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      Assessing heterogeneity of treatment effect analyses in health-related cluster randomized trials: A systematic review

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          Abstract

          Background

          Cluster-randomized trials (CRTs) are being increasingly used to test a range of interventions, including medical interventions commonly used in clinical practice. Policies created by the NIH and the Food and Drug Administration (FDA) require the reporting of demographics and the examination of demographic heterogeneity of treatment effect (HTE) for individually randomized trials. Little is known about how frequent demographics are reported and HTE analyses are conducted in CRTs.

          Objectives

          We sought to understand the prevalence of HTE analyses and the statistical methods used to conduct them in CRTs focused on treating cardiovascular disease, cancer, and chronic lower respiratory diseases. Additionally, we also report on the proportion of CRTs that reported on baseline demographics of its populations and conducted demographic HTE analyses.

          Data sources

          We searched PubMed and Embase for CRTs published between 1/1/2010 and 3/29/2016 that focused on treating the top 3 Center for Disease Control causes of death (cardiovascular disease, chronic lower respiratory disease, and cancer).

          Evidence Screening And Review: Of 1,682 unique titles, 117 abstracts were screened. After excluding 53 articles, we included 64 CRT publications and abstracted information on study characteristics and demographic information, statistical analysis, HTE analysis, and study quality.

          Results

          Age and sex were reported in greater than 95.3% of CRTs, while race and ethnicity were reported in only 20.3% of CRTs. HTE analyses were conducted in 28.1% (n = 18) of included CRTs and 77.8% (n = 12) were prespecified analyses. Four CRTs conducted a demographic subgroup analysis. Only 6/18 CRTs used interaction testing to determine whether HTE existed.

          Conclusions

          Baseline demographic reporting was high for age and sex in CRTs, but was uncommon for race and ethnicity. HTE analyses were uncommon and was rare for demographic subgroups, which limits the ability to examine the extent of benefits or risks for treatments tested with CRT designs.

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          Most cited references20

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          Mechanical versus manual chest compression for out-of-hospital cardiac arrest (PARAMEDIC): a pragmatic, cluster randomised controlled trial.

          Mechanical chest compression devices have the potential to help maintain high-quality cardiopulmonary resuscitation (CPR), but despite their increasing use, little evidence exists for their effectiveness. We aimed to study whether the introduction of LUCAS-2 mechanical CPR into front-line emergency response vehicles would improve survival from out-of-hospital cardiac arrest.
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            Lessons for cluster randomized trials in the twenty-first century: a systematic review of trials in primary care.

            Evidence suggests that cluster randomized trials are often poorly designed and analysed. There is little recent research on the methodologic quality of cluster randomized trials and none focuses on primary health care where these trials are increasingly common. We conducted a systematic review of recent cluster randomized trials in primary health care, searching the Cochrane Controlled Trials Register. We also searched for unpublished trials in conference proceedings, and the UK National Research Register. We assess methodologic quality using a checklist, articulate problems facing investigators conducting these trials, and examine the extent to which carrying out a cluster randomized trial (as opposed to an individually randomized trial) in primary care may reduce power. We found 367 trial reports. Many trials were reported more than once. We characterize 152 independent cluster randomized trials in primary health care published between 1997 and 2000, and briefly describe 47 trials unpublished at December 2000. The quality of design and analysis was variable. Of published trials reporting sample size calculations 20% accounted for clustering in these calculations, 59% of published trials accounted for clustering in analyses. Unpublished trials were more recent and of higher quality. Reporting quality was better in journals reporting more cluster randomized trials. Many trial investigators reported problems with adherence to protocol, recruitment and type of intervention. Methodologic quality of cluster randomized trials in primary health care is variable and reporting needs improvement. The use of cluster randomization should be indicated in the title or abstract so these kinds of trials are easier to identify. Communicating appropriate methodology to health care researchers continues to be a challenge. Cluster randomized trials should always be piloted and information from pilots and unsuccessful trials shared more widely.
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              Deaths: Final Data for 2013.

              This report presents final 2013 data on U.S. deaths, death rates, life expectancy, infant mortality, and trends, by selected characteristics such as age, sex, Hispanic origin, race, state of residence, and cause of death.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: MethodologyRole: ResourcesRole: SupervisionRole: VisualizationRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: SupervisionRole: ValidationRole: Writing – review & editing
                Role: InvestigationRole: ValidationRole: Writing – review & editing
                Role: InvestigationRole: ValidationRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: MethodologyRole: Project administrationRole: SoftwareRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                12 August 2019
                2019
                : 14
                : 8
                : e0219894
                Affiliations
                [1 ] Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, United States of America
                [2 ] Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC, United States of America
                [3 ] Department of Family and Community Medicine, Wake Forest School of Medicine; Winston-Salem, NC, United States of America
                [4 ] Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Duke University School of Medicine, Durham, NC, United States of America
                [5 ] Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, United States of America
                University of Zurich, SWITZERLAND
                Author notes

                Competing Interests: MA Starks - none; GD Sanders - none; RR Coeytaux - none; IL Riley - none; LR Jackson - education support from Medtronic and Biotronik; honoraria from Biotronik; AM Brooks - none; KL Thomas - Consultant: Pfizer, BMS, Janssen; KR Choudhury - none; RM Califf - sits on the corporate board for Cytokinetics and is board chair for the People-Centered Research Foundation. He receives personal fees for consulting from Merck, Amgen, Biogen, Genentech, Eli Lilly, and Boehringer Ingelheim. He is also employed as an advisor by Verily Life Sciences (Alphabet); AF Hernandez - consulting fees from Sanofi, Johnson & Johnson, AstraZeneca, and Cortera; research support from Amylin and Scios/Johnson & Johnson. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                Author information
                http://orcid.org/0000-0003-4719-399X
                Article
                PONE-D-18-02021
                10.1371/journal.pone.0219894
                6690528
                31404063
                43b6fb54-6bb7-4efe-a440-fccc8099dd2e
                © 2019 Starks et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 19 January 2018
                : 4 July 2019
                Page count
                Figures: 1, Tables: 3, Pages: 13
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: 3U54AT007748-02S1
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: 1U54AT007748-01
                Award Recipient :
                This work was supported primarily by the National Institutes of Health Common Fund research supplements to promote diversity in health-related research under award number 3U54AT007748-02S1, and the Health Care Systems Research Collaboratory Coordinating Center under award number 1U54AT007748-01 from the National Institutes of Health. The views presented here are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. The funders had no role in the authoring or revision of this manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Clinical Medicine
                Clinical Trials
                Cluster Trials
                Medicine and Health Sciences
                Pharmacology
                Drug Research and Development
                Clinical Trials
                Cluster Trials
                Research and Analysis Methods
                Clinical Trials
                Cluster Trials
                Medicine and Health Sciences
                Epidemiology
                Ethnic Epidemiology
                Medicine and Health Sciences
                Cardiovascular Medicine
                Cardiovascular Diseases
                Research and Analysis Methods
                Research Assessment
                Systematic Reviews
                Medicine and Health Sciences
                Oncology
                Cancer Treatment
                People and Places
                Population Groupings
                Ethnicities
                Research and Analysis Methods
                Mathematical and Statistical Techniques
                Statistical Methods
                Physical Sciences
                Mathematics
                Statistics
                Statistical Methods
                Medicine and Health Sciences
                Clinical Medicine
                Clinical Trials
                Randomized Controlled Trials
                Medicine and Health Sciences
                Pharmacology
                Drug Research and Development
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