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Objectives: The estimation of lifetime quality-adjusted life-years (QALYs) requires the extrapolation of both length and quality of life (QoL). The extrapolation of QoL has received little attention in the literature. Here we explore the predictive value of “time to death” (TTD) for extrapolating QoL in oncology. Methods: We used QoL and survival data from the Patient Reported Outcomes Following Initial Treatment and Long-Term Evaluation of Survivorship registry, which is linked to The Netherlands Cancer Registry. QoL was assessed with EQ-5D and SF-6D. We tested the relationship between TTD and QoL using linear, 2-part, and beta regression models. Incremental QALYs were compared using the TTD approach and an annual age-related disutility approach using artificial survival data with varying mortality rates. Results: A total of 6 samples with >100 patients each were used for the analysis. A declining pattern in QoL was observed when patients were closer to death, confirming the predictive value of TTD for QoL. The declining pattern in QoL was most pronounced when QoL was measured with SF-6D. Proximity to death had a larger impact on QoL than age. Incremental QALYs were higher using the TTD approach than annual age-related disutility, ranging from +0.139 to +0.00003 depending on mortality rates. Conclusions: TTD is a predictor variable for QoL. Using TTD allows cost-effectiveness models that lack QoL data to extrapolate morbidity using overall survival estimates. The TTD approach generates more incremental QALYs than an annual age-related disutility, most notably for longer survival periods.

A cost-effectiveness analysis has become an important method to inform allocation decisions and reimbursement of new technologies in healthcare. A cost-effectiveness analysis requires a threshold to which the cost effectiveness of a new intervention can be compared. In principle, the threshold ought to reflect opportunity costs of reimbursing a new technology. In this paper, we contrast the practical use of this threshold within a CEA with its theoretical underpinnings. We argue that several assumptions behind the theoretical models underlying this threshold are violated in practice. This implies that a simple application of the decision rules of CEA using a single estimate of the threshold does not necessarily improve population health or societal welfare. Conceptual differences regarding the interpretation of the threshold, widely varying estimates of its value, and an inconsistent use within and outside the healthcare sector are important challenges in informing policy makers on optimal reimbursement decision and setting appropriate healthcare budgets.

Time trade-off utilities have been suggested to be biased upwards. This bias is a result of the method being applied assuming linear utility of life duration, which is violated when individuals discount future life years or are loss averse for health. Applying a “corrective approach”, that is, measuring individuals' discount function and loss aversion and correcting time trade-off utilities for these individual characteristics, may reduce this bias in utilities. Earlier work has developed this approach for time trade-off in a student sample. In this study, the corrective approach was extended to composite time trade-off (cTTO) methodology, which enabled correcting utilities for health states worse than dead. In digital interviews a sample of 150 members of the general public completed cTTO tasks for six health states, and afterward they completed measurements of loss aversion and discounting. cTTO utilities were corrected using these measurements under multiple specifications. Respondents were also asked to reflect on and adjust their cTTO utilities directly. Our results show considerable loss aversion and both positive and negative discounting were prevalent. As predicted, correction generally resulted in lower utilities. This was in accordance with the direction of adjustments made by respondents themselves.

Objectives: Most patients with multiple sclerosis (MS) switch between disease-modifying therapies (DMTs) during their lifetime. Our aim was to develop an MS cost-utility model that takes treatment switching into account to provide a more realistic estimate of treatment benefit than previous models that assume lifetime use of 1 DMT. Methods: A treatment sequence model using a microsimulation framework with a lifetime time horizon and a societal perspective was developed in R. Clinical plausibility and decision rules for switching were defined in consultation with Dutch MS neurologists. The ability of DMTs to prevent relapses and delay disease progression was modeled by applying DMT-specific estimates derived from a network meta-analysis of randomized controlled trials to natural history data. A total of 2 treatment strategies were compared: a first-line DMT sequence (peginterferon-glatiramer-teriflunomide-interferon-beta-dimethyl fumarate) and an escalation DMT sequence (peginterferon-glatiramer-ocrelizumab-natalizumab-alemtuzumab). Scenario analyses explored impact of alternative sources of natural history data, societal versus healthcare perspective, and condition-specific versus generic utilities. Predicted short-term switches (

Purpose The purpose of this study was to develop and psychometrically evaluate a new quality of life measure for use in people with mental health problems—the Mental Health Quality of Life questionnaire (MHQoL). Methods The MHQoL dimensions were based on prior research by Connell and colleagues, highlighting the seven most important quality of life dimensions in the context of mental health. Items were generated following a systematic review we performed and through inviting expert opinion. A focus group and an online qualitative study (N = 120) were carried out to assess the face and content validity of the MHQoL. The MHQoL was further tested for its internal consistency, convergent validity, known-group validity and test–retest reliability among mental healthcare service users (N = 479) and members of the general population (N = 110). Results The MHQoL consists of a descriptive system (MHQoL-7D), including s items covering seven dimensions (self-image, independence, mood, relationships, daily activities, physical health, future) and a visual analogue scale of general psychological well-being (MHQoL-VAS). Internal consistency was high (Cronbach's ∝ = 0.85) and correlations between MHQoL-7D scores and related measures (EQ-5D-5L, MANSA, ICECAP-A, and BSI) supported convergent validity. The intraclass correlation coefficient of the MHQoL-7D sum score for test–retest reliability was 0.85. Known-group validity was supported by the ability to detect significant differences in MHQoL-7D levels between service users and the general population, and between groups with different levels of psychological distress. Conclusion The MHQoL demonstrated favourable psychometric properties and showed promise as a simple and effective measure to assess quality of life in people with mental health problems.

The emergence of gene therapies challenge health economists to evaluate interventions that are often provided to a small patient population with a specific gene mutation in a single dose with high upfront costs and uncertain long-term benefits. The objective of this study was to illustrate the methodological challenges of evaluating gene therapies and their implications by discussing four economic evaluations of voretigene neparvovec (VN) for the treatment of RPE65-mediated inherited retinal disease. The checklist for economic evaluations of gene therapies of Drummond et al. was applied to the economic evaluations of VN performed by US Institute for Clinical and Economic Review, two country adaptations of the company model in the UK and the Netherlands, and another US publication. The main differences in methodological choices and their impact on cost-effectiveness results were assessed and further explored with sensitivity analyses using the Dutch model. To enable comparison between the economic evaluations, costs were converted to US dollars. Different methodological choices were made in the economic evaluations of VN resulting in large differences in the incremental cost-effectiveness ratio varying from US$79,618 to US$643,813 per QALY. The chosen duration of treatment effect, source of utility values, discount rate and model structure had the largest impact on the cost-effectiveness. This study underlines the findings from Drummond et al. that standard methods can be used to evaluate gene therapies. However, given uncertainty about (particularly long-term) outcomes of gene therapies, guidance is required on the acceptable extrapolation of treatment effect of gene therapies and on how to handle the uncertainty around this extrapolation in scenario and sensitivity analyses to aid health technology assessment research and align submissions of future gene therapies.

