Statistical analyses of ordinal outcomes in randomised controlled trials: a scoping review.

BACKGROUND: Randomised controlled trials (RCTs) aim to estimate the causal effect of one or more interventions relative to a control. One type of outcome that can be of interest in an RCT is an ordinal outcome, which is useful to answer clinical questions regarding complex and evolving patient states. The target parameter of interest for an ordinal outcome depends on the research question and the assumptions the analyst is willing to make. This review aimed to provide an overview of how ordinal outcomes have been used and analysed in RCTs. METHODS: The review included RCTs with an ordinal primary or secondary outcome published between 2017 and 2022 in four highly ranked medical journals (the British Medical Journal, New England Journal of Medicine, The Lancet, and the Journal of the American Medical Association) identified through PubMed. Details regarding the study setting, design, the target parameter, and statistical methods used to analyse the ordinal outcome were extracted. RESULTS: The search identified 309 studies, of which 144 were eligible for inclusion. The most used target parameter was an odds ratio, reported in 78 (54%) studies. The ordinal outcome was dichotomised for analysis in 47 ( 33 % ) studies, and the most common statistical model used to analyse the ordinal outcome on the full ordinal scale was the proportional odds model (64 [ 44 % ] studies). Notably, 86 (60%) studies did not explicitly check or describe the robustness of the assumptions for the statistical method(s) used. CONCLUSIONS: The results of this review indicate that in RCTs that use an ordinal outcome, there is variation in the target parameter and the analytical approaches used, with many dichotomising the ordinal outcome. Few studies provided assurance regarding the appropriateness of the assumptions and methods used to analyse the ordinal outcome. More guidance is needed to improve the transparent reporting of the analysis of ordinal outcomes in future trials.

TMPRSS2 inhibitors for the treatment of COVID-19 in adults: a systematic review and meta-analysis of randomized clinical trials of nafamostat and camostat mesylate.

BACKGROUND: Synthetic serine protease inhibitors block the cellular enzyme transmembrane protease serine 2, thus preventing SARS-CoV-2 cell entry. There are two relevant drugs in this class, namely, nafamostat (intravenous formulation) and camostat (oral formulation). OBJECTIVE: To determine whether transmembrane protease serine 2 inhibition with nafamostat or camostat is associated with a reduced risk of 30-day all-cause mortality in adults with COVID-19. DATA SOURCES: Scientific databases and clinical trial registry platforms. STUDY ELIGIBILITY CRITERIA, INTERVENTIONS, AND PARTICIPANTS: Preprints or published randomized clinical trials (RCTs) of nafamostat or camostat vs. usual care or placebo in adults requiring treatment for COVID-19. METHODS OF DATA SYNTHESIS AND RISK-OF-BIAS ASSESSMENT: The primary outcome of the meta-analysis was 30-day all-cause mortality. Secondary outcomes included time to recovery, adverse events, and serious adverse events. Risk of bias (RoB) was assessed using the revised Cochrane RoB 2 tool for individually randomized trials. Meta-analysis was conducted in the R package meta (v7.0-0) using inverse variance and random effects. Protocol registration number was INPLASY202320120. RESULTS: Twelve RCTs were included. Overall, the number of available patients was small (nafamostat = 387; camostat = 1061), the number of enrolled patients meeting the primary outcome was low (nafamostat = 12; camostat = 13), and heterogeneity was high. In hospitalized adults, we did not identify differences in 30-day all-cause mortality (risk ratio [95% CI]: 0.58 [0.19, 1.80], p 0.34; I2 = 0%; n = 6) and time to recovery (mean difference [95% CI]: 0.08 days [-0.74, 0.89], p 0.86; n = 2) between nafamostat vs. usual care; and for 30-day all-cause mortality (risk ratio [95% CI]: 0.99 [0.31, 3.18], p 0.99; n = 2) between camostat vs. placebo. CONCLUSION: The RCT evidence is inconclusive to determine whether there is a mortality reduction and safety with either nafamostat or camostat for the treatment of adults with COVID-19. There were high RoB, small sample size, and high heterogeneity between RCTs.

