title: Bias due to lack of patient blinding in clinical trials. A systematic review of trials randomizing patients to blind and nonblind sub-studies.
abstract: BACKGROUND
  Blinding patients in clinical trials is a key methodological procedure, but the expected degree of bias due to nonblinded patients on estimated treatment effects is unknown.
  
  
  METHODS
  Systematic review of randomized clinical trials with one sub-study (i.e. experimental vs control) involving blinded patients and another, otherwise identical, sub-study involving nonblinded patients. Within each trial, we compared the difference in effect sizes (i.e. standardized mean differences) between the sub-studies. A difference <0 indicates that nonblinded patients generated a more optimistic effect estimate. We pooled the differences with random-effects inverse variance meta-analysis, and explored reasons for heterogeneity.
  
  
  RESULTS
  Our main analysis included 12 trials (3869 patients). The average difference in effect size for patient-reported outcomes was -0.56 (95% confidence interval -0.71 to -0.41), (I(2)=60%, P=0.004), i.e. nonblinded patients exaggerated the effect size by an average of 0.56 standard deviation, but with considerable variation. Two of the 12 trials also used observer-reported outcomes, showing no indication of exaggerated effects due lack of patient blinding. There was a larger effect size difference in 10 acupuncture trials [-0.63 (-0.77 to -0.49)], than in the two non-acupuncture trials [-0.17 (-0.41 to 0.07)]. Lack of patient blinding also increased attrition and use of co-interventions: ratio of control group attrition risk 1.79 (1.18 to 2.70), and ratio of control group co-intervention risk 1.55 (0.99 to 2.43).
  
  
  CONCLUSIONS
  This study provides empirical evidence of pronounced bias due to lack of patient blinding in complementary/alternative randomized clinical trials with patient-reported outcomes.
authors.affiliation: Nordic Cochrane Centre, Rigshospitalet, Copenhagen, Denmark, Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark and Department of Orthopaedic Surgery, Herlev University Hospital, Herlev, Denmark ah@cochrane.dk.
authors.forename: Asbjørn
authors.initials: A
authors.lastname: Hróbjartsson
authors.affiliation: Nordic Cochrane Centre, Rigshospitalet, Copenhagen, Denmark, Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark and Department of Orthopaedic Surgery, Herlev University Hospital, Herlev, Denmark.
authors.forename: Frida
authors.initials: F
authors.lastname: Emanuelsson
authors.affiliation: Nordic Cochrane Centre, Rigshospitalet, Copenhagen, Denmark, Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark and Department of Orthopaedic Surgery, Herlev University Hospital, Herlev, Denmark.
authors.forename: Ann Sofia
authors.initials: AS
authors.lastname: Skou Thomsen
authors.affiliation: Nordic Cochrane Centre, Rigshospitalet, Copenhagen, Denmark, Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark and Department of Orthopaedic Surgery, Herlev University Hospital, Herlev, Denmark.
authors.forename: Jørgen
authors.initials: J
authors.lastname: Hilden
authors.affiliation: Nordic Cochrane Centre, Rigshospitalet, Copenhagen, Denmark, Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark and Department of Orthopaedic Surgery, Herlev University Hospital, Herlev, Denmark.
authors.forename: Stig
authors.initials: S
authors.lastname: Brorson
mesh_terms: D015982:Bias; D004311:Double-Blind Method; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D016037:Single-Blind Method
keywords: Bias; blinding; patient blinding; randomized clinical trials; systematic review