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BackgroundNetwork meta-analysis (NMA) is increasingly used in guideline development and other aspects of evidence-based decision-making. We aimed to develop a risk of bias (RoB) tool to assess NMAs (RoB NMA tool). An international steering committee recommended that the RoB NMA tool to be used in combination with the Risk of Bias in Systematic reviews (ROBIS) tool (i.e. because it was designed to assess biases only) or other similar quality appraisal tools (eg, A MeaSurement Tool to Assess systematic Reviews 2 [AMSTAR 2]) to assess quality of systematic reviews. The RoB NMA tool will assess NMA biases and limitations regarding how the analysis was planned, data were analysed and results were presented, including the way in which the evidence was assembled and interpreted.ObjectivesConduct (a) a Delphi process to determine expert opinion on an item’s inclusion and (b) a knowledge user survey to widen its impact.DesignCross-sectional survey and Delphi process.MethodsDelphi panellists were asked to rate whether items should be included. All agreed-upon item were included in a second round of the survey (defined as 70% agreement). We surveyed knowledge users’ views and preferences about the importance, utility and willingness to use the RoB NMA tool to evaluate evidence in practice and in policymaking. We included 12 closed and 10 open-ended questions, and we followed a knowledge translation plan to disseminate the survey through social media and professional networks.Results22 items were entered into a Delphi survey of which 28 respondents completed round 1, and 22 completed round 2. Seven items did not reach consensus in round 2. A total of 298 knowledge users participated in the survey (14% respondent rate). 75% indicated that their organisation produced NMAs, and 78% showed high interest in the tool, especially if they had received adequate training (84%). Most knowledge users and Delphi panellists preferred a tool to assessbothbias in individual NMA resultsandauthors’ conclusions. Response bias in our sample is a major limitation as knowledge users working in high-income countries were more represented. One of the limitations of the Delphi process is that it depends on the purposive selection of experts and their availability, thus limiting the variability in perspectives and scientific disciplines.ConclusionsThis Delphi process and knowledge user survey informs the development of the RoB NMA tool.

Background Evidence has shown that private industry-sponsored randomized controlled trials (RCTs) and meta-analyses are more likely to report intervention-favourable results compared with other sources of funding. However, this has not been assessed in network meta-analyses (NMAs). Objectives To (a) explore the recommendation rate of industry-sponsored NMAs on their company’s intervention, and (b) assess reporting in NMAs of pharmacologic interventions according to their funding type. Methods Design: Scoping review of published NMAs with RCTs. Information Sources: We used a pre-existing NMA database including 1,144 articles from MEDLINE, EMBASE and Cochrane Database of Systematic Reviews, published between January 2013 and July 2018. Study Selection: NMAs with transparent funding information and comparing pharmacologic interventions with/without placebo. Synthesis: We captured whether NMAs recommended their own or another company’s intervention, classified NMAs according to their primary outcome findings (i.e., statistical significance and direction of effect), and according to the overall reported conclusion. We assessed reporting using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension to NMA (PRISMA-NMA) 32-item checklist. We matched and compared industry with non-industry NMAs having the same research question, disease, primary outcome, and pharmacologic intervention against placebo/control. Results We retrieved 658 NMAs, which reported a median of 23 items in the PRISMA-NMA checklist (interquartile range [IQR]: 21–26). NMAs were categorized as 314 publicly-sponsored (PRISMA-NMA median 24.5, IQR 22–27), 208 non-sponsored (PRISMA-NMA median 23, IQR 20–25), and 136 industry/mixed-sponsored NMAs (PRISMA-NMA median 21, IQR 19–24). Most industry-sponsored NMAs recommended their own manufactured drug (92%), suggested a statistically significant positive treatment-effect for their drug (82%), and reported an overall positive conclusion (92%). Our matched NMAs (25 industry vs 25 non-industry) indicated that industry-sponsored NMAs had favourable conclusions more often (100% vs 80%) and were associated with larger (but not statistically significantly different) efficacy effect sizes (in 61% of NMAs) compared with non–industry-sponsored NMAs. Conclusions Differences in completeness of reporting and author characteristics were apparent among NMAs with different types of funding. Publicly-sponsored NMAs had the best reporting and published their findings in higher impact-factor journals. Knowledge users should be mindful of this potential funding bias in NMAs.

Background The global spread of COVID-19 created an explosion in rapid tests with results in Methods Design: Rapid review and diagnostic test accuracy network meta-analysis (DTA-NMA). Eligibility criteria: Randomized controlled trials (RCTs) and observational studies assessing rapid antigen and/or rapid molecular test(s) to detect SARS-CoV-2 in participants of any age, suspected or not with SARS-CoV-2 infection. Information sources: Embase, MEDLINE, and Cochrane Central Register of Controlled Trials, up to September 12, 2021. Outcome measures: Sensitivity and specificity of rapid antigen and molecular tests suitable for detecting SARS-CoV-2. Data extraction and risk of bias assessment: Screening of literature search results was conducted by one reviewer; data abstraction was completed by one reviewer and independently verified by a second reviewer. Risk of bias was not assessed in the included studies. Data synthesis: Random-effects meta-analysis and DTA-NMA. Results We included 93 studies (reported in 88 articles) relating to 36 rapid antigen tests in 104,961 participants and 23 rapid molecular tests in 10,449 participants. Overall, rapid antigen tests had a sensitivity of 0.75 (95% confidence interval 0.70–0.79) and specificity of 0.99 (0.98–0.99). Rapid antigen test sensitivity was higher when nasal or combined samples (e.g., combinations of nose, throat, mouth, or saliva samples) were used, but lower when nasopharyngeal samples were used, and in those classified as asymptomatic at the time of testing. Rapid molecular tests may result in fewer false negatives than rapid antigen tests (sensitivity: 0.93, 0.88–0.96; specificity: 0.98, 0.97–0.99). The tests with the highest sensitivity and specificity estimates were the Xpert Xpress rapid molecular test by Cepheid (sensitivity: 0.99, 0.83–1.00; specificity: 0.97, 0.69–1.00) among the 23 commercial rapid molecular tests and the COVID-VIRO test by AAZ-LMB (sensitivity: 0.93, 0.48–0.99; specificity: 0.98, 0.44–1.00) among the 36 rapid antigen tests we examined. Conclusions Rapid molecular tests were associated with both high sensitivity and specificity, while rapid antigen tests were mainly associated with high specificity, according to the minimum performance requirements by WHO and Health Canada. Our rapid review was limited to English, peer-reviewed published results of commercial tests, and study risk of bias was not assessed. A full systematic review is required. Review registration PROSPERO CRD42021289712