A blueprint for a multi-disease, multi-domain Bayesian adaptive platform trial incorporating adult and paediatric subgroups: the Staphylococcus aureus Network Adaptive Platform trial.

The Staphylococcus aureus Network Adaptive Platform (SNAP) trial is a multifactorial Bayesian adaptive platform trial that aims to improve the way that S. aureus bloodstream infection, a globally common and severe infectious disease, is treated. In a world first, the SNAP trial will simultaneously investigate the effects of multiple intervention modalities within multiple groups of participants with different forms of S. aureus bloodstream infection. Here, we formalise the trial structure, modelling approach, and decision rules that will be used for the SNAP trial. By summarising the statistical principles governing the design, our hope is that the SNAP trial will serve as an adaptable template that can be used to improve comparative effectiveness research efficiency in other disease areas.Trial registration NCT05137119 . Registered on 30 November 2021.

Developing and validating a multi-criteria decision analytic tool to assess the value of cancer clinical trials: evaluating cancer clinical trial value.

BACKGROUND: Demonstrating safety and efficacy of new medical treatments requires clinical trials but clinical trials are costly and may not provide value proportionate to their costs. As most health systems have limited resources, it is therefore important to identify the trials with the highest value. Tools exist to assess elements of a clinical trial such as statistical validity but are not wholistic in their valuation of a clinical trial. This study aims to develop a measure of clinical trials value and provide an online tool for clinical trial prioritisation. METHODS: A search of the academic and grey literature and stakeholder consultation was undertaken to identify a set of criteria to aid clinical trial valuation using multi-criteria decision analysis. Swing weighting and ranking exercises were used to calculate appropriate weights of each of the included criteria and to estimate the partial-value function for each underlying metric. The set of criteria and their respective weights were applied to the results of six different clinical trials to calculate their value. RESULTS: Seven criteria were identified: 'unmet need', 'size of target population', 'eligible participants can access the trial', 'patient outcomes', 'total trial cost', 'academic impact' and 'use of trial results'. The survey had 80 complete sets of responses (51% response rate). A trial designed to address an 'Unmet Need' was most commonly ranked as the most important with a weight of 24.4%, followed by trials demonstrating improved 'Patient Outcomes' with a weight of 21.2%. The value calculated for each trial allowed for their clear delineation and thus a final value ranking for each of the six trials. CONCLUSION: We confirmed that the use of the decision tool for valuing clinical trials is feasible and that the results are face valid based on the evaluation of six trials. A proof-of-concept applying this tool to a larger set of trials with an external validation is currently underway.

Early oral antibiotic switch in Staphylococcus aureus bacteraemia: The Staphylococcus aureus Network Adaptive Platform (SNAP) Trial Early Oral Switch Protocol.

BACKGROUND: Staphylococcus aureus bloodstream infection (bacteraemia) is traditionally treated with at least two weeks of IV antibiotics in adults, 3-7 days in children, and often longer for those with complicated disease. The current practice of treating S. aureus bacteraemia (SAB) with prolonged IV antibiotics (rather than oral antibiotics) is based on historical observational research and expert opinion. Prolonged IV antibiotic therapy has significant disadvantages for patients and healthcare systems, and there is growing interest in whether a switch to oral antibiotics following an initial period of IV therapy is a safe alternative for clinically stable patients. PROTOCOL: The early oral switch (EOS) domain of the S. aureus Network Adaptive Platform (SNAP) trial will assess early switch to oral antibiotics compared with continued IV treatment in clinically stable patients with SAB. The primary endpoint is 90-day all-cause mortality. Hospitalised SAB patients are assessed at platform day 7 +/- 2 (uncomplicated SAB) and day 14 +/-2 (complicated SAB) to determine their eligibility for randomisation to EOS (intervention) or continued IV treatment (current standard of care). DISCUSSION: Recruitment is occurring to the EOS domain of the SNAP trial. As of August 2023, 21% of all SNAP participants had been randomised to the EOS domain, a total of 264 participants across 77 centres, with an aim to recruit at least 1000 participants. We describe challenges and facilitators to enrolment in this domain to aid those planning similar trials.

