Statistical modelling of cognitive decline to improve estimation, identifying risk factors and population benefits.

Lead Research Organisation: MRC Biostatistics Unit

Abstract

Age related cognitive decline is a major public health concern. Most statistical methods used to measure it model the average change over time. However, scientists have reached a consensus that cognitive decline is too complex to be described as an overall mean, and rather person specific models are needed to fully understand it. I will investigate the effect of missing data due to death and ill health on estimates of cognitive decline, an investigation that will produce more realistic estimates of true cognitive decline and its potential causes. Core hypotheses of two large population based studies of older individuals will be investigated. These studies are the CC75C and the MRC CFA study.
The work proposed on the models of cost effectiveness of drugs for Alzheimer's disease will combine epidemiological data and clinical trials data within a sound framework that introduces realism into policy decisions. Models of individuals' trajectories combined with cost information and outcomes from clinical trials will provide a robust framework of the true cost of treatment for dementia.

Technical Summary

Background: Longitudinal studies provide the framework to investigate age related cognitive change. This modelling is complex due to factors such as the shape of the change, study design and missing data; factors that are often ignored. Preventing and slowing cognitive change is a target for drug interventions including those aimed at individuals with Alzheimer's disease. However, these investigations also suffer from similar modelling complexities. Investigating cost-effectiveness must consider these difficulties and also difficulties in modelling treatment effect at the individual and carer level.
Aims: To explore parametric random effects and growth mixture models that will allow for the identification of potential risk factors for cognitive decline, either for all participants or class specific groups including the modelling of missing data. To improve health economic models for Alzheimer's disease drugs by modelling the epidemiological setting as well as the clinical effectiveness.
Methodology:
" Random change point models will be fitted to investigate terminal decline with missing data using selection model approach (Bayesian analysis in WinBugs)
" Growth mixture models will investigate the analysis of class specific risk factors including the potential for test re-test effects (Using Mplus).
" Extension of investigation of the time matrix for analysis (such as time in study, age and time before death).
" Complex study design issues will be investigated via the incorporation of sampling weights into the models.
" Investigation of analysis modelling of missing data (including non ignorable data) such as inverse probability weighting, multiple imputation and pattern mixture models.
" The Cambridge City over 75 Cohort study, MRC Cognitive Function and Ageing Study and simulation studies will be used to develop the methodology and produce the applied papers.
" A literature review will initially be conducted to produce all necessary evidence regarding economic models for cholinesterase inhibitors.
" A Bayesian evidence synthesis will be undertaken to include the effect of Alzheimer's disease on mortality, the severity of the disease, the effect of transfer to institutional care as well as carers and the individuals' response to treatments. Initially the cholinesterase inhibitors will be modelled, but the framework will be flexible should new treatment strategies arise.
Opportunities. Proper models will describe potential risk factors for cognitive decline that could have population impact. Cost-effectiveness models using Bayesian synthesis for Alzheimer's disease will provide results of direct clinical usage.

Publications

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Aarsland D (2011) Nonlinear decline of mini-mental state examination in Parkinson's disease. in Movement disorders : official journal of the Movement Disorder Society

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Muniz-Terrera G (2011) Are terminal decline and its potential indicators detectable in population studies of the oldest old? in International journal of geriatric psychiatry

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Piccinin AM (2011) Terminal decline from within- and between-person perspectives, accounting for incident dementia. in The journals of gerontology. Series B, Psychological sciences and social sciences

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Piccinin AM (2011) An evaluation of analytical approaches for understanding change in cognition in the context of aging and health. in The journals of gerontology. Series B, Psychological sciences and social sciences

 
Description University of Victoria, Canada/IALSA
Amount £1,000 (GBP)
Organisation Integrative Analysis of Longitudinal Studies on Aging (IALSA) 
Sector Academic/University
Country Global
Start 07/2010 
End 07/2010
 
Description University of Victoria, Canada/IALSA
Amount £1,000 (GBP)
Organisation Integrative Analysis of Longitudinal Studies on Aging (IALSA) 
Sector Academic/University
Country Global
Start 06/2010 
End 06/2010
 
Title Random change point methods 
Description Identification of individual level change points 
Type Of Material Data analysis technique 
Year Produced 2010 
Provided To Others? Yes  
Impact PMID: 21337356 
URL http://europepmc.org/abstract/MED/21337356
 
Title Change points 
Description I have developed statistical methods for estimation of change points representing the onset of accelerated decline. Previously, these were assumed to be common to all individuals, i have relaxed this assumption permitting the estimation of individual change points 
Type Of Material Data analysis technique 
Year Produced 2013 
Provided To Others? Yes  
Impact The model developed is much more realistic than previous ones 
URL http://www.homepages.ucl.ac.uk/~ucakadl/
 
Description Analysis of associations between Vitamin D and cognitive decline 
Organisation University of Exeter
Department School of Psychology
Country United Kingdom 
Sector Academic/University 
PI Contribution Developed research methods
Collaborator Contribution One paper published in the Archives of Internal Medicine (2010)
Impact PMID: 20625021
Start Year 2008
 
Description Analysis of longitudinal data for Parkinsons disease patients 
Organisation Stavanger University Hospital
Country Norway 
Sector Hospitals 
PI Contribution Developed statistical methodology and contributted to manuscript
Collaborator Contribution One published paper "Non-linear cognitive decline in Parkinson disease" (Journal of Movement Disorders, 2010)
Impact PMID: 20960482
Start Year 2010
 
