Trial sequential analysis for assessing imprecision in GRADE evaluations – protocol for a methodological study

Abstract Background: Assessing statistical imprecision of summary estimates is an essential element in evaluating the strength of evidence. The GRADE framework recommends assessing imprecision by confidence intervals (CI) in relation to thresholds of interest and in selected cases to assess the relationship between the acquired information size and the calculated optimal information size (OIS). Trial sequential analysis (TSA) calculates multiplicity-adjusted confidence intervals and can be used to calculate a required information size. In a recent methodological study of 544 systematic reviews and meta-analysis reports of clinical trials with TSA, we gathered data regarding the methods used for grading imprecision, specifically regarding the impact of TSA (the METSA project). The questions regarding GRADE imprecision were initially superficially defined and were substantialized only during the project and in the preparations for this protocol. With this add-on study, we investigate the methods of grading imprecision in the GRADE framework by authors of systematic reviews and meta-analysis reports of clinical trials with TSA. Methods: The outlined methodological study will be pre-planned but designed with knowledge about existing but not yet reviewed data on the study questions. The METSA project was not initially designed for the questions raised in the current study protocol, which warrants a critical review of the collected data. We aim to improve precision and accuracy of the collected data regarding imprecision methodology by a redesign of selected data fields, adding new data fields to the data extraction form and a subsequent revision of the existing data extraction accordingly. For each individual study, we will extract or review data regarding the specified methodology including methods for calculating CI and OIS, and thresholds of interest (definitions of important benefit and/or harm). For each topic, we will assess completeness in transparency of described methods and protocolisation, including coherence with the protocol (if relevant). Results: We will report frequencies of observed methods, lack of transparency, and protocolisation. From data gathered in the METSA project, we will report the proportion of imprecision assessments that may have differed in their conclusions if the results of the TSA had been used. Informed by our findings, we will outline new suggestions on how to grade imprecision using TSA. Conclusion: This protocol outlines a methodological study of methods and reporting characteristics imprecision assessment within the GRADE framework in recent systematic reviews and meta-analysis reports of clinical trials utilising trial sequential analysis

Reliability, usability and coverage of AMSTAR 2 assessing 544 systematic reviews and meta analysis reports - protocol for a descriptive analytic study

Background: The AMSTAR 2 tool (second version of Assessing Methodological Quality in Systematic Reviews) is useful for critical appraisal of systematic reviews of clinical trials. In a methodological study of systematic reviews and meta-analysis reports of randomised clinical trials which used the sequential meta-analysis trial sequential analysis (the METSA study), we used the AMSTAR 2 to assess the overall quality of each included study. With the study outlined in this protocol, we aim to explore the interrater reliability of the AMSTAR 2, qualitatively describe our experiences using the tool, and discuss the tool’s coverage of critical domains. Methods: In the METSA study, we investigated statistical methodology and transparency in 544 systematic reviews and meta-analysis reports of randomised clinical trials which used trial sequential analysis (TSA). All systematic reviews (with a protocol) were assessed with AMSTAR 2 by two independent authors (n=270). Meta-analysis reports – defined as not having a protocol – were automatically rated as ‘critically low confidence’ and did no undergo further AMSTAR 2 assessment. Disagreement on the AMSTAR 2 rating was resolved through discussion between the authors. Principal issues were discussed at weekly meetings. Thoughts on the usability and coverage of AMSTAR 2 was shared at these meetings and noted throughout and will be collected post-hoc for the current study. Here, we will analyse the level of agreement on the initial ratings by raw agreement rates and Cohen’s kappa and test for trends concerning the effect of the consensus process (rating up or down confidence) as well as the overall effect of assessor experience. We will compare the AMSTAR 2 rating with the assessments of TSA transparency performed during the METSA study. Conclusion: This methodological study will provide insights in some of the characteristics of AMSTAR 2, including interrater reliability and usability in the context of assessing 270 systematic reviews of clinical trials. We will provide group consensus-based suggestions regarding usability and coverage

Interactions in the 2x2x2 factorial randomised clinical STEPCARE trial and the potential effects on conclusions : a protocol for a simulation study

Background: Randomised clinical trials with a factorial design may assess the effects of multiple interventions in the same population. Factorial trials are carried out under the assumption that the trial interventions have no interactions on outcomes. Here, we present a protocol for a simulation study investigating the consequences of different levels of interactions between the trial interventions on outcomes for the future 2x2x2 factorial designed randomised clinical Sedation, TEmperature, and Pressure after Cardiac Arrest and REsuscitation (STEPCARE) trial in comatose patients after out-of-hospital cardiac arrest. Methods: By simulating a multisite trial with 50 sites and 3278 participants, and a presumed six-month all- cause mortality of 60% in the control population, we will investigate the validity of the trial results with different levels of interaction effects on the outcome. The primary simulation outcome of the study is the risks of type-1 and type-2 errors in the simulated scenarios, i.e. at what level of interaction is the desired alpha and beta level exceeded. When keeping the overall risk of type-1 errors Discussion: This protocol for a simulation study will inform the design of a 2x2x2 factorial randomised clinical trial of how potential interactions between the assessed interventions might affect conclusions. Protocolising this simulation study is important to ensure valid and unbiased results.Peer reviewe

Reference values for intracranial pressure and lumbar cerebrospinal fluid pressure: a systematic review.

