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When considering the introduction of a new intervention in a budget constrained healthcare system, priority setting based on fair principles is fundamental. In many jurisdictions, a multi-criteria approach with several different considerations is employed, including severity and cost-effectiveness. Such multi-criteria approaches raise questions about how to balance different considerations against each other, and how to understand the logical or normative relations between them. For example, some jurisdictions make explicit reference to a large patient benefit as such a consideration. However, since patient benefit is part of a cost-effectiveness assessment it is not clear how to balance considerations of greater patient benefit against considerations of severity and cost-effectiveness. The aim of this paper is to explore the role of a large patient benefit as an independent criterion for priority setting in a healthcare system also considering severity and cost-effectiveness. By taking the opportunity cost of new interventions (i.e., the health forgone in patients already receiving treatment) into account, we argue that patient benefit has a complex relationship to priority setting. More specifically, it cannot be reasonably concluded that large patient benefits should be given priority if severity, cost-effectiveness, and opportunity costs are held constant. Since we cannot find general support for taking patient benefit into account as an independent criterion from any of the most discussed theories about distributive justice: utilitarianism, prioritarianism, telic egalitarianism and sufficientarianism, it is reasonable to avoid doing so. Hence, given the complexity of the role of patient benefit, we conclude that in priority practice, a large patient benefit should not be considered as an independent criterion, on top of considerations of severity and cost-effectiveness. [ABSTRACT FROM AUTHOR]

Whole genome sequencing (WGS) has the potential to be a comprehensive genetic test, especially relevant for individuals with neurodevelopmental disorders, syndromes and congenital malformations. However, the cost consequences of using whole genome sequencing as a first-line genetic test for these individuals are not well understood. The study objective was to compare the healthcare costs and diagnostic yield when WGS is performed as the first-line test instead of chromosomal microarray analysis (CMA). Two cohorts were analyzed retrospectively using register data, cohort CMA (418 patients referred for CMA at the department of Clinical Genetics, Karolinska University Hospital, during 2015) and cohort WGS (89 patients included in a WGS-first prospective study in 2017). The analysis compared healthcare consumption over a 2-year period after referral for genetic testing, the diagnostic yield over a 2- and 3-year period after referral was also compiled. The mean healthcare cost per patient in cohort WGS was $2,339 lower compared to cohort CMA ($ − 2339, 95% CI − 12,238–7561; P = 0.64) including higher costs for genetic investigations ($1065, 95% CI 834–1295; P < 0.001) and lower costs for outpatient care ($ − 2330, 95% CI − 3992 to (− 669); P = 0.006). The diagnostic yield was 23% higher for cohort WGS (cohort CMA 20.1%, cohort WGS 24.7%) (0.046, 95% CI − 0.053–0.145; P = 0.36). WGS as a first-line diagnostic test for individuals with neurodevelopmental disorders is associated with statistically non-significant lower costs and higher diagnostic yield compared with CMA. This indicates that prioritizing WGS over CMA in health care decision making will yield positive expected outcomes as well as showing a need for further research. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to investigate inequality and heterogeneity in health-related quality of life (HRQoL) and to provide EQ-5D-5L population reference data for Sweden. Methods: Based on a large Swedish population-based survey, 25,867 respondents aged 30‒104 years, HRQoL is described by sex, age, education, income, economic activity, health-related behaviours, self-reported diseases and conditions. Results are presented by EQ-5D-5L dimensions, respondents rating of their overall health on the EQ visual analogue scale (EQ VAS), VAS index value and TTO (time trade-off) index value allowing for calculation of quality-adjusted life years (QALYs). Ordinary Least Squares and multivariable logistic regression analyses were used to study inequalities in observed EQ VAS score between socioeconomic groups and the likelihood to report problems on the dimensions, respectively, adjusted for confounders. Results: In total, 896 different health states were reported; 24.1% did not report any problems. Most problems were reported with pain/discomfort. Women reported worse HRQoL than men, and health deteriorated with age. The strongest association between diseases and conditions and EQ VAS score was seen for depression and mental health problems. There was a socioeconomic gradient in HRQoL; adjusting for health-related behaviours, diseases and conditions slightly reduced the differences between educational groups and income groups, but socioeconomic inequalities largely remained. Conclusion: EQ-5D-5L population reference (norms) data are now available for Sweden, including socioeconomic differentials. Results may be used for comparisons with disease-specific populations and in health economic evaluations. The observed socioeconomic inequality in HRQoL should be of great importance for policy makers concerned with equity aspects. [ABSTRACT FROM AUTHOR]

