Fragility Quotient Research Articles

Fragility index and fragility quotient in randomized clinical trials.

Fragility index and fragility quotient in randomized clinical trials.

The Fragility of Tourniquet Use in Total Knee Arthroplasty: A Systematic Review of Randomized Controlled Trials

BackgroundPhysicians utilize P-values to interpret clinical trial data and guide patient-care decisions. Fragility analysis assesses the stability of statistical findings in relation to outcome event reversals. This study assessed the statistical fragility of recent randomized controlled trials (RCTs) investigating tourniquet use in total knee arthroplasty (TKA). MethodsWe queried PubMed, EMBASE, and MEDLINE for RCTs comparing outcomes in TKA based on tourniquet use. Fragility index (FI) and reverse fragility index (reverse FI) were calculated – for significant and nonsignificant outcomes, respectively – as the number of outcome reversals required to change statistical significance. The fragility quotient (FQ) was calculated by dividing the FI or reverse FI by the sample size. Median overall FI and FQ were calculated for all included outcomes, and sub-analyses were performed by reported significance. The literature search yielded 23 studies reporting 91 total dichotomous outcomes. ResultsOverall median FI was 4 with an interquartile range (IQR) of 3 to 6. Overall median FQ was 0.0476 (IQR 0.0291 to 0.0867). A total of 11 outcomes were statistically significant with a median FI and FQ of 2 (IQR 1.5 to 5) and 0.0200 (IQR 0.0148 to 0.0484), respectively. There were 80 outcomes that were nonsignificant with a median reverse FI of 4 (IQR 3 to 6). Loss to follow-up was greater than the median FI in 17.6% of outcomes. ConclusionAltering a small number of outcomes is often sufficient to reverse findings in RCTs evaluating tourniquet use in TKA. We recommend including fragility analyses to increase reliability in the interpretation of study conclusions.

The fragility of statistical significance in distal femur fractures: systematic review of randomized controlled trials.

The purpose of this study was to apply both the fragility index (FI) and fragility quotient (FQ) to evaluate the degree of statistical fragility in the distal femur fracture (DFF) literature. We hypothesized that the dichotomous outcomes within the DFF literature are statistically fragile. Using preferred reporting items for systematic reviews and meta-analyses, we performed a PubMed search for distal femur fractures clinical trials from 2000 to 2022 reporting dichotomous outcomes. The FI of each outcome was calculated through the reversal of a single outcome event until significance was reversed. The FQ was calculated by dividing each fragility index by study sample size. The interquartile range (IQR) was also calculated for the FI and FQ. Of the 4258 articles screened, 92 met the search criteria, with eleven RCTs included for analysis. Ninety eight outcome events with 25 significant (P < 0.05) outcomes and 73 nonsignificant (P > 0.05) outcomes were identified. The overall FI and FQ for all 98 outcomes were 5 (IQR 4-6) and 0.130 (IQR 0.087-0.174), respectively. Three studies (33.3%) reported loss to follow (LTF) greater than 5. The randomized controlled trials in the peer-reviewed distal femur fracture literature may not be as robust as previously thought, as incorporating statistical analyses solely on a P value threshold is misleading. Standardized reporting of the P value, FI and FQ can help the clinician reliably draw conclusions based on the fragility of outcome measures.

Empirical assessment of fragility index based on a large database of clinical studies in the Cochrane Library.

