Impact of GOS misclassification on ordinal outcome analysis of traumatic brain injury clinical trials

Abstract

This study extends our previous investigation regarding the effect of nondifferential dichotomous Glasgow Outcome Scale (GOS) misclassification in traumatic brain injury (TBI) clinical trials to the effect of GOS misclassification on ordinal analysis in TBI clinical trials. The impact of GOS misclassification and ordinal outcome analysis was explored via probabilistic sensitivity analyses using TBI patient datasets from the IMPACT database (n = 9205). Three patterns of misclassification were explored given the pre-specified misclassification distributions. For the random pattern, we specified a trapezoidal distribution (minimum: 80%, mode: 85%, and 95%, maximum: 100%) for both sensitivity and specificity; for the upward pattern, the same trapezoidal distribution for sensitivity but with a perfect specificity; and for the downward pattern, the same trapezoidal distribution for specificity but with a perfect sensitivity. The conventional 95% confidence intervals and simulation intervals, which accounts for the misclassification and random errors together, were reported. The results showed that given the specified misclassification distributions, the misclassification with a random or upward pattern would have caused a slightly underestimated outcome in the observed data. However, the misclassification with a downward pattern would have resulted in an inflated estimation. Thus the sensitivity analysis suggests that the nondifferential misclassification can cause uncertainties on the primary outcome estimation in TBI trials. However, such an effect is likely to be small when ordinal analysis is applied, compared with the impact of dichotomous GOS misclassifications. The result underlines that the ordinal GOS analysis may gain from both statistical efficiency, as suggested by several recent studies, and a relatively smaller impact from misclassification as compared with conventional binary GOS analysis.

FIG. 1.

Diagram illustrating the scenario of Glasgow Outcome Scale (GOS) misclassification. To simulate the situation, we assumed that (1) the misclassification can only be made between moderate disability (MD) and two adjacent categories (good recovery [GR] and severe disability [SD]), and (2) no misclassification for the category of vegetative status (VS). Based on these assumptions, the GOS misclassification was simulated through two independent binary situations, that is, between MD and GR, and between MD and SD, and the overall expected MD was recalculated provided the above, which is the observed MD plus the differences between the two independently reclassified MDs and the observed data.

FIG. 2.

Graphs showing the probability distributions of the classification parameters. The parameters are used to describe three patterns of misclassification for the study. Panel A shows the random pattern for which we specified a trapezoidal distribution (minimum of 80%, modes of 85 and 95%, and a maximum of 100%), for both sensitivity and specificity. Panel B shows the upward pattern for which we specified the same trapezoidal distribution for sensitivity, but a perfect specificity. Panel C shows the downward pattern, for which we specified the same trapezoidal distribution for specificity, but a perfect sensitivity.

FIG. 3.

Graphs showing the observed Glasgow Outcome Scale (GOS) distribution at 6 months post-injury from 11 traumatic brain injury studies contained in the IMPACT database, representing the moderate-to-severe head-injury population. A 10% treatment effect is added for each treatment group via a proportional odds model to symbolize a trial effect. The GOS includes categories of good recovery (GR), moderate disability (MD), severe disability (SD), and combined vegetative status and death (VS/D). The plain pattern represents the placebo group, while the textured pattern represents the treatment group. For each placebo group, the proportions of the individual GOS categories are shown (IMPACT, International Mission for Prognosis And Clinical Trial; TINT, The International Tirilazad Trial; TIUS, The North American Tirilazad Trial; SLIN, The International NMDA Antagonist Selfotel Trial; SAP, The Saphir Study; PEG, The PEGSOD Trial; HITI, The Nimodipine I Trial; HITII, The Nimodipine II Trial; SKB, The Bradycor Trial; TCDB, Traumatic Coma Data Bank; UK4, U.K. Four Center Study; EBIC, The European Brain Injury Consortium Core Data).