Evidence synthesis of clinical trials and human genome epidemiology

Lead Research Organisation: MRC Biostatistics Unit

Abstract

Science is cumulative: new studies need to reflect on the existing evidence in order to decide what should be studied and how, and clinical practice needs to reflect on the existing evidence to determine what is likely to benefit patients. This research programme addresses a variety of methods for compiling, assessing and combining existing evidence.||The main emphasis is on combining evidence from multiple, sometimes disparate, sources; a process often termed meta-analysis. The main areas of application are clinical trials and genetic epidemiology. Within the former area we look at comparing many treatments for the same disease, and how to combine results from studies conducted or reported in different ways. Within the latter area we consider the distribution of genetic mutations across the population, the extent to which mutations predict common diseases such as heart disease and cancer, and the usefulness of tests for mutations in clinical practice.

Technical Summary

The proposed research programme addresses issues in evidence synthesis, working largely to improve the methods used in systematic reviews undertaken by international organisations such as The Cochrane Collaboration. Parallel streams of work in clinical trials and human genome epidemiology include consideration of meta-analysis methods, advanced evidence syntheses, sequential methods and dealing with biases. Some major areas of work will be (i) generalised synthesis of clinical trials, including multiple treatments and variation in their delivery; (ii) understanding the extent and causes of heterogeneity in clinical trials; (iii) evaluating the properties of genetic tests; (iv) developing sequential methods for meta-analyses of clinical trials and epidemiological studies; (v) developing approaches for assessing potential reporting biases; (vi) major contributions to organisations that undertake and promote systematic reviews, and to the generic methodological guidance they offer.

Publications

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Anzures-Cabrera J (2010) Graphical displays for meta-analysis: An overview with suggestions for practice. in Research synthesis methods

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Barlow J (2012) Group-based parent training programmes for improving parental psychosocial health. in The Cochrane database of systematic reviews

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Borenstein M (2013) Meta-analysis and subgroups. in Prevention science : the official journal of the Society for Prevention Research

 
Description Cochrane Collaboration Steering Group
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
Impact Substantial input into decisions affecting the Cochrane Collaboration, including co-leading development of methodological standards for Cochrane reviews and leading development and implementation of methods funding programme.
 
Description EFSA
Geographic Reach Europe 
Policy Influence Type Participation in a advisory committee
Impact EFSA to use systematic review methods in preparing scientific opinions
 
Description Membership of advisory boards
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in advisory committee
Impact Member of advisory boards for international organisations
 
Description Text book: Cochrane Handbook for Systematic Reviews of Interventions
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact This is global guidance for preparing Cochrane reviews, co-edited by me. Versions published Dec 2003, May 2005, Sept 2006, Feb 2008, Sept 2008, Sept 2009, Sept 2011 Cited over 22000 times (data from Google Scholar)
 
Description Text book: Human Genome Epidemiology, 2nd edition
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact None known
 
Description Text book: Introduction to Meta-analysis
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact 3500 sales worldwide in the first 6 months after release cited over 5000 times (data from Google Scholar)
 
Description MRC Methodology Research Programme
Amount £227,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2013 
End 06/2016
 
Description MRC Population Health Sciences Research Network Grant
Amount £100,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2007 
End 09/2010
 
Description PHG Foundation
Amount £130,312 (GBP)
Organisation PHG Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2007 
End 06/2009
 
Title Annotated CDSR 
Description A complete issue of the Cochrane database with all treatments, diseases and outcomes manually categorized 
Type Of Material Improvements to research infrastructure 
Provided To Others? No  
Impact A basis for novel empirical studies 
 
Title Approach to re-express results of meta-analyses of continuous data in terms of absolute risk 
Description Approach to re-express results of meta-analyses of continuous data in terms of absolute risk (with Judith Anzures) 
Type Of Material Improvements to research infrastructure 
Year Produced 2008 
Provided To Others? Yes  
Impact Too early to judge; should have major impact on 'Summary of Findings' tables in Cochrane reviews. Paper recently published in Statistics in Medicine 
 
Title Best use of evidence 
Description Analyses to investigate the extent of heterogeneity in meta-analysis of clinical trials and estimating and adjusting for bias in meta-analyses 
Type Of Material Improvements to research infrastructure 
Year Produced 2010 
Provided To Others? Yes  
Impact Articles are published/ in press regarding these techniques 
 
