Does EQ-5D Tell the Whole Story? Statistical Methods for Comparing the Thematic Coverage of Clinical and Generic Outcome Measures, With Application to Breast Cancer.

OBJECTIVES: This study aimed to develop the following: (1) methods for assessing claims in any specific application that a generic outcome measure, such as EQ-5D is deficient in its coverage of 1 or more specified domains, and (2) a simple method of judging whether any such deficiency is likely to be quantitatively important enough to call into question evaluations based on the generic instrument. Also to demonstrate the applicability of the methods in the important area of breast cancer. METHODS: The methodology requires a data set with observations from a generic instrument (eg, EQ-5D) and also a more comprehensive clinical instrument (eg, FACT-B [Functional Assessment of Cancer Therapy - Breast]). A standardized 3-component statistical analysis is proposed for investigating the claim that the generic measure inadequately captures some specified dimension covered by the latter instrument. A theoretically based upper bound on the bias induced by deficient coverage is derived based on the assumption that the designers of the (k-dimensional) generic instrument did succeed in identifying the k most important domains. RESULTS: Data from the MARIANNE breast cancer trial were analyzed and results suggested that impacts on personal appearance and relationships may be inadequately represented by EQ-5D. Nevertheless, the indications are that the bias in quality-adjusted life-year differences from deficient coverage by EQ-5D is likely to be modest. CONCLUSIONS: The methodology offers a systematic approach to determining whether there is clear evidence consistent with any claim that a generic outcome measure such as EQ-5D misses an important specific domain. The approach is readily implementable using data sets that are available in many randomized controlled trials.

Mapping the EORTC QLQ-C30 to EQ-5D-3L in patients with breast cancer.

BACKGROUND: The types of outcomes measured collected in clinical studies and those required for cost-effectiveness analysis often differ. Decision makers routinely use quality adjusted life years (QALYs) to compare the benefits and costs of treatments across different diseases and treatments using a common metric. QALYs can be calculated using preference-based measures (PBMs) such as EQ-5D-3L, but clinical studies often focus on objective clinician or laboratory measured outcomes and non-preference-based patient outcomes, such as QLQ-C30. We model the relationship between the generic, preference-based EQ-5D-3L and the cancer specific quality of life questionnaire, QLQ-C30 in patients with breast cancer. This will result in a mapping that allows users to convert QLQ-C30 scores into EQ-5D-3L scores for the purposes of cost-effectiveness analysis or economic evaluation. METHODS: We use data from a randomized trial of 602 patients with HER2-positive advanced breast cancer provided 3766 EQ-5D-3L observations. Direct mapping using adjusted, limited dependent variable mixture models (ALDVMM) is compared to a random effects linear regression and indirect mapping using seemingly unrelated ordered probit models. EQ-5D-3L was estimated as a function of the summary scales of the QLQ-C30 and other patient characteristics. RESULTS: A four component mixture model outperformed other models in terms of summary fit statistics. A close fit to the observed data was observed across the range of disease severity. Simulated data from the model closely aligned to the original data and showed that mapping did not significantly underestimate uncertainty. In the simulated data, 22.15% were equal to 1 compared to 21.93% in the original data. Variance was 0.0628 in the simulated data versus 0.0693 in the original data. The preferred mapping is provided in Excel and Stata files for the ease of users. CONCLUSION: A four component adjusted mixture model provides reliable, non-biased estimates of EQ-5D-3L from the QLQ-C30, to link clinical studies to economic evaluation of health technologies for breast cancer. This work adds to a growing body of literature demonstrating the appropriateness of mixture model based approaches in mapping.

Mapping the FACT-B Instrument to EQ-5D-3L in Patients with Breast Cancer Using Adjusted Limited Dependent Variable Mixture Models versus Response Mapping.

