Small Treatment Effects Research Articles

Randomized trials of invasive cardiovascular interventions that include a placebo control: a systematic review and meta-analysis.

The difference in the benefit of invasive cardiovascular interventions compared with placebo controls has not been analysed systematically. MEDLINE and Web of Science were searched through 29 March 2020. Randomized, placebo-controlled trials of invasive cardiovascular interventions (including catheter-based interventions and pacemaker-like devices) investigating predefined primary outcomes were included. Standardized mean differences (SMD) and odds ratios were calculated for continuous and dichotomous outcomes, respectively. Meta-regression analyses were performed to assess whether estimates of treatment effects were associated with methodological characteristics of trials. Thirty trials, including 4102 patients, were analysed. The overall risk of bias was judged to be low in only 43% of the trials. Ten trials (33%) demonstrated statistically significant superiority of invasive interventions over placebo controls for the respective predefined primary outcomes. In almost half of the 16 trials investigating continuous predefined primary outcomes, the SMD between the active and placebo procedure indicated a small (n = 4) to moderate (n = 3) treatment effect of active treatment over placebo. In contrast, one trial indicated a small treatment effect in favour of the placebo procedure. In the remaining trials, there was no relevant treatment effect of active treatment over placebo. In trials with a protocol-mandated stable and symmetrical use of co-interventions, the superiority of active procedures vs. invasive placebo procedures was significantly larger as compared with trials with frequent or unbalanced changes in co-interventions (P for interaction 0.027). The additional treatment effect of invasive cardiovascular interventions compared with placebo controls was small in most trials.

Variability in Open-Field Locomotor Scoring Following Force-Defined Spinal Cord Injury in Rats: Quantification and Implications.

Spinal cord injury research in experimental animals aims to define mechanisms of tissue damage and identify interventions that can be translated into effective clinical therapies. Highly reliable models of injury and outcome measurement are essential to achieve these aims and avoid problems with reproducibility. Functional scoring is a critical component of outcome assessment and is currently commonly focused on open field locomotion (the “BBB score”). Here we analyze variability of observed locomotor outcome after a highly regulated spinal cord contusion in a large group of rats that had not received any therapeutic intervention. Our data indicate that, despite tight regulation of the injury severity, there is considerable variability in open-field score of individual rats at 21 days after injury, when the group as a whole reaches a functional plateau. The bootstrapped reference interval (that defines boundaries that contain 95% scores in the population without regard for data distributional character) for the score at 21 days was calculated to range from 2.3 to 15.9 on the 22-point scale. Further analysis indicated that the mean day 21 score of random groups of 10 individuals drawn by bootstrap sampling from the whole study population varies between 9.5 and 13.5. Wide variability between individuals implies that detection of small magnitude group-level treatment effects will likely be unreliable, especially if using small experimental group sizes. To minimize this problem in intervention studies, consideration should be given to assessing treatment effects by comparing proportions of animals in comparator groups that attain pre-specified criterion scores.

Boxing training in patients with stroke causes improvement of upper extremity, balance, and cognitive functions but should it be applied as virtual or real?

ABSTRACT Background: Upper extremity hemiparesis is one of the most common post-stroke disabilities requiring rehabilitation. Objective: To compare the effects of virtual and real boxing training in addition to neurodevelopmental treatment on the upper extremity, balance, and cognitive functions in hemiparetic stroke patients. Methods: Forty hemiparetic stroke patients were assigned to either real boxing group-RBG (n=20) or virtual boxing group-VBG (n=20), for a total of 24 sessions (3 sessions/week for 8 weeks). The primary outcome was upper extremity motor ability (Wolf Motor Function Test-WMFT). The secondary outcomes were arm-hand dexterity (Manual Dexterity Test-MMDT), goal-oriented performance (Video Boxing Analysis-VBA), balance functions (Fullerton Advanced Balance Scale-FAB-T), and cognitive functions (Addenbrooke’s Cognitive Examination-Revised-ACE-R). Results: There was small treatment effect on ACE-R, small-medium effect for WFMT and MMDT and large effect on bilateral punching time [VBA (Cohen’s d- VBG=0.83; RBG=0.95)] and balance [FAB-T (Cohen’s d - VBG=0.89; RBG=0.82)] after treatment in both groups. No significant differences were found for training effects between the groups for upper extremity functions [WMFT (p=0.799; Cohen’s d=-0.07), MMDT-PT (p=0.327; Cohen’s d=-0.10), MMDT-THTPT (p=0.779; Cohen’s d=-0.17) and VBA bilateral punch number (p=0.068; Cohen's d=0.15)], balance functions [FAB-T (p=0.602; Cohen’s d=-0.19)] and cognitive functions [ACE-R total (p=0.947, Cohen’s d=0.09)]. Conclusion: The study showed that virtual and real boxing training methods, in addition to neurodevelopmental treatment, are effective in improving upper extremity, balance, and cognitive functions in patients with hemiparetic stroke. The training effects were higher on bilateral punching time and balance functions for both groups. There was no superiority of either approach.

