Search

OBJECTIVES: The Mount Hood Diabetes Challenge Network aimed to examine the impact of model structural uncertainty on the estimated cost-effectiveness of interventions for type 2 diabetes. METHODS: Ten independent modeling groups completed a blinded simulation exercise to estimate the cost-effectiveness of 3 interventions in 2 type 2 diabetes populations. Modeling groups were provided with a common baseline population, cost and utility values associated with different model health states, and instructions regarding time horizon and discounting. We collated the results to identify variation in predictions of net monetary benefit (NMB) and the drivers of those differences. RESULTS: Overall, modeling groups agreed which interventions had a positive NMB (ie, were cost-effective), Although estimates of NMB varied substantially-by up to £23 696 for 1 intervention. Variation was mainly driven through differences in risk equations for complications of diabetes and their implementation between models. The number of modeled health states was also a significant predictor of NMB. CONCLUSIONS: This exercise demonstrates that structural uncertainty between different health economic models affects cost-effectiveness estimates. Although it is reassuring that a decision maker would likely reach similar conclusions on which interventions were cost-effective using most models, the range in numerical estimates generated across different models would nevertheless be important for price-setting negotiations with intervention developers. Minimizing the impact of structural uncertainty on healthcare decision making therefore remains an important priority. Model registries, which record and compare the impact of structural assumptions, offer one potential avenue to improve confidence in the robustness of health economic modeling.

BACKGROUND: Structural uncertainty can affect model-based economic simulation estimates and study conclusions. Unfortunately, unlike parameter uncertainty, relatively little is known about its magnitude of impact on life-years (LYs) and quality-adjusted life-years (QALYs) in modeling of diabetes. We leveraged the Mount Hood Diabetes Challenge Network, a biennial conference attended by international diabetes modeling groups, to assess structural uncertainty in simulating QALYs in type 2 diabetes simulation models. METHODS: Eleven type 2 diabetes simulation modeling groups participated in the 9th Mount Hood Diabetes Challenge. Modeling groups simulated 5 diabetes-related intervention profiles using predefined baseline characteristics and a standard utility value set for diabetes-related complications. LYs and QALYs were reported. Simulations were repeated using lower and upper limits of the 95% confidence intervals of utility inputs. Changes in LYs and QALYs from tested interventions were compared across models. Additional analyses were conducted postchallenge to investigate drivers of cross-model differences. RESULTS: Substantial cross-model variability in incremental LYs and QALYs was observed, particularly for HbA1c and body mass index (BMI) intervention profiles. For a 0.5%-point permanent HbA1c reduction, LY gains ranged from 0.050 to 0.750. For a 1-unit permanent BMI reduction, incremental QALYs varied from a small decrease in QALYs (-0.024) to an increase of 0.203. Changes in utility values of health states had a much smaller impact (to the hundredth of a decimal place) on incremental QALYs. Microsimulation models were found to generate a mean of 3.41 more LYs than cohort simulation models (P = 0.049). CONCLUSIONS: Variations in utility values contribute to a lesser extent than uncertainty captured as structural uncertainty. These findings reinforce the importance of assessing structural uncertainty thoroughly because the choice of model (or models) can influen

Objectives: The cardiovascular outcomes challenge examined the predictive accuracy of 10 diabetes models in estimating hard outcomes in 2 recent cardiovascular outcomes trials (CVOTs) and whether recalibration can be used to improve replication. Methods: Participating groups were asked to reproduce the results of the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) and the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program. Calibration was performed and additional analyses assessed model ability to replicate absolute event rates, hazard ratios (HRs), and the generalizability of calibration across CVOTs within a drug class. Results: Ten groups submitted results. Models underestimated treatment effects (ie, HRs) using uncalibrated models for both trials. Calibration to the placebo arm of EMPA-REG OUTCOME greatly improved the prediction of event rates in the placebo, but less so in the active comparator arm. Calibrating to both arms of EMPA-REG OUTCOME individually enabled replication of the observed outcomes. Using EMPA-REG OUTCOME–calibrated models to predict CANVAS Program outcomes was an improvement over uncalibrated models but failed to capture treatment effects adequately. Applying canagliflozin HRs directly provided the best fit. Conclusions: The Ninth Mount Hood Diabetes Challenge demonstrated that commonly used risk equations were generally unable to capture recent CVOT treatment effects but that calibration of the risk equations can improve predictive accuracy. Although calibration serves as a practical approach to improve predictive accuracy for CVOT outcomes, it does not extrapolate generally to other settings, time horizons, and comparators. New methods and/or new risk equations for capturing these CV benefits are needed.