Transparent reporting of adaptive clinical trials using concurrently randomised cohorts.

Adaptive clinical trials have designs that evolve over time because of changes to treatments or changes to the chance that participants will receive these treatments. These changes might introduce confounding that biases crude comparisons of the treatment arms and makes the results from standard reporting methods difficult to interpret for adaptive trials. To deal with this shortcoming, a reporting framework for adaptive trials was developed based on concurrently randomised cohort reporting. A concurrently randomised cohort is a subgroup of participants who all had the same treatments available and the same chance of receiving these treatments. The reporting of pre-randomisation characteristics and post-randomisation outcomes for each concurrently randomised cohort in the study is recommended. This approach provides a transparent and unbiased display of the degree of baseline balance and the randomised treatment comparisons for adaptive trials. The key concepts, terminology, and recommendations underlying concurrently randomised cohort reporting are presented, and its routine use in adaptive trial reporting is advocated.

Statistical analyses of ordinal outcomes in randomised controlled trials: protocol for a scoping review.

INTRODUCTION: Randomised controlled trials (RCTs) aim to assess the effect of one (or more) unproven health interventions relative to other reference interventions. RCTs sometimes use an ordinal outcome, which is an endpoint that comprises of multiple, monotonically ordered categories that are not necessarily separated by a quantifiable distance. Ordinal outcomes are appealing in clinical settings as specific disease states can represent meaningful categories that may be of clinical importance to researchers. Ordinal outcomes can also retain information and increase statistical power compared to dichotomised outcomes and can allow multiple clinical outcomes to be comprised in a single endpoint. Target parameters for ordinal outcomes in RCTs may vary depending on the nature of the research question, the modelling assumptions and the expertise of the data analyst. The aim of this scoping review is to systematically describe the use of ordinal outcomes in contemporary RCTs. Specifically, we aim to: [Formula: see text] Identify which target parameters are of interest in trials that use an ordinal outcome, and whether these parameters are explicitly defined. [Formula: see text] Describe how ordinal outcomes are analysed in RCTs to estimate a treatment effect. [Formula: see text] Describe whether RCTs that use an ordinal outcome adequately report key methodological aspects specific to the analysis of the ordinal outcome. Results from this review will outline the current state of practice of the use of ordinal outcomes in RCTs. Ways to improve the analysis and reporting of ordinal outcomes in RCTs will be discussed. METHODS AND ANALYSIS: We will review RCTs that are published in the top four medical journals (British Medical Journal, New England Journal of Medicine, The Lancet and the Journal of the American Medical Association) between 1 January 2012 and 31 July 2022 that use an ordinal outcome as either a primary or a secondary outcome. The review will identify articles through a PubMed-specific search strategy. Our review will adhere to guidelines for scoping reviews as described in the PRISMA-ScR checklist. The study characteristics and details of the study design and analysis, including the target parameter(s) and statistical methods used to analyse the ordinal outcome, will be extracted from eligible studies. The screening, review and data extraction will be conducted using Covidence, a web-based tool for managing systematic reviews. The data will be summarised using descriptive statistics.

Real-world clinical outcomes and cost estimates of metastatic castration-resistant prostate cancer treatment: does sequencing of taxanes and androgen receptor-targeted agents matter?

INTRODUCTION: Health economic outcomes of real-world treatment sequencing of androgen receptor-targeted agents (ARTA) and docetaxel (DOC) remain unclear. MATERIAL AND METHODS: Data from the electronic Castration-resistant Prostate cancer Australian Database (ePAD) were analyzed including median overall survival (mOS) and median time-to-treatment failure (mTTF). Mean total costs (mTC) and incremental cost-effectiveness ratios (ICER) of treatment sequences were estimated using the average sample method and Zhao and Tian estimator. RESULTS: Of 752 men, 441 received ARTA, 194 DOC, and 175 both sequentially. Of participants treated with both, first-line DOC followed by ARTA was the more common sequence (n = 125, 71%). mOS for first-line ARTA was 8.38 years (95% CI: 3.48, not-estimated) vs. 3.29 years (95% CI: 2.92, 4.02) for DOC. mTTF was 15.7 months (95% CI: 14.2, 23.7) for the ARTA-DOC sequence and 18.2 months (95% CI: 16.2, 23.2) for DOC-ARTA. In first-line, ARTA cost an additional $13,244 per mTTF month compared to DOC. In second-line, ARTA cost $6726 per mTTF month. The DOC-ARTA sequence saved $2139 per mTTF compared to ARTA-DOC, though not statistically significant. CONCLUSION: ICERs show ARTA had improved clinical benefit compared to DOC but at higher cost. There were no significant cost differences between combined sequences.

