scholarly journals Comparing the use of aggregate data and various methods of integrating individual patient data to network meta-analysis and its application to first-line ART

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Steve Kanters ◽  
Mohammad Ehsanul Karim ◽  
Kristian Thorlund ◽  
Aslam H. Anis ◽  
Michael Zoratti ◽  
...  
Keyword(s):  
Meta Analysis ◽  
Evidence Base ◽  
Aggregate Data ◽  
World Health ◽  
Coefficient Estimates ◽  
Two Stage ◽  
Individual Patient Level ◽  
One Stage ◽  
Meta Regression ◽  
Empirical Priors

Abstract Background The 2018 World Health Organization HIV guidelines were based on the results of a network meta-analysis (NMA) of published trials. This study employed individual patient-level data (IPD) and aggregate data (AgD) and meta-regression methods to assess the evidence supporting the WHO recommendations and whether they needed any refinements. Methods Access to IPD from three trials was granted through ClinicalStudyDataRequest.com (CSDR). Seven modelling approaches were applied and compared: 1) Unadjusted AgD network meta-analysis (NMA) – the original analysis; 2) AgD-NMA with meta-regression; 3) Two-stage IPD-AgD NMA; 4) Unadjusted one-stage IPD-AgD NMA; 5) One-stage IPD-AgD NMA with meta-regression (one-stage approach); 6) Two-stage IPD-AgD NMA with empirical-priors (empirical-priors approach); 7) Hierarchical meta-regression IPD-AgD NMA (HMR approach). The first two were the models used previously. Models were compared with respect to effect estimates, changes in the effect estimates, coefficient estimates, DIC and model fit, rankings and between-study heterogeneity. Results IPD were available for 2160 patients, representing 6.5% of the evidence base and 3 of 24 edges. The aspect of the model affected by the choice of modeling appeared to differ across outcomes. HMR consistently generated larger intervals, often with credible intervals (CrI) containing the null value. Discontinuations due to adverse events and viral suppression at 96 weeks were the only two outcomes for which the unadjusted AgD NMA would not be selected. For the first, the selected model shifted the principal comparison of interest from an odds ratio of 0.28 (95% CrI: 10.17, 0.44) to 0.37 (95% CrI: 0.23, 0.58). Throughout all outcomes, the regression estimates differed substantially between AgD and IPD methods, with the latter being more often larger in magnitude and statistically significant. Conclusions Overall, the use of IPD often impacted the coefficient estimates, but not sufficiently as to necessitate altering the final recommendations of the 2018 WHO Guidelines. Future work should examine the features of a network where adjustments will have an impact, such as how much IPD is required in a given size of network.

Standardization of Factor VIII – IV. Establishment of the 3rd International Standard for Factor VIII: C Concentrate

1983 ◽  
Vol 50 (03) ◽  
pp. 697-702 ◽  
Author(s):  
T W Barrowcliffe ◽  
A D Curtis ◽  
D P Thomas
Keyword(s):  
Factor Viii ◽  
High Purity ◽  
Collaborative Study ◽  
World Health ◽  
Current Standard ◽  
Two Stage ◽  
International Standard ◽  
One Stage ◽  
The One ◽  
Health Organization

SummaryAn international collaborative study was carried out to establish a replacement for the current (2nd) international standard for Factor VIII: C, concentrate. Twenty-six laboratories took part, of which 17 performed one-stage assays, three performed two-stage assays and six used both methods. The proposed new standard, an intermediate purity concentrate, was assayed against the current standard, against a high-purity concentrate and against an International Reference Plasma, coded 80/511, previously calibrated against fresh normal plasma.Assays of the proposed new standard against the current standard gave a mean potency of 3.89 iu/ampoule, with good agreement between laboratories and between one-stage and two- stage assays. There was also no difference between assay methods in the comparison of high-purity and intermediate purity concentrates. In the comparison of the proposed standard with the plasma reference preparation, the overall mean potency was 4.03 iu/ampoule, but there were substantial differences between laboratories, and the two-stage method gave significantly higher results than the one stage method. Of the technical variables in the one-stage method, only the activation time with one reagent appeared to have any influence on the results of this comparison of concentrate against plasma.Accelerated degradation studies showed that the proposed standard is very stable. With the agreement of the participants, the material, in ampoules coded 80/556, has been established by the World Health Organization as the 3rd International Standard for Factor VIII :C, Concentrate, with an assigned potency of 3.9 iu/ampoule.