No acclimation: instantaneous responses to temperature maintain homeostatic photosynthetic rates under experimental warming across a precipitation gradient in Ulmus americana

AbstractPast research has shown that plants possess the capacity to alter their instantaneous response of photosynthesis to temperature in response to a longer-term change in temperature (i.e. acclimate). This acclimation is typically the result of processes that influence net photosynthesis (Anet), including leaf biochemical processes such as the maximum rate of Rubisco carboxylation (Vcmax) and the maximum rate of photosynthetic electron transport (Jmax), stomatal conductance (gs) and dark respiration (Rd). However, these processes are rarely examined in the field or in concert with other environmental factors, such as precipitation amount. Here, we use a fully factorial warming (active heating up to +4 °C; mean = +3.1 °C) by precipitation (−50 % ambient to 150 % ambient) manipulation experiment in an old-field ecosystem in the north-eastern USA to examine the degree to which Ulmus americana saplings acclimate through biochemical and stomatal adjustments. We found that rates of Anet at ambient CO2 levels of 400 µmol mol−1 (A400) did not differ across climate treatments or with leaf temperatures from 20 to 30 °C. Canopy temperatures rarely reached above 30 °C in any treatment, suggesting that seasonal carbon assimilation was relatively homeostatic across all treatments. Assessments of the component processes of A400 revealed that decreases in gs with leaf temperature from 20 to 30 °C were balanced by increases in Vcmax, resulting in stable A400 rates despite concurrent increases in Rd. Photosynthesis was not affected by precipitation treatments, likely because the relatively dry year led to small treatment effects on soil moisture. As temperature acclimation is likely to come at a cost to the plant via resource reallocation, it may not benefit plants to acclimate to warming in cases where warming would not otherwise reduce assimilation. These results suggest that photosynthetic temperature acclimation to future warming will be context-specific and that it is important to consider assimilatory benefit when assessing acclimation responses.

The Help for Hay Fever community pharmacy-based pilot randomised controlled trial for intermittent allergic rhinitis

Management of intermittent allergic rhinitis (IAR) is suboptimal in the UK. An Australian community pharmacy-based intervention has been shown to help patients better self-manage their IAR. We conducted a pilot cluster RCT in 12 Scottish community pharmacies to assess transferability of the Australian intervention. Trained staff in intervention pharmacies delivered the intervention to eligible customers (n = 60). Non-intervention pharmacy participants (n = 65) received usual care. Outcome measures included effect size of change in the mini-Rhinoconjunctivitis Quality of Life Questionnaire (miniRQLQ) between baseline, 1-week and 6-week follow-up. Trial procedures were well received by pharmacy staff, and customer satisfaction with the intervention was high. The standardised effect size for miniRQLQ total score was −0.46 (95% CI, −1.05, 0.13) for all participants and −0.14 (95% CI,−0.86, 0.57) in the complete case analysis, suggesting a small overall treatment effect in the intervention group. A full-scale RCT is warranted to fully evaluate the effectiveness of this service.

Correspondence between Fail-Safe k and Dual-Criteria Methods: Analysis of Data Series Stability.