Description Association of neuropathology and cognition 
Organisation University of Cambridge
Department Cambridge Institute of Public Health
Country United Kingdom 
Sector Academic/University 
PI Contribution Methodological developments. Co-supervision of MPhil thesis at the University of Cambridge
Collaborator Contribution One submitted/under review paper at the Lancet Neurology and one paper in preparation
Impact Publications submitted and under review: Neuropathological profile of different cognitive states before death in a non-demented population-based sample. Submitted to Lancet Neurology. July 2011 One paper in preparation
Start Year 2009
 
Description CC75C 
Organisation University of Cambridge
Department Cambridge Institute of Public Health
Country United Kingdom 
Sector Academic/University 
PI Contribution Data analysis
Collaborator Contribution Data provision, joint papers
Impact PMID: PMID: 18485192; PMID: 19252209; 21480375 Publications submitted and under review: - Investigating terminal decline: results from a UK population-based study of ageing. Submitted to Psychology and Ageing- September 2011 - Education associated with a delayed onset of terminal decline. Submitted to Age and Ageing. September 2011
 
Description Change point 
Organisation University of Cambridge
Department MRC Biostatistics Unit
Country United Kingdom 
Sector Public 
PI Contribution Research and data analysis
Collaborator Contribution Research collaboration
Impact DOI: 10.1080/02664760903563668 Two papers in preparation and one presentation held at the ISCB 2011 (August)
Start Year 2010
 
Description Collaboration on longitudinal models of blood pressure 
Organisation University College London
Department MRC Unit for Lifelong Health and Ageing
Country United Kingdom 
Sector Public 
PI Contribution Methodological improvement of blood pressure models
Collaborator Contribution Two papers submitted/under revision and three in preparation
Impact Publications submitted and under review: - Analysing cognitive test data: distributions and non-parametric random effects. Submitted to Statistical Methods in Medical Research. August 2011 - A latent-class semi-parametric change point model for cognitive ability in older age. Submitted to Lifetime and Computational data Analysis. October 2011. Three papers in preparation
Start Year 2008
 
Description Collaboration on longitudinal models of cognition 
Organisation London Metropolitan University
Department Department of Mathematics and Statistics
Country United Kingdom 
Sector Academic/University 
PI Contribution Developed methodology research
Collaborator Contribution One published paper ("Proceeding of the 25th workshop of the International Society of statistical models"), one submitted/under review and one in preparation.
Impact Publications: - Modelling random effects using GAMLSS. G. Muniz, A. van den Hout, M. Stasinopoulos, and R. Rigby. Proceedings of the International Workshop of Statistical Modelling, (2010) - A latent-class semi-parametric change point model for cognitive ability in older age. A. van den Hout, G. Muniz, F. Matthews. Proceedings of the International Workshop of Statistical Modelling, (2011).
Start Year 2009
 
Description Delirium 
Organisation University of Cambridge
Department Cambridge Institute of Public Health
Country United Kingdom 
Sector Academic/University 
PI Contribution Data analysis
Collaborator Contribution Project proposal
Impact Paper submited and under revision: Delirium increases risk of dementia but not through Alzheimer-type, infarcts or Lewy body pathology: a population-based cohort study. Submitted to BMJ. October 2011
Start Year 2010
 
Description Improvement of statistical models of cognitive data 
Organisation University of Cambridge
Department MRC Biostatistics Unit
Country United Kingdom 
Sector Public 
PI Contribution Developed research methods
Collaborator Contribution One accepted paper "Smooth random change points", to appear in the Statistics in Medicine (2010)
Impact PMID: 21337356
Start Year 2008
 
Description Investigation of cognitive change in a American network of longitudinal studies of ageing 
Organisation University of Victoria
Country Australia 
Sector Academic/University 
PI Contribution Statistical input
Collaborator Contribution Discussed models and written 2 publications (submitted and under review) (2009) Discussed models and written 3 publications (submitted and under review) and 1 publication under preparation (2010) Collaboration with a post doc (Annie Robbittaille) on models for the investigation of moderating effects in cognitive outcomes. (2010-2011)
Impact PMID: 21743051; PMID: 21389088 Publications submitted and under review: - Investigation of the association between change in memory scores and death. Submitted to Geropsych. July 2011. - Bivariate longitudinal modeling of cognitive aging: Relationship between processing speed and visual spatial ability. Submitted to Geropsych. July 2011.
Start Year 2008
 
Description Investigation on effect of study design on longitudinal model parameters. 
Organisation Albert Einstein College of Medicine
Country United States 
Sector Academic/University 
PI Contribution data analysis
Collaborator Contribution provided the data for the analysis
Impact Papers in preparation
Start Year 2010
 
Description Cambridge Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Participated in and helped managing the Unit's display for Cambridge Science Festival (2009)
Assisted in attending the public (2011)

Raised profile for the work of the Unit in the local schools community
Year(s) Of Engagement Activity 2007,2008,2009,2011
 
Description IPH Open Day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact 100 people attended the presentation on cognitive decline in old age

Health professionals asked me to assist them in fitting similar models
Year(s) Of Engagement Activity 2009,2010
 
Description MPlus UK users meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact 70 people attended the presentation on terminal decline in cognitive outcomes

Invitation to speak at the RSS (2011)
Year(s) Of Engagement Activity 2009,2011