Liu-Seifert Hong, Andersen Scott, Case Michael, Sparks JonDavid, Holdridge Karen C, Wessels Alette M, Hendrix Suzanne, Aisen Paul, Siemers Eric
a Lilly Research Laboratories , Lilly Corporate Center, Indianapolis , Indiana , USA.
b Pentara Corporation , Salt Lake City , Utah , USA.
J Biopharm Stat. 2017;27(6):1104-1114. doi: 10.1080/10543406.2017.1315819. Epub 2017 Apr 27.
Little research has been conducted on the statistical properties of composite measures comprising linear combinations of continuous component scales. We assessed the quantitative relationship between the composites and their individual components regarding their abilities to detect treatment effects. In particular, we developed the mathematical derivation of the treatment effect size of a continuous composite in relation to the treatment effect sizes of its components and proved multiple properties of the composite. We demonstrated that the treatment effect size of a composite is greater than the minimum treatment effect size of its components and that above certain thresholds of correlations of components and ratios of component effect sizes, the composite may outperform its components. Examples from Alzheimer's disease (AD) clinical studies of solanezumab and donepezil using the composite Integrated AD Rating Scale (iADRS) and its components, the AD Assessment Scale-Cognitive subscale (ADAS-Cog) and AD Cooperative Study-Activities of Daily Living inventory, instrumental items (ADCS-iADL) were consistent with the theoretical statistical properties. The understanding of the quantitative relationships between continuous composites and their components will be useful in clinical trial design and the development of new scales and composites across therapeutic areas.
关于由连续分量量表的线性组合构成的综合测量指标的统计特性，所开展的研究甚少。我们评估了综合指标与其各个组成部分在检测治疗效果能力方面的定量关系。具体而言，我们推导了连续综合指标的治疗效应大小与其各组成部分的治疗效应大小之间的数学关系，并证明了该综合指标的多个特性。我们证明，综合指标的治疗效应大小大于其各组成部分的最小治疗效应大小，并且在各组成部分的相关性和组成部分效应大小的比率达到特定阈值以上时，综合指标可能优于其各组成部分。在阿尔茨海默病（AD）临床研究中，使用综合指标综合AD评定量表（iADRS）及其组成部分，即AD认知评定量表（ADAS-Cog）和AD协作研究日常生活活动量表工具性项目（ADCS-iADL），对solanezumab和多奈哌齐进行研究的实例，与理论统计特性相符。了解连续综合指标与其组成部分之间的定量关系，将有助于临床试验设计以及跨治疗领域开发新的量表和综合指标。
