Low awareness of the transitivity assumption in complex networks of interventions: a systematic survey from 721 network meta-analyses.

BACKGROUND: The transitivity assumption is the cornerstone of network meta-analysis (NMA). Violating transitivity compromises the credibility of the indirect estimates and, by extent, the estimated treatment effects of the comparisons in the network. The present study offers comprehensive empirical evidence on the completeness of reporting and evaluating transitivity in systematic reviews with multiple interventions. METHODS: We screened the datasets of two previous empirical studies, resulting in 361 systematic reviews with NMA published between January 2011 and April 2015. We updated our evidence base with an additional 360 systematic reviews with NMA published between 2016 and 2021, employing a pragmatic approach. We devised assessment criteria for reporting and evaluating transitivity using relevant methodological literature and compared their reporting frequency before and after the PRISMA-NMA statement. RESULTS: Systematic reviews published after PRISMA-NMA were more likely to provide a protocol (odds ratio (OR): 3.94, 95% CI: 2.79-5.64), pre-plan the transitivity evaluation (OR: 3.01, 95% CI: 1.54-6.23), and report the evaluation and results (OR: 2.10, 95% CI: 1.55-2.86) than those before PRISMA-NMA. However, systematic reviews after PRISMA-NMA were less likely to define transitivity (OR: 0.57, 95% CI: 0.42-0.79) and discuss the implications of transitivity (OR: 0.48, 95% CI: 0.27-0.85) than those published before PRISMA-NMA. Most systematic reviews evaluated transitivity statistically than conceptually (40% versus 12% before PRISMA-NMA, and 54% versus 11% after PRISMA-NMA), with consistency evaluation being the most preferred (34% before versus 47% after PRISMA-NMA). One in five reviews inferred the plausibility of the transitivity (22% before versus 18% after PRISMA-NMA), followed by 11% of reviews that found it difficult to judge transitivity due to insufficient data. In justifying their conclusions, reviews considered mostly the comparability of the trials (24% before versus 30% after PRISMA-NMA), followed by the consistency evaluation (23% before versus 16% after PRISMA-NMA). CONCLUSIONS: Overall, there has been a slight improvement in reporting and evaluating transitivity since releasing PRISMA-NMA, particularly in items related to the systematic review report. Nevertheless, there has been limited attention to pre-planning the transitivity evaluation and low awareness of the conceptual evaluation methods that align with the nature of the assumption.

Comparative effectiveness of medical treatment vs. metabolic surgery for histologically proven non-alcoholic steatohepatitis and fibrosis: a matched network meta-analysis.

Background: Non-alcoholic steatohepatitis (NASH) comprises a major healthcare problem affecting up to 30% of patients with obesity and the associated risk for cardiovascular and liver-related mortality. Several new drugs for NASH-treatment are currently investigated. No study thus far directly compared surgical and non-surgical therapies for NASH. This network meta-analysis compares for the first time the effectiveness of different therapies for NASH using a novel statistical approach. Methods: The study was conducted according to the PRISMA guidelines for network meta-analysis. PubMed, CENTRAL and Web of Science were searched without restriction of time or language using a validated search strategy. Studies investigating therapies for NASH in adults with liver biopsies at baseline and after at least 12 months were selected. Patients with liver cirrhosis were excluded. Risk of bias was assessed with ROB-2 and ROBINS-I-tools. A novel method for population-adjusted indirect comparison to include and compare single-arm trials was applied. Main outcomes were NASH-resolution and improvement of fibrosis. Results: Out of 7,913 studies, twelve randomized non-surgical studies and twelve non-randomized surgical trials were included. NASH-resolution after non-surgical intervention was 29% [95% confidence interval (CI): 23-40%] and 79% (95% CI: 72-88%) after surgery. The network meta-analysis showed that surgery had a higher chance of NASH-resolution than medication [odds ratio (OR) =2.68; 95% CI: 1.44-4.97] while drug treatment was superior to placebo (OR =2.24; 95% CI: 1.55-3.24). Surgery (OR =2.18; 95% CI: 1.34-3.56) and medication (OR =1.79; 95% CI: 1.39-2.31) were equally effective to treat fibrosis compared to placebo without difference between them. The results did not change when only new drugs specifically developed for the treatment of NASH were included. Conclusions: Metabolic surgery has a higher effectiveness for NASH-therapy than medical therapy while both were equally effective regarding improvement of fibrosis. Trials directly comparing surgery with medication must be urgently conducted. Patients with NASH should be informed about surgical treatment options.

Supermicrosurgical treatment for lymphedema: a systematic review and network meta-analysis protocol.

