The "carryover effects" mixed-effects model for syndrome differentiation treatment on bronchiectasis: a series of N-of-1 trials_Chinese Journal of Evidence-Based Medicine

Authors：

CHEN Huijia ^1,2 , WANG Zhenwei ¹ , ZHANG Yi ¹ , ZHANG Ensi ¹ , NIAN Hua ¹ , MA Ying ¹ , YANG Peilan ¹ ,  CHEN Xinlin ³ , HUANG Haiyin ¹

1. Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, P. R. China;
2. Minhang Hospital, Fudan University, Shanghai 201199, P. R. China;
3. Basic Medical College, Guangzhou University of Traditional Chinese Medicine, Guangzhou 510006, P. R. China;

Corresponding author：

CHEN Xinlin, Email: haiyin_huang@126.com

Keywords：

N-of-1 trials; Bronchiectasis; Carryover effects; Syndrome differentiation; Traditional Chinese medicine

DOI：

10.7507/1672-2531.202210022

Video：

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Objective A series of single-case randomized controlled trials (N-of-1 trials), with placebo Chinese herbs used as a control, were conducted to observe the efficacy of the syndrome differentiation treatment formula in the stable phase of bronchiectasis by using a modified mixed-effects model (MEM) to detect the "carryover effects" of Chinese herbs, and to explore the establishment of an N-of-1 trial method that reflects the characteristics of syndrome differentiation treatment in traditional Chinese medicine (TCM). Methods A single-center clinical trial was conducted in which a single case was studied in a multiple crossover, randomized controlled, and blinded manner. There were three rounds of the trial, each with two observation periods (treatment period and control period) of 4 weeks each. In the treatment period, an individualized formula based on syndrome differentiation was given, and in the control period, a placebo formula was administered. The primary indicator was the patients’ self-rated 7-point symptom Likert scale score, and other indicators included chronic obstructive pulmonary disease assessment test (CAT) score, 24 h sputum volume, TCM syndrome score, and safety index. Paired t test was used to analyze single case data and MEM designed for "carryover effects" was used to analyze group data. Results A total of 21 subjects were formally enrolled, and 15 (75%) completed three rounds of N-of-1 trials. Three of the cases showed statistically significant differences in overall symptom Likert scale score. At the group level, the MEM designed for "carryover effects" found statistically significant residual effects on three indicators (overall symptom score, respiratory symptom score, and CAT score). After excluding the "carryover effects", the model analyzed the statistically significant differences between the intervention effects of the two formulas on the overall symptom score, respiratory symptom score, CAT score and TCM syndrome score. The sensitivity of the MEM was higher than that of the meta-analysis when residual effects existed in the N-of-1 trials. Conclusion The N-of-1 trials of Chinese herbs designed in this study can well demonstrate the characteristics of TCM syndrome differentiation and treatment. The modified MEM can detect the residual effects of TCM and improve the sensitivity of data statistics. However, due to the inherent nature of N-of-1 trials, the sensitivity of this study method at the individual level is low and more cases and diseases need to be studied for further improvement.

Citation： CHEN Huijia, WANG Zhenwei, ZHANG Yi, ZHANG Ensi, NIAN Hua, MA Ying, YANG Peilan, CHEN Xinlin, HUANG Haiyin. The "carryover effects" mixed-effects model for syndrome differentiation treatment on bronchiectasis: a series of N-of-1 trials. Chinese Journal of Evidence-Based Medicine, 2023, 23(5): 504-512. doi: 10.7507/1672-2531.202210022 Copy

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11.	黄海茵, 杨佩兰, 汤杰, 等. 扶正化痰清热法治疗支气管扩张症46例远期疗效观察. 中医杂志, 2012, 53(10): 848-852.
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25.	陈敏, 黄宁静, 王祎晟. 泻火止痛方治疗肝火上炎型偏头痛的临床研究. 中西医结合心脑血管病杂志, 2015, 13(12): 1375-1377.
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31.	Senior HE, Mitchell GK, Nikles J, et al. Using aggregated single patient (N-of-1) trials to determine the effectiveness of psychostimulants to reduce fatigue in advanced cancer patients: a rationale and protocol. BMC Palliat Care, 2013, 12(1): 17.

