The natural history of asthma and wheezing illnesses from birth to adolescence: Determinants of the remission of asthma

Lead Research Organisation: University of Bristol
Department Name: Cellular and Molecular Medicine

Abstract

We aim to discover factors associated with the resolution of asthma during adolescence. This may lead to the development of interventions that will resolve or minimise asthma symptoms.
Most asthma begins in childhood but, despite intensive research efforts, the causes of asthma remain elusive. A substantial proportion of children with asthma appear to outgrow their symptoms during teenage years. By concentrating on events during this period of childhood, we hope to identify important differences between children who outgrow their asthma and those in whom it persists.
We will study an established cohort of children (the ALSPAC study) in whom we have extensive information about early life environment and symptoms. We will study the progression of asthma as the participants go through puberty and link this to aspects of their lifestyle (such as diet, smoking, and exercise). An evolving database of variations in genes associated with asthma will also allow us to find out if environmental factors interact with particular genes to cause persistence or resolution of asthma.
No interventions have been discovered that prevent the development of asthma. Exposures that appear to favour asthma resolution in this study will be developed into intervention studies to test whether these show promise in helping to resolve asthma symptoms once they have become established.

Technical Summary

Background: The proposed project is based on the accompanying core programme for the Avon Longitudinal Study of Parents & Children (ALSPAC), a longitudinal birth cohort of 13,971 infants followed from before birth. This proposal builds on well-characterised asthma phenotypes, including objective measures of allergy and lung function, to age 8? years in this cohort, detailed assessments of early childhood environmental exposures, and collection of information on exposures during adolescence and asthma outcomes in late puberty as part of the accompanying core proposal.
Aims & Objectives: The aims are to describe the natural history of asthma from birth to adolescence and to examine the factors that influence asthma remission. The principal hypothesis to be tested is that exposures during the critical period of pubertal development will interact with asthma phenotype to determine remission, persistence or incidence of asthma symptoms from 8? to 15+ years. Within this overall aim, specific hypotheses will be tested relating to individual exposures during adolescence, including nutrition, changes in body size, including objective measures of fat mass and body composition (DXA), activity measurements using an accelerometer, and smoking uptake validated by measurement of urinary cotinine concentrations.
Methods: The data for this project will be available from existing information collected by ALSPAC and from new data collection included in the core proposal. No specific fieldwork is planned apart from measurement of urinary cotinine. The project will utilise these data to analyse wheezing trajectories from birth to adolescence using novel statistical approaches, including multilevel modelling and structural equations, to determine the contribution of environmental exposures to defined outcomes, including remission of asthma symptoms. The outcomes at 15+ years will include remission or persistence or asthma symptoms linked to objective lung function measurements, including reversibility to bronchodilator. Existing data on asthma phenotype in earlier childhood will be used to examine interactions between these detailed phenotypes and subsequent exposures in the remission or persistence of asthma symptoms.
Outcomes: The project will produce novel information on exposures associated with the natural history of asthma through adolescence in a contemporary cohort of children. Knowledge of factors associated with remission of asthma may give rise to new therapeutic approaches in future studies. In addition, these data will provide a platform for studies of gene-environment interaction studies to determine the effects of exposures on candidate genotypes in determining the natural history of asthma throughout childhood.

Publications

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Cookson H (2009) Mothers' anxiety during pregnancy is associated with asthma in their children. in The Journal of allergy and clinical immunology

 
Description Just in Time (JIT) RO3
Amount $104,220 (USD)
Funding ID HD070663-01 
Organisation National Institute of Allergy and Infectious Diseases (NIAID) 
Sector Public
Country United States
Start 09/2012 
End 08/2014
 
Description MRC Project Grant
Amount £1,500,000 (GBP)
Funding ID MR/K001035/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start  
 
Description MRC Project Grant
Amount £405,750 (GBP)
Funding ID G0700920 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 03/2008 
End 04/2010
 
Description MRC Project Grant
Amount £795,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start  
 
Description NIH RO1
Amount $600,986 (USD)
Funding ID 1R01AI121226-01 
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 01/2016 
End 12/2020
 
Description Population Health Sciences Fellowship
Amount £359,587 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start  
 
Description RO1
Amount $3,184,226 (USD)
Funding ID 1R01HL132321-01A1 
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 09/2016 
End 07/2021
 
Title Latent class analysis of wheezing 
Description Novel application of statistical method to define disease phenotype classification 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2008 
Provided To Others? Yes  
Impact Paper published in 2008. Disseminated methods through meetings and seminars. Validation has been completed in an independent cohort (PIAMA, Groningen, NL). Paper published (Savenije et al.). Several publications arising in literature using this approach to asthma phenotype classification, replicating our broad findings. 
 
