Publications by authors named "Deborah M Caldwell"

52 Publications

Cost-Effectiveness of Different Formats for Delivery of Cognitive Behavioral Therapy for Depression: A Systematic Review Based Economic Model.

Value Health 2020 12 24;23(12):1662-1670. Epub 2020 Sep 24.

Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, England, UK.

Objectives: Cognitive behavioral therapy (CBT) is an effective treatment for depression. Different CBT delivery formats (face-to-face [F2F], multimedia, and hybrid) and intensities have been used to expand access to the treatment. The aim of this study is to estimate the long-term cost-effectiveness of different CBT delivery modes.

Methods: A decision-analytic model was developed to evaluate the cost-effectiveness of different CBT delivery modes and variations in intensity in comparison with treatment as usual (TAU). The model covered an average treatment period of 4 months with a 5-year follow-up period. The model was populated using a systematic review of randomized controlled trials and various sources from the literature.

Results: Incremental cost-effectiveness ratios of treatments compared with the next best option after excluding all the dominated and extended dominated options are: £209/quality-adjusted life year (QALY) for 6 (sessions) × 30 (minutes) F2F-CBT versus TAU; £4 453/QALY for 8 × 30 F2F versus 6 × 30 F2F; £12 216/QALY for 8 × 60 F2F versus 8 × 30 F2F; and £43 072/QALY for 16 × 60 F2F versus 8 × 60 F2F. The treatment with the highest net monetary benefit for thresholds of £20 000 to £30 000/QALY was 8 × 30 F2F-CBT. Probabilistic sensitivity analysis illustrated 6 × 30 F2F-CBT had the highest probability (32.8%) of being cost-effective at £20 000/QALY; 16 × 60 F2F-CBT had the highest probability (31.0%) at £30 000/QALY.

Conclusions: All CBT delivery modes on top of TAU were found to be more cost-effective than TAU alone. Four F2F-CBT options (6 × 30, 8 × 30, 8 × 60, 16 × 60) are on the cost-effectiveness frontier. F2F-CBT with intensities of 6 × 30 and 16 × 60 had the highest probabilities of being cost-effective. The results, however, should be interpreted with caution owing to the high level of uncertainty.
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http://dx.doi.org/10.1016/j.jval.2020.07.008DOI Listing
December 2020

Effects of non-pharmacological interventions as vaccine adjuvants in humans: a systematic review and network meta-analysis.

Health Psychol Rev 2020 Dec 3:1-27. Epub 2020 Dec 3.

School of Social & Community Medicine, University of Bristol, Bristol, UK.

Introduction: Psychological and behavioural may enhance vaccine effectiveness. We conducted a systematic review and network meta-analysis (NMA) to examine the effects of non-pharmacological adjuvants on vaccine effectiveness, as measured by antibody responses to vaccination.

Areas Covered: Electronic databases (EMBASE, Medline, PsychINFO, CINAHL) were searched from inception to 6th February 2018. This yielded 100 eligible papers, reporting 106 trials: 79 interventions associated with diet and/or nutrition; 12 physical activity interventions and 9 psychological interventions.Over half (58/106) of trials reported evidence of an enhanced antibody response to vaccination across one or more outcomes. The NMA considered the comparative effects between all intervention types, control and placebo for antibody titres (48 studies), seroconversion (25 studies) and seroprotection (23 studies) separately. The NMA provided weak evidence in support of nutritional formulae and probiotics in increasing antibody titres.

Expert Opinion: This review offers a comprehensive summary of the literature on non-pharmacological interventions as vaccine adjuvants. The evidence is characterised by considerable heterogeneity but provides early evidence in support of nutritional formulae and probiotic interventions. Psychological and exercise-based interventions were characterised by limited and unreliable evidence. Large, well-designed studies including consistent core outcomes and measures of intervention adherence and fidelity are required.
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http://dx.doi.org/10.1080/17437199.2020.1854050DOI Listing
December 2020

Comparative effectiveness of treatments for patellofemoral pain: a living systematic review with network meta-analysis.

Br J Sports Med 2020 Oct 26. Epub 2020 Oct 26.

Centre for General Practice at Aalborg University, Aalborg, Denmark.

Objective: To investigate the comparative effectiveness of all treatments for patellofemoral pain (PFP).

Design: Living systematic review with network meta-analysis (NMA).

Data Sources: Sensitive search in seven databases, three grey literature resources and four trial registers.

Eligibility Criteria: Randomised controlled trials evaluating any treatment for PFP with outcomes 'any improvement', and pain intensity.

Data Extraction: Two reviewers independently extracted data and assessed risk of bias with Risk of Bias Tool V.2. We used Grading of Recommendations, Assessment, Development and Evaluation to appraise the strength of the evidence.

Primary Outcome Measure: 'Any improvement' measured with a Global Rating of Change Scale.

Results: Twenty-two trials (with forty-eight treatment arms) were included, of which approximately 10 (45%) were at high risk of bias for the primary outcome. Most comparisons had a low to very low strength of the evidence. All treatments were better than wait and see for any improvement at 3 months (education (OR 9.6, 95% credible interval (CrI): 2.2 to 48.8); exercise (OR 13.0, 95% CrI: 2.4 to 83.5); education+orthosis (OR 16.5, 95% CrI: 4.9 to 65.8); education+exercise+patellar taping/mobilisations (OR 25.2, 95% CrI: 5.7 to 130.3) and education+exercise+patellar taping/mobilisations+orthosis (OR 38.8, 95% CrI: 7.3 to 236.9)). Education+exercise+patellar taping/mobilisations, with (OR 4.0, 95% CrI: 1.5 to 11.8) or without orthosis (OR 2.6, 95% CrI: 1.7 to 4.2), were superior to education alone. At 12 months, education or education+any combination yielded similar improvement rates.

Summary/conclusion: Education combined with a physical treatment (exercise, orthoses or patellar taping/mobilisation) is most likely to be effective at 3 months. At 12 months, education appears comparable to education with a physical treatment. There was insufficient evidence to recommend a specific type of physical treatment over another. All treatments in our NMA were superior to wait and see at 3 months, and we recommend avoiding a wait-and-see approach.

Prospero Registeration Number: PROSPERO registration CRD42018079502.
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http://dx.doi.org/10.1136/bjsports-2020-102819DOI Listing
October 2020

Protocol for a systematic review and network meta-analysis of randomised controlled trials examining the effectiveness of early parenting interventions in preventing internalising problems in children and adolescents.

Syst Rev 2020 10 19;9(1):244. Epub 2020 Oct 19.

Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BP, UK.

Background: Internalising problems, such as depression and anxiety, are common and represent an important economical and societal burden. The effectiveness of parenting interventions in reducing the risk of internalising problems in children and adolescents has not yet been summarised. The aims of this review are to assess the effectiveness of parenting interventions in the primary, secondary and tertiary prevention of internalising problems in children and adolescents and to determine which intervention components and which intervention aspects are most effective for reducing the risk of internalising problems in children and adolescents.

