Identification of Asthma Phenotypes Using Cluster Analysis in the Severe Asthma Research Program

The Severe Asthma Research Program cohort includes subjects with persistent asthma who have undergone detailed phenotypic characterization. Previous univariate methods compared features of mild, moderate, and severe asthma. To identify novel asthma phenotypes using an unsupervised hierarchical clust...

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Published inAmerican journal of respiratory and critical care medicine Vol. 181; no. 4; pp. 315 - 323
Main Authors Moore, Wendy C, Meyers, Deborah A, Wenzel, Sally E, Teague, W. Gerald, Li, Huashi, Li, Xingnan, D'Agostino, Ralph, Jr, Castro, Mario, Curran-Everett, Douglas, Fitzpatrick, Anne M, Gaston, Benjamin, Jarjour, Nizar N, Sorkness, Ronald, Calhoun, William J, Chung, Kian Fan, Comhair, Suzy A. A, Dweik, Raed A, Israel, Elliot, Peters, Stephen P, Busse, William W, Erzurum, Serpil C, Bleecker, Eugene R, National Heart, Lung, and Blood Institute's Severe Asthma Research Program
Format Journal Article
LanguageEnglish
Published New York, NY Am Thoracic Soc 15.02.2010
American Thoracic Society
Subjects
Adolescent
Adrenal Cortex Hormones - therapeutic use
Adult
Age Factors
Age of Onset
Aged
Aged, 80 and over
Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy
Anti-Asthmatic Agents - therapeutic use
Asthma
Asthma - classification
Asthma - drug therapy
Asthma - physiopathology
B. Asthma and Allergy
Biological and medical sciences
Biomarkers
Bronchodilator Agents - therapeutic use
Child
Chronic obstructive pulmonary disease, asthma
Cluster Analysis
Cohort Studies
Discriminant Analysis
Female
Health services utilization
Humans
Infections
Intensive care medicine
Male
Medical sciences
Middle Aged
Phenotype
Pneumology
Questionnaires
Respiratory Function Tests
Sex Factors
Steroids
Variables
Young Adult
Lung disease
Intensive care
Respiratory disease
Asthma
Phenotype
Research program
asthma phenotype
severe asthma
Bronchus disease
definition
Obstructive pulmonary disease
cluster analysis
Resuscitation
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Summary:The Severe Asthma Research Program cohort includes subjects with persistent asthma who have undergone detailed phenotypic characterization. Previous univariate methods compared features of mild, moderate, and severe asthma. To identify novel asthma phenotypes using an unsupervised hierarchical cluster analysis. Reduction of the initial 628 variables to 34 core variables was achieved by elimination of redundant data and transformation of categorical variables into ranked ordinal composite variables. Cluster analysis was performed on 726 subjects. Five groups were identified. Subjects in Cluster 1 (n = 110) have early onset atopic asthma with normal lung function treated with two or fewer controller medications (82%) and minimal health care utilization. Cluster 2 (n = 321) consists of subjects with early-onset atopic asthma and preserved lung function but increased medication requirements (29% on three or more medications) and health care utilization. Cluster 3 (n = 59) is a unique group of mostly older obese women with late-onset nonatopic asthma, moderate reductions in FEV(1), and frequent oral corticosteroid use to manage exacerbations. Subjects in Clusters 4 (n = 120) and 5 (n = 116) have severe airflow obstruction with bronchodilator responsiveness but differ in to their ability to attain normal lung function, age of asthma onset, atopic status, and use of oral corticosteroids. Five distinct clinical phenotypes of asthma have been identified using unsupervised hierarchical cluster analysis. All clusters contain subjects who meet the American Thoracic Society definition of severe asthma, which supports clinical heterogeneity in asthma and the need for new approaches for the classification of disease severity in asthma.
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This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
A complete list of SARP contributors can be found at the end of this article.
Conflict of Interest Statement: W.C.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. D.A.M. received $1,001–$5,000 from Centocor and $1,001–$5,000 from Aerovance in advisory board fees, $10,001–$50,000 from Centocor, and $10,001–$50,000 from Aerovance in industry sponsored grants (institutional – genetics research). S.E.W. received $5,001–$10,000 from Centocor, $10,001–$50,000 from GlaxoSmithKline, $1,001–$5,000 from AstraZeneca, $5,001–$10,000 from Wyeth, and $5,001–$10,000 from Genentech in consultancy fees; $1,001–$5,000 from Merck, $1,001–$5,000 from GlaxoSmithKline, $10,001–$50,000 from Amira, $10,001–$50,000 from Epigenesis, and $10,001–$50,000 from Novartis in advisory board fees; $1,001–$5,000 from Merck, $1,001–$5,000 from AstraZeneca, $1,001–$5,000 from Critical Therapeutics, and $1,001–$5,000 from Genentech in lecture fees; and $50,001–$100,000 from Centocor, $5,001–$10,000 from Amgen, $50,001–$100,000 from MedImmune, $50,001–$100,000 from Ception, and $10,001–$50,000 from AstraZeneca in industry-sponsored grants. W.G.T. received $5,001–$10,000 from Merck and Co. and up to $1,000 from Aerocrine in lecture fees. H.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. X.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. R.