Description EAGLE 
Organisation University of Copenhagen
Country Denmark 
Sector Academic/University 
PI Contribution Contibution of reseach expertise, phenotype and genetic data to GWAS of asthma dn related phenotypes.
Collaborator Contribution Sharing of data on asthma phenotypes and genetic data to enable large scale genomewide association studies.
Impact Paternoster L, Standl M, Chen CM, Ramasamy A, Bønnelykke K, Duijts L, et al. Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis. Nat Genet. 2011 Dec 25;44(2):187-92. Bonnelykke et al. Genome-wide association study of allergic sensitization shows evidence of association at 10 independent loci and explains considerable fraction of disease risk. Nat Genet 2013; 45: 902-6.
Start Year 2011
 
Description GABRIEL - A multidisciplinary study to identify the genetic and environmental causes of asthma in the European Community 
Organisation Imperial College London
Department Faculty of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of phenotype data; cleaning of genetic data and secondary analysis for studies of gene*environment interactions
Collaborator Contribution Whole genome typing of 1300 case control sample of asthma/non-asthma subjects' DNA
Impact Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S, von Mutius E, Farrall M, Lathrop M, Cookson WO; GABRIEL Consortium. A large-scale, consortium-based genomewide association study of asthma. N Engl J Med. 2010 Sep 23;363(13):1211-21. GABRIEL Paediatric consortium ongoing with a programme of 5 agreed GWAS of childhood asthma phenotypes. My group is leading first of these in collaboration with EAGLE (The EArly Genetics and Lifecourse Epidemiology) consortium.
Start Year 2007
 
Description PIAMA 
Organisation Prevention and Incidence of Asthma and Mite Allergy (PIAMA)
Country Netherlands 
Sector Public 
PI Contribution We have collaborated on a joint approach to phenotype definitions in early childhood asthma and wheezing, applying methods developed by my group to an independent birth cohort.
Collaborator Contribution We have collaborated on joint methods of phenotype definition and are collaborating on genetic associations with asthma in early childhood.
Impact Savenije OE, Granell R, Caudri D, Koppelman GH, Smit HA, Wijga A, de Jongste JC, Brunekreef B, Sterne JA, Postma DS, Henderson J, Kerkhof M. Comparison of childhood wheezing phenotypes in 2 birth cohorts: ALSPAC and PIAMA. J Allergy Clin Immunol. 2011 Jun;127(6):1505-12.e14. Epub 2011 Mar 16.
Start Year 2010
 
Description STELAR 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Project management; collaboration on phenotype specification
Collaborator Contribution Development of datamining methods using unsupervised machine-learning techniques.
Impact Phenotyping field work in progress in partner centres; no notable publications of other output to date.
Start Year 2006
 
Description STELAR 
Organisation University of Aberdeen
Country United Kingdom 
Sector Academic/University 
PI Contribution Project management; collaboration on phenotype specification
Collaborator Contribution Development of datamining methods using unsupervised machine-learning techniques.
Impact Phenotyping field work in progress in partner centres; no notable publications of other output to date.
Start Year 2006
 
Description STELAR 
Organisation University of Manchester
Country United Kingdom 
Sector Academic/University 
PI Contribution Project management; collaboration on phenotype specification
Collaborator Contribution Development of datamining methods using unsupervised machine-learning techniques.
Impact Phenotyping field work in progress in partner centres; no notable publications of other output to date.
Start Year 2006
 
Description STELAR 
Organisation University of Southampton
Country United Kingdom 
Sector Academic/University 
PI Contribution Project management; collaboration on phenotype specification
Collaborator Contribution Development of datamining methods using unsupervised machine-learning techniques.
Impact Phenotyping field work in progress in partner centres; no notable publications of other output to date.
Start Year 2006
 
Description SpiroMeta 
Organisation University of Leicester
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of lung function data and genome wide analysis of lung function.
Collaborator Contribution Meta-analysis of whole genome association studies of lung function
Impact Repapis et al. Genome-wide association study identifies five loci associated with lung function. Nat Genet 2010; 42: 36-44. Obeidat et al. A comprehensive evaluation of potential lung function associated genes in the SpiroMeta general population sample. PLOS One 2011; 6: e19382.
Start Year 2008
 
Description CIPP 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Health professionals
Results and Impact Description of asthma phenotypes in children, including new data evolving from this project.

Review paper published (Henderson J. What have we learned from prospective cohort studies of asthma in children? Chronic Respiratory Disease 2008; 5: 225-31).
Year(s) Of Engagement Activity 2008
 
Description Excellence in Paediatrics 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Health professionals
Results and Impact Presentation of clinical context of research results

None
Year(s) Of Engagement Activity 2009
 
Description NIH Workshop 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact 30 scientists and funders' representatives met to discuss research agenda for asthma phenotypes research.

Expect a consensus paper to be published early 2013.
Year(s) Of Engagement Activity 2012
 
Description Public Engagement talk 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Round table discussion with up to 10 members of public, addressing their questions about my research & discussing implications of research findings for public health.

Request for repeat events, including presentation to participants in cohort study.
Year(s) Of Engagement Activity 2010
 
Description The One Show 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Television interview on research work and implications

None
Year(s) Of Engagement Activity 2009