Graham Ellen, Heltshe Sonya L, Magaret Amalia S
MS University of Washington, Department of Biostatistics, United States of America.
University of Washington, Departments of Pediatrics and Biostatistics Seattle Children's Research Institute, Center for Respiratory Biology and Therapeutics, United States of America.
Contemp Clin Trials Commun. 2024 Oct 5;42:101378. doi: 10.1016/j.conctc.2024.101378. eCollection 2024 Dec.
It has been commonly reported that therapeutic treatments in cystic fibrosis (CF) have ceiling effects, such that their efficacy is diminished for persons with high pre-treatment health (Montgomery et al., 2012 and Newsome et al., 2019). Floor effects have also been reported where decline is of lower magnitude in those with below-average pre-treatment health (Harun et al., 2016; Konstan et al., 2012 and Szczesniak et al., 2017). When measurement error is present, the statistical literature has warned of exaggerated or spurious associations between pre-treatment measures and subsequent change (Chambless and Davis, 2003 and Yanez et al., 1998). Measurement error, equivalently described as day-to-day variation, has been described to occur in CF outcome measurements such as forced expiratory volume in 1 s taken by spirometry (FEV pp) (Magaret et al., 2024; Stanojevic et al., 2020 and Thornton et al., 2023).
We conducted a simulation study to assess the potential for spurious floor or ceiling effects in studies of CF therapeutics. We considered uncontrolled or single-arm studies, and evaluated estimated association between pre-treatment FEV pp and treatment-induced change: post-versus pre-treatment.
When day-to-day variation was present in FEV pp, at levels equivalent to those reported in large studies measuring spirometry both at home and in clinic, naive analytic approaches found spurious associations of change with baseline (Paynter et al., 2022 and Saiman et al., 2003). Type I error ranged from 31.9% to 98.3% for day-to-day variation as high as 3% to 15% relative to biological variation. Incorporating known day-to-day variation, the regression calibration approach corrected bias and controlled type I error (Chambless and Davis, 2003).
Exaggerated ceiling effects are possible. Further studies could provide meaningful confirmation of ceiling effects in CF, perhaps reducing day-to-day variation by incorporating multiple pre- and post-treatment measurements.
普遍报道称，囊性纤维化（CF）的治疗方法存在天花板效应，即对于治疗前健康状况良好的患者，其疗效会降低（蒙哥马利等人，2012年；纽瑟姆等人，2019年）。也有报道称存在地板效应，即治疗前健康状况低于平均水平的患者病情下降幅度较小（哈伦等人，2016年；康斯坦等人，2012年；斯切斯尼亚克等人，2017年）。当存在测量误差时，统计文献警告说，治疗前测量与后续变化之间可能存在夸大或虚假的关联（钱布利斯和戴维斯，2003年；亚涅斯等人，1998年）。测量误差，也被称为每日变化，已被描述为在CF结果测量中出现，如通过肺活量测定法测量的1秒用力呼气量（FEV pp）（马加雷特等人，2024年；斯托诺耶维奇等人，2020年；桑顿等人，2023年）。
我们进行了一项模拟研究，以评估CF治疗研究中出现虚假地板效应或天花板效应的可能性。我们考虑了非对照或单臂研究，并评估了治疗前FEV pp与治疗引起的变化之间的估计关联：治疗后与治疗前。
当FEV pp中存在每日变化时，在与家庭和诊所中测量肺活量的大型研究报告的水平相当的情况下，单纯的分析方法发现变化与基线之间存在虚假关联（佩因特等人，2022年；赛曼等人，2003年）。相对于生物学变异，高达3%至15%的每日变化的I型错误率在31.9%至98.3%之间。纳入已知的每日变化后，回归校准方法校正了偏差并控制了I型错误（钱布利斯和戴维斯，2003年）。
可能存在夸大的天花板效应。进一步的研究可以为CF中的天花板效应提供有意义的证实，或许可以通过纳入多次治疗前和治疗后的测量来减少每日变化。
