Methodological comparison and clinical application of single-case experimental designs_Chinese Journal of Evidence-Based Medicine

Authors：

WANG Mingli ¹ ,  WANG Zhenwei ¹ , CHEN Xinlin ² , LU Lizhi ¹ , ZHANG Yi ¹ , ZHANG Ensi ¹ , HUANG Haiying ¹

1. Department of Respiratory Disease and Department of Pharmacy, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, P. R. China;
2. Basic Medical College of Guangzhou University of Traditional Chinese Medicine, Guangzhou 510006, P. R. China;

Corresponding author：

WANG Zhenwei, Email: haiyin_huang@126.com

Keywords：

N-of-1 trials; Multiple-baseline designs; Method; Traditional Chinese medicine

DOI：

10.7507/1672-2531.202112138

Video：

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Objective To improve the sensitivity and broaden the applicability of N-of-1 trials in traditional Chinese medicine (TCM), the clinical application and methodology of single-case experimental designs (N-of-1trials, multiple-baseline designs; MBDs) were expounded, compared, and discussed. Methods This paper introduced the current utility of N-of-1 trials in TCM research, introduced MBDs, and compared the methodologies of N-of-1 trials, MBDs and crossover design. Finally, two design schemes to improve the sensitivity and applicability of N-of-1 trials were illustrated. Results N-of-1 trials conformed to the TCM concept of treatment based on syndrome differentiation; however, due to the complex composition of TCM, the results were easily affected by carryover effect. In MBDs, the intervention was introduced in a staggered way, no washout period was needed, and the required sample size was small. MBDs were generally used to preliminarily indicate the effect of intervention; however, the statistical analysis was relatively complicated, and there were few MBDs used in clinical trials of TCM at present. Compared with crossover trials, single-case experimental designs had advantages and disadvantages. N-of-1 trials might best reflect the individualized treatment of TCM and a suitable statistical model (e.g., hierarchical Bayesian statistical method) was expected to improve the sensitivity and applicability of N-of-1 trials in TCM. Combining clinical trial designs (e.g., the combination of N-of-1 trials and MBDs) would complement the limitations of N-of-1 trials, and expand the scope of conditions applicable for study. Conclusion N-of-1 trials have both advantages and disadvantages in TCM research. Improved statistical models or combined study designs will improve the sensitivity and broaden the applicability of N-of-1 trials in TCM.

Citation： WANG Mingli, WANG Zhenwei, CHEN Xinlin, LU Lizhi, ZHANG Yi, ZHANG Ensi, HUANG Haiying. Methodological comparison and clinical application of single-case experimental designs. Chinese Journal of Evidence-Based Medicine, 2022, 22(4): 468-474. doi: 10.7507/1672-2531.202112138 Copy