Methods: Electronic searches in OVID SP versions of MEDLINE, EMBASE and PsycINFO; Cochrane Central Register of Controlled Trials; EBSCO version of ERIC and ClinicalTrials.gov have been performed to identify randomised controlled trials or quasi-randomised controlled trials of parenting interventions. At least two independent researchers will assess studies for inclusion and extract data from each paper. The risk of bias assessment will be conducted independently by two reviewers using the Cochrane Collaboration's Risk of Bias Assessment Tool. Statistical heterogeneity is anticipated given potential variation in participant characteristics, intervention type and mode of delivery, and outcome measures. Random effects models, assuming a common between-study variability, will be used to account for statistical heterogeneity. Results will be analysed using a network meta-analysis (NMA). If appropriate, we will also conduct a component-level NMA, where the 'active ingredients' of interventions are modelled using a network meta-regression approach.

Discussion: Preventing and reducing internalising problems could have major beneficial effects at the economic and societal level. Informing policy makers on the effectiveness of parenting interventions and on which intervention's component is driving the effect is important for the development of treatment strategies.

Systematic Review Registration: International Prospective Register for Systematic Reviews (PROSPERO) number CRD42020172251.
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http://dx.doi.org/10.1186/s13643-020-01500-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574314PMC
October 2020

Which treatment is most effective for patients with Achilles tendinopathy? A living systematic review with network meta-analysis of 29 randomised controlled trials.

Br J Sports Med 2021 Mar 10;55(5):249-256. Epub 2020 Jun 10.

Department of Orthopaedics and Sports Medicine, Erasmus University Rotterdam, Rotterdam, Zuid-Holland, The Netherlands.

Objective: To provide a consistently updated overview of the comparative effectiveness of treatments for Achilles tendinopathy.

Design: Living systematic review and network meta-analysis.

Data Sources: Multiple databases including grey literature sources were searched up to February 2019.

Study Eligibility Criteria: Randomised controlled trials examining the effectiveness of any treatment in patients with both insertional and/or midportion Achilles tendinopathy. We excluded trials with 10 or fewer participants per treatment arm or trials investigating tendon ruptures.

Data Extraction And Synthesis: Reviewers independently extracted data and assessed the risk of bias. We used the Grading of Recommendations Assessment, Development and Evaluation to appraise the certainty of evidence.

Primary Outcome Measure: The validated patient-reported Victorian Institute of Sport Assessment-Achilles questionnaire.

Results: 29 trials investigating 42 different treatments were included. 22 trials (76%) were at high risk of bias and 7 (24%) had some concerns. Most trials included patients with midportion tendinopathy (86%). Any treatment class seemed superior to wait-and-see for midportion Achilles tendinopathy at 3 months (very low to low certainty of evidence). At 12 months, exercise therapy, exercise+injection therapy and exercise+night splint therapy were all comparable with injection therapy for midportion tendinopathy (very low to low certainty). No network meta-analysis could be performed for insertional Achilles tendinopathy.

Summary/conclusion: In our living network meta-analysis no trials were at low risk of bias and there was large uncertainty in the comparative estimates. For midportion Achilles tendinopathy, wait-and-see is not recommended as all active treatments seemed superior at 3-month follow-up. There seems to be no clinically relevant difference in effectiveness between different active treatments at either 3-month or 12-month follow-up. As exercise therapy is easy to prescribe, can be of low cost and has few harms, clinicians could consider starting treatment with a calf-muscle exercise programme.

Prospero Registration Number: CRD42018086467.
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http://dx.doi.org/10.1136/bjsports-2019-101872DOI Listing
March 2021

Agreement was moderate between data-based and opinion-based assessments of biases affecting randomized trials within meta-analyses.

J Clin Epidemiol 2020 09 13;125:16-25. Epub 2020 May 13.

Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; NIHR Applied Research Collaboration (ARC) West, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.

Background And Objective: Randomized trials included in meta-analyses are often affected by bias caused by methodological flaws or limitations, but the degree of bias is unknown. Two proposed methods adjust the trial results for bias using empirical evidence from published meta-epidemiological studies or expert opinion.

Methods: We investigated agreement between data-based and opinion-based approaches to assessing bias in each of four domains: sequence generation, allocation concealment, blinding, and incomplete outcome data. From each sampled meta-analysis, a pair of trials with the highest and lowest empirical model-based bias estimates was selected. Independent assessors were asked which trial within each pair was judged more biased on the basis of detailed trial design summaries.

Results: Assessors judged trials to be equally biased in 68% of pairs evaluated. When assessors judged one trial as more biased, the proportion of judgments agreeing with the model-based ranking was highest for allocation concealment (79%) and blinding (79%) and lower for sequence generation (59%) and incomplete outcome data (56%).

Conclusion: Most trial pairs found to be discrepant empirically were judged to be equally biased by assessors. We found moderate agreement between opinion and data-based evidence in pairs where assessors ranked one trial as more biased.
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http://dx.doi.org/10.1016/j.jclinepi.2020.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482431PMC
September 2020

School-based interventions to prevent anxiety and depression in children and young people: a systematic review and network meta-analysis.

Lancet Psychiatry 2019 12 14;6(12):1011-1020. Epub 2019 Nov 14.

Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

Background: Rates of anxiety and depression are increasing among children and young people. Recent policies have focused on primary prevention of mental disorders in children and young people, with schools at the forefront of implementation. There is limited information for the comparative effectiveness of the multiple interventions available.

Methods: We did a systematic review and network meta-analysis, searching MEDLINE, Embase, PsycINFO, and Cochrane Central Register of Controlled trials for published and unpublished, passive and active-controlled randomised and quasi-randomised trials. We included educational setting-based, universal, or targeted interventions in which the primary aim was the prevention of anxiety and depression in children and young people aged 4-18 years. Primary outcomes were post-intervention self-report anxiety and depression, wellbeing, suicidal ideation, or self-harm. We assessed risk of bias following the Cochrane Handbook for Systematic Reviews of Interventions. We estimated standardised mean differences (SMD) using random effects network meta-analysis in a Bayesian framework. The study is registered with PROPSERO, number CRD42016048184.

Findings: 1512 full-text articles were independently screened for inclusion by two reviewers, from which 137 studies of 56 620 participants were included. 20 studies were assessed as being at low risk of bias for both random sequence generation and allocation concealment. There was weak evidence to suggest that cognitive behavioural interventions might reduce anxiety in primary and secondary settings. In universal secondary settings, mindfulness and relaxation-based interventions showed a reduction in anxiety symptoms relative to usual curriculum (SMD -0·65, 95% credible interval -1·14 to -0·19). There was a lack of evidence to support any one type of intervention being effective to prevent depression in universal or targeted primary or secondary settings. Comparison-adjusted funnel plots suggest the presence of small-study effects for the universal secondary anxiety analysis. Network meta-analysis was not feasible for wellbeing or suicidal ideation or self-harm outcomes, and results are reported narratively.

Interpretation: Considering unclear risk of bias and probable small study effects for anxiety, we conclude there is little evidence that educational setting-based interventions focused solely on the prevention of depression or anxiety are effective. Future research could consider multilevel, systems-based interventions as an alternative to the downstream interventions considered here.

Funding: UK National Institute for Health Research.
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http://dx.doi.org/10.1016/S2215-0366(19)30403-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029281PMC
December 2019

The effects of interactive training of healthcare providers on the management of life-threatening emergencies in hospital.

Cochrane Database Syst Rev 2019 Sep 24;9:CD012177. Epub 2019 Sep 24.

Population Health Sciences, Bristol Medical School, University of Bristol, Department of Women's and Children's Health, The Chilterns, Bristol, UK, BS10 5NB.

