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Abstract：
OBJECTIVE: The fragility index (FI), which is the minimum number of changes in status from \"event\" to \"non-event\" resulting in a loss of statistical significance, serves as a significant supplementary indicator for clinical physicians in interpreting clinical trial results and aids in understanding the outcomes of randomized controlled trials (RCTs). In this systematic literature survey, we evaluated the FI for RCTs evaluating Chinese herbal medicine (CHM) for irritable bowel syndrome (IBS), and explored potential associations between study characteristics and the robustness of RCTs.
METHODS: A comprehensive search was conducted in four databases in Chinese and four databases in English from their inception to January 1, 2023. RCTs encompassed 1:1 ratio into two parallel arms and reported at least one binary outcome that demonstrated statistical significance were included. FI was calculated by the iterative reduction of a target outcome event in the treatment group and concomitant subtraction of a non-target event from that group, until positive significance (defined as P < 0.05 by Fisher\'s exact test) is lost. The lower the FI (minimum 1) of a trial outcome, the more fragile the positive result of the outcome was. Linear regression models were adopted to explore influence factors of the value of FI.
RESULTS: A total of 30 trials from 2 4118 potentially relevant citations were finally included. The median FI of total trials included was 1.5 (interquartile range [IQR], 1-5), and half of the trials (n = 15) had a FI equal to 1. In 12 trials (40%), the total number of participants lost to follow-up surpassed the respective FI. The study also identified that increased FI was significantly associated with no TCM syndrome differentiation for inclusion criteria of the patients, larger total sample size, low risk of bias, and larger numbers of events.
CONCLUSIONS: The majority of CHM IBS RCTs with positive results were found to be fragile. Ensuring adequate sample size, scientifically rigorous study design, proper control of confounding factors, and a quality control calibration for consistency of TCM diagnostic results among clinicians should be addressed to increase the robustness of the RCTs. We recommend reporting the FI as one of the components of sensitivity analysis in future RCTs to facilitate the assessment of the fragility of trials.
METHODS: A comprehensive search was conducted in four databases in Chinese and four databases in English from their inception to January 1, 2023. RCTs encompassed 1:1 ratio into two parallel arms and reported at least one binary outcome that demonstrated statistical significance were included. FI was calculated by the iterative reduction of a target outcome event in the treatment group and concomitant subtraction of a non-target event from that group, until positive significance (defined as P < 0.05 by Fisher\'s exact test) is lost. The lower the FI (minimum 1) of a trial outcome, the more fragile the positive result of the outcome was. Linear regression models were adopted to explore influence factors of the value of FI.
RESULTS: A total of 30 trials from 2 4118 potentially relevant citations were finally included. The median FI of total trials included was 1.5 (interquartile range [IQR], 1-5), and half of the trials (n = 15) had a FI equal to 1. In 12 trials (40%), the total number of participants lost to follow-up surpassed the respective FI. The study also identified that increased FI was significantly associated with no TCM syndrome differentiation for inclusion criteria of the patients, larger total sample size, low risk of bias, and larger numbers of events.
CONCLUSIONS: The majority of CHM IBS RCTs with positive results were found to be fragile. Ensuring adequate sample size, scientifically rigorous study design, proper control of confounding factors, and a quality control calibration for consistency of TCM diagnostic results among clinicians should be addressed to increase the robustness of the RCTs. We recommend reporting the FI as one of the components of sensitivity analysis in future RCTs to facilitate the assessment of the fragility of trials.
摘要：
目标：脆弱性指数(FI)，即从“事件”到“非事件”的状态变化导致统计显著性丧失的最小次数，作为临床医师解释临床试验结果的重要补充指标,并有助于理解随机对照试验(RCTs)的结果.在这个系统的文献调查中，我们评估了评价中药（CHM）对肠易激综合征（IBS），并探讨了研究特征与随机对照试验的稳健性之间的潜在关联。
方法：从成立到2023年1月1日，在四个中文数据库和四个英文数据库中进行了全面搜索。RCTs将1:1的比例纳入两个平行的组,并且报道了至少一个显示统计学显著性的二元结果。FI是通过在治疗组中反复减少目标结果事件并同时从该组中减去非目标事件来计算的。直至失去正显著性(Fisher精确检验定义为P<0.05)。试验结果的FI越低(最小1)，结果的积极结果越脆弱。采用线性回归模型探讨FI值的影响因素。
结果：最终纳入了24118篇潜在相关引文中的30项试验。纳入的全部试验的中位FI为1.5(四分位数间距[IQR]，1-5),一半的试验（n=15）的FI等于1。在12项试验中（40%），失去随访的参与者总数超过了各自的FI.该研究还发现，患者的纳入标准与无中医辨证显著相关，总样本量更大，低偏见风险，和更多的事件。
结论：发现大多数结果阳性的CHMIBS随机对照试验是脆弱的。确保足够的样本量，科学严谨的学习设计，适当控制混杂因素，应针对临床医生之间中医诊断结果的一致性进行质量控制校准，以提高随机对照试验的稳健性。我们建议在未来的随机对照试验中报告FI作为敏感性分析的组成部分之一，以促进对试验脆弱性的评估。
方法：从成立到2023年1月1日，在四个中文数据库和四个英文数据库中进行了全面搜索。RCTs将1:1的比例纳入两个平行的组,并且报道了至少一个显示统计学显著性的二元结果。FI是通过在治疗组中反复减少目标结果事件并同时从该组中减去非目标事件来计算的。直至失去正显著性(Fisher精确检验定义为P<0.05)。试验结果的FI越低(最小1)，结果的积极结果越脆弱。采用线性回归模型探讨FI值的影响因素。
结果：最终纳入了24118篇潜在相关引文中的30项试验。纳入的全部试验的中位FI为1.5(四分位数间距[IQR]，1-5),一半的试验（n=15）的FI等于1。在12项试验中（40%），失去随访的参与者总数超过了各自的FI.该研究还发现，患者的纳入标准与无中医辨证显著相关，总样本量更大，低偏见风险，和更多的事件。
结论：发现大多数结果阳性的CHMIBS随机对照试验是脆弱的。确保足够的样本量，科学严谨的学习设计，适当控制混杂因素，应针对临床医生之间中医诊断结果的一致性进行质量控制校准，以提高随机对照试验的稳健性。我们建议在未来的随机对照试验中报告FI作为敏感性分析的组成部分之一，以促进对试验脆弱性的评估。