BACKGROUND: Preference-based measures of health, such as the three-level EuroQol five-dimensional questionnaire (EQ-5D-3L), are required to calculate quality-adjusted life-years for use in cost-effectiveness analysis, but are often not recorded in clinical studies. In these cases, mapping can be used to estimate preference-based measures. OBJECTIVES: To model the relationship between the EQ-5D-3L and the Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B) instrument, comparing indirect and direct mapping methods, and the use of FACT-B summary score versus FACT-B subscale scores. METHODS: We used data from three clinical studies for advanced breast cancer providing 11,958 observations with full information on FACT-B and the EQ-5D-3L. We compared direct mapping using adjusted limited dependent variable mixture models (ALDVMMs) with indirect mapping using seemingly unrelated ordered probit models. The EQ-5D-3L was estimated as a function of FACT-B and other patient-related covariates. RESULTS: The use of FACT-B subscale scores was better than using the total FACT-B score. A good fit to the observed data was observed across the entire range of disease severity in all models. ALDVMMs outperformed the indirect mapping. The breast cancer-specific scale had a strong influence in predicting the pain/discomfort and self-care dimensions of the EQ-5D-3L. CONCLUSIONS: This article adds to the growing literature that demonstrates the performance of the ALDVMM method for mapping. Regardless of which model is used, the subscales of FACT-B should be included as independent variables wherever possible. The breast cancer-specific subscale of FACT-B is important in predicting the EQ-5D-3L. This suggests that generic cancer measures should not be used for utility mapping in patients with breast cancer.

Development of Methods for the Mapping of Utilities Using Mixture Models: Mapping the AQLQ-S to the EQ-5D-5L and the HUI3 in Patients with Asthma.

BACKGROUND: Studies have shown that methods based on mixture models work well when mapping clinical to preference-based methods. OBJECTIVES: To develop these methods in different ways and to compare performance in a case study. METHODS: Data from 856 patients with asthma allowed mapping between the Asthma Quality of Life Questionnaire and both the five-level EuroQol five-dimensional questionnaire (EQ-5D-5L) and the health utilities index mark 3 (HUI3). Adjusted limited dependent variable mixture models and beta-based mixture models were estimated. Optional inclusion of the gap between full health and the next value as well as a mass point at the next feasible value were explored. RESULTS: In all cases, model specifications formally modeling the gap between full health and the next feasible value were an improvement on those that did not. Mapping to the HUI3 required more components in the mixture models than did mapping to the EQ-5D-5L because of its uneven distribution. The optimal beta-based mixture models mapping to the HUI3 included a probability mass at the utility value adjacent to full health. This is not the case when estimating the EQ-5D-5L, because of the low proportion of observations at this point. CONCLUSIONS: Beta-based mixture models marginally outperformed adjusted limited dependent variable mixture models with the same number of components in this data set. Nevertheless, they require a larger number of parameters and longer estimation time. Both mixture model types closely fit both EQ-5D-5L and HUI data. Standard mapping approaches typically lead to biased estimates of health gain. The mixture model approaches exhibit no such bias. Both can be used with confidence in applied cost-effectiveness studies. Future mapping studies in other disease areas should consider similar methods.

Valuing health at the end of life: A review of stated preference studies in the social sciences literature.

A source of debate in the health care priority setting literature is whether to weight health gains to account for equity considerations, such as concern for those with very short life expectancy. This paper reviews the empirical evidence in the published social sciences literature relevant to the following research question: do members of the public wish to place greater weight on a unit of health gain for end-of-life patients than on that for other types of patients? An electronic search of the Social Sciences Citation Index for articles published until October 2017 was conducted, with follow-up of references to obtain additional data. Hierarchical criteria were applied to select empirical studies reporting stated preferences relating to hypothetical health care priority setting contexts. Twenty-three studies met the inclusion criteria and were included in the review. Choice exercises were the most common method used to elicit preferences; other approaches included budget allocation, person trade-off and willingness-to-pay. Some studies found that observed preferences regarding end-of-life patients are influenced by information about the patients' ages. Overall, the evidence is mixed, with eight studies that report evidence consistent with a 'premium' for end-of-life treatments and 11 studies that do not. Methodological and design aspects that appear to influence the findings of end-of-life-related preference studies are identified and discussed. The findings of the UK studies have particular relevance for assessing the legitimacy of the National Institute for Health and Care Excellence's policy for appraising life-extending end-of-life treatments.

