real-world data to determine how well a blood-based test (BBT) could work compared to existing tests. We studied people starting CRC screening at age 45. The model looked at two adherence scenarios: assuming everyone follows guidelines, and using real-world data about how people follow screening guidelines over time. The BBT's performance was based on a recent study, and we compared it to existing methods using data from the literature. Results per 1,000 simulated patients showed that the BBT outperforms two guideline-recommended stool-based tests, fecal immunochemical test (FIT) and the multitarget stool DNA (mtsDNA) test, with more CRC deaths averted (13) compared to FIT and mtsDNA (7, 11), more CRC cases averted (27 vs. 16, 22) and higher LYG (214 vs. 157, 199). BBT prevents less CRC deaths than colonoscopy (13 vs. 15), but it leads to fewer colonoscopies (1,053 compared to 1,928). Despite some limitations due to limited data, our model relies on informed assumptions for the natural history of CRC and real-world adherence. In conclusion, our CAN-SCREEN model shows that CRC screening strategies combining good test performance with high adherence give better health outcomes. Adding a blood test, which could be easier for people to use, could save lives and reduce the number of colonoscopies needed.

Changes in the characteristics and levels of comorbidity among new patients into methadone maintenance treatment program in British Columbia during its expansion period from 1998-2006.

We described the changing characteristics and comorbidity levels of new patients into Methadone maintenance treatment (MMT) program in British Columbia, Canada, during its expansion period of 1998-2006. Analyses used administrative data. Generalized regression models were applied using Charlson Comorbidity Index (CCI) and Chronic Disease Score (CDS) as outcomes. 12,615 individuals initiated MMT during 1998-2006, while their odds of having moderate CCI (1 ≤ CCI ≤ 4) and mean CDS increased by 60% and 11%, respectively, after adjusting for confounders. MMT entrants were presented with progressively higher levels of comorbidity, independent of other characteristics. Future MMT policies should address higher levels of comorbidity among new patients.

Wait time management strategies at centralized intake system for hip and knee replacement surgery: A need for a blended evidence-based and patient-centered approach.

Objectives: Delays in access to specialty care and elective hip and knee total joint replacement (TJR) surgery remain a major concern among patients with osteoarthritis (OA) in Canada. Centralized intake systems as a wait time management strategy in the face of resource constraints can increase access and patient flow through the system but are not standard practice. We examine how wait time management strategies for the assessment and triaging referrals in a centralized intake system can inform quality improvement initiatives. Design: We developed a discrete-event simulation model using all referrals to the Edmonton Bone and Joint Centre centralized intake system from 2012 to 2016 for the base case model. We assessed the combined effect of three wait time management strategies: improved prioritization, improved sorting through screening, and increased conservative management. Outcomes were measured in terms of patient flow and wait times. Results: The screener sees more patient referrals (7094 compared to 6922), and the number of patients who proceed to surgery is reduced by 282 patients (4%) in the wait time management scenario compared to the base case model. Wait times from referral to surgery are reduced by 54 days for surgical patients. Furthermore, urgent surgical patients experienced lower wait times in all stages of care than non-urgent patients, with wait times from referral to surgery reduced by 86 days. Conclusions: Triaging processes addressing prioritization, screening and conservative management of non-surgical patients can improve patient flow and significantly reduce patient wait times in a centralized intake process for TJR.

Economic Evaluation of Cost and Time Required for a Platform Trial vs Conventional Trials.

Importance: Platform trial design allows the introduction of new interventions after the trial is initiated and offers efficiencies to clinical research. However, limited guidance exists on the economic resources required to establish and maintain platform trials. Objective: To compare cost (US dollars) and time requirements of conducting a platform trial vs a series of conventional (nonplatform) trials using a real-life example. Design, Setting, and Participants: For this economic evaluation, an online survey was administered to a group of international experts (146 participants) with publication records of platform trials to elicit their opinions on cost and time to set up and conduct platform, multigroup, and 2-group trials. Using the reported entry dates of 10 interventions into Systemic Therapy in Advancing Metastatic Prostate Cancer: Evaluation of Drug Efficacy, the longest ongoing platform trial, 3 scenarios were designed involving a single platform trial (scenario 1), 1 multigroup followed by 5 2-group trials (scenario 2), and a series of 10 2-group trials (scenario 3). All scenarios started with 5 interventions, then 5 more interventions were either added to the platform or evaluated independently. Simulations with the survey results as inputs were used to compare the platform vs conventional trial designs. Data were analyzed from July to September 2021. Exposure: Platform trial design. Main Outcomes and Measures: Total trial setup and conduct cost and cumulative duration. Results: Although setup time and cost requirements of a single trial were highest for the platform trial, cumulative requirements of setting up a series of multiple trials in scenarios 2 and 3 were larger. Compared with the platform trial, there was a median (IQR) increase of 216.7% (202.2%-242.5%) in cumulative setup costs for scenario 2 and 391.1% (365.3%-437.9%) for scenario 3. In terms of total cost, there was a median (IQR) increase of 17.4% (12.1%-22.5%) for scenario 2 and 57.5% (43.1%-69.9%) for scenario 3. There was a median (IQR) increase in cumulative trial duration of 171.1% (158.3%-184.3%) for scenario 2 and 311.9% (282.0%-349.1%) for scenario 3. Cost and time reductions in the platform trial were observed in both the initial and subsequently evaluated interventions. Conclusions and Relevance: Although setting up platform trials can take longer and be costly, the findings of this study suggest that having a single infrastructure can improve efficiencies with respect to costs and efforts.