Background: Preparing healthcare providers to manage relatively rare life-threatening emergency situations effectively is a challenge. Training sessions enable staff to rehearse for these events and are recommended by several reports and guidelines. In this review we have focused on interactive training, this includes any element where the training is not solely didactic but provides opportunity for discussions, rehearsals, or interaction with faculty or technology. It is important to understand the effective methods and essential elements for successful emergency training so that resources can be appropriately targeted to improve outcomes.

Objectives: To assess the effects of interactive training of healthcare providers on the management of life-threatening emergencies in hospital on patient outcomes, clinical care practices, or organisational practices, and to identify essential components of effective interactive emergency training programmes.

Search Methods: We searched CENTRAL, MEDLINE, Embase, CINAHL and ERIC and two trials registers up to 11 March 2019. We searched references of included studies, conference proceedings, and contacted study authors.

Selection Criteria: We included randomised trials and cluster-randomised trials comparing interactive training for emergency situations with standard/no training. We defined emergency situations as those in which immediate lifesaving action is required, for example cardiac arrests and major haemorrhage. We included all studies where healthcare workers involved in providing direct clinical care were participants. We excluded studies outside of a hospital setting or where the intervention was not targeted at practicing healthcare workers. We included trials irrespective of publication status, date, and language.

Data Collection And Analysis: We used standard methodological procedures expected by Cochrane and Cochrane Effective Practice and Organisation of Care (EPOC) Group. Two review authors independently extracted data and assessed the risk of bias of each included trial. Due to the small number of studies and the heterogeneity in outcome measures, we were unable to perform the planned meta-analysis. We provide a structured synthesis for the following outcomes: survival to hospital discharge, morbidity rate, protocol or guideline adherence, patient outcomes, clinical practice outcomes, and organisation-of-care outcomes. We used the GRADE approach to rate the certainty of the evidence and the strength of recommendations for each outcome.

Main Results: We included 11 studies that reported on 2000 healthcare providers and over 300,000 patients; one study did not report the number of participants. Seven were cluster randomised trials and four were single centre studies. Four studies focused on obstetric training, three on obstetric and neonatal care, two on neonatal training, one on trauma and one on general resuscitations. The studies were spread across high-, middle- and low-income settings.Interactive training may make little or no difference in survival to hospital discharge for patients requiring resuscitation (1 study; 30 participants; 98 events; low-certainty evidence). We are uncertain if emergency training changes morbidity rate, as the certainty of the evidence is very low (3 studies; 1778 participants; 57,193 patients, when reported). We are uncertain if training alters healthcare providers' adherence to clinical protocols or guidelines, as the certainty of the evidence is very low (3 studies; 156 participants; 558 patients). We are uncertain if there were improvements in patient outcomes following interactive training for emergency situations, as we assessed the evidence as very low-certainty (5 studies, 951 participants; 314,055 patients). We are uncertain if training for emergency situations improves clinical practice outcomes as the certainty of the evidence is very low (4 studies; 1417 participants; 28,676 patients, when reported). Two studies reported organisation-of-care outcomes, we are uncertain if interactive emergency training has any effect on this outcome as the certainty of the evidence is very low (634 participants; 179,400 patient population).We examined prespecified subgroups and found no clear commonalities in effect of multidisciplinary training, location of training, duration of the course, or duration of follow-up. We also examined areas arising from the studies including focus of training, proportion of staff trained, leadership of intervention, and incentive/trigger to participate, and again identified no clear mediating factors. The sources of funding for the studies were governmental, local organisations, or philanthropic donors.

Authors' Conclusions: We are uncertain if there are any benefits of interactive training of healthcare providers on the management of life-threatening emergencies in hospital as the certainty of the evidence is very low. We were unable to identify any factors that may have allowed us to identify an essential element of these interactive training courses.We found a lack of consistent reporting, which contributed to the inability to meta-analyse across specialities. More trials are required to build the evidence base for the optimum way to prepare healthcare providers for rare life-threatening emergency events. These trials need to be conducted with attention to outcomes important to patients, healthcare providers, and policymakers. It is vitally important to develop high-quality studies adequately powered and with attention to minimising the risk of bias.
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http://dx.doi.org/10.1002/14651858.CD012177.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6757513PMC
September 2019

Directly Acting Oral Anticoagulants for the Prevention of Stroke in Atrial Fibrillation in England and Wales: Cost-Effectiveness Model and Value of Information Analysis.

MDM Policy Pract 2019 Jul-Dec;4(2):2381468319866828. Epub 2019 Aug 17.

Bristol Medical School, University of Bristol, Bristol, UK.

Determine the optimal, licensed, first-line anticoagulant for prevention of ischemic stroke in patients with non-valvular atrial fibrillation (AF) in England and Wales from the UK National Health Service (NHS) perspective and estimate value to decision making of further research. We developed a cost-effectiveness model to compare warfarin (international normalized ratio target range 2-3) with directly acting (or non-vitamin K antagonist) oral anticoagulants (DOACs) apixaban 5 mg, dabigatran 150 mg, edoxaban 60 mg, and rivaroxaban 20 mg, over 30 years post treatment initiation. In addition to death, the 17-state Markov model included the events stroke, bleed, myocardial infarction, and intracranial hemorrhage. Input parameters were informed by systematic literature reviews and network meta-analysis. Expected value of perfect information (EVPI) and expected value of partial perfect information (EVPPI) were estimated to provide an upper bound on value of further research. At willingness-to-pay threshold £20,000, all DOACs have positive expected incremental net benefit compared to warfarin, suggesting they are likely cost-effective. Apixaban has highest expected incremental net benefit (£7533), followed by dabigatran (£6365), rivaroxaban (£5279), and edoxaban (£5212). There was considerable uncertainty as to the optimal DOAC, with the probability apixaban has highest net benefit only 60%. Total estimated population EVPI was £17.94 million (17.85 million, 18.03 million), with relative effect between apixaban versus dabigatran making the largest contribution with EVPPI of £7.95 million (7.66 million, 8.24 million). At willingness-to-pay threshold £20,000, all DOACs have higher expected net benefit than warfarin but there is considerable uncertainty between the DOACs. Apixaban had the highest expected net benefit and greatest probability of having highest net benefit, but there is considerable uncertainty between DOACs. A head-to-head apixaban versus dabigatran trial may be of value.
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http://dx.doi.org/10.1177/2381468319866828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699015PMC
August 2019

The process and delivery of CBT for depression in adults: a systematic review and network meta-analysis.

Psychol Med 2019 09 10;49(12):1937-1947. Epub 2019 Jun 10.

Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

Cognitive-behavioural therapy (CBT) is an effective treatment for depressed adults. CBT interventions are complex, as they include multiple content components and can be delivered in different ways. We compared the effectiveness of different types of therapy, different components and combinations of components and aspects of delivery used in CBT interventions for adult depression. We conducted a systematic review of randomised controlled trials in adults with a primary diagnosis of depression, which included a CBT intervention. Outcomes were pooled using a component-level network meta-analysis. Our primary analysis classified interventions according to the type of therapy and delivery mode. We also fitted more advanced models to examine the effectiveness of each content component or combination of components. We included 91 studies and found strong evidence that CBT interventions yielded a larger short-term decrease in depression scores compared to treatment-as-usual, with a standardised difference in mean change of -1.11 (95% credible interval -1.62 to -0.60) for face-to-face CBT, -1.06 (-2.05 to -0.08) for hybrid CBT, and -0.59 (-1.20 to 0.02) for multimedia CBT, whereas wait list control showed a detrimental effect of 0.72 (0.09 to 1.35). We found no evidence of specific effects of any content components or combinations of components. Technology is increasingly used in the context of CBT interventions for depression. Multimedia and hybrid CBT might be as effective as face-to-face CBT, although results need to be interpreted cautiously. The effectiveness of specific combinations of content components and delivery formats remain unclear. Wait list controls should be avoided if possible.
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http://dx.doi.org/10.1017/S003329171900120XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712954PMC
September 2019

Psychological interventions as vaccine adjuvants: A systematic review.

