Model and Empirical Data-Based Cost-Utility Studies of Continuous Glucose Monitoring in Individuals with Type 1 Diabetes: A Protocol of a Systematic Review on Methodology and Quality.

INTRODUCTION: This review aims to critically appraise differences in methodology and quality of model-based and empirical-data-based cost-utility studies to address key limitations, opportunities, and challenges to inform future cost-utility analyses of continuous glucose monitoring (CGM) in type 1 diabetes. This protocol is registered at PROSPERO (CRD42023391284). METHODS: The review will be conducted in accordance with the PRISMA guideline for systematic reviews. Searches will be conducted in MEDLINE, Embase, Web of Science, Cochrane Library, and Econlit from 2000 to January 2023. Model and empirical data-based studies evaluating the cost-utility of any CGM system in type 1 diabetes will be considered for inclusion. Studies that only report on cost per life year or any other clinical outcome, or reporting only costs or only clinical outcomes studies in type 2 diabetes populations, and studies on bi-hormonal closed loops and do-it-yourself hybrid closed loop devices will be excluded. Two reviewers will independently screen each study for inclusion. Data on the intervention, population, model settings (such as perspective, time horizon), model type and structure, clinical outcomes used to populate the model, validation, and uncertainty will be extracted and qualitatively synthesised. Quality will be assessed using the Philips et al. 2006 (model-based studies) or Consensus Health Economic Criteria (empirical data-based studies) checklists. Model validation will be assessed using the AdViSHE checklist. DISCUSSION: Now that CGM is being used more broadly in practice, critical appraisal of existing cost-utility methodology and quality is important to inform future cost-utility analyses of CGM in type 1 diabetes in various settings.

In vitro studies show synergistic effects of a procoagulant bispecific antibody and bypassing agents.

Essentials Patients with hemophilia A and inhibitors receiving emicizumab experience breakthrough bleeding. Safety concerns may exist when combining emicizumab with bypassing agents. Combined bypassing agent and bispecific antibody increased thrombin generation up to 17-fold. Thrombotic effects should be considered when combining emicizumab with plasma bypassing agent. SUMMARY: Background Investigational non-factor products such as emicizumab offer a treatment option for patients with hemophilia and inhibitors. However, their mechanism of action raises questions regarding safety when they are combined with treatments for breakthrough bleeding. Objectives To evaluate in vitro thrombin generation (TG) and clot formation for combinations of activated prothrombin complex concentrate (aPCC), recombinant activated factor VII (rFVIIa), and a sequence-identical analog of emicizumab (SIA). Methods Therapeutic concentrations of SIA (20-600 nm) alone or with aPCC (0.05-1 U mL-1 ), isolated aPCC components or rFVIIa (0.88-5.25 µg mL-1 ) were tested for TG and compared with reference ranges for healthy donor plasma. Coagulation of FVIII-inhibited blood was determined with a widely established method, i.e. rotational thromboelastometry (ROTEM), and confirmed with the Total Thrombus-formation Analysis System. Results and conclusions SIA (600 nm) or aPCC (0.5 U mL-1 ) alone resulted in peak thrombin levels of 21.4 nm and 38.6 nm, respectively, both of which are lower than normal (83.7 ± 29.8 nm). SIA plus aPCC (0.5 U mL-1 ) increased the peak thrombin level 17-fold over SIA alone, exceeding the reference plasma value by 4.2-fold. This hypercoagulable effect occurred with 600 nmSIA combined with as little as 0.25 U mL-1 aPCC, confirmed by ROTEM. FIX was the main driver for enhanced TG. SIA plus rFVIIa (1.75 µg mL-1 ) induced a 1.8-fold increase in the peak thrombin level in platelet-rich plasma, but it did not reach the normal range. These in vitro experiments demonstrate excessive TG after administration of a combination of aPCC and SIA at clinically relevant doses. Careful judgement may be required when breakthrough bleeding is treated in patients receiving emicizumab.

The relationship between diabetes, diabetes-related complications and productive activities among older Europeans.