The fragility index (FI) and fragility quotient (FQ) are increasingly used measures for assessing the robustness of clinical studies with binary outcomes in terms of statistical significance. The FI is the minimum number of event status modifications that can alter a study result's statistical significance (or nonsignificance), and the FQ is calculated as the FI divided by the study's total sample size. The literature has no widely recognized criteria for interpreting the fragility measures' magnitudes. This article aims to provide an empirical assessment for the FI and FQ based on a large database of clinical studies in the Cochrane Library. We explored the overall empirical distributions of the FI and FQ based on five common methods (Fisher's exact test, χ2 test, risk difference, odds ratio, and relative risk) for determining statistical significance of binary outcomes in clinical research. We also considered three different scenarios for the FI calculation and evaluated the relationship between pvalues and FIs or FQs using Spearman's . Finally, we summarized empirical thresholds based on the overall distributions of the FI and FQ to facilitate their interpretations in future research. For about 20% of studies with significant results, the statistical significance was changed after modifying the event status of only one participant. Studies with significant results were considered slightly fragile if the significance hinged on the statuses of about five events. Studies were extremely fragile if FI 1 or FQ 0.01. The FIs were strongly correlated with pvalues for significant studies, while Spearman's varied according to the total sample sizes of studies. The statistical significance of clinical studies could be changed after modifying a few events' statuses. Many studies' findings are fairly fragile. The distributions of the FI and FQ provide insights for appraising the robustness of evidence in clinical decision-making.

Robustness of meta-analysis results in Cochrane systematic reviews: A case for acupuncture trials

BackgroundFragility index (FI) refers to the smallest value that change statistical significance of study results. Meta-analyses of Cochrane systematic reviews are considered as the best evidence for stake holders because they enable effect size estimation that cannot be derived by individual studies, particularly in the field of complementary and integrative medicine (CIM). Thus, this study aimed to evaluate robustness of meta-analysis in Cochrane systematic reviews of acupuncture, one of the most used CIM treatment, using FI of meta-analysis. MethodsMeta-analyses of acupuncture Cochrane systematic reviews with binary benefit outcome measures were searched in PubMed, Embase, and CENTRAL and subject to analysis. Randomized clinical trials (RCTs) or quasi RCTs adopted penetrating needles as treatment and compared with controls such as sham acupuncture, usual care, and active control were included. FI of meta-analyses was calculated in web (https://clinicalepidemio.fr/fragility_ma/); and fragility quotient (FQ) was calculated by dividing FI by total sample size of meta-analysis. ResultsOf 248 retrieved studies, 12 Cochrane systematic reviews with 48 meta-analyses were analyzed. The median FI for statistically significant and non-significant meta-analyses was 7 [interquartile range: 3 - 12] and 6 [interquartile range: 3 - 10]. FQ was similar irrespective of statistical significance. Among controls, meta-analyses adopting sham acupuncture displayed the widest range of FI and FQ. ConclusionRobustness of meta-analyses in Cochrane systematic reviews for acupuncture was similar irrespective of statistical significance. Impact of control intervention cannot be determined in this study. As FI enables intuitive interpretation, applications for CIM field can be useful.

The Statistical Fragility of Platelet-Rich Plasma as Treatment for Achilles Tendinopathy: A Systematic Review and Meta-Analysis

Category: Basic Sciences/Biologics; Hindfoot; Sports Introduction/Purpose: Randomized controlled trial (RCT) outcomes reaching statistical significance, frequently determined by p&lt;0.05, are often used to guide decision-making. Noted lack of reproducibility of some RCTs has brought special attention to the limitations of this approach. In this meta-analysis, we assessed the robustness of RCTs evaluating platelet-rich plasma (PRP) for the treatment of Achilles tendinopathy (AT) by using fragility indices. Methods: RCTs comparing outcomes after PRP injection versus alternative treatment in patients with chronic AT were evaluated. Representative datasets were generated for each reported continuous outcome event using summary statistics. The fragility index (FI) and continuous FI (CFI) were determined for dichotomous and continuous outcomes, respectively, by manipulating each dataset until reversal of significance (a=0.05) was achieved. The corresponding fragility quotient (FQ) and continuous FQ (CFQ) were calculated by dividing FI/CFI by sample size. Results: Of 432 studies screened, 8 studies (52 outcome events) were included in the present analysis. The 12 dichotomous outcomes had a median FI of 4.5 (FQ: 0.111), and the 40 continuous outcomes had a median CFI of 5 (CFQ: 0.154). All 52 outcome events included lost-to-follow-up data, and 12 (23.1%) indicated a greater number of patients lost to follow-up than the FI or CFI. Conclusion: Our findings suggest that RCTs evaluating PRP for AT therapy lack statistical robustness, since changing only a small number of events may alter outcome significance. Given the importance of RCTs in clinical decision-making, fragility indices should be reported alongside p-values to indicate the strength of statistical findings. It is paramount that future RCTs be designed with consideration of sample size from both recruitment and retention perspectives to maximize protocol robustness and determine the true therapeutic effect of PRP in AT.

