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.
Highlights
Asthma is a global health problem, and there is a pressing need for better understanding of its pathogenesis (Global Initiative for Asthma, 2015)
By applying non-paremetric expectation-maximiation (npEM)-based clustering and classification to Childhood Asthma Study (CAS), we identified three distinct clusters from 217 individuals and 174 clustering features (Figure 1): low-risk CAS1 (N = 88, 25% wheeze at age 5), low-risk but allergy-susceptible CAS2 (N = 107, 21% wheeze at age 5) and high-risk CAS3 (N = 22, 76% wheeze at age 5)
After applying our npEM classifier to these external cohorts, we found that individuals classified into ‘Cluster 3’ (MAAS3/ COAST3) had a persistent disease phenotype extending into late adolescence, with consistently high rates of parent-reported wheeze and physician-diagnosed asthma from birth to age 16
Summary
Asthma is a global health problem, and there is a pressing need for better understanding of its pathogenesis (Global Initiative for Asthma, 2015). Asthma is strongly associated with allergy, and both genetic and environmental factors may be involved (Ober and Yao, 2011; Dick et al, 2014). Computational and Systems Biology eLife digest Asthma causes wheezy and troubled breathing, and can be life-threatening. Scientists and doctors understand that asthma begins in early childhood. Exposure to bacteria, viruses, and allergies may cause or trigger asthma. One person with asthma may not have the same origins as another. It is not yet clear how various triggers may interact to trigger or exacerbate asthma
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