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.C. received $10,001–$50,000 from Asthmatx and $1,001–$5,000 from Ception in consultancy fees; $5,001–$10,000 from Genentech in advisory board fees; $50,001–$100,000 from AstraZeneca, $10,001–$50,000 from Boehringer Ingelheim, $10,001–$50,000 from Pfizer, $5,001–$10,000 from Genentech, and $1,001–$5,000 from Novartis in lecture fees; more than $100,001 from Asthmatx, more than $100,001 from Amgen, more than $100,001 from Centocor, more than $100,001 from Ception, and more than $100,001 from GlaxoSmithKline in industry-sponsored grants; $1,001–$5,000 from Elsevier in royalties; and $10,001–$50,000 from Pfizer, more than $100,001 from Genentech, more than $100,001 from MedImmune, more than $100,001 from Merck, and more than $100,001 from Novartis for contracted research. D.C-E. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.M.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. B.G. received $1,001–$5,000 as a consultant for Galleon Pharmaceuticals, $10,001–$50,000 from Galleon Pharmaceuticals in industry-sponsored grants, and holds $5,001–$10,000 as a minority shareholder for Respiratory Research, and controls a patent for inhibition of S-nitrosothiol breakdown to treat asthma. N.N.J. received $10,001–$50,000 from Asthmatx for review of CT scans, concept discussions, and advisory group meetings; $1,001–$5,000 from GlaxoSmithKline and $1,001–$5,000 from Genentech in advisory board fees; $1,001–$5,000 from Merck and Co. in lecture fees; and more than $100,001 from GlaxoSmithKline and more than $100,001 from Genentech in industry-sponsored grants. R.S.' spouse/life partner received $5,001–$10,000 from GlaxoSmithKline in advisory board fees, $5,001–$10,000 from GlaxoSmithKline, and $1,001–$5,000 from AstraZeneca in lecture fees. R.S. received more than $100,001 from Modus Biological Membranes in industry-sponsored grants. W.J.C. received $10,001–$50,000 from AstraZeneca and $5,001–$10,000 from Sepracor in consultancy fees, $5,001–$10,000 in advisory board fees from Merck, and more than $100,001 research grant from Alcon. K.F.C. received $1,001–$5,000 for ad hoc consulting from Gilead; $1,001–$5,000 from GlaxoSmithKline, $1,001–$5,000 from Chiesi, and $1,001 to $5,000 from Merck for serving on an advisory board; $1,001–$5,000 from AstraZeneca, $1,001–$5,000 from GlaxoSmithKline, and $1,001–$5,000 from Chiesi for nonpromotional lecture fees; $10,001–$50,000 from Novartis for a Phase 3 clinical trial; $1,001–$5,000 from Schering Plough for a Phase 3 clinical trial; $1,001–$5,000 from AstraZeneca for Phase 3 clinical research; and $50,001–$100,000 collaborative from GlaxoSmithKline in industry-sponsored grants. S.A.A.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. R.A.D. received more than $100,001 from Actelion in industry-sponsored grants. E.I. received $1,001–$5,000 from Amgen, $1,001–$5,000 from Astellas Pharma US, Inc., $10,001–$50,000 from Asthmatx, $10,001–$50,000 from Genentech, $5,001–$50,000 for Icagen, Inc., $10,001–$50,000 from MedImmune, $10,001–$50,000 from Merck & Co, Inc., $10,001–$50,000 from Novartis, $10,001–$50,000 from BioPharma, $5,001–$10,000 from Pfizer, $10,001–$50,000 from Schering Plough, $1,001–$5,000 from Sepracor, and $10,001–$50,000 from Teva Specialty Pharmaceuticals in consultancy fees; $10,001–$50,000 from Genentech, $10,001–$50,000 from Merck and Co., Inc., and $10,001–$50,000 from Novartis in lecture fees; $5,001–$10,000 from Ficksman & Conley, LLP and $1,001–$5,000 from Prince, Lobel, Glovsky & Tye, LLP for serving as an expert witness; and $50,001–$100,000 from Aerovance, $50,001–$100,000 from Asthmatx, $50,001–$100,000 from Boehringer Ingelheim, $50,001–$100,000 from Centocor, $50,001–$100,000 from Ception Therapeutics, $50,001–$100,000 from Genentech, $50,001–$100,000 from Icagen, Inc., $50,001–$100,000 from Johnson & Johnson, $50,001–$100,000 from MedImmune, $50,001–$100,000 from Merck & Co, Inc., $50,001–$100,000 from PDL BioPharma, and $50,001–$100,000 from Schering Plough in industry-sponsored grants. S.P.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. W.W.B. received up to $1,000 from Novartis, up to $1,000 from AstraZeneca, $1,001–$5,000 from Eisai, up to $1,000 from TEVA, $1,001–$5,000 from CompleWare, and $1,001–$5,000 from Schering Plough in consultancy fees; up to $1,000 from Altair, $1,001–$5,000 from GlaxoSmithKline, $5,001–$10,000 from Merck, $1,001–$5,000 from Wyeth, $5,001–$10,000 from Pfizer, up to $1,000 from Centocor, $1,001–$5,000 from Amgen, $1,001–$5,000 from UCB, $1,001–$5,000 from Johnson & Johnson, and up to $1,000 from Bristol-Myers Squib in advisory board fees; up to $1,000 from Merck in lecture fees, more than $100,001 from Novartis, $5,001–$10,000 from Centocor, $5,001–$10,000 from Ception, $10,00–$50,000 from MedImmune, and more than $100,001 from GlaxoSmithKline in industry-sponsored grants; and up to $1,000 from KaloBios in advisory board fees, up to $1,000 from Boehringer Ingelheim, up to $1,000 from Sandoz, up to $1,000 from Alexion, and up to $1,000 from Dainippion Sumitomo in consultancy fees. S.C.E. received more than $100,001 institutional grant from Asthmatx. E.R.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
Supported by National Institute of Health grants HL69116, HL69130, HL69149, HL69155, HL69167, HL69170, HL69174, HL69349, M01 RR018390, M01RR07122, M01 RR03186, and HL087665.
ISSN:1073-449X
1535-4970
1535-4970
DOI:10.1164/rccm.200906-0896OC