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Objective: To evaluate how often the precise question being addressed about an intervention (the estimand) is stated or can be worked out from reported methods, and to identify what types of questions are addressed in phase II-IV randomised trials. Design: A systematic review of the clarity of research questions addressed in randomised trials in 2020 in six leading general medical journals. Eligibility criteria: Phase II-IV randomised trials, with no restrictions on medical conditions or interventions. Cluster randomised, cross-over, non-inferiority, and equivalence trials were excluded. Data source: A search of PubMed was performed in February 2021. Main outcome measures: The number of trials which stated the precise primary question being addressed about an intervention (the primary estimand) or for which this could be unambiguously worked out from the reported methods using statistical knowledge. The strategies being used to handle post-randomisation events that affect the interpretation or existence of patient outcomes, such as intervention discontinuations or uses of additional medications (termed intercurrent events), and the corresponding types of questions being addressed. Results: A total of 255 eligible randomised trials were identified. No trials clearly stated all the attributes of the estimand. In 117/255 (46%) trials the primary question addressed could be worked out from the reported methods. Intercurrent events occurred in 95% of trials; but the handling of these could only be determined in 125/255 (49%) trials. Most trials which provided this information considered the occurrence of intercurrent events as irrelevant in the calculation of the treatment effect and addressed the effect of the intervention regardless (96/125, 76%) i.e. as if introduced into routine practice (treatment policy strategy). 4/99 (4%) trials with treatment non-adherence due to adverse events estimated the treatment effect in a hypothetical setting (the effect as if participants continued treatment despite adverse events) and 19/24 (79%) trials where some patients died estimated the treatment effect in a hypothetical setting (the effect as if participants did not die). Conclusions: It is unclear in most trials what precise research question is being addressed. The main driver for this is lack of clarity on the approach to handling intercurrent events. Clear reporting of estimands is necessary in trial reports so all stakeholders, including clinicians, patients and policy makers, can make fully informed decisions about medical interventions.

Introduction With mental ill health listed as a top cause of global disease burden, there is an urgent need to prioritise mental health promotion programmes. Mindfulness–based programmes (MBPs) are being widely implemented to reduce stress in non-clinical settings. In a recent aggregate-level meta-analysis we found that, compared with no intervention, these MBPs reduce average psychological distress. However, heterogeneity between studies impedes generalisation of effects across every setting. Study-level moderators were insufficient to reduce heterogeneity; studying individual–level moderators is warranted. This requires individual participant data (IPD) and larger samples than those found in existing individual trials. Methods and analysis We propose an IPD meta–analysis. Our primary aim is to see if, and how, baseline psychological distress, gender, age, education, and dispositional mindfulness moderate the effect of MBPs on distress. We will search 13 databases for good-quality randomised controlled trials (RCTs) comparing in–person, expert–defined MBPs in non-clinical settings with passive controls. Two researchers will independently select, extract, and appraise trials using the revised Cochrane Risk–of–Bias Tool (RoB2). Anonymised IPD of eligible trials will be sought from authors, who will be invited to collaborate. The primary outcome will be psychological distress measured using psychometrically-validated questionnaires at 1 to 6 months after programme completion. Pairwise random-effects two-stage IPD meta-analyses will be conducted. Moderator analyses will follow a “deft” approach. We will estimate subgroup-specific intervention effects. Secondary outcomes and sensitivity analyses are pre-specified. Multiple imputation strategies will be applied to missing data. Ethics and dissemination The findings will refine our knowledge on the effectiveness of MBPs and help improve the targeting of MBPs in non-clinical settings. They will be shared in accessible formats with a range of stakeholders. Public and professional stakeholders are being involved in the planning, conduct and dissemination of this project. PROSPERO registration number CRD42020200117

OBJECTIVE: To identify the most cost-effective policy for detection and management of fetal macrosomia in late-stage pregnancy. DESIGN: Health economic simulation model. SETTING: All English NHS antenatal services. POPULATION: Nulliparous women in the third trimester treated within the UK NHS. METHODS: A health economic simulation model was used to compare long-term maternal-fetal health and cost outcomes for two detection strategies (universal ultrasound scanning at approximately 36 weeks of gestation versus selective ultrasound scanning), combined with three management strategies (planned caesarean section versus induction of labour versus expectant management) of suspected fetal macrosomia. Probabilities, costs and health outcomes were taken from literature. MAIN OUTCOME MEASURES: Expected costs to the NHS and quality-adjusted life-years (QALYs) gained from each strategy, calculation of net benefit and hence identification of most cost-effective strategy. RESULTS: Compared with selective ultrasound, universal ultrasound increased QALYs by 0.0038 (95% CI 0.0012-0.0076), but also costs by £123.50 (95% CI 99.6-149.9). Overall, the health gains were too small to justify the cost increase given current UK thresholds cost-effective policy was selective ultrasound coupled with induction of labour where macrosomia was suspected. CONCLUSIONS: The most cost-effective policy for detection and management of fetal macrosomia is selective ultrasound scanning coupled with induction of labour for all suspected cases of macrosomia. Universal ultrasound scanning for macrosomia in late-stage pregnancy is not cost-effective. TWEETABLE ABSTRACT: Universal late-pregnancy ultrasound screening for fetal macrosomia is not warranted.

