title: Confounders and intermediaries in case-control study designs: a strategy for distinguishing between the two when measured using the same variable.
abstract: OBJECTIVE
  An intermediary falls within the exposure-outcome pathway and is distinct from a confounder. In case-control studies, it may be difficult to discern between the two when both are measured by the same variable. Using data from a study on the effects of antipsychotic initiation on risk of death among older adults, where hospital use is both a confounder and intermediary, we illustrate the bias introduced when this distinction is overlooked and propose a modified exposure classification strategy to mitigate this.
  
  
  METHODS
  We identified 5391 cases and 25,937 controls. Three analyses were completed: traditional analytic adjustment including hospital use (full), traditional analytic adjustment excluding hospital use (reduced) and exposure classification incorporating hospital use prior to antipsychotic initiation (extended).
  
  
  RESULTS
  The unadjusted odds ratio (OR) was 2.8 (95% confidence interval (CI) 2.1-3.8). Full and reduced analytic adjustment resulted in ORs of 0.8 (95% CI 0.6-1.2) and 1.4 (95% CI 1.0-1.9), respectively. The extended exposure classification strategy produced an OR of 1.4 (95% CI 0.9-2.1) among those without hospital use prior to antipsychotic initiation.
  
  
  CONCLUSIONS
  Full analytic adjustment resulted in a biased estimate of effect. The extended exposure analysis differentiated between hospital use that occurred prior (confounder) and subsequent (intermediary) to antipsychotic initiation. This strategy may overcome the limitations of analytic adjustment alone.
authors.affiliation: Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada. andrea.gruneir@wchospital.ca
authors.forename: Andrea
authors.initials: A
authors.lastname: Gruneir
authors.forename: Connie
authors.initials: C
authors.lastname: Marras
authors.forename: Hadas
authors.initials: H
authors.lastname: Fischer
authors.forename: Xuesong
authors.initials: X
authors.lastname: Wang
authors.forename: Sudeep
authors.initials: S
authors.lastname: Gill
authors.forename: Paula A
authors.initials: PA
authors.lastname: Rochon
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Anderson
mesh_terms: D000369:Aged, 80 and over; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects; D016022:Case-Control Studies; D015986:Confounding Factors, Epidemiologic; D005260:Female; D006801:Humans; D008297:Male; D015233:Models, Statistical; D009026:Mortality; D015588:Observer Variation; D012107:Research Design / Q000592:standards / Q000706:statistics & numerical data*; D016896:Treatment Outcome
chemical_list: D014150:Antipsychotic Agents