title: The Association Between Rate and Severity of Exacerbations in Chronic Obstructive Pulmonary Disease: An Application of a Joint Frailty-Logistic Model.
abstract: Exacerbations are a hallmark of chronic obstructive pulmonary disease (COPD). Evidence suggests the presence of substantial between-individual variability (heterogeneity) in exacerbation rates. The question of whether individuals vary in their tendency towards experiencing severe (versus mild) exacerbations, or whether there is an association between exacerbation rate and severity, has not yet been studied. We used data from the MACRO Study, a 1-year randomized trial of the use of azithromycin for prevention of COPD exacerbations (United States and Canada, 2006-2010; n = 1,107, mean age = 65.2 years, 59.1% male). A parametric frailty model was combined with a logistic regression model, with bivariate random effects capturing heterogeneity in rate and severity. The average rate of exacerbation was 1.53 episodes/year, with 95% of subjects having a model-estimated rate of 0.47-4.22 episodes/year. The overall ratio of severe exacerbations to total exacerbations was 0.22, with 95% of subjects having a model-estimated ratio of 0.04-0.60. We did not confirm an association between exacerbation rate and severity (P = 0.099). A unified model, implemented in standard software, could estimate joint heterogeneity in COPD exacerbation rate and severity and can have applications in similar contexts where inference on event time and intensity is considered. We provide SAS code (SAS Institute, Inc., Cary, North Carolina) and a simulated data set to facilitate further uses of this method.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Sadatsafavi
authors.forename: Don D
authors.initials: DD
authors.lastname: Sin
authors.forename: Zafar
authors.initials: Z
authors.lastname: Zafari
authors.forename: Gerard
authors.initials: G
authors.lastname: Criner
authors.forename: John E
authors.initials: JE
authors.lastname: Connett
authors.forename: Stephen
authors.initials: S
authors.lastname: Lazarus
authors.forename: Meilan
authors.initials: M
authors.lastname: Han
authors.forename: Fernando
authors.initials: F
authors.lastname: Martinez
authors.forename: Richard
authors.initials: R
authors.lastname: Albert
mesh_terms: D000368:Aged; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D017963:Azithromycin / Q000627:therapeutic use*; D018450:Disease Progression; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D009656:North America; D016016:Proportional Hazards Models; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications* / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data; D012720:Severity of Illness Index
chemical_list: D000900:Anti-Bacterial Agents; D017963:Azithromycin
keywords: chronic obstructive pulmonary disease; nonlinear mixed models; random effects; randomized trials; survival analysis