Evaluating the Fragility of Long-Term Outcomes for Neoadjuvant versus Adjuvant Chemotherapy Prescription in Early Breast Cancer: Pooled Data from 10 Randomised Clinical Trials.

IntroductionRandomised clinical trials (RCTs) report similar outcomes following neoadjuvant (NAC) and adjuvant chemotherapy (AC) in breast cancer. “Fragility Indices” (FI) test significance reversal reported in RCTs.AimTo evaluate the FI of findings from RCTs assessing outcomes of NAC and AC.MethodsA systematic review was performed as per PRISMA guidelines. RCTs of interest were identified and data pooled. Fisher’s exact test was used to calculate FI for reversal of statistical significance for dichotomous outcomes. “Fragility Quotient” (FQ) was calculated by division of the calculated FI by the sample size.ResultsTen RCTs including 4928 patients. Mean follow-up was 8.2 years. For breast conservation surgery (BCS), the FI was 500 and FQ was 0.10781. For local recurrence (LR), the FI was 42 and FQ was 0.00852. FI and FQ varied for LR at 0–4 years (FI: 9), 5–9 years (FI: 2), 10–14 years (FI: 4), and 15+ years (FI: 3). Regarding distant recurrence (DR), the FI was 13 and FQ was 0.00264. FI and FQ trended downwards over time: 0–4 years (FI: 56), 5–9 years (FI: 18), 10–14 years (FI: 4), and 15+ years (FI: 4). For breast-cancer-specific mortality (BCSM), the overall FI was 51 and FQ was 0.01035. FI and FQ varied for BCSM at 0–4 years (FI: 5), 5–9 years (FI: 19), 10–14 years (FI: 8), and 15+ years (FI: 5). For overall survival (OS), the FI was 17 and FQ was 0.00345. FI and FQ were calculated with respect to OS at 0–4 years (FI: 19), 5–9 years (FI: 17), 10–14 years (FI: 19), and 15+ years (FI: 1).ConclusionFIs comparing survival following NAC and AC were of moderate-to-high fragility, indicating weak statistical significance. BCS eligibility following NAC was of low fragility, ratifying the oncological and surgical safety of NAC versus AC.Level of EvidenceSystematic Review of Level I Randomised Control Trials.

The Statistical Fragility of Platelet-Rich Plasma as Treatment for Plantar Fasciitis: A Systematic Review and Meta-Analysis