scholarly journals Approaches for combining primary care electronic health record data from multiple sources: a systematic review of observational studies

BMJ Open ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. e037405
Author(s):  
Daniel Dedman ◽  
Melissa Cabecinha ◽  
Rachael Williams ◽  
Stephen J W Evans ◽  
Krishnan Bhaskaran ◽  
...  
Keyword(s):  
Systematic Review ◽  
Primary Care ◽  
Electronic Health Record ◽  
Observational Studies ◽  
Meta Analysis ◽  
Data Sources ◽  
Health Record ◽  
Two Stage ◽  
One Stage ◽  
Electronic Health

ObjectiveTo identify observational studies which used data from more than one primary care electronic health record (EHR) database, and summarise key characteristics including: objective and rationale for using multiple data sources; methods used to manage, analyse and (where applicable) combine data; and approaches used to assess and report heterogeneity between data sources.DesignA systematic review of published studies.Data sourcesPubmed and Embase databases were searched using list of named primary care EHR databases; supplementary hand searches of reference list of studies were retained after initial screening.Study selectionObservational studies published between January 2000 and May 2018 were selected, which included at least two different primary care EHR databases.Results6054 studies were identified from database and hand searches, and 109 were included in the final review, the majority published between 2014 and 2018. Included studies used 38 different primary care EHR data sources. Forty-seven studies (44%) were descriptive or methodological. Of 62 analytical studies, 22 (36%) presented separate results from each database, with no attempt to combine them; 29 (48%) combined individual patient data in a one-stage meta-analysis and 21 (34%) combined estimates from each database using two-stage meta-analysis. Discussion and exploration of heterogeneity was inconsistent across studies.ConclusionsComparing patterns and trends in different populations, or in different primary care EHR databases from the same populations, is important and a common objective for multi-database studies. When combining results from several databases using meta-analysis, provision of separate results from each database is helpful for interpretation. We found that these were often missing, particularly for studies using one-stage approaches, which also often lacked details of any statistical adjustment for heterogeneity and/or clustering. For two-stage meta-analysis, a clear rationale should be provided for choice of fixed effect and/or random effects or other models.

scholarly journals Deriving percentage study weights in multi-parameter meta-analysis models: with application to meta-regression, network meta-analysis and one-stage individual participant data models

2017 ◽  
Vol 27 (10) ◽  
pp. 2885-2905 ◽  
Author(s):  
Richard D Riley ◽  
Joie Ensor ◽  
Dan Jackson ◽  
Danielle L Burke
Keyword(s):  
Meta Analysis ◽  
Information Matrix ◽  
Indirect Evidence ◽  
Parameter Estimates ◽  
Individual Participant Data ◽  
One Stage ◽  
Individual Participant ◽  
Meta Regression ◽  
Multiple Treatments ◽  
Analysis Models

Many meta-analysis models contain multiple parameters, for example due to multiple outcomes, multiple treatments or multiple regression coefficients. In particular, meta-regression models may contain multiple study-level covariates, and one-stage individual participant data meta-analysis models may contain multiple patient-level covariates and interactions. Here, we propose how to derive percentage study weights for such situations, in order to reveal the (otherwise hidden) contribution of each study toward the parameter estimates of interest. We assume that studies are independent, and utilise a decomposition of Fisher’s information matrix to decompose the total variance matrix of parameter estimates into study-specific contributions, from which percentage weights are derived. This approach generalises how percentage weights are calculated in a traditional, single parameter meta-analysis model. Application is made to one- and two-stage individual participant data meta-analyses, meta-regression and network (multivariate) meta-analysis of multiple treatments. These reveal percentage study weights toward clinically important estimates, such as summary treatment effects and treatment-covariate interactions, and are especially useful when some studies are potential outliers or at high risk of bias. We also derive percentage study weights toward methodologically interesting measures, such as the magnitude of ecological bias (difference between within-study and across-study associations) and the amount of inconsistency (difference between direct and indirect evidence in a network meta-analysis).