AIMS: To assess the impact of diabetes and diabetes-related complications on two measures of productivity for people in the labour force and out of it, namely "being afraid health limits ability to work before retirement" and "volunteering". METHODS AND DATA: Logistic regressions were run to test the impact of diabetes and its complications on the probability of being afraid health limits work and being a formal volunteer. The longitudinal sample for the former outcome includes 53,631 observations, clustered in 34,393 individuals, aged 50-65 years old whereas the latter consists of 45,384 observations, grouped in 29,104 individuals aged 65 and above across twelve European countries taken from the Survey of Health, Ageing and Retirement in Europe, from 2006 to 2013. RESULTS: Diabetes increased the probability of being afraid health limited work by nearly 11% points, adjusted by clinical complications, and reduced the likelihood of being a formal volunteer by 2.7% points, additionally adjusted by mobility problems. We also found that both the probability of being afraid health limits work and the probability of being a formal volunteer increased during and after the crisis. Moreover, having diabetes had a larger effect on being afraid health limits work during the year 2010, possibly related to the financial crisis. CONCLUSIONS: Our findings show that diabetes significantly affects the perception of people regarding the effects of their condition on work, increasing the fear that health limits their ability to work, especially during the crisis year 2010, as well as the participation in volunteering work among retired people.

The design of a Social Cost-Benefit Analysis of preventive interventions for toxoplasmosis: An example of the One Health approach.

Toxoplasma gondii infections cause a large disease burden in the Netherlands, with an estimated health loss of 1,900 Disability Adjusted Life Years and a cost-of-illness estimated at €44 million annually. Infections in humans occur via exposure to oocysts in the environment and after eating undercooked meat containing tissue cysts, leading to asymptomatic or mild symptoms, but potentially leading to the development of ocular toxoplasmosis. Infection in pregnant women can lead to stillbirth and disorders in newborns. At present, prevention is only targeted at pregnant women. Cat vaccination, freezing of meat destined for undercooked consumption and enhancing biosecurity in pig husbandries are possible interventions to prevent toxoplasmosis. As these interventions bear costs for sectors in society that differ from those profiting from the benefits, we perform a social cost-benefit analysis (SCBA). In an SCBA, costs and benefits of societal domains affected by the interventions are identified, making explicit which stakeholder pays and who benefits. Using an epidemiological model, we consider transmission of T. gondii after vaccination of all owned cats or cats at livestock farms. To identify relevant high-risk meat products that will be eaten undercooked, a quantitative microbial risk assessment model developed to attribute predicted T. gondii infections to specific meat products will be used. In addition, we evaluate serological monitoring of pigs at slaughter followed by an audit and tailor made advice for farmers in case positive results were found. The benefits will be modelled stochastically as reduction in DALYs and monetized in Euro's following reference prices for DALYs. If the balance of total costs and benefits is positive, this will lend support to implementation of these preventive interventions at the societal level. Ultimately, the SCBA will provide guidance to policy makers on the most optimal intervention measures to reduce the disease burden of T. gondii in the Netherlands.

[Costs and benefits of smoking]. / De rekening van roken.

- Two recent societal cost-benefit analyses have documented the costs of smoking and the cost-effectiveness of preventing smoking.- Smoking costs the Netherlands society EUR 33 billion per year.- The majority of this is the monetary value of health loss; these are "soft" euros that cannot be re-spent.- There is not a great deal of difference between costs and benefits when expressed in "hard" euros, which means that there is no clear business case for anti-smoking policy.- The greatest benefit of discouraging smoking is improved health for the individual and increased productivity for the business sector; however, the benefits cannot be easily realised, because even in the most favourable scenario the number of smokers will decrease slowly.- Excise duties seem to offer the most promising avenue for combating smoking. The benefits of anti-smoking policy, therefore, consist mainly of tax revenues for the government.- Stringent policy is required to transform tax revenues into health gains.

Adhesion of Escherichia coli under flow conditions reveals potential novel effects of FimH mutations.

