Two-stage or not two-stage? That is the question for IPD meta-analysis projects

Individual participant data meta-analysis (IPDMA) projects obtain, check, harmonise and synthesise raw data from multiple studies. When undertaking the meta-analysis, researchers must decide between a two-stage or a one-stage approach. In a two-stage approach, the IPD are first analysed separately within each study to obtain aggregate data (e.g., treatment effect estimates and standard errors); then, in the second stage, these aggregate data are combined in a standard meta-analysis model (e.g., common-effect or random-effects). In a one-stage approach, the IPD from all studies are analysed in a single step using an appropriate model that accounts for clustering of participants within studies and, potentially, between-study heterogeneity (e.g., a general or generalised linear mixed model). The best approach to take is debated in the literature, and so here we provide clearer guidance for a broad audience. Both approaches are important tools for IPDMA researchers and neither are a panacea. If most studies in the IPDMA are small (few participants or events), a one-stage approach is recommended due to using a more exact likelihood. However, in other situations, researchers can choose either approach, carefully following best practice. Some previous claims recommending to always use a one-stage approach are misleading, and the two-stage approach will often suffice for most researchers. When differences do arise between the two approaches, often it is caused by researchers using different modelling assumptions or estimation methods, rather than using one or two stages per se

Textkohärenz beim schriftlichen Ausdruck. Theoretische Ansätze und didaktische Überlegungen auf B2-Niveau.

Στόχος της εργασίας μου είναι να δείξω πώς ορισμένοι τομείς της κειμενογλωσσολογίας, όπως οι τρόποι αναφοράς και οι σύνδεσμοι, θα μπορούσαν να είναι χρήσιμοι στη διδασκαλία ξένων γλωσσών για την καλύτερη κατανόηση και παραγωγή κειμένων. Για το σκοπό αυτό, θα συγκεντρώσω εκθέσεις μαθητών και θα καθορίσω αν και σε ποιο βαθμό αυτοί χρησιμοποίησαν σωστά τους συνδέσμους και τους τρόπους αναφοράς. Στη συνέχεια θα κάνω προτάσεις και ασκήσεις που θα τους βοηθήσουν να βελτιώσουν τις εκθέσεις τους.Ziel meiner Hausarbeit ist es zu zeigen, wie einige Bereiche der Textlinguistik, wie Referenzformen und Konnektoren, im Fremdsprachenunterricht hilfreich sein könnten, um Texte besser zu verstehen und zu produzieren. Zu diesem Ziel werde ich Aufsätze sammeln und feststellen, ob und inwieweit die Schüler die Konnektoren und die Referenzformen richtig verwendet haben. Anschließend werde ich Vorschläge machen bzw. Übungen anfertigen, die ihnen helfen werden, ihre Aufsätze zu verbesser

Pattern-mixture model in network meta-analysis of binary missing outcome data: one-stage or two-stage approach?

Background!#!Trials with binary outcomes can be synthesised using within-trial exact likelihood or approximate normal likelihood in one-stage or two-stage approaches, respectively. The performance of the one-stage and the two-stage approaches has been documented extensively in the literature. However, little is known about how these approaches behave in the presence of missing outcome data (MOD), which are ubiquitous in clinical trials. In this work, we compare the one-stage versus two-stage approach via a pattern-mixture model in the network meta-analysis using Bayesian methods to handle MOD appropriately.!##!Methods!#!We used 29 published networks to empirically compare the two approaches concerning the relative treatment effects of several competing interventions and the between-trial variance (τ!##!Results!#!The empirical study did not reveal any systematic bias between the compared approaches regarding the log OR, but showed systematically larger uncertainty around the log OR under the one-stage approach for networks with at least one small trial or low event risk and moderate MOD. For these networks, the simulation study revealed that the bias in log OR for comparisons with the reference intervention in the network was relatively higher in the two-stage approach. Contrariwise, the bias in log OR for the remaining comparisons was relatively higher in the one-stage approach. Overall, bias increased for large MOD. For these networks, the empirical results revealed slightly higher τ!##!Conclusions!#!Due to considerable bias in the log ORs overall, especially for large MOD, none of the competing approaches was superior. Until a more competent model is developed, the researchers may prefer the one-stage approach to handle MOD, while acknowledging its limitations

How robust are findings of pairwise and network meta-analysis in the presence of missing participant outcome data?