Category: Basic Sciences/Biologics; Hindfoot; Sports Introduction/Purpose: Plantar fasciitis (PF) is estimated to account for 8% of all running-related injuries, affecting nearly 1 out of every 10 adults aged 50 and older. Recent randomized controlled trials (RCTs) suggest platelet-rich plasma (PRP) injection may be an effective non-operative treatment option for chronic, refractory PF. However, RCTs in general have come under scrutiny due to a frequent lack of reproducibility, which is largely attributable to shortcomings of the commonly used p&lt;0.05 threshold for significance. Fragility indices may be an appropriate tool to gauge the clinical importance of RCT findings in these situations. In this study, we utilize the continuous fragility index (CFI) and continuous fragility quotient (CFQ) to determine the statistical robustness of data from RCTs evaluating PRP for PF. Methods: RCTs comparing outcomes after PRP injection versus other conservative treatment in chronic PF patients were evaluated. Representative datasets were generated for each reported outcome event using summary statistics. The CFI was determined by manipulating each dataset until reversal of significance (a=0.05) was achieved. The corresponding CFQ was calculated by dividing the CFI by the sample size. Results: Of 259 studies screened, 27 studies (59 outcome events) were included in this analysis. The median CFI for all events was 9 (CFQ=0.177), suggesting that altering the treatment of only 9 patients (or 17.7 out of 100) would be sufficient to reverse trial significance (Table 1). Of the 36 outcome events reporting lost to follow-up data, 10 events (27.8%) lost &gt;=9 patients. Outcome events that were originally reported as significant (p&lt;0.05) were considerably more fragile (CFI=5; CFQ=0.122) than events that were reported as nonsignificant (CFI=10; CFQ=0.179). Conclusion: Fragility indices are a useful adjunct to p-values and provide an assessment of how easily statistical significance can be overturned. While there is some preliminary evidence supporting the clinical efficacy of PRP, our fragility analysis suggests that RCT findings may be underpowered in some cases. Over 27% of outcome events may have experienced a reversal of significance if the studies had simply maintained follow-up. Given the importance of RCTs in clinical decision-making, fragility indices should be reported alongside p-values to indicate the strength of statistical findings.

The Statistical Fragility of Operative vs Nonoperative Management for Achilles Tendon Rupture: A Systematic Review of Comparative Studies.

Background:The statistical significance of randomized controlled trials (RCTs) and comparative studies is often conveyed utilizing the P value. However, P values are an imperfect measure and may be vulnerable to a small number of outcome reversals to alter statistical significance. The interpretation of the statistical strength of these studies may be aided by the inclusion of a Fragility Index (FI) and Fragility Quotient (FQ). This study examines the statistical stability of studies comparing operative vs nonoperative management for Achilles tendon rupture.Methods:A systematic search was performed of 10 orthopaedic journals between 2000 and 2021 for comparative studies focusing on management of Achilles tendon rupture reporting dichotomous outcome measures. FI for each outcome was determined by the number of event reversals necessary to alter significance (P < .05). FQ was calculated by dividing the FI by the respective sample size. Additional subgroup analyses were performed.Results:Of 8020 studies screened, 1062 met initial search criteria with 17 comparative studies ultimately included for analysis, 10 of which were RCTs. A total of 40 outcomes were examined. Overall, the median FI was 2.5 (interquartile range [IQR] 2-4), the mean FI was 2.90 (±1.58), the median FQ was 0.032 (IQR 0.012-0.069), and the mean FQ was 0.049 (±0.062). The FI was less than the number of patients lost to follow-up for 78% of outcomes.Conclusion:Studies examining the efficacy of operative vs nonoperative management of Achilles tendon rupture may not be as statistically stable as previously thought. The average number of outcome reversals needed to alter the significance of a given study was 2.90. Future analyses may benefit from the inclusion of a fragility index and a fragility quotient in their statistical analyses.

The Fragility of Statistical Findings in Distal Radius Fractures: A Systematic Review of Randomized Controlled Trials

PurposeProbability analysis with reporting of P values is often used to determine the statistical significance of study findings in the orthopedic literature. The fragility index (FI) has been used to evaluate the robustness of a significant result. The purpose of this study was to determine the utility of applying a fragility analysis to randomized controlled trials (RCTs) evaluating distal radius fractures (DRFs). MethodsWe identified all dichotomous outcome data for randomized controlled trials of distal radius fractures (DRFs) published in 13 orthopedic journals from 2000 to 2020. The fragility index (FI) was determined by the number of event reversals required to change a P value from less than 0.05 to greater than 0.05, or vice-versa. The associated fragility quotient (FQ) was determined by dividing the FI by the sample size. The interquartile ranges (IQR) for the FI and FQ were calculated as the difference between the 25th and 75th percentiles for the overall study. ResultsOf the 7352 studies screened, 221 met the search criteria, with 34 randomized controlled trials evaluating distal radius fractures and 151 total outcome events included for analysis. The overall FI was 9 (IQR 6.5–11) with an associated fragility quotient of 0.097 (IQR 0.060–0.140). However, a majority of outcomes (78.8%) were not significant. Fragility analysis of statistically significant outcomes had an FI of 4 (IQR 1–10). All of the studies reported lost to follow-up (LTF) data where 20.6% reported lost to follow-up of greater or equal to 9. ConclusionThe RCTs in distal radius fracture outcomes have comparable statistical robustness to literature in other orthopedic surgical specialties, are not as statistically stable as previously thought and should be interpreted with caution. We recommend that orthopedic literature report the FI and FQ along with the P values to help the reader draw reliable conclusions based on the fragility of outcome measures. Level of EvidenceLevel I