Objectives Patients with atrial fibrillation (AF) have rapid and irregular heart rates, increasing the risk of comorbidities and mortality. Next to formal medical care, many patients receive informal care from their social environment. The objective of this study was to examine the well-being and economic burden of providing informal care to patients with AF in the UK, Italy, and Germany. Methods Caregivers of patients with AF completed an online survey based on the iMTA Valuation of Informal Care Questionnaire, with questions about their caregiving situation, perceived burden of caregiving, and absence from work due to health problems resulting from caregiving. Care-related quality-of-life utilities were calculated using the Care-related Quality of Life instrument and associated tariffs. Societal costs of caregiving were calculated based on the proxy good method. Results A total of 585 caregivers participated in this study. On average, caregivers provided 33 hours of informal care per week to patients (SD 29 hours). On a scale from 0 to 10, their self-rated burden was 5.4. The average Care-related Quality of Life utility was 72. Caregivers primarily indicated problems with daily activities, mental health, and physical health. Still, the vast majority of caregivers (87%) derived fulfillment from providing care. Weekly societal costs of caregiving were on average €636. Comorbidities contributed substantially to the caregiver time and burden. Conclusions Caring for a patient with AF is associated with substantial objective and subjective burden, but also provides fulfillment from being able to care for a loved one.

ObjectivesA respiratory bolt-on dimension for the EQ-5D-5L has recently been developed and valued by the general public. This study aimed to validate the EQ-5D-5L plus respiratory dimension (EQ-5D-5L+R) in a large group of patients with chronic obstructive pulmonary disease (COPD).MethodsValidation was undertaken with data from the Birmingham COPD Cohort Study, a longitudinal UK study of COPD primary care patients. Data on the EQ-5D-5L+R were collected from 1008 responding participants during a follow-up questionnaire in 2017 and combined with (previously collected) data on patient and disease characteristics. Descriptive and correlation analyses were performed on the EQ-5D-5L+R dimensions and utilities, in relation to COPD characteristics and compared with the EQ-5D-5L without respiratory dimension. Multivariate regression models were estimated to test whether regression coefficients of clinical characteristics differed between the EQ-5D-5L+R utility and the EQ-5D-5L utility.ResultsCorrelation coefficients for the EQ-5D-5L+R utility with COPD parameters were slightly higher than the EQ-5D-5L utility. Both instruments displayed discriminant validity but analyses in clinical subgroups of patients showed larger absolute differences in utilities for the EQ-5D-5L+R. In the multivariate analyses, only the coefficient for the COPD Assessment Test score was higher for the model using the EQ-5D-5L+R utility as outcome.ConclusionsThis study showed that the addition of a respiratory domain to the EQ-5D-5L led to small improvements in the instrument’s performance. Comparability of the EQ-5D across diseases, currently considered one of its strengths, would have to be traded off against a modest improvement in utility difference when adding the respiratory dimension.

Objectives: Cost-effectiveness analyses typically require measurement of health-related quality of life (HRQoL) to estimate quality-adjusted life-years. Challenges with measuring HRQoL arise in the context of episodic conditions if patients are less likely—or even unable—to complete surveys when having disease symptoms. This article explored whether HRQoL measured at regular time intervals adequately reflects the HRQoL of people with epilepsy (PWE). Methods: Follow-up data from the Epilepsy Support Dog Evaluation study on the (cost-)effectiveness of seizure dogs were used in which HRQoL is measured in 25 PWE with the EQ-5D at baseline and every 3 months thereafter. Seizure count is recorded daily using a seizure diary. Regression models were employed to explore whether PWE were more likely to complete the HRQoL survey on a good day (ie, when seizures are absent or low in frequency compared with other days) and to provide an estimate of the impact of reporting HRQoL on a good day on EQ-5D utility scores. Results: A total of 111 HRQoL measurements were included in the analyses. Regression analyses indicated that the day of reporting HRQoL was associated with a lower seizure count (P

(1) Background: Monitoring of Multiple Sclerosis (MS) with eHealth interventions or digital biomarkers provides added value to the current care path. Evidence in the literature is currently scarce. MS sherpa is an eHealth intervention with digital biomarkers, aimed at monitoring symptom progression and disease activity. To show the added value of digital biomarker–based eHealth interventions to the MS care path, an early Health Technology Assessment (eHTA) was performed, with MS sherpa as an example, to assess the potential impact on treatment switches. (2) Methods: The eHTA was performed according to the Dutch guidelines for health economic evaluations. A decision analytic MS model was used to estimate the costs and benefits of MS standard care with and without use of MS sherpa, expressed in incremental cost-effectiveness ratios (ICERs) from both societal and health care perspectives. The efficacy of MS sherpa on early detection of active disease and the initiation of a treatment switch were modeled for a range of assumed efficacy (5%, 10%, 15%, 20%). (3) Results: From a societal perspective, for the efficacy of 15% or 20%, MS sherpa became dominant, which means cost-saving compared to the standard of care. MS sherpa is cost-effective in the 5% and 10% scenarios (ICERs EUR 14,535 and EUR 4069, respectively). From the health care perspective, all scenarios were cost-effective. Sensitivity analysis showed that increasing the efficacy of MS sherpa in detecting active disease early leading to treatment switches be the most impactful factor in the MS model. (4) Conclusions: The results indicate the potential of eHealth interventions to be cost-effective or even cost-saving in the MS care path. As such, digital biomarker–based eHealth interventions, like MS sherpa, are promising cost-effective solutions in optimizing MS disease management for people with MS, by detecting active disease early and helping neurologists in decisions on treatment switch.

Medical interventions that increase life expectancy of patients result in additional consumption of non-medical goods and services in 'added life years'. This paper focuses on the distributional consequences across socio-economic groups of including these costs in cost effectiveness analysis. In that context, it also highlights the role of remaining quality of life and household economies of scale. Data from a Dutch household spending survey was used to estimate non-medical consumption and household size by age and educational attainment. Estimates of non-medical consumption and household size were combined with life tables to estimate what the impact of including non-medical survivor costs would be on the incremental cost effectiveness ratio (ICER) of preventing a death at a certain age. Results show that including non-medical survivor costs increases estimated ICERs most strongly when interventions are targeted at the higher educated. Adjusting for household size (lower educated people less often live additional life years in multi-person households) and quality of life (lower educated people on average spend added life years in poorer health) mitigates this difference. Ignoring costs of non-medical consumption in economic evaluations implicitly favors interventions targeted at the higher educated and thus potentially amplifies socio-economic inequalities in health.