BACKGROUND: Lymphedema is a condition that affects up to 130 million subjects worldwide. Since it is related to several complications and a significant reduction in terms of quality of life, it is a heavy burden not only to the patients but also for the healthcare system worldwide. Despite the development of supermicrosurgery, such as vascularized lymph node transfer (VLNT) and lymphovenous anastomosis LVA, the indications and outcomes of these complex groups of interventions remain a controversial topic in the field of reconstructive plastic surgery. METHODS: This systematic review and network meta-analysis aims to assess the evidence of outcomes of LVA and VLNT in patients with lymphedema. Secondary aims of the project are to determine if for any outcomes, LVA or VLNT is superior to conservative therapy alone, and whether the available evidence favors any kind of supermicrosurgical interventions for lymphedema patients. This study will include original studies of patients with lymphedema on the extremities indexed in PubMed, EMBASE, CENTRAL, PASCAL, FRANCIS, ISTEX, LILACS, CNKI, and IndMED that reported microsurgery (supermicrosurgery) of all techniques aiming the re-functionalization of the lymphatic system. As comparators, mere observation, conservative treatment of any kind, and the other subgroups of supermicrosurgery are planned. The primary outcome of this systematic review and network meta-analysis is the difference of the limb volume, while the secondary outcomes of interest will be erysipelas rates, major and minor complications, postoperative necessity of continuous compression garments, and patient satisfaction, measured by already published and validated scores for quality of life. DISCUSSION: We will provide an overview and evidence grade analysis of the scientific literature available on the effectiveness of the subcategories of supermicrosurgical interventions for lymphedema.

Safety and donor site morbidity of the transverse musculocutaneous gracilis (TMG) flap in autologous breast reconstruction-A systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: The transverse musculocutaneous gracilis (TMG) flap has gained popularity for breast reconstruction. However, the literature regarding its donor site morbidity is heterogeneous. This systematic review sought to clarify the evidence on donor site morbidity. METHODS: A systematic literature search was conducted. We included all articles reporting on donor-site morbidity of the TMG flap for breast reconstruction. The results were analyzed in R and its extension meta. A generalized linear mixed model was used to combine proportions and their 95% confidence intervals (CIs) in a random-effects meta-analysis. RESULTS: Nineteen articles provided an overall sample of 843 TMG flaps. The total flap loss was low at 2% (95% CI, 1%-3%). All patients were normal weight (pooled body mass index 22.75, 95% CI, 21.88-23.63). The incidence of wound dehiscence (8%, 95% CI, 4%-16%), seroma (4%, 95% CI, 2%-7%), hematoma (2%, 95% CI, 1%-4%) and infection (0%-5%) on the TMG donor site was low. Functional impairments included sensory disturbance (0%-74%), motoric deficits (0%-50%), and changes in the genital region (0%-24%), all of which were modest. CONCLUSIONS: This review confirms the safety and low donor site morbidity of the TMG flap in normal-weight patients, which is comparable to that of other popular free flaps in breast reconstruction.

Prognostic role of the Donor Risk Index, the Eurotransplant Donor Risk Index, and the Balance of Risk score on graft loss after liver transplantation.

This study aimed to identify cutoff values for donor risk index (DRI), Eurotransplant (ET)-DRI, and balance of risk (BAR) scores that predict the risk of liver graft loss. MEDLINE and Web of Science databases were searched systematically and unrestrictedly. Graft loss odds ratios and 95% confidence intervals were assessed by meta-analyses using Mantel-Haenszel tests with a random-effects model. Cutoff values for predicting graft loss at 3 months, 1 year, and 3 years were analyzed for each of the scores. Measures of calibration and discrimination used in studies validating the DRI and the ET-DRI were summarized. DRI ≥ 1.4 (six studies, n = 35 580 patients) and ET-DRI ≥ 1.4 (four studies, n = 11 666 patients) were associated with the highest risk of graft loss at all time points. BAR > 18 was associated with the highest risk of 3-month and 1-year graft loss (n = 6499 patients). A DRI cutoff of 1.8 and an ET-DRI cutoff of 1.7 were estimated using a summary receiver operator characteristic curve, but the sensitivity and specificity of these cutoff values were low. A DRI and ET-DRI score ≥ 1.4 and a BAR score > 18 have a negative influence on graft survival, but these cutoff values are not well suited for predicting graft loss.

Automated mechanical cardiopulmonary resuscitation devices versus manual chest compressions in the treatment of cardiac arrest: protocol of a systematic review and meta-analysis comparing machine to human.

