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Analysis of multiple secondary outcomes in a clinical trial leads to an increased probability of at least one false significant result among all secondary outcomes studied. In this paper, we question the notion that that if no multiplicity adjustment has been applied to multiple secondary outcome analyses in a clinical trial, then they must necessarily be regarded as exploratory. Instead, we argue that if individual secondary outcome results are interpreted carefully and precisely, there is no need to downgrade our interpretation to exploratory. This is because the probability of a false significant result for each comparison, the per-comparison wise error rate, does not increase with multiple testing. Strong effects on secondary outcomes should always be taken seriously and must not be dismissed purely on the basis of multiplicity concerns.

Background Rigorous, informative meta-analyses rely on availability of appropriate summary statistics or individual participant data. For continuous outcomes, especially those with naturally skewed distributions, summary information on the mean or variability often goes unreported. While full reporting of original trial data is the ideal, we sought to identify methods for handling unreported mean or variability summary statistics in meta-analysis. Methods We undertook two systematic literature reviews to identify methodological approaches used to deal with missing mean or variability summary statistics. Five electronic databases were searched, in addition to the Cochrane Colloquium abstract books and the Cochrane Statistics Methods Group mailing list archive. We also conducted cited reference searching and emailed topic experts to identify recent methodological developments. Details recorded included the description of the method, the information required to implement the method, any underlying assumptions and whether the method could be readily applied in standard statistical software. We provided a summary description of the methods identified, illustrating selected methods in example meta-analysis scenarios. Results For missing standard deviations (SDs), following screening of 503 articles, fifteen methods were identified in addition to those reported in a previous review. These included Bayesian hierarchical modelling at the meta-analysis level; summary statistic level imputation based on observed SD values from other trials in the meta-analysis; a practical approximation based on the range; and algebraic estimation of the SD based on other summary statistics. Following screening of 1124 articles for methods estimating the mean, one approximate Bayesian computation approach and three papers based on alternative summary statistics were identified. Illustrative meta-analyses showed that when replacing a missing SD the approximation using the range minimised loss of precision and generally performed better than omitting trials. When estimating missing means, a formula using the median, lower quartile and upper quartile performed best in preserving the precision of the meta-analysis findings, although in some scenarios, omitting trials gave superior results. Conclusions Methods based on summary statistics (minimum, maximum, lower quartile, upper quartile, median) reported in the literature facilitate more comprehensive inclusion of randomised controlled trials with missing mean or variability summary statistics within meta-analyses.

Adaptive designs can make clinical trials more flexible by utilising results accumulating in the trial to modify the trial’s course in accordance with pre-specified rules. Trials with an adaptive design are often more efficient, informative and ethical than trials with a traditional fixed design since they often make better use of resources such as time and money, and might require fewer participants. Adaptive designs can be applied across all phases of clinical research, from early-phase dose escalation to confirmatory trials. The pace of the uptake of adaptive designs in clinical research, however, has remained well behind that of the statistical literature introducing new methods and highlighting their potential advantages. We speculate that one factor contributing to this is that the full range of adaptations available to trial designs, as well as their goals, advantages and limitations, remains unfamiliar to many parts of the clinical community. Additionally, the term adaptive design has been misleadingly used as an all-encompassing label to refer to certain methods that could be deemed controversial or that have been inadequately implemented. We believe that even if the planning and analysis of a trial is undertaken by an expert statistician, it is essential that the investigators understand the implications of using an adaptive design, for example, what the practical challenges are, what can (and cannot) be inferred from the results of such a trial, and how to report and communicate the results. This tutorial paper provides guidance on key aspects of adaptive designs that are relevant to clinical triallists. We explain the basic rationale behind adaptive designs, clarify ambiguous terminology and summarise the utility and pitfalls of adaptive designs. We discuss practical aspects around funding, ethical approval, treatment supply and communication with stakeholders and trial participants. Our focus, however, is on the interpretation and reporting of results from adaptive design trials, which we consider vital for anyone involved in medical research. We emphasise the general principles of transparency and reproducibility and suggest how best to put them into practice.

