期刊
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
卷 205, 期 8, 页码 883-893出版社
AMER THORACIC SOC
DOI: 10.1164/rccm.202108-1821OC
关键词
wheezing phenotypes; asthma; latent class; genetics; 17q12-21
资金
- UK Medical Research Council (UK MRC) [MR/S025340/1, G0601361, MR/K002449/1]
- Wellcome Trust Strategic Award [108818/15/Z]
- UK MRC [MR/L012693/1]
- Asthma UK [301, 362, 01/012, 04/014]
- British Medical Association James Trust
- JP Moulton Charitable Foundation
- North West Lung Centre Charity
- Wellcome [217065/Z/19/Z]
This study proposes a more comprehensive method to describe the development of wheezing and identifies five different phenotypes of wheezing. The spell-based approach proves to be more robust and able to capture the characteristics of wheezing development better than binary information.
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 (54A%), 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.
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