Transparency in health economic decision modelling is important for engendering confidence in the models and in the reliability of model-based cost-effectiveness analyses. The Mount Hood Diabetes Challenge Network has taken a lead in promoting transparency through validation with biennial conferences in which diabetes modelling groups meet to compare simulated outcomes of pre-specified scenarios often based on the results of pivotal clinical trials. Model registration is a potential method for promoting transparency, while also reducing the duplication of effort. An important network initiative is the ongoing construction of a diabetes model registry (https://www.mthooddiabeteschallenge.com). Following the 2012 International Society for Pharmacoeconomics and Outcomes Research and the Society of Medical Decision Making (ISPOR-SMDM) guidelines, we recommend that modelling groups provide technical and non-technical documentation sufficient to enable model reproduction, but not necessarily provide the model code. We also request that modelling groups upload documentation on the methods and outcomes of validation efforts, and run reference case simulations so that model outcomes can be compared. In this paper, we discuss conflicting definitions of transparency in health economic modelling, and describe the ongoing development of a registry of economic models for diabetes through the Mount Hood Diabetes Challenge Network, its objectives and potential further developments, and highlight the challenges in its construction and maintenance. The support of key stakeholders such as decision-making bodies and journals is key to ensuring the success of this and other registries. In the absence of public funding, the development of a network of modellers is of huge value in enhancing transparency, whether through registries or other means.

OBJECTIVES: The Eighth Mount Hood Challenge (held in St. Gallen, Switzerland, in September 2016) evaluated the transparency of model input documentation from two published health economics studies and developed guidelines for improving transparency in the reporting of input data underlying model-based economic analyses in diabetes. METHODS: Participating modeling groups were asked to reproduce the results of two published studies using the input data described in those articles. Gaps in input data were filled with assumptions reported by the modeling groups. Goodness of fit between the results reported in the target studies and the groups' replicated outputs was evaluated using the slope of linear regression line and the coefficient of determination (R2). After a general discussion of the results, a diabetes-specific checklist for the transparency of model input was developed. RESULTS: Seven groups participated in the transparency challenge. The reporting of key model input parameters in the two studies, including the baseline characteristics of simulated patients, treatment effect and treatment intensification threshold assumptions, treatment effect evolution, prediction of complications and costs data, was inadequately transparent (and often missing altogether). Not surprisingly, goodness of fit was better for the study that reported its input data with more transparency. To improve the transparency in diabetes modeling, the Diabetes Modeling Input Checklist listing the minimal input data required for reproducibility in most diabetes modeling applications was developed. CONCLUSIONS: Transparency of diabetes model inputs is important to the reproducibility and credibility of simulation results. In the Eighth Mount Hood Challenge, the Diabetes Modeling Input Checklist was developed with the goal of improving the transparency of input data reporting and reproducibility of diabetes simulation model results.

