1. Computational and Systems Biology
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Trajectories of childhood immune development and respiratory health relevant to asthma and allergy

  1. Howard HF Tang  Is a corresponding author
  2. Shu Mei Teo
  3. Danielle CM Belgrave
  4. Michael D Evans
  5. Daniel J Jackson
  6. Marta Brozynska
  7. Merci MH Kusel
  8. Sebastian L Johnston
  9. James E Gern
  10. Robert F Lemanske
  11. Angela Simpson
  12. Adnan Custovic
  13. Peter D Sly
  14. Patrick G Holt
  15. Kathryn E Holt
  16. Michael Inouye  Is a corresponding author
  1. Baker Heart and Diabetes Institute, Australia
  2. Imperial College London, United Kingdom
  3. University of Wisconsin School of Medicine and Public Health, United States
  4. University of Western Australia, Australia
  5. University of Manchester, United Kingdom
  6. The University of Melbourne, Australia
  7. University of Cambridge, United Kingdom
Research Article
  • Cited 12
  • Views 1,651
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Cite this article as: eLife 2018;7:e35856 doi: 10.7554/eLife.35856

Abstract

Events in early life contribute to subsequent risk of asthma; however, the causes and trajectories of childhood wheeze are heterogeneous and do not always result in asthma. Similarly, not all atopic individuals develop wheeze, and vice versa. The reasons for these differences are unclear. Using unsupervised model-based cluster analysis, we identified latent clusters within a prospective birth cohort with deep immunological and respiratory phenotyping. We characterised each cluster in terms of immunological profile and disease risk, and replicated our results in external cohorts from the UK and USA. We discovered three distinct trajectories, one of which is a high-risk 'atopic' cluster with increased propensity for allergic diseases throughout childhood. Atopy contributes varyingly to later wheeze depending on cluster membership. Our findings demonstrate the utility of unsupervised analysis in elucidating heterogeneity in asthma pathogenesis and provide a foundation for improving management and prevention of childhood asthma.

Data availability

This study utilises extensive data from human subjects, specifically paediatric cohorts, for which eLife's policies recognise that there can be strong reasons to restrict access. For each of the cohorts involved in our study (CAS, COAST, MAAS), parents were consented on the use of biomedical data for allergy and asthma research, but not for the open sharing of their or their children's data. Studies were run in the late 1990s and early 2000s and we do not have ethics permission to attempt to recontact families to seek consent. Importantly, we note that key data features could risk re-identification of subjects (e.g. demographic data from small communities).However, we have provided public data at the summary level which can be used for subsequent studies, such as replication and meta-analysis. This is standard practice in sensitive data settings, such as genome-wide association studies. These data have been uploaded as Excel spreadsheets to FigShare for ease of data extraction:Supplementary Table 4 https://figshare.com/articles/Supplementary_File_1_1/6934052Supplementary Table 7 https://figshare.com/articles/Supplementary_File_1_2/6934055

Article and author information

Author details

  1. Howard HF Tang

    Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Australia
    For correspondence
    Howard.Tang@baker.edu.au
    Competing interests
    The authors declare that no competing interests exist.
  2. Shu Mei Teo

    Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  3. Danielle CM Belgrave

    Department of Paediatrics, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Michael D Evans

    University of Wisconsin School of Medicine and Public Health, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7449-3993
  5. Daniel J Jackson

    University of Wisconsin School of Medicine and Public Health, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Marta Brozynska

    Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  7. Merci MH Kusel

    Telethon Kids Institute, University of Western Australia, Perth, Australia
    Competing interests
    The authors declare that no competing interests exist.
  8. Sebastian L Johnston

    Airway Disease Infection Section, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. James E Gern

    University of Wisconsin School of Medicine and Public Health, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Robert F Lemanske

    University of Wisconsin School of Medicine and Public Health, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Angela Simpson

    Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Adnan Custovic

    Department of Paediatrics, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5218-7071
  13. Peter D Sly

    Telethon Kids Institute, University of Western Australia, Perth, Australia
    Competing interests
    The authors declare that no competing interests exist.
  14. Patrick G Holt

    Telethon Kids Institute, University of Western Australia, Perth, Australia
    Competing interests
    The authors declare that no competing interests exist.
  15. Kathryn E Holt

    Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  16. Michael Inouye

    Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    mi336@medschl.cam.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9413-6520

Funding

National Health and Medical Research Council (1049539)

  • Michael Inouye

National Health and Medical Research Council (PhD Scholarship)

  • Howard HF Tang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: Ethics approval and consent requirements for each cohort were met as follows: The CAS study was approved by the ethics committees of the King Edward Memorial and Princess Margaret Hospitals in Western Australia; fully informed parental consent was obtained for all subjects. The COAST study was approved by the Human Subjects Committee of the University of Wisconsin. The MAAS study was approved by a Manchester Local Research Ethics Committee (ERP/94/032; SOU/00/258; 03/SM/400; Study registration ISRCTN72673620); fully informed parental consent was obtained for all subjects across all cohorts.

Reviewing Editor

  1. M Dawn Teare, University of Sheffield, United Kingdom

Publication history

  1. Received: February 12, 2018
  2. Accepted: October 5, 2018
  3. Accepted Manuscript published: October 15, 2018 (version 1)
  4. Version of Record published: November 7, 2018 (version 2)

Copyright

© 2018, Tang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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