Barnard-Brak, Richman, Little, and Yang (Behaviour Research and Therapy, 102, 8-15, 2018) developed a structured-criteria metric, fail-safe k, which quantifies the stability of data series within single-case experimental designs (SCEDs) using published baseline and treatment data. Fail-safe k suggests the optimal point in time to change phases (e.g., move from Phase B to Phase C, reverse back to Phase A). However, this tool has not been tested with clinical data obtained in the course of care. Thus, the purpose of the current study was to replicate the procedures described by Barnard-Brak et al. with clinical data. We also evaluated the correspondence between the fail-safe k metric with outcomes obtained via dual-criteria and conservative-dual criteria methods, which are empirically supported methods for evaluating data-series trends within SCEDs. Our results provide some degree of support for use of this approach as a research tool with clinical data, in particular when evaluating small or medium treatment effect sizes, but further research is needed before this can be used widely by practitioners.

S221. THE EFFICACY OF LUMATEPERONE 42 MG IN THE TREATMENT OF SCHIZOPHRENIA SYMPTOMS ASSOCIATED WITH SOCIAL FUNCTIONING: POST HOC ANALYSIS OF AN ACUTE PLACEBO- AND ACTIVE-CONTROLLED TRIAL

BackgroundDeficits in social functioning are a core feature of schizophrenia and may be due to the interaction of multiple factors including negative symptoms, depression symptoms, and deficits in social cognition. Social and functional impairment in schizophrenia can be difficult to treat, may not correlate with improvements in psychotic symptoms, and has been associated with poor long-term patient outcomes.Lumateperone (lumateperone tosylate, ITI-007) is a mechanistically novel agent for the treatment of schizophrenia that simultaneously modulates serotonin, dopamine, and glutamate neurotransmission. Lumateperone was shown to be efficacious and well tolerated in 2 acute placebo-controlled studies and its safety and effectiveness was further supported in a long-term open-label study.The effects of lumateperone 42 mg (ITI-007 60 mg) on schizophrenia symptoms associated with social function were investigated in a post hoc analysis of a study that included risperidone 4 mg as an active control (Study 005, NCT01499563). Symptoms associated with social functioning were assessed with the Positive and Negative Syndrome Scale (PANSS)-derived Prosocial factor (PANSS items P3, P6, N2, N4, N7, G16), which has been utilized previously to evaluate the efficacy of various antipsychotics on this functional domain.MethodsThis is a post hoc analysis of data from a positive placebo- and active-controlled study in patients with an acute exacerbation of schizophrenia. Change from baseline in the PANSS Prosocial factor was assessed in the intent-to-treat (ITT) population and in patients with prominent negative symptoms (PNS, score ≥4 on at least 3 negative symptom items) or moderate-to-severe depression symptoms (Calgary Depression Scale for Schizophrenia [CDSS] ≥6) at baseline. Inferential analysis was conducted using a mixed-effects model for repeated measures (MMRM).ResultsThe ITT population comprised 231 patients (placebo, n=80; lumateperone 42 mg, n=76; risperidone 4 mg, n=75); the PNS and CDSS ≥6 populations comprised 110 and 54 patients, respectively. Lumateperone 42-mg treatment was associated with significantly greater improvement compared with placebo on the PANSS Prosocial factor (least-squares mean difference [LSMD] vs placebo = −2.7; P<.001). Risperidone also was superior to placebo on the PANSS Prosocial factor (LSMD= −1.8; P=.011). Similar treatment effects for lumateperone 42 mg were seen on the PANSS Prosocial factor in patients with PNS at baseline (LSMD −2.6, P=.006). Conversely, in patients with PNS, risperidone treatment showed small and non-significant treatment effects on the PANSS Prosocial factor (LSMD= −0.4; P=.707). In patients with moderate-to-severe depression symptoms at baseline, marked and significant improvements on the PANSS Prosocial factor were seen in lumateperone-treated patients (LSMD= −4.9; P<.001) but not in risperidone-treated patients (LSMD=−1.3; P=.397).DiscussionLumateperone 42 mg significantly improved schizophrenia symptoms related to social functioning. In contrast to risperidone, lumateperone was associated with similar or greater treatment effects on the PANSS Prosocial factor in patients with prominent negative symptoms or moderate-to-severe depression symptoms at baseline. These results suggest that lumateperone may have benefits on schizophrenia symptoms associated with social function.

Mega-trials in heart failure: effects of dilution in examination of new therapies.