Purpose: Acute respiratory distress syndrome (ARDS) is common in patients with acute brain injury admitted to the ICU. We aimed to identify factors associated with ARDS in this population. Methods: We searched MEDLINE, Embase, Cochrane Central, Scopus, and Web of Science from inception to January 14, 2022. Three reviewers independently screened articles and selected English-language studies reporting risk factors for ARDS in brain-injured adult patients. Data were extracted on ARDS incidence, adjusted and unadjusted risk factors, and clinical outcomes. Risk of bias was reported using the Quality in Prognostic Studies tool. Certainty of evidence was assessed using GRADE. Results: We selected 23 studies involving 6,961,284 patients with acute brain injury. The pooled cumulative incidence of ARDS after brain injury was 17.0% (95%CI 10.7–25.8). In adjusted analysis, factors associated with ARDS included sepsis (odds ratio (OR) 4.38, 95%CI 2.37–8.10; high certainty), history of hypertension (OR 3.11, 95%CI 2.31–4.19; high certainty), pneumonia (OR 2.69, 95%CI 2.35–3.10; high certainty), acute kidney injury (OR 1.44, 95%CI 1.30–1.59; moderate certainty), admission hypoxemia (OR 1.67, 95%CI 1.29–2.17; moderate certainty), male sex (OR 1.30, 95%CI 1.06–1.58; moderate certainty), and chronic obstructive pulmonary disease (OR 1.27, 95%CI 1.13–1.44; moderate certainty). Development of ARDS was independently associated with increased odds of in-hospital mortality (OR 3.12, 95% CI 1.39–7.00). Conclusions: Multiple risk factors are associated with ARDS in brain-injured patients. These findings could be used to develop prognostic models for ARDS or as prognostic enrichment strategies for patient enrolment in future clinical trials.

Background: Network meta-analysis (NMA) is increasingly used in guideline development and other aspects of evidence-based decision-making. We aimed to develop a risk of bias (RoB) tool to assess NMAs (RoB NMA tool). An international steering committee intended the RoB NMA tool to be used in combination with ROBIS (recommend as it was designed to assess biases only) or other similar quality appraisal tools (e.g., AMSTAR 2) to assess quality of systematic reviews. The RoB NMA tool will assess NMA biases and limitations regarding how the analysis was planned, data were analysed, and results were presented, including the way in which the evidence was assembled and interpreted. Objectives: Conduct (a) a Delphi process to determine expert opinion on an item’s inclusion, and (b) a knowledge user survey to widen its impact. Design: Cross sectional survey and Delphi process Methods: Delphi panellists were asked to rate whether items should be included. All agreed-upon item were included in a second round of the survey (defined as 70% agreement). We surveyed knowledge users’ views and preferences about the importance, utility, and willingness to use the RoB NMA tool to evaluate evidence in practice and in policymaking. We included 12 closed and 10 open-ended questions, and we followed a knowledge translation plan to disseminate the survey through social media and professional networks. Results: 22 items were entered into a Delphi survey of which 28 respondents completed round 1, and 22 completed round 2.Seven items did not reach consensus in round 2. A total of 298 knowledge users participated in the survey (14% respondent rate). 75% indicated that their organization produced NMAs, and 78% showedhigh interest in the tool, especially if they had received adequate training (84%). Most knowledge users and Delphi panellists preferred a tool to assess both bias in individual NMA results and authors’ conclusions. Response bias in our sample is a major limitation as knowledge users working in higher income countries were more represented. One of the limitations of the Delphi process is that it depends on the purposive selection of experts and their availability, thus limiting the variability in perspectives and scientific disciplines. Conclusions: This Delphi process and knowledge user survey informs the development of the RoB NMA tool. Registration: We uploaded our study protocol on the Open Science Framework at https://osf.io/da4uy/

Background Systematic reviews (SRs) are being published at an accelerated rate. Decision makers are often faced with the challenge of comparing and choosing between multiple SRs on the same topic. We surveyed individuals in the healthcare field to understand what criteria they use to compare and select one or more SRs from multiple on the same topic. Methods We developed a survey with 21 open and closed questions. We disseminated it through social media and professional networks. Results Of the 684 respondents, 25% were health practitioners, 9% policymakers, 39% researchers, and 13% were students. Policymakers, practitioners and researchers frequently sought out SRs (98.1%) as a source of evidence to inform decision making. They frequently (97.7%) found more than one SR on a given topic of interest to them. Half (50%) struggled to choose the most valid and trustworthy SR amongst multiple. These difficulties related to lack of time (55.2%), insufficient skills/ experience in quality appraisal (27.7%), and difficulty comparing different SRs (54.3%). Respondents compared SRs based on: relevance to their question of interest; its methodological quality, and recency of SR search date. Conclusions The exponential growth in the number of SRs leads to duplication of research on similar questions and compounds the problem of identifying which evidence is of the highest quality for decision makers. Failure to critically appraise and choose the highest quality SRs means that practice and policy decisions may not reflect the best evidence, the implementation of better intervention strategies is delayed, and patients may unduly suffer.