INTRODUCTION: Cardiac arrest is a leading cause of death in industrialised countries. Cardiopulmonary resuscitation (CPR) guidelines follow the principles of closed chest compression as described for the first time in 1960. Mechanical CPR devices are designed to improve chest compression quality, thus considering the improvement of resuscitation outcomes. This protocol outlines a systematic review and meta-analysis methodology to assess trials investigating the therapeutic effect of automated mechanical CPR devices at the rate of return of spontaneous circulation, neurological state and secondary endpoints (including short-term and long-term survival, injuries and surrogate parameters for CPR quality) in comparison with manual chest compressions in adults with cardiac arrest. METHODS AND ANALYSIS: A sensitive search strategy will be employed in established bibliographic databases from inception until the date of search, followed by forward and backward reference searching. We will include randomised and quasi-randomised trials in qualitative analysis thus comparing mechanical to manual CPR. Studies reporting survival outcomes will be included in quantitative analysis. Two reviewers will assess independently publications using a predefined data collection form. Standardised tools will be used for data extraction, risks of bias and quality of evidence. If enough studies are identified for meta-analysis, the measures of association will be calculated by dint of bivariate random-effects models. Statistical heterogeneity will be evaluated by I2-statistics and explored through sensitivity analysis. By comprehensive subgroup analysis we intend to identify subpopulations who may benefit from mechanical or manual CPR techniques. The reporting follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. ETHICS AND DISSEMINATION: No ethical approval will be needed because data from previous studies will be retrieved and analysed. Most resuscitation studies are conducted under an emergency exception for informed consent. This publication contains data deriving from a dissertation project. We will disseminate the results through publication in a peer-reviewed journal and at scientific conferences. PROSPERO REGISTRATION NUMBER: CRD42017051633.

Utilizing radar graphs in the visualization of simulation and estimation results in network meta-analysis.

Traditional visualization in meta-analysis uses forest plots to illustrate the combined treatment effect, along with the respective results from primary trials. While the purpose of visualization is clear in the pairwise setting, additional treatments broaden the focus and extend the results to be illustrated in network meta-analysis. The complexity increases further in situations where all potential contrasts in the network are compared to a predefined fixed value of interest, such as the 95% coverage evaluated against the nominal value of 95% in simulation studies. We propose utilizing radar graphs to illustrate results from network meta-analysis in cases where the interest lies in the comparison of estimated results (after fitting a network meta-analysis in a specific data set) or a performance measure (simulation study) to a pre-defined fixed reference value. Accounting for the complex high-dimensional data structure, the general picture of the full network is captured at once without increasing the space needed for visualization. Especially in large simulation studies, where multiple scenarios need to be visually combined to gain an overview on different scenarios, this type of illustration facilitates the discussion of results. Further properties, such as the expected variation due to the Monte-Carlo error or the differentiation between directly and indirectly estimated treatment contrasts in simulation studies, as well as the indication of well-connected and sparsely connected treatments in an applied network meta-analysis, can additionally be included in the visualization. While we used the radar-graph mainly for a simulation study, other applications are suitable whenever relative contributions of treatment (contrasts) are of interest.

Adverse drug reactions associated with amitriptyline - protocol for a systematic multiple-indication review and meta-analysis.

BACKGROUND: Unwanted anticholinergic effects are both underestimated and frequently overlooked. Failure to identify adverse drug reactions (ADRs) can lead to prescribing cascades and the unnecessary use of over-the-counter products. The objective of this systematic review and meta-analysis is to explore and quantify the frequency and severity of ADRs associated with amitriptyline vs. placebo in randomized controlled trials (RCTs) involving adults with any indication, as well as healthy individuals. METHODS: A systematic search in six electronic databases, forward/backward searches, manual searches, and searches for Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval studies, will be performed. Placebo-controlled RCTs evaluating amitriptyline in any dosage, regardless of indication and without restrictions on the time and language of publication, will be included, as will healthy individuals. Studies of topical amitriptyline, combination therapies, or including < 100 participants, will be excluded. Two investigators will screen the studies independently, assess methodological quality, and extract data on design, population, intervention, and outcomes ((non-)anticholinergic ADRs, e.g., symptoms, test results, and adverse drug events (ADEs) such as falls). The primary outcome will be the frequency of anticholinergic ADRs as a binary outcome (absolute number of patients with/without anticholinergic ADRs) in amitriptyline vs. placebo groups. Anticholinergic ADRs will be defined by an experienced clinical pharmacologist, based on literature and data from Martindale: The Complete Drug Reference. Secondary outcomes will be frequency and severity of (non-)anticholinergic ADRs and ADEs. The information will be synthesized in meta-analyses and narratives. We intend to assess heterogeneity using meta-regression (for indication, outcome, and time points) and I2 statistics. Binary outcomes will be expressed as odds ratios, and continuous outcomes as standardized mean differences. Effect measures will be provided using 95% confidence intervals. We plan sensitivity analyses to assess methodological quality, outcome reporting etc., and subgroup analyses on age, dosage, and duration of treatment. DISCUSSION: We will quantify the frequency of anticholinergic and other ADRs/ADEs in adults taking amitriptyline for any indication by comparing rates for amitriptyline vs. placebo, hence, preventing bias from disease symptoms and nocebo effects. As no standardized instrument exists to measure it, our overall estimate of anticholinergic ADRs may have limitations. SYSTEMATIC REVIEW REGISTRATION: Submitted to PROSPERO; assignment is in progress.

