Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston-Salem, NC, United States of America.
Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States of America.
PLoS One. 2022 May 5;17(5):e0267779. doi: 10.1371/journal.pone.0267779. eCollection 2022.
Clinical trials conventionally test aggregate mean differences and assume homogeneous variances across treatment groups. However, significant response heterogeneity may exist. The purpose of this study was to model treatment response variability using gait speed change among older adults participating in caloric restriction (CR) trials. Eight randomized controlled trials (RCTs) with five- or six-month assessments were pooled, including 749 participants randomized to CR and 594 participants randomized to non-CR (NoCR). Statistical models compared means and variances by CR assignment and exercise assignment or select subgroups, testing for treatment differences and interactions for mean changes and standard deviations. Continuous equivalents of dichotomized variables were also fit. Models used a Bayesian framework, and posterior estimates were presented as means and 95% Bayesian credible intervals (BCI). At baseline, participants were 67.7 (SD = 5.4) years, 69.8% female, and 79.2% white, with a BMI of 33.9 (4.4) kg/m2. CR participants reduced body mass [CR: -7.7 (5.8) kg vs. NoCR: -0.9 (3.5) kg] and increased gait speed [CR: +0.10 (0.16) m/s vs. NoCR: +0.07 (0.15) m/s] more than NoCR participants. There were no treatment differences in gait speed change standard deviations [CR-NoCR: -0.002 m/s (95% BCI: -0.013, 0.009)]. Significant mean interactions between CR and exercise assignment [0.037 m/s (95% BCI: 0.004, 0.070)], BMI [0.034 m/s (95% BCI: 0.003, 0.066)], and IL-6 [0.041 m/s (95% BCI: 0.009, 0.073)] were observed, while variance interactions were observed between CR and exercise assignment [-0.458 m/s (95% BCI: -0.783, -0.138)], age [-0.557 m/s (95% BCI: -0.900, -0.221)], and gait speed [-0.530 m/s (95% BCI: -1.018, -0.062)] subgroups. Caloric restriction plus exercise yielded the greatest gait speed benefit among older adults with obesity. High BMI and IL-6 subgroups also improved gait speed in response to CR. Results provide a novel statistical framework for identifying treatment heterogeneity in RCTs.
临床研究通常测试总体均值差异，并假设治疗组之间具有同质方差。然而，可能存在显著的反应异质性。本研究旨在使用参加热量限制（CR）试验的老年人的步态速度变化来建立治疗反应的可变性模型。将 8 项具有 5 或 6 个月评估的随机对照试验（RCT）进行汇总，包括 749 名被随机分配到 CR 组和 594 名被随机分配到非 CR（NoCR）组的参与者。统计模型比较了 CR 分配和运动分配或选择亚组的均值和方差，检验了均值变化和标准差的治疗差异和交互作用。还拟合了二分类变量的连续等效物。模型使用贝叶斯框架，后验估计以均值和 95%贝叶斯可信区间（BCI）表示。在基线时，参与者的年龄为 67.7（SD=5.4）岁，女性占 69.8%，白人占 79.2%，BMI 为 33.9（4.4）kg/m2。CR 组参与者减轻体重[CR：-7.7（5.8）kg 比 NoCR：-0.9（3.5）kg]，并增加步态速度[CR：+0.10（0.16）m/s 比 NoCR：+0.07（0.15）m/s]比 NoCR 组参与者更多。在步态速度变化标准差方面没有治疗差异[CR-NoCR：-0.002 m/s（95% BCI：-0.013，0.009）]。在 CR 和运动分配之间观察到显著的均值交互作用[0.037 m/s（95% BCI：0.004，0.070）]，BMI[0.034 m/s（95% BCI：0.003，0.066）]和 IL-6[0.041 m/s（95% BCI：0.009，0.073）]，而在 CR 和运动分配之间观察到方差交互作用[-0.458 m/s（95% BCI：-0.783，-0.138）]，年龄[-0.557 m/s（95% BCI：-0.900，-0.221）]和步态速度[-0.530 m/s（95% BCI：-1.018，-0.062）]亚组。热量限制加运动为肥胖老年人提供了最大的步态速度益处。高 BMI 和 IL-6 亚组也对 CR 做出了改善步态速度的反应。结果为识别 RCT 中的治疗异质性提供了一种新的统计框架。