Objective To assess the comparative effectiveness and ranking of minimally invasive treatments (MITs) for lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH). Materials and methods We searched multiple databases up to 24 February 2021. We included randomized controlled trials assessing the following treatments: convective radiofrequency water vapour thermal therapy (WVTT or Rezum); prostatic arterial embolization (PAE); prostatic urethral lift (PUL or Urolift); temporary implantable nitinol device (TIND); and transurethral microwave thermotherapy (TUMT) compared to transurethral resection of the prostate (TURP) or sham surgery. We performed a frequentist network meta-analysis. Results We included 27 trials involving 3017 men. The overall certainty of the evidence of most outcomes according to GRADE was low to very low. Compared to TURP, PUL and PAE may result in little to no difference in urologic symptoms while WVTT, TUMT, and TIND may result in worse urologic symptoms. MITs may result in little to no difference in the quality of life (QoL), compared to TURP. MITs may result in a large reduction of major adverse events compared to TURP. We are uncertain about the effects of PAE and PUL on retreatment compared to TURP, however, TUMT may result in higher retreatment rates. We are very uncertain of the effects of MITs on erectile function and ejaculatory function. Among MITs, PUL and PAE have the highest likelihood of being the most efficacious for urinary symptoms and QoL, TUMT for major adverse events, WVTT and TIND for erectile function and PUL for ejaculatory function. Excluding WVTT and TIND, for which there were only studies with short-term (three months) follow-up, PUL had the highest likelihood of being the most efficacious for retreatment. Conclusions MITs may result in similar or worse effects concerning urinary symptoms and QoL compared to TURP at short-term follow-up.

Background The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension statement for network meta-analysis (NMA) published in 2015 promotes comprehensive reporting in published systematic reviews with NMA. PRISMA-NMA includes 32 items: 27 core items as indicated in the 2009 PRISMA Statement and five items specific to the reporting of NMAs. Although NMA reporting is improving, it is unclear whether PRISMA-NMA has accelerated this improvement. We aimed to investigate the impact of PRISMA-NMA and highlight key items that require attention and improvement. Methods We updated our previous collection of NMAs with articles published between April 2015 and July 2018. We assessed the completeness of reporting for each NMA, including main manuscript and online supplements, using the PRISMA-NMA checklist. The PRISMA-NMA checklist originally includes 32 total items (i.e. a 32-point scale original PRISMA-NMA score). We also prepared a modified version of the PRISMA-NMA checklist with 49 items to evaluate separately at a more granular level all multiple-content items (i.e. a 49-point scale modified PRISMA-NMA score). We compared average reporting scores of articles published until and after 2015. Results In the 1144 included NMAs the mean modified PRISMA-NMA score was 32.1 (95% CI 31.8–32.4) of a possible 49-excellence-score. For 1-year increase, the mean modified score increased by 0.96 (95% CI 0.32 to 1.59) for 389 NMAs published until 2015 and by 0.53 (95% CI 0.02 to 1.04) for 755 NMAs published after 2015. The mean modified PRISMA-NMA score for NMAs published after 2015 was higher by 0.81 (95% CI 0.23 to 1.39) compared to before 2015 when adjusting for journal impact factor, type of review, funding, and treatment category. Description of summary effect sizes to be used, presentation of individual study data, sources of funding for the systematic review, and role of funders dropped in frequency after 2015 by 6–16%. Conclusions NMAs published after 2015 more frequently reported the five items associated with NMA compared to those published until 2015. However, improvement in reporting after 2015 is compatible with that observed on a yearly basis until 2015, and hence, it could not be attributed solely to the publication of the PRISMA-NMA.

ObjectivesIndividual participant data (IPD) from randomised controlled trials (RCTs) can be used in network meta-analysis (NMA) to underpin patient care and are the best analyses to support the development of guidelines about the use of healthcare interventions for a specific condition. However, barriers to IPD retrieval pose a major threat. The aim of this study was to present barriers we encountered during retrieval of IPD from RCTs in two published systematic reviews with IPD-NMA.MethodsWe evaluated retrieval of IPD from RCTs for IPD-NMA in Alzheimer’s dementia and type 1 diabetes. We requested IPD from authors, industry sponsors and data repositories, and recorded IPD retrieval, reasons for IPD unavailability, and retrieval challenges.ResultsIn total, we identified 108 RCTs: 78 industry sponsored, 11 publicly sponsored and 19 with no funding information. After failing to obtain IPD from any trial authors, we requested it from industry sponsors. Seven of the 17 industry sponsors shared IPD for 12 950 participants (59%) through proprietary-specific data sharing platforms from 26 RCTs (33%). We found that lack of RCT identifiers (eg, National Clinical Trial number) and unclear data ownership were major challenges in IPD retrieval. Incomplete information in retrieved datasets was another important problem that led to exclusion of RCTs from the NMA. There were also practical challenges in obtaining IPD from or analysing it within platforms, and additional costs were incurred in accessing IPD this way.ConclusionsWe found no clear evidence of retrieval bias (where IPD availability was linked to trial findings) in either IPD-NMA, but because retrieval bias could impact NMA findings, subsequent decision-making and guideline development, this should be considered when assessing risk of bias in IPD syntheses.

