scholarly journals Assessing the impact of case-mix heterogeneity in individual participant data meta-analysis: Novel use of I2 statistic and prediction interval

2020 ◽  
Vol 2 (1) ◽  
pp. 12-30
Author(s):  
Tat-Thang Vo ◽  
Raphaël Porcher ◽  
Stijn Vansteelandt
Keyword(s):  
Prediction Interval ◽  
Meta Analysis ◽  
Target Population ◽  
Prediction Intervals ◽  
Case Mix ◽  
Individual Participant Data ◽  
New Approaches ◽  
Statistical Heterogeneity ◽  
Individual Participant ◽  
The Impact

Case mix differences between trials form an important factor that contributes to the statistical heterogeneity observed in a meta-analysis. In this paper, we propose two methods to assess whether important heterogeneity would remain if the different trials in the meta-analysis were conducted in one common population defined by a given case-mix. To achieve this goal, we first standardize results of different trials over the case-mix of a target population. We then quantify the amount of heterogeneity arising from case-mix and beyond case-mix reasons by using corresponding I2 statistics and prediction intervals. These new approaches enable a better understanding of the overall heterogeneity between trial results, and can be used to support standard heterogeneity assessments in individual participant data meta-analysis practice.

scholarly journals Exercise-based cardiac rehabilitation for chronic heart failure: the EXTRAMATCH II individual participant data meta-analysis

2019 ◽  
Vol 23 (25) ◽  
pp. 1-98 ◽  
Author(s):  
Rod S Taylor ◽  
Sarah Walker ◽  
Oriana Ciani ◽  
Fiona Warren ◽  
Neil A Smart ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Exercise Capacity ◽  
Meta Analysis ◽  
Patient Characteristics ◽  
Individual Participant Data ◽  
Significant Difference ◽  
Individual Participant ◽  
The Impact

Background Current national and international guidelines on the management of heart failure (HF) recommend exercise-based cardiac rehabilitation (ExCR), but do not differentiate this recommendation according to patient subgroups. Objectives (1) To obtain definitive estimates of the impact of ExCR interventions compared with no exercise intervention (control) on mortality, hospitalisation, exercise capacity and health-related quality of life (HRQoL) in HF patients; (2) to determine the differential (subgroup) effects of ExCR in HF patients according to their age, sex, left ventricular ejection fraction, HF aetiology, New York Heart Association class and baseline exercise capacity; and (3) to assess whether or not the change in exercise capacity mediates for the impact of the ExCR on final outcomes (mortality, hospitalisation and HRQoL), and determine if this is an acceptable surrogate end point. Design This was an individual participant data (IPD) meta-analysis. Setting An international literature review. Participants HF patients in randomised controlled trials (RCTs) of ExCR. Interventions ExCR for at least 3 weeks compared with a no-exercise control, with 6 months’ follow-up. Main outcome measures All-cause and HF-specific mortality, all-cause and HF-specific hospitalisation, exercise capacity and HRQoL. Data sources IPD from eligible RCTs. Review methods RCTs from the Exercise Training Meta-Analysis of Trials for Chronic Heart Failure (ExTraMATCH/ExTraMATCH II) IPD meta-analysis and a 2014 Cochrane systematic review of ExCR (Taylor RS, Sagar VA, Davies EJ, Briscoe S, Coats AJ, Dalal H, et al. Exercise-based rehabilitation for heart failure. Cochrane Database Syst Rev 2014;4:CD003331). Results Out of the 23 eligible RCTs (4398 patients), 19 RCTs (3990 patients) contributed data to this IPD meta-analysis. There was a wide variation in exercise programme prescriptions across included studies. Compared with control, there was no statistically significant difference in pooled time-to-event estimates in favour of ExCR, although confidence intervals (CIs) were wide: all-cause mortality had a hazard ratio (HR) of 0.83 (95% CI 0.67 to 1.04); HF-related mortality had a HR of 0.84 (95% CI 0.49 to 1.46); all-cause hospitalisation had a HR of 0.90 (95% CI 0.76 to 1.06); and HF-related hospitalisation had a HR of 0.98 (95% CI 0.72 to 1.35). There was a statistically significant difference in favour of ExCR for exercise capacity and HRQoL. Compared with the control, improvements were seen in the 6-minute walk test (6MWT) (mean 21.0 m, 95% CI 1.57 to 40.4 m) and Minnesota Living with Heart Failure Questionnaire score (mean –5.94, 95% CI –1.0 to –10.9; lower scores indicate improved HRQoL) at 12 months’ follow-up. No strong evidence for differential intervention effects across patient characteristics was found for any outcomes. Moderate to good levels of correlation (R 2 trial > 50% and p > 0.50) between peak oxygen uptake (VO2peak) or the 6MWT with mortality and HRQoL were seen. The estimated surrogate threshold effect was an increase of 1.6 to 4.6 ml/kg/minute for VO2peak. Limitations There was a lack of consistency in how included RCTs defined and collected the outcomes: it was not possible to obtain IPD from all includable trials for all outcomes and patient-level data on exercise adherence was not sought. Conclusions In comparison with the no-exercise control, participation in ExCR improved the exercise and HRQoL in HF patients, but appeared to have no effect on their mortality or hospitalisation. No strong evidence was found of differential intervention effects of ExCR across patient characteristics. VO2peak and 6MWT may be suitable surrogate end points for the treatment effect of ExCR on mortality and HRQoL in HF. Future studies should aim to achieve a consensus on the definition of outcomes and promote reporting of a core set of HF data. The research team also seeks to extend current policies to encourage study authors to allow access to RCT data for the purpose of meta-analysis. Study registration This study is registered as PROSPERO CRD42014007170. Funding The National Institute for Health Research Health Technology Assessment programme.