A Randomized Trial of Nafamostat for Covid-19.

A Randomized Trial of Nafamostat for Covid-19Nafamostat mesylate is a potent in vitro antiviral that inhibits the host transmembrane protease serine 2 enzyme used by SARS-CoV-2 for cell entry. Morpeth et al report the results of an open-label randomized clinical trial of nafamostat for noncritically ill patients with Covid-19.

The Staphylococcus aureus Network Adaptive Platform Trial Protocol: New Tools for an Old Foe.

Staphylococcus aureus bloodstream (SAB) infection is a common and severe infectious disease, with a 90-day mortality of 15%-30%. Despite this, <3000 people have been randomized into clinical trials of treatments for SAB infection. The limited evidence base partly results from clinical trials for SAB infections being difficult to complete at scale using traditional clinical trial methods. Here we provide the rationale and framework for an adaptive platform trial applied to SAB infections. We detail the design features of the Staphylococcus aureus Network Adaptive Platform (SNAP) trial that will enable multiple questions to be answered as efficiently as possible. The SNAP trial commenced enrolling patients across multiple countries in 2022 with an estimated target sample size of 7000 participants. This approach may serve as an exemplar to increase efficiency of clinical trials for other infectious disease syndromes.

Improving clinical trials using Bayesian adaptive designs: a breast cancer example.

BACKGROUND: To perform virtual re-executions of a breast cancer clinical trial with a time-to-event outcome to demonstrate what would have happened if the trial had used various Bayesian adaptive designs instead. METHODS: We aimed to retrospectively "re-execute" a randomised controlled trial that compared two chemotherapy regimens for women with metastatic breast cancer (ANZ 9311) using Bayesian adaptive designs. We used computer simulations to estimate the power and sample sizes of a large number of different candidate designs and shortlisted designs with the either highest power or the lowest average sample size. Using the real-world data, we explored what would have happened had ANZ 9311 been conducted using these shortlisted designs. RESULTS: We shortlisted ten adaptive designs that had higher power, lower average sample size, and a lower false positive rate, compared to the original trial design. Adaptive designs that prioritised small sample size reduced the average sample size by up to 37% when there was no clinical effect and by up to 17% at the target clinical effect. Adaptive designs that prioritised high power increased power by up to 5.9 percentage points without a corresponding increase in type I error. The performance of the adaptive designs when applied to the real-world ANZ 9311 data was consistent with the simulations. CONCLUSION: The shortlisted Bayesian adaptive designs improved power or lowered the average sample size substantially. When designing new oncology trials, researchers should consider whether a Bayesian adaptive design may be beneficial.

A scoping review of studies using observational data to optimise dynamic treatment regimens.