© 2016 The Authors. Published by Elsevier Inc. Objectives To assess the risk posed by missing data (MD) to the power and validity of trials evaluating palliative interventions. Study Design and Setting A systematic review of MD in published randomized controlled trials (RCTs) of palliative interventions in participants with life-limiting illnesses was conducted, and random-effects meta-analyses and metaregression were performed. CENTRAL, MEDLINE, and EMBASE (2009-2014) were searched with no language restrictions. Results One hundred and eight RCTs representing 15,560 patients were included. The weighted estimate for MD at the primary endpoint was 23.1% (95% confidence interval [CI] 19.3, 27.4). Larger MD proportions were associated with increasing numbers of questions/tests requested (odds ratio [OR], 1.19; 95% CI 1.05, 1.35) and with longer study duration (OR, 1.09; 95% CI 1.02, 1.17). Meta-analysis found evidence of differential rates of MD between trial arms, which varied in direction (OR, 1.04; 95% CI 0.90, 1.20; I2 35.9, P = 0.001). Despite randomization, MD in the intervention arms (vs. control) were more likely to be attributed to disease progression unrelated to the intervention (OR, 1.31; 95% CI 1.02, 1.69). This was not the case for MD due to death (OR, 0.92; 95% CI 0.78, 1.08). Conclusion The overall proportion and differential rates and reasons for MD reduce the power and potentially introduce bias to palliative care trials.

Summary Background Uncertainties persist about the magnitude of associations of diabetes mellitus and fasting glucose concentration with risk of coronary heart disease and major stroke subtypes. We aimed to quantify these associations for a wide range of circumstances. Methods We undertook a meta-analysis of individual records of diabetes, fasting blood glucose concentration, and other risk factors in people without initial vascular disease from studies in the Emerging Risk Factors Collaboration. We combined within-study regressions that were adjusted for age, sex, smoking, systolic blood pressure, and body-mass index to calculate hazard ratios (HRs) for vascular disease. Findings Analyses included data for 698 782 people (52 765 non-fatal or fatal vascular outcomes; 8·49 million person-years at risk) from 102 prospective studies. Adjusted HRs with diabetes were: 2·00 (95% CI 1·83–2·19) for coronary heart disease; 2·27 (1·95–2·65) for ischaemic stroke; 1·56 (1·19–2·05) for haemorrhagic stroke; 1·84 (1·59–2·13) for unclassified stroke; and 1·73 (1·51–1·98) for the aggregate of other vascular deaths. HRs did not change appreciably after further adjustment for lipid, inflammatory, or renal markers. HRs for coronary heart disease were higher in women than in men, at 40–59 years than at 70 years and older, and with fatal than with non-fatal disease. At an adult population-wide prevalence of 10%, diabetes was estimated to account for 11% (10–12%) of vascular deaths. Fasting blood glucose concentration was non-linearly related to vascular risk, with no significant associations between 3·90 mmol/L and 5·59 mmol/L. Compared with fasting blood glucose concentrations of 3·90–5·59 mmol/L, HRs for coronary heart disease were: 1·07 (0·97–1·18) for lower than 3·90 mmol/L; 1·11 (1·04–1·18) for 5·60–6·09 mmol/L; and 1·17 (1·08–1·26) for 6·10–6·99 mmol/L. In people without a history of diabetes, information about fasting blood glucose concentration or impaired fasting glucose status did not significantly improve metrics of vascular disease prediction when added to information about several conventional risk factors. Interpretation Diabetes confers about a two-fold excess risk for a wide range of vascular diseases, independently from other conventional risk factors. In people without diabetes, fasting blood glucose concentration is modestly and non-linearly associated with risk of vascular disease. Funding British Heart Foundation, UK Medical Research Council, and Pfizer.