Composite endpoints for malaria case-management: not simplifying the picture?

Rapid diagnostic tests (RDTs) for infection with Plasmodium spp. offer two main potential advantages related to malaria treatment: 1) ensuring that individuals with malaria are promptly treated with an effective artemisinin-based combination therapy, and 2) ensuring that individuals without malaria do not receive an anti-malarial they do not need (and instead receive a more appropriate treatment). Some studies of the impact of RDTs on malaria case management have combined these two different successes into a binary outcome describing 'correct management'. However combining correct management of positives and negatives into a single summary measure can be misleading. The problems, which are analogous to those encountered in the evaluation of diagnostic tests, can largely be avoided if data for patients with and without malaria are presented and analysed separately. Where a combined metric is necessary, then one of the established approaches to summarise the performance of diagnostic tests could be considered, although these are not without their limitations. Two graphical approaches to help understand case management performance are illustrated

Cluster randomized trials with a small number of clusters: which analyses should be used?

BACKGROUND: Cluster randomized trials (CRTs) are increasingly used to assess the effectiveness of health interventions. Three main analysis approaches are: cluster-level analyses, mixed-models and generalized estimating equations (GEEs). Mixed models and GEEs can lead to inflated type I error rates with a small number of clusters, and numerous small-sample corrections have been proposed to circumvent this problem. However, the impact of these methods on power is still unclear. METHODS: We performed a simulation study to assess the performance of 12 analysis approaches for CRTs with a continuous outcome and 40 or fewer clusters. These included weighted and unweighted cluster-level analyses, mixed-effects models with different degree-of-freedom corrections, and GEEs with and without a small-sample correction. We assessed these approaches across different values of the intraclass correlation coefficient (ICC), numbers of clusters and variability in cluster sizes. RESULTS: Unweighted and variance-weighted cluster-level analysis, mixed models with degree-of-freedom corrections, and GEE with a small-sample correction all maintained the type I error rate at or below 5% across most scenarios, whereas uncorrected approaches lead to inflated type I error rates. However, these analyses had low power (below 50% in some scenarios) when fewer than 20 clusters were randomized, with none reaching the expected 80% power. CONCLUSIONS: Small-sample corrections or variance-weighted cluster-level analyses are recommended for the analysis of continuous outcomes in CRTs with a small number of clusters. The use of these corrections should be incorporated into the sample size calculation to prevent studies from being underpowered

Coach-Supported Versus Self-guided Digital Training Course for a Problem-solving Psychological Intervention for Nonspecialists: Protocol for a Pre-Post Nested Randomized Controlled Trial

BACKGROUND: Psychosocial interventions delivered by nonspecialists can be effective at reducing common adolescent mental health problems in low-resource settings. However, there is a lack of evidence on resource-efficient methods for building capacity to deliver these interventions. OBJECTIVE: The objective of this study is to evaluate the effects of a digital training (DT) course, delivered in a self-guided format or with coaching, on nonspecialists' competency to deliver a problem-solving intervention intended for adolescents with common mental health problems in India. METHODS: We will conduct a pre-post study with a nested parallel, 2-arm, individually randomized controlled trial. The study aims to recruit 262 participants, randomized 1:1 to receive either a self-guided DT course or a DT course with weekly individualized coaching provided remotely by telephone. In both arms, the DT will be accessed over 4 to 6 weeks. Participants will be nonspecialists (ie, without prior practice-based training in psychological therapies) recruited from among university students and affiliates of nongovernmental organizations in Delhi and Mumbai, India. RESULTS: Outcomes will be assessed at baseline and 6 weeks post randomization using a knowledge-based competency measure that incorporates a multiple-choice quiz format. The primary hypothesis is that self-guided DT will lead to increased competency scores among novices with no prior experience of delivering psychotherapies. The secondary hypothesis is that digital training with coaching will have an incremental effect on competency scores compared with DT alone. The first participant was enrolled on April 4, 2022. CONCLUSIONS: The study will address an evidence gap on the effectiveness of training methods for nonspecialist providers of adolescent mental health interventions in low-resource settings. The findings from this study will be used to support wider efforts to scale up evidence-based mental health interventions for young people. TRIAL REGISTRATION: ClinicalTrials.gov NCT05290142; https://clinicaltrials.gov/ct2/show/NCT05290142. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/41981

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

Cost-effectiveness analyses (CEA) of randomised controlled trials are a key source of information for health care decision makers. Missing data are, however, a common issue that can seriously undermine their validity. A major concern is that the chance of data being missing may be directly linked to the unobserved value itself [missing not at random (MNAR)]. For example, patients with poorer health may be less likely to complete quality-of-life questionnaires. However, the extent to which this occurs cannot be ascertained from the data at hand. Guidelines recommend conducting sensitivity analyses to assess the robustness of conclusions to plausible MNAR assumptions, but this is rarely done in practice, possibly because of a lack of practical guidance. This tutorial aims to address this by presenting an accessible framework and practical guidance for conducting sensitivity analysis for MNAR data in trial-based CEA. We review some of the methods for conducting sensitivity analysis, but focus on one particularly accessible approach, where the data are multiply-imputed and then modified to reflect plausible MNAR scenarios. We illustrate the implementation of this approach on a weight-loss trial, providing the software code. We then explore further issues around its use in practice

