Missing data in trial-based cost-effectiveness analysis: An incomplete journey

Cost-effectiveness analyses (CEA) conducted alongside randomised trials provide key evidence for informing healthcare decision making, but missing data pose substantive challenges. Recently, there have been a number of developments in methods and guidelines addressing missing data in trials. However, it is unclear whether these developments have permeated CEA practice. This paper critically reviews the extent of and methods used to address missing data in recently published trial-based CEA. Issues of the Health Technology Assessment journal from 2013 to 2015 were searched. Fifty-two eligible studies were identified. Missing data were very common; the median proportion of trial participants with complete cost-effectiveness data was 63% (interquartile range: 47%-81%). The most common approach for the primary analysis was to restrict analysis to those with complete data (43%), followed by multiple imputation (30%). Half of the studies conducted some sort of sensitivity analyses, but only 2 (4%) considered possible departures from the missing-at-random assumption. Further improvements are needed to address missing data in cost-effectiveness analyses conducted alongside randomised trials. These should focus on limiting the extent of missing data, choosing an appropriate method for the primary analysis that is valid under contextually plausible assumptions, and conducting sensitivity analyses to departures from the missing-at-random assumption

Cost-effectiveness analysis with informative missing data: tools and strategies

Cost effectiveness analysis (CEA) of randomised trials are an important source of evidence for informing policy makers on how to best allocate limited resources. Missing data are a common issue in trial-based CEA, and methods such as multiple imputation are now commonly used to account for the missing values, assuming the data are ‘missing at random’ (MAR). This implies that the reasons for the missing data can be explained by the observed data. However, the missingness is often related to unobserved values, that is data are ‘missing not at random’ (MNAR, or ‘informative’). For example, patients whose health status is relatively poor may be less likely to return health questionnaires, even conditional on their observed characteristics. In these settings, methodological guidance recommends assessing whether conclusions are sensitive to departures from the MAR assumption. Sensitivity analysis strategies for handling MNAR is an area of rapid development in medical statistics, but this form of uncertainty has not yet been appropriately addressed in health economics. This PhD thesis aims to develop practical, accessible sensitivity analysis strategies and software tools to handle MNAR data in trial-based CEA. The thesis critically assessed the statistical methods for handling MNAR data in CEA practice, and identified barriers to more widespread use of these methods, via a systematic review and stakeholder focus groups. The research then focused on two strategies to conduct sensitivity analysis under MNAR assumptions: pattern-mixture models, which involve imputing the data assuming MAR, then modifying the imputed values to reflect possible departures from that assumption; and reference-based imputation, where the data are imputed assuming a distribution borrowed from a ‘reference group’. These approaches were illustrated in CEAs of 10TT and CoBalT trials, which evaluated weight loss and depression interventions. Software code and practical guidance are provided to facilitate implementation in practice

The management of behavioural and psychological symptoms of dementia in the acute general medical hospital: A longitudinal cohort study

yesBackground: The acute hospital is a challenging place for a person with dementia. Behavioural and psychological symptoms of dementia (BPSD) are common and may be exacerbated by the hospital environment. Concerns have been raised about how BPSD are managed in this setting and about over reliance on neuroleptic medication. This study aimed to investigate how BPSD are managed in UK acute hospitals. Method(s): A longitudinal cohort of 230 patients with dementia admitted to two acute NHS hospitals. BPSD were measured every four days (Behave-AD scale), as well as documentation of pharmacological prescriptions and non-pharmacological management. Results: The overall prevalence of BPSD was 75%, with aggression and activity disturbance being the most common. Antipsychotics were prescribed for 28 (12%) patients; 70% of these prescriptions were new on admission. Benzodiazepines were prescribed for 27 (12%) patients, antidepressants were prescribed for 37 (16%) patients, and sedatives were prescribed for 14 (3%) patients. Patients who were prescribed antipsychotics, after adjusting for end of life medication, age and dementia severity, were significantly more likely to die (adjusted hazard ratio 5.78, 95% CI 1.57, 21.26, p= 0.008). Nonpharmacological management was used in 55% of participants, most commonly psychosocial interventions (36%) with little evidence of monitoring their effectiveness. A form of restraint was used during 50 (22%) patients’ admissions. Conclusions: Antipsychotic medications and psychosocial interventions were the main methods used to manage BPSD; however, these were not implemented or monitored in a systematic fashion.Alzheimer's Society; BUPA Foundatio

Is positive school climate and adolescent mental health: Longitudinal study of young people in England