How to design the cost-effectiveness appraisal process of new healthcare technologies to maximise population health: A conceptual framework.

This paper presents a conceptual framework to analyse the design of the cost-effectiveness appraisal process of new healthcare technologies. The framework characterises the appraisal processes as a diagnostic test aimed at identifying cost-effective (true positive) and non-cost-effective (true negative) technologies. Using the framework, factors that influence the value of operating an appraisal process, in terms of net gain to population health, are identified. The framework is used to gain insight into current policy questions including (a) how rigorous the process should be, (b) who should have the burden of proof, and (c) how optimal design changes when allowing for appeals, price reductions, resubmissions, and re-evaluations. The paper demonstrates that there is no one optimal appraisal process and the process should be adapted over time and to the specific technology under assessment. Optimal design depends on country-specific features of (future) technologies, for example, effect, price, and size of the patient population, which might explain the difference in appraisal processes across countries. It is shown that burden of proof should be placed on the producers and that the impact of price reductions and patient access schemes on the producer's price setting should be considered when designing the appraisal process.

The HTA Risk Analysis Chart: Visualising the Need for and Potential Value of Managed Entry Agreements in Health Technology Assessment.

BACKGROUND: Recent changes to the regulatory landscape of pharmaceuticals may sometimes require reimbursement authorities to issue guidance on technologies that have a less mature evidence base. Decision makers need to be aware of risks associated with such health technology assessment (HTA) decisions and the potential to manage this risk through managed entry agreements (MEAs). OBJECTIVE: This work develops methods for quantifying risk associated with specific MEAs and for clearly communicating this to decision makers. METHODS: We develop the 'HTA risk analysis chart', in which we present the payer strategy and uncertainty burden (P-SUB) as a measure of overall risk. The P-SUB consists of the payer uncertainty burden (PUB), the risk stemming from decision uncertainty as to which is the truly optimal technology from the relevant set of technologies, and the payer strategy burden (PSB), the additional risk of approving a technology that is not expected to be optimal. We demonstrate the approach using three recent technology appraisals from the UK National Institute for Health and Clinical Excellence (NICE), each of which considered a price-based MEA. RESULTS: The HTA risk analysis chart was calculated using results from standard probabilistic sensitivity analyses. In all three HTAs, the new interventions were associated with substantial risk as measured by the P-SUB. For one of these technologies, the P-SUB was reduced to zero with the proposed price reduction, making this intervention cost effective with near complete certainty. For the other two, the risk reduced substantially with a much reduced PSB and a slightly increased PUB. CONCLUSIONS: The HTA risk analysis chart shows the risk that the healthcare payer incurs under unresolved decision uncertainty and when considering recommending a technology that is not expected to be optimal given current evidence. This allows the simultaneous consideration of financial and data-collection MEA schemes in an easily understood format. The use of HTA risk analysis charts will help to ensure that MEAs are considered within a standard utility-maximising health economic decision-making framework.

Mapping to Estimate Health-State Utility from Non-Preference-Based Outcome Measures: An ISPOR Good Practices for Outcomes Research Task Force Report.

Economic evaluation conducted in terms of cost per quality-adjusted life-year (QALY) provides information that decision makers find useful in many parts of the world. Ideally, clinical studies designed to assess the effectiveness of health technologies would include outcome measures that are directly linked to health utility to calculate QALYs. Often this does not happen, and even when it does, clinical studies may be insufficient for a cost-utility assessment. Mapping can solve this problem. It uses an additional data set to estimate the relationship between outcomes measured in clinical studies and health utility. This bridges the evidence gap between available evidence on the effect of a health technology in one metric and the requirement for decision makers to express it in a different one (QALYs). In 2014, ISPOR established a Good Practices for Outcome Research Task Force for mapping studies. This task force report provides recommendations to analysts undertaking mapping studies, those that use the results in cost-utility analysis, and those that need to critically review such studies. The recommendations cover all areas of mapping practice: the selection of data sets for the mapping estimation, model selection and performance assessment, reporting standards, and the use of results including the appropriate reflection of variability and uncertainty. This report is unique because it takes an international perspective, is comprehensive in its coverage of the aspects of mapping practice, and reflects the current state of the art.