BACKGROUND: Dynamic treatment regimens (DTRs) formalise the multi-stage and dynamic decision problems that clinicians often face when treating chronic or progressive medical conditions. Compared to randomised controlled trials, using observational data to optimise DTRs may allow a wider range of treatments to be evaluated at a lower cost. This review aimed to provide an overview of how DTRs are optimised with observational data in practice. METHODS: Using the PubMed database, a scoping review of studies in which DTRs were optimised using observational data was performed in October 2020. Data extracted from eligible articles included target medical condition, source and type of data, statistical methods, and translational relevance of the included studies. RESULTS: From 209 PubMed abstracts, 37 full-text articles were identified, and a further 26 were screened from the reference lists, totalling 63 articles for inclusion in a narrative data synthesis. Observational DTR models are a recent development and their application has been concentrated in a few medical areas, primarily HIV/AIDS (27, 43%), followed by cancer (8, 13%), and diabetes (6, 10%). There was substantial variation in the scope, intent, complexity, and quality between the included studies. Statistical methods that were used included inverse-probability weighting (26, 41%), the parametric G-formula (16, 25%), Q-learning (10, 16%), G-estimation (4, 6%), targeted maximum likelihood/minimum loss-based estimation (4, 6%), regret regression (3, 5%), and other less common approaches (10, 16%). Notably, studies that were primarily intended to address real-world clinical questions (18, 29%) tended to use inverse-probability weighting and the parametric G-formula, relatively well-established methods, along with a large amount of data. Studies focused on methodological developments (45, 71%) tended to be more complicated and included a demonstrative real-world application only. CONCLUSIONS: As chronic and progressive conditions become more common, the need will grow for personalised treatments and methods to estimate the effects of DTRs. Observational DTR studies will be necessary, but so far their use to inform clinical practice has been limited. Focusing on simple DTRs, collecting large and rich clinical datasets, and fostering tight partnerships between content experts and data analysts may result in more clinically relevant observational DTR studies.

The Joint Effect of Physical Multimorbidity and Mental Health Conditions Among Adults in Australia.

INTRODUCTION: The prevalence of chronic physical and mental health conditions is rising globally. Little evidence exists on the joint effect of physical and mental health conditions on health care use, work productivity, and health-related quality of life in Australia. METHODS: We analyzed data from the Household, Income and Labour Dynamics in Australia (HILDA) Survey, waves 9 (2009), 13 (2013), and 17 (2017). Economic effects associated with multimorbidity were measured through health service use, work productivity loss, and health-related quality of life. We used generalized estimating equations to assess the effect of the association between physical multimorbidity and mental health conditions and economic outcomes. RESULTS: From 2009 through 2017 the prevalence of physical multimorbidity increased from 15.1% to 16.2%, and the prevalence of mental health conditions increased from 11.2% to 17.3%. The number of physical health conditions was associated with the number of health services used (general practitioner visits, incidence rate ratio = 1.41), work productivity loss (labor force participation, adjusted odds ratio = 0.71), and reduced health-related quality of life (SF-6D score: Coefficient = -0.03). These effects were exacerbated by the presence of mental health conditions and low socioeconomic status. CONCLUSION: Having multiple physical health conditions (physical multimorbidity) creates substantial health and financial burdens on individuals, the health system, and society, including increased use of health services, loss of work productivity, and decreased health-related quality of life. The adverse effects of multimorbidity on health, quality of life, and economic well-being are exacerbated by the co-occurrence of mental health conditions and low socioeconomic status.

Bayesian modelling of lung function data from multiple-breath washout tests.

Paediatric respiratory researchers have widely adopted the multiple-breath washout (MBW) test because it allows assessment of lung function in unsedated infants and is well suited to longitudinal studies of lung development and disease. However, a substantial proportion of MBW tests in infants fail current acceptability criteria. We hypothesised that a model-based approach to analysing the data, in place of traditional simple empirical summaries, would enable more efficient use of these tests. We therefore developed a novel statistical model for infant MBW data and applied it to 1197 tests from 432 individuals from a large birth cohort study. We focus on Bayesian estimation of the lung clearance index, the most commonly used summary of lung function from MBW tests. Our results show that the model provides an excellent fit to the data and shed further light on statistical properties of the standard empirical approach. Furthermore, the modelling approach enables the lung clearance index to be estimated by using tests with different degrees of completeness, something not possible with the standard approach. Our model therefore allows previously unused data to be used rather than discarded, as well as routine use of shorter tests without significant loss of precision. Beyond our specific application, our work illustrates a number of important aspects of Bayesian modelling in practice, such as the importance of hierarchical specifications to account for repeated measurements and the value of model checking via posterior predictive distributions.

Effectiveness and risks of cricoid pressure during rapid sequence induction for endotracheal intubation.