scholarly journals A novel approach for identifying and addressing case‐mix heterogeneity in individual participant data meta‐analysis

2019 ◽  
Vol 10 (4) ◽  
pp. 582-596 ◽  
Author(s):  
Tat‐Thang Vo ◽  
Raphael Porcher ◽  
Anna Chaimani ◽  
Stijn Vansteelandt
Keyword(s):  
Meta Analysis ◽  
Case Mix ◽  
Individual Participant Data ◽  
Novel Approach ◽  
Individual Participant

scholarly journals Vitamin D status and risk of incident tuberculosis disease: a systematic review and individual participant data meta-analysis

2018 ◽  
Author(s):  
Omowunmi Aibana ◽  
Chuan-Chin Huang ◽  
Said Aboud ◽  
Alberto Arnedo-Pena ◽  
Mercedes C. Becerra ◽  
...  
Keyword(s):  
Vitamin D ◽  
Clinical Trials ◽  
Meta Analysis ◽  
Vitamin D Supplementation ◽  
Dependent Manner ◽  
Individual Participant Data ◽  
Vitamin D Levels ◽  
Clinical Trials Unit ◽  
Individual Participant ◽  
The Impact

ABSTRACTBackgroundFew studies have evaluated the association between pre-existing vitamin D deficiency (VDD) and incident TB. We assessed the impact of baseline vitamin D on TB risk.MethodsWe assessed the association between baseline vitamin D and incident TB in a prospective cohort of 6751 household contacts of TB patients in Peru. We also conducted a one-stage individual participant data meta-analysis searching PubMed and Embase for studies of vitamin D and TB until December 31, 2017. We included studies that assessed vitamin D before TB diagnosis. We defined VDD as 25–(OH)D <50 nmol/L, insufficiency as 50–75 nmol/L and sufficiency as >75nmol/L. We estimated the association between vitamin D and incident TB using conditional logistic regression in the Peru cohort and generalized linear mixed models in the meta-analysis.FindingsIn Peru, baseline VDD was associated with a statistically insignificant increase in incident TB (aOR 1·70, 95% CI 0·84–3·46; p=0·14). We identified seven studies for the meta-analysis and analyzed 3544 participants. Individuals with VDD and very low vitamin D (<25nmol/L) had increased TB risk (aOR 1·48, 95% CI 1·04–210;p=0· 03 and aOR 2 08, 95% CI 0·88–4·92; p trend=002 respectively). Among HIV-positive patients, VDD and very low vitamin D conferred a 2-fold (aOR 2.18, 95% CI 1· 22–3·90; p=0· 01) and 4-fold (aOR 4·28, 95% CI 0·85–21·44; p trend=0·01) increased risk of TB respectively.InterpretationOur findings suggest vitamin D predicts TB risk in a dose-dependent manner and vitamin D supplementation may play a role in TB prevention.FundingNational Institute of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID), National Institute on Drug Abuse (NIDA), National Institute of Mental Health (NIMH), International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Dental and Craniofacial Research (NIDCR), Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Foundation, Ujala Foundation, Wyncote Foundation, NIH - Fogarty International Center Program of International Training Grants in Epidemiology Related to AIDS, NIAID Byramjee Jeejeebhoy Medical College HIV Clinical Trials Unit, NIAID’s Baltimore-Washington-India Clinical Trials Unit, National Commission on Biotechnology, the Higher Education Commission, International Research Support Initiative Program of the Higher Education Commission Government of Pakistan, the Bill and Melinda Gates Foundation, and the NIH Fogarty International Center.Research in ContextEvidence before this studyNumerous studies have found lower serum vitamin D levels among patients with active TB disease compared to healthy controls. However, research has not clarified whether low vitamin D increases TB risk or whether TB disease leads to decreased vitamin D levels. We conducted PubMed and Medline searches for all studies available through December 31, 2017 on the association between vitamin D status and TB disease. We included the following keywords: “vitamin D,” “vitamin D deficiency,” “hypovitaminosis D,” “25-hydroxyvitamin D,” “1,25-dihydroxyvitamin D,” “vitamin D2,” “vitamin D3,” “ergocalciferol,” “cholecalciferol,” and “tuberculosis.” We found only seven studies had prospectively evaluated the impact of baseline vitamin D levels on risk of progression to TB disease.We report here the results of a case control study nested within a large prospective longitudinal cohort study of household contacts of TB cases and the results of an individual participant data (IPD) metaanalysis of available evidence on the association between vitamin D levels and incident TB disease.Added value of this studyWe demonstrated that low vitamin D levels predicts risk of future progression to TB disease in a dose-dependent manner.Implications of all the available evidenceThese findings suggest the possibility that vitamin D supplementation among individuals at high risk for developing TB disease might play a role in TB prevention efforts.