FimH-mediated adhesion of Escherichia coli to bladder epithelium is a prerequisite for urinary tract infections. FimH is also essential for blood-borne bacterial dissemination, but the mechanisms are poorly understood. The purpose of this study was to assess the influence of different FimH mutations on bacterial adhesion using a novel adhesion assay, which models the physiological flow conditions bacteria are exposed to. We introduced 12 different point mutations in the mannose binding pocket of FimH in an E. coli strain expressing type 1 fimbriae only (MSC95-FimH). We compared the bacterial adhesion of each mutant across several commonly used adhesion assays, including agglutination of yeast, adhesion to mono- and tri-mannosylated substrates, and static adhesion to bladder epithelial and endothelial cells. We performed a comparison of these assays to a novel method that we developed to study bacterial adhesion to mammalian cells under flow conditions. We showed that E. coli MSC95-FimH adheres more efficiently to microvascular endothelium than to bladder epithelium, and that only endothelium supports adhesion at physiological shear stress. The results confirmed that mannose binding pocket mutations abrogated adhesion. We demonstrated that FimH residues E50 and T53 are crucial for adhesion under flow conditions. The coating of endothelial cells on biochips and modelling of physiological flow conditions enabled us to identify FimH residues crucial for adhesion. These results provide novel insights into screening methods to determine the effect of FimH mutants and potentially FimH antagonists.

Individual patient information to select patients for different radiation techniques.

BACKGROUND AND PURPOSE: Proton therapy is an emerging technique in radiotherapy which results in less dose to the normal tissues with similar target dose than photon therapy, the current standard. Patient-level simulation models support better decision making on which patients would benefit most. MATERIALS AND METHODS: A simulation model was developed tracking individual patients' status regarding the primary tumour and multiple complications. As a proof of principle, the model was populated based on information from a cohort of 1013 head and neck cancer patients. Dose-volume parameters for photon and proton radiation treatment plans were then fed into the model to compare outcomes in terms of length and quality of life and select patients that would benefit most. RESULTS: The illustrative model could adequately replicate the outcomes of photon therapy in the cohort. Improvements from proton therapy varied considerably between patients. The model projects medium-term outcomes for specific individuals and determines the benefits of applying proton rather than photon therapy. CONCLUSIONS: While the model needs to be fed with more and especially recent data before being fully ready for use in clinical practice, it could already distinguish between patients with high and low potential benefits from proton therapy. Benefits are highest for patients with both good prognosis and high expected damage to adjacent organs. The model allows for selecting such patients a priori based on patient relevant outcomes.

AdViSHE: A Validation-Assessment Tool of Health-Economic Models for Decision Makers and Model Users.

BACKGROUND: A trade-off exists between building confidence in health-economic (HE) decision models and the use of scarce resources. We aimed to create a practical tool providing model users with a structured view into the validation status of HE decision models, to address this trade-off. METHODS: A Delphi panel was organized, and was completed by a workshop during an international conference. The proposed tool was constructed iteratively based on comments from, and the discussion amongst, panellists. During the Delphi process, comments were solicited on the importance and feasibility of possible validation techniques for modellers, their relevance for decision makers, and the overall structure and formulation in the tool. RESULTS: The panel consisted of 47 experts in HE modelling and HE decision making from various professional and international backgrounds. In addition, 50 discussants actively engaged in the discussion at the conference workshop and returned 19 questionnaires with additional comments. The final version consists of 13 items covering all relevant aspects of HE decision models: the conceptual model, the input data, the implemented software program, and the model outcomes. CONCLUSIONS: Assessment of the Validation Status of Health-Economic decision models (AdViSHE) is a validation-assessment tool in which model developers report in a systematic way both on validation efforts performed and on their outcomes. Subsequently, model users can establish whether confidence in the model is justified or whether additional validation efforts should be undertaken. In this way, AdViSHE enhances transparency of the validation status of HE models and supports efficient model validation.

To screen or not to screen for breast cancer? How do modelling studies answer the question?