Background Delirium affects > 15% of hospitalised patients but is grossly underdetected, contributing to poor care. The 4 ‘A’s Test (4AT, www.the4AT.com ) is a short delirium assessment tool designed for routine use without special training. The primary objective was to assess the accuracy of the 4AT for delirium detection. The secondary objective was to compare the 4AT with another commonly used delirium assessment tool, the Confusion Assessment Method (CAM). Methods This was a prospective diagnostic test accuracy study set in emergency departments or acute medical wards involving acute medical patients aged ≥ 70. All those without acutely life-threatening illness or coma were eligible. Patients underwent (1) reference standard delirium assessment based on DSM-IV criteria and (2) were randomised to either the index test (4AT, scores 0–12; prespecified score of > 3 considered positive) or the comparator (CAM; scored positive or negative), in a random order, using computer-generated pseudo-random numbers, stratified by study site, with block allocation. Reference standard and 4AT or CAM assessments were performed by pairs of independent raters blinded to the results of the other assessment. Results Eight hundred forty-three individuals were randomised: 21 withdrew, 3 lost contact, 32 indeterminate diagnosis, 2 missing outcome, and 785 were included in the analysis. Mean age was 81.4 (SD 6.4) years. 12.1% (95/785) had delirium by reference standard assessment, 14.3% (56/392) by 4AT, and 4.7% (18/384) by CAM. The 4AT had an area under the receiver operating characteristic curve of 0.90 (95% CI 0.84–0.96). The 4AT had a sensitivity of 76% (95% CI 61–87%) and a specificity of 94% (95% CI 92–97%). The CAM had a sensitivity of 40% (95% CI 26–57%) and a specificity of 100% (95% CI 98–100%). Conclusions The 4AT is a short, pragmatic tool which can help improving detection rates of delirium in routine clinical care. Trial registration International standard randomised controlled trial number (ISRCTN) 53388093 . Date applied 30/05/2014; date assigned 02/06/2014.

The CONSORT (CONsolidated Standards Of Reporting Trials) 2010 statement is the standard guideline for reporting completed randomised trials. The CONSORT Dose-finding Extension (DEFINE) extends the guidance (with 21 new items and 19 modified items) to early phase dose-finding trials with interim dose escalation or de-escalation strategies. Such trials generally focus on safety, tolerability, activity, and recommending dosing and scheduling regimens for further clinical development. These trials are often inadequately reported, hampering their informativeness and making evidence informed decisions difficult. The CONSORT-DEFINE guidance aims to develop an international, consensus driven guideline for reporting early phase dose-finding trials to promote transparency, completeness, reproducibility, and facilitate the interpretation of the results. The CONSORT-DEFINE guidance provides recommendations for essential items that should be reported in early phase dose-finding trials to promote greater clarity, reproducibility, informativeness, and usefulness of results.

The Bland-Altman limits of agreement method is widely used to assess how well the measurements produced by two raters, devices or systems agree with each other. However, mixed effects versions of the method which take into account multiple sources of variability are less well described in the literature. We address the practical challenges of applying mixed effects limits of agreement to the comparison of several devices to measure respiratory rate in patients with chronic obstructive pulmonary disease (COPD). Respiratory rate was measured in 21 people with a range of severity of COPD. Participants were asked to perform eleven different activities representative of daily life during a laboratory-based standardised protocol of 57 minutes. A mixed effects limits of agreement method was used to assess the agreement of five commercially available monitors (Camera, Photoplethysmography (PPG), Impedance, Accelerometer, and Chest-band) with the current gold standard device for measuring respiratory rate. Results produced using mixed effects limits of agreement were compared to results from a fixed effects method based on analysis of variance (ANOVA) and were found to be similar. The Accelerometer and Chest-band devices produced the narrowest limits of agreement (-8.63 to 4.27 and -9.99 to 6.80 respectively) with mean bias -2.18 and -1.60 breaths per minute. These devices also had the lowest within-participant and overall standard deviations (3.23 and 3.29 for Accelerometer and 4.17 and 4.28 for Chest-band respectively). The mixed effects limits of agreement analysis enabled us to answer the question of which devices showed the strongest agreement with the gold standard device with respect to measuring respiratory rates. In particular, the estimated within-participant and overall standard deviations of the differences, which are easily obtainable from the mixed effects model results, gave a clear indication that the Accelerometer and Chest-band devices performed best.

Introduction The continual reassessment method (CRM) is a model-based design for phase I trials, which aims to find the maximum tolerated dose (MTD) of a new therapy. The CRM has been shown to be more accurate in targeting the MTD than traditional rule-based approaches such as the 3 + 3 design, which is used in most phase I trials. Furthermore, the CRM has been shown to assign more trial participants at or close to the MTD than the 3 + 3 design. However, the CRM’s uptake in clinical research has been incredibly slow, putting trial participants, drug development and patients at risk. Barriers to increasing the use of the CRM have been identified, most notably a lack of knowledge amongst clinicians and statisticians on how to apply new designs in practice. No recent tutorial, guidelines, or recommendations for clinicians on conducting dose-finding studies using the CRM are available. Furthermore, practical resources to support clinicians considering the CRM for their trials are scarce. Methods To help overcome these barriers, we present a structured framework for designing a dose-finding study using the CRM. We give recommendations for key design parameters and advise on conducting pre-trial simulation work to tailor the design to a specific trial. We provide practical tools to support clinicians and statisticians, including software recommendations, and template text and tables that can be edited and inserted into a trial protocol. We also give guidance on how to conduct and report dose-finding studies using the CRM. Results An initial set of design recommendations are provided to kick-start the design process. To complement these and the additional resources, we describe two published dose-finding trials that used the CRM. We discuss their designs, how they were conducted and analysed, and compare them to what would have happened under a 3 + 3 design. Conclusions The framework and resources we provide are aimed at clinicians and statisticians new to the CRM design. Provision of key resources in this contemporary guidance paper will hopefully improve the uptake of the CRM in phase I dose-finding trials.