Vaccine 2019 05 6;37(25):3255-3266. Epub 2019 May 6.

University of Nottingham Health Service, Cripps Health Centre, University of Nottingham, NG7 2QW, UK.

Objectives: The effectiveness of vaccines is known to be altered by a range of psychological factors. We conducted a systematic review to evaluate the effects of psychological interventions on the ability of vaccines to protect against disease, as measured by antibody responses.

Methods: Electronic databases (EMBASE, Medline, PsychINFO, CINAHL) were searched from their inception to 6th February 2018.

Results: The search yielded 9 eligible trials conducted with 1603 participants and four broad categories of intervention: meditation/mindfulness (n = 3), massage (n = 3), expressive writing (n = 2) and cognitive behavioural stress management (n = 1). Some evidence of benefit on the antibody response to vaccination was observed in 6/9 of all trials and in 4/7 of randomised controlled trials. However, effects on antibody levels were often mixed, with only 3 of 6 trials showing benefit demonstrating an improvement in all antibody outcomes and at all time points assessed. Trials demonstrating benefit also provided direct or indirect evidence of adequate adherence with the intervention; and in 50% of these trials, there was also evidence that the intervention was effective in changing the mediating psychological constructs targeted by the intervention.

Conclusions: This literature is characterised by considerable heterogeneity in terms of intervention type, vaccine type, age of participants and the temporal relationship between vaccination and intervention. We conclude that there is early evidence to suggest that psychological interventions may enhance the antibody response to vaccination. However, the effects are inconsistent, with the greatest likelihood of benefit seen in trials evidencing adequate adherence with the intervention. Future work would benefit from rigorous intervention development that focuses on achieving adequate adherence and large well-controlled randomised trials with a focus on an agreed set of outcomes.
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http://dx.doi.org/10.1016/j.vaccine.2019.04.091DOI Listing
May 2019

Threshold Analysis as an Alternative to GRADE for Assessing Confidence in Guideline Recommendations Based on Network Meta-analyses.

Ann Intern Med 2019 04 26;170(8):538-546. Epub 2019 Mar 26.

University of Bristol, Bristol, United Kingdom (D.M.P., N.J.W., D.M.C., A.A.).

Guideline development requires the synthesis of evidence on several treatments of interest, typically by using network meta-analysis (NMA). Because treatment effects may be estimated imprecisely or be based on evidence lacking internal or external validity, guideline developers must assess the robustness of recommendations made on the basis of the NMA to potential limitations in the evidence. Such limitations arise because the observed estimates differ from the true effects of interest, for example, because of study biases, sampling variation, or issues of relevance. The widely used GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework aims to assess the quality of evidence supporting a recommendation by using a structured series of qualitative judgments. This article argues that GRADE approaches proposed for NMA are insufficient for the purposes of guideline development, because the influence of the evidence on the final recommendation is not taken into account. It outlines threshold analysis as an alternative approach, demonstrating the method with 2 examples of clinical guidelines from the National Institute for Health and Care Excellence (NICE) in the United Kingdom. Threshold analysis quantifies precisely how much the evidence could change (for any reason, such as potential biases, or simply sampling variation) before the recommendation changes, and what the revised recommendation would be. If it is judged that the evidence could not plausibly change by more than this amount, then the recommendation is considered robust; otherwise, it is sensitive to plausible changes in the evidence. In this manner, threshold analysis directly informs decision makers and guideline developers of the robustness of treatment recommendations.
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http://dx.doi.org/10.7326/M18-3542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739230PMC
April 2019

Synthesising quantitative evidence in systematic reviews of complex health interventions.

BMJ Glob Health 2019 25;4(Suppl 1):e000858. Epub 2019 Jan 25.

Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

Public health and health service interventions are typically complex: they are multifaceted, with impacts at multiple levels and on multiple stakeholders. Systematic reviews evaluating the effects of complex health interventions can be challenging to conduct. This paper is part of a special series of papers considering these challenges particularly in the context of WHO guideline development. We outline established and innovative methods for synthesising quantitative evidence within a systematic review of a complex intervention, including considerations of the complexity of the system into which the intervention is introduced. We describe methods in three broad areas: non-quantitative approaches, including tabulation, narrative and graphical approaches; standard meta-analysis methods, including meta-regression to investigate study-level moderators of effect; and advanced synthesis methods, in which models allow exploration of intervention components, investigation of both moderators and mediators, examination of mechanisms, and exploration of complexities of the system. We offer guidance on the choice of approach that might be taken by people collating evidence in support of guideline development, and emphasise that the appropriate methods will depend on the purpose of the synthesis, the similarity of the studies included in the review, the level of detail available from the studies, the nature of the results reported in the studies, the expertise of the synthesis team and the resources available.
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http://dx.doi.org/10.1136/bmjgh-2018-000858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350707PMC
January 2019

Which treatment is most effective for patients with patellofemoral pain? A protocol for a living systematic review including network meta-analysis.

BMJ Open 2018 11 18;8(11):e022920. Epub 2018 Nov 18.

Research Unit for General Practice in Aalborg, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.

Introduction: Patellofemoral pain (PFP) affects 1 in every 14 adults. Many treatments for PFP have been evaluated, but the comparative effectiveness of all available treatments has never been examined. Network meta-analysis is the only design to study the comparative effectiveness of all available treatments in one synthesis. This protocol describes the methods for a systematic review including network meta-analysis to assess which treatment is most likely to be effective for patients with PFP.

Methods And Analysis: The primary outcome measures of this network meta-analysis are the global rating of change scale at 6-12 weeks, 13-52 weeks and >52 weeks. The secondary outcome measures are patient-rated pain scales at 6-12 weeks, 13-52 weeks and >52 weeks. Completed published and unpublished randomised controlled trials with full-text reports are eligible for inclusion. We will search Embase, PubMed (including MEDLINE), CENTRAL, Scopus, Web of Science, and CINAHL, SPORTDiscus, OpenGrey, WorldCat, conference Proceedings and multiple trial registers for relevant reports. Two researchers will appraise the study eligibility and perform data extraction. Risk of bias will be assessed with the Cochrane Risk of Bias Tool V.2.0.Bayesian network meta-analyses will be constructed for global rating of change scale and patient-rated pain. Consistency between direct and indirect comparisons will be assessed. Between study variability will be explored, and a threshold analysis for the credibility of the network meta-analyses' conclusions will be performed.

Ethics And Dissemination: Ethical approval is not required, as this study will be based on published data. The study commenced at 1 February 2018, and its expected completion date is 15 January 2019. Full publication of the work will be sought in an international peer-reviewed journal, as well as translational articles to disseminate the work to clinical practitioners.

Prospero Registration Number: CRD42018079502.
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http://dx.doi.org/10.1136/bmjopen-2018-022920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6252644PMC
November 2018

Network meta-analysis explained.