Objective. Quantitatively summarize patient preferences for European licensed relapsing-remitting multiple sclerosis (RRMS) disease-modifying treatment (DMT) options. Methods. To identify and summarize the most important RRMS DMT characteristics, a literature review, exploratory physician interviews, patient focus groups, and confirmatory physician interviews were conducted in Germany, the United Kingdom, and the Netherlands. A discrete choice experiment (DCE) was developed and executed to measure patient preferences for the most important DMT characteristics. The resulting DCE data ( n=799 and n=363 respondents in the United Kingdom and Germany, respectively) were analyzed using Bayesian mixed logit models. The estimated individual-level patient preferences were subsequently summarized using 3 additional analyses: the quality of the choice data was assessed using individual-level R2estimates, individual-level preferences for the available DMTs were aggregated into DMT-specific preference shares, and a principal component analysis was performed to explain the patients’ choice process. Results. DMT usage differed between RRMS patients in Germany and the United Kingdom but aggregate patient preferences were similar. Across countries, 42% of all patients preferred oral medications, 38% infusions, 16% injections, and 4% no DMT. The most often preferred DMT was natalizumab (26%) and oral DMT cladribine tablets (22%). The least often preferred were mitoxantrone and the beta-interferon injections (1%–3%). Patient preferences were strongly correlated with patients’ MS disease duration and DMT experience, and differences in patient preferences could be summarized using 8 principle components that together explain 99% of the variation in patients’ DMT preferences. Conclusion. This study summarizes patient preferences for the included DMTs, facilitates shared decision making along the dimensions that are relevant to RRMS patients, and introduces methods in the medical DCE literature that are ideally suited to summarize the impact of DMT introductions in preexisting treatment landscapes.

Background In the context of priority setting, a differential cost-effectiveness threshold can be used to reflect a higher societal willingness to pay for quality-adjusted life-year gains in the worse off. However, uncertainty in the estimate of severity can lead to problems when evaluating the outcomes of cost-effectiveness analyses. Objectives This study standardizes the assessment of severity, integrates its uncertainty with the uncertainty in cost-effectiveness results and provides decision makers with a new estimate: the severity-adjusted probability of being cost effective. Methods Severity is expressed in proportional and absolute shortfall and estimated using life tables and country-specific EQ-5D values. We use the three severity-based cost-effectiveness thresholds (€20.000, €50.000 and €80.000, per QALY) adopted in The Netherlands. We exemplify procedures of integrating uncertainty with a stylized example of a hypothetical oncology treatment. Results Applying our methods, taking into account the uncertainty in the cost-effectiveness results and in the estimation of severity identifies the likelihood of an intervention being cost effective when there is uncertainty about the appropriate severity-based cost-effectiveness threshold. Conclusions Higher willingness-to-pay thresholds for severe diseases are implemented in countries to reflect societal concerns for an equitable distribution of resources. However, the estimates of severity are uncertain, patient populations are heterogeneous, and this can be accounted for with the severity-adjusted probability of being cost effective proposed in this study. The application to the Netherlands suggests that not adopting the new method could result in incorrect decisions in the reimbursement of new health technologies.

Chronic diseases and functional limitations may have serious and persistent consequences for one's quality of life (QoL). Over time, however, their negative impact on QoL may diminish because of adaptation. Understanding how much people adapt helps to correctly separate the effects attributable to interventions from those arising from adaptation and thus facilitates a better estimation of the effects of disease and treatment on QoL. To date, however, there is little empirical evidence on adaptation in older populations. In particular, it is unclear to which extent dimensions of QoL like health and overall experience with life are influenced by adaptation. This paper studies adaptation to functional limitations in 5000 respondents of the Survey of Health, Ageing and Retirement in Europe (SHARE) who develop disabilities during the span of the 5 waves of data collection between 2004 and 2015. To examine the association between time since the onset of functional limitations and self-perceived health and life satisfaction, a fixed effects ordered logit model is used. We found evidence supporting adaptation in life satisfaction, corresponding to a return to pre-onset levels of life satisfaction. Also in the self-perceived health dimension, adaptation does occur, but it does not occur fast enough to offset the negative changes in underlying health. This means that observational studies that measure one of these two outcome measures should be aware that part or all of the effects found are due to adaptation.

Background: HIV is now considered a chronic condition, and people living with HIV, when treated, have a similar life expectancy as compared to the general population. Consequently, improving and ensuring a good health-related quality of life (HrQoL) among people living with HIV (people living with HIV) is increasingly important and has risen on the global agenda in recent years. A ‘fourth 90’ as 90% of people with viral load suppression have a good HrQoL should therefore be adopted alongside the other 90-90-90 targets. This study aims to report the progress on HrQoL as the ‘fourth 90’ and compare against the general population in the Netherlands and England. Methods: In the Netherlands, individuals attending the HIV outpatient clinic of a tertiary hospital were asked to complete the EQ-5D-5L from June 2016 until December 2018. In England, individuals attending one of 73 HIV outpatient clinics were randomly sampled to complete the Positive Voices survey, which included the EQ-5D-5L, from January to September 2017. HrQoL scores were combined with demographic data and compared to general population data. Findings: The EQ-5D-5L was filled-out by 895 people living with HIV in the NL and 4,137 in England. HrQoLutility was 0·85 among Dutch and 0·83 among English people living with HIV. This equated to 98% and 94% of the general population HrQoLutility in the Netherlands and England, respectively. Of the EQ-5D domains, anxiety/depression was mostly affected, with one-third in Dutch (35%) and almost half (47%) of English people living with HIV reporting symptoms. This was higher compared to their respective general populations (21% NL and 31% England). Interpretation: Overall, HrQoLutility for people living with HIV was high in both countries and highly comparable to the general populations Nevertheless, there should be an increased focus on anxiety and depression in the people living with HIV population The EQ-5D-5L proved an easy HrQoL measurement tool and identified areas for improvement by social and behavioural interventions. Funding: The study received funding (unrestricted grants) from: Gilead sciences, ViiV Healthcare, MSD, and Jansen pharmaceuticals.

