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
Abstract
Abstract 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 CDHR3polymorphisms 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.