Over the last 30 years, many medicine development programmes in acute and chronic heart failure (HF) with preserved ejection fraction (HFpEF) have failed, in contrast to those in HF with reduced ejection fraction (HFrEF). We explore how the neutral results in larger HF trials may be attributable to chance and/or the dilution of statistical power. Using simulations, we examined the probability that a positive finding in a Phase2 trial would result in the study of a truly effective medicine in a Phase3 trial. We assessed the similarity of clinical trial and registry patient populations. We conducted a meta-analysis of paired Phase 2 and 3 trials in HFrEF and acute HF examining the associations of trial phase and size with placebo event rates and treatment effects for HF events and death. We estimated loss in trial power attributable to dilution with increasing trial size. Appropriately powered Phase3 trials should have yielded ∼35% positive results. Patient populations in Phase3 trials are similar to those in Phase2 trials but both differ substantially from the populations of 'real-life' registries. We observed decreasing placebo event rates and smaller treatment effects with increasing trial size, especially for HF events (and less so for mortality). This was more pronounced in trials in acute HF patients. The selection of more positive Phase2 trials for further development does not explain the failure of HFpEF and acute HF medicine development. Increasing sample size may lead to reduced event rates and smaller treatment effects, resulting in a high rate of neutral Phase3 trials.

Variable Magnitude and Frequency Financial Reinforcement is Effective at Increasing Adults' Free-Living Physical Activity.

Financial rewards can increase health behaviors, but little research has quantified the effects of different reinforcement schedules on this process. This analysis compares the average moderate-to-vigorous physical activity (MVPA) associated with six distinct positive reinforcement schedules implemented within a physical activity promotion clinical trial. In this trial, participants (N = 512) wore an accelerometer for 1 year and were prescribed one of two types of MVPA goals: a static 30-min goal or an adaptive goal based on the MVPA produced over the previous 9 days. As participants met goals, they transitioned through a sequence of reinforcement stages, beginning with a continuous-fixed magnitude (CRF-FM), then CRF-variable magnitude (CRF-VM), followed by a series of variable ratio-VM (VR-VM) schedules. The average accumulation of MVPA bouts over the last 24 days of each stage was compared to each other. Average MVPA during stage transitions was also examined. The results indicated that immediate reinforcement resulted in more MVPA relative to a comparison group and that the relative effectiveness of adaptive versus static goals was dependent on the magnitude of daily MVPA goals. Schedule effects were qualitatively different for individuals who frequently met their daily goals (Large Intervention Effect subgroup) versus those who did not (Small Intervention Effect subgroup). For the Large Intervention Effect group, the CRF-VM schedule produced the most MVPA, in particular within the adaptive goal condition, with increases observed immediately upon encountering this schedule. In contrast, the CRF-FM schedule produced small amounts of MVPA. This pattern was reversed for the Small Intervention Effect subgroup, where the most MVPA was associated with the CRF-FM stage. Future interventions should focus on discriminating small versus large intervention effects as quickly as possible so that the optimal reinforcement schedule can be used.

Effects of intense assessment on statistical power in randomized controlled trials: Simulation study on depression

Smartphone-based devices are increasingly recognized to assess disease symptoms in daily life (e.g. ecological momentary assessment, EMA). Despite this development in digital psychiatry, clinical trials are mainly based on point assessments of psychopathology. This study investigated expectable increases in statistical power by intense assessment in randomized controlled trials (RCTs).A simulation study, based on three scenarios and several empirical data sets, estimated power gains of two- or fivefold pre-post-assessment. For each condition, data sets of various effect sizes were generated, and AN(C)OVAs were applied to the sample of interest (N = 50–N = 200).Power increases ranged from 6% to 92%, with higher gains in more underpowered scenarios and with higher number of repeated assessments. ANCOVA profited from a more precise estimation of the baseline covariate, resulting in additional gains in statistical power. Fivefold pre-post EMA resulted in highest absolute statistical power and clearly outperformed traditional questionnaire assessments. For example, ANCOVA of automatized PHQ-9 questionnaire data resulted in absolute power of 55 (for N = 200 and d = 0.3). Fivefold EMA, however, resulted in power of 88.9. Non-parametric and multi-level analyses resulted in comparable outcomes.Besides providing psychological treatment, digital mental health can help optimizing sensitivity in RCT-based research. Intense assessment appears advisable whenever psychopathology needs to be assessed with high precision at pre- and post-assessment (e.g. small sample sizes, small treatment effects, or when applying optimization problems like machine learning). First empiric studies are promising, but more evidence is needed. Simulations for various effects and a short guide for popular power software are provided for study planning.