Introduction: Nowadays, HIV is a chronic condition with a similar life expectancy as the general population. Consequently, improving and ensuring a good health-related quality of life (HrQoL) among people living with HIV (PLWH) is increasingly important and has risen on the global agenda in recent years. A ‘fourth 90’ as 90% of people with viral load suppression have a good HrQoL should therefore be adopted alongside the other 90-90-90 targets. This study aims to report the progress on HrQoL as the ‘fourth 90’ and compare against the general population in the Netherlands and England. Methods: In the Netherlands, individuals attending the HIV outpatient clinic of a tertiary hospital were asked to complete the EQ-5D-5L from June 2016 until December 2018. In England, individuals attending one of 73 HIV outpatient clinics were randomly sampled to complete the Positive Voices survey, which included the EQ-5D-5L, from January to September 2017. HrQoL scores were combined with demographic data and compared to general population data. Findings: The EQ-5D-5L was filled-out by 895 PLWH in the NL and 4,137 in England. HrQoLutility was 0.85 among Dutch and 0.83 among English PLWH. This equated to 98% and 94% of the general population HrQoLutility in the Netherlands and England, respectively. Of the EQ-5D domains, anxiety/depression was mostly affected, with one-third in Dutch (35%) and almost half (47%) of English PLWH reporting symptoms. This was significantly higher compared to their respective general populations (21% NL and 31% England). Interpretation: Overall, HrQoLutility for PLWH was high in both countries and highly comparable to the general populations Nevertheless, focus on anxiety and depression should be increased. The EQ-5D-5L proved an easy HrQoL measurement tool and identified areas for improvement by social and behavioural interventions. Funding Statement: The study received funding (unrestricted grants) from: Gilead sciences, ViiV Healthcare, MSD and MSD, Janssen pharmaceuticals. Declaration of Interests: SP reports an unrestricted educational grant from Gilead Sciences; DvdV reports unrestricted research grant from Gilead Sciences, MSD, ViiV and Janssen Pharmaceuticals; CAB reports personal fees from speaker honoraria from ViiV outside the submitted work; AvS reports grants from Dutch Ministry of Health, Welfare and Sport, during the conduct of the study; grants from European Centre for Disease Prevention and Control, outside the submitted work. MV: Dr. Versteegh reports grants from ZonMW, grants from EuroQoL Research Foundation, during the conduct of the study; grants from EuroQoL Research Foundation, outside the submitted work; MK, ES, BN, LV, VD, AV have nothing to disclose. Ethics Approval Statement: The Netherlands study was reviewed and approved by the local Medical Ethics Committee (MEC-2016-264). Additionally, all participants were asked to sign an informed consent form and all data were anonymized. The England study was reviewed and approved by the London – Harrow Research Ethics Committee (13/LO/0279).

Background: Cost-effectiveness models require quality of life utilities calculated from generic preference-based questionnaires, such as EQ-5D. We evaluated the performance of available algorithms for QLQ-C30 conversion into EQ-5D-3L based utilities in a metastatic colorectal cancer (mCRC) patient population and subsequently developed a mCRC specific algorithm. Influence of mapping on cost-effectiveness was evaluated. Methods: Three available algorithms were compared with observed utilities from the CAIRO3 study. Six models were developed using 5-fold cross-validation: predicting EQ-5D-3L tariffs from QLQ-C30 functional scale scores, continuous QLQ-C30 scores or dummy levels with a random effects model (RE), a most likely probability method on EQ-5D-3L functional scale scores, a beta regression model on QLQ-C30 functional scale scores and a separate equations subgroup approach on QLQ-C30 functional scale scores. Performance was assessed, and algorithms were tested on incomplete QLQ-C30 questionnaires. Influence of utility mapping on incremental cost/QALY gained (ICER) was evaluated in an existing Dutch mCRC cost-effectiveness model. Results: The available algorithms yielded mean utilities of 1: 0.87 ± sd:0.14,2: 0.81 ± 0.15 (both Dutch tariff) and 3: 0.81 ± sd:0.19. Algorithm 1 and 3 were significantly different from the mean observed utility (0.83 ± 0.17 with Dutch tariff, 0.80 ± 0.20 with U.K. tariff). All new models yielded predicted utilities drawing close to observed utilities; differences were not statistically significant. The existing algorithms resulted in an ICER difference of €10,140 less and €1765 more compared to the observed EQ-5D-3L based ICER (€168,048). The preferred newly developed algorithm was €5094 higher than the observed EQ-5D-3L based ICER. Disparity was explained by minimal diffences in incremental QALYs between models. Conclusion: Available mapping algorithms sufficiently accurately predict utilities. With the commonly used statistical methods, we did not succeed in developping an improved mapping algorithm. Importantly, cost-effectiveness outcomes in this study were comparable to the original model outcomes between different mapping algorithms. Therefore, mapping can be an adequate solution for cost-effectiveness studies using either a previously designed and validated algorithm or an algorithm developed in this study.

Purpose Based on improvements of progression-free survival (PFS), new agents for metastatic renal cell carcinoma (mRCC) have been approved. It is assumed that one of the benefits is a delay in health-related quality of life (HRQoL) deterioration as a result of a delay in progression of disease. However, little data are available supporting this relationship. This study aims to provide insight into the most important determinants of HRQoL (including progression of disease) of patients with mRCC. Methods A patient registry (PERCEPTION) was created to evaluate treatment of patients with (m)RCC in the Netherlands. HRQoL was measured, using the EORTC QLQ-C30 and EQ-5D-5L, every 3 months in the first year of participation in the study, and every 6 months in the second year. Participation started as soon as possible following a diagnosis of (m)RCC. Random effects models were used to study associations between HRQoL and patient and disease characteristics, symptoms and treatment. Results Eighty-seven patients with mRCC completed 304 questionnaires. The average EORTC QLQ-C30 global health status was 69 (SD, 19) before progression and 61 (SD, 22) after progression of disease. Similarly, the average EQ-5D utility was 0.75 (SD, 0.19) before progression and 0.66 (SD, 0.30) after progression of disease. The presence of fatigue, pain, dyspnoea, and the application of radiotherapy were associated with significantly lower EQ-5D utilities. Conclusions Key drivers for reduced HRQoL in mRCC are disease symptoms. Since symptoms increase with progression of disease, targeted therapies that increase PFS are expected to postpone reductions in HRQoL in mRCC. Electronic supplementary material The online version of this article (doi:10.1007/s11136-017-1704-4) contains supplementary material, which is available to authorized users.

