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Original Article
Functional phenotypes determined by fluctuation-based clustering of lung function measurements in healthy and asthmatic cohort participants
  1. Edgar Delgado-Eckert1,2,
  2. Oliver Fuchs3,4,
  3. Nitin Kumar1,
  4. Juha Pekkanen5,6,
  5. Jean-Charles Dalphin7,
  6. Josef Riedler8,
  7. Roger Lauener9,
  8. Michael Kabesch10,11,
  9. Maciej Kupczyk12,13,
  10. Sven-Erik Dahlen12,
  11. Erika von Mutius3,
  12. Urs Frey1
    1. 1 University Children’s Hospital (UKBB), University of Basel, Basel, Switzerland
    2. 2 Endothelial Cell Biology Unit and Department of Applied Mathematics, School of Molecular & Cellular Biology, School of Mathematics, University of Leeds, Leeds, UK
    3. 3 Dr von Hauner Children’s Hospital, Ludwig Maximilians University, Member of the German Center for Lung Research (DZL), Munchen, Germany
    4. 4 Department of Paediatric Respiratory Medicine, Inselspital, University Children’s Hospital of Bern, University of Bern, Bern, Switzerland
    5. 5 Department of Health Protection, National Institute for Health and Welfare, Kuopio, Finland
    6. 6 Department of Public Health, University of Helsinki, Helsinki, Finland
    7. 7 Department of Respiratory Disease, University Hospital of Besançon, Besançon, France
    8. 8 Children’s Hospital, Schwarzach, Austria
    9. 9 Children’s Hospital of Eastern Switzerland, St. Gallen, Switzerland
    10. 10 Department of Pediatric Pneumology and Allergy Campus St. Hedwig, KUNO Children’s University Hospital, Regensburg, Germany
    11. 11 Clinic for Pediatric Pneumology and Neonatology, Hannover Medical School, Hannover, Germany
    12. 12 Experimental Asthma and Allergy Research Unit, The National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
    13. 13 Department of Internal Medicine, Asthma and Allergy, Medical University of Lodz, Lodz, Poland
    1. Correspondence to Dr Edgar Delgado-Eckert, University of Basel, University Children’s Hospital (UKBB), Spitalstrasse 33, Postfach, Basel 4031, Switzerland; edgar.delgado-eckert{at}unibas.ch

    Abstract

    Rationale Asthma is characterised by inflammation and reversible airway obstruction. However, these features are not always closely related. Fluctuations of daily lung function contain information on asthma phenotypes, exacerbation risk and response to long-acting β-agonists.

    Objectives In search of subgroups of asthmatic participants with specific lung functional features, we developed and validated a novel clustering approach to asthma phenotyping, which exploits the information contained within the fluctuating behaviour of twice-daily lung function measurements.

    Methods Forced expiratory volume during the first second (FEV1) and peak expiratory flow (PEF) were prospectively measured over 4 weeks in 696 healthy and asthmatic school children (Protection Against Allergy – Study in Rural Environments (PASTURE)/EFRAIM cohort), and over 1 year in 138 asthmatic adults with mild-to-moderate or severe asthma (Pan-European Longitudinal Assessment of Clinical Course and BIOmarkers in Severe Chronic AIRway Disease (BIOAIR) cohort). Using enrichment analysis, we explored whether the method identifies clinically meaningful, distinct clusters of participants with different lung functional fluctuation patterns.

    Measurements and main results In the PASTURE/EFRAIM dataset, we found four distinct clusters. Two clusters were enriched in children with well-known clinical characteristics of asthma. In cluster 3, children from a farming environment predominated, whereas cluster 4 mainly consisted of healthy controls. About 79% of cluster 3 carried the asthma-risk allele rs7216389 of the 17q21 locus. In the BIOAIR dataset, we found two distinct clusters clearly discriminating between individuals with mild-to-moderate and severe asthma.

    Conclusions Our method identified dynamic functional asthma and healthy phenotypes, partly independent of atopy and inflammation but related to genetic markers on the 17q21 locus. The method can be used for disease phenotyping and possibly endotyping. It may identify participants with specific functional abnormalities, potentially needing a different therapeutic approach.

    • asthma
    • asthma mechanisms
    • lung physiology
    • paediatric asthma
    • respiratory measurement
    • not applicable

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    Footnotes

    • Some of the results of these studies have been previously reported in the form of an abstract (see reference 32).

    • OF and NK contributed equally.