Introduction: Network meta-analyses (NMAs) have gained popularity and grown in number due to their ability to provide estimates of comparative effectiveness of multiple treatments for the same condition. The aim of this study is to conduct a methodological review to compile a preliminary list of concepts related to bias in NMAs. Methods and Analysis: We included papers that present items related to bias, reporting, or methodological quality, papers assessing the quality of NMAs, or methods papers. We searched MEDLINE, the Cochrane library, and unpublished literature. We extracted items related to bias in NMAs. An item was excluded if it was an item related to general systematic review quality or bias, and included in currently available tools such as ROBIS or AMSTAR 2. We reworded items, typically structured as questions, into concepts (i.e. general notions). Results: 181 articles were assessed at full text and 57 were included. Of these articles, 12 were tools, checklists or journal standards, 12 were guidance documents for NMAs, 26 were articles related to bias or methods, and 7 were papers that assessed the quality of NMAs. These studies yielded 99 items of which the majority related to general systematic review quality and biases and were therefore excluded. The items we included were reworded into 22 concepts specific to bias in NMAs. Conclusions: A list of 22 concepts were included. This list is not intended to be used to assess biases in NMAs, but to inform the development of items to be included in our tool.

ObjectiveTo explore the efficacy of human papillomavirus (HPV) vaccination on the risk of HPV infection and recurrent diseases related to HPV infection in individuals undergoing local surgical treatment.DesignSystematic review and meta-analysisData sourcesPubMed (Medline), Scopus, Cochrane, Web of Science, and ClinicalTrials.gov were screened from inception to 31 March 2021.Review methodsStudies reporting on the risk of HPV infection and recurrence of disease related to HPV infection after local surgical treatment of preinvasive genital disease in individuals who were vaccinated were included. The primary outcome measure was risk of recurrence of cervical intraepithelial neoplasia grade 2 or higher (CIN2+) after local surgical treatment, with follow-up as reported by individual studies. Secondary outcome measures were risk of HPV infection or other lesions related to HPV infection. Independent and in duplicate data extraction and quality assessment were performed with ROBINS-I and RoB-2 tools for observational studies and randomised controlled trials, respectively. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was implemented for the primary outcome. Observational studies and randomised controlled trials were analysed separately from post hoc analyses of randomised controlled trials. Pooled risk ratios and 95% confidence intervals were calculated with a random effects meta-analysis model. The restricted maximum likelihood was used as an estimator for heterogeneity, and the Hartung-Knapp-Sidik-Jonkman method was used to derive confidence intervals.Results22 articles met the inclusion criteria of the review; 18 of these studies also reported data from a non-vaccinated group and were included in the meta-analyses (12 observational studies, two randomised controlled trials, and four post hoc analyses of randomised controlled trials). The risk of recurrence of CIN2+ was reduced in individuals who were vaccinated compared with those who were not vaccinated (11 studies, 19 909 participants; risk ratio 0.43, 95% confidence interval 0.30 to 0.60; I2=58%, τ2=0.14, median follow-up 36 months, interquartile range 24-43.5). The effect estimate was even stronger when the risk of recurrence of CIN2+ was assessed for disease related to HPV subtypes HPV16 or HPV18 (six studies, 1879 participants; risk ratio 0.26, 95% confidence interval 0.16 to 0.43; I2=0%, τ2=0). Confidence in the meta-analysis for CIN2+ overall and CIN2+ related to HPV16 or HPV18, assessed by GRADE, ranged from very low to moderate, probably because of publication bias and inconsistency in the studies included in the meta-analysis. The risk of recurrence of CIN3 was also reduced in patients who were vaccinated but uncertainty was large (three studies, 17 757 participants; 0.28, 0.01 to 6.37; I2=71%, τ2=1.23). Evidence of benefit was lacking for recurrence of vulvar, vaginal, and anal intraepithelial neoplasia, genital warts, and persistent and incident HPV infections, although the number of studies and participants in each outcome was low.ConclusionHPV vaccination might reduce the risk of recurrence of CIN, in particular when related to HPV16 or HPV18, in women treated with local excision. GRADE assessment for the quality of evidence indicated that the data were inconclusive. Large scale, high quality randomised controlled trials are required to establish the level of effectiveness and cost of HPV vaccination in women undergoing treatment for diseases related to HPV infection.Systematic review registrationPROSPERO CRD42021237350.

Publisher Copyright: © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Background: The trade-off between comparative effectiveness and reproductive morbidity of different treatment methods for cervical intraepithelial neoplasia (CIN) remains unclear. We aimed to determine the risks of treatment failure and preterm birth associated with various treatment techniques. Methods: In this systematic review and network meta-analysis, we searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials database for randomised and non-randomised studies reporting on oncological or reproductive outcomes after CIN treatments from database inception until March 9, 2022, without language restrictions. We included studies of women with CIN, glandular intraepithelial neoplasia, or stage IA1 cervical cancer treated with excision (cold knife conisation [CKC], laser conisation, and large loop excision of the transformation zone [LLETZ]) or ablation (radical diathermy, laser ablation, cold coagulation, and cryotherapy). We excluded women treated with hysterectomy. The primary outcomes were any treatment failure (defined as any abnormal histology or cytology) and preterm birth (