Arch Dis Child Fetal Neonatal Ed 2019 Jan 13;104(1):F8-F12. Epub 2018 Nov 13.

Bristol Medical School, University of Bristol, Bristol, UK.

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http://dx.doi.org/10.1136/archdischild-2018-315224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761999PMC
January 2019

ROBIS: guida all'uso.

Recenti Prog Med 2018 Sep;109(9):1e-26e

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http://dx.doi.org/10.1701/2990.29932DOI Listing
September 2018

[ROBIS: a new tool to assess risk of bias in systematic reviews was developed.]

Recenti Prog Med 2018 Sep;109(9):421-431

School of Social and Community Medicine, University of Bristol, UK.

Objective: To develop ROBIS, a new tool for assessing the risk of bias in systematic reviews (rather than in primary studies).

Study Design And Setting: We used four-stage approach to develop ROBIS: define the scope, review the evidence base, hold a face-to-face meeting, and refine the tool through piloting.

Results: ROBIS is currently aimed at four broad categories of reviews mainly within health care settings: interventions, diagnosis, prognosis, and etiology. The target audience of ROBIS is primarily guideline developers, authors of overviews of systematic reviews ("reviews of reviews"), and review authors who might want to assess or avoid risk of bias in their reviews. The tool is completed in three phases: 1) assess relevance (optional), 2) identify concerns with the review process, and 3) judge risk of bias. Phase 2 covers four domains through which bias may be introduced into a systematic review: 1) study eligibility criteria; 2) identification and selection of studies; 3) data collection and study appraisal; and 4) synthesis and findings. Phase 3 assesses the overall risk of bias in the interpretation of review findings and whether this considered limitations identified in any of the phase 2 domains. Signaling questions are included to help judge concerns with the review process (phase 2) and the overall risk of bias in the review (phase 3); these questions flag aspects of review design related to the potential for bias and aim to help assessors judge risk of bias in the review process, results, and conclusions.

Conclusions: ROBIS is the first rigorously developed tool designed specifically to assess the risk of bias in systematic reviews.
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http://dx.doi.org/10.1701/2990.29928DOI Listing
September 2018

Individual-, family-, and school-level interventions targeting multiple risk behaviours in young people.

Cochrane Database Syst Rev 2018 10 5;10:CD009927. Epub 2018 Oct 5.

Population Health Sciences, Bristol Medical School, University of Bristol, 39 Whatley Road, Bristol, UK, BS8 2PS.

Background: Engagement in multiple risk behaviours can have adverse consequences for health during childhood, during adolescence, and later in life, yet little is known about the impact of different types of interventions that target multiple risk behaviours in children and young people, or the differential impact of universal versus targeted approaches. Findings from systematic reviews have been mixed, and effects of these interventions have not been quantitatively estimated.

Objectives: To examine the effects of interventions implemented up to 18 years of age for the primary or secondary prevention of multiple risk behaviours among young people.

Search Methods: We searched 11 databases (Australian Education Index; British Education Index; Campbell Library; Cumulative Index to Nursing and Allied Health Literature (CINAHL); Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library; Embase; Education Resource Information Center (ERIC); International Bibliography of the Social Sciences; MEDLINE; PsycINFO; and Sociological Abstracts) on three occasions (2012, 2015, and 14 November 2016)). We conducted handsearches of reference lists, contacted experts in the field, conducted citation searches, and searched websites of relevant organisations.

Selection Criteria: We included randomised controlled trials (RCTs), including cluster RCTs, which aimed to address at least two risk behaviours. Participants were children and young people up to 18 years of age and/or parents, guardians, or carers, as long as the intervention aimed to address involvement in multiple risk behaviours among children and young people up to 18 years of age. However, studies could include outcome data on children > 18 years of age at the time of follow-up. Specifically,we included studies with outcomes collected from those eight to 25 years of age. Further, we included only studies with a combined intervention and follow-up period of six months or longer. We excluded interventions aimed at individuals with clinically diagnosed disorders along with clinical interventions. We categorised interventions according to whether they were conducted at the individual level; the family level; or the school level.

Data Collection And Analysis: We identified a total of 34,680 titles, screened 27,691 articles and assessed 424 full-text articles for eligibility. Two or more review authors independently assessed studies for inclusion in the review, extracted data, and assessed risk of bias.We pooled data in meta-analyses using a random-effects (DerSimonian and Laird) model in RevMan 5.3. For each outcome, we included subgroups related to study type (individual, family, or school level, and universal or targeted approach) and examined effectiveness at up to 12 months' follow-up and over the longer term (> 12 months). We assessed the quality and certainty of evidence using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach.

Main Results: We included in the review a total of 70 eligible studies, of which a substantial proportion were universal school-based studies (n = 28; 40%). Most studies were conducted in the USA (n = 55; 79%). On average, studies aimed to prevent four of the primary behaviours. Behaviours that were most frequently addressed included alcohol use (n = 55), drug use (n = 53), and/or antisocial behaviour (n = 53), followed by tobacco use (n = 42). No studies aimed to prevent self-harm or gambling alongside other behaviours.Evidence suggests that for multiple risk behaviours, universal school-based interventions were beneficial in relation to tobacco use (odds ratio (OR) 0.77, 95% confidence interval (CI) 0.60 to 0.97; n = 9 studies; 15,354 participants) and alcohol use (OR 0.72, 95% CI 0.56 to 0.92; n = 8 studies; 8751 participants; both moderate-quality evidence) compared to a comparator, and that such interventions may be effective in preventing illicit drug use (OR 0.74, 95% CI 0.55 to 1.00; n = 5 studies; 11,058 participants; low-quality evidence) and engagement in any antisocial behaviour (OR 0.81, 95% CI 0.66 to 0.98; n = 13 studies; 20,756 participants; very low-quality evidence) at up to 12 months' follow-up, although there was evidence of moderate to substantial heterogeneity (I² = 49% to 69%). Moderate-quality evidence also showed that multiple risk behaviour universal school-based interventions improved the odds of physical activity (OR 1.32, 95% CI 1.16 to 1.50; I² = 0%; n = 4 studies; 6441 participants). We considered observed effects to be of public health importance when applied at the population level. Evidence was less certain for the effects of such multiple risk behaviour interventions for cannabis use (OR 0.79, 95% CI 0.62 to 1.01; P = 0.06; n = 5 studies; 4140 participants; I² = 0%; moderate-quality evidence), sexual risk behaviours (OR 0.83, 95% CI 0.61 to 1.12; P = 0.22; n = 6 studies; 12,633 participants; I² = 77%; low-quality evidence), and unhealthy diet (OR 0.82, 95% CI 0.64 to 1.06; P = 0.13; n = 3 studies; 6441 participants; I² = 49%; moderate-quality evidence). It is important to note that some evidence supported the positive effects of universal school-level interventions on three or more risk behaviours.For most outcomes of individual- and family-level targeted and universal interventions, moderate- or low-quality evidence suggests little or no effect, although caution is warranted in interpretation because few of these studies were available for comparison (n ≤ 4 studies for each outcome).Seven studies reported adverse effects, which involved evidence suggestive of increased involvement in a risk behaviour among participants receiving the intervention compared to participants given control interventions.We judged the quality of evidence to be moderate or low for most outcomes, primarily owing to concerns around selection, performance, and detection bias and heterogeneity between studies.

