Several clinical trials studied the effect of a new antiviral agent on symptomatic relief of genital herpes simplex virus infection. All trials were based on physician report of symptom improvement; valacyclovir was used as a comparator. The pooled analysis of studies that blinded only patients favored valacyclovir with an odds ratio for valacyclovir of 1.65 (95% confidence interval, 1.53-1.75). The pooled analysis of studies that blinded both patients and treating physicians favored the new agent with an odds ratio for valacyclovir of 0.64 (95% confidence interval, 0.38-0.79). Which of the following best explains the difference in the reported odds ratios?
A)Effect modification
B)Lead-time bias
C)Observer bias
D)Publication bias
E)Randomization failure

Question

Several clinical trials studied the effect of a new antiviral agent on symptomatic relief of genital herpes simplex virus infection.  All trials were based on physician report of symptom improvement; valacyclovir was used as a comparator.  The pooled analysis of studies that blinded only patients favored valacyclovir with an odds ratio for valacyclovir of 1.65 (95% confidence interval, 1.53-1.75).  The pooled analysis of studies that blinded both patients and treating physicians favored the new agent with an odds ratio for valacyclovir of 0.64 (95% confidence interval, 0.38-0.79).  Which of the following best explains the difference in the reported odds ratios?
A)Effect modification
B)Lead-time bias
C)Observer bias
D)Publication bias
E)Randomization failure

Quizplus · Accepted Answer

Explanation: There is a difference in odds ratio between the studies that only blinded patients and those that blinded both patients and physicians. This is most likely due to observer bias, which occurs when observers misclassify data due to individual differences in interpretation or preconceived expectations regarding the treatment. Observer bias is particularly likely when the studied outcome is qualitative (eg, symptomatic relief of herpes simplex virus infection in this study). In this example, unblinded physicians had knowledge about which drug their patients were taking. It is possible that some of these physicians had a preconceived preference regarding valacyclovir and reported more symptom improvement in the patients taking this drug. (Choice A) Effect modification occurs when an external variable differentially modifies (positively or negatively) the effect of a risk factor on the disease of interest in different groups. (Choice B) Lead-time bias occurs when 2 disease interventions are compared and one of the interventions diagnoses the disease earlier than the other. This leads to the erroneous presumption that there is an effect on the outcome (eg, the intervention prolongs survival outcome). In actuality, the intervention only diagnoses the disease sooner and has no effect on survival. (Choice D) Publication bias occurs when trials with significant positive results are published but trials with negative/null results are not. (Choice E) Randomization failure is not likely to occur in all of the studied trials. Observer bias is a more likely explanation for the observed difference. Educational objective: Observer bias generally occurs in the absence of blinding, when observers misclassify data due to individual differences in interpretation or preconceived expectations regarding the treatment. Observer bias is particularly likely when the studied outcome is qualitative. References: Observer bias in randomised clinical trials with binary outcomes: systematic review of trials with both blinded and non-blinded outcome assessors (http://www.ncbi.nlm.nih.gov/pubmed/22371859)

Several Clinical Trials Studied the Effect of a New Antiviral