Abstract
IntroductionAdjudication of the primary outcome in randomised trials is thought to control misclassification. We investigated the amount of misclassification needed before adjudication changed the primary trial results.Patients (or materials) and methods: We included data from five randomised stroke trials. Differential misclassification was introduced for each primary outcome until the estimated treatment effect was altered. This was simulated 1000 times. We calculated the between-simulation mean proportion of participants that needed to be differentially misclassified to alter the treatment effect. In addition, we simulated hypothetical trials with a binary outcome and varying sample size (1000–10,000), overall event rate (10%–50%) and treatment effect (0.67–0.90). We introduced non-differential misclassification until the treatment effect was non-significant at 5% level.ResultsFor the five trials, the range of unweighted kappa values were reduced from 0.89–0.97 to 0.65–0.85 before the treatment effect was altered. This corresponded to 2.1%–6% of participants misclassified differentially for trials with a binary outcome. For the hypothetical trials, those with a larger sample size, stronger treatment effect and overall event rate closer to 50% needed a higher proportion of events non-differentially misclassified before the treatment effect became non-significant.Discussion:We found that only a small amount of differential misclassification was required before adjudication altered the primary trial results, whereas a considerable proportion of participants needed to be misclassified non-differentially before adjudication changed trial conclusions. Given that differential misclassification should not occur in trials with sufficient blinding, these results suggest that central adjudication is of most use in studies with unblinded outcome assessment.Conclusion:For trials without adequate blinding, central adjudication is vital to control for differential misclassification. However, for large blinded trials, adjudication is of less importance and may not be necessary.
Highlights
Adjudication of the primary outcome in randomised trials is thought to control misclassification
Previous studies have shown that site investigators often exaggerate treatment effect estimates,[1] so we introduced differential misclassification for outcomes assessed by site investigators to make the treatment effect estimates more beneficial
After simulation of differential misclassification, as planned, the treatment effect was more beneficial for every trial such that the upper bound of the CI for the RTE was 0.99 (Table 4)
Summary
Adjudication of the primary outcome in randomised trials is thought to control misclassification. We calculated the between-simulation mean proportion of participants that needed to be differentially misclassified to alter the treatment effect. Results: For the five trials, the range of unweighted kappa values were reduced from 0.89–0.97 to 0.65–0.85 before the treatment effect was altered This corresponded to 2.1%–6% of participants misclassified differentially for trials with a binary outcome. Discussion: We found that only a small amount of differential misclassification was required before adjudication altered the primary trial results, whereas a considerable proportion of participants needed to be misclassified non-differentially before adjudication changed trial conclusions. To control for differential and non-differential misclassification, many trials use a central adjudication committee, made up of blinded independent experts who assess the trial outcome in addition to the site investigators. Central adjudication is commonly included in vascular trials,[2] including those that are investigating stroke,[3,4] the value of adjudication has been questioned.[5,6,7]
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