Health-state valuation using discrete choice models

The aim of this thesis was to investigate specific problems associated with preference-based measures (values) of health states and with the methodology used to derive health-state values. The first chapter covers the changes in phrasing and differences in measurement methods in the EQ-5D instrument after the five-level version was introduced alongside the conventional three-level version. Specifically, a head-to-head comparison of the values elicited from a large sample showed slight differences between the two versions. The study described in the second chapter was motivated by the fact that most instruments do not take into account the interactions of distinct health attributes (reduction in perceived health status may intensify if two different health problems interact). Our study revealed that the inclusion of interactions between various EQ-5D health aspects leads to different values for health states. The third chapter shows that people with experience of disease tend to value health states differently, or assign importance to certain health attributes differently than healthy respondents do. The fourth chapter presents a separate discrete choice study that we conducted to determine the importance of criteria regarding new medical treatments. We found four criteria to be important, based on preferences of the general population and patients: health gains, patient's age, patient's initial health condition, and cause of the disease. In the fifth chapter we present an eye-tracking study, which proved to support a basic assumption in health-state measurement: that respondents pay attention to all elements of the health state description and do not disregard information

Immunosuppressant drugs and quality-of-life outcomes in kidney transplant recipients: An international cohort study (EU-TRAIN)

Immunosuppressant; Quality of life; TransplantationImmunosupressor; Qualitat de vida; TrasplantamentInmunosupresor; Calidad de vida; TrasplanteIntroduction: Patient-Reported Outcomes (PRO) integrate a wide range of holistic dimensions that arenot captured within clinical outcomes. Particularly, from induction treatment to maintenance therapy, patient quality-of-life (QoL) of kidney transplant recipients have been sparsely investigated in international settings. Methods: In a prospective, multi-centric cohort study, including nine transplant centers in four countries, we explored the QoL during the year following transplantation using validated elicitation instruments (EQ-5D-3L index with VAS) in a population of kidney transplant patients receiving immunosuppressive therapies. Calcineurin inhibitors (tacrolimus and ciclosporin), IMPD inhibitor (mycophenolate mofetil), and mTOR inhibitors (everolimus and sirolimus) were the standard-of-care (SOC) medications, together with tapering glucocorticoid therapy. We used EQ-5D and VAS data as QoL measures alongside descriptive statistics at inclusion, per country and hospital center. We computed the proportions of patients with different immunosuppressive therapy patterns, and using bivariate and multivariate analyses, assessed the variations of EQ-5D and VAS between baseline (i.e., inclusion Month 0) and follow up visits (Month 12). Results: Among 542 kidney transplant patients included and followed from November 2018 to June 2021, 491 filled at least one QoL questionnaire at least at baseline (Month 0). The majority of patients in all countries received tacrolimus and mycophenolate mofetil, ranging from 90.0% in Switzerland and Spain to 95.8% in Germany. At M12, a significant proportion of patients switched immunosuppressive drugs, with proportion varying from 20% in Germany to 40% in Spain and Switzerland. At visit M12, patients who kept SOC therapy had higher EQ-5D (by 8 percentage points, p < 0.05) and VAS (by 4 percentage points, p < 0.1) scores than switchers. VAS scores were generally lower than EQ-5D (mean 0.68 [0.5–0.8] vs. 0.85 [0.8–1]). Discussion: Although overall a positive trend in QoL was observed, the formal analyses did not show any significant improvements in EQ-5D scores or VAS. Only when the effect of a therapy use was separated from the effect of switching, the VAS score was significantly worse for switchers during the follow up period, irrespective of the therapy type. If adjusted for patient characteristics and medical history (e.g., gender, BMI, eGRF, history of diabetes), VAS and EQ-5D delivered sound PRO measures for QoL assessments during the year following renal transplantation.The project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 754995. Open access funding by University of Lausanne

Continuity of care of Swiss residents aged 50+: a longitudinal study using claims data

Background Continuity of care (COC) should be measured for healthcare quality monitoring and evaluation and is a key process indicator for integrated care. Measurement of COC using routinely collected data is widespread, but there is no consensus on which indicator to use and the relevant time horizon to apply. Information about COC is especially warranted in highly fragmented healthcare systems, such as in Switzerland. Our study aimed to compare COC measures in Swiss residents aged 50+ obtained with various indices and time horizons. Methods Using insurance claims data, we computed and compared several commonly used visit-based Continuity of Care Indices (COCIs): Bice-Boxerman Index, Usual Provider of Care, Herfindahl-Hirschman Index, Modified, Modified Continuity Index and Modified Continuity Index, based on all doctor visits and on primary care (PC) visits only. Indices were computed over short (1 year) and medium (4 years) terms. Results The mean indices based on all visits varied between 0.51 and 0.77, while PC indices presented less variation with a median of 1.00 for all but one index. Indices focusing on a variety of individual providers decreased with time horizon, while indices focusing on the overall number of visits and providers showed the opposite trend. These findings suggest fundamental differences in the interpretation of COCIs. Conclusions Broad COC appeared moderately low in Switzerland, although comparable to other countries, and PC COC was close to one. The choice of indices and time horizon influenced their interpretation. Understanding these differences is key to select the appropriate index for the monitoring of COC

Association between continuity of care (COC), healthcare use and costs: what can we learn from claims data? A rapid review.