Epidemiology, healthcare resource utilization and healthcare costs for spinal muscular atrophy in Alberta, Canada.

AIMS: Spinal muscular atrophy (SMA) is a progressive neuromuscular disease associated with the degeneration of motor neurons in the brainstem and spinal cord. Studies examining the epidemiology and economic impact of SMA are limited in Canada. This study aimed to estimate the epidemiology as well as healthcare resource utilization (HRU) and healthcare costs for children with SMA in Alberta, Canada. MATERIALS AND METHODS: We conducted a retrospective study using anonymized data from administrative healthcare databases provided by Alberta Health. Data from 1 April 2010 to 31 March 2018, were extracted for patients <18 years of age identified with SMA. Five-year incidence and prevalence were calculated for cases identified between 1 April 2012 and 31 March 2017. HRU and healthcare costs were assessed one year after SMA diagnosis, including hospitalizations, physician visits, ambulatory care visits and long-term care admissions. RESULTS: The five-year incidence and prevalence of pediatric onset SMA were 1.03 per 100,000 person-years and 9.97 per 100,000 persons, respectively. General practitioner, specialist, and ambulatory care visits were common among children with SMA in the first-year post-diagnosis. The mean (SD) total annual direct cost per patient in the first-year post-diagnosis was $29,774 ($38,407); hospitalizations accounted for 41.7% of these costs ($12,412 [$21,170]), followed by practitioner visits at 32.3% ($9,615 [$13,054]), and ambulatory care visits at 26.0% ($7,746 [$9,988]). CONCLUSIONS: Children with SMA experience substantial HRU, particularly for hospitalizations and practitioner visits, following diagnosis. Given the high costs of SMA, timely access to effective treatment strategies, such as the novel survival motor neuron (SMN)-restoring treatments recently approved for use, are needed to improve health outcomes and HRU.

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.

Qualitative study to elicit patients' and primary care physicians' perspectives on the use of a self-management mobile health application for knee osteoarthritis.

OBJECTIVE: To elicit perspectives of family physicians and patients with knee osteoarthritis (KOA) on KOA, its treatment/management and the use of a mobile health application (app) to help patients self-manage their KOA. DESIGN: A qualitative study using Cognitive Task Analysis for physician interviews and peer-to-peer semistructured interviews for patients according to the Patient and Community Engagement Research (PaCER) method. SETTING: Primary care practices and patient researchers at an academic centre in Southern Alberta. PARTICIPANTS: Intentional sampling of family physicians (n=4; 75% women) and patients with KOA who had taken part in previous PaCER studies and had experienced knee pain on most days of the month at any time in the past (n=5; 60% women). RESULTS: Physician and patient views about KOA were starkly contrasting. Patient participants expressed that KOA seriously impacted their lives and lifestyles, and they wanted their knee pain to be considered as important as other health problems. In contrast, physicians uniformly conceptualised KOA as a relatively minor health problem, although they still recognised it as a painful condition that often limits patients' activities. Consequently, physicians did not regard KOA as a condition to be proactively and aggressively managed. The gap between physicians' and patients' conceptualisation of KOA and its treatment extended to the use of an app for self-management. While patients were supportive of the app, physicians were sceptical of its use and focused more on accountability and patient resources. CONCLUSIONS: The clear discord between physicians' mental models and patients' lived experience and perceived needs around KOA emphasised a gap in understanding and communication about treatment and management of KOA. As such, this preliminary and formative research will inform a codesign approach to develop an app that will act as a communications tool between patients and physicians, enabling patient-physician discussions regarding modifiable self-management options based on a patient's perspectives and needs.

Association of Metabolic Markers with self-reported osteoarthritis among middle-aged BMI-defined non-obese individuals: a cross-sectional study.

