title: Exhaled biomarkers and gene expression at preschool age improve asthma prediction at 6 years of age.
abstract: BACKGROUND
  A reliable asthma diagnosis is difficult in wheezing preschool children.
  
  
  OBJECTIVE
  To assess whether exhaled biomarkers, expression of inflammation genes, and early lung function measurements can improve a reliable asthma prediction in preschool wheezing children.
  
  
  METHODS
  Two hundred two preschool recurrent wheezers (aged 2-4 yr) were prospectively followed up until 6 years of age. At 6 years of age, a diagnosis (asthma or transient wheeze) was based on symptoms, lung function, and asthma medication use. The added predictive value (area under the receiver operating characteristic curve [AUC]) of biomarkers to clinical information (assessed with the Asthma Predictive Index [API]) assessed at preschool age in diagnosing asthma at 6 years of age was determined with a validation set. Biomarkers in exhaled breath condensate, exhaled volatile organic compounds (VOCs), gene expression, and airway resistance were measured.
  
  
  RESULTS
  At 6 years of age, 198 children were diagnosed (76 with asthma, 122 with transient wheeze). Information on exhaled VOCs significantly improved asthma prediction (AUC, 89% [increase of 28%]; positive predictive value [PPV]/negative predictive value [NPV], 82/83%), which persisted in the validation set. Information on gene expression of toll-like receptor 4, catalase, and tumor necrosis factor-α significantly improved asthma prediction (AUC, 75% [increase of 17%]; PPV/NPV, 76/73%). This could not be confirmed after validation. Biomarkers in exhaled breath condensate and airway resistance (pre- and post- bronchodilator) did not improve an asthma prediction. The combined model with VOCs, gene expression, and API had an AUC of 95% (PPV/NPV, 90/89%).
  
  
  CONCLUSIONS
  Adding information on exhaled VOCs and possibly expression of inflammation genes to the API significantly improves an accurate asthma diagnosis in preschool children. Clinical trial registered with www.clinicaltrial.gov (NCT 00422747).
authors.affiliation: 1 Department of Pediatric Pulmonology and.
authors.forename: Ester M M
authors.initials: EM
authors.lastname: Klaassen
authors.forename: Kim D G
authors.initials: KD
authors.lastname: van de Kant
authors.forename: Quirijn
authors.initials: Q
authors.lastname: Jöbsis
authors.forename: Onno C P
authors.initials: OC
authors.lastname: van Schayck
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Smolinska
authors.forename: Jan W
authors.initials: JW
authors.lastname: Dallinga
authors.forename: Frederik J
authors.initials: FJ
authors.lastname: van Schooten
authors.forename: Gertjan J M
authors.initials: GJ
authors.lastname: den Hartog
authors.forename: Johan C
authors.initials: JC
authors.lastname: de Jongste
authors.forename: Ger T
authors.initials: GT
authors.lastname: Rijkers
authors.forename: Edward
authors.initials: E
authors.lastname: Dompeling
mesh_terms: D000403:Airway Resistance / Q000235:genetics / Q000502:physiology; D001249:Asthma / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology; D015415:Biomarkers / Q000378:metabolism; D001944:Breath Tests; D002374:Catalase / Q000097:blood / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003937:Diagnosis, Differential; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D007249:Inflammation / Q000175:diagnosis* / Q000209:etiology / Q000235:genetics; D016015:Logistic Models; D008297:Male; D009426:Netherlands; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012372:ROC Curve; D012135:Respiratory Sounds / Q000175:diagnosis* / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000097:blood / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics; D055549:Volatile Organic Compounds / Q000032:analysis
chemical_list: D015415:Biomarkers; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D055549:Volatile Organic Compounds; D002374:Catalase
keywords: children; exhaled breath condensate; gene expression; volatile organic compounds; wheeze