Paracetamol overdose (POD) is common, with approximately 100,000 cases attending UK hospitals annually. Timely antidote administration is crucial for patients at risk of developing acute liver failure. A rapid point-of-care (POC) assay is required to identify high-risk patients with fit-for-purpose sensitivity and specificity. Here we show that by measuring a circulating biomarker, cytokeratin-18 (K18), accurate detection of drug-induced liver injury (DILI) is possible. To achieve this, we created an in vitro diagnostic medical device designed to quantitatively detect serum K18, consisting of a Lateral Flow Immunoassay (LFIA) paired with a bespoke handheld Raman Reader (HRR) to produce quantitative surface-enhanced Raman scattering (SERS). The diagnostic was assessed in 2 performance evaluation studies using 199 serum samples from individuals following POD. The device achieves diagnostic accuracy for DILI with a specificity of 94% and sensitivity of 82%. Here we show that SERS-LFIA can rapidly identify patients with DILI, allowing individualised treatment pathways. There is an unmet clinical need for a rapid point-of-care tests to identify patients at high-risk of developing acute liver failure following a paracetamol overdose. Here, authors assess a diagnostic test, consisting of a lateral flow immunoassay paired with a handheld Raman reader, in performance evaluation studies.

Background and Aims Young people’s engagement in gambling can be linked to gambling-related harm. This can cause stress, anxiety, relationship issues, debt, and lost opportunities. There is a lack of independently funded, and evidence-based school-based interventions that seek to prevent and reduce the harms associated with gambling. PRoGRAM-A is one of the first independently research funded interventions to prevent gambling related harm in adolescents. This paper presents findings from an embedded process evaluation of the pilot cluster randomised control trial of PRoGRAM-A, with a specific focus on intervention fidelity, feasibility and acceptability. Method Multi-modal study design comprised of qualitative focus groups with students ( N  =  42 ); and individual interviews with teachers ( N  =  7 ), PRoGRAM-A trainers ( N  =  5 ), student friends and family ( N  =  2 ) and stakeholders ( N  =  8 ). Structured Observations of the full cycle of PRoGRAM-A across two intervention schools were also undertaken. Results PRoGRAM-A was delivered with a high degree of fidelity (95%) to the training manual. It was also found to be both feasible and acceptable to students, staff and parents. It was appealing to schools as it allowed teachers to address the topic of gambling, which had already been flagged as an issue for some of the schools, but they lacked the skill and capacity to take action. Peer Supporters enjoyed the interactive nature of the training workshop. Parents and carers were supportive of the intervention and stakeholders recognised the growing need for a non-industry funded school-based intervention to raise awareness among students of gambling and gambling-related harm (GRH). Suggested intervention refinements include embedding examples of lived experience to aid students’ engagement with the topic of gambling and GRH. Increasing social skills activities to ensure students are comfortable and confident when initiating conversations and making follow-up sessions more interactive (in-line with the two-day workshop). Conclusions This study demonstrated that it is feasible and acceptable to deliver the PRoGRAM-A gambling harm reduction intervention within secondary schools with a high degree of fidelity. Addressing the topic of gambling and GRH within the school curriculum was deemed to be acceptable by all sample groups, including students. Trial registration Research Registry researchregistry8699.

The high-sensitivity cardiac troponin on presentation to rule out myocardial infarction (HiSTORIC) study was a stepped-wedge cluster randomised trial with long before-and-after periods, involving seven hospitals across Scotland. Results were divergent for the binary safety endpoint (type 1 or type 4b myocardial infarction or cardiac death) across certain pre-specified analyses, which warranted further investigation. In particular, the calendar-matched analysis produced an odds ratio in the opposite direction to the primary logistic mixed-effects model analysis. Several post-hoc statistical models were fitted to each of the co-primary outcomes of length of hospital stay and safety events, which included adjusting for exposure time, incorporating splines, and fitting a random time effect. We improved control of patient characteristics over time by adjusting for multiple additional covariates using different methods: direct inclusion, regression adjustment for propensity score, and weighting. A data augmentation approach was also conducted aiming to reduce the effect of sparse data bias. Finally, the raw data was examined. The new statistical models confirmed the results of the pre-specified trial analysis. In particular, the observed divergence between the calendar-matched and other analyses remained, even after performing the covariate adjustment methods, and after using data augmentation. Divergence was particularly acute for the safety endpoint, which had an event rate of 0.36% overall. Examining the raw data was particularly helpful to assess the sensitivity of the results to small changes in event rates and identify patterns in the data. Our experience reveals the importance of conducting multiple pre-specified sensitivity analyses and examining the raw data, particularly for stepped wedge trials with low event rates or with a small number of sites. Before-and-after analytical approaches that adjust for differences in patient populations but avoid direct modelling of the time trend should be considered in future stepped wedge trials with similar designs.