Flexible Bayesian longitudinal models for cost-effectiveness analyses with informative missing data.

Cost-effectiveness analyses (CEA) are recommended to include sensitivity analyses which make a range of contextually plausible assumptions about missing data. However, with longitudinal data on, for example, patients' health-related quality of life (HRQoL), the missingness patterns can be complicated because data are often missing both at specific timepoints (interim missingness) and following loss to follow-up. Methods to handle these complex missing data patterns have not been developed for CEA, and must recognize that data may be missing not at random, while accommodating both the correlation between costs and health outcomes and the non-normal distribution of these endpoints.

Joint Longitudinal Models for Dealing With Missing at Random Data in Trial-Based Economic Evaluations.

Objectives: In trial-based economic evaluation, some individuals are typically associated with missing data at some time point, so that their corresponding aggregated outcomes (eg, quality-adjusted life-years) cannot be evaluated. Restricting the analysis to the complete cases is inefficient and can result in biased estimates, while imputation methods are often implemented under a missing at random (MAR) assumption. We propose the use of joint longitudinal models to extend standard approaches by taking into account the longitudinal structure to improve the estimation of the targeted quantities under MAR.

Reduced exposure to vasopressors through permissive hypotension to reduce mortality in critically ill people aged 65 and over: the 65 RCT.

Background: Vasopressors are administered to critical care patients to avoid hypotension, which is associated with myocardial injury, kidney injury and death. However, they work by causing vasoconstriction, which may reduce blood flow and cause other adverse effects. A mean arterial pressure target typically guides administration.

Evaluating the clinical and cost-effectiveness of permissive hypotension in critically ill patients aged 65 years or over with vasodilatory hypotension: Statistical and health economic analysis plan for the 65 trial in article.

The 65 trial is a pragmatic, multicentre, parallel-group, open-label, randomised clinical trial of permissive hypotension (targeting a mean arterial pressure target of 60-65 mmHg during vasopressor therapy) versus usual care in critically ill patients aged 65 years or over with vasodilatory hypotension. The trial will recruit 2600 patients from 65 United Kingdom adult general critical care units. The primary outcome is all-cause mortality at 90 days.

A flexible hierarchical framework for improving inference in area-referenced environmental health studies.

Study designs where data have been aggregated by geographical areas are popular in environmental epidemiology. These studies are commonly based on administrative databases and, providing a complete spatial coverage, are particularly appealing to make inference on the entire population. However, the resulting estimates are often biased and difficult to interpret due to unmeasured confounders, which typically are not available from routinely collected data.

The impact of resuscitation system factors on in-hospital cardiac arrest outcomes across UK hospitals: An observational study.

Purpose Of The Study: To explore whether variation in in-hospital cardiac arrest (IHCA) survival can be explained by differences in resuscitation service provision across UK acute hospitals.

Methods: We linked information on key clinical practices with patient data of adults who had a cardiac arrest on a general hospital ward or emergency admissions unit in 2016/17. We used multi-level Bayesian models to explore associations between system quality indicators (number of resuscitation officers, audits time to first shock, review unexpected non-survivors, arrest team meets at handover, hot debrief, cold debrief, real-time audio-visual feedback, frequency of mock arrest provision) and adjusted hospital survival.

A framework for extending trial design to facilitate missing data sensitivity analyses.

Background: Missing data are an inevitable challenge in Randomised Controlled Trials (RCTs), particularly those with Patient Reported Outcome Measures. Methodological guidance suggests that to avoid incorrect conclusions, studies should undertake sensitivity analyses which recognise that data may be 'missing not at random' (MNAR). A recommended approach is to elicit expert opinion about the likely outcome differences for those with missing versus observed data.

Effect of Reduced Exposure to Vasopressors on 90-Day Mortality in Older Critically Ill Patients With Vasodilatory Hypotension: A Randomized Clinical Trial.

Importance: Vasopressors are commonly administered to intensive care unit (ICU) patients to raise blood pressure. Balancing risks and benefits of vasopressors is a challenge, particularly in older patients.

Objective: To determine whether reducing exposure to vasopressors through permissive hypotension (mean arterial pressure [MAP] target, 60-65 mm Hg) reduces mortality at 90 days in ICU patients aged 65 years or older with vasodilatory hypotension.

Vasopressin in septic shock: an individual patient data meta-analysis of randomised controlled trials.

Purpose: We performed an individual patient data meta-analysis to investigate the possible benefits and harms of vasopressin therapy in adults with septic shock both overall and in pre-defined subgroups.

Methods: Our pre-specified study protocol is published on PROSPERO, CRD42017071698. We identified randomised clinical trials up to January 2019 investigating vasopressin therapy versus any other vasoactive comparator in adults with septic shock.

Effect of a Nurse-Led Preventive Psychological Intervention on Symptoms of Posttraumatic Stress Disorder Among Critically Ill Patients: A Randomized Clinical Trial.

