Age-Binned Normalization of Vinelandtm-II Increases Variability in Standard Scores: Implication for Clinical Trials in ASD.
Objectives: To estimate the impact of the age binning on simulated clinical trial VinelandTM-II change data and to develop a continuous normalization function for the age normalization.
Methods: The means of the 9 VinelandTM-II raw-scores were extracted from the manual and interpolated with smooth splines to derive continuous estimates of the developmental trajectory. Then 1000 “average” study subjects (i.e. lying on the mean of the distribution) were simulated with an enrolment age randomly selected between 5 and 7 years. The standard domain scores were estimated for enrolment and 12 or 24 week assessments and the variances in the differences were estimated. By definition the difference should be 0 (i.e. effect of treatment was modeled) but as a result of age quantization, variance was induced that was set into relation to the variance observed in several studies that employed VinelandTM-II.
Results: Simulations of 12-week long VinelandTM-II clinical trial data with subjects aged 5 to 7 years showed that age binning increased variability of domain standard change scores by up to 2 units. Since the naturally occurring variation in domain change scores is as low as 6 standard scores in some clinical trials, this increase in variability corresponds to up to 12.5% of the variance. As expected, the continuous normalization function generated zero increase in change score variability in the simulated clinical trial data.
Conclusions: The use of VinelandTM-II in clinical trials should take into consideration the increased variability introduced by the age binned normalization. Larger sample sizes should be considered to compensate for this higher variability. Alternatively, validation of continuous age normalization will improve the VinelandTM-II use in clinical trials and observational studies.