title: U-BIOPRED clinical adult asthma clusters linked to a subset of sputum omics.
abstract: BACKGROUND
  Asthma is a heterogeneous disease in which there is a differential response to asthma treatments. This heterogeneity needs to be evaluated so that a personalized management approach can be provided.
  
  
  OBJECTIVE
  We stratified patients with moderate-to-severe asthma based on clinicophysiologic parameters and performed an omics analysis of sputum.
  
  
  METHODS
  Partition-around-medoids clustering was applied to a training set of 266 asthmatic participants from the European Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes (U-BIOPRED) adult cohort using 8 prespecified clinic-physiologic variables. This was repeated in a separate validation set of 152 asthmatic patients. The clusters were compared based on sputum proteomics and transcriptomics data.
  
  
  RESULTS
  Four reproducible and stable clusters of asthmatic patients were identified. The training set cluster T1 consists of patients with well-controlled moderate-to-severe asthma, whereas cluster T2 is a group of patients with late-onset severe asthma with a history of smoking and chronic airflow obstruction. Cluster T3 is similar to cluster T2 in terms of chronic airflow obstruction but is composed of nonsmokers. Cluster T4 is predominantly composed of obese female patients with uncontrolled severe asthma with increased exacerbations but with normal lung function. The validation set exhibited similar clusters, demonstrating reproducibility of the classification. There were significant differences in sputum proteomics and transcriptomics between the clusters. The severe asthma clusters (T2, T3, and T4) had higher sputum eosinophilia than cluster T1, with no differences in sputum neutrophil counts and exhaled nitric oxide and serum IgE levels.
  
  
  CONCLUSIONS
  Clustering based on clinicophysiologic parameters yielded 4 stable and reproducible clusters that associate with different pathobiological pathways.
authors: European Institute for Systems Biology and Medicine, CIRI UMR5308, CNRS-ENS-UCBL-INSERM, Lyon, France.
authors: Diane
authors: D
authors: Lefaudeux
authors: European Institute for Systems Biology and Medicine, CIRI UMR5308, CNRS-ENS-UCBL-INSERM, Lyon, France.
authors: Bertrand
authors: B
authors: De Meulder
authors: Janssen Research and Development LLC, Spring House, Pa.
authors: Matthew J
authors: MJ
authors: Loza
authors: Janssen Research and Development LLC, Spring House, Pa.
authors: Nancy
authors: N
authors: Peffer
authors: Janssen Research and Development Ltd, High Wycombe, United Kingdom.
authors: Anthony
authors: A
authors: Rowe
authors: Janssen Research and Development LLC, Spring House, Pa.
authors: Frédéric
authors: F
authors: Baribaud
authors: Acclarogen, St John's Innovation Centre, Cambridge, United Kingdom.
authors: Aruna T
authors: AT
authors: Bansal
authors: Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors: Rene
authors: R
authors: Lutter
authors: Respiratory Therapeutic Unit, GlaxoSmithKline, Stockley Park, United Kingdom.
authors: Ana R
authors: AR
authors: Sousa
authors: AstraZeneca R&D Molndal, and Areteva R&D, Nottingham, United Kingdom.
authors: Julie
authors: J
authors: Corfield
authors: Data Science Institute, Imperial College London, London, United Kingdom.
authors: Ioannis
authors: I
authors: Pandis
authors: Department of Clinical Science, University of Bergen, Bergen, Norway.
authors: Per S
authors: PS
authors: Bakke
authors: Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.
authors: Massimo
authors: M
authors: Caruso
authors: Département des Maladies Respiratoires, Aix Marseille Université Marseille, Marseille, France.
authors: Pascal
authors: P
authors: Chanez
authors: Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden.
authors: Sven-Erik
authors: SE
authors: Dahlén
authors: National Heart and Lung Institute, Imperial College & Biomedical Research Unit, Royal Brompton & Harefield NHS Trust, London, United Kingdom.
authors: Louise J
authors: LJ
authors: Fleming
authors: Centre for Respiratory Medicine and Allergy, University of Manchester, Manchester, United Kingdom.
authors: Stephen J
authors: SJ
authors: Fowler
authors: Department of Pulmonology, Semmelweis University, Budapest, Hungary.
authors: Ildiko
authors: I
authors: Horvath
authors: Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany.
authors: Norbert
authors: N
authors: Krug
authors: Faculty of Medicine, Catholic University of the Sacred Heart, Rome, Italy.
authors: Paolo
authors: P
authors: Montuschi
authors: Department of Medicine, Jagiellonian University Medical School, Krakow, Poland.
authors: Marek
authors: M
authors: Sanak
authors: Department of Public Health and Clinical Medicine, Medicine, Umeå university, Umeå, Sweden.
authors: Thomas
authors: T
authors: Sandstrom
authors: Respiratory Research Unit, University of Nottingham, Nottingham, United Kingdom.
authors: Dominic E
authors: DE
authors: Shaw
authors: University Children's Hospital Bern, Bern, Switzerland.
authors: Florian
authors: F
authors: Singer
authors: NIHR Respiratory Biomedical Research Unit, Clinical and Experimental Sciences, Southampton, United Kingdom.
authors: Peter J
authors: PJ
authors: Sterk
authors: Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors: Graham
authors: G
authors: Roberts
authors: National Heart and Lung Institute, Imperial College & Biomedical Research Unit, Royal Brompton & Harefield NHS Trust, London, United Kingdom.
authors: Ian M
authors: IM
authors: Adcock
authors: Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors: Ratko
authors: R
authors: Djukanovic
authors: European Institute for Systems Biology and Medicine, CIRI UMR5308, CNRS-ENS-UCBL-INSERM, Lyon, France.
authors: Charles
authors: C
authors: Auffray
authors: National Heart and Lung Institute, Imperial College & Biomedical Research Unit, Royal Brompton & Harefield NHS Trust, London, United Kingdom. Electronic address: f.chung@imperial.ac.uk.
authors: Kian Fan
authors: KF
authors: Chung
mesh_terms: D000328:Adult; D000368:Aged; D000465:Algorithms; D001249:Asthma / Q000145:classification / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D040901:Proteomics; D012720:Severity of Illness Index; D013183:Sputum / Q000166:cytology / Q000378:metabolism
chemical_list: D015415:Biomarkers
keywords: Severe asthma; clustering; partition-around-medoids algorithm; sputum eosinophilia