title: A most stubborn bias: no adjustment method fully resolves confounding by indication in observational studies.
abstract: OBJECTIVE
  To evaluate the effectiveness of methods that control for confounding by indication, we compared breast cancer recurrence rates among women receiving adjuvant chemotherapy with those who did not.
  
  
  METHODS
  In a medical record review-based study of breast cancer treatment in older women (n=1798) diagnosed between 1990 and 1994, our crude analysis suggested that adjuvant chemotherapy was positively associated with recurrence (hazard ratio [HR]=2.6; 95% confidence interval [CI]=1.9, 3.5). We expected a protective effect, so postulated that the crude association was confounded by indications for chemotherapy. We attempted to adjust for this confounding by restriction, multivariable regression, propensity scores (PSs), and instrumental variable (IV) methods.
  
  
  RESULTS
  After restricting to women at high risk for recurrence (n=946), chemotherapy was not associated with recurrence (HR=1.1; 95% CI=0.7, 1.6) using multivariable regression. PS adjustment yielded similar results (HR=1.3; 95% CI=0.8, 2.0). The IV-like method yielded a protective estimate (HR=0.9; 95% CI=0.2, 4.3); however, imbalances of measured factors across levels of the IV suggested residual confounding.
  
  
  CONCLUSIONS
  Conventional methods do not control for unmeasured factors, which often remain important when addressing confounding by indication. PS and IV analysis methods can be useful under specific situations, but neither method adequately controlled confounding by indication in this study.
authors.affiliation: Department of Medicine, Geriatrics Section, Boston University School of Medicine, Boston, MA 02118, USA. jfong@bu.edu
authors.forename: Jaclyn L F
authors.initials: JL
authors.lastname: Bosco
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Silliman
authors.forename: Soe Soe
authors.initials: SS
authors.lastname: Thwin
authors.forename: Ann M
authors.initials: AM
authors.lastname: Geiger
authors.forename: Diana S M
authors.initials: DS
authors.lastname: Buist
authors.forename: Marianne N
authors.initials: MN
authors.lastname: Prout
authors.forename: Marianne Ulcickas
authors.initials: MU
authors.lastname: Yood
authors.forename: Reina
authors.initials: R
authors.lastname: Haque
authors.forename: Feifei
authors.initials: F
authors.lastname: Wei
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Lash
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D015982:Bias; D001943:Breast Neoplasms / Q000188:drug therapy; D017024:Chemotherapy, Adjuvant / Q000009:adverse effects; D015986:Confounding Factors, Epidemiologic; D003627:Data Interpretation, Statistical; D005260:Female; D006801:Humans; D057216:Propensity Score; D012008:Recurrence; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents