title: A Transcriptome-driven Analysis of Epithelial Brushings and Bronchial Biopsies to Define Asthma Phenotypes in U-BIOPRED.
abstract: BACKGROUND
  Asthma is a heterogeneous disease driven by diverse immunologic and inflammatory mechanisms.
  
  
  OBJECTIVE
  Using transcriptomic profiling of airway tissues, we sought to define the molecular phenotypes of severe asthma.
  
  
  METHODS
  The transcriptome derived from bronchial biopsies and epithelial brushings of 107 subjects with moderate to severe asthma were annotated by gene set variation analysis using 42 gene signatures relevant to asthma, inflammation, and immune function. Topological data analysis of clinical and histologic data was performed to derive clusters, and the nearest shrunken centroid algorithm was used for signature refinement.
  
  
  RESULTS
  Nine gene set variation analysis signatures expressed in bronchial biopsies and airway epithelial brushings distinguished two distinct asthma subtypes associated with high expression of T-helper cell type 2 cytokines and lack of corticosteroid response (group 1 and group 3). Group 1 had the highest submucosal eosinophils, as well as high fractional exhaled nitric oxide levels, exacerbation rates, and oral corticosteroid use, whereas group 3 patients showed the highest levels of sputum eosinophils and had a high body mass index. In contrast, group 2 and group 4 patients had an 86% and 64% probability, respectively, of having noneosinophilic inflammation. Using machine learning tools, we describe an inference scheme using the currently available inflammatory biomarkers sputum eosinophilia and fractional exhaled nitric oxide levels, along with oral corticosteroid use, that could predict the subtypes of gene expression within bronchial biopsies and epithelial cells with good sensitivity and specificity.
  
  
  CONCLUSIONS
  This analysis demonstrates the usefulness of a transcriptomics-driven approach to phenotyping that segments patients who may benefit the most from specific agents that target T-helper cell type 2-mediated inflammation and/or corticosteroid insensitivity.
authors: 1 Department of Computing.|2 Data Science Institute, and.|3 Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors: Chih-Hsi Scott
authors: CS
authors: Kuo
authors: 1 Department of Computing.|2 Data Science Institute, and.|4 Janssen Research and Development, High Wycombe, United Kingdom.
authors: Stelios
authors: S
authors: Pavlidis
authors: 4 Janssen Research and Development, High Wycombe, United Kingdom.
authors: Matthew
authors: M
authors: Loza
authors: 4 Janssen Research and Development, High Wycombe, United Kingdom.
authors: Fred
authors: F
authors: Baribaud
authors: 4 Janssen Research and Development, High Wycombe, United Kingdom.
authors: Anthony
authors: A
authors: Rowe
authors: 1 Department of Computing.|2 Data Science Institute, and.
authors: Ioannis
authors: I
authors: Pandis
authors: 3 Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.|5 Biomedical Research Unit, Royal Brompton & Harefield National Health Service Trust, London, United Kingdom.
authors: Uruj
authors: U
authors: Hoda
authors: 3 Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors: Christos
authors: C
authors: Rossios
authors: 6 Respiratory Therapeutic Unit, GlaxoSmithKline, Stockley Park, United Kingdom.
authors: Ana
authors: A
authors: Sousa
authors: 7 Faculty of Medicine, Southampton University, Southampton, United Kingdom.
authors: Susan J
authors: SJ
authors: Wilson
authors: 7 Faculty of Medicine, Southampton University, Southampton, United Kingdom.
authors: Peter
authors: P
authors: Howarth
authors: 8 Centre for Allergy Research, Karolinska Institute, Stockholm, Sweden.
authors: Barbro
authors: B
authors: Dahlen
authors: 8 Centre for Allergy Research, Karolinska Institute, Stockholm, Sweden.
authors: Sven-Erik
authors: SE
authors: Dahlen
authors: 9 Université de la Méditerranee, Marseille, France.
authors: Pascal
authors: P
authors: Chanez
authors: 10 Centre for Respiratory Research, University of Nottingham, Nottingham, United Kingdom.
authors: Dominick
authors: D
authors: Shaw
authors: 11 Fraunhofer Institute of Toxicology and Experimental Medicine, Hannover, Germany.
authors: Norbert
authors: N
authors: Krug
authors: 12 Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
authors: Thomas
authors: T
authors: Sandstrӧm
authors: 13 European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL, University of Lyon, Lyon, France.
authors: Bertrand
authors: B
authors: De Meulder
authors: 13 European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL, University of Lyon, Lyon, France.
authors: Diane
authors: D
authors: Lefaudeux
authors: 14 Centre for Respiratory Medicine and Allergy, University of Manchester, Manchester, United Kingdom.
authors: Stephen
authors: S
authors: Fowler
authors: 3 Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.|5 Biomedical Research Unit, Royal Brompton & Harefield National Health Service Trust, London, United Kingdom.
authors: Louise
authors: L
authors: Fleming
authors: 15 AstraZeneca R&D, Molndal, Sweden.|16 Areteva R&D, Nottingham, United Kingdom; and.
authors: Julie
authors: J
authors: Corfield
authors: 13 European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL, University of Lyon, Lyon, France.
authors: Charles
authors: C
authors: Auffray
authors: 17 Faculty of Medicine, University of Amsterdam, Amsterdam, the Netherlands.
authors: Peter J
authors: PJ
authors: Sterk
authors: 7 Faculty of Medicine, Southampton University, Southampton, United Kingdom.
authors: Ratko
authors: R
authors: Djukanovic
authors: 1 Department of Computing.|2 Data Science Institute, and.
authors: Yike
authors: Y
authors: Guo
authors: 3 Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.|5 Biomedical Research Unit, Royal Brompton & Harefield National Health Service Trust, London, United Kingdom.
authors: Ian M
authors: IM
authors: Adcock
authors: 3 Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.|5 Biomedical Research Unit, Royal Brompton & Harefield National Health Service Trust, London, United Kingdom.
authors: Kian Fan
authors: KF
authors: Chung
mesh_terms: D000305:Adrenal Cortex Hormones / Q000276:immunology* / Q000494:pharmacology / Q000627:therapeutic use; D000328:Adult; D001249:Asthma / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D015415:Biomarkers / Q000032:analysis; D001706:Biopsy; D001944:Breath Tests; D001980:Bronchi / Q000473:pathology*; D001999:Bronchoscopy / Q000295:instrumentation / Q000379:methods; D015331:Cohort Studies; D004351:Drug Resistance / Q000235:genetics / Q000276:immunology; D004804:Eosinophils / Q000166:cytology / Q000276:immunology; D005260:Female; D020869:Gene Expression Profiling / Q000295:instrumentation / Q000379:methods; D006801:Humans; D007249:Inflammation; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012720:Severity of Illness Index; D013183:Sputum / Q000166:cytology / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology
chemical_list: D000305:Adrenal Cortex Hormones; D015415:Biomarkers
keywords: T-helper type 2; corticosteroid insensitivity; exhaled nitric oxide; gene set variation analysis; severe asthma