The Cost-effectiveness of Sequences of Biological Disease-modifying Antirheumatic Drug Treatment in England for Patients with Rheumatoid Arthritis Who Can Tolerate Methotrexate.

OBJECTIVE: To ascertain whether strategies of treatment with a biological disease-modifying antirheumatic drug (bDMARD) are cost-effective in an English setting. Results are presented for those patients with moderate to severe rheumatoid arthritis (RA) and those with severe RA. METHODS: An economic model to assess the cost-effectiveness of 7 bDMARD was developed. A systematic literature review and network metaanalysis was undertaken to establish relative clinical effectiveness. The results were used to populate the model, together with estimates of Health Assessment Questionnaire (HAQ) score following European League Against Rheumatism response; annual costs, and utility, per HAQ band; trajectory of HAQ for patients taking bDMARD; and trajectory of HAQ for patients using nonbiologic therapy (NBT). Results were presented as those associated with the strategy with the median cost-effectiveness. Supplementary analyses were undertaken assessing the change in cost-effectiveness when only patients with the most severe prognoses taking NBT were provided with bDMARD treatment. The costs per quality-adjusted life-year (QALY) values were compared with reported thresholds from the UK National Institute for Health and Care Excellence of £20,000 to £30,000 (US$24,700 to US$37,000). RESULTS: In the primary analyses, the cost per QALY of a bDMARD strategy was £41,600 for patients with severe RA and £51,100 for those with moderate to severe RA. Under the supplementary analyses, the cost per QALY fell to £25,300 for those with severe RA and to £28,500 for those with moderate to severe RA. CONCLUSION: The cost-effectiveness of bDMARD in RA in England is questionable and only meets current accepted levels in subsets of patients with the worst prognoses.

Cost-Effectiveness of Haemorrhoidal Artery Ligation versus Rubber Band Ligation for the Treatment of Grade II-III Haemorrhoids: Analysis Using Evidence from the HubBLe Trial.

AIM: Haemorrhoids are a common condition, with nearly 30,000 procedures carried out in England in 2014/15, and result in a significant quality-of-life burden to patients and a financial burden to the healthcare system. This study examined the cost effectiveness of haemorrhoidal artery ligation (HAL) compared with rubber band ligation (RBL) in the treatment of grade II-III haemorrhoids. METHOD: This analyses used data from the HubBLe study, a multicentre, open-label, parallel group, randomised controlled trial conducted in 17 acute UK hospitals between September 2012 and August 2015. A full economic evaluation, including long-term cost effectiveness, was conducted from the UK National Health Service (NHS) perspective. Main outcomes included healthcare costs, quality-adjusted life-years (QALYs) and recurrence. Cost-effectiveness results were presented in terms of incremental cost per QALY gained and cost per recurrence avoided. Extrapolation analysis for 3 years beyond the trial follow-up, two subgroup analyses (by grade of haemorrhoids and recurrence following RBL at baseline), and various sensitivity analyses were undertaken. RESULTS: In the primary base-case within-trial analysis, the incremental total mean cost per patient for HAL compared with RBL was £1027 (95% confidence interval [CI] £782-£1272, p < 0.001). The incremental QALYs were 0.01 QALYs (95% CI -0.02 to 0.04, p = 0.49). This generated an incremental cost-effectiveness ratio (ICER) of £104,427 per QALY. In the extrapolation analysis, the estimated probabilistic ICER was £21,798 per QALY. Results from all subgroup and sensitivity analyses did not materially change the base-case result. CONCLUSIONS: Under all assessed scenarios, the HAL procedure was not cost effective compared with RBL for the treatment of grade II-III haemorrhoids at a cost-effectiveness threshold of £20,000 per QALY; therefore, economically, its use in the NHS should be questioned.