Breast cancer screening is a topic of hot debate, and currently no general consensus has been reached on starting and ending ages and screening intervals, in part because of a lack of precise estimations of the benefit-harm ratio. Simulation models are often applied to account for the expected benefits and harms of regular screening; however, the degree to which the model outcomes are reliable is not clear. In a recent systematic review, we therefore aimed to assess the quality of published simulation models for breast cancer screening of the general population. The models were scored according to a framework for qualitative assessment. We distinguished seven original models that utilized a common model type, modelling approach, and input parameters. The models predicted the benefit of regular screening in terms of mortality reduction; and overall, their estimates compared well to estimates of mortality reduction from randomized controlled trials. However, the models did not report on the expected harms associated with regular screening. We found that current simulation models for population breast cancer screening are prone to many pitfalls; their outcomes bear a high overall risk of bias, mainly because of a lack of systematic evaluation of evidence to calibrate the input parameters and a lack of external validation. Our recommendations concerning future modelling are therefore to use systematically evaluated data for the calibration of input parameters, to perform external validation of model outcomes, and to account for both the expected benefits and the expected harms so as to provide a clear balance and cost-effectiveness estimation and to adequately inform decision-makers.

Policy evaluation in diabetes prevention and treatment using a population-based macro simulation model: the MICADO model.

AIMS: To test a simulation model, the MICADO model, for estimating the long-term effects of interventions in people with and without diabetes. METHODS: The MICADO model includes micro- and macrovascular diseases in relation to their risk factors. The strengths of this model are its population scope and the possibility to assess parameter uncertainty using probabilistic sensitivity analyses. Outcomes include incidence and prevalence of complications, quality of life, costs and cost-effectiveness. We externally validated MICADO's estimates of micro- and macrovascular complications in a Dutch cohort with diabetes (n = 498,400) by comparing these estimates with national and international empirical data. RESULTS: For the annual number of people undergoing amputations, MICADO's estimate was 592 (95% interquantile range 291-842), which compared well with the registered number of people with diabetes-related amputations in the Netherlands (728). The incidence of end-stage renal disease estimated using the MICADO model was 247 people (95% interquartile range 120-363), which was also similar to the registered incidence in the Netherlands (277 people). MICADO performed well in the validation of macrovascular outcomes of population-based cohorts, while it had more difficulty in reflecting a highly selected trial population. CONCLUSIONS: Validation by comparison with independent empirical data showed that the MICADO model simulates the natural course of diabetes and its micro- and macrovascular complications well. As a population-based model, MICADO can be applied for projections as well as scenario analyses to evaluate the long-term (cost-)effectiveness of population-level interventions targeting diabetes and its complications in the Netherlands or similar countries.

The value of PET/CT with FES or FDG tracers in metastatic breast cancer: a computer simulation study in ER-positive patients.

BACKGROUND: The aim of this study was to evaluate the effect on the number of performed biopsies and costs associated with implementing positron emission tomography (PET) and computed tomography (PET/CT) with 16α-[(18)F]fluoro-17ß-oestradiol (FES) or 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG) as an upfront imaging test for diagnosing metastatic breast cancer (MBC) in comparison with the standard work-up in oestrogen receptor-positive women with symptoms. METHODS: A published computer simulation model was adapted and validated. Three follow-up strategies were evaluated in a simulated cohort of women with primary breast cancer over a 5-year-time horizon: (1) the standard work-up, (2) upfront FES-PET/CT and (3) upfront FDG-PET/CT. The main outcome was the number of avoided biopsies to assess MBC. The costs for all three strategies were calculated based on the number of imaging tests and biopsies. The incremental cost-effectiveness ratio (ICER) to avoid a biopsy was calculated only based on the costs of initial imaging and staging tests. RESULTS: The FES-PET/CT strategy decreased the number of biopsies by 39 ± 9%, while upfront FDG-PET/CT increased the number of biopsies by 38 ± 15% when compared with the standard work-up. Both PET/CT strategies reduced the number of imaging tests and false positives when compared with the standard work-up. The number of false negatives decreased only in the FES-PET/CT strategy. The ICER in the FES-PET/CT strategy per avoided biopsy was 12.1 ± 3.4 thousand Euro. In the FDG-PET/CT strategy, the costs were higher and there were no avoided biopsies as compared with the standard work-up, hence this was an inferior strategy in terms of cost effectiveness. CONCLUSIONS: The number of performed biopsies was lower in the FES-PET/CT strategy at an ICER of 12.1 ± 3.4 thousand Euro per biopsy avoided, whereas the application of the FDG-PET/CT did not reduce the number of biopsies and was more expensive. Whether the FES-PET/CT strategy has additional benefits for patients in terms of therapy management has to be evaluated in clinical studies.