Continuous wound infiltration versus epidural analgesia for midline abdominal incisions - a randomized-controlled pilot trial (Painless-Pilot trial; DRKS Number: DRKS00008023).

OBJECTIVES: To test the feasibility of a randomized controlled study design comparing epidural analgesia (EDA) with continuous wound infiltration (CWI) in respect to postoperative complications and mobility to design a future multicentre randomized controlled trial. DESIGN, SETTING, PARTICIPANTS: CWI has been developed to address drawbacks of EDA. Previous studies have established the equivalent analgesic potential of CWI compared to EDA. This is a single centre, non-blinded pilot randomized controlled trial at a tertiary surgical centre. Patients undergoing elective non-colorectal surgery via a midline laparotomy were randomized to EDA or CWI. Endpoints included recruitment, feasibility of assessing postoperative mobility with a pedometer and morbidity. No primary endpoint was defined and all analyses were explorative. INTERVENTIONS: CWI with local anaesthetics (experimental group) vs. thoracic EDA (control). RESULTS: Of 846 patients screened within 14 months, 71 were randomized and 62 (31 per group) included in the intention-to-treat analysis. Mobility was assessed in 44 of 62 patients and revealed no differences within the first 3 postoperative days. Overall morbidity did not differ between the two groups (measured via the comprehensive complication index). Median pain scores at rest were comparable between the two groups, while EDA was superior in pain treatment during movement on the first, but not on the second and third postoperative day. Duration of preoperative induction of anaesthesia was shorter with CWI than with EDA. Of 17 serious adverse events, 3 were potentially related to EDA, while none was related to CWI. CONCLUSION: This trial confirmed the feasibility of a randomized trial design to compare CWI and EDA regarding morbidity. Improvements in the education and training of team members are necessary to improve recruitment. TRIAL REGISTRATION: DRKS00008023.

A comparison of Bayesian and frequentist methods in random-effects network meta-analysis of binary data.

The performance of statistical methods is often evaluated by means of simulation studies. In case of network meta-analysis of binary data, however, simulations are not currently available for many practically relevant settings. We perform a simulation study for sparse networks of trials under between-trial heterogeneity and including multi-arm trials. Results of the evaluation of two popular frequentist methods and a Bayesian approach using two different prior specifications are presented. Methods are evaluated using coverage, width of intervals, bias, and root mean squared error (RMSE). In addition, deviations from the theoretical surface under the cumulative rankings (SUCRAs) or P-scores of the treatments are evaluated. Under low heterogeneity and when a large number of trials informs the contrasts, all methods perform well with respect to the evaluated performance measures. Coverage is observed to be generally higher for the Bayesian than the frequentist methods. The width of credible intervals is larger than those of confidence intervals and is increasing when using a flatter prior for between-trial heterogeneity. Bias was generally small, but increased with heterogeneity, especially in netmeta. In some scenarios, the direction of bias differed between frequentist and Bayesian methods. The RMSE was comparable between methods but larger in indirectly than in directly estimated treatment effects. The deviation of the SUCRAs or P-scores from their theoretical values was mostly comparable over the methods but differed depending on the heterogeneity and the geometry of the investigated network. Multivariate meta-regression or Bayesian estimation using a half-normal prior scaled to 0.5 seems to be promising with respect to the evaluated performance measures in network meta-analysis of sparse networks.

Atherosclerosis is aggravated by iron overload and ameliorated by dietary and pharmacological iron restriction.

