title: A systematic approach to subgroup analyses in a smoking cessation trial.
abstract: BACKGROUND
  Traditional approaches to subgroup analyses that test each moderating factor as a separate hypothesis can lead to erroneous conclusions due to the problems of multiple comparisons, model misspecification, and multicollinearity.
  
  
  OBJECTIVE
  To demonstrate a novel, systematic approach to subgroup analyses that avoids these pitfalls.
  
  
  METHODS
  A Best Approximating Model (BAM) approach that identifies multiple moderators and estimates their simultaneous impact on treatment effect sizes was applied to a randomized, controlled, 11-week, double-blind efficacy trial on smoking cessation of adult smokers with attention-deficit/hyperactivity disorder (ADHD), randomized to either OROS-methylphenidate (n = 127) or placebo (n = 128), and treated with nicotine patch. Binary outcomes measures were prolonged smoking abstinence and point prevalence smoking abstinence.
  
  
  RESULTS
  Although the original clinical trial data analysis showed no treatment effect on smoking cessation, the BAM analysis showed significant subgroup effects for the primary outcome of prolonged smoking abstinence: (1) lifetime history of substance use disorders (adjusted odds ratio [AOR] 0.27; 95% confidence interval [CI] 0.10-0.74), and (2) more severe ADHD symptoms (baseline score >36; AOR 2.64; 95% CI 1.17-5.96). A significant subgroup effect was also shown for the secondary outcome of point prevalence smoking abstinence--age 18 to 29 years (AOR 0.23; 95% CI 0.07-0.76).
  
  
  CONCLUSIONS
  The BAM analysis resulted in different conclusions about subgroup effects compared to a hypothesis-driven approach. By examining moderator independence and avoiding multiple testing, BAMs have the potential to better identify and explain how treatment effects vary across subgroups in heterogeneous patient populations, thus providing better guidance to more effectively match individual patients with specific treatments.
authors.affiliation: a Department of Psychiatry and.|b Department of Clinical Sciences , University of Texas Southwestern Medical Center , Dallas , TX .
authors.forename: Arthur N
authors.initials: AN
authors.lastname: Westover
authors.affiliation: a Department of Psychiatry and.|c Department of Medicine , Loma Linda University School of Medicine , Loma Linda , CA .|d Veterans Health Administration Office of Academic Affiliations , Washington , DC .
authors.forename: T Michael
authors.initials: TM
authors.lastname: Kashner
authors.affiliation: e Department of Psychiatry and Behavioral Neuroscience , University of Cincinnati College of Medicine , Cincinnati , OH .
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Winhusen
authors.affiliation: f University of Texas at Dallas, School of Behavioral and Brain Sciences , Richardson , TX .
authors.forename: Richard M
authors.initials: RM
authors.lastname: Golden
authors.affiliation: a Department of Psychiatry and.|b Department of Clinical Sciences , University of Texas Southwestern Medical Center , Dallas , TX .
authors.forename: Paul A
authors.initials: PA
authors.lastname: Nakonezny
authors.affiliation: a Department of Psychiatry and.|g VA North Texas Health Care System , Dallas VAMC , Dallas , TX , and.
authors.forename: Bryon
authors.initials: B
authors.lastname: Adinoff
authors.affiliation: c Department of Medicine , Loma Linda University School of Medicine , Loma Linda , CA .|h Martingale Research Corporation , Plano , TX , USA.
authors.forename: Steven S
authors.initials: SS
authors.lastname: Henley
mesh_terms: D000293:Adolescent; D000328:Adult; D003627:Data Interpretation, Statistical; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008774:Methylphenidate / Q000627:therapeutic use; D008875:Middle Aged; D015233:Models, Statistical; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D016540:Smoking Cessation; D061485:Tobacco Use Cessation Devices; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D008774:Methylphenidate
keywords: Attention deficit hyperactivity disorder; methylphenidate; modeling; statistics; subgroup analysis; tobacco