Modelling wheezing spells identifies phenotypes with different outcomes and genetic associates
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Published version
Author(s)
Type
Journal Article
Abstract
Background: Longitudinal modelling of current wheezing identified similar phenotypes, but their characteristics often differ between studies. We propose that more comprehensive description of wheeze may better describe trajectories than binary information on presence/absence of wheezing. Methods: We derived 6 multi-dimensional 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 to binary latent class analysis models (LCA-phenotypes), and ascertained associations of these phenotypes with asthma and lung function, and with polymorphisms in asthma loci 17q12-21 and CDHR3. Findings: Analysis among 7719 participants with complete data identified 5 spell-based wheeze phenotypes with high degree of certainty: Never (NWZ-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 to 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. LCA- 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 more stable and internally homogenous. Conclusions: Modelling of spell variables identified a novel intermittent wheeze phenotype associated with lung function decline to early adulthood. Using multi-dimensional spells variables may better capture wheeze development and provide a more robust input for phenotype derivation.
Date Issued
2022-01-20
Date Acceptance
2021-12-22
Citation
American Journal of Respiratory and Critical Care Medicine, 2022, 205 (8), pp.883-893
ISSN
1073-449X
Publisher
American Thoracic Society
Start Page
883
End Page
893
Journal / Book Title
American Journal of Respiratory and Critical Care Medicine
Volume
205
Issue
8
Copyright Statement
© 2022 The Author(s). This article is open access and distributed under the terms of the Creative Commons Attribution International License 4.0.
License URL
Sponsor
Medical Research Council (MRC)
Identifier
https://www.atsjournals.org/doi/10.1164/rccm.202108-1821OC
Grant Number
MR/S025340/1
Subjects
17q12–21
asthma
genetics
latent class
wheezing phenotypes
Adult
Asthma
Cadherin Related Proteins
Cadherins
Humans
Infant
Latent Class Analysis
Membrane Proteins
Phenotype
Respiratory Function Tests
Respiratory Sounds
Risk Factors
Respiratory System
11 Medical and Health Sciences
Publication Status
Published
Date Publish Online
2022-01-20