scholarly journals The impact of inclusion, dose and duration of pyrazinamide (PZA) on efficacy and safety outcomes in tuberculosis: systematic review and meta-analysis protocol

2019 ◽  
Vol 8 (1) ◽  
Author(s):  
James D. Millard ◽  
Elizabeth A. Mackay ◽  
Laura J. Bonnett ◽  
Geraint R. Davies
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Meta Analysis ◽  
World Health ◽  
Controlled Trials ◽  
Cochrane Central Register ◽  
Efficacy And Safety ◽  
Safety Outcomes ◽  
Meta Regression ◽  
Indirect Comparisons

Abstract Background Pyrazinamide (PZA) is a key component of current and future regimens for tuberculosis (TB). Inclusion of PZA at higher doses and for longer durations may improve efficacy outcomes but must be balanced against the potential for worse safety outcomes. Methods We will search for randomised and quasi-randomised clinical trials in adult participants with and without the inclusion of PZA in TB treatment regimens in the Cochrane infectious diseases group’s trials register, Cochrane central register of controlled trials (CENTRAL), MEDLINE, EMBASE, LILACS, the metaRegister of Controlled Trials (mRCT) and the World Health Organization (WHO) international clinical trials registry platform. One author will screen abstracts and remove ineligible studies (10% of which will be double-screened by a second author). Two authors will review full texts for inclusion. Safety and efficacy data will be extracted to pre-piloted forms by one author (10% of which will be double-extracted by a second author). The Cochrane risk of bias tool will be used to assess study quality. The study has three objectives: the association of (1) inclusion, (2) dose and (3) duration of PZA with efficacy and safety outcomes. Risk ratios as relative measures of effect for direct comparisons within trials (all objectives) and proportions as absolute measures of effect for indirect comparisons across trials (for objectives 2 and 3) will be calculated. If there is insufficient data for direct comparisons within trials for objective 1, indirect comparisons between trials will be performed. Measures of effect will be pooled, with corresponding 95% confidence intervals and p values. Meta-analysis will be performed using the generalised inverse variance method for fixed effects models (FEM) or the DerSimonian-Laird method for random effects models (REM). For indirect comparisons, meta-regression for absolute measures against dose and duration data will be performed. Heterogeneity will be quantified through the I2-statistic for direct comparisons and the τ2 statistic for indirect comparisons using meta-regression. Discussion The current use of PZA for TB is based on over 60 years of clinical trial data, but this has never been synthesised to guide rationale use in future regimens and clinical trials. Systematic review registration: International Prospective Register of Systematic Reviews (PROSPERO) CRD42019138735

An International Collaborative Assay of Factor VIII Clotting Activity

1978 ◽  
Vol 40 (02) ◽  
pp. 260-271 ◽  
Author(s):  
T W Barrowcliffe ◽  
T B L Kirkwood
Keyword(s):  
Factor Viii ◽  
World Health ◽  
Expert Committee ◽  
Two Stage ◽  
International Standard ◽  
One Stage ◽  
Normal Plasma ◽  
Freeze Dried ◽  
The Mean ◽  
International Collaborative

