Statistical Methods for Longitudinal Data and Meta-Analysis

Lead Research Organisation: MRC Biostatistics Unit

Abstract

One aspect of my work is to develop statistical methods to analyse data from the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Data from this trial consists of up to six annual sets of questionnaires from each participant. The questionnaires assess anxiety, sexual function and acceptability of the screening process. I will model how these three processes change over time, and how they depend on one another. There are several approaches to analysing this type of data, and I will explore the pros and cons of three different methods. The challenge in this work lies in the complexity of the UKCTOCS data-set. I will also use some of these methods to analyse data from the MRC Cognitive Function and Ageing Study.

A second aspect of my work is to develop methods for use in meta-analysis. Meta-analysis refers to the pooling of data from different studies, and is used to provide an overview of the available evidence. I will investigate methods for the meta-analysis of data which consists of times to events. I will also explore the meta-analysis of treatment `networks', investigating the relative effects of a set of treatments for a given condition.

Technical Summary

Objective: to carry out a diverse program of original research in biostatistics, incorporating two broad research areas, longitudinal data analysis and meta-analysis.
Longitudinal data analysis: My research will be motivated by two studies, the MRC Cognitive Function and Ageing Study (CFAS) and the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Regarding MRC CFAS, our aim is to model simultaneously two processes - cognitive impairment and death. From this study we have interval-censored data with possibly informative loss-to-followup. We will use a five-state model, with loss-to-followup as an explicit state in the model. We will fit the model using maximum likelihood, imposing constraints to make all parameters identifiable. For the UKCTOCS trial we again have longitudinal data in the form of annual questionnaires. Our aim is to model simultaneously three outcomes of the trial, anxiety, sexual function, and the acceptability of two screening procedures. We will compare three different methods of analysis, random effects, dynamic variables and multi-state models. We will explore the pros and cons of these three methods in addressing the objectives of the UKCTOCS study, such as the effect of treatment allocation on outcomes, and identifying causal relations between the outcomes. Additional complexities which we will address are the inclusion of baseline covariates, adjustments for individual/treatment interactions, the possibility of informative loss-to-followup and multiplicity.
Meta-analysis: My research will focus on the individual patient data meta-analysis of time-to-event outcomes and on multiple treatment meta-analysis. For the meta-analysis of time-to-event outcomes we will explore alternatives to the use of the proportional hazards assumption, for example the use of accelerated failure time models. We will also develop non-parametric methods for constructing a summary survival curve. In multiple treatment meta-analysis we will investigate methods of allowing for inconsistency between direct and indirect evidence. We will model the inconsistency as a treatment by study `design' interaction, where the `design' of a study here means the set of treatments used in the study.
Scientific opportunities: The applications of my research are very topical, and results will be of interest to the wider medical community. In addition, methodological developments will be of use to the statistical community in a variety of other applications.

Publications

10 25 50

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Barrett J (2015) Joint modelling of repeated measurements and time-to-event outcomes: flexible model specification and exact likelihood inference. in Journal of the Royal Statistical Society. Series B, Statistical methodology

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Barrett JK (2014) Doubly Robust Estimation of Optimal Dynamic Treatment Regimes. in Statistics in biosciences

 
Description Allele associations with psoriatic disease
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical reviews
 
Description Methods for detecting inconsistency in meta-analysis
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in systematic reviews
 
Description Methods for detecting inconsistency in network meta-analysis
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in systematic reviews
 
Description Methods for detecting the presence of inconsistency in network meta-analysis
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in systematic reviews
 
Description Stem cell therapy for Parkinsons disease
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical reviews
 
Description MRC Early Career Centenary Award Fellowship Scheme
Amount £53,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2012 
End 09/2013
 
Title Discrete-time joint modelling 
Description New method for fitting joint models of longitudinal and survival data when there is a discrete survival timescale. 
Type Of Material Data analysis technique 
Year Produced 2015 
Provided To Others? Yes  
Impact The method is being applied in one clinical paper in preparation and the method has been further developed in one published paper and one paper in preparation. 
 
Title Inconsistency in network meta-analysis 
Description Development of a new method for detecting inconsistecny in netowrk meta-analysis. 
Type Of Material Data analysis technique 
Year Produced 2012 
Provided To Others? Yes  
Impact The papers describing the method have been highly cited in over 200 paperss, including systematic reviews, the PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions and the GRADE Working Group approach for rating the quality of treatment effect estimates from network meta-analysis. 
 
