Sensitivity analysis - the effects of Glasgow Outcome Scale misclassification on traumatic brain injury clinical trials

SENSITIVITY ANALYSIS – THE EFFECTS OF GLASGOW OUTCOME SCALE MISCLASSIFICATION ON TRAUMATIC BRAIN INJURY CLINICAL TRIALS By Juan Lu, M.D., M.P.H. , Ph.D. Three manuscripts submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University. Virginia Commonwealth University, 2010 Director: Kate L. Lapane Ph.D. Professor and Chair, Department of Epidemiology and Community Health I. EFFECTS OF GLASGOW OUTCOME SCALE MISCLASSIFICATION ON TRAUMATIC BRAIN INJURY CLINICAL TRIALS The Glasgow Outcome Scale (GOS) is the primary endpoint for efficacy analysis of clinical trials in traumatic brain injury (TBI). Accurate and consistent assessment of outcome after TBI is essential to the evaluation of treatment results, particularly in the context of multicenter studies and trials. The inconsistent measurement or interobserver variation on GOS outcome, or for that matter, on any outcome scales, may adversely affect the sensitivity to detect treatment effects in clinical trial. The objective of this study is to examine effects of nondifferential misclassification of the widely used five-category GOS outcome scale and in particular to assess the impact of this misclassification on detecting a treatment effect and statistical power. We followed two approaches. First, outcome differences were analyzed before and after correction for misclassification using a dataset of 860 patients with severe brain injury randomly sampled from two TBI trials with known differences in outcome. Second, the effects of misclassification on outcome distribution and statistical power were analyzed in simulation studies on a hypothetical 800-patient dataset. Three potential patterns of nondifferential misclassification (random, upward and downward) on the dichotomous GOS outcome were analyzed, and the power of finding treatments differences was investigated in detail. All three patterns of misclassification reduce the power of detecting the true treatment effect and therefore lead to a reduced estimation of the true efficacy. The magnitude of such influence not only depends on the size of the misclassification, but also on the magnitude of the treatment effect. In conclusion, nondifferential misclassification directly reduces the power of finding the true treatment effect. An awareness of this procedural error and methods to reduce misclassification should be incorporated in TBI clinical trials. II. IMPACT OF MISCLASSIFICATION ON THE ORDINAL GLASGOW OUTCOME SCALE IN TRAUMATIC BRIAN INJURY CLINICAL TRIALS The methods of ordinal GOS analysis are recommended to increase efficiency and optimize future TBI trials. To further explore the utility of the ordinal GOS in TBI trials, this study extends our previous investigation regarding the effect of misclassification on the dichotomous GOS to examine the impact of misclassification on the 5-point ordinal scales. The impact of nondifferential misclassification on the ordinal GOS was explored via probabilistic sensitivity analyses using TBI patient datasets contained in the IMPACT database (N=9,205). Three patterns of misclassification including random, upward and downward patterns were extrapolated, with the pre-specified outcome classification error distributions. The conventional 95% confidence intervals and the simulation intervals, which account for the misclassification only and the misclassification and random errors together, were reported. Our simulation results showed that given a specification of a minimum of 80%, modes of 85% and 95% and a maximum of 100% for both sensitivity and specificity (random pattern), or given the same trapezoidal distributed sensitivity but a perfect specificity (upward pattern), the misclassification would have caused an underestimated ordinal GOS in the observed data. In another scenario, given the same trapezoidal distributed specificity but a perfect sensitivity (downward pattern), the misclassification would have resulted in an inflated GOS estimation. Thus, the probabilistic sensitivity analysis suggests that the effect of nondifferential misclassification on the ordinal GOS is likely to be small, compared with the impact on the binary GOS situation. The results indicate that the ordinal GOS analysis may not only gain the efficiency from the nature of the ordinal outcome, but also from the relative smaller impact of the potential misclassification, compared with the conventional binary GOS analysis. Nevertheless, the outcome assessment following TBI is a complex problem. The assessment quality could be influenced by many factors. All possible aspects must be considered to ensure the consistency and reliability of the assessment and optimize the success of the trial. III. A METHOD FOR REDUCING MISCLASSIFICATION IN THE EXTENDED GLASGOW OUTCOME SCORE The eight-point extended Glasgow Outcome Scale (GOSE) is commonly used as the primary outcome measure in traumatic brain injury (TBI) clinical trials. The outcome is conventionally collected through a structured interview with the patient alone or together with a caretaker. Despite the fact that using the structured interview questionnaires helps reach agreement in GOSE assessment between raters, significant variation remains among different raters. We introduce an alternate GOSE rating system as an aid in determining GOSE scores, with the objective of reducing inter-rater variation in the primary outcome assessment in TBI trials. Forty-five trauma centers were randomly assigned to three groups to assess GOSE scores on sample cases, using the alternative GOSE rating system coupled with central quality control (Group 1), the alternative system alone (Group 2), or conventional structured interviews (Group 3). The inter-rater variation between an expert and untrained raters was assessed for each group and reported through raw agreement and with weighted kappa (k) statistics. Groups 2 and 3 without central review yielded inter-rater agreements of 83% (weighted k1⁄40.81; 95% CI 0.69, 0.92) and 83% (weighted k1⁄40.76, 95% CI 0.63, 0.89), respectively, in GOS scores. In GOSE, the groups had an agreement of 76% (weighted k1⁄40.79; 95% CI 0.69, 0.89), and 63% (weighted k1⁄40.70; 95% CI 0.60, 0.81), respectively. The group using the alternative rating system coupled with central monitoring yielded the highest inter-rater agreement among the three groups in rating GOS (97%; weighted k1⁄40.95; 95% CI 0.89, 1.00), and GOSE (97%; weighted k1⁄40.97; 95% CI 0.91, 1.00). The alternate system is an improved GOSE rating method that reduces inter-rater variations and provides for the first time, source documentation and structured narratives that allow a thorough central review of information. The data suggest that a collective effort can be made to minimize inter-rater variation.