To describe how longitudinal continuity of care (COC) is measured using claims-based data and to review its association with healthcare use and costs. Rapid review of the literature. We searched Medline (PubMed), EMBASE and Cochrane Central, manually checked the references of included studies, and hand-searched websites for potentially additional eligible studies. We included 46 studies conducted in North America, East Asia and Europe, which used 14 COC indicators. Most reported studies (39/46) showed that higher COC was associated with lower healthcare use and costs. Most studies (37/46) adjusted for possible time bias and discussed causality between the outcomes and COC, or at least acknowledged the lack of it as a limitation. Whereas a wide range of indicators is used to measure COC in claims-based data, associations between COC and healthcare use and costs were consistent, showing lower healthcare use and costs with higher COC. Results were observed in various population groups from multiple countries and settings. Further research is needed to make stronger causal claims

Does Inclusion of Interactions Result in Higher Precision of Estimated Health State Values?

Background: Most preference-based instruments producing overall values for health states are devised on the simplifying assumption that the overall effect of distinct health-related quality of life domains (attributes) of the instrument equals the sum of the attributes. Nevertheless, health attributes are often inter-related and depend on each other. Objectives: To investigate whether inclusion of second-order interactions in the three-level EuroQol five-dimensional questionnaire (EQ-5D-3L) value function would result in better fit and lead to different health state values than a model with main effects only. Methods: Using an efficient design, 400 pairs of EQ-5D-3L health states were generated in a pairwise choice format. We analyzed responses of 4000 people from the general population using a conditional logit model, and we tested goodness of fit using pseudo R2, Akaike information criterion, differences in log-likelihood, and likelihood ratio. We compared accuracies of models’ predictions based on root mean square error and mean absolute error. Results: The interaction-effects model showed systematically lower values than the main-effects model. Inclusion of interactions resulted only in a slightly better model fit. Interactions comprising mobility and self-care were the most salient. Conclusions: For the EQ-5D-3L, a value function based on interactions produces systematically lower values than a main-effects model, meaning that the effect of two or more health problems combined is stronger than the sum of the individual main effects

Comprehensive space-time hydrometeorological simulations for estimating very rare floods at multiple sites in a large river basin

Estimates for rare to very rare floods are limited by the relatively short streamflow records available. Often, pragmatic conversion factors are used to quantify such events based on extrapolated observations, or simplifying assumptions are made about extreme precipitation and resulting flood peaks. Continuous simulation (CS) is an alternative approach that better links flood estimation with physical processes and avoids assumptions about antecedent conditions. However, long-term CS has hardly been implemented to estimate rare floods (i.e. return periods considerably larger than 100 years) at multiple sites in a large river basin to date. Here we explore the feasibility and reliability of the CS approach for 19 sites in the Aare River basin in Switzerland (area: 17 700 km2) with exceedingly long simulations in a hydrometeorological model chain. The chain starts with a multi-site stochastic weather generator used to generate 30 realizations of hourly precipitation and temperature scenarios of 10 000 years each. These realizations were then run through a bucket-type hydrological model for 80 sub-catchments and finally routed downstream with a simplified representation of main river channels, major lakes and relevant floodplains in a hydrologic routing system. Comprehensive evaluation over different temporal and spatial scales showed that the main features of the meteorological and hydrological observations are well represented and that meaningful information on low-probability floods can be inferred. Although uncertainties are still considerable, the explicit consideration of important processes of flood generation and routing (snow accumulation, snowmelt, soil moisture storage, bank overflow, lake and floodplain retention) is a substantial advantage. The approach allows for comprehensively exploring possible but unobserved spatial and temporal patterns of hydrometeorological behaviour. This is of particular value in a large river basin where the complex interaction of flows from individual tributaries and lake regulations are typically not well represented in the streamflow observations. The framework is also suitable for estimating more frequent floods, as often required in engineering and hazard mapping

Comprehensive space–time hydrometeorological simulations for estimating very rare floods at multiple sites in a large river basin