Funder: Rigshospitalet; doi: http://dx.doi.org/10.13039/501100005111Funder: The DMSK FoundationBACKGROUND: Although widely used in the evaluation of the diseased, normal intracranial pressure and lumbar cerebrospinal fluid pressure remain sparsely documented. Intracranial pressure is different from lumbar cerebrospinal fluid pressure. In addition, intracranial pressure differs considerably according to the body position of the patient. Despite this, the current reference values do not distinguish between intracranial and lumbar cerebrospinal fluid pressures, and body position-dependent reference values do not exist. In this study, we aim to establish these reference values. METHOD: A systematic search was conducted in MEDLINE, EMBASE, CENTRAL, and Web of Sciences. Methodological quality was assessed using an amended version of the Joanna Briggs Quality Appraisal Checklist. Intracranial pressure and lumbar cerebrospinal fluid pressure were independently evaluated and subdivided into body positions. Quantitative data were presented with mean ± SD, and 90% reference intervals. RESULTS: Thirty-six studies were included. Nine studies reported values for intracranial pressure, while 27 reported values for the lumbar cerebrospinal fluid pressure. Reference values for intracranial pressure were -  5.9 to 8.3 mmHg in the upright position and 0.9 to 16.3 mmHg in the supine position. Reference values for lumbar cerebrospinal fluid pressure were 7.2 to 16.8 mmHg and 5.7 to 15.5 mmHg in the lateral recumbent position and supine position, respectively. CONCLUSIONS: This systematic review is the first to provide position-dependent reference values for intracranial pressure and lumbar cerebrospinal fluid pressure. Clinically applicable reference values for normal lumbar cerebrospinal fluid pressure were established, and are in accordance with previously used reference values. For intracranial pressure, this study strongly emphasizes the scarcity of normal pressure measures, and highlights the need for further research on the matter

An Internet-based emotion regulation intervention versus no intervention for non-suicidal self-injury in adolescents:a statistical analysis plan for a feasibility randomised clinical trial

BACKGROUND: Non-suicidal self-injury (NSSI) has a lifetime prevalence of 17% in adolescents in the general population and up to 74% in adolescents with psychiatric disorders. NSSI is one of the most important predictors of later suicidal behaviour and death by suicide. The TEENS feasibility trial was initiated to assess the feasibility and safety of Internet-based Emotion Regulation Individual Therapy for Adolescents (ERITA) as an add-on to treatment as usual in 13–17-year-old patients with NSSI referred to the Child and Adolescent Mental Health Services. METHODS: The TEENS feasibility trial is a randomised clinical trial with a parallel-group design. The trial intervention is an 11-week online therapy which is tested as an add-on to treatment as usual versus treatment as usual. The primary feasibility outcomes are the fraction of participants who (1) completed 12 weeks of follow-up interview or assessment, (2) consented to inclusion and randomisation out of all eligible participants, and (3) were compliant with the experimental intervention, assessed as completion of at least six out of eleven modules in the programme. Since this is a feasibility trial, we did not predefine a required sample size. The exploratory clinical outcome, the frequency of NSSI episodes, assessed using Deliberate Self-Harm Inventory – Youth version (DSHI-Y), at the end of intervention, is planned to be the future primary outcome in a larger pragmatic definitive randomised clinical trial. After completion of the feasibility trial, blinded data will be analysed by two independent statisticians blinded to the intervention, where ‘A’ and ‘B’ refer to the two groups. A third party will compare these reports, and discrepancies will be discussed. The statistical report with the analyses chosen for the manuscript is being tracked using a version control system, and both statistical reports will be published as a supplementary material. Based on the final statistical report, two blinded conclusions will be drawn by the steering group. DISCUSSION: We present a pre-defined statistical analysis plan for the TEENS feasibility trial, which limits bias, p-hacking, data-driven interpretations. This statistical analysis plan is accompanied by a pre-programmed version-controlled statistical report with simulated data, which increases transparency and reproducibility. TRIAL REGISTRATION: ClinicalTrials.govNCT04243603. Registered on 28 January 2020 SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13063-021-05406-2

