title: Cluster analysis in the COPDGene study identifies subtypes of smokers with distinct patterns of airway disease and emphysema.
abstract: 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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  Cluster analysis identifies four subgroups of smokers that show robust associations with clinical characteristics of COPD and known COPD-associated genetic variants.
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, , Boston, Massachusetts, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Castaldi
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dy
authors.forename: James
authors.initials: J
authors.lastname: Ross
authors.forename: Yale
authors.initials: Y
authors.lastname: Chang
authors.forename: George R
authors.initials: GR
authors.lastname: Washko
authors.forename: Douglas
authors.initials: D
authors.lastname: Curran-Everett
authors.forename: Andre
authors.initials: A
authors.lastname: Williams
authors.forename: David A
authors.initials: DA
authors.lastname: Lynch
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Make
authors.forename: James D
authors.initials: JD
authors.lastname: Crapo
authors.forename: Russ P
authors.initials: RP
authors.lastname: Bowler
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Regan
authors.forename: John E
authors.initials: JE
authors.lastname: Hokanson
authors.forename: Greg L
authors.initials: GL
authors.lastname: Kinney
authors.forename: Meilan K
authors.initials: MK
authors.lastname: Han
authors.forename: Xavier
authors.initials: X
authors.lastname: Soler
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Ramsdell
authors.forename: R Graham
authors.initials: RG
authors.lastname: Barr
authors.forename: Marilyn
authors.initials: M
authors.lastname: Foreman
authors.forename: Edwin
authors.initials: E
authors.lastname: van Beek
authors.forename: Richard
authors.initials: R
authors.lastname: Casaburi
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Criner
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Lutz
authors.forename: Steven I
authors.initials: SI
authors.lastname: Rennard
authors.forename: Stephanie
authors.initials: S
authors.lastname: Santorico
authors.forename: Frank C
authors.initials: FC
authors.lastname: Sciurba
authors.forename: Dawn L
authors.initials: DL
authors.lastname: DeMeo
authors.forename: Craig P
authors.initials: CP
authors.lastname: Hersh
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
authors.forename: Michael H
authors.initials: MH
authors.lastname: Cho
mesh_terms: D016000:Cluster Analysis; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D029424:Pulmonary Disease, Chronic Obstructive / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D011656:Pulmonary Emphysema / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D012189:Retrospective Studies; D012720:Severity of Illness Index; D012907:Smoking / Q000009:adverse effects*; D013147:Spirometry; D014057:Tomography, X-Ray Computed
keywords: COPD epidemiology; Emphysema