Culturally Adapted Psychotherapeutic Interventions for Latino Depression and Anxiety: A Meta-Analysis

Objectives: Culturally adapted psychotherapeutic interventions have been developed to treat Latino depression and anxiety. Evidence is lacking regarding the overall effectiveness and generalizability of these adapted interventions. This study conducted a systematic review and meta-analysis of psychotherapeutic interventions for Latino depression or anxiety. Method: A search of nine electronic databases and manual review of reference lists were conducted. Thirteen studies of randomized controlled trials were eligible and included for meta-analysis using robust variance estimation in meta-regression. Results: An overall small treatment effect that is statistically significant was identified for Latino depression or anxiety of d = 0.334, 95% confidence interval [0.049, 0.619], p &lt; .05. Discussion and Implications: More research is needed to determine the effectiveness of culturally adapted psychotherapeutic interventions for Latino depression or anxiety.

Game Over? No Main or Subgroup Effects of the Good Behavior Game in a Randomized Trial in English Primary Schools

This study aimed to examine the impact of a universal, school-based intervention, the Good Behavior Game (GBG), on children’s behavior, and to explore any subgroup moderator effects among children at varying levels of cumulative risk (CR) exposure. A 2-year cluster-randomized controlled trial was conducted comprising 77 primary schools in England. Teachers in intervention schools delivered the GBG, whereas their counterparts in control schools continued their usual provision. Behavior (specifically disruptive behavior, concentration problems, and pro-social behavior) was assessed via the checklist version of the Teacher Observation of Classroom Adaptation. A CR index was calculated by summing the number of risk factors to which each child was exposed. Multilevel models indicated that no main or subgroup effects were evident. These findings were largely insensitive to the modeling of CR although a small intervention effect on disruptive behavior was found when the curvilinear trend was used. Further sensitivity analyses revealed no apparent influence of the level of program differentiation. In sum, our findings indicate that the GBG does not improve behavior when implemented in this sample of English schools.

Evidence-based policy analysis? The strange case of the randomized controlled trials of community-led total sanitation

AbstractOur purpose in this paper is to review the findings of 14 randomized controlled trials (RCTs) of community-led total sanitation (CLTS) and recent rural sanitation interventions to assess their usefulness and implications for sanitation policy-making in low- and middle-income countries. The results of the RCT research programme to evaluate CLTS and related sanitation interventions suggest that the magnitude of the treatment effects was much smaller and uncertain than proponents once anticipated. For example, of the ten studies that reported results for reductions in childhood diarrhoea, only three found statistically significant decreases. Surprisingly, the RCT research teams and their funders do not seem to have thought about how their multi-million dollar research agenda would support decision-making on sanitation. Information on the parameters needed for cost-effectiveness analysis or benefit–cost analysis was not collected. However, making reasonable assumptions about the missing information on parameter values, we show that cost–benefit analysis may still ‘save’ CLTS because small treatment effects may still yield net positive economic benefits if the costs of implementing CLTS programmes are modest. We also discuss the need to move beyond the desire for sanitation policies that are proven to be effective globally, and the importance of focusing on analysis of the local sanitation situation. We describe the data needed to make this shift in policy focus from the global to the local level and stress the importance of interdisciplinary communication between the proponents of RCTs and ‘evidence-based policy’, and economists who will be responsible for the economic analysis of investments in CLTS and other sanitation interventions. We also argue that the results of these RCTs highlight the importance of coordinating investments in piped water and sanitation with investments in improved housing.

Proton-pump inhibitors and chronic kidney disease: Hidden consequences of an inappropriate drug use?