Background Assessing haemodynamic congestion based on filling pressures instead of clinical congestion can be a way to further improve quality of life (QoL) and clinical outcome by intervening before symptoms or weight gain occur in heart failure (HF) patients. The clinical efficacy of remote monitoring of pulmonary artery (PA) pressures (CardioMEMS; Abbott Inc., Atlanta, GA, USA) has been demonstrated in the USA. Currently, the PA sensor is not reimbursed in the European Union as its benefit when applied in addition to standard HF care is unknown in Western European countries, including the Netherlands. Aims To demonstrate the efficacy and cost-effectiveness of haemodynamic PA monitoring in addition to contemporary standard HF care in a high-quality Western European health care system. Methods The current study is a prospective, multi-centre, randomised clinical trial in 340 patients with chronic HF (New York Heart Association functional class III) randomised to HF care including remote monitoring with the CardioMEMS PA sensor or standard HF care alone. Eligible patients have at least one hospitalisation for HF in 12 months before enrolment and will be randomised in a 1:1 ratio. Minimum follow-up will be 1 year. The primary endpoint is the change in QoL as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ). Secondary endpoints are the number of HF hospital admissions and changes in health status assessed by EQ-5D-5L questionnaire including health care utilisation and formal cost-effectiveness analysis. Conclusion The MONITOR HF trial will evaluate the efficacy and cost-effectiveness of haemodynamic monitoring by CardioMEMS in addition to standard HF care in patients with chronic HF. Clinical Trial Registration number NTR7672.

Background: In 2009, a new version of the EuroQol five-dimensional questionnaire (EQ-5D) was introduced with five rather than three answer levels per dimension. This instrument is known as the EQ-5D-5L. To make the EQ-5D-5L suitable for use in economic evaluations, societal values need to be attached to all 3125 health states. Objectives: To derive a Dutch tariff for the EQ-5D-5L. Methods: Health state values were elicited during face-to-face interviews in a general population sample stratified for age, sex, and education, using composite time trade-off (cTTO) and a discrete choice experiment (DCE). Data were modeled using ordinary least squares and tobit regression (for cTTO) and a multinomial conditional logit model (for DCE). Model performance was evaluated on the basis of internal consistency, parsimony, goodness of fit, handling of left-censored values, and theoretical considerations. Results: A representative sample (N = 1003) of the Dutch population participated in the valuation study. Data of 979 and 992 respondents were included in the analysis of the cTTO and the DCE, respectively. The cTTO data were left-censored at -1. The tobit model was considered the preferred model for the tariff on the basis of its handling of the censored nature of the data, which was confirmed through comparison with the DCE data. The predicted values for the EQ-5D-5L ranged from -0.446 to 1. Conclusions: This study established a Dutch tariff for the EQ-5D-5L on the basis of cTTO. The values represent the preferences of the Dutch population. The tariff can be used to estimate the impact of health care interventions on quality of life, for example, in context of economic evaluations.

Background Families and friends provide a considerable proportion of care for patients and elderly people. Caregiving can have substantial effects on caregivers’ lives, health, and well-being. However, because clinical trials rarely assess these effects, no information on caregiver burden is available when evaluating the cost effectiveness of treatments. Objective This study develops an algorithm for estimating caregiver time using information that is typically available in clinical trials: the EQ-5D scores of patients and their gender. Methods Four datasets with a total of 8012 observations of dyads of caregivers and a gamma model with a log-link estimated with the Bayesian approach were used to estimate the statistical association between patient scores on the EQ-5D-3L dimensions and the numbers of hours of care provided by caregivers during the previous week. The model predicts hours of care as mean point estimates with 95% credible intervals or entire distributions. Results Model predictions of hours of care based on the five EQ-5D dimensions ranged from 13.06 (12.7–14.5) h/week for female patients reporting no health problems but receiving informal care to 52.82 (39.38–66.26) for male patients with the highest level of problems on all EQ-5D dimensions. Conclusions The iCARE algorithm developed in this study allows researchers who only have patient-level EQ-5D data to estimate the mean hours of informal care received per week, including a 95% Bayesian credible interval. Caregiver time can be multiplied with a monetary value for caregiving, enabling the inclusion of informal care costs in economic evaluations. We recommend using the tool for samples that fall within the confidence intervals of the characteristics of our samples: men (age range 47.0–104.2 years), women (age range 55–103 years). Electronic supplementary material The online version of this article (10.1007/s40273-018-0706-6) contains supplementary material, which is available to authorized users.

Traditionally, threshold levels of cost‐effectiveness have been derived from willingness‐to‐pay studies, indicating the consumption value of health (v‐thresholds). However, it has been argued that v‐thresholds need to be supplemented by so‐called k‐thresholds, which are based on the marginal returns to health care. The objective of this research is to estimate a k‐threshold based on the marginal returns to cardiovascular disease (CVD) hospital care in the Netherlands. To estimate a k‐threshold for hospital care on CVD, we proceed in two steps: First, we estimate the impact of hospital spending on mortality using a Bayesian regression modelling framework, using data on CVD mortality and CVD hospital spending by age and gender for the period 1994–2010. Second, we use life tables in combination with quality of life data to convert these estimates into a k‐threshold expressed in euros per quality‐adjusted life year gained. Our base case estimate resulted in an estimate of 41,000 per quality‐adjusted life year gained. In our sensitivity analyses, we illustrated how the incorporation of prior evidence into the estimation pushes estimates downwards. We conclude that our base case estimate of the k‐threshold may serve as a benchmark value for decision making in the Netherlands as well as for future research regarding k‐thresholds.

Many countries have national guidelines for performing economic evaluations in healthcare.1 These guidelines should ensure the comparability and quality of such evaluations, which should facilitate making well informed policy decisions regarding reimbursement of interventions. Given the developments in both the methodology and policy context of economic evaluation of healthcare interventions, these guidelines require periodical revision. Recently, the Dutch National Health Care Institute issued new guidance for economic evaluations in healthcare [1]. The new guidelines update and replace three separately published previous guidelines: those for pharmacoeconomic evaluation (latest version 2006), outcomes research (latest version 2008) as well as the Dutch costing manual (latest version 2010). In this editorial, we highlight the distinguishing features of the new Dutch guidelines. Moreover, we highlight which developments, in our opinion, are desirable in coming updates, but are still in development or controversial.

Mogen kosten meewegen bij het voorschrijven van een behandeling, terwijl artsen beloofd of gezworen hebben om de gezondheid van hun patienten te bevorderen? In dit hoofdstuk gaat het over doelmatigheid in de gezondheidszorg. Er wordt betoogd dat een arts de opvatting kan hebben dat voor diens patienten ‘kosten geen rol spelen’ en dat daarom alle nieuwe effectieve behandelingen verzekerde zorg moeten zijn, maar dat die opvatting er toe kan leiden dat patienten van collega’s uiteindelijk slechter af zijn.