Background!#!To investigate the prevalence of robust conclusions in systematic reviews addressing missing (participant) outcome data via a novel framework of sensitivity analyses and examine the agreement with the current sensitivity analysis standards.!##!Methods!#!We performed an empirical study on systematic reviews with two or more interventions. Pairwise meta-analyses (PMA) and network meta-analyses (NMA) were identified from empirical studies on the reporting and handling of missing outcome data in systematic reviews. PMAs with at least three studies and NMAs with at least three interventions on one primary outcome were considered eligible. We applied Bayesian methods to obtain the summary effect estimates whilst modelling missing outcome data under the missing-at-random assumption and different assumptions about the missingness mechanism in the compared interventions. The odds ratio in the logarithmic scale was considered for the binary outcomes and the standardised mean difference for the continuous outcomes. We calculated the proportion of primary analyses with robust and frail conclusions, quantified by our proposed metric, the robustness index (RI), and current sensitivity analysis standards. Cohen's kappa statistic was used to measure the agreement between the conclusions derived by the RI and the current sensitivity analysis standards.!##!Results!#!One hundred eight PMAs and 34 NMAs were considered. When studies with a substantial number of missing outcome data dominated the analyses, the number of frail conclusions increased. The RI indicated that 59% of the analyses failed to demonstrate robustness compared to 39% when the current sensitivity analysis standards were employed. Comparing the RI with the current sensitivity analysis standards revealed that two in five analyses yielded contradictory conclusions concerning the robustness of the primary analysis results.!##!Conclusions!#!Compared with the current sensitivity analysis standards, the RI offers an explicit definition of similar results and does not unduly rely on statistical significance. Hence, it may safeguard against possible spurious conclusions regarding the robustness of the primary analysis results

Two‐stage or not two‐stage? That is the question for IPD meta‐analysis projects

Individual participant data meta‐analysis (IPDMA) projects obtain, check, harmonise and synthesise raw data from multiple studies. When undertaking the meta‐analysis, researchers must decide between a two‐stage or a one‐stage approach. In a two‐stage approach, the IPD are first analysed separately within each study to obtain aggregate data (e.g., treatment effect estimates and standard errors); then, in the second stage, these aggregate data are combined in a standard meta‐analysis model (e.g., common‐effect or random‐effects). In a one‐stage approach, the IPD from all studies are analysed in a single step using an appropriate model that accounts for clustering of participants within studies and, potentially, between‐study heterogeneity (e.g., a general or generalised linear mixed model). The best approach to take is debated in the literature, and so here we provide clearer guidance for a broad audience. Both approaches are important tools for IPDMA researchers and neither are a panacea. If most studies in the IPDMA are small (few participants or events), a one‐stage approach is recommended due to using a more exact likelihood. However, in other situations, researchers can choose either approach, carefully following best practice. Some previous claims recommending to always use a one‐stage approach are misleading, and the two‐stage approach will often suffice for most researchers. When differences do arise between the two approaches, often it is caused by researchers using different modelling assumptions or estimation methods, rather than using one or two stages per se

Supplemental Material - Dealing with censoring in a network meta-analysis of time-to-event data

Supplemental Material for Dealing with censoring in a network meta-analysis of time-to-event data by Chrysostomos Kalyvas, Katerina Papadimitropoulou, William Malbecq and Loukia M. Spineli in Research Methods in Medicine & Health Sciences</p