BACKGROUND/OBJECTIVES: Virtual (i.e., telephone or videoconference) care was broadly implemented because of the COVID-19 pandemic. Our objectives were to compare the diagnostic accuracy of virtual to in-person cognitive assessments and tests and barriers to virtual cognitive assessment implementation. DESIGN: Systematic review and meta-analysis. SETTING: MEDLINE, EMBASE, CDSR, CENTRAL, PsycINFO, and gray literature (inception to April 1, 2020). PARTICIPANTS AND INTERVENTIONS: Studies describing the accuracy or reliability of virtual compared with in-person cognitive assessments (i.e., reference standard) for diagnosing dementia or mild cognitive impairment (MCI), identifying virtual cognitive test cutoffs suggestive of dementia or MCI, or describing correlations between virtual and in-person cognitive test scores in adults. MEASUREMENTS: Reviewer pairs independently conducted study screening, data abstraction, and risk of bias appraisal. RESULTS: Our systematic review included 121 studies (15,832 patients). Two studies demonstrated that virtual cognitive assessments could diagnose dementia with good reliability compared with in-person cognitive assessments: weighted kappa 0.51 (95% confidence interval [CI] 0.41-0.62) and 0.63 (95% CI 0.4-0.9), respectively. Videoconference-based cognitive assessments were 100% sensitive and specific for diagnosing dementia compared with in-person cognitive assessments in a third study. No studies compared telephone with in-person cognitive assessment accuracy. The Telephone Interview for Cognitive Status (TICS; maximum score 41) and modified TICS (maximum score 50) were the only virtual cognitive tests compared with in-person cognitive assessments in >2 studies with extractable data for meta-analysis. The optimal TICS cutoff suggestive of dementia ranged from 22 to 33, but it was 28 or 30 when testing was conducted in English (10 studies; 1673 patients). Optimal modified TICS cutoffs suggestive of MCI ranged from 28 to 31 (3 studies; 525 patients). Sensory impairment was the most often voiced condition affecting assessment. CONCLUSION: Although there is substantial evidence supporting virtual cognitive assessment and testing, we identified critical gaps in diagnostic certainty.

BACKGROUND: Increasing availability of competing biosimilar alternatives makes it challenging to make treatment decisions. The purpose of this review is to evaluate the comparative efficacy and safety of ultra-long-/long-/intermediate-acting insulin products and biosimilar insulin compared to human/animal insulin in adults with type 1 diabetes mellitus (T1DM). METHODS: MEDLINE, EMBASE, CENTRAL, and grey literature were searched from inception to March 27, 2019. Randomized controlled trials (RCTs), quasi-experimental studies, and cohort studies of adults with T1DM receiving ultra-long-/long-/intermediate-acting insulin, compared to each other, as well as biosimilar insulin compared to human/animal insulin were eligible for inclusion. Two reviewers independently screened studies, abstracted data, and appraised risk-of-bias. Pairwise meta-analyses and network meta-analyses (NMA) were conducted. Summary effect measures were mean differences (MD) and odds ratios (OR). RESULTS: We included 65 unique studies examining 14,200 patients with T1DM. Both ultra-long-acting and long-acting insulin were superior to intermediate-acting insulin in reducing A1c, FPG, weight gain, and the incidence of major, serious, or nocturnal hypoglycemia. For fasting blood glucose, long-acting once a day (od) was superior to long-acting twice a day (bid) (MD - 0.44, 95% CI: - 0.81 to - 0.06) and ultra-long-acting od was superior to long-acting bid (MD - 0.73, 95% CI - 1.36 to - 0.11). For weight change, long-acting od was inferior to long-acting bid (MD 0.58, 95% CI: 0.05 to 1.10) and long-acting bid was superior to long-action biosimilar od (MD - 0.90, 95% CI: - 1.67 to - 0.12). CONCLUSIONS: Our results can be used to tailor insulin treatment according to the desired results of patients and clinicians and inform strategies to establish a competitive clinical market, address systemic barriers, expand the pool of potential suppliers, and favor insulin price reduction. PROSPERO REGISTRATION: CRD42017077051 SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11606-021-06642-7.

Systematic Reviews of diagnostic test accuracy (DTA) studies are increasingly comparing the accuracy of multiple tests to facilitate selection of the best performing test(s). Common approaches to compare multiple tests include multiple meta-analyses or meta-regression with the test type as a covariate. Within-study correlation between tests are typically not considered in these approaches. Several DTA network meta-analysis (DTA-NMA) models have been suggested to compare the accuracy of multiple index tests in a single model. Our aim was to identify all DTA-NMA methods for comparing the accuracy of multiple diagnostic tests. We conducted a methodological review of the DTA-NMA models. We searched PubMed, Web of Science, and Scopus from inception until the end of July 2019. Studies of any design published in English were eligible for inclusion. We also reviewed relevant unpublished material. The methods were applied in a network of 37 studies comparing human papillomavirus (HPV) DNA, mRNA, and cytology (ASCUS+/ LSIL+ threshold) for the diagnosis of invasive cervical cancer (CIN2+). We included 10 relevant studies, and identified four Bayesian hierarchical DTA-NMA methods including the 2×2 data table for each index test. Using CIN2+ as a case study, we applied the DTA-NMA methods to determine the most promising test, in terms of sensitivity and specificity. All models showed the mRNA test as the most accurate test followed by HPV DNA: relative sensitivity compared to the cytology test 1.36-1.39 and 1.33-1.35, respectively. However, both tests had similar or worse specificity than cytology (relative specificity range in mRNA 0.96-0.98 and in HPV-DNA 0.94-0.95). Both sensitivity and specificity of mRNA were associated with the highest uncertainty across all models (widest 95% credible intervals 0.68-0.97 and 0.74-0.94, respectively). Precision and estimation of between-study and within-study variability vary across models, which might be due to the differences in the key properties of the models. Different DTA-NMA methods may lead to different results. The choice of a DTA-NMA method for the comparison of multiple diagnostic tests may depend on the available data, e.g., threshold data, as well as on clinically-related factors.