    • Contributors ED-E, OF, JP, J-CD, JR, RL, EvM and UF planned the study; ED-E, NK, OF and the PASTURE Study Group were involved in the acquisition, management and interpretation of data; ED-E conceived the computational methodology and the algorithms, selected statistical tests to be used and implemented algorithms; NK conceived and implemented algorithms and performed data processing; MK planned genetic analyses and interpreted genetic data. ED-E, NK and OF performed statistical analyses; MK, S-ED and the BIOAIR Study Group were responsible for the study design, cohort collection and data analysis of the BIOAIR Study; ED-E, OF, EvM and UF wrote the manuscript; all authors provided substantial revisions and approval of the final manuscript.

    • Funding The PASTURE/EFRAIM study was supported by the European Commission research grants QLK4-CT-2001-00250, FOOD-CT-2006-31708 and KBBE-2007-2-2-06. OF (PASTURE/EFRAIM study) is the recipient of a Long-Term Research Fellowship by the European Respiratory Society (no. 675) and a training scholarship by the Austrian, German and Swiss Paediatric Respiratory Society. The BIOAIR study was supported by the following Swedish research funding bodies: The Medical Research Council, the Heart-Lung Foundation, the Vårdal Foundation, the Stockholm County Council (ALF), the Swedish Asthma and Allergy Association, the Swedish Foundation for Strategic Research, Konsul Th C Berghs Foundation, the Karolinska Institutet SciLifeLab collaborations on translational medicine (ChAMP project), the Innovative Medicines Initiative project U-BIOPRED (unbiased biomarkers for the prediction of respiratory disease outcomes) and Karolinska Institutet.

    • Competing interests None declared.

    • Ethics approval Ethics committees of the corresponding participating study centres.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Collaborators The members of the PASTURE study group are (in alphabetical order): Sondhja BitterA, B, Charlotte Braun-FahrländerA, B, Gisela BücheleC, Marie-Laure DalphinD, Martin DepnerH, Gert DoekesE, Markus J. EgeH, Remo FreiF, Jon GenuneitC, Maija-Riitta HirvonenG, Anne HyvärinenK, Anne M. KarvonenK, Vincent KaulekD, Georg LossA, B, H, Petra Ina PfefferleN, Sami RemesI, Harald RenzJ, Caroline RoduitO, Marjut RoponenG, Bianca SchaubH, Pekka TiittanenK, Juliane WeberH. ASwiss Tropical and Public Health Institute, Basel, Switzerland. BUniversity of Basel, Basel, Switzerland. CInstitute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany. DDepartment of Respiratory Disease, UMR/CNRS 6249 chrono-environnement, University Hospital of Besançon, France. EUtrecht University, Institute for Risk Assessment Sciences (IRAS), Division of Environmental Epidemiology, Utrecht, Netherlands. FUniversity of Zurich, Children’s Hospital, and Christine Kühne-Center for Allergy Research and Education, Zurich, Switzerland. GDepartment of Environmental Science, University of Eastern Finland, Kuopio, Finland. HDr von Hauner Children’s Hospital, Ludwig Maximilians University, Munich, Germany; Member of the German Center for Lung Research (DZL). IDepartment of Paediatrics, Kuopio University Hospital, Kopio, Finland. JInstitute for Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Philipps University of Marburg, Marburg, Germany. KDepartment of Health Protection, National Institute for Health and Welfare, Kuopio, Finland. NInstitute for Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Philipps University of Marburg, Marburg, Germany. OChildren’s Hospital, University of Zurich, and Christine Kühne-Center for Allergy Research and Education, Zurich, Switzerland. The members of the BIOAIR study group are: Dr Roelinde Middelveld, Karolinska Institutet, Stockholm, Sweden. Professor Barbro Dahlén, Karolinska Institutet, Stockholm, Sweden. Dr Mina Gaga, University of Athens, Greece. Professor Nikos M. Siafakas, University of Crete, Greece. Professor Alberto Papi, University of Ferrara, Italy. Leonardo M. Fabbri, University of Modena, Italy. Professor Guy Joos, University of Gent, Belgium. Professor Klaus F. Rabe, Christian Albrechts University Kiel, Germany. Professor Sebastian L. Johnston, The Imperial College of Science and Technology, London, UK. Professor Pascal Chanez, University of Marseilles, France. Dr Mark Gjormarkaj, Italian Research Council, Palermo, Italy. Dr Peter H. Howarth, University of Southampton, UK. Professor Ewa Niżankowska-Mogilnicka, The Jagellonian University, Krakow, Poland.

    • Correction notice This article has been corrected since it was published Online First. The following changes have been made: 1) Sven-Erik Dahlen’s name was corrected; 2) Affiliation 12 was corrected; 3) Reference 13 citation was incorrect, this has now been corrected; 4) Collaborators section has been corrected.

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