scholarly journals An Individual Participant Data Meta-Analysis of 13 Randomized Trials to Evaluate the Impact of Prophylactic Use of Heparin in Oncological Patients

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 626-626
Author(s):  
Holger Schünemann ◽  
Matthew Ventresca ◽  
Mark Crowther ◽  
Marcello Di Nisio ◽  
Matthias Briel ◽  
...  
Keyword(s):  
Relative Risk ◽  
Research Funding ◽  
Meta Analysis ◽  
Cancer Type ◽  
Adjusted Relative Risk ◽  
Individual Participant Data ◽  
Trial Duration ◽  
Individual Participant ◽  
Conference Attendance ◽  
The Impact

Abstract Background: Parenteral anticoagulants may improve outcomes in patients with cancer by reducing the risk of venous thromboembolism (VTE) and through a direct anti-tumour effect. Study-level meta-analysis indicates a reduction in VTE and provide moderate certainty that a small survival benefit exists; it is unclear if patients with specific cancers benefit more or less. Utilizing data from randomized controlled trials (RCT), this individual participant data meta-analysis examines the impact of heparin on survival, VTE and major bleeding in oncological patients randomized to low-molecular weight heparin (LMWH) or no LMWH. Methods: We performed a comprehensive systematic search for all RCTS (last search date March 2017) and contacted authors and sponsors to obtain individual participant data of patients with solid cancers and no other indication for prophylactic or therapeutic anticoagulation. We utilized the GRADE approach to evaluate the certainty of evidence and produce an evidence profile. All analyses followed the intention-to-treat principle. We calculated the impact on mortality through multivariable hierarchical models with patient-level variables as fixed effects and a categorical trial variable as a random effect. We adjusted the analysis for age, cancer type and metastasis status. To investigate whether intervention effects vary by predefined subgroups, including type of cancer, we tested interaction terms in the statistical model. Results: A total of 18 RCTs (n=10,041 participants) were eligible for inclusion and we obtained data from 82.4% of the participants (13 RCTs, n=8,278; n=4,139 for LMWH and n=4,139 for no LMWH). The meta-analysis revealed an adjusted relative risk of mortality within one year of 0.99 (95% CI: 0.95, 1.03) and a hazard ratio of 0.97 (95% CI: 0.82, 1.14) after one year. The relative risk for VTE was 0.58 (95% CI: 0.48, 0.71), 0.57 (95% CI: 0.44, 0.74) for symptomatic deep vein thrombosis and 0.58 (95%CI: 0.44, 0.77) for symptomatic pulmonary embolism, separately. For every 1,000 patients treated, approximately 16 fewer would experience symptomatic DVT and 16 fewer would experience any PE. The adjusted relative risk for major bleeding throughout trial duration was 1.24 (95% CI: 0.91, 1.69; P=0.17). Subgroup analysis, by cancer type, of VTE occurrence throughout trial duration identified lung cancer OR=0.52 (95% CI: 0.39, 0.68; P&lt;0.001) and pancreatic cancer OR=0.55 (95% CI: 0.35, 0.88; P=0.01) patients as experiencing the greatest benefit from LMWH treatment. The certainty of the evidence for the outcomes was moderate to high. Conclusion: LMWH reduces risk of VTE without increasing risk of bleeding but does not improve survival across all patients. Funding: Canadian Institutes of Health Research knowledge synthesis grant, KRS 126594 Registration: International Prospective Register for Systematic Reviews (PROSPERO), CRD42013003526. Disclosures Schünemann: Canadian Institutes of Health Research: Research Funding. Crowther: Alexion: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boehringer Ingelheim: Speakers Bureau; Leo Pharma: Research Funding; Pfizer: Honoraria; Portola: Consultancy; Shinogi: Consultancy. Macbeth: Pfizer: Other: Provision of Dalteparin for FRAGMATIC trial; Cancer Research UK: Research Funding. Griffiths: Pfizer: Consultancy, Other: Comment: I run an academic clinical trials unit, have received educational/investigator intiated research grants from companies that make these heparin agents. As consultant &gt; 3 years ago, advised Pfizer on clinical trial designs unrelated to this study., Research Funding. Van Es: Pfizer: Employment, Other: Comment: Dr. van Es reports personal fees from Pfizer as a member of their advisory board. These fees are unrelated to this project.. Streiff: Roche: Research Funding; Portola: Research Funding; Janssen Scientific Affairs, LLC: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding. Ageno: BMS-Pfizer: Consultancy, Honoraria; Bayer AG: Consultancy, Honoraria, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria. Bozas: PharmaMar: Honoraria. McBane: Bristol Myers Squibb: Other: Research grant for cancer associated VTE. Maraveyas: Bayer: Other: Personal fees and conference attendance; Bristol-Myers Squibb: Other: Grants and personal fees; Leo Pharma: Other: Grants, personal fees and conference attendance; Pfizer: Other: Personal fees. Loprinzi: Bristol Myers: Other: Grant - unrelated to this project; Janssen: Other: Grant - unrelated to this project.