Achieving greater continuation of treatment is a key element to improve treatment outcomes in schizophrenia patients. However, reported treatment continuation can differ markedly depending on the study design. In a retrospective setting, treatment continuation remains overall poor among patients using antipsychotics. This study aimed to document the difference in treatment continuation between four long-acting injectable antipsychotics based on the QuintilesIMS LRx databases, national, longitudinal, panel based prescription databases of retail pharmacies, in the Netherlands and Belgium. Paliperidone palmitate once monthly, risperidone microspheres, haloperidol decanoate, and olanzapine pamoate were studied. This study demonstrated significantly higher treatment continuation of paliperidone palmitate once monthly compared to risperidone microspheres (p-value<0,01) and haloperidol decanoate (p-value<0,01) in both countries, a significantly higher treatment continuation of paliperidone palmitate once monthly compared to olanzapine pamoate in the Netherlands (p-value<0,01), and a general trend towards better treatment continuation versus olanzapine pamoate in Belgium. Analysing the subgroup of patients without previous exposure to long-acting antipsychotic treatment revealed the positive impact of previous exposure on treatment continuation with a subsequent long acting treatment. Additionally, the probability of restarting the index therapy was higher among patients treated with paliperidone palmitate once monthly compared to patients treated with risperidone microspheres and haloperidol decanoate. The data source used and the methodology defined ensured for the first time a comparison of treatment continuation in a non-interventional study design for the four long-acting injectable antipsychotics studied.

Aim: Reductions in arterial oxygen partial pressure activate the peripheral chemoreceptors which increase ventilation, and, after cessation of breathing, reduce heart rate. We tested the hypothesis that facial cooling facilitates these peripheral chemoreflex mechanisms. Methods: Chemoreflex control was assessed by the ventilatory response to hypoxia (10% O2 in N 2) and the bradycardic response to voluntary end-expiratory apnoeas of maximal duration in 12 young, healthy subjects. We recorded minute ventilation, haemoglobin O2 saturation, RR interval (the time between two R waves of the QRS complex) and the standard deviation of the RR interval (SDNN), a marker of cardiac vagal activity throughout the study. Measurements were performed with the subject's face exposed to air flow at 23 and 4°C. Results: Cold air decreased facial temperature by 11°C (P < 0.0001) but did not affect minute ventilation during normoxia. However, facial cooling increased the ventilatory response to hypoxia (P < 0.05). The RR interval increased by 31 ± 8% of the mean RR preceding the apnoea during the hypoxic apnoeas in the presence of cold air, compared to 17 ± 5% of the mean RR preceding the apnoea in the absence of facial cooling (P < 0.05). This increase occurred despite identical apnoea durations and reductions in oxygen saturation. Finally, facial cooling increased SDNN during normoxia and hypoxia, as well as during the apnoeas performed in hypoxic conditions (all P < 0.05). Conclusion: The larger ventilatory response to hypoxia suggests that facial cooling facilitates peripheral chemoreflex mechanisms in normal humans. Moreover, simultaneous diving reflex and peripheral chemoreflex activation enhances cardiac vagal activation, and favours further bradycardia upon cessation of breathing. © 2008 The Authors.

Contains fulltext : 51193.pdf (publisher's version ) (Closed access), Low-dose aspirin is a standard care for secondary prevention of cardiovascular disease (CVD). Its use in primary prevention is less widely accepted, however, despite recent meta-analyses and US and European guidelines supporting its use in individuals at increased CVD risk. The aim of this study was to define which patients should receive aspirin for primary prevention of CVD using data from four European countries. Based on the clinical data from two meta-analyses, a state-transition model was developed to compare the costs and effects of no treatment and low-dose aspirin as primary prevention for CVD over 10 years. The model was applied to patients at different 10-year risks (2-5%) of fatal CVD according to the SCORE equation. Direct costs from the perspective of the healthcare payer were used (base year 2003). Country-specific discounting was applied. Treating patients with a 10-year risk of fatal CVD of 2% or higher with low-dose aspirin resulted in lower total costs and more quality-adjusted life-years gained in the UK, Germany and Spain. In Italy, savings started at a 10-year fatal CVD risk of 3%. This difference was due to the higher cost of gastrointestinal bleeding in Italy. Monte Carlo analysis showed that aspirin was dominant in more than 90% of patients at a 10-year risk of 4% and 5% in the four countries. In conclusion, low-dose aspirin treatment becomes cost-saving at a very low 10-year risk of fatal CVD. The cost of gastrointestinal bleeding defines the level at which low-dose aspirin becomes cost-saving.

