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Am J Respir Crit Care Med. 2019 Jun 1;199(11):1358-1367. doi: 10.1164/rccm.201808-1543OC.

Multiview Cluster Analysis Identifies Variable Corticosteroid Response Phenotypes in Severe Asthma.

Author information

1
1 Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania.
2
2 Department of Medicine, University of Arizona, Tucson, Arizona.
3
3 Washington University, St. Louis, Missouri.
4
4 University of Wisconsin-Madison, Madison, Wisconsin.
5
5 Cleveland Clinic, Cleveland, Ohio.
6
6 University of California San Francisco, San Francisco, California.
7
7 Emory University, Atlanta, Georgia.
8
8 School of Medicine, Case Western Reserve University, Cleveland, Ohio.
9
9 School of Medicine, Wake Forest University, Winston-Salem, North Carolina.
10
10 Harvard Medical School, Boston, Massachusetts.
11
11 Brigham and Women's Hospital, Boston, Massachusetts.
12
12 Pennsylvania State University, University Park, Pennsylvania.
13
13 Boston Children's Hospital, Boston, Massachusetts; and.
14
14 Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.

Abstract

Rationale: Corticosteroids (CSs) are the most effective asthma therapy, but responses are heterogeneous and systemic CSs lead to long-term side effects. Therefore, an improved understanding of the contributing factors in CS responses could enhance precision management. Although several factors have been associated with CS responsiveness, no integrated/cluster approach has yet been undertaken to identify differential CS responses. Objectives: To identify asthma subphenotypes with differential responses to CS treatment using an unsupervised multiview learning approach. Methods: Multiple-kernel k-means clustering was applied to 100 clinical, physiological, inflammatory, and demographic variables from 346 adult participants with asthma in the Severe Asthma Research Program with paired (before and 2-3 weeks after triamcinolone administration) sputum data. Machine-learning techniques were used to select the top baseline variables that predicted cluster assignment for a new patient. Measurements and Main Results: Multiple-kernel clustering revealed four clusters of individuals with asthma and different CS responses. Clusters 1 and 2 consisted of young, modestly CS-responsive individuals with allergic asthma and relatively normal lung function, separated by contrasting sputum neutrophil and macrophage percentages after CS treatment. The subjects in cluster 3 had late-onset asthma and low lung function, high baseline eosinophilia, and the greatest CS responsiveness. Cluster 4 consisted primarily of young, obese females with severe airflow limitation, little eosinophilic inflammation, and the least CS responsiveness. The top 12 baseline variables were identified, and the clusters were validated using an independent Severe Asthma Research Program test set. Conclusions: Our machine learning-based approaches provide new insights into the mechanisms of CS responsiveness in asthma, with the potential to improve disease treatment.

KEYWORDS:

asthma phenotype; corticosteroids; eosinophils; severe asthma

PMID:
30682261
PMCID:
PMC6543720
[Available on 2020-06-01]
DOI:
10.1164/rccm.201808-1543OC

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