Authors' Conclusions: Available evidence is strongest for universal school-based interventions that target multiple- risk behaviours, demonstrating that they may be effective in preventing engagement in tobacco use, alcohol use, illicit drug use, and antisocial behaviour, and in improving physical activity among young people, but not in preventing other risk behaviours. Results of this review do not provide strong evidence of benefit for family- or individual-level interventions across the risk behaviours studied. However, poor reporting and concerns around the quality of evidence highlight the need for high-quality multiple- risk behaviour intervention studies to further strengthen the evidence base in this field.
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http://dx.doi.org/10.1002/14651858.CD009927.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517301PMC
October 2018

Educational interventions for improving primary caregiver complementary feeding practices for children aged 24 months and under.

Cochrane Database Syst Rev 2018 05 18;5:CD011768. Epub 2018 May 18.

Cochrane Nigeria, Institute of Tropical Diseases Research and Prevention, University of Calabar Teaching Hospital, Calabar, Cross River State, Nigeria, 540261.

Background: Although complementary feeding is a universal practice, the methods and manner in which it is practiced vary between cultures, individuals and socioeconomic classes. The period of complementary feeding is a critical time of transition in the life of an infant, and inappropriate complementary feeding practices, with their associated adverse health consequences, remain a significant global public health problem. Educational interventions are widely acknowledged as effective in promoting public health strategy, and those aimed at improving complementary feeding practices provide information about proper complementary feeding practices to caregivers of infants/children. It is therefore important to summarise evidence on the effectiveness of educational interventions to improve the complementary feeding practices of caregivers of infants.

Objectives: To assess the effectiveness of educational interventions for improving the complementary feeding (weaning) practices of primary caregivers of children of complementary feeding age, and related health and growth outcomes in infants.

Search Methods: In November 2017, we searched CENTRAL, MEDLINE, Embase, 10 other databases and two trials registers. We also searched the reference lists of relevant studies and reviews to identify any additional studies. We did not limit the searches by date, language or publication status.

Selection Criteria: Randomised controlled trials (RCTs), comparing educational interventions to no intervention, usual practice, or educational interventions provided in conjunction with another intervention, so long as the educational intervention was only available in the experimental group and the adjunctive intervention was available to the control group. Study participants included caregivers of infants aged 4 to 24 months undergoing complementary feeding. Pregnant women who were expected to give birth and commence complementary feeding during the period of the study were also included.

Data Collection And Analysis: Two review authors independently extracted data on participants, settings, interventions, methodology and outcomes using a specifically-developed and piloted data extraction form. We calculated risk ratios (RR) and 95% confidence intervals (CIs) for dichotomous data, and mean differences (MD) and 95% CIs for continuous data. Where data permitted, we conducted a meta-analysis using a random-effects model. We assessed the included studies for risk of bias and also assessed the quality of evidence using the GRADE approach.

Main Results: We included 23 studies (from 35 reports) with a total of 11,170 caregiver-infant pairs who were randomly assigned to receive an educational intervention delivered to the caregiver or usual care. Nineteen of the included studies were community-based studies while four were facility-based studies. In addition, 13 of the included studies were cluster-randomised while the others were individually randomised. Generally, the interventions were focused on the introduction of complementary feeding at the appropriate time, the types and amount of complementary foods to be fed to infants, and hygiene. Using the GRADE criteria, we assessed the quality of the evidence as moderate, mostly due to inadequate allocation concealment and insufficient blinding.Educational interventions led to improvements in complementary feeding practices for age at introduction of complementary foods (average RR 0.88, 95% CI 0.83 to 0.94; 4 studies, 1738 children; moderate-quality evidence) and hygiene practices (average RR 1.38, 95% CI 1.23 to 1.55; 4 studies, 2029 participants; moderate-quality evidence). For duration of exclusive breastfeeding, pooled results were compatible with both a reduction and an increase in the outcome (average RR 1.58, 95% CI 0.77 to 3.22; 3 studies, 1544 children; very low-quality evidence). There was limited (low to very low-quality) evidence of an effect for all growth outcomes.Quality of evidenceThere is moderate to very low-quality evidence that educational interventions can improve complementary feeding practices but insufficient evidence to conclude that it impacts growth outcomes.

Authors' Conclusions: Overall, we found evidence that education improves complementary feeding practices.
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http://dx.doi.org/10.1002/14651858.CD011768.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494551PMC
May 2018

Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis.

BMJ 2017 Nov 28;359:j5058. Epub 2017 Nov 28.

Faculty of Population Health Sciences, University College London, London, UK.

 To compare the efficacy, safety, and cost effectiveness of direct acting oral anticoagulants (DOACs) for patients with atrial fibrillation. Systematic review, network meta-analysis, and cost effectiveness analysis.  Medline, PreMedline, Embase, and The Cochrane Library. Published randomised trials evaluating the use of a DOAC, vitamin K antagonist, or antiplatelet drug for prevention of stroke in patients with atrial fibrillation. 23 randomised trials involving 94 656 patients were analysed: 13 compared a DOAC with warfarin dosed to achieve a target INR of 2.0-3.0. Apixaban 5 mg twice daily (odds ratio 0.79, 95% confidence interval 0.66 to 0.94), dabigatran 150 mg twice daily (0.65, 0.52 to 0.81), edoxaban 60 mg once daily (0.86, 0.74 to 1.01), and rivaroxaban 20 mg once daily (0.88, 0.74 to 1.03) reduced the risk of stroke or systemic embolism compared with warfarin. The risk of stroke or systemic embolism was higher with edoxaban 60 mg once daily (1.33, 1.02 to 1.75) and rivaroxaban 20 mg once daily (1.35, 1.03 to 1.78) than with dabigatran 150 mg twice daily. The risk of all-cause mortality was lower with all DOACs than with warfarin. Apixaban 5 mg twice daily (0.71, 0.61 to 0.81), dabigatran 110 mg twice daily (0.80, 0.69 to 0.93), edoxaban 30 mg once daily (0.46, 0.40 to 0.54), and edoxaban 60 mg once daily (0.78, 0.69 to 0.90) reduced the risk of major bleeding compared with warfarin. The risk of major bleeding was higher with dabigatran 150 mg twice daily than apixaban 5 mg twice daily (1.33, 1.09 to 1.62), rivaroxaban 20 mg twice daily than apixaban 5 mg twice daily (1.45, 1.19 to 1.78), and rivaroxaban 20 mg twice daily than edoxaban 60 mg once daily (1.31, 1.07 to 1.59). The risk of intracranial bleeding was substantially lower for most DOACs compared with warfarin, whereas the risk of gastrointestinal bleeding was higher with some DOACs than warfarin. Apixaban 5 mg twice daily was ranked the highest for most outcomes, and was cost effective compared with warfarin. The network meta-analysis informs the choice of DOACs for prevention of stroke in patients with atrial fibrillation. Several DOACs are of net benefit compared with warfarin. A trial directly comparing DOACs would overcome the need for indirect comparisons to be made through network meta-analysis. PROSPERO CRD 42013005324.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704695PMC
http://dx.doi.org/10.1136/bmj.j5058DOI Listing
November 2017

Oral anticoagulants for primary prevention, treatment and secondary prevention of venous thromboembolic disease, and for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis and cost-effectiveness analysis.

Health Technol Assess 2017 03;21(9):1-386

University College London, London, UK.