Protocol for an individual patient data meta-analysis on blood pressure targets after cardiac arrest

Background Hypotension is common after cardiac arrest (CA), and current guidelines recommend using vasopressors to target mean arterial blood pressure (MAP) higher than 65 mmHg. Pilot trials have compared higher and lower MAP targets. We will review the evidence on whether higher MAP improves outcome after cardiac arrest. Methods This systematic review and meta-analysis will be conducted based on a systematic search of relevant major medical databases from their inception onwards, including MEDLINE, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL), as well as clinical trial registries. We will identify randomised controlled trials published in the English language that compare targeting a MAP higher than 65-70 mmHg in CA patients using vasopressors, inotropes and intravenous fluids. The data extraction will be performed separately by two authors (a third author will be involved in case of disagreement), followed by a bias assessment with the Cochrane Risk of Bias tool using an eight-step procedure for assessing if thresholds for clinical significance are crossed. The outcomes will be all-cause mortality, functional long-term outcomes and serious adverse events. We will contact the authors of the identified trials to request individual anonymised patient data to enable individual patient data meta-analysis, aggregate data meta-analyses, trial sequential analyses and multivariable regression, controlling for baseline characteristics. The certainty of the evidence will be assessed by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. We will register this systematic review with Prospero and aim to redo it when larger trials are published in the near future. Conclusions This protocol defines the performance of a systematic review on whether a higher MAP after cardiac arrest improves patient outcome. Repeating this systematic review including more data likely will allow for more certainty regarding the effect of the intervention and possible sub-groups differences.Peer reviewe

Prompt closure versus gradual weaning of external ventricular drainage for hydrocephalus following aneurysmal subarachnoid haemorrhage: Protocol for the DRAIN randomised clinical trial

Background: Aneurysmal subarachnoid haemorrhage (aSAH) is a life-threatening disease caused by rupture of an intracranial aneurysm. A common complication following aSAH is hydrocephalus, for which placement of an external ventricular drain (EVD) is an important first-line treatment. Once the patient is clinically stable, the EVD is either removed or replaced by a ventriculoperitoneal shunt. The optimal strategy for cessation of EVD treatment is, however, unknown. Gradual weaning may increase the risk of EVD-related infection, whereas prompt closure carries a risk of acute hydrocephalus and redundant shunt implantations. We designed a randomised clinical trial comparing the two commonly used strategies for cessation of EVD treatment in patients with aSAH. Methods: DRAIN is an international multi-centre randomised clinical trial with a parallel group design comparing gradual weaning versus prompt closure of EVD treatment in patients with aSAH. Participants are randomised to either gradual weaning which comprises a multi-step increase of resistance over days, or prompt closure of the EVD. The primary outcome is a composite outcome of VP-shunt implantation, all-cause mortality, or ventriculostomy-related infection. Secondary outcomes are serious adverse events excluding mortality, functional outcome (modified Rankin scale), health-related quality of life (EQ-5D) and Fatigue Severity Scale (FSS). Outcome assessment will be performed 6 months after ictus. Based on the sample size calculation (event proportion 80% in the gradual weaning group, relative risk reduction 20%, type I error 5%, power 80%), 122 patients are needed in each intervention group. Outcome assessment for the primary outcome, statistical analyses and conclusion drawing will be blinded

Prevalence of near-death experiences in people with and without REM sleep intrusion

Background The origin and prevalence of near-death experiences are unknown. A recent study suggested a link with REM sleep intrusion but was criticized for its selection of control participants. We therefore assessed the association of REM intrusion and near-death experiences with different methods. Methods Using a crowd-sourcing platform, we recruited 1,034 lay people from 35 countries to investigate the prevalence of near-death experiences and self-reported REM sleep intrusion. Reports were validated using the Greyson Near-Death Experiences Scale (GNDES) with ≥7 points as cut-off for near-death experiences. Results Near-death experiences were reported by 106 of 1,034 participants (10%; 95% CI [8.5–12%]). Evidence of REM intrusion was more common in people with near-death experiences (n = 50∕106; 47%) than in people with experiences with 6 points or less on the GNDES (n = 47∕183; 26%) or in those without such experiences (n = 107∕744; 14%; p = < 0.0001). Following multivariate regression analysis to adjust for age, gender, place of residence, employment and perceived danger, this association remained highly significant; people with REM intrusion were more likely to exhibit near-death experiences than those without (OR 2.85; 95% CI [1.68–4.88]; p = 0.0001). Discussion Using a crowd-sourcing approach, we found a prevalence of near-death experiences of 10%. While age, gender, place of residence, employment status and perceived threat do not seem to influence the prevalence of near-death experiences, we confirmed a possible association with REM sleep intrusion