Application of the Reverse Fragility Index to Statistically Nonsignificant Randomized Clinical Trial Results

Khan, Muhammad Shahzeb; Fonarow, Gregg C.; Friede, Tim; Lateef, Noman; Khan, Safi U.; Anker, Stefan D.; Harrell, Frank E.; Butler, Javed

doi:10.1001/jamanetworkopen.2020.12469

Cited by 66 publications

(69 citation statements)

References 33 publications

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“…Similar studies examining the FI/RFI in broad research areas are common in the literature. 26 The protocol of the study was published at the Center for Open Science https:// osf. io/ mnx2c/.…”

Section: Research Question and Search Strategymentioning

confidence: 99%

“…At the moment, there is no recognised cut-off for categorising either the FI or the RFI. 26 For the current analyses, 2×2 tables were created in Microsoft Excel and the Fischer's exact test was used to calculate and verify the FIs and RFIs of the included trials. For one trial, 31 32 the reported sample and events in each group were used to calculate the FI, and for another, 33 the incidence and the total number of participants allocated in each group were applied in the FI calculations.…”

Section: Calculation Of the Fi And Rfimentioning

confidence: 99%

“…[22][23][24][25] Today, clinical research continues to emphasise the P threshold of 0.05 when interpreting RCT results. 26 For this, it is additionally important to evaluate the robustness of RCTs with MD interventions and attain an additional measure of the quality of MD RCTs. Two indexes have been proposed for the evaluation of an RCTs' robustness, 27 namely the fragility index (FI) and the reverse fragility index (RFI), for trials with significant or nonsignificant findings, respectively.…”

Section: Introductionmentioning

confidence: 99%

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How fragile are Mediterranean diet interventions? A research-on-research study of randomised controlled trials

Grammatikopoulou

Nigdelis

Theodoridis

et al. 2021

BMJNPH

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IntroductionThe Mediterranean diet (MD) is a traditional regional dietary pattern and a healthy diet recommended for the primary and secondary prevention of various diseases and health conditions. Results from the higher level of primary evidence, namely randomised controlled trials (RCTs), are often used to produce dietary recommendations; however, the robustness of RCTs with MD interventions is unknown.MethodsA systematic search was conducted and all MD RCTs with dichotomous primary outcomes were extracted from PubMed. The fragility (FI) and the reverse fragility index (RFI) were calculated for the trials with significant and non-significant comparisons, respectively.ResultsOut of 27 RCTs of parallel design, the majority failed to present a significant primary outcome, exhibiting an FI equal to 0. The median FI of the significant comparisons was 5, ranging between 1 and 39. More than half of the comparisons had an FI <5, indicating that the addition of 1–4 events to the treatment arm eliminated the statistical significance. For the comparisons with an FI=0, the RFI ranged between 1 and 29 (Median RFI: 7). When the included RCTs were stratified according to masking, the use of a composite primary endpoint, sample size, outcome category, or dietary adherence assessment method, no differences were exhibited in the FI and RFI between groups, except for the RFI among different compliance assessment methods.ConclusionsIn essence, the present study shows that even in the top tiers of evidence hierarchy, research on the MD may lack robustness, setting concerns for the formulation of nutrition recommendations.

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Section: Research Question and Search Strategymentioning

confidence: 99%

Section: Calculation Of the Fi And Rfimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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How fragile are Mediterranean diet interventions? A research-on-research study of randomised controlled trials

Grammatikopoulou

Nigdelis

Theodoridis

et al. 2021

BMJNPH

View full text Add to dashboard Cite

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“…RFI was calculated according to the method described in a recent publication. 8 The RFI was calculated by subtracting events from the group with a lower number of events while simultaneously adding nonevents to the same group to keep the number of participants constant until the Fisher's exact test two-sided p value became less than 0.05. 8 A similar method was used to calculate RFI at a p value of 0.01.…”

Section: Aterials and M Ethodsmentioning

confidence: 99%

“…To check the robustness of a statistically nonsignificant trial, reverse fragility index (RFI) has been used. 8 RFI provides a measure of robustness in the neutrality of results when assessed from a clinical perspective.…”

Section: Introductionmentioning

confidence: 99%

How Robust are the Evidences that Formulate Surviving Sepsis Guidelines? An Analysis of Fragility and Reverse Fragility of Randomized Controlled Trials that were Referred in these Guidelines