Objectives: To describe the adaptation of a global health economic model to determine whether treatment with the angiotensin receptor neprilysin inhibitor LCZ696 is cost effective compared with the angiotensin-converting enzyme inhibitor enalapril in adult patients with chronic heart failure with reduced left ventricular ejection fraction in the Netherlands; and to explore the effect of performing the cost-effectiveness analyses according to the new pharmacoeconomic Dutch guidelines (updated during the submission process of LCZ696), which require a value-of-information analysis and the inclusion of indirect medical costs of life-years gained.Methods: We adapted a UK model to reflect the societal perspective in the Netherlands by including travel expenses, productivity loss, informal care costs, and indirect medical costs during the life-years gained and performed a preliminary value-of-information analysis.Results: The incremental cost-effectiveness ratio obtained was (sic)17,600 per quality-adjusted life-year (QALY) gained. This was robust to changes in most structural assumptions and across different subgroups of patients. Probability sensitivity analysis results showed that the probability that LCZ696 is cost-effective at a (sic)50,000 per QALY threshold is 99.8%, with a population expected value of perfect information of (sic)297,128. On including indirect medical costs of life-years gained, the incremental cost-effectiveness ratio was (sic)26,491 per QALY gained, and LCZ696 was 99.46% cost effective at (sic)50,000 per QALY, with a population expected value of perfect information of (sic)2,849,647.Conclusions: LCZ696 is cost effective compared with enalapril under the former and current Dutch guidelines. However, the (monetary) consequences of making a wrong decision were considerably different in both scenarios. Copyright (C) 2017, International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc.

There is no scientific consensus on the optimal specification of the time trade-off (TTO) task. As a consequence, studies using TTO to value health states may share the core element of trading length of life for quality of life, but can differ considerably on many other elements. While this pluriformity in specifications advances the understanding of TTO from a methodological point of view, it also results in incomparable health state values. Health state values are applied in health technology assessments, and in that context comparability of information is desired. In this article, we discuss several alternative specifications of TTO presented in the literature. The defining elements of these specifications are identified as being either methodological, procedural or analytical in nature. Where possible, it is indicated how these elements affect health state values (i.e., upward or downward). Finally, a checklist for TTO studies is presented, which incorporates a list of choices to be made by researchers who wish to perform a TTO task. Such a checklist enables other researchers to align methodologies in order to enhance the comparability of health state values.

This article examines the effect that different specifications of the time trade-off (TTO) valuation task may have on values for EQ-5D-5L health states. The new variants of the TTO, namely lead-time TTO and lag-time TTO, along with the classic approach to TTO were compared using two durations for the health states (15 and 20 years). The study tested whether these methods yield comparable health-state values. TTO tasks were administered online. It was found that lag-time TTO produced lower values than lead-time TTO and that the difference was larger in the longer time frame. Classic TTO values most resembled those of the lag-time TTO in a 20-year time frame in terms of mean absolute difference. The relative importance of different domains of health was systematically affected by the duration of the health state. In the tasks with a 10-year health-state duration, anxiety/depression had the largest negative impact on health-state values; in the tasks with a 5-year duration, the pain/discomfort domain had the largest negative impact.

Introduction This study was designed to test the feasibility and face validity of the composite time trade-off (composite TTO), a new approach to TTO allowing for a more consistent elicitation of negative health state values. Methods The new instrument combines a conventional TTO to elicit values for states regarded better than dead and a lead-time TTO for states worse than dead. Results A total of 121 participants completed the composite TTO for ten EQ-5D-5L health states. Mean values ranged from -0.104 for health state 53555 to 0.946 for 21111. The instructions were clear to 98 % of the respondents, and 95 % found the task easy to understand, indicating feasibility. Further, the average number of steps taken in the iteration procedure to achieve the point of indifference in the TTO and the average duration of each task were indicative of a deliberate cognitive process. Conclusion Face validity was confirmed by the high mean values for the mild health states ([0.90) and low mean values for the severe states (\0.42). In conclusion, this study demonstrates the feasibility and face validity of the composite TTO in a face-to-face standardized computer-assisted interview setting.

Health state valuations of patients and non-patients are not the same, whereas health state values obtained from general population samples are a weighted average of both. The latter constitutes an often-overlooked source of bias. This study investigates the resulting bias and tests for the impact of reference dependency on health state valuations using an efficient discrete choice experiment administered to a Dutch nationally representative sample of 788 respondents. A Bayesian discrete choice experiment design consisting of eight sets of 24 (matched pairwise) choice tasks was developed, with each set providing full identification of the included parameters. Mixed logit models were used to estimate health state preferences with respondents' own health included as an additional predictor. Our results indicate that respondents with impaired health worse than or equal to the health state levels under evaluation have approximately 30% smaller health state decrements. This confirms that reference dependency can be observed in general population samples and affirms the relevance of prospect theory in health state valuations. At the same time, the limited number of respondents with severe health impairments does not appear to bias social tariffs as obtained from general population samples. Copyright © 2016 John Wiley & Sons, Ltd.

The time tradeoff (TTO) method is frequently used to calculate the quality adjustment of the quality adjusted life year and is therefore an important element in the calculation of the benefits of medical interventions. New specifications of TTO, known as 'lead time' TTO and 'lag time' TTO, have been developed to overcome methodological issues of the 'classic' TTO. In the lead time TTO, ill-health is explicitly placed in the future, after a period of good health, whereas in lag time TTO, a health state starts immediately and is followed by a 'lag time' of good health. In this study, we take advantage of these timing properties of lead and lag time TTO. In particular, we use data from a previous study that employed lead and lag time TTO to estimate their implied discounting parameters. We show that individuals prefer being ill later, rather than now, with larger per-period discount rates for longer durations of the health states.

Although cancer-specific Health-related Quality-of-Life measures are commonly included in randomized clinical trials or other prospective non-randomized clinical studies, it is rare that preference-based instruments are used, which allow the calculation of a Utility weight suitable for estimating Quality-adjusted Life-Years gained.To test the external validity of a previously published mapping algorithm to transform the EORTC QLQ-C30 questionnaire responses into EQ-5D-derived utilities by predicting EQ-5D utilities from QLQ-C30 scores.Comparative retrospective data analysis of four multicentre, prospective clinical trials in Breast, Multiple Myeloma, Non-Hodgkin Lymphoma and Non-Small-Cell Lung cancer patients with, respectively, 219, 172, 132 and 172 patients. Regression analysis of individual pairs of EQ-5D and QLQ-C30 scores.Although the internal predictive power of a previously published mapping equation was high, its external validity when tested on a set of unrelated external data sets in other cancers proved to underestimate both the mean and variance of the mapped EQ-5D utilities. Furthermore, it appears that the relationship between QLQ-C30 scores and EQ-5D values is not stable across the different data sets.Validation of the proposed algorithm in other external clinical data sets should be encouraged as well as the application of other more complex mapping methods to enhance accuracy of mapping. In the meanwhile, direct mapping from QLQ-C30 profiles to EQ-5D utilities using published algorithms should be performed with reservations.