Contains fulltext : 51193.pdf (publisher's version ) (Closed access), Low-dose aspirin is a standard care for secondary prevention of cardiovascular disease (CVD). Its use in primary prevention is less widely accepted, however, despite recent meta-analyses and US and European guidelines supporting its use in individuals at increased CVD risk. The aim of this study was to define which patients should receive aspirin for primary prevention of CVD using data from four European countries. Based on the clinical data from two meta-analyses, a state-transition model was developed to compare the costs and effects of no treatment and low-dose aspirin as primary prevention for CVD over 10 years. The model was applied to patients at different 10-year risks (2-5%) of fatal CVD according to the SCORE equation. Direct costs from the perspective of the healthcare payer were used (base year 2003). Country-specific discounting was applied. Treating patients with a 10-year risk of fatal CVD of 2% or higher with low-dose aspirin resulted in lower total costs and more quality-adjusted life-years gained in the UK, Germany and Spain. In Italy, savings started at a 10-year fatal CVD risk of 3%. This difference was due to the higher cost of gastrointestinal bleeding in Italy. Monte Carlo analysis showed that aspirin was dominant in more than 90% of patients at a 10-year risk of 4% and 5% in the four countries. In conclusion, low-dose aspirin treatment becomes cost-saving at a very low 10-year risk of fatal CVD. The cost of gastrointestinal bleeding defines the level at which low-dose aspirin becomes cost-saving.

Contains fulltext : 51193.pdf (publisher's version ) (Closed access), Low-dose aspirin is a standard care for secondary prevention of cardiovascular disease (CVD). Its use in primary prevention is less widely accepted, however, despite recent meta-analyses and US and European guidelines supporting its use in individuals at increased CVD risk. The aim of this study was to define which patients should receive aspirin for primary prevention of CVD using data from four European countries. Based on the clinical data from two meta-analyses, a state-transition model was developed to compare the costs and effects of no treatment and low-dose aspirin as primary prevention for CVD over 10 years. The model was applied to patients at different 10-year risks (2-5%) of fatal CVD according to the SCORE equation. Direct costs from the perspective of the healthcare payer were used (base year 2003). Country-specific discounting was applied. Treating patients with a 10-year risk of fatal CVD of 2% or higher with low-dose aspirin resulted in lower total costs and more quality-adjusted life-years gained in the UK, Germany and Spain. In Italy, savings started at a 10-year fatal CVD risk of 3%. This difference was due to the higher cost of gastrointestinal bleeding in Italy. Monte Carlo analysis showed that aspirin was dominant in more than 90% of patients at a 10-year risk of 4% and 5% in the four countries. In conclusion, low-dose aspirin treatment becomes cost-saving at a very low 10-year risk of fatal CVD. The cost of gastrointestinal bleeding defines the level at which low-dose aspirin becomes cost-saving.