Background:Older adults experience symptoms of depression, leading to suffering and increased morbidity and mortality. Although we have effective depression therapies, physical distancing and other public health measures have severely limited access to in-person interventions.Objective:To describe the efficacy of virtual interventions for reducing symptoms of depression in community-dwelling older adults.Design:Systematic review.Setting:We searched MEDLINE, EMBASE, Cochrane Libraries, PsycINFO, and gray literature from inception to July 5, 2021.Participants and interventions:We included randomized trials (RCTs) comparing the efficacy of virtual interventions to any other virtual intervention or usual care in community-dwelling adults ≥60 years old experiencing symptoms of depression or depression as an outcome.Measurements:The primary outcome was change in symptoms of depression measured by any depression scale.Results:We screened 12,290 abstracts and 830 full text papers. We included 15 RCTs (3100 participants). Five RCTs examined persons with depression symptoms at baseline and ten examined depression as an outcome only. Included studies demonstrated feasibility of interventions such as internet or telephone cognitive behavioral therapy with some papers showing statistically significant improvement in depressive symptoms.Conclusions:There is a paucity of studies examining virtual interventions in older adults with depression. Given difficulty in accessing in-person therapies in a pandemic and poor access for people living in rural and remote regions, there is an urgent need to explore efficacy, effectiveness, and implementation of virtual therapies.

ObjectiveTo examine the comparative efficacy and safety of cognitive enhancers by patient characteristics for managing Alzheimer’s dementia (AD).DesignSystematic review and individual patient data (IPD) network meta-analysis (NMA) based on our previously published systematic review and aggregate data NMA.Data sourcesMEDLINE, Embase, Cochrane Methodology Register, CINAHL, AgeLine and Cochrane Central Register of Controlled Trials up to March 2016.Participants80 randomised controlled trials (RCTs) including 21 138 adults with AD, and 12 RCTs with IPD including 6906 patients.InterventionsCognitive enhancers (donepezil, rivastigmine, galantamine and memantine) alone or in any combination against other cognitive enhancers or placebo.Data extraction and synthesisWe requested IPD from authors, sponsors and data sharing platforms. When IPD were not available, we used aggregate data. We appraised study quality with the Cochrane risk-of-bias. We conducted a two-stage random-effects IPD-NMA, and assessed their findings using CINeMA (Confidence in Network Meta-Analysis).Primary and secondary outcomesWe included trials assessing cognition with the Mini-Mental State Examination (MMSE), and adverse events.ResultsOur IPD-NMA compared nine treatments (including placebo). Donepezil (mean difference (MD)=1.41, 95% CI: 0.51 to 2.32) and donepezil +memantine (MD=2.57, 95% CI: 0.07 to 5.07) improved MMSE score (56 RCTs, 11 619 participants; CINeMA score: moderate) compared with placebo. According to P-score, oral rivastigmine (OR=1.26, 95% CI: 0.82 to 1.94, P-score=16%) and donepezil (OR=1.08, 95% CI: 0.87 to 1.35, P-score=30%) had the least favourable safety profile, but none of the estimated treatment effects were sufficiently precise when compared with placebo (45 RCTs, 15 649 patients; CINeMA score: moderate to high). For moderate-to-severe impairment, donepezil, memantine and their combination performed best, but for mild-to-moderate impairment donepezil and transdermal rivastigmine ranked best. Adjusting for MMSE baseline differences, oral rivastigmine and galantamine improved MMSE score, whereas when adjusting for comorbidities only oral rivastigmine was effective.ConclusionsThe choice among the different cognitive enhancers may depend on patient’s characteristics. The MDs of all cognitive enhancer regimens except for single-agent oral rivastigmine, galantamine and memantine, against placebo were clinically important for cognition (MD larger than 1.40 MMSE points), but results were quite imprecise. However, two-thirds of the published RCTs were associated with high risk of bias for incomplete outcome data, and IPD were only available for 15% of the included RCTs.PROSPERO registration numberCRD42015023507.

Introduction: Network meta-analysis (NMA) is increasingly used in guideline development and other aspects of evidence-based decision-making. We engaged with stakeholders in early phases of the development of a new tool to assess risk of bias (RoB) in NMA to facilitate its later use and potentially widen its impact. Methods: We surveyed stakeholders’ views and preferences about the importance, utility, and willingness to use the RoB NMA tool to evaluate evidence in practice and in policymaking. We included 12 closed and 10 open-ended questions, and followed a knowledge translation plan to disseminate the survey through social media and professional networks. Results: A total of 298 stakeholders participated in the survey (14% respondent rate) which took on average 2 minutes to complete. 75% of stakeholders indicated that their organization produced NMAs, and 78% of respondents showed high interest in the tool. Most stakeholders (84%) reported they would use the tool to assess an NMA if they had received adequate training, while half reported they preferred a tool to assess both bias in individual NMA results and authors’ conclusions. Twelve (8%) stakeholders said they would use the tool to conduct an overview of reviews, while 24 (17%) respondents indicated that they would use the tool to distinguish between NMAs at high and low risk of bias. Conclusions: This survey informs the development of a RoB tool for NMAs and is a pillar in an integrated knowledge translation approach. Stakeholders preferred a tool to assess both bias in individual NMA results and authors’ conclusions.