Statistical robustness of randomized controlled trials in high-impact journals has improved but was low across medical specialties

ObjectivesTo determine whether the statistical fragility of randomized controlled trials (RCTs) in high-impact journals has improved in the last decade and to perform an umbrella review of all published data on the Fragility Index (FI) across medical specialties. Study Design and SettingThe FI was calculated for all eligible RCTs published from 2014–2021 in the New England Journal of Medicine, The Lancet, the Journal of the American Medical Association, the British Medical Journal, and the Annals of Internal Medicine. Trials reporting dichotomous, statistically significant, superiority results were eligible. All previously published systematic reviews on the FI were included in the umbrella review and analyzed by medical (sub) specialty. ResultsOf 2,544 screened RCTs, 643 were eligible for the FI analysis. These had a median sample size of 625 (interquartile range [IQR]: 265–2,056), a median FI of 12 (IQR: 3–28), and a median Fragility Quotient of 0.015 (IQR: 0.004–0.045). This is an improvement compared with the median FI of 8 (IQR: 3–18) of RCTs published a decade earlier in the same five journals (P < 0.001). The umbrella review included 57 publications across 15 different medical specialties, with a total of between 10 and 692 RCTs for each specialty. The median FI ranged between two and four for all disciplines. ConclusionIn the last decade, the median statistical robustness of RCTs published in high-impact journals has improved, yet the unchanged lower bound of the interquartile range reveals that statistical significance in 25% of trials is still dependent on three or less events. The umbrella review revealed that statistical fragility is prevalent across all medical specialties. The FI is an easy-to-understand metric that can be used to supplement reported P values and help readers look beyond merely reaching statistical significance.

Side effects and treatment initiation barriers of sodium-glucose cotransporter 2 inhibitors in heart failure: a systematic review and meta-analysis.

Physicians are sometimes reluctant to initiate guideline-directed therapy in patients with heart failure and reduced ejection fraction (HFrEF) due to concerns of adverse events. We explored the risk of hypotension, volume depletion, and acute kidney injury (AKI) on sodium-glucose cotransporter 2 (SGLT2) inhibitors in HFrEF populations. We determined summary risk ratios (RRs) by conducting a meta-analysis on reported aforementioned adverse events on SGLT2 inhibitors from randomized controlled trials. We explored robustness of meta-analyses by computing fragility and/or reverse fragility index (FI or RFI) and its corresponding fragility quotient (FQ or RFQ) for each outcome. A total of 10 050 patients with HFrEF entered the final meta-analysis. Hypotension was reported in 4.5% (219/4836) on SGLT2 inhibitors and in 4.1% (202/4846) on placebo (RR 1.09, 95% confidence interval [CI] 0.91-1.31, p = 0.36). An RFI of 21 and RFQ of 0.002 suggest robust findings for hypotension. Volume depletion occurred in 9.4% (473/5019) on SGLT2 inhibitors and in 8.7% (438/5031) on placebo (RR 1.07, 95% CI 0.95-1.21, p = 0.25), respectively. RFI of 19 and RFQ of 0.001 suggest moderately robust findings for volume depletion. AKI was reported in fewer patients (1.9% [95/4888]) on SGLT2 inhibitors than on placebo (2.8% [140/4899]) providing lower incidence of AKI (RR 0.69, 95% CI 0.51-0.93, p = 0.02). FI of 14 and RFQ of 0.001 suggest moderately robust findings for AKI. Sodium-glucose cotransporter 2 inhibitor therapy is not associated with a clinically relevant risk of hypotension and volume depletion. Its use reduces the risk of AKI. This analysis supports current guideline recommendations on early use of SGLT2 inhibitors.