Background and Objective: Although value sets for the five-level version of the generic health-related quality-of-life instrument EQ-5D are emerging, there is still no value set available in the literature based on time trade-off valuations made by individuals experiencing the valued health states. The aim of this study was to estimate experience-based value sets for the EQ-5D-5L for Sweden using time trade-off and visual analogue scale valuation methods. Methods: In a large, cross-sectional, population-based, self-administered postal health survey, the EQ-5D-5L descriptive system, EQ visual analogue scale and a time trade-off question were included. Time trade-off and visual analogue scale valuations of the respondent's current health status were used in statistical modelling to estimate a single-index value of health for each of the 3125 health states. Ordinary least-squares and generalised linear models were estimated with the main effect within each of the five dimensions represented by 20 dummy variables reflecting the additional decrement in value for levels 2–5 when the severity increases by one level sequentially beginning from having no problem. Interaction variables representing the occurrence of severity levels in at least one of the dimensions were tested: severity level 2 or worse (N2); severity level 3 or worse (N3); severity level 4 or worse (N4); severity level 5 (N5). Results: A total of 896 health states (28.7% of the 3125 possible EQ-5D-5L health states) were reported by the 25,867 respondents. Visual analogue scale (n = 23,899) and time trade-off (n = 13,381) responders reported valuations of their currently experienced health state. The preferred regression models used ordinary least-squares estimation for both time trade-off and visual analogue scale values and showed consistency in all coefficients after combining certain levels. Levels 4 and 5 for the dimensions of mobility, self-care and usual activities were combined in the time trade-off model. Including the interaction variable N5, indicating severity level 5 in at least one of the five dimensions, made it possible to distinguish between the two worst severity levels where no other dimension is at level 5 as this coefficient is applied only once. In the visual analogue scale regression model, levels 4 and 5 of the mobility dimension were combined. The interaction variables N2–N4 were included, indicating that each of these terms reflect a statistically significant decrement in visual analogue scale value if any of the dimensions is at severity level 2, 3 or 4, respectively. Conclusions: Time trade-off and visual analogue scale value sets for the EQ-5D-5L are now available for Sweden. The time trade-off value set is the first such value set based on experience-based time trade-off valuation. For decision makers with a preference for experience-based valuations of health states from a representative population-based sample, the reported value sets may be considered fit for purpose to support resource allocation decision as well as evaluating population health and healthcare performance. [ABSTRACT FROM AUTHOR]

Priority setting in health care is ubiquitous and health authorities are increasingly recognising the need for priority setting guidelines to ensure efficient, fair, and equitable resource allocation. While cost-effectiveness concerns seem to dominate many policies, the tension between utilitarian and deontological concerns is salient to many, and various severity criteria appear to fill this gap. Severity, then, must be subjected to rigorous ethical and philosophical analysis. Here we first give a brief history of the path to today's severity criteria in Norway and Sweden. The Scandinavian perspective on severity might be conducive to the international discussion, given its long-standing use as a priority setting criterion, despite having reached rather different conclusions so far. We then argue that severity can be viewed as a multidimensional concept, drawing on accounts of need, urgency, fairness, duty to save lives, and human dignity. Such concerns will often be relative to local mores, and the weighting placed on the various dimensions cannot be expected to be fixed. Thirdly, we present what we think are the most pertinent questions to answer about severity in order to facilitate decision making in the coming years of increased scarcity, and to further the understanding of underlying assumptions and values that go into these decisions. We conclude that severity is poorly understood, and that the topic needs substantial further inquiry; thus we hope this article may set a challenging and important research agenda. [ABSTRACT FROM AUTHOR]

Although cost-effectiveness analysis has a long tradition of supporting healthcare decision-making in Sweden, there are no clear criteria for when an intervention is considered too expensive. In particular, the opportunity cost of healthcare resource use in terms of health forgone has not been investigated empirically. In this work, we therefore seek to estimate the marginal cost of a life year in Sweden's public healthcare sector using time series and panel data at the national and regional levels, respectively. We find that estimation using time series is unfeasible due to reversed causality. However, through panel instrumental variable estimation we are able to derive a marginal cost per life year of about SEK 370,000 (EUR 39,000). Although this estimate is in line with emerging evidence from other healthcare systems, it is associated with uncertainty, primarily due to the inherent difficulties of causal inference using aggregate observational data. The implications of these difficulties and related methodological issues are discussed. [ABSTRACT FROM AUTHOR]