Haemorrhoidal artery ligation versus rubber band ligation for the management of symptomatic second-degree and third-degree haemorrhoids (HubBLe): a multicentre, open-label, randomised controlled trial.

BACKGROUND: Optimum surgical intervention for low-grade haemorrhoids is unknown. Haemorrhoidal artery ligation (HAL) has been proposed as an efficacious, safe therapy while rubber band ligation (RBL) is a commonly used outpatient treatment. We compared recurrence after HAL versus RBL in patients with grade II-III haemorrhoids. METHODS: This multicentre, open-label, parallel group, randomised controlled trial included patients from 17 acute UK NHS trusts. We screened patients aged 18 years or older presenting with grade II-III haemorrhoids. We excluded patients who had previously received any haemorrhoid surgery, more than one injection treatment for haemorrhoids, or more than one RBL procedure within 3 years before recruitment. Eligible patients were randomly assigned (in a 1:1 ratio) to either RBL or HAL with Doppler. Randomisation was computer-generated and stratified by centre with blocks of random sizes. Allocation concealment was achieved using a web-based system. The study was open-label with no masking of participants, clinicians, or research staff. The primary outcome was recurrence at 1 year, derived from the patient's self-reported assessment in combination with resource use from their general practitioner and hospital records. Recurrence was analysed in patients who had undergone one of the interventions and been followed up for at least 1 year. This study is registered with the ISRCTN registry, ISRCTN41394716. FINDINGS: From Sept 9, 2012, to May 6, 2014, of 969 patients screened, 185 were randomly assigned to the HAL group and 187 to the RBL group. Of these participants, 337 had primary outcome data (176 in the RBL group and 161 in the HAL group). At 1 year post-procedure, 87 (49%) of 176 patients in the RBL group and 48 (30%) of 161 patients in the HAL group had haemorrhoid recurrence (adjusted odds ratio [aOR] 2·23, 95% CI 1·42-3·51; p=0·0005). The main reason for this difference was the number of extra procedures required to achieve improvement (57 [32%] participants in the RBL group and 23 [14%] participants in the HAL group had a subsequent procedure for haemorrhoids). The mean pain 1 day after procedure was 3·4 (SD 2·8) in the RBL group and 4·6 (2·8) in the HAL group (difference -1·2, 95% CI -1·8 to -0·5; p=0·0002); at day 7 the scores were 1·6 (2·3) in the RBL group and 3·1 (2·4) in the HAL group (difference -1·5, -2·0 to -1·0; p<0·0001). Pain scores did not differ between groups at 21 days and 6 weeks. 15 individuals reported serious adverse events requiring hospital admission. One patient in the RBL group had a pre-existing rectal tumour. Of the remaining 14 serious adverse events, 12 (7%) were among participants treated with HAL and two (1%) were in those treated with RBL. Six patients had pain (one treated with RBL, five treated with HAL), three had bleeding not requiring transfusion (one treated with RBL, two treated with HAL), two in the HAL group had urinary retention, two in the HAL group had vasovagal upset, and one in the HAL group had possible sepsis (treated with antibiotics). INTERPRETATION: Although recurrence after HAL was lower than a single RBL, HAL was more painful than RBL. The difference in recurrence was due to the need for repeat bandings in the RBL group. Patients (and health commissioners) might prefer such a course of RBL to the more invasive HAL. FUNDING: NIHR Health Technology Assessment programme.

Valuing health at the end of life: a stated preference discrete choice experiment.