Proton-pump inhibitors (PPIs) are the most effective therapy for gastric acid- related diseases. They are generally well tolerated with rare, often self-limiting adverse reactions. On the other hand, there is growing concern regarding the increased public access and inappropriate PPI use. This review aims to give a critical appraisal of current literature and to analyze a possible relationship between renal disorders and PPI use. A plethora of observational pharmacoepidemiological studies link PPI therapy to the development of acute interstitial nephritis (AIN). Most of these studies show a higher risk for acute kidney injury, de novo chronic kidney disease, and end-stage renal disease. However, current evidence is inadequate to establish a causal relationship between PPI use and many of the proposed renal syndromes. Residual confounding and bias related to study design and the over extrapolation of quantitatively small treatment effects contributed to the unnecessary controversy about PPI safety. Undoubtedly, PPI use may rarely induce AIN. Given the worldwide use of PPIs, the number of patients with biopsy- proven AIN is extremely small. However, more research is required to explore the underlying pathophysiological mechanisms and possible differences between commercially available PPIs regarding adverse renal effects. Till then, the PPIs should be used in the lowest effective dose, and inappropriate use should be avoided.

Do Compulsory Schooling Laws Always Work? A Study of Youth Crime in Brazilian Municipalities

We examine if compulsory schooling laws (CSL) necessarily lower crimes. We focus on violent youth crime (homicides by assault and guns) among 15-19 years age group in all Brazilian municipalities over 2000-13, taking advantage of the 2009 Brazilian Constitutional Amendment that required introduction of compulsory high schooling of 15-17-year-olds by 2016. Only about 53% municipalities adopted the Amendment by 2013. Difference-in-difference estimates with municipality fixed effects to account for the endogenous adoption of the Amendment by municipalities show small treatment effects for homicides, but insignificant effects for homicide rates in the full sample. In the absence of any significant increase in income/employment among this age group, we attribute this to the incapacitation effect of CSL, which was, however, weakened by overcrowding in day and night schools in treated municipalities after 2009. In contrast, poorer treated municipalities witnessed increased class size, worse school performance and increased crime too. The crime reduction effects of CSL thus crucially depend on whether/how it affects class size and school quality especially in less promising jurisdictions.

Randomized placebo-controlled trial of emricasan for non-alcoholic steatohepatitis-related cirrhosis with severe portal hypertension

Emricasan, an oral pan-caspase inhibitor, decreased portal pressure in experimental cirrhosis and in an open-label study in patients with cirrhosis and severe portal hypertension, defined as a hepatic venous pressure gradient (HVPG) ≥12 mmHg. We aimed to confirm these results in a placebo-controlled study in patients with non-alcoholic steatohepatitis (NASH)-related cirrhosis. We performed a multicenter double-blinded study, randomizing 263 patients with NASH-related cirrhosis and baseline HVPG ≥12 mmHg to twice daily oral emricasan 5 mg, 25 mg, 50 mg or placebo in a 1:1:1:1 ratio for up to 48 weeks. The primary endpoint was change in HVPG (ΔHVPG) at week 24. Secondary endpoints were changes in biomarkers (aminotransferases, caspases, cytokeratins) and development of liver-related outcomes. There were no significant differences in ΔHVPG for any emricasan dose vs. placebo (-0.21,-0.45,-0.58 mmHg, respectively) adjusted for baseline HVPG, compensation status, and non-selective beta-blocker use. Compensated patients (n= 201 [76%]) tended to have a greater decrease in HVPG (emricasan all vs. placebo, p= 0.06), the decrease being greater in those with higher baseline HVPG (p= 0.018), with a significant interaction between baseline HVPG (continuous, p= 0.024; dichotomous at 16 mmHg [median], p= 0.013) and treatment. Biomarkers decreased significantly with emricasan at week 24 but returned to baseline levels by week 48. New or worsening decompensating events (∼10% over median exposure of 337 days), progression in model for end-stage liver disease and Child-Pugh scores, and treatment-emergent adverse events were similar among treatment groups. Despite a reduction in biomarkers indicating target engagement, emricasan was not associated with improvement in HVPG or clinical outcomes in patients with NASH-related cirrhosis and severe portal hypertension. Compensated patients with higher baseline HVPG had evidence of a small treatment effect. Emricasan treatment appeared safe and well-tolerated. Cirrhosis (scarring of the liver) is the main consequence of non-alcoholic steatohepatitis (NASH). Cirrhosis leads to high pressure in the portal vein which accounts for most of the complications of cirrhosis. Reducing portal pressure is beneficial in patients with cirrhosis. We studied the possibility that emricasan, a drug that improves inflammation and scarring in the liver, would reduce portal pressure in patients with NASH-related cirrhosis and severe portal hypertension. Our results in a large, prospective, double-blind study could not demonstrate a beneficial effect of emricasan in these patients. Clinical Trials.gov #NCT02960204.