scholarly journals Impact of BMI on Growth Hormone Stimulation Tests in Children and Adolescents: A Systematic Review and Meta-Analysis

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A678-A678
Author(s):  
Ozair Abawi ◽  
Dieuwertje Augustijn ◽  
Sanne Hoeks ◽  
Yolanda B de Rijke ◽  
Erica L T van den Akker
Keyword(s):  
Systematic Review ◽  
Growth Hormone ◽  
Short Stature ◽  
Meta Analysis ◽  
Overweight And Obesity ◽  
Individual Participant Data ◽  
Study Heterogeneity ◽  
Individual Participant ◽  
Stimulation Tests ◽  
The Impact

Abstract Background: Peak stimulated growth hormone (GH) levels are known to decrease with increasing BMI, possibly leading to overdiagnosis of GH deficiency (GHD) in children with overweight and obesity. However, current guidelines do not provide guidance how to interpret peak GH values of these children, nor has this been assessed systematically. The aim of this systematic review and meta-analysis was to study the effect of BMI on stimulated peak GH values in children, and to quantify to which extent peak GH values in children with obesity are decreased. Methods: We searched the Medline, Embase, Cochrane, Web of Science, and Google Scholar databases (13 July 2020) for studies reporting impact of BMI on peak GH in children. Where possible, individual participant data was extracted and/or obtained from the authors. Primary outcome was the association between peak GH values and BMI standard deviation score (SDS). Pooled correlation coefficients were calculated under a random effects model, and exploratory moderator analyses and meta-regression were performed. Study heterogeneity was assessed using the I2 statistic. For studies with available individual participant data, linear mixed-models regression analysis was performed with BMI SDS as predictor and ln(peak GH) as outcome, accounting for used GH stimulation agent (fixed effect) and study (random effect). This systematic review was performed in accordance to the PRISMA guidelines. Results: In total, 56 studies were included, providing data on n=5100 children (1346 with individual participant data). Across all studies, a pooled r of -0.37 (95% CI -0.44 to -0.31, n=2785) was found. Study heterogeneity was large (I2=58%). Pubertal status, sex, presence of syndromic obesity, and mean age and BMI SDS of the population did not significantly moderate the pooled r (all p&gt;0.05). Individual participant data analysis revealed a beta of -0.11 (95% CI -0.08 to -0.15, p&lt;0.001), i.e., per 1 point increase in BMI SDS, peak GH decreases by 11% (95% CI 7 to 14%). In the 8 studies performed in children referred for short stature, obesity was present in 27/893 (3.02%) children without GHD and in 36/615 (5.85%) children with GHD (p=0.0069). This corresponds to a RR of 1.43 (95% CI 1.14 to 1.78, p=0.002) for a diagnosis of GHD in children with short stature with obesity compared to children without obesity. Discussion: To our knowledge, this is the first systematic review and meta-analysis to investigate the impact of BMI on peak GH values in children, showing a significant negative correlation and risk of overdiagnosis of GHD in children with obesity. All in all, with ever-rising prevalence of pediatric obesity, our study highlights the urgent need for BMI (SDS)-specific cut-off values for GH stimulation tests in children.