A source of debate in the field of health care priority setting is whether health gains should be weighted differently for different groups of patients. The debate has recently focused on the relative value of life extensions for patients with short life expectancy. However, few studies have examined empirically whether society is prepared to fund life-extending end-of-life treatments that would not meet the reimbursement criteria used for other treatments. A web-based discrete choice experiment was conducted in 2012 using a sample of 3969 members of the general public in England and Wales. The study design was informed by the National Institute for Health and Care Excellence's supplementary policy for the appraisal of life-extending end-of-life treatments. The choice tasks involved asking respondents which of two hypothetical patients they would prefer to treat, assuming that the health service has enough funds to treat only one of them. Conditional logit regressions were used for modelling. Choices about which patient to treat were influenced more by the sizes of treatment gains than by patients' life expectancy without treatment. Some respondents appear to support a health-maximisation type objective throughout, whilst a small minority always seek to treat those who are worse off without treatment. The majority of respondents, however, seem to advocate a mixture of the two approaches. Overall, we find little evidence that members of the general public prefer to give higher priority to life-extending end-of-life treatments than to other types of treatment. When asked to make decisions about the treatment of hypothetical patients with relatively short life expectancies, most people's choices are driven by the size of the health gains offered by treatment.

Choosing vs. allocating: discrete choice experiments and constant-sum paired comparisons for the elicitation of societal preferences.

BACKGROUND: There is growing evidence of a reluctance to allocate health care solely on the basis of maximizing quality-adjusted life years (QALYs). Stated preference methods can be used to elicit preferences for efficiency vs. equity in the allocation of health-care resources. OBJECTIVE: To compare discrete choice experiment (DCE) and constant-sum paired comparison (CSPC) methods for eliciting societal preferences. METHODS: Over a series of choice pairs, DCE respondents allocated a fixed budget to one preferred group and CSPC respondents allocated budget percentages between the groups. Questionnaires were compared in terms of completion rates, preference consistency, dominant preferences and derived attribute importance. RESULTS: There was no significant difference in the proportions that rated the questionnaires somewhat or extremely difficult, but a significantly greater proportion completed the DCE compared to the CSPC. Preference consistency was also higher in the DCE. The incidence of dominant preferences, including for aggregate QALYs, was low and not significantly different between questionnaires. Similarly, no CSCP respondents equalized budgets or outcomes in every task. Final health state was the most important attribute in both questionnaires, but the rankings diverged for the other attributes. Notably, the total patients' treated attribute was important in the CSPC but insignificant in the DCE, perhaps reflecting a 'prominence effect'. CONCLUSIONS: Despite lower completion rates and preference consistency, CSPC may offer advantages over DCE in eliciting preferences over the distribution of resources and/or outcomes as well as attribute levels, avoiding extreme 'all-or-nothing' distributions and possibly aligning respondent attention more closely with a societal perspective.

Health Assessment Questionnaire disability progression in early rheumatoid arthritis: systematic review and analysis of two inception cohorts.

OBJECTIVE: The Health Assessment Questionnaire is widely used for patients with inflammatory polyarthritis (IP) and its subset, rheumatoid arthritis (RA). In this study, we evaluated the progression of HAQ scores in RA (i) by systematically reviewing the published literature on the methods used to assess changes in functional disability over time and (ii) to study in detail HAQ progression in two large prospective observational studies from the UK. METHODS: Data from two large inception cohorts, ERAS and NOAR, were studied to determine trajectories of HAQ progression over time by applying latent class growth models (LCGMs) to each dataset separately. Age, sex, baseline DAS28, symptom duration, rheumatoid factor, fulfilment of the 1987 ACR criteria and socio-economic status (SES) were included as potential predictors of HAQ trajectory subgroup membership. RESULTS: The literature search identified 49 studies showing that HAQ progression has mainly been based on average changes in the total study population. In the HAQ progression study, a LCGM with four HAQ trajectory subgroups was selected as providing the best fit in both cohorts. In both the cohorts, older age, female sex, longer symptom duration, fulfilment of the 1987 ACR criteria, higher DAS28 and lower SES were associated with increased likelihood of membership of subgroups with worse HAQ progression. CONCLUSION: Four distinct HAQ trajectory subgroups were derived from the ERAS and NOAR cohorts. The fact that the subgroups identified were nearly identical supports their validity. Identifying distinct groups of patients who are at risk of poor functional outcome may help to target therapy to those who are most likely to benefit.

Adjusting survival time estimates to account for treatment switching in randomized controlled trials--an economic evaluation context: methods, limitations, and recommendations.