BACKGROUND: Rapid sequence induction (RSI) for endotracheal intubation is a technique widely used in anaesthesia, emergency and intensive care medicine to secure an airway in patients deemed at risk of pulmonary aspiration. Cricoid pressure is conceptually used to reduce the risk of aspiration by compressing the oesophagus. OBJECTIVES: To identify and evaluate all randomized controlled trials (RCTs) involving participants undergoing elective or emergency airway management via RSI and compare participants who have cricoid pressure administered with participants who do not have cricoid pressure administered. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 4), MEDLINE via OvidSP (1946 to May 2015), EMBASE via OvidSP (1980 to May 2015), ISI Web of Science (from 1940 to May 2015) and CINAHL via EBSCOhost (1982 to May 2015). SELECTION CRITERIA: We included all RCTs comparing people undergoing RSI who have cricoid pressure applied, either intermittently or continuously, with people undergoing RSI who do not have cricoid pressure applied in the context of endotracheal intubation using a direct laryngoscopic technique. We included both elective and emergency cases. We included studies of blinded and unblinded participants. Participants (male or female) were involved in any type of procedure where general anaesthetic utilizing RSI or emergency airway management utilizing RSI and endotracheal intubation was undertaken. We expected the control arm to be the absence of cricoid pressure at any stage during RSI. The primary outcome of interest was the reported event rate or prevalence of aspiration determined by a) documented gastric aspiration determined by visual inspection of aspirated stomach contents on laryngoscopy; b) pepsin detection in tracheal aspirate using the Ufberg method; c) post-anaesthetic radiographic changes suggestive of aspiration pneumonitis or d) any combination of a to c. Secondary outcomes of interest included documented impaired visualization of the airway by a treating laryngoscopist, force applied during cricoid pressure, the direction of application of force of applied cricoid pressure, independent risk factors for aspiration and whether the person applying cricoid pressure had previously done so in an emergency airway context. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles and abstracts of all the studies obtained from the search using recognition of words such as 'cricoid pressure', 'rapid sequence intubation', 'emergency airway management' and 'aspiration'. Two authors independently determined the study inclusion by using a study eligibility form that we developed for the purpose of this review. We also reported the decisions regarding inclusion and exclusion in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement. We assumed that studies that did not describe the use of RSI in their title, abstract or methodology used an alternative method of anaesthetic induction or emergency airway management and thus we excluded them. Data extracted from included studies comprised study characteristics, participant demographics, intervention and comparison details plus outcome measures and results. We contacted primary authors of studies with missing or unreported but potentially relevant data to obtain missing data. MAIN RESULTS: Of 493 records that we identified from databases as a result of the search (excluding duplicates), we regarded 70 abstracts/titles as potentially relevant studies. Independent scrutiny of these 70 titles and abstracts identified 29 potentially relevant studies. Of the 29 potentially relevant studies, one study met the criteria for inclusion. This study was a RCT that compared participants undergoing RSI and endotracheal intubation in the context of elective surgery requiring a general anaesthetic. Forty participants were recruited, 20 of whom had cricoid pressure applied and 20 of whom had cricoid pressure simulated. The main outcomes reported were systolic arterial pressure and heart rate after laryngoscopy and tracheal intubation. We did not consider these outcomes relevant for the purposes of this systematic review. The search also identified one study that could potentially be included in an updated systematic review in the future, but was at the time of the search a proposal for a trial only and had no reported outcomes at this time. AUTHORS' CONCLUSIONS: There is currently no information available from published RCTs on clinically relevant outcome measures with respect to the application of cricoid pressure during RSI in the context of endotracheal intubation. On the basis of the findings of non-RCT literature, however, cricoid pressure may not be necessary to undertake RSI safely, and therefore well-designed and conducted RCTs should nonetheless be encouraged to properly assess the safety and effectiveness of cricoid pressure.

Interventions for reducing wrong-site surgery and invasive clinical procedures.