Background: Warfarin is effective for stroke prevention in atrial fibrillation (AF), but anticoagulation is underused in clinical care. The risk of venous thromboembolic disease during hospitalisation can be reduced by low-molecular-weight heparin (LMWH): warfarin is the most frequently prescribed anticoagulant for treatment and secondary prevention of venous thromboembolism (VTE). Warfarin-related bleeding is a major reason for hospitalisation for adverse drug effects. Warfarin is cheap but therapeutic monitoring increases treatment costs. Novel oral anticoagulants (NOACs) have more rapid onset and offset of action than warfarin, and more predictable dosing requirements.

Objective: To determine the best oral anticoagulant/s for prevention of stroke in AF and for primary prevention, treatment and secondary prevention of VTE.

Design: Four systematic reviews, network meta-analyses (NMAs) and cost-effectiveness analyses (CEAs) of randomised controlled trials.

Setting: Hospital (VTE primary prevention and acute treatment) and primary care/anticoagulation clinics (AF and VTE secondary prevention).

Participants: Patients eligible for anticoagulation with warfarin (stroke prevention in AF, acute treatment or secondary prevention of VTE) or LMWH (primary prevention of VTE).

Interventions: NOACs, warfarin and LMWH, together with other interventions (antiplatelet therapy, placebo) evaluated in the evidence network.

Main Outcome Measures:  Stroke, symptomatic VTE, symptomatic deep-vein thrombosis and symptomatic pulmonary embolism.  Major bleeding, clinically relevant bleeding and intracranial haemorrhage. We also considered myocardial infarction and all-cause mortality and evaluated cost-effectiveness.

Data Sources: MEDLINE and PREMEDLINE In-Process & Other Non-Indexed Citations, EMBASE and The Cochrane Library, reference lists of published NMAs and trial registries. We searched MEDLINE and PREMEDLINE In-Process & Other Non-Indexed Citations, EMBASE and The Cochrane Library. The stroke prevention in AF review search was run on the 12 March 2014 and updated on 15 September 2014, and covered the period 2010 to September 2014. The search for the three reviews in VTE was run on the 19 March 2014, updated on 15 September 2014, and covered the period 2008 to September 2014.

Review Methods: Two reviewers screened search results, extracted and checked data, and assessed risk of bias. For each outcome we conducted standard meta-analysis and NMA. We evaluated cost-effectiveness using discrete-time Markov models.

Results: Apixaban (Eliquis, Bristol-Myers Squibb, USA; Pfizer, USA) [5 mg bd (twice daily)] was ranked as among the best interventions for stroke prevention in AF, and had the highest expected net benefit. Edoxaban (Lixiana, Daiichi Sankyo, Japan) [60 mg od (once daily)] was ranked second for major bleeding and all-cause mortality. Neither the clinical effectiveness analysis nor the CEA provided strong evidence that NOACs should replace postoperative LMWH in primary prevention of VTE. For acute treatment and secondary prevention of VTE, we found little evidence that NOACs offer an efficacy advantage over warfarin, but the risk of bleeding complications was lower for some NOACs than for warfarin. For a willingness-to-pay threshold of > £5000, apixaban (5 mg bd) had the highest expected net benefit for acute treatment of VTE. Aspirin or no pharmacotherapy were likely to be the most cost-effective interventions for secondary prevention of VTE: our results suggest that it is not cost-effective to prescribe NOACs or warfarin for this indication.

Conclusions: NOACs have advantages over warfarin in patients with AF, but we found no strong evidence that they should replace warfarin or LMWH in primary prevention, treatment or secondary prevention of VTE.

Limitations: These relate mainly to shortfalls in the primary data: in particular, there were no head-to-head comparisons between different NOAC drugs.

Future Work: Calculating the expected value of sample information to clarify whether or not it would be justifiable to fund one or more head-to-head trials.

Study Registration: This study is registered as PROSPERO CRD42013005324, CRD42013005331 and CRD42013005330.

Funding: The National Institute for Health Research Health Technology Assessment programme.
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http://dx.doi.org/10.3310/hta21090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5366855PMC
March 2017

Additional considerations are required when preparing a protocol for a systematic review with multiple interventions.

J Clin Epidemiol 2017 Mar 11;83:65-74. Epub 2017 Jan 11.

Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, University Campus, Ioannina 45110, Greece; Institute of Social and Preventive Medicine (ISPM), University of Bern, Finkenhubelweg 11, Bern 3012, Switzerland; Institute of Primary Health Care (BIHAM), University of Bern, Gesellschaftsstrasse 49, Bern CH-3012, Switzerland.

Objectives: The number of systematic reviews that aim to compare multiple interventions using network meta-analysis is increasing. In this study, we highlight aspects of a standard systematic review protocol that may need modification when multiple interventions are to be compared.

Study Design And Setting: We take the protocol format suggested by Cochrane for a standard systematic review as our reference and compare the considerations for a pairwise review with those required for a valid comparison of multiple interventions. We suggest new sections for protocols of systematic reviews including network meta-analyses with a focus on how to evaluate their assumptions. We provide example text from published protocols to exemplify the considerations.

Conclusion: Standard systematic review protocols for pairwise meta-analyses need extensions to accommodate the increased complexity of network meta-analysis. Our suggested modifications are widely applicable to both Cochrane and non-Cochrane systematic reviews involving network meta-analyses.
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http://dx.doi.org/10.1016/j.jclinepi.2016.11.015DOI Listing
March 2017

Network meta-analyses and treatment recommendations for obsessive-compulsive disorder - Authors' reply.

Lancet Psychiatry 2016 Oct;3(10):921-922

Division of Psychiatry, University College London, London, UK.

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http://dx.doi.org/10.1016/S2215-0366(16)30282-6DOI Listing
October 2016

Which method is best for the induction of labour? A systematic review, network meta-analysis and cost-effectiveness analysis.

Health Technol Assess 2016 08;20(65):1-584

School of Social and Community Medicine, University of Bristol, Bristol, UK.

Background: More than 150,000 pregnant women in England and Wales have their labour induced each year. Multiple pharmacological, mechanical and complementary methods are available to induce labour.

Objective: To assess the relative effectiveness, safety and cost-effectiveness of labour induction methods and, data permitting, effects in different clinical subgroups.

Methods: We carried out a systematic review using Cochrane methods. The Cochrane Pregnancy and Childbirth Group's Trials Register was searched (March 2014). This contains over 22,000 reports of controlled trials (published from 1923 onwards) retrieved from weekly searches of OVID MEDLINE (1966 to current); Cochrane Central Register of Controlled Trials (The Cochrane Library); EMBASE (1982 to current); Cumulative Index to Nursing and Allied Health Literature (1984 to current); ClinicalTrials.gov; the World Health Organization International Clinical Trials Registry Portal; and hand-searching of relevant conference proceedings and journals. We included randomised controlled trials examining interventions to induce labour compared with placebo, no treatment or other interventions in women eligible for third-trimester induction. We included outcomes relating to efficacy, safety and acceptability to women. In addition, for the economic analysis we searched the Database of Abstracts of Reviews of Effects, and Economic Evaluations Databases, NHS Economic Evaluation Database and the Health Technology Assessment database. We carried out a network meta-analysis (NMA) using all of the available evidence, both direct and indirect, to produce estimates of the relative effects of each treatment compared with others in a network. We developed a de novo decision tree model to estimate the cost-effectiveness of various methods. The costs included were the intervention and other hospital costs incurred (price year 2012-13). We reviewed the literature to identify preference-based utilities for the health-related outcomes in the model. We calculated incremental cost-effectiveness ratios, expected costs, utilities and net benefit. We represent uncertainty in the optimal intervention using cost-effectiveness acceptability curves.