Choupoo

Das

Saikia

et al. 2021

Indian Journal of Critical Care Medicine

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A bstract Objectives “Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016” provides guidelines in regard to prompt management and resuscitation of sepsis or septic shock. The study is aimed to assess the robustness of randomized controlled trials (RCTs) that formulate these guidelines in terms of fragility index and reverse fragility index. Method RCTs that contributed to these guidelines having parallel two-group design, 1:1 allocation ratio, and at least one dichotomous outcome were included in the study. The median fragility index was calculated for RCTs with significant statistical outcomes, whereas the median reverse fragility index was calculated for RCTs with nonsignificant statistical results. Results Hundred RCTs that met the inclusion criteria were analyzed. The median fragility index was 5.5 [95% confidence interval (CI) 1–30] and median reverse fragility index was 13 (95% CI 12.07–16.8) at a p value of 0.05. The median reverse fragility index was 16 (95% CI 10–26) at a p value of 0.01. Most of the RCTs included in this analysis were of good quality, having a median Jadad score of 6. Conclusion This analysis found that the surviving sepsis guidelines were based on highly robust RCTs with statistically insignificant results and on some moderately robust RCTs with statistically significant results. RCTs with statistically insignificant results were more robust than RCTs with statistically significant results in regard to these guidelines. Highlights The study assessed the robustness of randomized controlled trials (RCTs) that were used to formulate surviving sepsis guidelines. Most RCTs showed statistically nonsignificant results. RCTs with statistically significant results were moderately fragile whereas RCTs with nonsignificant results were more robust. How to cite this article Choupoo NS, Das SK, Saikia P, Dey S, Ray S. How Robust are the Evidences that Formulate Surviving Sepsis Guidelines? An Analysis of Fragility and Reverse Fragility of Randomized Controlled Trials that were Referred in these Guidelines. Indian J Crit Care Med 2021;25(7):773–779.

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Robustness of outcomes in trials evaluating sodium–glucose co‐transporter 2 inhibitors for heart failure

et al. 2022

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Aims Recent trials have evaluated sodium-glucose co-transporter 2 inhibitors in patients with heart failure (HF). We sought to assess the robustness of findings from these trials using the fragility index (FI). Methods and resultsFragility index is defined as the minimum number of patients that must be moved from the 'non-event' to the 'event' group to turn a statistically significant result to non-significant. In addition to FI, fragility quotient [(FQ); FI divided by the sample size] was calculated to assess the proportion of events that must be moved to change the significance. For statistically non-significant outcomes, reverse fragility index (RFI) and reverse fragility quotient (RFQ) were calculated. Robustness of findings after pooling data from all three trials was also assessed. A robust reduction in first HF hospitalization or cardiovascular mortality was seen with dapagliflozin (FI = 62 and FQ = 0.013), empagliflozin (FI = 50 and FQ = 0.013), and sotagliflozin (FI = 60 and FQ = 0.049). Dapagliflozin nominally improved all-cause and cardiovascular mortality, with modest FI (n = 8 and 5) and FQ (0.002 and 0.001). Empagliflozin and sotagliflozin did not demonstrate statistically significant reductions in all-cause mortality, with modest RFI (empagliflozin: RFI = 26 and RFQ = 0.007; sotagliflozin: RFI = 6 and RFQ = 0.005). A similar trend was seen with cardiovascular mortality (empagliflozin: RFI = 24 and RFQ = 0.006; sotagliflozin: RFI = 7 and RFQ = 0.006). Upon meta-analysis, the result for first HF hospitalization or cardiovascular mortality was robust (FI = 95 and FQ = 0.010). The reductions in all-cause (FI = 12 and FQ = 0.001) and cardiovascular mortality (FI = 9 and FQ = 0.001), while statistically significant, were fragile. Conclusion Improvement in the composite outcome of first HF hospitalization or cardiovascular death was highly concordant and robust across sodium-glucose co-transporter 2 inhibitor trials. In contrast, secondary endpoints of all-cause and cardiovascular mortality were statistically fragile, underscoring the need to power trials for mortality to fully understand the benefit of therapies on fatal events.

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Application of the Reverse Fragility Index to Statistically Nonsignificant Randomized Clinical Trial Results

Cited by 66 publications

References 33 publications

How fragile are Mediterranean diet interventions? A research-on-research study of randomised controlled trials

How fragile are Mediterranean diet interventions? A research-on-research study of randomised controlled trials

How Robust are the Evidences that Formulate Surviving Sepsis Guidelines? An Analysis of Fragility and Reverse Fragility of Randomized Controlled Trials that were Referred in these Guidelines

Robustness of outcomes in trials evaluating sodium–glucose co‐transporter 2 inhibitors for heart failure

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