Baseline-dependent improvement in CF studies, plausibility of bias

IF 1.4 Q4 MEDICINE, RESEARCH & EXPERIMENTAL Contemporary Clinical Trials Communications Pub Date : 2024-10-05 DOI:10.1016/j.conctc.2024.101378
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Abstract

Background:

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 (FEV1pp) (Magaret et al., 2024; Stanojevic et al., 2020 and Thornton et al., 2023).

Methods:

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 FEV1pp and treatment-induced change: post-versus pre-treatment.

Results:

When day-to-day variation was present in FEV1pp, 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).

Conclusion:

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.
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基于基线的 CF 研究改进,偏差的合理性
背景:据普遍报道,囊性纤维化(CF)的治疗方法具有天花板效应,即治疗前健康状况较好的患者的疗效会降低(Montgomery等人,2012年和Newsome等人,2019年)。也有报道称,在治疗前健康状况低于平均水平的人群中,地板效应的下降幅度较低(Harun等人,2016年;Konstan等人,2012年和Szczesniak等人,2017年)。如果存在测量误差,统计文献就会警告治疗前的测量结果与后续变化之间存在夸大或虚假的关联(Chambless 和 Davis,2003 年;Yanez 等人,1998 年)。方法:我们进行了一项模拟研究,以评估 CF 治疗药物研究中可能出现的虚假最低或最高效应。结果:当 FEV1pp 存在日间变化,且变化水平与在家庭和诊所测量肺活量的大型研究中报告的水平相当时,天真的分析方法会发现变化与基线之间存在虚假关联(Paynter 等人,2022 年;Saiman 等人,2003 年)。I型误差从31.9%到98.3%不等,日常变化相对于生物变化高达3%到15%。结合已知的日变化,回归校准方法纠正了偏差并控制了 I 类误差(Chambless 和 Davis,2003 年)。进一步的研究可以对 CF 中的上限效应进行有意义的确认,或许可以通过结合治疗前后的多次测量来减少日常变化。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Contemporary Clinical Trials Communications
Contemporary Clinical Trials Communications Pharmacology, Toxicology and Pharmaceutics-Pharmacology
CiteScore
2.70
自引率
6.70%
发文量
146
审稿时长
20 weeks
期刊介绍: Contemporary Clinical Trials Communications is an international peer reviewed open access journal that publishes articles pertaining to all aspects of clinical trials, including, but not limited to, design, conduct, analysis, regulation and ethics. Manuscripts submitted should appeal to a readership drawn from a wide range of disciplines including medicine, life science, pharmaceutical science, biostatistics, epidemiology, computer science, management science, behavioral science, and bioethics. Contemporary Clinical Trials Communications is unique in that it is outside the confines of disease specifications, and it strives to increase the transparency of medical research and reduce publication bias by publishing scientifically valid original research findings irrespective of their perceived importance, significance or impact. Both randomized and non-randomized trials are within the scope of the Journal. Some common topics include trial design rationale and methods, operational methodologies and challenges, and positive and negative trial results. In addition to original research, the Journal also welcomes other types of communications including, but are not limited to, methodology reviews, perspectives and discussions. Through timely dissemination of advances in clinical trials, the goal of Contemporary Clinical Trials Communications is to serve as a platform to enhance the communication and collaboration within the global clinical trials community that ultimately advances this field of research for the benefit of patients.
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