Intensity and spectral characteristics of the fluorescence of water samples collected along the transect Cherbourg-Isle of Wight during four cruises for excitations at 370, 313 and 270 nm have been investigated within the framework of the FluxManche II program. Seasonal and spatial differences appeared to reflect on the one hand, variations in terrestrial inputs, and on the other hand, waters masses structuring. The observed linear variation of the fluorescence intensity with salinity indicates a gradual dilution of the continental humic material in going from the coasts to the central part of the English Channel. The largest signal was observed for the English coastal waters in agreement with important terrestrial inputs from the Solent river. While the fluorescence intensity was not found to be correlated with the DOG, it shows a good correlation with the nutrients. This result could indicate both a supply from terrestrial inputs and an almost simultaneous autochtonous regeneration. As similarly reported for waters in the eastern part of the French coastal zone, excitation at 313 nm gives evidence for the presence of two classes of fluorescent dissolved organic matter. These two fluorescent components are indicative of the simultaneous presence of continental humic substances and substances whose assignment to marine humic substances or to heterotrophic related substances are still an open question. As compared to the eastern part of the Channel along the French coasts, excitation at 270 nm indicates a lower content of protein-like compounds which may be related to a lower biological activity along the transect or may be due to the fact that the samplings were made out of the phytoplanktonic bloom period (April-May 1995)., Quatre campagnes de prélèvements des eaux du transect Cherbourg — île de Wight en Manche centrale ont été menées dans le cadre du programme FluxManche II. La matière organique dissoute fluorescente a étéétudiée par spectrofluorimétrie sous le double aspect quantitatif et qualitatif. La fluorescence naturelle des eaux étudiées montre des variations spatiales et saisonnières en relation avec l'influence des apports terrestres et avec la structuration des masses d'eaux. Des relations linéaires négatives entre la fluorescence et la salinité suggèrent une dilution graduelle du matériel humique continental des côtes vers le centre de la Manche. Le signal le plus élevé est observé dans les eaux côtières anglaises en relation avec l'influence des apports du Solent. Alors que la fluorescence diffère entre le matériel humique et la matière organique dissoute globale, en raison principalement de cinétiques d'évolution différentes, elle est liée aux sels nutritifs (Si, NO3−, PO43−) par des relations linéaires positives indiquant des apports terrestres concomitants et une régénération commune autochtone de ces deux paramètres. L'excitation à 313 nm met en évidence deux composantes spectrales; l'une est attribuée aux substances humiques continentales, l'autre semble caractéristique du milieu marin. L'origine et les mécanismes aboutissant à la formation de cette composante fluorescente marine restent àétablir. Par comparaison à la Manche orientale, le long des côtes françaises, l'excitation à 270 nm indique une faible teneur en composés de type protéinique, probablement liée à la faible activité biologique le long du transect ou au fait que les prélèvements ont eu lieu en dehors (avril–mai 1995) de la période de floraison phytoplanctonique.

Intensity and spectral characteristics of the fluorescence of water samples collected along the transect Cherbourg-Isle of Wight during four cruises for excitations at 370, 313 and 270 nm have been investigated within the framework of the FluxManche II program. Seasonal and spatial differences appeared to reflect on the one hand, variations in terrestrial inputs, and on the other hand, waters masses structuring. The observed linear variation of the fluorescence intensity with salinity indicates a gradual dilution of the continental humic material in going from the coasts to the central part of the English Channel. The largest signal was observed for the English coastal waters in agreement with important terrestrial inputs from the Solent river. While the fluorescence intensity was not found to be correlated with the DOG, it shows a good correlation with the nutrients. This result could indicate both a supply from terrestrial inputs and an almost simultaneous autochtonous regeneration. As similarly reported for waters in the eastern part of the French coastal zone, excitation at 313 nm gives evidence for the presence of two classes of fluorescent dissolved organic matter. These two fluorescent components are indicative of the simultaneous presence of continental humic substances and substances whose assignment to marine humic substances or to heterotrophic related substances are still an open question. As compared to the eastern part of the Channel along the French coasts, excitation at 270 nm indicates a lower content of protein-like compounds which may be related to a lower biological activity along the transect or may be due to the fact that the samplings were made out of the phytoplanktonic bloom period (April-May 1995)., Quatre campagnes de prélèvements des eaux du transect Cherbourg — île de Wight en Manche centrale ont été menées dans le cadre du programme FluxManche II. La matière organique dissoute fluorescente a étéétudiée par spectrofluorimétrie sous le double aspect quantitatif et qualitatif. La fluorescence naturelle des eaux étudiées montre des variations spatiales et saisonnières en relation avec l'influence des apports terrestres et avec la structuration des masses d'eaux. Des relations linéaires négatives entre la fluorescence et la salinité suggèrent une dilution graduelle du matériel humique continental des côtes vers le centre de la Manche. Le signal le plus élevé est observé dans les eaux côtières anglaises en relation avec l'influence des apports du Solent. Alors que la fluorescence diffère entre le matériel humique et la matière organique dissoute globale, en raison principalement de cinétiques d'évolution différentes, elle est liée aux sels nutritifs (Si, NO3−, PO43−) par des relations linéaires positives indiquant des apports terrestres concomitants et une régénération commune autochtone de ces deux paramètres. L'excitation à 313 nm met en évidence deux composantes spectrales; l'une est attribuée aux substances humiques continentales, l'autre semble caractéristique du milieu marin. L'origine et les mécanismes aboutissant à la formation de cette composante fluorescente marine restent àétablir. Par comparaison à la Manche orientale, le long des côtes françaises, l'excitation à 270 nm indique une faible teneur en composés de type protéinique, probablement liée à la faible activité biologique le long du transect ou au fait que les prélèvements ont eu lieu en dehors (avril–mai 1995) de la période de floraison phytoplanctonique.