The Statistical Fragility of Platelet-Rich Plasma as Treatment for Chronic Noninsertional Achilles Tendinopathy: A Systematic Review and Meta-analysis.

Background:Randomized controlled trial (RCT) outcomes reaching statistical significance, frequently determined by P <.05, are often used to guide decision making. Noted lack of reproducibility of some RCTs has brought special attention to the limitations of this approach. In this meta-analysis, we assessed the robustness of RCTs evaluating platelet-rich plasma (PRP) for the treatment of chronic noninsertional Achilles tendinopathy (AT) by using fragility indices.Methods:The present study was a systematic review and meta-analysis of RCTs comparing outcomes after PRP injection vs alternative treatment in patients with AT. Representative data sets were generated for each reported continuous outcome event using summary statistics. Fragility indices refer to the minimal number of patients whose status would have to change from a nonevent to an event to turn a statistically significant result into a nonsignificant result, or vice versa. The fragility index (FI) and continuous FI (CFI) were determined for dichotomous and continuous outcomes, respectively, by manipulating each data set until reversal of significance (a=0.05) was achieved. The corresponding fragility quotient (FQ) and continuous FQ (CFQ) were calculated by dividing FI/CFI by sample size.Results:Of 432 studies screened, 8 studies (52 outcome events) were included in this analysis. The 12 dichotomous outcomes had a median FI of 4.5 (FQ: 0.111), and the 40 continuous outcomes had a median CFI of 5 (CFQ: 0.154). All 52 outcome events included lost-to-follow-up data, and 12 (23.1%) indicated a greater number of patients lost to follow-up than the FI or CFI.Conclusion:Our findings suggest that RCTs evaluating PRP for AT therapy lack statistical robustness, because changing only a small number of events may alter outcome significance.Level of Evidence:Level II, therapeutic study.

Analysis of Robustness of the Landmark Cardiovascular Outcome Trials of Antidiabetic Drugs - A Systematic Review.

It is essential for randomized controlled trials (RCTs) to report results in a comprehensive manner. Hence, it is necessary to assess the robustness of the trials with statistically significant and as well as non-significant results. Robustness can be evaluated using fragility index (FI), while reverse fragility index (RFI) can be used for trials with statistically significant as well as non-significant results. The primary aim of this study was to calculate FI and RFI for cardiovascular outcome trials (CVOT). PubMed/MEDLINE was searched to identify all RCTs of antidiabetic drugs where the primary objective was to evaluate the cardiovascular outcomes. We recorded the trial characteristics of each CVOT trial. The FI, RFI, fragility quotient (FQ), and reverse fragility quotient (RFQ) were calculated to evaluate the robustness of the trials. Spearman rank correlation test was used for correlation. A total of 889 studies were identified and 24 RCTs were included. Among the 24 trials, 12 (50%) trials achieved statistical significance. The median FI and RFI were 29 (4-12) and 22.5 (1-37) for trials with statistically significant and non-significant results. The median FQ and RFQ were 0.0075 (0.002-0.013) and 0.0003 (0.0001-0.004) for trials with statistically significant and non-significant results. The hazard ratio, p-value, and NNT-B had a strong negative relationship with FI. Our study showed that half of the trials showing the superiority of cardioprotective benefits have favourable FI. The trials that failed to show superiority also have a reasonable RFI indicating the robustness of these trials. However, the results of the trials where patients lost to follow- up exceed the FI of that trial demands caution during interpretation.

The Fragility Index of Randomized Controlled Trials for Preterm Neonates.