Which screening strategy should be offered to women with BRCA1 or BRCA2 mutations? A simulation of comparative cost-effectiveness.

BACKGROUND: There is no consensus on the most effective strategy (mammography or magnetic resonance imaging (MRI)) for screening women with BRCA1 or BRCA2 mutations. The effectiveness and cost-effectiveness of the Dutch, UK and US screening strategies, which involve mammography and MRI at different ages and intervals were evaluated in high-risk women with BRCA1 or BRCA2 mutations. METHODS: Into a validated simulation screening model, outcomes and cost parameters were integrated from published and cancer registry data. Main outcomes were life-years gained and incremental cost-effectiveness ratios. The simulation was situated in the Netherlands as well as in the United Kingdom, comparing the Dutch, UK and US strategies with the population screening as a reference. A discount rate of 3% was applied to both costs and health benefits. RESULTS: In terms of life-years gained, the strategies from least to most cost-effective were the UK, Dutch and US screening strategy, respectively. However, the differences were small. Applying the US strategy in the Netherlands, the costs were €43 800 and 68 800 for an additional life-year gained for BRCA1 and BRCA2, respectively. At a threshold of €20 000 per life-year gained, implementing the US strategy in the Netherlands has a very low probability of being cost-effective. Stepping back to the less-effective UK strategy would save relatively little in costs and results in life-years lost. When implementing the screening strategies in the United Kingdom, the Dutch, as well as the US screening strategy have a high probability of being cost-effective. CONCLUSION: From a cost-effectiveness perspective, the Dutch screening strategy is preferred for screening high-risk women in the Netherlands as well as in the United Kingdom.

Communicating uncertainty in economic evaluations: verifying optimal strategies.

BACKGROUND: In cost-effectiveness analysis (CEA), it is common to compare a single, new intervention with 1 or more existing interventions representing current practice ignoring other, unrelated interventions. Sectoral CEAs, in contrast, take a perspective in which the costs and effectiveness of all possible interventions within a certain disease area or health care sector are compared to maximize health in a society given resource constraints. Stochastic league tables (SLT) have been developed to represent uncertainty in sectoral CEAs but have 2 shortcomings: 1) the probabilities reflect inclusion of individual interventions and not strategies and 2) data on robustness are lacking. The authors developed an extension of SLT that addresses these shortcomings. METHODS: Analogous to nonprobabilistic MAXIMIN decision rules, the uncertainty of the performance of strategies in sectoral CEAs may be judged with respect to worst possible outcomes, in terms of health effects obtainable within a given budget. Therefore, the authors assessed robustness of strategies likely to be optimal by performing optimization separately on all samples and on samples yielding worse than expected health benefits. The approach was tested on 2 examples, 1 with independent and 1 with correlated cost and effect data. RESULTS: The method was applicable to the original SLT example and to a new example and provided clear and easily interpretable results. Identification of interventions with robust performance as well as the best performing strategies was straightforward. Furthermore, the robustness of strategies was assessed with a MAXIMIN decision rule. CONCLUSION: The SLT extension improves the comprehensibility and extends the usefulness of outcomes of SLT for decision makers. Its use is recommended whenever an SLT approach is considered.

Potential reach of effective smoking prevention programmes in vocational schools: determinants of school directors' intention to adopt these programmes.