BACKGROUND: Treatment switching commonly occurs in clinical trials of novel interventions in the advanced or metastatic cancer setting. However, methods to adjust for switching have been used inconsistently and potentially inappropriately in health technology assessments (HTAs). OBJECTIVE: We present recommendations on the use of methods to adjust survival estimates in the presence of treatment switching in the context of economic evaluations. METHODS: We provide background on the treatment switching issue and summarize methods used to adjust for it in HTAs. We discuss the assumptions and limitations associated with adjustment methods and draw on results of a simulation study to make recommendations on their use. RESULTS: We demonstrate that methods used to adjust for treatment switching have important limitations and often produce bias in realistic scenarios. We present an analysis framework that aims to increase the probability that suitable adjustment methods can be identified on a case-by-case basis. We recommend that the characteristics of clinical trials, and the treatment switching mechanism observed within them, should be considered alongside the key assumptions of the adjustment methods. Key assumptions include the "no unmeasured confounders" assumption associated with the inverse probability of censoring weights (IPCW) method and the "common treatment effect" assumption associated with the rank preserving structural failure time model (RPSFTM). CONCLUSIONS: The limitations associated with switching adjustment methods such as the RPSFTM and IPCW mean that they are appropriate in different scenarios. In some scenarios, both methods may be prone to bias; "2-stage" methods should be considered, and intention-to-treat analyses may sometimes produce the least bias. The data requirements of adjustment methods also have important implications for clinical trialists.

Valuing health at the end of life: an empirical study of public preferences.

In 2009, the National Institute for Health and Clinical Excellence (NICE) issued supplementary advice to its Appraisal Committees to be taken into account when appraising life-extending, 'end-of-life' treatments. This indicated that if certain criteria are met, it may be appropriate to recommend the use of such treatments even if they would not normally be considered cost-effective. However, NICE's public consultation revealed concerns that there is little scientific evidence to support such a policy. This study examines whether there is public support for giving higher priority to life-extending, end-of-life treatments than to other types of treatment. In face-to-face interviews, respondents answered six questions asking them to choose which of two hypothetical patients they would prefer to treat, assuming that the health service has enough funds to treat one but not both of them. The various scenarios were designed so as to control for age- and time-related preferences. Fifty members of the general public in England were interviewed in July 2011. We find some evidence of support for giving priority to the patient with shorter remaining life expectancy, but note that a nontrivial minority of respondents expressed the opposite preference. Substantial preference for quality-of-life improvement over life extension was observed. Very few respondents expressed indifference or unwillingness to choose between the patients. Whilst there cannot be described to be a single 'consensus' set of preferences, we conclude that there are ways in which the results suggest that the current NICE policy may be insufficient.

Estimating health state utility values for joint health conditions: a conceptual review and critique of the current evidence.

BACKGROUND: Analysts frequently estimate the health state utility values (HSUVs) for joint health conditions (JHCs) using data from cohorts with single health conditions. The methods can produce very different results, and there is currently no consensus on the most appropriate technique. OBJECTIVE: To conduct a detailed critical review of existing empirical literature to gain an understanding of the reasons for differences in results and identify where uncertainty remains that may be addressed by further research. RESULTS: Of the 11 studies identified, 10 assessed the additive method, 10 the multiplicative method, 7 the minimum method, and 3 the combination model. Two studies evaluated just 1 of the techniques, whereas the others compared results generated using 2 or more. The range of actual HSUVs can influence general findings, and methods are sometimes compared using descriptive statistics that may not be appropriate for assessing predictive ability. None of the methods gave consistently accurate results across the full range of possible HSUVs, and the values assigned to normal health influence the accuracy of the methods. CONCLUSIONS: Within the limitations of the current evidence base, we would advocate the multiplicative method, conditional on adjustment for baseline utility, as the preferred technique to estimate HSUVs for JHCs when using mean values obtained from cohorts with single conditions. We would recommend that a range of sensitivity analyses be performed to explore the effect on results when using the estimated HSUVs in economic models. Although the linear models appeared to give more accurate results in the studies we reviewed, these models require validating in external data before they can be recommended.