Estimates for rare to very rare floods are limited by the relatively short streamflow records available. Often, pragmatic conversion factors are used to quantify such events based on extrapolated observations, or simplifying assumptions are made about extreme precipitation and resulting flood peaks. Continuous simulation (CS) is an alternative approach that better links flood estimation with physical processes and avoids assumptions about antecedent conditions. However, long-term CS has hardly been implemented to estimate rare floods (i.e. return periods considerably larger than 100 years) at multiple sites in a large river basin to date. Here we explore the feasibility and reliability of the CS approach for 19 sites in the Aare River basin in Switzerland (area: 17 700 km2) with exceedingly long simulations in a hydrometeorological model chain. The chain starts with a multi-site stochastic weather generator used to generate 30 realizations of hourly precipitation and temperature scenarios of 10 000 years each. These realizations were then run through a bucket-type hydrological model for 80 sub-catchments and finally routed downstream with a simplified representation of main river channels, major lakes and relevant floodplains in a hydrologic routing system. Comprehensive evaluation over different temporal and spatial scales showed that the main features of the meteorological and hydrological observations are well represented and that meaningful information on low-probability floods can be inferred. Although uncertainties are still considerable, the explicit consideration of important processes of flood generation and routing (snow accumulation, snowmelt, soil moisture storage, bank overflow, lake and floodplain retention) is a substantial advantage. The approach allows for comprehensively exploring possible but unobserved spatial and temporal patterns of hydrometeorological behaviour. This is of particular value in a large river basin where the complex interaction of flows from individual tributaries and lake regulations are typically not well represented in the streamflow observations. The framework is also suitable for estimating more frequent floods, as often required in engineering and hazard mapping

Immunosuppressant drugs and quality-of-life outcomes in kidney transplant recipients: An international cohort study (EU-TRAIN)

Introduction: Patient-Reported Outcomes (PRO) integrate a wide range of holistic dimensions that arenot captured within clinical outcomes. Particularly, from induction treatment to maintenance therapy, patient quality-of-life (QoL) of kidney transplant recipients have been sparsely investigated in international settings.Methods: In a prospective, multi-centric cohort study, including nine transplant centers in four countries, we explored the QoL during the year following transplantation using validated elicitation instruments (EQ-5D-3L index with VAS) in a population of kidney transplant patients receiving immunosuppressive therapies. Calcineurin inhibitors (tacrolimus and ciclosporin), IMPD inhibitor (mycophenolate mofetil), and mTOR inhibitors (everolimus and sirolimus) were the standard-of-care (SOC) medications, together with tapering glucocorticoid therapy. We used EQ-5D and VAS data as QoL measures alongside descriptive statistics at inclusion, per country and hospital center. We computed the proportions of patients with different immunosuppressive therapy patterns, and using bivariate and multivariate analyses, assessed the variations of EQ-5D and VAS between baseline (i.e., inclusion Month 0) and follow up visits (Month 12).Results: Among 542 kidney transplant patients included and followed from November 2018 to June 2021, 491 filled at least one QoL questionnaire at least at baseline (Month 0). The majority of patients in all countries received tacrolimus and mycophenolate mofetil, ranging from 90.0% in Switzerland and Spain to 95.8% in Germany. At M12, a significant proportion of patients switched immunosuppressive drugs, with proportion varying from 20% in Germany to 40% in Spain and Switzerland. At visit M12, patients who kept SOC therapy had higher EQ-5D (by 8 percentage points, p &lt; 0.05) and VAS (by 4 percentage points, p &lt; 0.1) scores than switchers. VAS scores were generally lower than EQ-5D (mean 0.68 [0.5–0.8] vs. 0.85 [0.8–1]).Discussion: Although overall a positive trend in QoL was observed, the formal analyses did not show any significant improvements in EQ-5D scores or VAS. Only when the effect of a therapy use was separated from the effect of switching, the VAS score was significantly worse for switchers during the follow up period, irrespective of the therapy type. If adjusted for patient characteristics and medical history (e.g., gender, BMI, eGRF, history of diabetes), VAS and EQ-5D delivered sound PRO measures for QoL assessments during the year following renal transplantation

Cell-free H-cluster Synthesis and [FeFe] Hydrogenase Activation: All Five CO and CN− Ligands Derive from Tyrosine

[FeFe] hydrogenases are promising catalysts for producing hydrogen as a sustainable fuel and chemical feedstock, and they also serve as paradigms for biomimetic hydrogen-evolving compounds. Hydrogen formation is catalyzed by the H-cluster, a unique iron-based cofactor requiring three carbon monoxide (CO) and two cyanide (CN−) ligands as well as a dithiolate bridge. Three accessory proteins (HydE, HydF, and HydG) are presumably responsible for assembling and installing the H-cluster, yet their precise roles and the biosynthetic pathway have yet to be fully defined. In this report, we describe effective cell-free methods for investigating H-cluster synthesis and [FeFe] hydrogenase activation. Combining isotopic labeling with FTIR spectroscopy, we conclusively show that each of the CO and CN− ligands derive respectively from the carboxylate and amino substituents of tyrosine. Such in vitro systems with reconstituted pathways comprise a versatile approach for studying biosynthetic mechanisms, and this work marks a significant step towards an understanding of both the protein-protein interactions and complex reactions required for H-cluster assembly and hydrogenase maturation