Cost-effectiveness of cognitive behaviour therapy versus talking and usual care for depressed older people in primary care

Background: Whilst evidence suggests cognitive behaviour therapy (CBT) may be effective for depressed older people in a primary care setting, few studies have examined its cost-effectiveness. The aim of this study was to compare the cost-effectiveness of cognitive behaviour therapy (CBT), a talking control (TC) and treatment as usual (TAU), delivered in a primary care setting, for older people with depression.Methods: Cost data generated from a single blind randomised controlled trial of 204 people aged 65 years or more were offered only Treatment as Usual, or TAU plus up to twelve sessions of CBT or a talking control is presented. The Beck Depression Inventory II (BDI-II) was the main outcome measure for depression. Direct treatment costs were compared with reductions in depression scores. Cost-effectiveness analysis was conducted using non-parametric bootstrapping. The primary analysis focussed on the cost-effectiveness of CBT compared with TAU at 10 months follow up.Results: Complete cost data were available for 198 patients at 4 and 10 month follow up. There were no significant differences between groups in baseline costs. The majority of health service contacts at follow up were made with general practitioners. Fewer contacts with mental health services were recorded in patients allocated to CBT, though these differences were not significant. Overall total per patient costs (including intervention costs) were significantly higher in the CBT group compared with the TAU group at 10 month follow up (difference 427 pound, 95% CI: 56 pound - 787 pound, p < 0.001). Reductions in BDI-II scores were significantly greater in the CBT group (difference 3.6 points, 95% CI: 0.7-6.5 points, p = 0.018). CBT is associated with an incremental cost of 120 pound per additional point reduction in BDI score and a 90% probability of being considered cost-effective if purchasers are willing to pay up to 270 pound per point reduction in the BDI-II score.Conclusions: CBT is significantly more costly than TAU alone or TAU plus TC, but more clinically effective. Based on current estimates, CBT is likely to be recommended as a cost-effective treatment option for this patient group if the value placed on a unit reduction in BDI-II is greater than 115 pound

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Cost-effectiveness of cognitive behaviour therapy versus talking and usual care for depressed older people in primary care

Abstract Background Whilst evidence suggests cognitive behaviour therapy (CBT) may be effective for depressed older people in a primary care setting, few studies have examined its cost-effectiveness. The aim of this study was to compare the cost-effectiveness of cognitive behaviour therapy (CBT), a talking control (TC) and treatment as usual (TAU), delivered in a primary care setting, for older people with depression. Methods Cost data generated from a single blind randomised controlled trial of 204 people aged 65 years or more were offered only Treatment as Usual, or TAU plus up to twelve sessions of CBT or a talking control is presented. The Beck Depression Inventory II (BDI-II) was the main outcome measure for depression. Direct treatment costs were compared with reductions in depression scores. Cost-effectiveness analysis was conducted using non-parametric bootstrapping. The primary analysis focussed on the cost-effectiveness of CBT compared with TAU at 10 months follow up. Results Complete cost data were available for 198 patients at 4 and 10 month follow up. There were no significant differences between groups in baseline costs. The majority of health service contacts at follow up were made with general practitioners. Fewer contacts with mental health services were recorded in patients allocated to CBT, though these differences were not significant. Overall total per patient costs (including intervention costs) were significantly higher in the CBT group compared with the TAU group at 10 month follow up (difference £427, 95% CI: £56 - £787, p Conclusions CBT is significantly more costly than TAU alone or TAU plus TC, but more clinically effective. Based on current estimates, CBT is likely to be recommended as a cost-effective treatment option for this patient group if the value placed on a unit reduction in BDI-II is greater than £115. Trial Registration isrctn.org Identifier: ISRCTN18271323</p

A cost-utility analysis of a rehabilitation service for people living with and beyond cancer.

BACKGROUND: We conducted a wait-list control randomised trial of an outpatient rehabilitation service for people living with and beyond cancer, delivered in a hospice day care unit. We report the results of an economic evaluation undertaken using the trial data. METHODS: Forty-one participants were recruited into the study. A within-trial stochastic cost-utility analysis was undertaken using Monte-Carlo simulation. The outcome measure for the economic evaluation was quality adjusted life years (QALYs). Costs were measured from the perspective of the NHS and personal social services. Uncertainty in the observed data was captured through probabilistic sensitivity analysis. Scenario analysis was conducted to explore the effects of changing the way QALYs were estimated and adjusting for baseline difference in the population. We also explore assumptions about the length of treatment benefit being maintained. RESULTS: The incremental cost-effectiveness ratio (ICER) for the base-case analysis was £14,231 per QALY. When QALYs were assumed to change linearly over time, this increased to £20,514 per QALY at three months. Adjusting the estimate of QALYs to account for differences in the population at baseline increased the ICER to £94,748 per QALY at three months. Increasing the assumed length of treatment benefit led to reduced ICERs in all scenarios. CONCLUSIONS: Although the intervention is likely to be cost-effective in some circumstances, there is considerable uncertainty surrounding the decision to implement the service. Further research, informed by a formal value of information analysis, would reduce this uncertainty