Objectives Some argue that generic preference-based measures (PBMs) are not sensitive to certain disease-specific improvements. To overcome this problem, new condition-specific PBMs (CS-PBMs) are being developed, but it is not yet clear how such measures compare with existing generic PBMs. Method We generated CS-PBMs from three condition-specific questionnaires (Health Assessment Questionnaire for arthritis, Quality of Life Questionnaire for Cancer 30 for cancer, and Multiple Sclerosis Impact Scale 29 for multiple sclerosis). First, the questionnaires were reduced in content, and then, a time trade-off study was conducted in the general public (N = 402) to obtain weights associated with the dimensions and levels of the new questionnaire. Finally, we compared utilities obtained by using the CS-PBMs with utilities obtained by using the EuroQol five-dimensional (EQ-5D) questionnaire in four data sets. Results Utility values generated by the CS-PBMs were higher than those of the EQ-5D questionnaire. The Health Assessment Questionnaire–based measure for arthritis proved to be insensitive to comorbidities. Measures based on the Multiple Sclerosis Impact Scale 29 and the Quality of Life Questionnaire for Cancer 30 discriminated comorbidities and side effect equally well as the EQ-5D questionnaire and were more sensitive than the EQ-5D questionnaire for mild impairments. Conclusions The introduction of PBMs that are specific to a certain disease may have the merit of sensitivity to disease-specific effects of interventions. That gain, however, is traded off to the loss of comparability of utility values and, in some cases, insensitivity to side effects and comorbidity. The use of a CS-PBM for cost-utility analysis is warranted only under strict conditions.

Background Responses on condition-specific instruments can be mapped on the EQ-5D to estimate utility values for economic evaluation. Mapping functions differ in predictive quality, and not all condition-specific measures are suitable for estimating EQ-5D utilities. We mapped QLQ-C30, HAQ, and MSIS-29 on the EQ-5D and compared the quality of the mapping functions with statistical and clinical indicators. Methods We used 4 data sets that included both the EQ-5D and a condition-specific measure to develop ordinary least squares regression equations. For the QLQ-C30, we used a multiple myeloma data set and a non-Hodgkin lymphoma one. An early arthritis cohort was used for the HAQ, and a cohort of patients with relapsing remitting or secondary progressive multiple sclerosis was used for the MSIS-29. We assessed the predictive quality of the mapping functions with the root mean square error (RMSE) and mean absolute error (MAE) and the ability to discriminate among relevant clinical subgroups. Pearson correlations between the condition-specific measures and items of the EQ-5D were used to determine if there is a relationship between the quality of the mapping functions and the amount of correlated content between the used measures. Results The QLQ-C30 had the highest correlation with EQ-5D items. Average %RMSE was best for the QLQ-C30 with 10.9%, 12.2% for the HAQ, and 13.6% for the MSIS-29. The mappings predicted mean EQ-5D utilities without significant differences with observed utilities and discriminated between relevant clinical groups, except for the HAQ model. Conclusions The preferred mapping functions in this study seem suitable for estimating EQ-5D utilities for economic evaluation. However, this research shows that lower correlations between instruments lead to less predictive quality. Using additional validation tests besides reporting statistical measures of error improves the assessment of predictive quality.

In economic evaluations of health care interventions, benefits are often expressed in terms of Quality-Adjusted Life-Years (QALYs). The QALY comprises length and quality of life into one measure which allows cross-disease comparability. The quality adjustment of the QALY is based on preferences for health states. An important normative choice is the question whose preferences for states of health we wish to capture. The answer to this question is directly related to the normative question regarding the appropriate maximand in health care decisions. Currently, preferences are commonly derived from the general public, rather than from actual patients. This choice, which can have large consequences on final outcomes of economic evaluations, has always been a topic of debate. This paper clarifies and furthers the discussion regarding the appropriate source of preferences for health state valuations, acknowledges the plurality of different perspectives, and argues that health economic guidelines could require analysis of benefit in terms of QALYs based on both patient and general public preferences.

Objectives Reimbursement decisions require evidence of effectiveness and, in general, a blinded randomised controlled trial (RCT) is the preferred study design to provide it. However, there are situations where a cohort study, or even patient series, can be deemed acceptable. The aim of this study was to develop an instrument that first examines which study characteristics of a blinded RCT are necessary, and then, if particular characteristics are considered necessary, examines whether these characteristics are feasible. Design We retrospectively studied 22 interventions from 20 reimbursement reports concerning medical specialist care made by the Dutch National Health Care Institute (ZIN) to identify any factors that influenced the necessity and feasibility of blinded RCTs, and their constituent study characteristics, that is, blinding, randomisation and a control group. A literature review was performed to identify additional factors. Additional expertise was included by interviewing eight experts in epidemiology, medicine and ethics. The resulting instrument was called the FIT instrument (Feasible Information Trajectory), and was prospectively validated using three consecutive reimbursement reports. Results (Blinded) RCT evidence was lacking in 5 of 11 positive reimbursement decisions and 3 of 11 negative decisions. In the reimbursement reports, we found no empirical evidence supporting situations where a blinded RCT is unnecessary. The literature also revealed few arguments against the necessity of a blinded RCT. In contrast, many factors influencing the feasibility of randomisation, a control group and blinding, were found in the reimbursement reports and the literature; for example, when a patient population is too small or when an intervention is common practice, randomisation will be hindered. Conclusions Policy regarding the necessity and feasibility of different types of evidence of effectiveness would benefit from systematic guidance. The FIT instrument has the potential to support transparent, reproducible and well-founded decisions on appropriate evidence of effectiveness in medical specialist care.

Background In order to estimate utilities for cancer studies where the EQ-5D was not used, the EORTC QLQ-C30 can be used to estimate EQ-5D using existing mapping algorithms. Several mapping algorithms exist for this transformation, however, algorithms tend to lose accuracy in patients in poor health states. The aim of this study was to test all existing mapping algorithms of QLQ-C30 onto EQ-5D, in a dataset of patients with malignant pleural mesothelioma, an invariably fatal malignancy where no previous mapping estimation has been published. Methods Health related quality of life (HRQoL) data where both the EQ-5D and QLQ-C30 were used simultaneously was obtained from the UK-based prospective observational SWAMP (South West Area Mesothelioma and Pemetrexed) trial. In the original trial 73 patients with pleural mesothelioma were offered palliative chemotherapy and their HRQoL was assessed across five time points. This data was used to test the nine available mapping algorithms found in the literature, comparing predicted against observed EQ-5D values. The ability of algorithms to predict the mean, minimise error and detect clinically significant differences was assessed. Results The dataset had a total of 250 observations across 5 timepoints. The linear regression mapping algorithms tested generally performed poorly, over-estimating the predicted compared to observed EQ-5D values, especially when observed EQ-5D was below 0.5. The best performing algorithm used a response mapping method and predicted the mean EQ-5D with accuracy with an average root mean squared error of 0.17 (Standard Deviation; 0.22). This algorithm reliably discriminated between clinically distinct subgroups seen in the primary dataset. Conclusions This study tested mapping algorithms in a population with poor health states, where they have been previously shown to perform poorly. Further research into EQ-5D estimation should be directed at response mapping methods given its superior performance in this study. Electronic supplementary material The online version of this article (doi:10.1186/s12955-014-0196-y) contains supplementary material, which is available to authorized users.