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2.	OCEBM Levels of Evidence Working Group. The Oxford levels of evidence 2, Oxford Centre for Evidence-Based Medicine. Available at: https://www.cebm.ox.ac.uk/resources/levels-of-evidence/ocebm-levels-of-evidence.
3.	黄海茵, 杨佩兰, 张誉清, 等. 单病例随机对照试验在中医药研究中的可行性与潜在价值. 上海中医药杂志, 2012, 46(8): 3-8.
4.	李宣霖, 余学庆, 谢洋, 等. 中国大陆中文期刊发表的中医药单病例随机对照试验的报告质量评价与思考. 中医杂志, 2020, 61(15): 1325-1329.
5.	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.
6.	刘志刚, 柴程芝, 朱欣佚, 等. 葛根汤治疗原发性痛经的多基线单病例随机对照试验. 中华中医药杂志, 2015, 30(7): 2473-2476.
7.	Tate R, Perdices M. Single-case experimental designs for clinical research and neurorehabilitation settings: planning, conduct, analysis and reporting. New York: Routledge, 2019.
8.	Vohra S, Shamseer L, Sampson M, et al. CONSORT extension for reporting N-of-1 trials (CENT) 2015 Statement. J Clin Epidemiol, 2016, 76: 9-17.
9.	朱文慧, 孟庆刚. 单病例随机对照试验的周期设计在中医药临床疗效评价中的应用研究. 中华中医药学刊, 2018, 36(10): 2509-2512.
10.	Kravitz RL, Duan N, Braslow J. Evidence-based medicine, heterogeneity of treatment effects, and the trouble with averages. Milbank Q, 2004, 82(4): 661-687.
11.	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.
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.	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.
14.	王洁, 黄海茵, 杨佩兰, 等. 个体化方治疗稳定期支气管扩张症的单病例随机对照临床研究. 上海中医药杂志, 2016, 50(3): 39-43.
15.	Zi S, Huang H, Yang P, et al. Evaluating the effects of heat-clearing traditional Chinese medicine in stable bronchiectasis by a series of N-of-1 trials. Evid Based Complement Alternat Med, 2022, 2022: 6690638.
16.	陈新林, 陈丽霞, 黄海茵, 等. 系列N-of-1试验定量数据混合效应模型的模拟研究. 中国循证医学杂志, 2021, 21(6): 689-695.
17.	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.
18.	Ruiz FJ, Luciano C, Flórez CL, et al. A multiple-baseline evaluation of acceptance and commitment therapy focused on repetitive negative thinking for comorbid generalized anxiety disorder and depression. Front Psychol, 2020, 11: 356.
19.	Watter K, Copley A, Finch E. Strategy-based reading comprehension therapy during early acquired brain injury rehabilitation: preliminary results. Disabil Rehabil, 2020: 1-17.
20.	Christ TJ. Experimental control and threats to internal validity of concurrent and nonconcurrent multiple baseline designs. Psychology Schools, 2007, 44(5): 451-459.
21.	Lane JD, Gast DL. Visual analysis in single case experimental design studies: brief review and guidelines. Neuropsychol Rehabil, 2014, 24(3-4): 445-463.
22.	Kazdin AE. Single-case research designs in clinical child psychiatry. J Am Acad Child Psychiatry, 1983, 22(5): 423-432.
23.	Bulté I, Onghena P. Randomization tests for multiple-baseline designs: an extension of the SCRT-R package. Behav Res Methods, 2009, 41(2): 477-485.
24.	Kazdin AE, Kopel SA. On resolving ambiguities of the multiple-baseline design: problems and recommendations. Behavior Therapy, 1975, 6(5): 601-608.
25.	Dallery J, Cassidy RN, Raiff BR. Single-case experimental designs to evaluate novel technology-based health interventions. J Med Internet Res, 2013, 15(2): e22.
26.	孙塑伦, 翁维良, 杨龙会. 中医临床研究实施方案设计与优化. 北京: 中国中医药出版社, 2008.
27.	Harris T, Nikes J. Herbal medicines used in the treatment of chronic insomnia and how they influence sleep patterns: a review. J Complement Med Alternat Healthcare, 2018, 6(1): 555680.
28.	Bradbury J, Avila C, Grace S. Practice-based research in complementary medicine: could N-of-1 trials become the new gold standard. Healthcare (Basel), 2020, 8(1): 15.
29.	苏炳华. 新药临床试验统计分析新进展. 上海: 上海科学技术文献出版社, 2000.
30.	金丕焕, 邓伟. 临床试验. 上海: 复旦大学出版社, 2004.
31.	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.
32.	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.
33.	Guyatt G, Sackett D, Adachi J, et al. A clinician's guide for conducting randomized trials in individual patients. CMAJ, 1988, 139(6): 497-503.
34.	Hesam-Shariati N, Newton-John T, Singh AK, et al. Evaluation of the effectiveness of a novel brain-computer interface neuromodulative intervention to relieve neuropathic pain following spinal cord injury: protocol for a single-case experimental design with multiple baselines. JMIR Res Protoc, 2020, 9(9): e20979.
35.	Parker RI, Vannest KJ, Davis JL, et al. Combining nonoverlap and trend for single-case research: Tau-U. Behav Ther, 2011, 42(2): 284-299.
36.	Duan N, Kravitz RL, Schmid CH. Single-patient (n-of-1) trials: a pragmatic clinical decision methodology for patient-centered comparative effectiveness research. J Clin Epidemiol, 2013, 66(8 Suppl): S21-28.
37.	Nikles J, Tate RL, Mitchell G, et al. Personalised treatments for acute whiplash injuries: a pilot study of nested N-of-1 trials in a multiple baseline single-case experimental design. Contemp Clin Trials Commun, 2019, 16: 100480.
38.	Brossart DF, Laird VC, Armstrong TW, et al. Interpreting Kendall’s Tau and Tau-U for single-case experimental designs. Cogent Psychology, 2018, 5(1): 1-26.
39.	Higgins JP, Whitehead A. Borrowing strength from external trials in a meta-analysis. Stat Med, 1996, 15(24): 2733-2749.

