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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4.	李宣霖, 余學慶, 謝洋, 等. 中國大陸中文期刊發表的中醫藥單病例隨機對照試驗的報告質量評價與思考. 中醫雜志, 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.	劉志剛, 柴程芝, 朱欣佚, 等. 葛根湯治療原發性痛經的多基線單病例隨機對照試驗. 中華中醫藥雜志, 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, 孟慶剛. 單病例隨機對照試驗的周期設計在中醫藥臨床療效評價中的應用研究. 中華中醫藥學刊, 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.	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.
14.	王潔, 黃海茵, 楊佩蘭, 等. 個體化方治療穩定期支氣管擴張癥的單病例隨機對照臨床研究. 上海中醫藥雜志, 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.	陳新林, 陳麗霞, 黃海茵, 等. 系列N-of-1試驗定量數據混合效應模型的模擬研究. 中國循證醫學雜志, 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.	孫塑倫, 翁維良, 楊龍會. 中醫臨床研究實施方案設計與優化. 北京: 中國中醫藥出版社, 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.	蘇炳華. 新藥臨床試驗統計分析新進展. 上海: 上海科學技術文獻出版社, 2000.
30.	金丕煥, 鄧偉. 臨床試驗. 上海: 復旦大學出版社, 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, 田貴華. 單病例隨機對照試驗: 理論與實踐(第1版). 北京: 人民衛生出版社, 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. 黃海茵, 楊佩蘭, 張譽清, 等. 單病例隨機對照試驗在中醫藥研究中的可行性與潛在價值. 上海中醫藥雜志, 2012, 46(8): 3-8.
4. 李宣霖, 余學慶, 謝洋, 等. 中國大陸中文期刊發表的中醫藥單病例隨機對照試驗的報告質量評價與思考. 中醫雜志, 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. 劉志剛, 柴程芝, 朱欣佚, 等. 葛根湯治療原發性痛經的多基線單病例隨機對照試驗. 中華中醫藥雜志, 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, 孟慶剛. 單病例隨機對照試驗的周期設計在中醫藥臨床療效評價中的應用研究. 中華中醫藥學刊, 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. 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.
14. 王潔, 黃海茵, 楊佩蘭, 等. 個體化方治療穩定期支氣管擴張癥的單病例隨機對照臨床研究. 上海中醫藥雜志, 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. 陳新林, 陳麗霞, 黃海茵, 等. 系列N-of-1試驗定量數據混合效應模型的模擬研究. 中國循證醫學雜志, 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. 孫塑倫, 翁維良, 楊龍會. 中醫臨床研究實施方案設計與優化. 北京: 中國中醫藥出版社, 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. 蘇炳華. 新藥臨床試驗統計分析新進展. 上海: 上海科學技術文獻出版社, 2000.
30. 金丕煥, 鄧偉. 臨床試驗. 上海: 復旦大學出版社, 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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