title: Control Outcomes and Exposures for Improving Internal Validity of Nonrandomized Studies.
abstract: OBJECTIVE
  Control outcomes and exposures can improve internal validity of nonrandomized studies by assessing residual bias in effect estimates. Control outcomes are those expected to have no treatment effect or the opposite effect of the primary outcome. Control exposures are treatments expected to have no effect on the primary outcome. We review examples of control outcomes and exposures from prior studies and provide recommendations for conducting and reporting these analyses.
  
  
  METHODS
  Review in Google Scholar and Medline of research studies employing control outcomes or exposures. We abstracted publication year, control outcome, control exposure, primary outcome, primary exposure, control outcome/exposure effect, proposed source of bias, and causal criteria.
  
  
  RESULTS
  There is inconsistent terminology for these concepts, making study identification challenging. Six of 11 studies found null associations between treatments and negative control outcomes/exposures, providing greater confidence that the primary study findings were not biased. Five studies found unexpected associations, suggesting bias in the primary association.
  
  
  CONCLUSIONS
  The rigor of nonrandomized studies can be improved with inclusion of control outcomes and exposures for bias detection. Given ongoing concern about clinical and policy inferences from nonrandomized studies, we recommend adoption of these measurement tools.
authors.affiliation: Division of Pharmaceutical Outcomes and Policy, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC.|Department of Health Policy and Management, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC.|Cecil G. Sheps Center for Health Services Research, University of North Carolina at Chapel Hill, Chapel Hill, NC.
authors.forename: Stacie B
authors.initials: SB
authors.lastname: Dusetzina
authors.affiliation: Cecil G. Sheps Center for Health Services Research, University of North Carolina at Chapel Hill, Chapel Hill, NC.|Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC.
authors.forename: M Alan
authors.initials: MA
authors.lastname: Brookhart
authors.affiliation: Center for Health Services Research in Primary Care, Department of Veterans Affairs, Duke University Medical Center, Durham, NC.|Division of General Internal Medicine, Department of Medicine, Duke University Medical Center, Durham, NC.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Maciejewski
mesh_terms: D000068456:Clinical Studies as Topic / Q000379:methods* / Q000592:standards*; D006801:Humans; D015203:Reproducibility of Results; D012107:Research Design
keywords: Control outcomes; control exposures; falsification tests; nonequivalent exposures; nonequivalent outcomes