An Evaluation of Survival Curve Extrapolation Techniques Using Long-Term Observational Cancer Data.

Objectives. Uncertainty in survival prediction beyond trial follow-up is highly influential in cost-effectiveness analyses of oncology products. This research provides an empirical evaluation of the accuracy of alternative methods and recommendations for their implementation. Methods. Mature (15-year) survival data were reconstructed from a published database study for “no treatment,” radiotherapy, surgery plus radiotherapy, and surgery in early stage non–small cell lung cancer in an elderly patient population. Censored data sets were created from these data to simulate immature trial data (for 1- to 10-year follow-up). A second data set with mature (9-year) survival data for no treatment was used to extrapolate the predictions from models fitted to the first data set. Six methodological approaches were used to fit models to the simulated data and extrapolate beyond trial follow-up. Model performance was evaluated by comparing the relative difference in mean survival estimates and the absolute error in the difference in mean survival v. the control with those from the original mature survival data set. Results. Model performance depended on the treatment comparison scenario. All models performed reasonably well when there was a small short-term treatment effect, with the Bayesian model coping better with shorter follow-up times. However, in other scenarios, the most flexible Bayesian model that could be estimated in practice appeared to fit the data less well than the models that used the external data separately. Where there was a large treatment effect (hazard ratio = 0.4), models that used external data separately performed best. Conclusions. Models that directly use mature external data can improve the accuracy of survival predictions. Recommendations on modeling strategies are made for different treatment benefit scenarios.

A Systematic Review and Meta-analysis of Interventions to Improve Play Skills in Children with Autism Spectrum Disorder

Children with autism spectrum disorders (ASD) experience difficulty with play, and a number of different interventions have been developed and evaluated to address this deficit. This systematic review of randomized controlled trials identified 19 studies reporting on play-based interventions for children with ASD aged 2–12 years. The components of each study, including elements of the interventions and methodological quality, were examined. A meta-analysis was completed for 11 studies, and a small but significant treatment effect was identified (Hedges’ g = 0.439). The current review supports future development of interventions with a focus on the child with ASD across social environments. Outcome measures and comprehensive reporting of intervention components are important considerations in future intervention development and testing. Significance for clinicians and future research is discussed. PROSPERO registration number: RD42015026263.

Psychosocial interventions for informal caregivers of people living with cancer.

Psychosocial interventions for informal caregivers of people living with cancer.

Effectiveness of occupational e-mental health interventions: a systematic review and meta-analysis of randomized controlled trials.

Objective This systematic review and meta-analysis investigated the effectiveness of occupational e-mental health interventions aimed at stress, depression, anxiety, burnout, insomnia, mindfulness, well-being, and alcohol misuse and their potential treatment moderators. Methods We systematically reviewed randomized control trials published in English using three electronic databases (MEDLINE, PsycINFO, CINAHL) and three register trials. A pooled effect size for each mental health area was calculated using random-effects modelling. For each meta-analysis, we conducted an analysis of potential moderators (ie, type of recruitment, age, gender, initial psychological symptoms, guidance, therapy type, and study quality). Results In total, 50 studies were included in the systematic review, and 34 studies were included in the meta-analyses. We noted moderate treatment effects on stress (Hedges'g=0.54), insomnia (g=0.70), and burnout (g=0.51) and small treatment effects on depression (g=0.30), anxiety (g=0.34), well-being (g=0.35), and mindfulness (g=0.42). The pooled effect on alcohol intake was small and nonsignificant. Conclusions Our results suggest that occupational e-mental health interventions are associated with significant health improvements. However, more research is required to understand which factors contribute to the variation in effectiveness of particular interventions depending on the mental health area and characteristics of participants and interventions.