Title I squared 
Description New statistic (called I-squared) for measuring inconsistency in meta-analysis (joint work with Simon Thompson, Doug Altman, Jon Deeks) 
Type Of Material Improvements to research infrastructure 
Year Produced 2006 
Provided To Others? Yes  
Impact Now part of the standard meta-analysis toolkit. Over 4000 citations (BMJ paper); over 2400 citations (Statistics in Medicine paper) 
 
Title Methods for meta-analysis of genetic association studies with diversely reported data 
Description Methods for meta-analysis of genetic association studies with diversely reported data (with Georgia Salanti) 
Type Of Material Improvements to research infrastructure 
Year Produced 2006 
Provided To Others? Yes  
Impact none as yet 
 
Title Methods for meta-analysis with missing data 
Description Methods for meta-analysis with missing data (with Ian White, Angela Wood and others) 
Type Of Material Improvements to research infrastructure 
Year Produced 2008 
Provided To Others? Yes  
Impact none as yet 
 
Title Methods for meta-analysis with skewed continuous outcomes 
Description Methods for meta-analysis with skewed continuous outcomes (with Judith Anzures, Ian White) 
Type Of Material Improvements to research infrastructure 
Year Produced 2008 
Provided To Others? Yes  
Impact none as yet 
 
Title New approach to determining statistical significance in meta-regression 
Description New approach to determining statistical significance in meta-regression 
Type Of Material Improvements to research infrastructure 
Year Produced 2009 
Provided To Others? Yes  
Impact Implementation in 'metareg', standard software for meta-regression 
 
Title New tool for assessing risk of bias in clinical trials, for application in systematic reviews 
Description New tool for assessing risk of bias in clinical trials, for application in systematic reviews (joint work with many others, led by me and Doug Altman). 
Type Of Material Improvements to research infrastructure 
Year Produced 2008 
Provided To Others? Yes  
Impact Now the standard method for use in Cochrane reviews and paper recently published in the BMJ 
 
Title Novel methods for meta-analysis with multiple treatment groups 
Description Novel methods for meta-analysis with multiple treatment groups 
Type Of Material Improvements to research infrastructure 
Year Produced 2008 
Provided To Others? Yes  
Impact Methods described here are the basis for standard methods in use today 
 
Title Prediction interval for random-effects meta-analysis 
Description Prediction interval for random-effects meta-analysis 
Type Of Material Improvements to research infrastructure 
Year Produced 2009 
Provided To Others? Yes  
Impact Implemented in 'metan', standard software for meta-analysis Paper recently published in the BMJ 
 
Title STREGA 
Description reporting guidelines for genetic association studies 
Type Of Material Improvements to research infrastructure 
Year Produced 2009 
Provided To Others? Yes  
Impact Simultaneous publication in 7 international journals illustrating the commitment of editors who have been convinced of the need for these guidelines 
 
Title Sequential Meta-analysis 
Description Application of sequential statistical methods to meta-analysis 
Type Of Material Improvements to research infrastructure 
Year Produced 2010 
Provided To Others? Yes  
Impact Paper published in Statistics in Medicine 
 
Description Britta Tendal 
Organisation Copenhagen University Hospital
Department Nordic Cochrane Centre
Country Denmark 
Sector Academic/University 
PI Contribution Supervision of a PhD student
Collaborator Contribution Research papers
Impact Winner of Thomas C Chalmers prize for best presentation- Cochrane colloquium- in both 2008 and 2009. PMCID: PMC2726927 One paper submitted (at 1 October 2010): Tendal B, Nüesch E, Higgins JPT, Jüni P, Gøtzsche PC. Multiplicity of data in trial reports creates an important challenge for the reliability of meta-analyses: an empirical study. Published by BMJ. Successful completion of PhD
Start Year 2007
 
Description EFSA gudiance on systematic reviews 
Organisation European Food Safety Authority
Country European Union (EU) 
Sector Public 
PI Contribution Expert input
Collaborator Contribution Intellectual contribution to widen research interest in food safety
Impact One publication: European Food Safety Authority (Working Group: Deeks J, Frampton G, Glanville J, Greiner M, Higgins J, Lövei G, O'Connor AM, Pullin A, Rajic A, Aiassa E, Amzal B, Verloo D, Afonso A, Dorne J-L, Nienstedt KM). Application of systematic review methodology to food and feed safety assessments to support decision making. EFSA Journal 2010; 8: 1637. doi: 10.2903/j.efsa.2010.1637. Available from: www.efsa.europa.eu. Poster presented in a conference: Cochrane Colloquium, October 2010
Start Year 2009
 