BACKGROUND: Specific clinical interventions are needed to reduce wrong-site surgery, which is a rare but potentially disastrous clinical error. Risk factors contributing to wrong-site surgery are variable and complex. The introduction of organisational and professional clinical strategies have a role in minimising wrong-site surgery. OBJECTIVES: To evaluate the effectiveness of organisational and professional interventions for reducing wrong-site surgery (including wrong-side, wrong-procedure and wrong-patient surgery), including non-surgical invasive clinical procedures such as regional blocks, dermatological, obstetric and dental procedures and emergency surgical procedures not undertaken within the operating theatre. SEARCH METHODS: For this update, we searched the following electronic databases: the Cochrane Effective Practice and Organisation of Care (EPOC) Group Specialised Register (January 2014), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2014), MEDLINE (June 2011 to January 2014), EMBASE (June 2011 to January 2014), CINAHL (June 2011 to January 2014), Dissertations and Theses (June 2011 to January 2014), African Index Medicus, Latin American and Caribbean Health Sciences database, Virtual Health Library, Pan American Health Organization Database and the World Health Organization Library Information System. Database searches were conducted in January 2014. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs), non-randomised controlled trials, controlled before-after studies (CBAs) with at least two intervention and control sites, and interrupted-time-series (ITS) studies where the intervention time was clearly defined and there were at least three data points before and three after the intervention. We included two ITS studies that evaluated the effectiveness of organisational and professional interventions for reducing wrong-site surgery, including wrong-side and wrong-procedure surgery. Participants included all healthcare professionals providing care to surgical patients; studies where patients were involved to avoid the incorrect procedures or studies with interventions addressed to healthcare managers, administrators, stakeholders or health insurers. DATA COLLECTION AND ANALYSIS: Two review authors independently assesses the quality and abstracted data of all eligible studies using a standardised data extraction form, modified from the Cochrane EPOC checklists. We contacted study authors for additional information. MAIN RESULTS: In the initial review, we included one ITS study that evaluated a targeted educational intervention aimed at reducing the incidence of wrong-site tooth extractions. The intervention included examination of previous cases of wrong-site tooth extractions, educational intervention including a presentation of cases of erroneous extractions, explanation of relevant clinical guidelines and feedback by an instructor. Data were reported from all patients on the surveillance system of a University Medical centre in Taiwan with a total of 24,406 tooth extractions before the intervention and 28,084 tooth extractions after the intervention. We re-analysed the data using the Prais-Winsten time series and the change in level for annual number of mishaps was statistically significant at -4.52 (95% confidence interval (CI) -6.83 to -2.217) (standard error (SE) 0.5380). The change in slope was statistically significant at -1.16 (95% CI -2.22 to -0.10) (SE 0.2472; P < 0.05).This update includes an additional study reporting on the incidence of neurological WSS at a university hospital both before and after the Universal Protocol's implementation. A total of 22,743 patients undergoing neurosurgical procedures at the University of Illionois College of Medicine at Peoria, Illinois, United States of America were reported. Of these, 7286 patients were reported before the intervention and 15,456 patients were reported after the intervention. The authors found a significant difference (P < 0.001) in the incidence of WSS between the before period, 1999 to 2004, and the after period, 2005 to 2011.  Similarly, data were re-analysed using Prais-Winsten regression to correct for autocorrelation. As the incidences were reported by year only and the intervention occurred in July 2004, the intervention year 2004 was excluded from the analysis. The change in level at the point the intervention was introduced was not statistically significant at -0.078 percentage points (pp) (95% CI -0.176 pp to 0.02 pp; SE 0.042; P = 0.103). The change in slope was statistically significant at 0.031 (95% CI 0.004 to 0.058; SE 0.012; P < 0.05). AUTHORS' CONCLUSIONS: The findings of this update added one additional ITS study to the previous review which contained one ITS study. The original review suggested that the use of a specific educational intervention in the context of a dental outpatient setting, which targets junior dental staff using a training session that included cases of wrong-site surgery, presentation of clinical guidelines and feedback by an instructor, was associated with a reduction in the incidence of wrong-site tooth extractions. The additional study in this update evaluated the annual incidence rates of wrong-site surgery in a neurosurgical population before and after the implementation of the Universal Protocol. The data suggested a strong downward trend in the incidence of wrong-site surgery prior to the intervention with the incidence rate approaching zero. The effect of the intervention in these studies however remains unclear, as data reflect only two small low-quality studies in very specific population groups.