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PLOS ONE  2012 

A New Framework for Interpreting the Outcomes of Imperfectly Blinded Controlled Clinical Trials

DOI: 10.1371/journal.pone.0048984

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It is well known that the outcome of an intervention is affected both by the inherent effects of the intervention and the patient's expectations. For this reason in comparative clinical trials an effort is made to conceal the nature of the administered intervention from the participants in the trial i.e. to blind the trial. Yet, in practice perfect blinding is impossible to ensure or even verify post hoc. The current clinical standard is to follow up the trial with an auxiliary questionnaire, which allows trial participants to express in closed form their belief concerning the intervention, i.e. trial group assignment (treatment or control). Auxiliary questionnaire responses are then used to compute the extent of blinding in the trial in the form of a blinding index. If the estimated extent of blinding exceeds a particular threshold the trial is deemed sufficiently blinded; otherwise, the strength of evidence of the trial is brought into question. This may necessitate that the trial is repeated. In this paper we make several contributions. Firstly, we identify a series of problems of the aforesaid clinical practice and discuss them in context of the most commonly used blinding indexes. Secondly, we formulate a novel approach for handling imperfectly blinded trials. We adopt a feedback questionnaire of the same form as that which is currently in use, but interpret the collected data using a novel statistical method, significantly different from that proposed in the previous work. Unlike the previously proposed approaches, our method is void of any ad hoc free parameters and robust to small changes in the participants' feedback responses. Our method also does not discard any data and is not predicated on any strong assumptions used to interpret participants' feedback. The key idea behind the present method is that it is meaningful to compare only the corresponding treatment and control participant sub-groups, that is, sub-groups matched by their auxiliary responses. A series of experiments on simulated trials is used to demonstrate the effectiveness of the proposed approach and its superiority over those currently in use.


[1]  Moerman DE, Jonas WB (2002) Deconstructing the placebo effect and finding the meaning response. Ann Intern Med 136: 471–476.
[2]  Benedetti F, Mayberg HS, Wager TD, Stohler CS, Zubieta JK (2005) Neurobiological mechanisms of the placebo effect. J Neurosci 25: 10390–10402.
[3]  Montgomery GH, Kirsch I (1997) Classical conditioning and the placebo effect. Pain 72: 107–113.
[4]  Kolahi J, Bang H, Park J (2009) Towards a proposal for assessment of blinding success in clinical trials: up-to-date review. Community Dent Oral Epidemiol 37: 477–484.
[5]  Colford JM, Rees JR, Wade TJ, Khalakdina A, Hilton JF, et al. (2002) Participant blinding and gastrointestinal illness in a randomized, controlled trial of an in-home drinking water intervention. Emerg Infect Dis 8: 29–36.
[6]  James KE, Bloch DA, Lee KK, Kraemer HC, Fuller RK (1996) An index for assessing blindness in a multi-centre clinical trial: disulfiram for alcohol cessation–a va cooperative study. Stat Med 15: 1421–1434.
[7]  Beecher HK (1955) The powerful placebo. JAMA 159: 1602–1606.
[8]  Mayberg HS, Silva JA, Brannan SK, Tekell JL, Mahurin RK, et al. (2002) The functional neuroanatomy of the placebo effect. Am J Psychiatry 159: 728–737.
[9]  Bang H, Ni L, Davis CE (2004) Assessment of blinding in clinical trials. Contemp Clin Trials 25: 143–156.
[10]  Hemil? H (2005) Assessment of blinding may be inappropriate after the trial. Contemp Clin Trials 26: 512–514.
[11]  Henneicke-von Zepelin HH (2005) Letter to the editor. Contemp Clin Trials 26: 512.
[12]  Berger V (2005) Selection Bias and Covariate Imbalances in Randomized Clinical Trials. Hoboken, New Jersey: Wiley.
[13]  Costantino G, Furfaro F, Belvedere A, Alibrandi A, Fries W (2011) Thiopurine treatment in in-ammatory bowel disease: Response predictors, safety, and withdrawal in follow-up. J Crohns Colitis
[14]  Karakitsos D, Papanikolaou J, Karabinis A, Alalawi R, Wachtel M, et al. (2012) Acute effect of sildenafil on central hemodynamics in mechanically ventilated patients with WHO group III pulmonary hypertension and right ventricular failure necessitating administration of dobutamine. Int J Cardiol
[15]  Bishop CM (2007) Pattern Recognition and Machine Learning. New York, USA: Springer-Verlag.


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