Description Multiple treatments meta-analyses 
Organisation University of Bristol
Department School of Social and Community Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaborative meta-analysis of multiple treatments
Collaborator Contribution Data sets for research, and inspiration for development of methodology
Impact Lancet publication, which had substantial media coverage. PMID: 19157778 Two papers published in Research Synthesis Methods, papers accepted in Clinical Trials and International Journal of Epidemiology
Start Year 2006
 
Description Multiple treatments meta-analyses 
Organisation University of Ioannina
Department Department of Hygiene and Epidemiology
Country Greece 
Sector Academic/University 
PI Contribution Collaborative meta-analysis of multiple treatments
Collaborator Contribution Data sets for research, and inspiration for development of methodology
Impact Lancet publication, which had substantial media coverage. PMID: 19157778 Two papers published in Research Synthesis Methods, papers accepted in Clinical Trials and International Journal of Epidemiology
Start Year 2006
 
Description Non-randomised studies in meta-analysis 
Organisation The Cochrane Collaboration
Country Global 
Sector Charity/Non Profit 
PI Contribution Helped plan the workshop. Gave a talk and lead a written paper
Collaborator Contribution They invited me to a workshop and asked me to lead a written paper
Impact Paper submitted
Start Year 2010
 
Description PHSRN 'Best use of randomized trial evidence' project 
Organisation The Cochrane Collaboration
Department UK Cochrane Centre
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Leadership of the project and discussions
Collaborator Contribution Allowed the development of my research group and have provided input into the project.
Impact PMIDs: 19381330 - Dias S, Welton NJ, Marinho VCC, Salanti G, Higgins JPT, Ades AE. Bias modelling in mixed treatment comparison meta-analysis. Journal of the Royal Statistical Society Series A. Published online 14 May 2010. doi: 10.1111/j.1467-985X.2010.00639.x.
Start Year 2007
 
Description PHSRN 'Best use of randomized trial evidence' project 
Organisation University of Bristol
Department School of Social and Community Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Leadership of the project and discussions
Collaborator Contribution Allowed the development of my research group and have provided input into the project.
Impact PMIDs: 19381330 - Dias S, Welton NJ, Marinho VCC, Salanti G, Higgins JPT, Ades AE. Bias modelling in mixed treatment comparison meta-analysis. Journal of the Royal Statistical Society Series A. Published online 14 May 2010. doi: 10.1111/j.1467-985X.2010.00639.x.
Start Year 2007
 
Description PHSRN 'Best use of randomized trial evidence' project 
Organisation University of Bristol
Department School of Social and Community Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Leadership of the project and discussions
Collaborator Contribution Allowed the development of my research group and have provided input into the project.
Impact PMIDs: 19381330 - Dias S, Welton NJ, Marinho VCC, Salanti G, Higgins JPT, Ades AE. Bias modelling in mixed treatment comparison meta-analysis. Journal of the Royal Statistical Society Series A. Published online 14 May 2010. doi: 10.1111/j.1467-985X.2010.00639.x.
Start Year 2007
 
Description PSI expert group on meta-analysis 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution I co-led the project with a colleague at GSK
Collaborator Contribution Helped conceive the project, participated in data collection and provided input into a recently submitted paper.
Impact Submitted two papers and several presentations to PSI (Statisticians in the Pharmaceutical Industry) annual conference
Start Year 2009
 
Description PSI expert group on meta-analysis 
Organisation F. Hoffmann-La Roche AG
Country Global 
Sector Private 
PI Contribution I co-led the project with a colleague at GSK
Collaborator Contribution Helped conceive the project, participated in data collection and provided input into a recently submitted paper.
Impact Submitted two papers and several presentations to PSI (Statisticians in the Pharmaceutical Industry) annual conference
Start Year 2009
 