Comparing Kadish and Modified Dulguerov Staging Systems for Olfactory Neuroblastoma: An Individual Participant Data Meta-analysis

2020 ◽  
Vol 163 (3) ◽  
pp. 418-427 ◽  
Author(s):  
Mark A. Arnold ◽  
Soroush Farnoosh ◽  
Mitchell R. Gore
Keyword(s):  
Meta Analysis ◽  
Olfactory Neuroblastoma ◽  
Heterogeneous Group ◽  
Superior Performance ◽  
Cochrane Library ◽  
Individual Participant Data ◽  
Curative Intent ◽  
Staging Systems ◽  
Individual Participant ◽  
The Impact

Objective To compare the Kadish and the modified Dulguerov staging of individual participants to determine the impact of stage and other prognostic factors on disease-free (DFS) and overall survival (OS). Data Sources Systematic review of EMBASE, MEDLINE, Cochrane Library, and CINAHL databases. Review Methods The Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) was followed for this study. Articles including patients with olfactory neuroblastoma (ONB) staged with both Kadish and Dulguerov staging systems were reviewed. The raw data from eligible studies were requested to perform an individual participant data (IPD) meta-analysis. Results Pooled data from 21 studies representing 399 patients with ONB undergoing treatment with curative intent showed that increasing age, treatment with chemotherapy, and positive or unreported margin status portended worse DFS ( P < .05). Increasing stage for both Kadish and Dulguerov staging systems was prognostic for worse DFS and OS ( P < .05), with Kadish C representing a heterogeneous group with regard to outcome and corresponding Dulguerov T stage. Using the Akaike information criterion, the Dulguerov staging system had superior performance to the Kadish system for DFS (1088.72 vs 1092.54) and OS (632.71 vs 644.23). Conclusion This study represents the first IPD meta-analysis of ONB directly comparing the outcomes of Kadish and Dulguerov staging systems in patients treated with primary surgery. Both systems correlated with DFS and OS, with superior performance in the Dulguerov system. Furthermore, the Kadish C group represented a heterogeneous group with regard to outcomes after stratification by the Dulguerov system. Dulguerov T4 patients had the worst outcome, with most being approached with open resection.

scholarly journals A Primer on Two-Stage Meta-Analysis with Individual Participant Data Obtained from Complex Sampling Surveys

2021 ◽  
Author(s):  
Diego Campos ◽  
Mike W.-L. Cheung ◽  
Ronny Scherer
Keyword(s):  
Meta Analysis ◽  
Sample Selection ◽  
Target Population ◽  
Primary Data ◽  
Complex Nature ◽  
Individual Participant Data ◽  
Two Stage ◽  
Complex Surveys ◽  
Complex Sampling ◽  
Individual Participant

The increasing availability of individual participant data (IPD) in the social sciences offers new possibilities to synthesize research evidence across primary studies. Two-stage IPD meta-analysis represents a framework that can utilize these possibilities. While most of the methodological research on two-stage IPD meta-analysis focused on its performance compared with other approaches, dealing with the complexities of the primary data has received little attention, particularly when IPD are drawn from complex sampling surveys. Complex sampling surveys often feature clustering, stratification, disproportionate sampling, and multiple stages of sample selection to obtain nationally or internationally representative data from a target population. Furthermore, IPD from these studies are likely to provide more than one effect size. To address the complexities of the primary and meta-analytic data obtained from complex surveys, we propose a two-stage IPD meta-analytic approach and illustrate its utility. To aid meta-analysts who wish to utilize complex survey data, we present a sequence of steps and discuss the methodological decisions and options within. Given its flexibility and ability to deal with the complex nature of the primary data, the proposed two-stage approach opens up new analytical possibilities for synthesizing knowledge meta-analytically.

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