AIMS: Whether and how iron affects the progression of atherosclerosis remains highly debated. Here, we investigate susceptibility to atherosclerosis in a mouse model (ApoE-/- FPNwt/C326S), which develops the disease in the context of elevated non-transferrin bound serum iron (NTBI). METHODS AND RESULTS: Compared with normo-ferremic ApoE-/- mice, atherosclerosis is profoundly aggravated in iron-loaded ApoE-/- FPNwt/C326S mice, suggesting a pro-atherogenic role for iron. Iron heavily deposits in the arterial media layer, which correlates with plaque formation, vascular oxidative stress and dysfunction. Atherosclerosis is exacerbated by iron-triggered lipid profile alterations, vascular permeabilization, sustained endothelial activation, elevated pro-atherogenic inflammatory mediators, and reduced nitric oxide availability. NTBI causes iron overload, induces reactive oxygen species production and apoptosis in cultured vascular cells, and stimulates massive MCP-1-mediated monocyte recruitment, well-established mechanisms contributing to atherosclerosis. NTBI-mediated toxicity is prevented by transferrin- or chelator-mediated iron scavenging. Consistently, a low-iron diet and iron chelation therapy strongly improved the course of the disease in ApoE-/- FPNwt/C326S mice. Our results are corroborated by analyses of serum samples of haemochromatosis patients, which show an inverse correlation between the degree of iron depletion and hallmarks of endothelial dysfunction and inflammation. CONCLUSION: Our data demonstrate that NTBI-triggered iron overload aggravates atherosclerosis and unravel a causal link between NTBI and the progression of atherosclerotic lesions. Our findings support clinical applications of iron restriction in iron-loaded individuals to counteract iron-aggravated vascular dysfunction and atherosclerosis.

Simulation and data-generation for random-effects network meta-analysis of binary outcome.

The performance of statistical methods is frequently evaluated by means of simulation studies. In case of network meta-analysis of binary data, however, available data-generating models (DGMs) are restricted to either inclusion of two-armed trials or the fixed-effect model. Based on data-generation in the pairwise case, we propose a framework for the simulation of random-effect network meta-analyses including multiarm trials with binary outcome. The only one of the common DGMs used in the pairwise case, which is directly applicable to a random-effects network setting uses strongly restrictive assumptions. To overcome these limitations, we modify this approach and derive a related simulation procedure using odds ratios as effect measure. The performance of this procedure is evaluated with synthetic data and in an empirical example.

Likelihood-based random-effects meta-analysis with few studies: empirical and simulation studies.

BACKGROUND: Standard random-effects meta-analysis methods perform poorly when applied to few studies only. Such settings however are commonly encountered in practice. It is unclear, whether or to what extent small-sample-size behaviour can be improved by more sophisticated modeling. METHODS: We consider likelihood-based methods, the DerSimonian-Laird approach, Empirical Bayes, several adjustment methods and a fully Bayesian approach. Confidence intervals are based on a normal approximation, or on adjustments based on the Student-t-distribution. In addition, a linear mixed model and two generalized linear mixed models (GLMMs) assuming binomial or Poisson distributed numbers of events per study arm are considered for pairwise binary meta-analyses. We extract an empirical data set of 40 meta-analyses from recent reviews published by the German Institute for Quality and Efficiency in Health Care (IQWiG). Methods are then compared empirically as well as in a simulation study, based on few studies, imbalanced study sizes, and considering odds-ratio (OR) and risk ratio (RR) effect sizes. Coverage probabilities and interval widths for the combined effect estimate are evaluated to compare the different approaches. RESULTS: Empirically, a majority of the identified meta-analyses include only 2 studies. Variation of methods or effect measures affects the estimation results. In the simulation study, coverage probability is, in the presence of heterogeneity and few studies, mostly below the nominal level for all frequentist methods based on normal approximation, in particular when sizes in meta-analyses are not balanced, but improve when confidence intervals are adjusted. Bayesian methods result in better coverage than the frequentist methods with normal approximation in all scenarios, except for some cases of very large heterogeneity where the coverage is slightly lower. Credible intervals are empirically and in the simulation study wider than unadjusted confidence intervals, but considerably narrower than adjusted ones, with some exceptions when considering RRs and small numbers of patients per trial-arm. Confidence intervals based on the GLMMs are, in general, slightly narrower than those from other frequentist methods. Some methods turned out impractical due to frequent numerical problems. CONCLUSIONS: In the presence of between-study heterogeneity, especially with unbalanced study sizes, caution is needed in applying meta-analytical methods to few studies, as either coverage probabilities might be compromised, or intervals are inconclusively wide. Bayesian estimation with a sensibly chosen prior for between-trial heterogeneity may offer a promising compromise.