Cluster analysis in the COPDGene study identifies subtypes of smokers with distinct patterns of airway disease and emphysema

被引：127

作者：

Castaldi, Peter J. ^{[1
,2
]}

Dy, Jennifer ^{[3
]}

Ross, James ^{[4
,5
]}

Chang, Yale ^{[3
,7
]}

Washko, George R. ^{[6
]}

Curran-Everett, Douglas ^{[8
]}

Williams, Andre ^{[8
]}

Lynch, David A. ^{[9
]}

Make, Barry J. ^{[10
]}

Crapo, James D. ^{[10
]}

Bowler, Russ P. ^{[10
]}

Regan, Elizabeth A. ^{[10
]}

Hokanson, John E. ^{[11
]}

Kinney, Greg L. ^{[11
]}

Han, Meilan K. ^{[12
]}

Soler, Xavier ^{[13
]}

Ramsdell, Joseph W. ^{[13
]}

Barr, R. Graham ^{[14
,15
]}

Foreman, Marilyn ^{[16
]}

van Beek, Edwin ^{[17
]}

Casaburi, Richard ^{[18
]}

Criner, Gerald J. ^{[19
]}

Lutz, Sharon M. ^{[20
]}

Rennard, Steven I. ^{[21
]}

Santorico, Stephanie ^{[22
]}

Sciurba, Frank C. ^{[23
]}

Demeo, Dawn L. ^{[1
,6
,7
]}

Hersh, Craig P. ^{[1
,6
,7
]}

Silverman, Edwin K. ^{[1
,6
,7
]}

Cho, Michael H. ^{[1
,6
,7
]}

机构：

[1] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA

[2] Brigham & Womens Hosp, Div Gen Med, Boston, MA 02115 USA

[3] Northeastern Univ, Dept Comp Sci, Boston, MA 02115 USA

[4] Brigham & Womens Hosp, Surg Planning Lab, Boston, MA 02115 USA

[5] Brigham & Womens Hosp, Lab Math Imaging, Boston, MA 02115 USA

[6] Brigham & Womens Hosp, Div Pulm & Crit Care, Boston, MA 02115 USA

[7] Harvard Univ, Sch Med, Boston, MA USA

[8] Natl Jewish Hlth, Div Biostat & Bioinformat, Denver, MA USA

[9] Natl Jewish Hlth, Dept Radiol, Denver, MA USA

[10] Natl Jewish Hlth, Dept Med, Denver, MA USA

[11] Univ Colorado, Dept Epidemiol, Colorado Sch Publ Hlth, Denver, CO 80202 USA

[12] Univ Michigan Hlth Syst, Div Pulm & Crit Care, Dept Internal Med, Ann Arbor, MI USA

[13] Univ Calif San Diego, Dept Med, Div Pulm & Crit Care Med, San Diego, CA 92103 USA

[14] Columbia Univ, Dept Med, Med Ctr, New York, NY USA

[15] Columbia Univ, Dept Epidemiol, Med Ctr, New York, NY USA

[16] Morehouse Sch Med, Atlanta, GA 30310 USA

[17] Univ Edinburgh, Queens Med Res Inst, Clin Res Imaging Ctr, Edinburgh, Midlothian, Scotland

[18] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Rehabil Clin Trials Ctr, Torrance, CA 90509 USA

[19] Temple Univ, Philadelphia, PA 19122 USA

[20] Univ Colorado, Dept Biostat, Denver, CO 80202 USA

[21] Univ Nebraska Med Ctr, Omaha, NE USA

[22] Univ Colorado, Dept Math & Stat Sci, Denver, CO 80202 USA

[23] Univ Pittsburgh, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA USA

来源：

THORAX | 2014年 / 69卷 / 05期

基金：

美国国家卫生研究院;

关键词：

OBSTRUCTIVE PULMONARY-DISEASE; GENOME-WIDE ASSOCIATION; PHENOTYPES; SUSCEPTIBILITY; CLASSIFICATION; STRATEGY; CHICAGO; LONDON;

D O I：

10.1136/thoraxjnl-2013-203601

中图分类号：

R56 [呼吸系及胸部疾病];

学科分类号：

摘要：

Background There is notable heterogeneity in the clinical presentation of patients with COPD. To characterise this heterogeneity, we sought to identify subgroups of smokers by applying cluster analysis to data from the COPDGene study. Methods We applied a clustering method, k-means, to data from 10 192 smokers in the COPDGene study. After splitting the sample into a training and validation set, we evaluated three sets of input features across a range of k (user-specified number of clusters). Stable solutions were tested for association with four COPD-related measures and five genetic variants previously associated with COPD at genome-wide significance. The results were confirmed in the validation set. Findings We identified four clusters that can be characterised as (1) relatively resistant smokers (ie, no/mild obstruction and minimal emphysema despite heavy smoking), (2) mild upper zone emphysema-predominant, (3) airway disease-predominant and (4) severe emphysema. All clusters are strongly associated with COPD-related clinical characteristics, including exacerbations and dyspnoea (p<0.001). We found strong genetic associations between the mild upper zone emphysema group and rs1980057 near HHIP, and between the severe emphysema group and rs8034191 in the chromosome 15q region (p<0.001). All significant associations were replicated at p<0.05 in the validation sample (12/12 associations with clinical measures and 2/2 genetic associations). Interpretation Cluster analysis identifies four subgroups of smokers that show robust associations with clinical characteristics of COPD and known COPD-associated genetic variants.

引用

页码：415 / 422

页数：8

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