Importance: A meta-analysis of outcomes during the 6 months after intensive care unit (ICU) discharge indicate a prevalence for clinically important posttraumatic stress disorder (PTSD) symptoms of 25%.

Objective: To determine whether a nurse-led preventive, complex psychological intervention, initiated in the ICU, reduces patient-reported PTSD symptom severity at 6 months.

Design, Setting, And Participants: A multicenter, parallel-group, cluster-randomized clinical trial with integrated economic and process evaluations conducted in 24 ICUs in the United Kingdom.

A full Bayesian model to handle structural ones and missingness in economic evaluations from individual-level data.

Economic evaluations from individual-level data are an important component of the process of technology appraisal, with a view to informing resource allocation decisions. A critical problem in these analyses is that both effectiveness and cost data typically present some complexity (eg, nonnormality, spikes, and missingness) that should be addressed using appropriate methods. However, in routine analyses, standardised approaches are typically used, possibly leading to biassed inferences.

Are large randomised controlled trials in severe sepsis and septic shock statistically disadvantaged by repeated inadvertent underestimates of required sample size?

Objectives: We sought to understand why randomised controlled trials in septic shock have failed to demonstrate effectiveness in the face of improving overall outcomes for patients and seemingly promising results of early phase trials of interventions.

Design: We performed a retrospective analysis of large critical care trials of severe sepsis and septic shock. Data were collected from the primary trial manuscripts, prepublished statistical plans or by direct communication with corresponding authors.

A Bayesian framework for health economic evaluation in studies with missing data.

Health economics studies with missing data are increasingly using approaches such as multiple imputation that assume that the data are "missing at random." This assumption is often questionable, as-even given the observed data-the probability that data are missing may reflect the true, unobserved outcomes, such as the patients' true health status. In these cases, methodological guidelines recommend sensitivity analyses to recognise data may be "missing not at random" (MNAR), and call for the development of practical, accessible approaches for exploring the robustness of conclusions to MNAR assumptions.

Handling Missing Data in Within-Trial Cost-Effectiveness Analysis: A Review with Future Recommendations.

Cost-effectiveness analyses (CEAs) alongside randomised controlled trials (RCTs) are increasingly designed to collect resource use and preference-based health status data for the purpose of healthcare technology assessment. However, because of the way these measures are collected, they are prone to missing data, which can ultimately affect the decision of whether an intervention is good value for money. We examine how missing cost and effect outcome data are handled in RCT-based CEAs, complementing a previous review (covering 2003-2009, 88 articles) with a new systematic review (2009-2015, 81 articles) focussing on two different perspectives.

Development of a practical approach to expert elicitation for randomised controlled trials with missing health outcomes: Application to the IMPROVE trial.

Background/aims: The analyses of randomised controlled trials with missing data typically assume that, after conditioning on the observed data, the probability of missing data does not depend on the patient's outcome, and so the data are 'missing at random' . This assumption is usually implausible, for example, because patients in relatively poor health may be more likely to drop out. Methodological guidelines recommend that trials require sensitivity analysis, which is best informed by elicited expert opinion, to assess whether conclusions are robust to alternative assumptions about the missing data.

Developing a Bayesian adaptive design for a phase I clinical trial: a case study for a novel HIV treatment.

The design of phase I studies is often challenging, because of limited evidence to inform study protocols. Adaptive designs are now well established in cancer but much less so in other clinical areas. A phase I study to assess the safety, pharmacokinetic profile and antiretroviral efficacy of C34-PEG -Chol, a novel peptide fusion inhibitor for the treatment of HIV infection, has been set up with Medical Research Council funding.

Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial.

Importance: Norepinephrine is currently recommended as the first-line vasopressor in septic shock; however, early vasopressin use has been proposed as an alternative.

Objective: To compare the effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock.

Design, Setting, And Participants: A factorial (2×2), double-blind, randomized clinical trial conducted in 18 general adult intensive care units in the United Kingdom between February 2013 and May 2015, enrolling adult patients who had septic shock requiring vasopressors despite fluid resuscitation within a maximum of 6 hours after the onset of shock.

Kisspeptin-54 triggers egg maturation in women undergoing in vitro fertilization.

Background: Patients with mutations that inactivate kisspeptin signaling are infertile. Kisspeptin-54, the major circulating isoform of kisspeptin in humans, potently stimulates reproductive hormone secretion in humans. Animal studies suggest that kisspeptin is involved in generation of the luteinizing hormone surge, which is required for ovulation; therefore, we hypothesized that kisspeptin-54 could be used to trigger egg maturation in women undergoing in vitro fertilization therapy.

Protocol for a randomised controlled trial of VAsopressin versus Noradrenaline as Initial therapy in Septic sHock (VANISH).

Introduction: Vasopressin is an alternative vasopressor in the management of septic shock. It spares catecholamine use but whether it improves outcome remains uncertain. Current evidence suggests that it may be most effective if used early and possibly in conjunction with corticosteroids.