Systematic reviews with network meta-analysis that ignore potential dose effects could limit the applicability and validity of review findings. This article aims to help content experts (eg, clinicians), methodologists, and statisticians better understand how to incorporate dose effects in network meta-analysis. Three models are described that make different clinical and statistical assumptions about how to model dose effects. This article also illustrates the importance of dose effects in understanding the potential risk of harm in people with dementia from cerebrovascular events associated with atypical antipsychotic drug use (quetiapine, olanzapine, and risperidone) and the potential risk of harm in people with nausea and headache associated with cholinesterase inhibitor use (donepezil, galantamine, and rivastigmine). Finally, important considerations when choosing between different network meta-analysis models incorporating dose effects are discussed.

Self-management interventions (SMIs) may improve outcomes in Chronic Obstructive Pulmonary Disease (COPD). However, accurate comparisons of their relative effectiveness are challenging, partly due to a lack of clarity and detail regarding the intervention content being evaluated. This study systematically describes intervention components and characteristics in randomized controlled trials (RCTs) related to COPD self-management using the COMPAR-EU taxonomy as a framework, identifying components that are insufficiently incorporated into the design of the intervention or insufficiently reported. Overall, 235 RCTs published between 2010 and 2018, from a systematic review were coded using the taxonomy, which includes 132 components across four domains: intervention characteristics, expected patient (or caregiver) self-management behaviours, patient relevant outcomes, and target population characteristics. Risk of bias was also assessed. Interventions mainly focused on physical activity (67.4%), and condition-specific behaviours like breathing exercise (63.5%), self-monitoring (50.8%), and medication use (33.9%). Support techniques like education and skills-training, self-monitoring, and goal setting (over 35% of the RCTs) were mostly used for this. Emotional-based techniques, problem-solving, and shared decision-making were less frequently reported (less than 15% of the studies). Numerous SMIs components were insufficiently incorporated into the design of COPD SMIs or insufficiently reported. Characteristics like mode of delivery, intensity, location, and providers involved were often not described. Only 8% of the interventions were tailored to the target population’s characteristics. Outcomes that are considered important by patients were hardly taken into account. There is still a lot to improve in both the design and description of SMIs for COPD. Using a framework such as the COMPAR-EU SMI taxonomy may contribute to better reporting and to better informing of replication efforts. In addition, prospective use of the taxonomy for developing and reporting intervention content would further aid in building a cumulative science of effective SMIs in COPD.

To (a) identify methodological and application papers reporting a model developed specifically for diagnostic test accuracy network meta-analysis (DTA-NMA) or a hierarchical meta-regression method for comparing at least three index tests; (b) review and summarize the characteristics of the methods and the application papers; and (c) compare DTA-NMA and hierarchical meta-regression methods empirically.We performed a scoping review and searched major databases until March 3rd, 2021. We assessed the characteristics of the identified methods, conducted a descriptive analysis of characteristics of the application articles, and applied the DTA-NMA and meta-regression methods to the available data.We included 49 articles (plus one companion report), of which nine were methodological (describing 11 DTA-NMA methods) and 40 were application papers (data available for 32 DTA-NMAs). Our results showed a steep increase in recent years in DTA-NMA publications. DTA-NMA models may lead to different results. Although sensitivity estimates were comparable between meta-regression and DTA-NMA models, specificity estimates were higher in meta-regression.The choice of a DTA-NMA model will depend on the available data, including the use of different thresholds for test positivity, different study designs, and software familiarity. Selection between the methods may impact on the NMA results, especially for specificity.

The rapid increase in diagnostic and screening techniques has urged the need to choose among multiple diagnostic tests. For the majority of diseases, there is more than a single test available, and studies usually compare a subset of these tests. In such cases, a separate meta-analysis of each test cannot provide a reliable answer on the relative accuracy of the multiple available tests. Extensions of standard (hierarchical) meta-analysis to network meta-analysis (NMA) models for the comparison of at least three diagnostic tests have been the subject of methodological research in recent years. NMA can be used to jointly analyze the totality of evidence in order to provide estimates of relative accuracy (sensitivity and specificity ), to compare tests that have not been compared head-to-head, and to obtain a ranking of all competing tests in order to further facilitate the decision-making process.In this chapter, we illustrate current methodology for meta-analysis of multiple test comparisons, introduce NMA methods of diagnostic tests as an extension to the standard meta-analysis of diagnostic test accuracy (DTA) studies, and present existing approaches to rank tests according to their accuracy, specificity , and sensitivity . We also describe the basic concepts, underlying assumptions, and challenges in NMA of multiple diagnostic tests.

There is a rapid increase in trials assessing healthcare interventions consisting of a combination of drugs (polytherapies) or multiple components. In the latter type of interventions (also known as complex interventions), the aspect of complexity is of paramount importance. For example, nonpharmacological interventions, such as psychological interventions or self-management interventions, usually share common components that relate to the nature of intervention, who delivers it, or where and how. In a network of trials, there is often the need to identify the most effective (or safest) component and/or combination of components. Four key meta-analytical approaches have been presented in the literature to handle complex interventions. These include (a) the single-effect model, (b) the full interaction model, (c) the additive main effects model, and (d) the two-way interaction model. In this chapter, we present and discuss the advantages and limitations of these approaches. We illustrate these methods using a network that assesses the relative effects of self-management interventions on waist size in patients with type 2 diabetes.