Background and objectives: Studies suggest that individual student-reported connection to school is associated with better mental health. However, there is less evidence for associations between schools’ overall school climate and the mental health of their students. This may reflect limitations in which mental health outcomes have been examined. We conducted a large longitudinal study in schools, hypothesising that we would find associations at both the student and school levels between student-reported positive school climate, and reduced student conduct and emotional problems and improved mental wellbeing. // Methods: We tracked students in 20 English secondary schools from near the end of the first year of secondary school (age 11/12) over 3 years using reliable measures of school climate and mental health. // Results: We found associations between student-level reports of positive school climate at baseline, and reduced conduct and emotional problems and better mental wellbeing at 3-year follow-up adjusting for various potential confounders. We also found some evidence of adjusted associations between baseline school-level measures of overall positive climate and better student mental health at follow-up. However, these student- and school-level associations reduced considerably when also adjusting for baseline mental health. // Conclusions: Our findings suggest that there are associations between school climate and student mental health at both the student and school level but these associations are complex and not necessarily causal

A brief intervention for weight control based on habit-formation theory delivered through primary care: results from a randomised controlled trial

Background: Primary care is the 'first port of call' for weight control advice, creating a need for simple, effective interventions that can be delivered without specialist skills. Ten Top Tips (10TT) is a leaflet based on habit-formation theory that could fill this gap. The aim of the current study was to test the hypothesis that 10TT can achieve significantly greater weight loss over 3 months than ‘usual care’. Methods: A two-arm, individually randomised, controlled trial in primary care. Adults with obesity were identified from 14 primary care providers across England. Patients were randomised to either 10TT or 'usual care' and followed up at 3, 6, 12, 18 and 24 months. The primary outcome was weight loss at 3 months, assessed by a health professional blinded to group allocation. Difference between arms was assessed using a mixed-effect linear model taking into account the health professionals delivering 10TT, and adjusted for baseline weight. Secondary outcomes included body mass index, waist circumference, the number achieving a 5% weight reduction, clinical markers for potential comorbidities, weight loss over 24 months and basic costs. Results: Five-hundred and thirty-seven participants were randomised to 10TT (n=267) or to ‘usual care' (n=270). Data were available for 389 (72%) participants at 3 months and for 312 (58%) at 24 months. Participants receiving 10TT lost significantly more weight over 3 months than those receiving usual care (mean difference =−0.87kg; 95% confidence interval: −1.47 to −0.27; P=0.004). At 24 months, the 10TT group had maintained their weight loss, but the ‘usual care’ group had lost a similar amount. The basic cost of 10TT was low, that is, around £23 ($32) per participant. Conclusions: The 10TT leaflet delivered through primary care is effective in the short-term and a low-cost option over the longer term. It is the first habit-based intervention to be used in a health service setting and offers a low-intensity alternative to ‘usual care’

Cost-effectiveness of habit-based advice for weight control versus usual care in general practice in the Ten Top Tips (10TT) trial: economic evaluation based on a randomised controlled trial

Objective: Ten Top Tips (10TT) is a primary care-led behavioural intervention which aims to help adults reduce and manage their weight by following 10 weight loss tips. The intervention promotes habit formation to encourage long-term behavioural changes. The aim of this study was to estimate the cost-effectiveness of 10TT in general practice from the perspective of the UK National Health Service. Design: An economic evaluation was conducted alongside an individually randomised controlled trial. Setting: 14 general practitioner practices in England. Participants: All patients were aged ≥18 years, with body mass index ≥30 kg/m2. A total of 537 patients were recruited; 270 received the usual care offered by their practices and 267 received the 10TT intervention. Outcomes measures: Health service use and quality-adjusted life years (QALYs) were measured over 2 years. Analysis was conducted in terms of incremental net monetary benefits (NMBs), using non-parametric bootstrapping and multiple imputation. Results: Over a 2-year time horizon, the mean costs and QALYs per patient in the 10TT group were £1889 (95% CI £1522 to £2566) and 1.51 (95% CI 1.44 to 1.58). The mean costs and QALYs for usual care were £1925 (95% CI £1599 to £2251) and 1.51 (95% CI 1.45 to 1.57), respectively. This generated a mean cost difference of −£36 (95% CI −£512 to £441) and a mean QALY difference of 0.001 (95% CI −0.080 to 0.082). The incremental NMB for 10TT versus usual care was £49 (95% CI −£1709 to £1800) at a maximum willingness to pay for a QALY of £20 000. 10TT had a 52% probability of being cost-effective at this threshold. Conclusions: Costs and QALYs for 10TT were not significantly different from usual care and therefore 10TT is as cost-effective as usual care. There was no evidence to recommend nor advice against offering 10TT to obese patients in general practices based on cost-effectiveness considerations