1. 商洪才, 田贵华. 单病例随机对照试验: 理论与实践(第1版). 北京: 人民卫生出版社, 2020.
2. OCEBM Levels of Evidence Working Group. The Oxford levels of evidence 2, Oxford Centre for Evidence-Based Medicine. Available at: https://www.cebm.ox.ac.uk/resources/levels-of-evidence/ocebm-levels-of-evidence.
3. 黄海茵, 杨佩兰, 张誉清, 等. 单病例随机对照试验在中医药研究中的可行性与潜在价值. 上海中医药杂志, 2012, 46(8): 3-8.
4. 李宣霖, 余学庆, 谢洋, 等. 中国大陆中文期刊发表的中医药单病例随机对照试验的报告质量评价与思考. 中医杂志, 2020, 61(15): 1325-1329.
5. 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.
6. 刘志刚, 柴程芝, 朱欣佚, 等. 葛根汤治疗原发性痛经的多基线单病例随机对照试验. 中华中医药杂志, 2015, 30(7): 2473-2476.
7. Tate R, Perdices M. Single-case experimental designs for clinical research and neurorehabilitation settings: planning, conduct, analysis and reporting. New York: Routledge, 2019.
8. Vohra S, Shamseer L, Sampson M, et al. CONSORT extension for reporting N-of-1 trials (CENT) 2015 Statement. J Clin Epidemiol, 2016, 76: 9-17.
9. 朱文慧, 孟庆刚. 单病例随机对照试验的周期设计在中医药临床疗效评价中的应用研究. 中华中医药学刊, 2018, 36(10): 2509-2512.
10. Kravitz RL, Duan N, Braslow J. Evidence-based medicine, heterogeneity of treatment effects, and the trouble with averages. Milbank Q, 2004, 82(4): 661-687.
11. 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.
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. 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.
14. 王洁, 黄海茵, 杨佩兰, 等. 个体化方治疗稳定期支气管扩张症的单病例随机对照临床研究. 上海中医药杂志, 2016, 50(3): 39-43.
15. Zi S, Huang H, Yang P, et al. Evaluating the effects of heat-clearing traditional Chinese medicine in stable bronchiectasis by a series of N-of-1 trials. Evid Based Complement Alternat Med, 2022, 2022: 6690638.
16. 陈新林, 陈丽霞, 黄海茵, 等. 系列N-of-1试验定量数据混合效应模型的模拟研究. 中国循证医学杂志, 2021, 21(6): 689-695.
17. 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.
18. Ruiz FJ, Luciano C, Flórez CL, et al. A multiple-baseline evaluation of acceptance and commitment therapy focused on repetitive negative thinking for comorbid generalized anxiety disorder and depression. Front Psychol, 2020, 11: 356.
19. Watter K, Copley A, Finch E. Strategy-based reading comprehension therapy during early acquired brain injury rehabilitation: preliminary results. Disabil Rehabil, 2020: 1-17.
20. Christ TJ. Experimental control and threats to internal validity of concurrent and nonconcurrent multiple baseline designs. Psychology Schools, 2007, 44(5): 451-459.
21. Lane JD, Gast DL. Visual analysis in single case experimental design studies: brief review and guidelines. Neuropsychol Rehabil, 2014, 24(3-4): 445-463.
22. Kazdin AE. Single-case research designs in clinical child psychiatry. J Am Acad Child Psychiatry, 1983, 22(5): 423-432.
23. Bulté I, Onghena P. Randomization tests for multiple-baseline designs: an extension of the SCRT-R package. Behav Res Methods, 2009, 41(2): 477-485.
24. Kazdin AE, Kopel SA. On resolving ambiguities of the multiple-baseline design: problems and recommendations. Behavior Therapy, 1975, 6(5): 601-608.
25. Dallery J, Cassidy RN, Raiff BR. Single-case experimental designs to evaluate novel technology-based health interventions. J Med Internet Res, 2013, 15(2): e22.
26. 孙塑伦, 翁维良, 杨龙会. 中医临床研究实施方案设计与优化. 北京: 中国中医药出版社, 2008.
27. Harris T, Nikes J. Herbal medicines used in the treatment of chronic insomnia and how they influence sleep patterns: a review. J Complement Med Alternat Healthcare, 2018, 6(1): 555680.
28. Bradbury J, Avila C, Grace S. Practice-based research in complementary medicine: could N-of-1 trials become the new gold standard. Healthcare (Basel), 2020, 8(1): 15.
29. 苏炳华. 新药临床试验统计分析新进展. 上海: 上海科学技术文献出版社, 2000.
30. 金丕焕, 邓伟. 临床试验. 上海: 复旦大学出版社, 2004.
31. 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.
32. 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.
33. Guyatt G, Sackett D, Adachi J, et al. A clinician's guide for conducting randomized trials in individual patients. CMAJ, 1988, 139(6): 497-503.
34. Hesam-Shariati N, Newton-John T, Singh AK, et al. Evaluation of the effectiveness of a novel brain-computer interface neuromodulative intervention to relieve neuropathic pain following spinal cord injury: protocol for a single-case experimental design with multiple baselines. JMIR Res Protoc, 2020, 9(9): e20979.
35. Parker RI, Vannest KJ, Davis JL, et al. Combining nonoverlap and trend for single-case research: Tau-U. Behav Ther, 2011, 42(2): 284-299.
36. Duan N, Kravitz RL, Schmid CH. Single-patient (n-of-1) trials: a pragmatic clinical decision methodology for patient-centered comparative effectiveness research. J Clin Epidemiol, 2013, 66(8 Suppl): S21-28.
37. Nikles J, Tate RL, Mitchell G, et al. Personalised treatments for acute whiplash injuries: a pilot study of nested N-of-1 trials in a multiple baseline single-case experimental design. Contemp Clin Trials Commun, 2019, 16: 100480.
38. Brossart DF, Laird VC, Armstrong TW, et al. Interpreting Kendall’s Tau and Tau-U for single-case experimental designs. Cogent Psychology, 2018, 5(1): 1-26.
39. Higgins JP, Whitehead A. Borrowing strength from external trials in a meta-analysis. Stat Med, 1996, 15(24): 2733-2749.

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