This paper mainly introduces the design, advantages, disadvantages and its application of single case of randomized controlled trials (N-of-1 trials), and also introduces the commonly used data analysis methods of N-of-1 trials including nonparametric test and parameter test methods (t-test, paired t-test, analysis of variance), mixed-effects model, and meta-analysis. N-of-1 trials are suitable for individualized treatment, and could be expected to be widely used in the research of modern medicine and traditional Chinese medicine.
The CONSORT extension for reporting N-of-1 trials (CENT 2015) is designed to guide N-of-1 and series N-of-1 reporting. This study introduced the terminology (period, block or pair, sequence, washout period, and run-in period), the scope, the checklist and the diagram of CENT 2015 and demonstrated the complete guide frame for N-of-1, and thus to provide reference for relevant studies and improve the reporting quality of N-of-1 in China.
N-of-1 trial is globally making rapid development as a patient-oriented individualized method with the development and improvement of methodology in clinical trial. The paper described the origin and development of N-of-1trial, so as to help improve awareness among medical researchers and clinicians, and improve the clinical medical quality and level of clinical diagnosis and treatment.
The study appeared the comparison between CONSORT and CENT, and promoted the combination with GRADE and N-of-1 trial. Our objective is to further develop the method of N-of-1 trial and to widely use it in clinical researches of some diseases.
An N-of-1 trial was conducted in a single patient. Statistical analysis is one of the most important parts of N-of-1 trials. The methods of statistical analysis for N-of-1 trials were reported in some reviews. However, there was still a lack of comparative analysis of these methods. In this study, we introduced the characteristics of statistical methods commonly used as well as some statistical problems which should be paid attention in N-of-1 trials. It is useful to provide some reference for statistical methods in order to high quality N-of-1 trials.
Bayesian N-of-1 trials is increasingly popular in recent years. This study introduced the principle, statistical requirements, application status, advantages and disadvantages of Bayesian N-of-1 trials. Although the application of Bayesian N-of-1 trials is still limited in small scale and some problems remain to be solved, but it can provide more posterior information, and it can be the most important type of N-of 1 trial in future.
With increasing amount of attention being paid to single case randomized controlled trial (N-of-1 trials), sample size estimation has become an important issue for clinical researchers. This paper mainly introduces the model and hypothesis of N-of-1 trials. Based on the hypothetical model, sample size estimation methods of fixed model and random model are proposed. The premises of the model application, formulas and examples are then given. It is expected in case of conduction N-of-1 trials, the correct methods are used to estimate sample size and improve the research quality of N-of-1 trials.
背景 单病例随机对照试验是评价中医药干预措施有效性和安全性较为理想和适宜的方法之一。目前已有一定数量的中医药单病例随机对照试验发表。然而，由于缺乏相应的报告规范，这些试验的报告质量普遍较差。鉴于中医药临床研究的独特性，工作组制定了单病例随机对照试验报告标准（CONSORT extension for reporting N-of-1 trials，CENT 2015）的中医药扩展版（中医药 CENT），以帮助研究者报告中医药单病例试验。 方法 我们在提高健康研究质量和透明度协作网（Enhancing the QUAlity and Transparency Of health Research，EQUATOR）上注册了中医药 CENT。中医药单病例随机对照试验报告规范的制定是一个综合过程，包括收集初始报告条目，与 17 名专家小组成员进行两轮科学的德尔菲共识调查，修订和形成最终报告清单。 结果 清单共包括 6 个领域的 25 项条目，其中的 8 项对 CENT 2015 清单条目进行了扩展和详细说明。中医药 CENT 清单充分考虑了中医药的诊疗特点，并详细阐释了中医药单病例随机对照试验中辨证的概念和不同的中医药干预措施。 结论 中医药 CENT 是中医临床研究的一个实用工具，可用于评价中医药单病例对照试验报告的完整性，并可指导中医药单病例对照试验的设计、实施和报告，期望此报告规范可切实提高中医药单病例试验的全面性和透明度。
N-of-1 trials are prospective clinical randomized cross-over controlled trials with multiple rounds of trial phase alternation designed with regard to a single patient. N-of-1 trials can provide clinical decision-makers with high-level evidence of the comparison of effect of intervention measures. Recently, an international team composed of many scholars published a SPIRIT extension for N-of-1 trials list (SPENT 2019) on the BMJ, with the purposes of clarifying the content design and improving the integrity and transparency of N-of-1 trial protocols. This article showed a detailed interpretation of the 14 main extension sub-items of the SPENT 2019 list with specific cases, aiming to further standardize the publication of domestic N-of-1 trials.
ObjectiveA 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). MethodsA 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. ResultsA 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. ConclusionThe 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.