SummaryAn International Collaborative Study was organised to replace the first International Standard for factor VIII. A freeze-dried concentrate, 73/552, and a freeze-dried plasma, 75/510, were assayed against the International Standard, and also compared to fresh normal plasma and local standards.In assays of the concentrate 73/552 against the first I.S. the mean potency was 1.14 i.u./ ampoule and there was no significant difference between one-stage and two-stage methods. When assayed against average fresh normal plasma, the potency was 1.05 “normal plasma units” per ampoule. It was agreed by the participants that the potency of 73/552 be regarded as the mean of these two figures, i.e. 1.10 i. u./ampoule.In assays of the freeze-dried plasma, 75/510, against the first I.S. the mean potency was 0. 68 i. u./ampoule, but the one-stage assays gave significantly higher potencies (mean 0.74 1. u./ampoule) than the two-stage assays (mean 0.59 i. u./ampoule). The same trend was also seen in the fresh normal plasmas, and in the local plasma standards. This finding has important implications for the standardisation of factor VIII.Stability studies on the concentrate 73/552 gave a predicted loss of 0.02% per year at – 20° C. All participants agreed that the material was suitable to serve as an International Standard, and at the 26th meeting of the Expert Committee on Biological Standardisation of the World Health Organization, the material in ampoules coded 73/552 was established as the 2nd International Standard for factor VIII, with a potency of 1.10 i. u./ampoule.

scholarly journals Flexible piecewise linear model for investigating dose-response relationship in meta-analysis: methodology, examples, and comparison

2018 ◽  
Author(s):  
Chang Xu ◽  
Lehana Thabane ◽  
Tong-Zu Liu ◽  
Ling Li ◽  
Sayem Borhan ◽  
...  
Keyword(s):  
Linear Model ◽  
Dose Response ◽  
Linear Trend ◽  
Piecewise Linear ◽  
Meta Analysis ◽  
Continuous Exposure ◽  
Response Relationship ◽  
Dose Response Relationship ◽  
Two Stage ◽  
One Stage

Objectives: Dose-response meta-analysis (DRMA) is widely employed to establishing the potential dose-response relationship between continuous exposures and disease outcomes. However, no method is readily available for exploring the relation between a discrete exposure and a binary or continuous outcome. We proposed a piecewise linear (PL) DRMA model as a solution to this issue. Methods: We illustrated the methodology of PL model in both one-stage DRMA approach and two-stage DRMA approach. The method by testing the equality of slopes of each piecewise was employed to judge if there is “piecewise effect” against simple linear trend. We then used sleep (continuous exposure) and parity (discrete exposure) data as examples to illustrate how to apply PL model in DRMA using the Stata code attached. We also empirically compared the slopes of PL model with simple linear as well as restricted cubic spline (RCS) model. Results: Both one-stage and two-stage PL DRMA model fitted well in our examples, and the results were similar. Obvious “piecewise effects” were detected in both the two examples by the method we used. In our example, the PL model showed better fitting effect and practical reliable results compared to simple linear model, while similar results for to RCS model. Conclusion: Piecewise linear function is a simple and valid method for DRMA and can be used for discrete exposures. It also represents a superior model to linear model in DRMA and may be an alternative model to non-linear model.

scholarly journals Multilevel Meta-Analysis of Individual Participant Data of Single-Case Experimental Designs: One-Stage versus Two-Stage Methods

2020 ◽  
pp. 1-20
Author(s):  
Lies Declercq ◽  
Laleh Jamshidi ◽  
Belén Fernández Castilla ◽  
Mariola Moeyaert ◽  
S. Natasha Beretvas ◽  
...  
Keyword(s):  
Single Case ◽  
Meta Analysis ◽  
Experimental Designs ◽  
Individual Participant Data ◽  
Stage Versus ◽  
Two Stage ◽  
One Stage ◽  
Individual Participant

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

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Loukia M. Spineli ◽  
Katerina Papadimitropoulou ◽  
Chrysostomos Kalyvas
Keyword(s):  
Mixture Model ◽  
Simulation Study ◽  
Meta Analysis ◽  
Credible Interval ◽  
Outcome Data ◽  
Systematic Bias ◽  
Two Stage ◽  
Pattern Mixture Model ◽  
One Stage ◽  
The One

Abstract 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 (τ2), while considering the extent and level of balance of MOD in the included trials. We additionally conducted a simulation study to compare the competing approaches regarding the bias and width of the 95% credible interval of the (summary) log odds ratios (OR) and τ2 in the presence of moderate and large MOD. 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 τ2 estimates under the one-stage approach irrespective of the extent of MOD. The one-stage approach also led to less precise log OR and τ2 when compared with the two-stage approach for large MOD. 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.

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