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.
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.
The method of evaluating clinical efficacy of traditional Chinese medicine is one of the hotspots in the field of traditional Chinese medicine in recent years. How to dynamically evaluate individual efficacy is one of the key scientific problems to explain the clinical efficacy of traditional Chinese medicine. At present, there are no recognized methods of evaluating individual efficacy of traditional Chinese medicine. In this study, we provided a method of dynamically evaluating individual efficacy of traditional Chinese medicine based on Bayesian N-of-1 trials after analyzing the current status of researches on methods of evaluating individual efficacy of traditional Chinese medicine. This method has the advantages of both N-of-1 trials and Bayesian multilevel models. It is feasible to evaluate individual efficacy of traditional Chinese medicine from the perspective of the design and analysis method. This study can provide an important basis for enriching and improving the methodology of evaluating individual efficacy of traditional Chinese medicine.
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.
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.
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.
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.
N-of-1 trial design offers a methodologically sound approach to determining optimum treatment for an individual patient and solves some limitations of randomized controlled trials. This design could offer an efficient method of reaching a personal treatment regime tailored to suit individual needs and preferences. The paper introduces practical application, objects and the implementation process of N-of-1 trial, to explore its design points and implementation.
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.