title: Identifying biomarkers for asthma diagnosis using targeted metabolomics approaches.
abstract: The diagnosis of asthma in children is challenging and relies on a combination of clinical factors and biomarkers including methacholine challenge, lung function, bronchodilator responsiveness, and presence of airway inflammation. No single test is diagnostic. We sought to identify a pattern of inflammatory biomarkers that was unique to asthma using a targeted metabolomics approach combined with data science methods.
  
  
  
  We conducted a nested case-control study of 100 children living in a peri-urban community in Lima, Peru. We defined cases as children with current asthma, and controls as children with no prior history of asthma and normal lung function. We further categorized enrollment following a factorial design to enroll equal numbers of children as either overweight or not. We obtained a fasting venous blood sample to characterize a comprehensive panel of targeted markers using a metabolomics approach based on high performance liquid chromatography-mass spectrometry.
  
  
  
  A statistical comparison of targeted metabolites between children with asthma (n = 50) and healthy controls (n = 49) revealed distinct patterns in relative concentrations of several metabolites: children with asthma had approximately 40-50% lower relative concentrations of ascorbic acid, 2-isopropylmalic acid, shikimate-3-phosphate, and 6-phospho-d-gluconate when compared to children without asthma, and 70% lower relative concentrations of reduced glutathione (all p < 0.001 after Bonferroni correction). Moreover, a combination of 2-isopropylmalic acid and betaine strongly discriminated between children with asthma (2-isopropylmalic acid ≤ 13 077 normalized counts/second) and controls (2-isopropylmalic acid > 13 077 normalized counts/second and betaine ≤ 16 47 121 normalized counts/second).
  
  
  
  By using a metabolomics approach applied to serum, we were able to discriminate between children with and without asthma by revealing different metabolic patterns. These results suggest that serum metabolomics may represent a diagnostic tool for asthma and may be helpful for distinguishing asthma phenotypes.
authors.affiliation: Division of Pulmonary and Critical Care, School of Medicine, Johns Hopkins University, Baltimore, USA. Electronic address: wcheckl1@jhmi.edu.
authors.forename: William
authors.initials: W
authors.lastname: Checkley
authors.affiliation: Division of Pulmonary and Critical Care, School of Medicine, Johns Hopkins University, Baltimore, USA.
authors.forename: Maria P
authors.initials: MP
authors.lastname: Deza
authors.affiliation: iC42 Clinical Research and Development, University of Colorado, Aurora, CO, USA.
authors.forename: Jost
authors.initials: J
authors.lastname: Klawitter
authors.affiliation: Division of Pulmonary and Critical Care, School of Medicine, Johns Hopkins University, Baltimore, USA; Biomedical Research Unit, A.B. PRISMA, Lima, Peru.
authors.forename: Karina M
authors.initials: KM
authors.lastname: Romero
authors.affiliation: iC42 Clinical Research and Development, University of Colorado, Aurora, CO, USA.
authors.forename: Jelena
authors.initials: J
authors.lastname: Klawitter
authors.affiliation: Division of Pulmonary and Critical Care, School of Medicine, Johns Hopkins University, Baltimore, USA.
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Pollard
authors.affiliation: Division of Pulmonary and Critical Care, School of Medicine, Johns Hopkins University, Baltimore, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Wise
authors.affiliation: iC42 Clinical Research and Development, University of Colorado, Aurora, CO, USA.
authors.forename: Uwe
authors.initials: U
authors.lastname: Christians
authors.affiliation: Division of Pulmonary and Critical Care, School of Medicine, Johns Hopkins University, Baltimore, USA.
authors.forename: Nadia N
authors.initials: NN
authors.lastname: Hansel
mesh_terms: D000293:Adolescent; D001249:Asthma / Q000150:complications / Q000175:diagnosis* / Q000503:physiopathology; D001622:Betaine / Q000097:blood; D015415:Biomarkers / Q000097:blood*; D001823:Body Composition; D016022:Case-Control Studies; D002648:Child; D005260:Female; D006801:Humans; D008293:Malates / Q000097:blood; D008297:Male; D055432:Metabolomics / Q000379:methods*; D050177:Overweight / Q000097:blood / Q000150:complications; D018384:Oxidative Stress / Q000502:physiology; D055815:Young Adult
chemical_list: C502920:2-isopropylmalic acid; D015415:Biomarkers; D008293:Malates; D001622:Betaine