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.
Organisations
- MRC Biostatistics Unit, United Kingdom (Lead Research Organisation)
- University of Edinburgh, United Kingdom (Collaboration)
- AstraZeneca plc (Collaboration)
- University of Bristol, United Kingdom (Collaboration)
- Copenhagen University Hospital (Collaboration)
- European Food Safety Authority (Collaboration)
- GlaxoSmithKline (GSK) (Collaboration)
- Royal Free Hospital (Collaboration)
- Lancaster University (Collaboration)
- F. Hoffmann-La Roche AG (Collaboration)
- University of Ioannina (Collaboration)
- The Cochrane Collaboration (Collaboration)
People |
ORCID iD |
| Julian Piers Higgins (Principal Investigator) |
Publications
Ryder JJ
(2008)
Genetic associations in peripheral joint osteoarthritis and spinal degenerative disease: a systematic review.
in Annals of the rheumatic diseases
Roloff V
(2013)
Planning future studies based on the conditional power of a meta-analysis.
in Statistics in medicine
Rodgers MA
(2013)
Reporting of industry funded study outcome data: comparison of confidential and published data on the safety and effectiveness of rhBMP-2 for spinal fusion.
in BMJ (Clinical research ed.)
Riley RD
(2011)
Interpretation of random effects meta-analyses.
in BMJ (Clinical research ed.)
Rhodes KM
(2015)
Predictive distributions were developed for the extent of heterogeneity in meta-analyses of continuous outcome data.
in Journal of clinical epidemiology
Reeves BC
(2013)
An introduction to methodological issues when including non-randomised studies in systematic reviews on the effects of interventions.
in Research synthesis methods
Petticrew M
(2013)
Synthesizing evidence on complex interventions: how meta-analytical, qualitative, and mixed-method approaches can contribute.
in Journal of clinical epidemiology
Palla L
(2010)
Challenges in the use of literature-based meta-analysis to examine gene-environment interactions.
in American journal of epidemiology
NSCLC Meta-Analyses Collaborative Group
(2008)
Chemotherapy in addition to supportive care improves survival in advanced non-small-cell lung cancer: a systematic review and meta-analysis of individual patient data from 16 randomized controlled trials.
in Journal of clinical oncology : official journal of the American Society of Clinical Oncology
NSCLC Meta-Analyses Collaborative Group
(2010)
Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data.
in Lancet (London, England)
| 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 | Public |
| 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 | Public |
| 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 | Italy |
| 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 |
| 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 | 2006,2007,2008,2009,2010,2011 |
| 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 | 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 | 2008,2009,2010,2011,2012,2013,2014,2015,2016,2017 |
| 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 |