The rapid increase in diagnostic and screening techniques has urged the need to choose among multiple diagnostic tests. For the majority of diseases, there is more than a single test available, and studies usually compare a subset of these tests. In such cases, a separate meta-analysis of each test cannot provide a reliable answer on the relative accuracy of the multiple available tests. Extensions of standard (hierarchical) meta-analysis to network meta-analysis (NMA) models for the comparison of at least three diagnostic tests have been the subject of methodological research in recent years. NMA can be used to jointly analyze the totality of evidence in order to provide estimates of relative accuracy (sensitivity and specificity ), to compare tests that have not been compared head-to-head, and to obtain a ranking of all competing tests in order to further facilitate the decision-making process.In this chapter, we illustrate current methodology for meta-analysis of multiple test comparisons, introduce NMA methods of diagnostic tests as an extension to the standard meta-analysis of diagnostic test accuracy (DTA) studies, and present existing approaches to rank tests according to their accuracy, specificity , and sensitivity . We also describe the basic concepts, underlying assumptions, and challenges in NMA of multiple diagnostic tests.

There is a rapid increase in trials assessing healthcare interventions consisting of a combination of drugs (polytherapies) or multiple components. In the latter type of interventions (also known as complex interventions), the aspect of complexity is of paramount importance. For example, nonpharmacological interventions, such as psychological interventions or self-management interventions, usually share common components that relate to the nature of intervention, who delivers it, or where and how. In a network of trials, there is often the need to identify the most effective (or safest) component and/or combination of components. Four key meta-analytical approaches have been presented in the literature to handle complex interventions. These include (a) the single-effect model, (b) the full interaction model, (c) the additive main effects model, and (d) the two-way interaction model. In this chapter, we present and discuss the advantages and limitations of these approaches. We illustrate these methods using a network that assesses the relative effects of self-management interventions on waist size in patients with type 2 diabetes.

While the contributing factors leading to endometriosis remain unclear, its clinical heterogeneity suggests a multifactorial causal background. Amongst others, caffeine has been studied extensively during the last decade as a putative contributing factor. In this systematic review and meta-analysis, we provide an overview/critical appraisal of studies that report on the association between caffeine consumption and the presence of endometriosis. In our search strategy, we screened PubMed and Scopus for human studies examining the above association. The main outcome was the relative risk of endometriosis in caffeine users versus women consuming little or no caffeine (300 mg/day) or moderate (100–300 mg/day). Ten studies were included in the meta-analysis (five cohort and five case-control studies). No statistically significant association was observed between overall caffeine consumption and risk for endometriosis (RR 1.12, 95% confidence interval (CI) 0.97–1.28, I2 = 70%) when compared to little or no (2 = 56%), whereas moderate intake did not reach nominal statistical significance (RR 1.18, 95%CI 0.99–1.40, I2 = 37%). In conclusion, caffeine consumption does not appear to be associated with increased risk for endometriosis. However, further research is needed to elucidate the potential dose-dependent link between caffeine and endometriosis or the probable role of caffeine intake as a measurement of other unidentified biases.

ObjectiveTo examine the comparative efficacy and complications of long-acting and intermediate-acting insulin for different patient characteristics for type 1 diabetes mellitus (T1DM).DesignSystematic review and individual patient data (IPD) network meta-analysis (NMA).Data sourcesMEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched through June 2015.Eligibility criteriaRandomised controlled trials (RCTs) on adults with T1DM assessing glycosylated haemoglobin (A1c) and severe hypoglycaemia in long-acting and intermediate-acting insulin regimens.Data extraction and synthesisWe requested IPD from authors and funders. When IPD were not available, we used aggregate data. We conducted a random-effects model, and specifically a one-stage IPD-NMA for those studies providing IPD and a two-stage IPD-NMA to incorporate those studies not providing IPD.ResultsWe included 28 RCTs plus one companion report, after screening 6680 titles/abstracts and 205 full-text articles. Of the 28 RCTs, 27 studies provided data for the NMA with 7394 participants, of which 12 RCTs had IPD on 4943 participants. The IPD-NMA for A1c suggested that glargine once daily (mean difference [MD]=−0.31, 95% confidence interval [CI]: −0.48 to −0.14) and detemir once daily (MD=−0.25, 95% CI: –0.41 to −0.09) were superior to neutral protamine Hagedorn (NPH) once daily. NPH once/two times per day improved A1c compared with NPH once daily (MD=−0.30, 95% CI: –0.50 to −0.11). Results regarding complications in severe hypoglycaemia should be considered with great caution due to inconsistency in the evidence network. Accounting for missing data, there was no evidence of inconsistency and long-acting insulin regimens ranked higher regarding reducing severe hypoglycaemia compared with intermediate-acting insulin regimens (two-stage NMA: glargine two times per day SUCRA (Surface Under the Cumulative Ranking curve)=89%, detemir once daily SUCRA=77%; one-stage NMA: detemir once daily/two times per day SUCRA=85%). Using multiple imputations and IPD only, complications in severe hypoglycaemia increased with diabetes-related comorbidities (regression coefficient: 1.03, 95% CI: 1.02 to 1.03).ConclusionsLong-acting insulin regimens reduced A1c compared with intermediate-acting insulin regimens and were associated with lower severe hypoglycaemia. Of the observed differences, only glargine once daily achieved a clinically significant reduction of 0.30%. Results should be interpreted with caution due to very low quality of evidence.PROSPERO registration numberCRD42015023511.