1. OCEBM Levels of Evidence Working Group. The Oxford levels of evidence 2.
2. Nikles J, Mitchell G, McKinlay L, et al. A series of n-of-1 trials of stimulants in brain injured children. NeuroRehabilitation, 2017, 40(1): 11-21.
3. Zucker DR, Ruthazer R, Schmid CH. Individual (N-of-1) trials can be combined to give population comparative treatment effect estimates: methodologic considerations. J Clin Epidemiol, 2010, 63(12): 1312-1323.
4. 陈新林, 黄海茵, 张长荣, 等. 2015版CENT声明简介: 单病例随机对照试验报告指南. 中国循证医学杂志, 2016, 16(7): 860-863.
5. 翟静波, 商洪才, 李江, 等. 单病例随机对照试验的统计分析方法. 中国循证医学杂志, 2017, 17(4): 494-496.
6. 于大君, 翁维良, 陆芳, 等. 慢性肾脏病Ⅲ期单病例随机对照临床试验. 中医杂志, 2012, 53(3): 222-224.
7. 张昕, 黄李法, 李徐. 高血压脑出血术后患者单病例随机对照临床试验. 浙江中医药大学学报, 2012, 36(8): 871-873,886.
8. Yuhong H, Qian L, Yu L, et al. An n-of-1 trial service in clinical practice: testing the effectiveness of Liuwei Dihuang decoction for kidney-Yin deficiency syndrome. Evid Based Complement Alternat Med, 2013, 2013: 827915.
9. Huang H, Yang P, Xue J, et al. Evaluating the individualized treatment of traditional Chinese medicine: a pilot study of N-of-1 trials. Evid Based Complement Alternat Med, 2014, 2014: 148730.
10. 成人支气管扩张症诊治专家共识编写组. 成人支气管扩张症诊治专家共识. 中华结核和呼吸杂志, 2012, 35(7): 485-492.
11. 黄海茵, 杨佩兰, 汤杰, 等. 扶正化痰清热法治疗支气管扩张症46例远期疗效观察. 中医杂志, 2012, 53(10): 848-852.
12. Huang H, Yang P, Wang J, et al. Investigation into the individualized treatment of traditional Chinese medicine through a series of N-of-1 trials. Evid Based Complement Alternat Med, 2018, 2018: 5813767.
13. Lu L, An J, Chen H, et al. A series of N-of-1 trials for traditional Chinese medicine using a Bayesian method: study rationale and protocol. Evid Based Complement Alternat Med, 2021, 2021: 9976770.
14. Huang H, An J, Lu L, et al. Methodological considerations in N-of-1 trials of traditional Chinese medicine. Evid Based Complement Alternat Med, 2021, 2021: 6634134.
15. Zucker DR, Schmid CH, McIntosh MW, et al. Combining single patient (N-of-1) trials to estimate population treatment effects and to evaluate individual patient responses to treatment. J Clin Epidemiol, 1997, 50(4): 401-410.
16. 陈新林, 李海文, 刘凤斌, 等. 单病例随机对照试验的设计和评价方法. 中国循证医学杂志, 2016, 16(2): 242-245.
17. Chen X, Chen P. A comparison of four methods for the analysis of N-of-1 trials. PLoS One, 2014, 9(2): e87752.
18. 陈新林, 刘凤斌, 赵菲, 等. 探索适合中医药N-of-1试验的设计方案及模型. 广州中医药大学学报, 2018, 35(1): 172-175.
19. Shamseer L, Sampson M, Bukutu C, et al. CONSORT extension for reporting N-of-1 trials (CENT) 2015: explanation and elaboration. BMJ, 2015, 350: h1793.
20. Guyatt G, Rennie D. Users' guides to the medical literature: essentials of evidence-based clinical practice (2nd edition). Chicago: American Medical Association Press, 2002: 3-11.
21. Guyatt GH, Keller JL, Jaeschke R, et al. The n-of-1 randomized controlled trial: clinical usefulness. Our three-year experience. Ann Intern Med, 1990, 112(4): 293-299.
22. Polverino E, Goeminne PC, McDonnell MJ, et al. European respiratory society guidelines for the management of adult bronchiectasis. Eur Respir J, 2017, 50(3): 1700629.
23. 国家中医药管理局. 中医病症诊断疗效标准. 南京: 南京大学出版社, 1994.
24. 张惠勇, 李欣, 倪伟, 等. 支气管扩张证中医辨证分型规律的研究. 上海中医药杂志, 2005, 39(1): 16-18.
25. 陈敏, 黄宁静, 王祎晟. 泻火止痛方治疗肝火上炎型偏头痛的临床研究. 中西医结合心脑血管病杂志, 2015, 13(12): 1375-1377.
26. Guyatt G, Sackett D, Adachi J, et al. A clinician’s guide for conduction randomized trials in individual patients. CAMJ, 1988, 13(139): 497-503.
27. Lee BY, Lee S, Lee JS, et al. Validity and reliability of CAT and dyspnea-12 in bronchiectasis and tuberculous destroyed lung. Tuberc Respir Dis (Seoul), 2012, 72(6): 467-474.
28. 郑筱萸. 中药新药临床研究指导原则. 北京: 中国医药科技出版社, 2002.
29. 武胜萍, 徐立鹏, 郭宇, 等. 中国近30年临床研究中安慰剂的应用现状. 中国中药杂志, 2015, 40(7): 1410-1414.
30. Dodd JW, Hogg L, Nolan J, et al. The COPD assessment test (CAT): response to pulmonary rehabilitation. a multicentre, prospective study. Thorax, 2011, 66(5): 425-429.
31. Senior HE, Mitchell GK, Nikles J, et al. Using aggregated single patient (N-of-1) trials to determine the effectiveness of psychostimulants to reduce fatigue in advanced cancer patients: a rationale and protocol. BMC Palliat Care, 2013, 12(1): 17.

Chinese Journal of Evidence-Based Medicine

The "carryover effects" mixed-effects model for syndrome differentiation treatment on bronchiectasis: a series of N-of-1 trials

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