OBJECTIVES: Investigating the current, intended and potential reach of two effective smoking prevention programs in Dutch vocational schools and identifying determinants of school directors' intention to adopt these programs. STUDY DESIGN: Cross-sectional survey. METHODS: Two questionnaires were developed based on the Diffusion of Innovation theory and the I-Change model, focussing on either the 'Healthy School and Stimulants program' (HSS program) or the 'Out-of-school Computer Tailoring program' (CT program). The questionnaires were distributed amongst all Dutch vocational school directors (n = 452) of which 34% completed the questionnaire. RESULTS: The potential reach of the HSS program was 29% whereas the potential reach of the CT program was 5%. Regression analyses revealed that being female, perceiving a higher percentage of smoking students in school, having a personality more open towards change, perceiving a low need for a smoking prevention program, fewer disadvantages of the program, a higher level of self-efficacy towards adopting the program and a more positive social norm towards adopting a smoking prevention program from other school directors resulted in a positive intention towards adopting either program. CONCLUSIONS: The present study showed that the reach of effective smoking prevention programs is fairly low. School-based smoking prevention efforts are likely to improve if schools choose to use programs that are proven to be effective, which can be encouraged by adapting existing and newly designed programs to school directors' characteristics and providing easy access to reliable information regarding available programs.

Case fatality of COPD exacerbations: a meta-analysis and statistical modelling approach.

The aim of our study was to estimate the case fatality of a severe exacerbation from long-term survival data presented in the literature. A literature search identified studies reporting ≥1.5 yr survival after a severe chronic obstructive pulmonary disease (COPD) exacerbation resulting in hospitalisation. The survival curve of each study was divided into a critical and a stable period. Mortality during the stable period was then estimated by extrapolating the survival curve during the stable period back to the time of exacerbation onset. Case fatality was defined as the excess mortality that results from an exacerbation and was calculated as 1 minus the (backwardly) extrapolated survival during the stable period at the time of exacerbation onset. The 95% confidence intervals (CI) of the estimated case fatalities were obtained by bootstrapping. A random effect model was used to combine all estimates into a weighted average with 95% CI. The meta-analysis based on six studies that fulfilled the inclusion criteria resulted in a weighted average case-fatality rate of 15.6% (95% CI 10.9-20.3), ranging from 11.4% to 19.0% for the individual studies. A severe COPD exacerbation requiring hospitalisation not only results in higher mortality risks during hospitalisation, but also in the time-period after discharge and contributes substantially to total COPD mortality.

[Morbidity due to smoking in The Netherlands: an estimated 90,000 clinical hospital admissions in 2005]. / Ziekte door roken in Nederland: naar schatting 90 duizend klinische ziekenhuisopnamen in 2005.

OBJECTIVE: To estimate the number of hospital admissions due to smoking tobacco. DESIGN: Theoretical study based on data from the Dutch National Medical Registration. METHOD: Attributive fractions were determined based on the percentages of smokers and ex-smokers and the relative risks for certain diseases. Applying the attributive fractions to the number of hospital admissions provided an estimation of the number of tobacco-related hospital admissions. RESULTS: In 2005, there were 89,800 clinical hospital admissions in the Netherlands that could be attributed to smoking in the age group 35 years or more. This amounts to 7.5% of all hospital admissions in this age group. CONCLUSION: A large number of hospital admissions can be attributed to smoking.

Cost-effectiveness analyses of health promotion programs: a case study of smoking prevention and cessation among Dutch students.

Little research has been done to connect health promotion programs to outcomes in terms of life expectancy, health care costs and cost-effectiveness. For a policy maker, economic evaluation may be an important tool to support decisions on how to allocate the health care budget. The aim of this paper was to determine the cost-effectiveness of a Dutch school-based smoking education program. The incremental cost-effectiveness ratio of the school program was estimated at euro19 900 per quality adjusted life year gained. For a complete analysis, not only intervention costs but also savings for smoking-related diseases and differences in total health care costs should be taken into account. As several assumptions had to be made in order to estimate cost-effectiveness, the study outcomes should be interpreted with caution. Main problem in estimating the cost-effectiveness was the lack of proper effectiveness data on daily smokers among adolescents. Absence of specific effectiveness data often is an obstacle in the economic evaluation of public health interventions. While some problems may be the result of insufficient sample size or follow-up, another possible explanation might be the different basic principles of analysis of health promoters and economists.