Correction to: Sensitivity Analysis for Not-at-Random Missing Data in Trial-Based Cost-Effectiveness Analysis: A Tutorial

The original article can be found online at https://doi.org/10.1007/s40273-018-0650-5

From Scattering Amplitudes to the Dilatation Generator in N=4 SYM

The complete spin chain representation of the planar N=4 SYM dilatation generator has long been known at one loop, where it involves leading nearest-neighbor 2 -> 2 interactions. In this work we use superconformal symmetry to derive the unique solution for the leading L -> 2 interactions of the planar dilatation generator for arbitrarily large L. We then propose that these interactions are given by the scattering operator that has N=4 SYM tree-level scattering amplitudes as matrix elements. We provide compelling evidence for this proposal, including explicit checks for L=2,3 and a proof of consistency with superconformal symmetry.Comment: 39 pages, v2: reference added and minor changes, published versio

Group art therapy as an adjunctive treatment for people with schizophrenia: a randomised controlled trial (MATISSE).

OBJECTIVE: To examine the clinical effectiveness and cost-effectiveness of referral to group art therapy plus standard care, compared with referral to an activity group plus standard care and standard care alone, among people with schizophrenia. DESIGN: A three-arm, parallel group, single-blind, pragmatic, randomised controlled trial. Participants were randomised via an independent and remote telephone randomisation service using permuted blocks, stratified by study centre. SETTING: Study participants were recruited from secondary care mental health and social services in four UK centres. PARTICIPANTS: Potential participants were aged 18 years or over, had a clinical diagnosis of schizophrenia, confirmed by an examination of case notes, and provided written informed consent. We excluded those who were unable to speak sufficient English to complete the baseline assessment, those with severe cognitive impairment and those already receiving arts therapy. INTERVENTIONS: Group art therapy was delivered by registered art therapists according to nationally agreed standards. Groups had up to eight members, lasted for 90 minutes and ran for 12 months. Members were given access to a range of art materials and encouraged to use these to express themselves freely. Activity groups were designed to control for the non-specific effects of group art therapy. Group facilitators offered various activities and encouraged participants to collectively select those they wanted to pursue. Standard care involved follow-up from secondary care mental health services and the option of referral to other services, except arts therapies, as required. MAIN OUTCOME MEASURES: Our co-primary outcomes were global functioning (measured using the Global Assessment of Functioning Scale - GAF) and mental health symptoms (measured using the Positive and Negative Syndrome Scale - PANSS) at 24 months. The main secondary outcomes were level of group attendance, social functioning, well-being, health-related quality of life, service utilisation and other costs measured 12 and 24 months after randomisation. RESULTS: Four hundred and seventeen people were recruited, of whom 355 (85%) were followed up at 2 years. Eighty-six (61%) of those randomised to art therapy and 73 (52%) of those randomised to activity groups attended at least one group. No differences in primary outcomes were found between the three study arms. The adjusted mean difference between art therapy and standard care at 24 months was -0.9 [95% confidence interval (CI) -3.8 to 2.1] on the GAF Scale and 0.7 (95% CI -3.1 to 4.6) on the PANSS Scale. Differences in secondary outcomes were not found, except that those referred to an activity group had fewer positive symptoms of schizophrenia at 24 months than those randomised to art therapy. Secondary analysis indicated that attendance at art therapy groups was not associated with improvements in global functioning or mental health. Although the total cost of the art therapy group was lower than the cost of the two comparison groups, referral to group art therapy did not appear to provide a cost-effective use of resources. CONCLUSIONS: Referring people with established schizophrenia to group art therapy as delivered in this randomised trial does not appear to improve global functioning or mental health of patients or provide a more cost-effective use of resources than standard care alone. TRIAL REGISTRATION: Current Controlled Trials ISRCTN 46150447. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 16, No. 8. See the HTA programme website for further project information

Correction to: A brief intervention for weight control based on habit-formation theory delivered through primary care: results from a randomised controlled trial.

The original version of this article unfortunately contained a mistake in Table 1. In the paper the authors report cholesterol as mg dl-1 (Table 1) however, the correct unit should be mmol/l. Glucose should be the same. The authors apologize for the error. The correct Table 1 can be found below. (Table presented.)