Modeling Wheezing Spells Identifies Phenotypes with Different Outcomes and Genetic Associates

Sadia Haider, Raquel Granell, John Curtin, Sara Fontanella, Alex Cucco, Stephen Turner, Angela Simpson, Graham Roberts, Clare S. Murray, John W. Holloway, Graham Devereux, Paul Cullinan, Syed Hasan Arshad, Adnan Custovic*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)
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Rationale: Longitudinal modeling of current wheezing identified similar phenotypes, but their characteristics often differ between studies. Objectives: We propose that a more comprehensive description of wheeze may better describe trajectories than binary information on the presence/absence of wheezing. Methods: We derived six multidimensional variables of wheezing spells from birth to adolescence (including duration, temporal sequencing, and the extent of persistence/recurrence). We applied partition-around-medoids clustering on these variables to derive phenotypes in five birth cohorts. We investigated within- and between-phenotype differences compared with binary latent class analysis models and ascertained associations of these phenotypes with asthma and lung function and with polymorphisms in asthma loci 17q12-21 and CDHR3 (cadherin-related family member 3). Measurements and Main Results: Analysis among 7,719 participants with complete data identified five spell-based wheeze phenotypes with a high degree of certainty: never (54.1%), early-transient (ETW) (23.7%), late-onset (LOW) (6.9%), persistent (PEW) (8.3%), and a novel phenotype, intermittent wheeze (INT) (6.9%). FEV1/FVC was lower in PEW and INT compared with ETW and LOW and declined from age 8 years to adulthood in INT. 17q12-21 and CDHR3 polymorphisms were associated with higher odds of PEW and INT, but not ETW or LOW. Latent class analysis- and spell-based phenotypes appeared similar, but within-phenotype individual trajectories and phenotype allocation differed substantially. The spell-based approach was much more robust in dealing with missing data, and the derived clusters were more stable and internally homogeneous. Conclusions: Modeling of spell variables identified a novel intermittent wheeze phenotype associated with lung function decline to early adulthood. Using multidimensional spell variables may better capture wheeze development and provide a more robust input for phenotype derivation.

Original languageEnglish
Pages (from-to)883-893
Number of pages11
JournalAmerican journal of respiratory and critical care medicine
Issue number8
Early online date20 Jan 2022
Publication statusPublished - 15 Apr 2022

Bibliographical note

Funding Information:
Supported by the UK Medical Research Council (UK MRC) Programme grant MR/S025340/1 and grants G0601361 and MR/K002449/1. R.G. is in part funded through Wellcome Trust Strategic Award 108818/15/Z. The UK MRC and Wellcome (grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC (Avon Longitudinal Study of Parents and Children). MAAS (Manchester Asthma and Allergy Study) was supported by the Asthma UK Grants No 301 (1995–1998), No 362 (1998–2001), No 01/012 (2001–2004), No 04/014 (2004–2007), British Medical Association James Trust (2005), and the JP Moulton Charitable Foundation (2004–2016), the North West Lung Centre Charity (1997–current), and the UK MRC grant MR/L012693/1 (2014–2018).

This article is dedicated to the memory of our wonderful colleague and friend Prof. John Henderson (1958–2019), whose contribution to the understanding of the heterogeneity of childhood asthma cannot be overstated. Rainbow chasers and UNICORN riders forever.


  • 17q12-21
  • asthma
  • genetics
  • latent class
  • Wheezing phenotypes


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