BACKGROUND: Osteoarthritis (OA) is a chronic degenerative joint disease. While it is well-established that obesity affects OA through increased axial loading on the joint cartilage, the indirect effect of obesity through metabolic processes among the body mass index (BMI)-defined non-obese population, i.e., BMI < 30 kg/m2, is less known. Our goal was to evaluate the association of metabolic markers including body fat percentage (BF%), waist circumference, maximum weight gain during adulthood and serum creatinine with self-reported OA to establish if such measures offer additional information over BMI among the non-obese population between 40 and 65 years of age. METHODS: Cross-sectional data from two cycles of the Canadian Health Measures Survey (CHMS) in 2007-2009 and 2009-2011 were analyzed. Sex-specific logistic regression models were developed to evaluate the association of self-reported OA with metabolic markers. Models were separately adjusted for age, BMI categories and serum creatinine, and a stratified analysis across BM categories was performed. In a secondary analysis, we evaluated the association of self-reported OA, cardiovascular diseases and hypertension across BF% categories. RESULTS: Of 2462 individuals, 217 (8.8%) self-reported OA. After adjusting for age and BMI, those within BF%-defined overweight/obese category had 2.67 (95% CI: 1.32-3.51) and 2.11(95% CI: 1.38-3.21) times higher odds of reporting self-reported OA compared to those within BF%-defined athletic/acceptable category for females and males, respectively. BF% was also significantly associated with self-reported OA after adjusting for age and serum creatinine only among females (OR: 1.47, 95%CI: 1.12-1.84). Furthermore, among the BMI-defined overweight group, the age-adjusted odds of self-reported OA was significantly higher for overweight/obese BF% compared to athletic/acceptable BF% in both females and males. In a secondary analysis, we showed that the association of self-reported OA and hypertension/cardiovascular diseases is significantly higher among BF% overweight/obese (OR: 1.37, 95%CI: 1.19-3.09) compared to BF% athletic/acceptable (OR: 1.13, 95%CI: 0.87-2.82). CONCLUSION: Our results provide corroborating evidence for a relationship between body fat and OA in a population-based study, while no significant independent correlates were found between other metabolic markers and OA prevalence. Future investigation on the longitudinal relationship between BF and OA among this sub-population may inform targeted prevention opportunities.

Distribution and Drivers of Average Direct Cost of Osteoarthritis in Canada From 2003 to 2010.

OBJECTIVE: To estimate the distribution and drivers of the average direct cost of osteoarthritis (OA) in Canada using a population-based health microsimulation model of OA from 2003 to 2010. METHODS: We used a previously published microsimulation model to estimate the distribution of average cost of OA across different cost components and OA stages. OA stages were defined according to the patient flow within the health care system. Cost components associated with pharmacologic and nonpharmacologic treatments, physician visits, and hospitalization were included. Scenario analysis was performed to evaluate average cost drivers from 2003 to 2010. RESULTS: During the study period, the OA population size grew from 2.9 to 3.6 million, while the average cost increased from $577 to $811 (Canadian) per patient per year. The highest increase in share of cost components was for total joint replacement (TJR) surgery (24% to 32%). The highest average cost was incurred by patients in stage 4 (during and after revision surgery), while around 80% of OA patients were in stage 1 (OA diagnosed but has not visited an orthopedic surgeon). Increase in the proportion of OA patients receiving TJR surgeries (34%) and price inflation (29%) were the most significant drivers of average cost. CONCLUSION: The average cost of OA has been increasing during the study period mostly due to an increase in the proportion of patients receiving TJR surgeries and price inflation. The distribution of average cost of OA across disease stages needs to be considered when designing policies targeting specific aspects of OA care.

Association of body mass index (BMI) and percent body fat among BMI-defined non-obese middle-aged individuals: Insights from a population-based Canadian sample.

OBJECTIVES: To evaluate the association between percent body fat (%BF) and body mass index (BMI) among BMI-defined non-obese individuals between 40 and 69 years of age using a population-based Canadian sample. DATA AND METHODS: Cross-sectional data from the Canadian Health Measures Survey (2007 and 2009) was used to select all middle-aged individuals with BMI < 30 kg/m2 (n = 2,656). %BF was determined from anthropometric skinfolds and categorized according to sex-specific equations. Association of other anthropometry measures and metabolic markers were evaluated across different %BF categories. Significance of proportions was evaluated using chi-squared and Bonferroni-adjusted Wald test. Diagnostic performance measures of BMI-defined overweight categories compared to those defined by %BF were reported. RESULTS: The majority (69%) of the sample was %BF-defined overweight/obese, while 55% were BMI-defined overweight. BMI category was not concordant with %BF classification for 30% of the population. The greatest discordance between %BF and BMI was observed among %BF-defined overweight/obese women (32%). Sensitivity and specificity of BMI-defined overweight compared to %BF-defined overweight/obese were (58%, 94%) among females and (82%, 59%) among males respectively. According to the estimated negative predictive value, if an individual is categorized as BMI-defined non-obese, he/she has a 52% chance of being in the %BF-defined overweight/obese category. CONCLUSION: Middle-aged individuals classified as normal by BMI may be overweight/obese based on measures of %BF. These individuals may be at risk for chronic diseases, but would not be identified as such based on their BMI classification. Quantifying %BF in this group could inform targeted strategies for disease prevention.

