Modeling Wheezing Spells Identifies Phenotypes with Different Outcomes and Genetic Associates

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.