Background: Critiques of cost-effectiveness modelling in type 1 diabetes mellitus (T1DM) are scarce and are often undertaken in combination with type 2 diabetes mellitus (T2DM) models. However, T1DM is a separate disease, and it is therefore important to appraise modelling methods in T1DM.Objectives: This review identified published economic models in T1DM and provided an overview of the characteristics and capabilities of available models, thus enabling a discussion of best-practice modelling approaches in T1DM.Methods: A systematic review of Embase(®), MEDLINE(®), MEDLINE(®) In-Process, and NHS EED was conducted to identify available models in T1DM. Key conferences and health technology assessment (HTA) websites were also reviewed. The characteristics of each model (e.g. model structure, simulation method, handling of uncertainty, incorporation of treatment effect, data for risk equations, and validation procedures, based on information in the primary publication) were extracted, with a focus on model capabilities.Results: We identified 13 unique models. Overall, the included studies varied greatly in scope as well as in the quality and quantity of information reported, but six of the models (Archimedes, CDM [Core Diabetes Model], CRC DES [Cardiff Research Consortium Discrete Event Simulation], DCCT [Diabetes Control and Complications Trial], Sheffield, and EAGLE [Economic Assessment of Glycaemic control and Long-term Effects of diabetes]) were the most rigorous and thoroughly reported. Most models were Markov based, and cohort and microsimulation methods were equally common. All of the more comprehensive models employed microsimulation methods. Model structure varied widely, with the more holistic models providing a comprehensive approach to microvascular and macrovascular events, as well as including adverse events. The majority of studies reported a lifetime horizon, used a payer perspective, and had the capability for sensitivity analysis.Conclusions: Several models have been developed that provide useful insight into T1DM modelling. Based on a review of the models identified in this study, we identified a set of 'best in class' methods for the different technical aspects of T1DM modelling. [ABSTRACT FROM AUTHOR]

Purpose: To estimate Swedish experience-based value sets for EQ-5D health states using general population health survey data. Methods: Approximately 45,000 individuals valued their current health status by means of time trade off (TTO) and visual analogue scale (VAS) methods and answered the EQ-5D questionnaire, making it possible to model the association between the experience-based TTO and VAS values and the EQ-5D dimensions and severity levels. The association between TTO and VAS values and the different severity levels of respondents' answers on a self-rated health (SRH) question was assessed. Results: Almost all dimensions (except usual activity) and severity levels had less impact on TTO valuations compared with the UK study based on hypothetical values. Anxiety/depression had the greatest impact on both TTO and VAS values. TTO and VAS values were consistently related to SRH. The inclusion of age, sex, education and socioeconomic group affected the main effect coefficients and the explanatory power modestly. Conclusions: A value set for EQ-5D health states based on Swedish valuations has been lacking. Several authors have recently advocated the normative standpoint of using experience-based values. Guidelines of economic evaluation for reimbursement decisions in Sweden recommend the use of experience-based values for QALY calculations. Our results that anxiety/depression had the greatest impact on both TTO and VAS values underline the importance of mental health for individuals' overall HRQoL. Using population surveys is in line with recent thinking on valuing health states and could reduce some of the focusing effects potentially appearing in hypothetical valuation studies. [ABSTRACT FROM AUTHOR]

Cancer cells fuel their increased need for nucleotide supply by upregulating one-carbon (1C) metabolism, including the enzymes methylenetetrahydrofolate dehydrogenase-cyclohydrolase 1 and 2 (MTHFD1 and MTHFD2). TH9619 is a potent inhibitor of dehydrogenase and cyclohydrolase activities in both MTHFD1 and MTHFD2, and selectively kills cancer cells. Here, we reveal that, in cells, TH9619 targets nuclear MTHFD2 but does not inhibit mitochondrial MTHFD2. Hence, overflow of formate from mitochondria continues in the presence of TH9619. TH9619 inhibits the activity of MTHFD1 occurring downstream of mitochondrial formate release, leading to the accumulation of 10-formyl-tetrahydrofolate, which we term a 'folate trap'. This results in thymidylate depletion and death of MTHFD2-expressing cancer cells. This previously uncharacterized folate trapping mechanism is exacerbated by physiological hypoxanthine levels that block the de novo purine synthesis pathway, and additionally prevent 10-formyl-tetrahydrofolate consumption for purine synthesis. The folate trapping mechanism described here for TH9619 differs from other MTHFD1/2 inhibitors and antifolates. Thus, our findings uncover an approach to attack cancer and reveal a regulatory mechanism in 1C metabolism., (© 2023. The Author(s).)