Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Victoria, Australia; School of BioSciences, The University of Melbourne, Victoria, Australia
Shu Mei Teo
Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Victoria, Australia; Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
Danielle CM Belgrave
Department of Paediatrics, Imperial College London, London, United Kingdom
Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; University of Wisconsin School of Medicine and Public Health, Madison, United States
Daniel J Jackson
University of Wisconsin School of Medicine and Public Health, Madison, United States
Marta Brozynska
Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Victoria, Australia; Department of Paediatrics, Imperial College London, London, United Kingdom
Merci MH Kusel
Telethon Kids Institute, University of Western Australia, Perth, Australia
Sebastian L Johnston
Airway Disease Infection Section, MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, National Heart and Lung Institute, Imperial College London, London, United Kingdom
James E Gern
University of Wisconsin School of Medicine and Public Health, Madison, United States
Robert F Lemanske
University of Wisconsin School of Medicine and Public Health, Madison, United States
Angela Simpson
Division of Infection, Immunity and Respiratory Medicine, The University of Manchester, Manchester, United Kingdom
Department of Paediatrics, Imperial College London, London, United Kingdom
Peter D Sly
Telethon Kids Institute, University of Western Australia, Perth, Australia; Child Health Research Centre, The University of Queensland, Brisbane, Australia
Patrick G Holt
Telethon Kids Institute, University of Western Australia, Perth, Australia; Child Health Research Centre, The University of Queensland, Brisbane, Australia
Kathryn E Holt
Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria, Australia; The London School of Hygiene and Tropical Medicine, London, United Kingdom
Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Victoria, Australia; Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; The Alan Turing Institute, London, United Kingdom
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.
