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.	黃海茵, 楊佩蘭, 湯杰, 等. 扶正化痰清熱法治療支氣管擴張癥46例遠期療效觀察. 中醫雜志, 2012, 53(10): 848-852.
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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.

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. 陳新林, 黃海茵, 張長榮, 等. 2015版CENT聲明簡介: 單病例隨機對照試驗報告指南. 中國循證醫學雜志, 2016, 16(7): 860-863.
5. 翟靜波, 商洪才, 李江, 等. 單病例隨機對照試驗的統計分析方法. 中國循證醫學雜志, 2017, 17(4): 494-496.
6. 于大君, 翁維良, 陸芳, 等. 慢性腎臟病Ⅲ期單病例隨機對照臨床試驗. 中醫雜志, 2012, 53(3): 222-224.
7. 張昕, 黃李法, 李徐. 高血壓腦出血術后患者單病例隨機對照臨床試驗. 浙江中醫藥大學學報, 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. 成人支氣管擴張癥診治專家共識編寫組. 成人支氣管擴張癥診治專家共識. 中華結核和呼吸雜志, 2012, 35(7): 485-492.
11. 黃海茵, 楊佩蘭, 湯杰, 等. 扶正化痰清熱法治療支氣管擴張癥46例遠期療效觀察. 中醫雜志, 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. 陳新林, 李海文, 劉鳳斌, 等. 單病例隨機對照試驗的設計和評價方法. 中國循證醫學雜志, 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. 陳新林, 劉鳳斌, 趙菲, 等. 探索適合中醫藥N-of-1試驗的設計方案及模型. 廣州中醫藥大學學報, 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. 國家中醫藥管理局. 中醫病癥診斷療效標準. 南京: 南京大學出版社, 1994.
24. 張惠勇, 李欣, 倪偉, 等. 支氣管擴張證中醫辨證分型規律的研究. 上海中醫藥雜志, 2005, 39(1): 16-18.
25. 陳敏, 黃寧靜, 王祎晟. 瀉火止痛方治療肝火上炎型偏頭痛的臨床研究. 中西醫結合心腦血管病雜志, 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. 鄭筱萸. 中藥新藥臨床研究指導原則. 北京: 中國醫藥科技出版社, 2002.
29. 武勝萍, 徐立鵬, 郭宇, 等. 中國近30年臨床研究中安慰劑的應用現狀. 中國中藥雜志, 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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