Comparative efficacy and tolerability of pharmacological and somatic interventions in adult patients with treatment-resistant depression: a systematic review and network meta-analysis

<p><b>Objective:</b> Major depressive disorder (MDD) affects about 10–15% of the general population in a lifetime. A considerable number of patients fail to achieve full symptom remission despite adequate treatment and are considered treatment resistant (TRD). The current study compared the relative efficacy and tolerability of pharmacological and somatic TRD interventions by means of a Bayesian network meta-analysis.</p> <p><b>Research design and methods:</b> An electronic literature search of MEDLINE, MEDLINE In-Process, EMBASE, PsycInfo, EconLit and Cochrane Library databases for trials published between September 2003 and September 2014 was conducted. Key outcomes extracted were disease severity change from baseline, response and remission rates at various timepoints and discontinuation due to adverse events.</p> <p><b>Results:</b> Of the 3876 abstracts identified, 31 publications/randomised controlled trials (RCTs) were included in the analysis; 19 RCTs investigating 13 pharmacological interventions and 12 RCTs investigating electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS). The evidence synthesis investigating efficacy outcomes of TRD treatments demonstrated superior efficacy for ketamine compared to pharmacological and somatic interventions at 2 weeks after treatment initiation. At 4, 6 and 8 weeks, quetiapine augmentation (800 mg/day) and risperidone augmentation were found to be the first and second best treatments, respectively. Networks were small for response rate and remission rate outcomes at most timepoints. The most tolerable treatment was lamotrigine augmentation showing a comparable profile to placebo/sham.</p> <p><b>Conclusions:</b> This analysis revealed scarcity of long-term data on sustained remission that would allow a comparative long-term efficacy assessment. Key limitations of the analysis can be considered the search timeframe and the use of mapping formula for the depression scores.</p

High correlation of VAS pain scores after 2 and 6 weeks of treatment with VAS pain scores at 12 weeks in randomised controlled trials in rheumatoid arthritis and osteoarthritis : meta-analysis and implications

BACKGROUND: Researchers in clinical trials in rheumatoid arthritis (RA) and osteoarthritis (OA) often measure pain levels with a visual analogue scale (VAS). Of interest to clinical practice and future clinical trial design are associations of change from baseline (CFB) between time points with predictive ability of earlier response for long-term treatment benefit. We assessed the association and predictive ability of CFB in VAS pain between 2, 6 and 12 weeks in randomised controlled trials (RCTs) of non-steroidal anti-inflammatory drugs (NSAIDs). METHODS: Aggregated VAS pain data at baseline and CFB at 2, 6 and 12 weeks were collected from a systematic literature review of 176 RCTs in OA and RA. The predictive ability of earlier assessments for longer-term pain reduction was estimated using correlation and regression analyses. Analysis was performed using the R software package for statistical programming, version 3.1.1. RESULTS: Appropriate data were available from 50 RCTs (22,854 patients). Correlations between time points were high (weighted correlation coefficients between 2 and 6 weeks, 0.84; between 2 and 12 weeks, 0.79; and between 6 and 12 weeks, 0.96). CFB at 6 weeks was highly predictive and close to CFB at 12 weeks (regression coefficient 0.9, 95 % confidence interval 0.9-1.0). CFB at 2 weeks was significantly associated with CFB at 12 (0.8, 0.7-0.8) and 6 weeks (0.9, 0.8-1.0). CONCLUSIONS: The results showed that early analgesic response measured by VAS for pain beyond 2 weeks of treatment with a particular NSAID is likely to be predictive of response at 12 weeks. Failure to achieve desired pain relief in OA and RA after 2 weeks should trigger reassessment of dosage and/or analgesic

Additional file 3: of High correlation of VAS pain scores after 2 and 6Â weeks of treatment with VAS pain scores at 12Â weeks in randomised controlled trials in rheumatoid arthritis and osteoarthritis: meta-analysis and implications

Patient characteristics. (PDF 321 kb