The HubBLe trial: haemorrhoidal artery ligation (HAL) versus rubber band ligation (RBL) for haemorrhoids.

BACKGROUND: Haemorrhoids (piles) are a very common condition seen in surgical clinics. After exclusion of more sinister causes of haemorrhoidal symptoms (rectal bleeding, perianal irritation and prolapse), the best option for treatment depends upon persistence and severity of the symptoms. Minor symptoms often respond to conservative treatment such as dietary fibre and reassurance. For more severe symptoms treatment such as rubber band ligation may be therapeutic and is a very commonly performed procedure in the surgical outpatient setting. Surgery is usually reserved for those who have more severe symptoms, as well as those who do not respond to non-operative therapy; surgical techniques include haemorrhoidectomy and haemorrhoidopexy. More recently, haemorrhoidal artery ligation has been introduced as a minimally invasive, non destructive surgical option.There are substantial data in the literature concerning efficacy and safety of 'rubber band ligation including multiple comparisons with other interventions, though there are no studies comparing it to haemorrhoidal artery ligation. A recent overview has been carried out by the National Institute for Health and Clinical Excellence which concludes that current evidence shows haemorrhoidal artery ligation to be a safe alternative to haemorrhoidectomy and haemorrhoidopexy though it also highlights the lack of good quality data as evidence for the advantages of the technique. METHODS/DESIGN: The aim of this study is to establish the clinical effectiveness and cost effectiveness of haemorrhoidal artery ligation compared with conventional rubber band ligation in the treatment of people with symptomatic second or third degree (Grade II or Grade III) haemorrhoids. DESIGN: A multi-centre, parallel group randomised controlled trial. OUTCOMES: The primary outcome is patient-reported symptom recurrence twelve months following the intervention. Secondary outcome measures relate to symptoms, complications, health resource use, health related quality of life and cost effectiveness following the intervention. PARTICIPANTS: 350 patients with grade II or grade III haemorrhoids will be recruited in surgical departments in up to 14 NHS hospitals. RANDOMISATION: A multi-centre, parallel group randomised controlled trial. Block randomisation by centre will be used, with 175 participants randomised to each group. DISCUSSION: The results of the research will help inform future practice for the treatment of grade II and III haemorrhoids. TRIAL REGISTRATION: ISRCTN41394716.

Tails from the peak district: adjusted limited dependent variable mixture models of EQ-5D questionnaire health state utility values.

OBJECTIVES: Health utility data generated by using the EuroQol five-dimensional (EQ-5D) questionnaire are right bounded at 1 with a substantial gap to the next set of observations, left bounded, and multimodal. These features present challenges to the estimation of the effect of clinical and socioeconomic characteristics on health utilities. Our objective was to develop and demonstrate an appropriate method for dealing with these features. METHODS: We developed a statistical model that incorporates an adjusted limited dependent variable approach to reflect the upper bound and the large gap in feasible EQ-5D questionnaire values. Further flexibility was then gained by adopting a mixture modeling framework to address the multimodality of the EQ-5D questionnaire distribution. We compared the performance of these approaches with that of those frequently adopted in the literature (linear and Tobit models) by using data from a clinical trial of patients with rheumatoid arthritis. RESULTS: We found that three latent classes are appropriate in estimating EQ-5D questionnaire values from function, pain, and sociodemographic factors. Superior performance of the adjusted limited dependent variable mixture model was achieved in terms of Akaike and Bayesian information criteria, root mean square error, and mean absolute error. Unlike other approaches, the adjusted limited dependent variable mixture model fits the data well at high EQ-5D questionnaire levels and cannot predict unfeasible EQ-5D questionnaire values. CONCLUSIONS: The distribution of the EQ-5D questionnaire is characterized by features that raise statistical challenges. It is well known that standard approaches do not perform well for this reason. This article developed an appropriate method to reflect these features by combining limited dependent variable and mixture modeling and demonstrated superior performance in a rheumatoid arthritis setting. Further refinement of the general framework and testing in other data sets are warranted. Analysis of utility data should apply methods that recognize the distributional features of the data.