Description PSI expert group on meta-analysis 
Organisation GlaxoSmithKline (GSK)
Department Quantitative Sciences (GSK)
Country United Kingdom 
Sector Private 
PI Contribution I co-led the project with a colleague at GSK
Collaborator Contribution Helped conceive the project, participated in data collection and provided input into a recently submitted paper.
Impact Submitted two papers and several presentations to PSI (Statisticians in the Pharmaceutical Industry) annual conference
Start Year 2009
 
Description PSI expert group on meta-analysis 
Organisation Lancaster University
Country United Kingdom 
Sector Academic/University 
PI Contribution I co-led the project with a colleague at GSK
Collaborator Contribution Helped conceive the project, participated in data collection and provided input into a recently submitted paper.
Impact Submitted two papers and several presentations to PSI (Statisticians in the Pharmaceutical Industry) annual conference
Start Year 2009
 
Description PSI expert group on meta-analysis 
Organisation Royal Free Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution I co-led the project with a colleague at GSK
Collaborator Contribution Helped conceive the project, participated in data collection and provided input into a recently submitted paper.
Impact Submitted two papers and several presentations to PSI (Statisticians in the Pharmaceutical Industry) annual conference
Start Year 2009
 
Description PSI expert group on meta-analysis 
Organisation University of Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution I co-led the project with a colleague at GSK
Collaborator Contribution Helped conceive the project, participated in data collection and provided input into a recently submitted paper.
Impact Submitted two papers and several presentations to PSI (Statisticians in the Pharmaceutical Industry) annual conference
Start Year 2009
 
Description Assessing risk of bias in included studies 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Primary Audience Health professionals
Results and Impact Cochrane Contributors Meeting, York
Cochrane Colloquium, 2009 and 2010

Recognition for the MRC and the Unit
Year(s) Of Engagement Activity 2008,2009,2010
 
Description Cambridge Science Fair 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach Regional
Primary Audience Schools
Results and Impact Participated as host on Unit's stall

Raised awareness of the work of the Unit in the local schools community
Year(s) Of Engagement Activity 2007,2008,2009,2012
 
Description Cambridge Science Fair 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Schools
Results and Impact Showcasing the work of the programme to school children (Aged 8-15) via simplifed text, activities and particiaption

Recognition for the grant and the Unit as a whole
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010
 
Description Cochrane Handbook for Systematic Reviews of Interventions 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact I co-edit this large and influential document, and contributed much of the core material

Recognition for the MRC and the Unit
Year(s) Of Engagement Activity 2008,2009,2010,2011,2012
URL http://training.cochrane.org/handbook
 
Description Compiling evidence on genetic predisposition to disease: the Human Genome Epidemiology Network 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Primary Audience Health professionals
Results and Impact Audience: epidemiologists, health researchers. Public Health Research Centre & Medical and Health Research Network, University Of Hong Kong

Recognition for the MRC and the unit
Year(s) Of Engagement Activity 2006
 
Description How to deal with heterogeneity in a meta-analysis 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Primary Audience Health professionals
Results and Impact Audience: clinical epidemiologists, health researchers. Clinical Epidemiology Program Rounds, Ottawa Health Research Institute, Ottawa

Recognition for the MRC and the unit
Year(s) Of Engagement Activity 2007
 
Description Preparing systematic reviews and meta-analyses of association between genes and disease: The Human Genome Epidemiology Network 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Primary Audience Health professionals
Results and Impact Audience: statisticians. Asia Pacific EBM Network Conference

Recognition for the MRC and the Unit.
Year(s) Of Engagement Activity 2006
 
Description Sense about Science 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Meeting and discussions with Sense about Science about preparation of a guide to journalistic interpretation of systematic reviews, culminating in their briefing 'Sense About Systematic Reviews' (Nov 2009)

Contacted subsequently by Sense about Science for advice on different issue. Recognition for the MRC and the unit
Year(s) Of Engagement Activity 2009
 
Description Systematic review training- Korea and Colombia 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Primary Audience Health professionals
Results and Impact Provided training in systematic reviews for clinicians at the launch of Korean branch of the Australasian Cochrane centre and for the University of Bogota in Colombia

Being invited to speak at the launch
Year(s) Of Engagement Activity 2009,2010
 
Description Workshops 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Primary Audience Health professionals
Results and Impact Invited and contributed training workshops held every year at the Cochrane Colloquium meeting (every October) and also at regional Cochrane meetings

Recognition for the MRC and the unit
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010