Modeling Wheezing Spells Identifies Phenotypes with Different Outcomes and Genetic Associates

Area of Science:

• Pediatric Pulmonology
• Respiratory Medicine
• Computational Biology

Background:

• Longitudinal wheeze phenotypes are inconsistently defined across studies.
• Current binary wheeze presence/absence may oversimplify complex wheezing trajectories.

Purpose of the Study:

• To develop and validate a multidimensional approach to wheeze phenotyping.
• To identify novel wheeze phenotypes and their associations with asthma risk factors and lung function.

Main Methods:

• Derived six multidimensional wheezing spell variables (duration, sequencing, persistence) from birth to adolescence.
• Applied partition-around-medoids clustering to five birth cohorts (n=7,719).
• Compared spell-based phenotypes with latent class analysis and assessed associations with lung function and genetic polymorphisms (17q12-21, CDHR3).

Main Results:

• Identified five spell-based wheeze phenotypes: never, early-transient wheeze (ETW), late-onset wheeze (LOW), persistent wheeze (PEW), and a novel intermittent wheeze (INT).
• PEW and INT phenotypes showed lower FEV1/FVC and INT exhibited lung function decline into adulthood.
• 17q12-21 and CDHR3 polymorphisms were associated with higher odds of PEW and INT phenotypes.

Conclusions:

• A novel intermittent wheeze phenotype (INT) is associated with lung function decline into early adulthood.
• Multidimensional modeling of wheezing spell variables provides a more robust and stable approach to phenotype derivation.
• This method enhances understanding of wheeze development and its clinical implications.