Optimal timing of influenza vaccination in patients with human immunodeficiency virus: a Markov cohort model based on serial study participant hemoagglutination inhibition titers.

BACKGROUND: Seasonal influenza vaccination offers one of the best population-level protections against influenza-like illness (ILI). For most people, a single dose prior to the flu season offers adequate immunogenicity. HIV+ patients, however, tend to exhibit a shorter period of clinical protection, and therefore may not retain immunogenicity for the entire season. Building on the work of Nosyk et al. (2011) that determined a single dose is the optimal dosing strategy for HIV+ patients, we investigate the optimal time to administer this vaccination. METHODS: Using data from the "single dose" treatment arm of an RCT conducted at 12 CIHR Canadian HIV Trials Network sites we estimated semimonthly clinical seroprotection levels for a cohort (N=93) based on HAI titer levels. These estimates were combined with CDC attack rate data for the three main strains of seasonal influenza to estimate instances of ILI over different vaccination timing strategies. Using bootstrap resampling of the cohort, nine years of CDC data, and parameter distributions, we developed a Markov cohort model that included probabilistic sensitivity analysis. Cost, quality adjusted life-years (QALYs), and net monetary benefits are presented for each timing strategy. RESULTS: The beginning of December is the optimal time for HIV+ patients to receive the seasonal influenza vaccine. Assuming a willingness-to-pay threshold of $50,000, the net monetary benefit associated with a Dec 1 vaccination date is $19,501.49 and the annual QALY was 0.833744. INTERPRETATION: Our results support a policy of administering the seasonal influenza vaccination for this population in the middle of November or beginning of December, assuming nothing is know about the upcoming flu season. But because the difference in between this strategy and the CDC guideline is small-12 deaths averted per year and a savings of $60 million across the HIV+ population in the US-more research is needed concerning strategies for subpopulations.

The cost-effectiveness and value of information of three influenza vaccination dosing strategies for individuals with human immunodeficiency virus.

BACKGROUND: Influenza vaccine immunogenicity is diminished in patients living with HIV/AIDS. We evaluated the cost-effectiveness and expected value of perfect information (EVPI) of three alternative influenza vaccine dosing strategies intended to increase immunogenicity in those patients. METHODS: A randomized, multi-centered, controlled, vaccine trial was conducted at 12 CIHR Canadian HIV Trials Network sites. Three dosing strategies with seasonal, inactivated trivalent, non-adjuvanted intramuscular vaccine were used in HIV infected adults: two standard doses over 28 days (Strategy A), two double doses over 28 days (Strategy B) and a single standard dose of influenza vaccine (Strategy C), administered prior to the 2008 influenza season. The comparator in our analysis was practice in the previous year, in which 82.8% of HIV/AIDS received standard-dose vaccination (Strategy D). A Markov cohort model was developed to estimate the monthly probability of Influenza-like Illness (ILI) over one influenza season. Costs and quality-adjusted life years, extrapolated to the lifetime of the hypothetical study cohorts, were estimated in calculating incremental cost-effectiveness ratios (ICER) and EVPI in conducting further research. RESULTS: 298 patients with median CD4 of 470 cells/µl and 76% with viral load suppression were randomized. Strategy C was the most cost-effective strategy for the overall trial population and for suppressed and unsuppressed individuals. Mean ICERs for Strategy A for unsuppressed patients could also be considered cost-effective. The level of uncertainty regarding the decision to implement strategy A versus C for unsuppressed individuals was high. The maximum acceptable cost of reducing decision uncertainty in implementing strategy A for individuals with unsuppressed pVL was $418,000--below the cost of conducting a larger-scale trial. CONCLUSION: Our results do not support a policy to implement increased antigen dose or booster dosing strategies with seasonal, inactivated trivalent, non-adjuvanted intramuscular vaccine for individuals with HIV in Canada. TRIAL REGISTRATION: ClinicalTrials.gov NCT00764998.