Title Two-stage Bayesian modelling 
Description New method for fitting a Bayesian model in two stages. 
Type Of Material Data analysis technique 
Year Produced 2013 
Provided To Others? Yes  
Impact The methods in this paper underpin new reserch on Markov melding, a more general modular approach to fitting Bayesian models. 
 
Description Breast cancer systematic reviews 
Organisation Hospital Sirio Libanes, Sao Paulo
Country Brazil 
Sector Hospitals 
PI Contribution Intellectual input, writing and data analysis.
Collaborator Contribution Intellectual input, literature searches, data extraction and analyses.
Impact One Cochrane review has been published. A second Cochrane review is under review. A third paper has been published in Reports of Practical Oncology and Radiotherapy.
Start Year 2012
 
Description Breast cancer systematic reviews 
Organisation The Cochrane Collaboration
Department Brazilian Cochrane Centre (BCC)
Country Brazil 
Sector Charity/Non Profit 
PI Contribution Intellectual input, writing and data analysis.
Collaborator Contribution Intellectual input, literature searches, data extraction and analyses.
Impact One Cochrane review has been published. A second Cochrane review is under review. A third paper has been published in Reports of Practical Oncology and Radiotherapy.
Start Year 2012
 
Description CFAS 
Organisation University of Athens
Department Department of Mathematics
Country Greece 
Sector Academic/University 
PI Contribution Intellectual input
Collaborator Contribution Intellectual input
Impact 1 article published in Statistics in Medicine, DOI 10.1002/sim.4071
Start Year 2008
 
Description CFAS 
Organisation University of Cambridge
Department MRC Biostatistics Unit
Country United Kingdom 
Sector Public 
PI Contribution Intellectual input
Collaborator Contribution Intellectual input
Impact 1 article published in Statistics in Medicine, DOI 10.1002/sim.4071
Start Year 2008
 
Description Cystic fibrosis 
Organisation Lancaster University
Department Faculty of Health and Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual input, data analysis, writing.
Collaborator Contribution Intellectual input, writing
Impact Article published in JRSSB, DOI 10.1111/rssb.12060. A second paper is ready for submission.
Start Year 2011
 
Description Cystic fibrosis 
Organisation Newcastle University
Department School of Mathematics and Statistics
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual input, data analysis, writing.
Collaborator Contribution Intellectual input, writing
Impact Article published in JRSSB, DOI 10.1111/rssb.12060. A second paper is ready for submission.
Start Year 2011
 
Description Cystic fibrosis 
Organisation University of Liverpool
Department Institute of Psychology, Health and Society
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual input, data analysis, writing.
Collaborator Contribution Intellectual input, writing
Impact Article published in JRSSB, DOI 10.1111/rssb.12060. A second paper is ready for submission.
Start Year 2011
 
Description Dynamic treatment regimes 
Organisation Newcastle University
Department School of Mathematics and Statistics
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual input
Collaborator Contribution Intellectual input
Impact 2 papers published for Statistics in Biosciences, DOIs 10.1007/s12561-013-9097-6 and 10.1007/s12561-013-9107-8.
Start Year 2011
 
Description Dynamic treatment regimes 
Organisation University of Copenhagen
Department Department of Public Health
Country Denmark 
Sector Academic/University 
PI Contribution Intellectual input
Collaborator Contribution Intellectual input
Impact 2 papers published for Statistics in Biosciences, DOIs 10.1007/s12561-013-9097-6 and 10.1007/s12561-013-9107-8.
Start Year 2011
 
Description Meta-analysis of survival data 
Organisation Medical Research Council (MRC)
Department MRC Clinical Trials Unit
Country United Kingdom 
Sector Public 
PI Contribution Intellectual input
Collaborator Contribution Provision of data and Intellectual input
Impact 2 journal articles published in Statistics in Medicine (DOIs 10.1002/sim.4086 and 10.1002/sim.5516)
Start Year 2007
 
Description Meta-analysis of survival data 
Organisation University of Athens
Department Department of Mathematics
Country Greece 
Sector Academic/University 
PI Contribution Intellectual input
Collaborator Contribution Provision of data and Intellectual input
Impact 2 journal articles published in Statistics in Medicine (DOIs 10.1002/sim.4086 and 10.1002/sim.5516)
Start Year 2007
 