Results: We identified 1190 studies; 611 were eligible for inclusion. The interventions most likely to achieve vaginal delivery (VD) within 24 hours were intravenous oxytocin with amniotomy [posterior rank 2; 95% credible intervals (CrIs) 1 to 9] and higher-dose (≥ 50 µg) vaginal misoprostol (rank 3; 95% CrI 1 to 6). Compared with placebo, several treatments reduced the odds of caesarean section, but we observed considerable uncertainty in treatment rankings. For uterine hyperstimulation, double-balloon catheter had the highest probability of being among the best three treatments, whereas vaginal misoprostol (≥ 50 µg) was most likely to increase the odds of excessive uterine activity. For other safety outcomes there were insufficient data or there was too much uncertainty to identify which treatments performed 'best'. Few studies collected information on women's views. Owing to incomplete reporting of the VD within 24 hours outcome, the cost-effectiveness analysis could compare only 20 interventions. The analysis suggested that most interventions have similar utility and differ mainly in cost. With a caveat of considerable uncertainty, titrated (low-dose) misoprostol solution and buccal/sublingual misoprostol had the highest likelihood of being cost-effective.

Limitations: There was considerable uncertainty in findings and there were insufficient data for some planned subgroup analyses.

Conclusions: Overall, misoprostol and oxytocin with amniotomy (for women with favourable cervix) is more successful than other agents in achieving VD within 24 hours. The ranking according to safety of different methods was less clear. The cost-effectiveness analysis suggested that titrated (low-dose) oral misoprostol solution resulted in the highest utility, whereas buccal/sublingual misoprostol had the lowest cost. There was a high degree of uncertainty as to the most cost-effective intervention.

Future Work: Future trials should be powered to detect a method that is more cost-effective than misoprostol solution and report outcomes included in this NMA.

Study Registration: This study is registered as PROSPERO CRD42013005116.

Funding: The National Institute for Health Research Health Technology Assessment programme.
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http://dx.doi.org/10.3310/hta20650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5027380PMC
August 2016

A threshold analysis assessed the credibility of conclusions from network meta-analysis.

J Clin Epidemiol 2016 12 16;80:68-76. Epub 2016 Jul 16.

School of Social and Community Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol BS8 2PS, UK.

Objective: To assess the reliability of treatment recommendations based on network meta-analysis (NMA).

Study Design And Setting: We consider evidence in an NMA to be potentially biased. Taking each pairwise contrast in turn, we use a structured series of threshold analyses to ask: (1) "How large would the bias in this evidence base have to be before it changed our decision?" and (2) "If the decision changed, what is the new recommendation?" We illustrate the method via two NMAs in which a Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment for NMAs has been implemented: weight loss and osteoporosis.

Results: Four of the weight-loss NMA estimates were assessed as "low" and six as "moderate" quality by GRADE; for osteoporosis, six were "low," nine were "moderate," and 1 was "high." The threshold analysis suggests plausible bias in 3 of 10 estimates in the weight-loss network could have changed the treatment recommendation. For osteoporosis, plausible bias in 6 of 16 estimates could change the recommendation. There was no relation between plausible bias changing a treatment recommendation and the original GRADE assessments.

Conclusions: Reliability judgments on individual NMA contrasts do not help decision makers understand whether a treatment recommendation is reliable. Threshold analysis reveals whether the final recommendation is robust against plausible degrees of bias in the data.
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http://dx.doi.org/10.1016/j.jclinepi.2016.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5176010PMC
December 2016

Pharmacological and psychotherapeutic interventions for management of obsessive-compulsive disorder in adults: a systematic review and network meta-analysis.

Lancet Psychiatry 2016 Aug 16;3(8):730-739. Epub 2016 Jun 16.

Division of Psychiatry, University College London, London, UK.

Background: Several interventions are available for management of obsessive-compulsive disorder in adults, but few studies have compared their relative efficacy in a single analysis. We aimed to simultaneously compare all available treatments using both direct and indirect data.

Methods: In this systematic review and network meta-analysis, we searched the two controlled trials registers maintained by the Cochrane Collaboration Common Mental Disorders group for trials published up to Feb 16, 2016. We selected randomised controlled trials in which an active psychotherapeutic or pharmacological intervention had been used in adults with obsessive-compulsive disorder. We allowed all comorbidities except for schizophrenia or bipolar disorder. We excluded studies that focused exclusively on treatment-resistant patient populations defined within the same study. We extracted data from published reports. The primary outcome was symptom severity as measured by the Yale-Brown Obsessive Compulsive Scale. We report mean differences with 95% credible intervals compared with placebo. This study is registered with PROSPERO, number CRD42012002441.

Findings: We identified 1480 articles in our search and included 53 articles (54 trials; 6652 participants) in the network meta-analysis. Behavioural therapy (mean difference -14·48 [95% credible interval -18·61 to -10·23]; 11 trials and 287 patients), cognitive therapy (-13·36 [-18·40 to -8·21]; six trials and 172 patients), behavioural therapy and clomipramine (-12·97 [-19·18 to -6·74]; one trial and 31 patients), cognitive behavioural therapy and fluvoxamine (-7·50 [-13·89 to -1·17]; one trial and six patients), cognitive behavioural therapy (-5·37 [-9·10 to -1·63]; nine trials and 231 patients), clomipramine (-4·72 [-6·85 to -2·60]; 13 trials and 831 patients), and all SSRIs (class effect -3·49 [95% credible interval -5·12 to -1·81]; 37 trials and 3158 patients) had greater effects than did drug placebo. Clomipramine was not better than were SSRIs (-1·23 [-3·41 to 0·94]). Psychotherapeutic interventions had a greater effect than did medications, but a serious limitation was that most psychotherapeutic trials included patients who were taking stable doses of antidepressants (12 [80%] of the 15 psychotherapy trials explicitly allowed antidepressants).

Interpretation: A range of interventions is effective in the management of obsessive-compulsive disorder, but considerable uncertainty and limitations exist regarding their relative efficacy. Taking all the evidence into account, the combination of psychotherapeutic and psychopharmacological interventions is likely to be more effective than are psychotherapeutic interventions alone, at least in severe obsessive-compulsive disorder.

Funding: National Institute for Health Research.
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http://dx.doi.org/10.1016/S2215-0366(16)30069-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967667PMC
August 2016

Approaches for synthesising complex mental health interventions in meta-analysis.

Evid Based Ment Health 2016 Feb 20;19(1):16-21. Epub 2016 Jan 20.

School of Social and Community Medicine, University of Bristol, Bristol, UK.

Clinical and statistical heterogeneity are commonplace in meta-analysis of mental health interventions. One possible source of this heterogeneity is the complexity of the intervention being evaluated. Complexity may relate to the intervention, or to the way in which it is implemented; however, the most common interpretation of a complex intervention is one which has multiple, potentially interacting components. In this article we outline different analytical strategies suggested for incorporating intervention complexity in a meta-analysis.
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http://dx.doi.org/10.1136/eb-2015-102275DOI Listing
February 2016