This paper examines the effect different specifications of the Time Tradeoff (TTO) task have on health state values. The new lead time TTO is compared to an equally viable method called lag time TTO, both in two time frames. We test whether the two methods yield comparable health state values and whether the relative importance of dimensions of health is similarly stable between TTO specifications. The tasks were applied online and compared to results from a study with identical TTO specifications but with a different mode of administration. Lag time TTO produced lower values than lead time TTO and the difference was larger in the longer time frame. The relative importance of different dimensions of health was affected by the duration of the health state. Generally, the lead time TTO performed in group sessions gave more favorable results than the online exercise based on feasibility and data quality.

The Overall Assessment of the Speaker's Experience of Stuttering for adults (OASES-A; Yaruss and Quesal, 2006 , Yaruss and Quesal, 2010 ) is a patient-reported outcome measure that was designed to provide a comprehensive assessment of “the experience of the stuttering disorder from the perspective of individuals who stutter” ( Yaruss & Quesal, 2006 , p. 90). This paper reports on the translation process and evaluates the psychometric performance of a Dutch version of the OASES-A. Translation of the OASES-A into Dutch followed a standard forward and backward translation process. The Dutch OASES-A (OASES-A-D) was then administered to 138 adults who stutter. A subset of 91 respondents also evaluated their speech on a 10-point Likert scale. For another subset of 45 respondents, a clinician-based stuttering severity rating on a 5-point Likert scale was available. Thirty-two of the respondents also completed the Dutch S-24 scale ( Brutten & Vanryckeghem, 2003 ). The OASES-A-D showed acceptable item properties. No ceiling effects were observed. For 30 out of 100 items, most of which were in Section IV (Quality of Life), floor effects were observed. Cronbach's α coefficients for all sections and subsections surpassed the 0.70 criterion of good internal consistency and reliability. Concurrent validity was moderate to high. Construct validity was confirmed by distinct scores on the OASES-A-D for groups with different levels of stuttering severity as rated by the speakers themselves or by clinicians. These results suggest that the OASES-A-D is a reliable and valid measure that can be used to assess the impact of stuttering on Dutch adults who stutter. Educational objectives: The reader will be able to: (a) describe the purpose of the Overall Assessment of the Speaker's Experience of Stuttering for adults (OASES-A) measurement tool; (b) summarize the translation process used in creating the Dutch version of the OASES-A (OASES-A-D); (c) evaluate the psychometric properties of the OASES-A-D; and (d) compare the psychometric properties of the OASES-A-D with those of the original American English OASES-A.

Background An increasing amount of studies report mapping algorithms which predict EQ-5 D utility values using disease specific non-preference-based measures. Yet many mapping algorithms have been found to systematically overpredict EQ-5 D utility values for patients in poor health. Currently there are no guidelines on how to deal with this problem. This paper is concerned with the question of why overestimation of EQ-5 D utility values occurs for patients in poor health, and explores possible solutions. Method Three existing datasets are used to estimate mapping algorithms and assess existing mapping algorithms from the literature mapping the cancer-specific EORTC-QLQ C-30 and the arthritis-specific Health Assessment Questionnaire (HAQ) onto the EQ-5 D. Separate mapping algorithms are estimated for poor health states. Poor health states are defined using a cut-off point for QLQ-C30 and HAQ, which is determined using association with EQ-5 D values. Results All mapping algorithms suffer from overprediction of utility values for patients in poor health. The large decrement of reporting 'extreme problems' in the EQ-5 D tariff, few observations with the most severe level in any EQ-5 D dimension and many observations at the least severe level in any EQ-5 D dimension led to a bimodal distribution of EQ-5 D index values, which is related to the overprediction of utility values for patients in poor health. Separate algorithms are here proposed to predict utility values for patients in poor health, where these are selected using cut-off points for HAQ-DI (> 2.0) and QLQ C-30 (< 45 average of QLQ C-30 functioning scales). The QLQ-C30 separate algorithm performed better than existing mapping algorithms for predicting utility values for patients in poor health, but still did not accurately predict mean utility values. A HAQ separate algorithm could not be estimated due to data restrictions. Conclusion Mapping algorithms overpredict utility values for patients in poor health but are used in cost-effectiveness analyses nonetheless. Guidelines can be developed on when the use of a mapping algorithms is inappropriate, for instance through the identification of cut-off points. Cut-off points on a disease specific questionnaire can be identified through association with the causes of overprediction. The cut-off points found in this study represent severely impaired health. Specifying a separate mapping algorithm to predict utility values for individuals in poor health greatly reduces overprediction, but does not fully solve the problem.

Objectives: Amidst conflicting expectations about the benefits of personalized medicine (PM) and the potentially high implementation costs, we reviewed the available evidence on the cost-effectiveness of PM relative to non-PM. Methods: We conducted a systematic literature review of economic evaluations of PM and extracted data, including incremental quality-adjusted life-years (ΔQALYs) and incremental costs (Δcosts). ΔQALYs and Δcosts were combined with estimates of national cost-effectiveness thresholds to calculate incremental net monetary benefit (ΔNMB). Regression analyses were performed with these variables as dependent variables and PM intervention characteristics as independent variables. Random intercepts were used to cluster studies according to country. Results: Of 4774 studies reviewed, 128 were selected, providing cost-effectiveness data for 279 PM interventions. Most studies were set in the United States (48%) and the United Kingdom (16%) and adopted a healthcare perspective (82%). Cancer treatments (60%) and pharmaceutical interventions (72%) occurred frequently. Prognostic tests (19%) and tests to identify (non)responders (37%) were least and most common, respectively. Industry sponsorship occurred in 32%. Median ΔQALYs, Δcosts, and ΔNMB per individual were 0.03, Int$575, and Int$18, respectively. We found large heterogeneity in cost-effectiveness. Regression analysis showed that gene therapies were associated with higher ΔQALYs than other interventions. PM interventions for neoplasms brought higher ΔNMB than PM interventions for other conditions. Nonetheless, average ΔNMB in the ‘neoplasm' group was found to be negative. Conclusions: PM brings improvements in health but often at a high cost, resulting in 0 to negative ΔNMB on average. Pricing policies may be needed to reduce the costs of interventions with negative ΔNMB.