Description Meta-analysis of survival data 
Organisation University of Cambridge
Department MRC Biostatistics Unit
Country United Kingdom 
Sector Public 
PI Contribution Intellectual input
Collaborator Contribution Provision of data and Intellectual input
Impact 2 journal articles published in Statistics in Medicine (DOIs 10.1002/sim.4086 and 10.1002/sim.5516)
Start Year 2007
 
Description Network meta-analysis 
Organisation University of Cambridge
Department MRC Biostatistics Unit
Country United Kingdom 
Sector Public 
PI Contribution Intellectual input and statistical program code
Collaborator Contribution Intellectual input
Impact 2 journal articles published in Research Synthesis Methods (DOIs 10.1002/jrsm.1044 and 10.1002/jrsm.1045), 2 articles published for Statistics in Medicine (DOIs 10.1002/sim.6188 and 10.1002/sim.6752)
Start Year 2009
 
Description Parkinsons 
Organisation University of Cambridge
Department Department of Clinical Neurosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual input and data analysis
Collaborator Contribution Intellectual input
Impact 1 paper published in the Lancet Neurology, DOI 10.1016/S1474-4422(12)70295-8
Start Year 2009
 
Description Psoriatic Arthritis 
Organisation Toronto Western Hospital
Department University of Toronto Psoriatic Arthritis Clinic
Country Canada 
Sector Hospitals 
PI Contribution Data analysis
Collaborator Contribution Provision of data and intellectual input
Impact 3 journal articles (DOIs 10.3899/jrheum.090412 , 10.1111/j.1399-0039.2011.01670.x and 10.1111/tan.12126)
Start Year 2007
 
Description Psoriatic Arthritis 
Organisation University of Cambridge
Department MRC Biostatistics Unit
Country United Kingdom 
Sector Public 
PI Contribution Data analysis
Collaborator Contribution Provision of data and intellectual input
Impact 3 journal articles (DOIs 10.3899/jrheum.090412 , 10.1111/j.1399-0039.2011.01670.x and 10.1111/tan.12126)
Start Year 2007
 
Description Splines for joint modelling 
Organisation Medical Research Council (MRC)
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual input and writing computer code
Collaborator Contribution Intellectual input
Impact One paper published in Statistics in Medicine, and one paper published in Biometrics.
Start Year 2013
 
Description Splines for joint modelling 
Organisation University of California, Berkeley
Department Department of Integrative Biology
Country United States 
Sector Academic/University 
PI Contribution Intellectual input and writing computer code
Collaborator Contribution Intellectual input
Impact One paper published in Statistics in Medicine, and one paper published in Biometrics.
Start Year 2013
 
Description Two-stage Bayesian meta-analysis 
Organisation University of Cambridge
Department MRC Biostatistics Unit
Country United Kingdom 
Sector Public 
PI Contribution Intellectual input
Collaborator Contribution Intellectual input
Impact 1 article published, DOI 10.1111/rssc.12007.
Start Year 2010
 
Description UKCTOCS 
Organisation University of Cambridge
Department MRC Biostatistics Unit
Country United Kingdom 
Sector Public 
PI Contribution Data analysis and intellectual input
Collaborator Contribution Provision of data and intellectual input
Impact 3 journal articles (DOIs 10.1038/sj.bjc.6605809 , 10.1111/1471-0528.12870 and 10.1097/IGC.0000000000000507)
Start Year 2008
 
Description UKCTOCS 
Organisation University of Sussex
Department Brighton and Sussex Medical School
Country United Kingdom 
Sector Academic/University 
PI Contribution Data analysis and intellectual input
Collaborator Contribution Provision of data and intellectual input
Impact 3 journal articles (DOIs 10.1038/sj.bjc.6605809 , 10.1111/1471-0528.12870 and 10.1097/IGC.0000000000000507)
Start Year 2008
 
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 Helped run an a display highlighting the work of the Unit at Cambridge Science on Saturday

Recognition for my fellowship and the work of the Unit
Year(s) Of Engagement Activity 2007,2008,2009,2010,2011
 
Description Insitute of Public Health's Bradford Hill Seminar series 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Health professionals
Results and Impact Regular seminar series which takes place at the University of Cambridge's Institute of Public health on Friday lunchtimes, regularly attended by a variety of health professionals

Further strengthening of intellectual collaboration with external institutions, e.g. the University of York and the University of Salford.
Year(s) Of Engagement Activity 2009,2010,2011