Intensity and spectral characteristics of the fluorescence of water samples collected along the transect Cherbourg-Isle of Wight during four cruises for excitations at 370, 313 and 270 nm have been investigated within the framework of the FluxManche II program. Seasonal and spatial differences appeared to reflect on the one hand, variations in terrestrial inputs, and on the other hand, waters masses structuring. The observed linear variation of the fluorescence intensity with salinity indicates a gradual dilution of the continental humic material in going from the coasts to the central part of the English Channel. The largest signal was observed for the English coastal waters in agreement with important terrestrial inputs from the Solent river. While the fluorescence intensity was not found to be correlated with the DOG, it shows a good correlation with the nutrients. This result could indicate both a supply from terrestrial inputs and an almost simultaneous autochtonous regeneration. As similarly reported for waters in the eastern part of the French coastal zone, excitation at 313 nm gives evidence for the presence of two classes of fluorescent dissolved organic matter. These two fluorescent components are indicative of the simultaneous presence of continental humic substances and substances whose assignment to marine humic substances or to heterotrophic related substances are still an open question. As compared to the eastern part of the Channel along the French coasts, excitation at 270 nm indicates a lower content of protein-like compounds which may be related to a lower biological activity along the transect or may be due to the fact that the samplings were made out of the phytoplanktonic bloom period (April-May 1995)., Quatre campagnes de prélèvements des eaux du transect Cherbourg — île de Wight en Manche centrale ont été menées dans le cadre du programme FluxManche II. La matière organique dissoute fluorescente a étéétudiée par spectrofluorimétrie sous le double aspect quantitatif et qualitatif. La fluorescence naturelle des eaux étudiées montre des variations spatiales et saisonnières en relation avec l'influence des apports terrestres et avec la structuration des masses d'eaux. Des relations linéaires négatives entre la fluorescence et la salinité suggèrent une dilution graduelle du matériel humique continental des côtes vers le centre de la Manche. Le signal le plus élevé est observé dans les eaux côtières anglaises en relation avec l'influence des apports du Solent. Alors que la fluorescence diffère entre le matériel humique et la matière organique dissoute globale, en raison principalement de cinétiques d'évolution différentes, elle est liée aux sels nutritifs (Si, NO3−, PO43−) par des relations linéaires positives indiquant des apports terrestres concomitants et une régénération commune autochtone de ces deux paramètres. L'excitation à 313 nm met en évidence deux composantes spectrales; l'une est attribuée aux substances humiques continentales, l'autre semble caractéristique du milieu marin. L'origine et les mécanismes aboutissant à la formation de cette composante fluorescente marine restent àétablir. Par comparaison à la Manche orientale, le long des côtes françaises, l'excitation à 270 nm indique une faible teneur en composés de type protéinique, probablement liée à la faible activité biologique le long du transect ou au fait que les prélèvements ont eu lieu en dehors (avril–mai 1995) de la période de floraison phytoplanctonique.