BackgroundAs a metric to determine the robustness of trial results, the fragility index (FI) is the number indicating how many patients would be required to reverse the significant results. This study aimed to calculate the FI in randomized controlled trials (RCTs) involving premature.MethodsTrials were included if they had a 1:1 study design, reported statistically significant dichotomous outcomes, and had an explicitly stated sample size or power calculation. The FI was calculated for binary outcomes using Fisher’s exact test, and the FIs of subgroups were compared. Spearman’s correlation was applied to determine correlations between the FI and study characteristics.ResultsFinally, 66 RCTs were included in the analyses. The median FI for these trials was 3.00 (interquartile range [IQR]: 1.00–5.00), with a median fragility quotient of 0.014 (IQR: 0.008–0.028). FI was ≤ 3 in 42 of these 66 RCTs (63.6%), and in 42.4% (28/66) of the studies, the number of patients lost to follow-up was greater than that of the FI. Significant differences were found in the FI among journals (p = 0.011). We observed that FI was associated with the sample size, total number of events, and reported p-values (rs = 0.437, 0.495, and −0.857, respectively; all p < 0.001).ConclusionFor RCTs in the premature population, a median of only three events was needed to change from a “non-event” to “event” to render a significant result non-significant, indicating that the significance may hinge on a small number of events.

Statistical Fragility of Single-Row Versus Double-Row Anchoring for Rotator Cuff Repair: A Systematic Review of Comparative Studies.

Background:Comparative studies and randomized controlled trials (RCTs) often use the P (probability) value to convey the statistical significance of their findings. P values are an imperfect measure, however, and are vulnerable to a small number of outcome reversals to alter statistical significance. The inclusion of a fragility index (FI) and fragility quotient (FQ) may aid in the interpretation of a study’s statistical strength.Purpose/Hypothesis:The purpose of this study was to examine the statistical stability of studies comparing single-row to double-row rotator cuff repair. It was hypothesized that the findings of these studies would be vulnerable to a small number of outcome event reversals, often fewer than the number of patients lost to follow-up.Study Design:Systematic review; Level of evidence, 3.Methods:We analyzed comparative studies and RCTs on primary single-row versus double-row rotator cuff repair that were published between 2000 and 2021 in 10 leading orthopaedic journals. Statistical significance was defined as a P < .05. The FI for each outcome was determined by the number of event reversals necessary to alter significance. The FQ was calculated by dividing the FI by the respective sample size.Results:Of 4896 studies screened, 22 comparative studies, 10 of which were RCTs, were ultimately included for analysis. A total of 74 outcomes were examined. Overall, the median FI was 2 (interquartile range [IQR], 1-3), and the median FQ was 0.035 (IQR, 0.020-0.057). The mean FI was 2.55 ± 1.29, and the mean FQ was 0.043 ± 0.027. In 64% of outcomes, the FI was less than the number of patients lost to follow-up.) Additionally, 81% of significant outcomes needed just a single outcome reversal to lose their significance.Conclusion:Over half of the studies currently used to guide clinical practice have a number of patients lost to follow-up greater than their FI. The results of these studies should be interpreted within the context of these limitations. Future analyses may benefit from the inclusion of the FI and the FQ in their statistical analyses.

Robustness of outcomes in trials evaluating sodium-glucose co-transporter 2 inhibitors for heart failure.

AimsRecent 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.ConclusionImprovement 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.

Static vs Dynamic Fixation of Distal Tibiofibular Syndesmosis: A Review of Overlapping Meta-Analyses

Category:Ankle; SportsIntroduction/Purpose:Multiple Level I meta-analyses have been led comparing traditional static vs. more recently-introduced dynamic strategies of fixation for injuries of the distal tibiofibular syndesmosis (TFS). The aim of this review was to assess their robustness and methodological quality, providing support in the choice of a treatment strategy in case of TFS injury using the highest level of evidence.Methods:In this systematic review, conducted in accordance with the PRISMA guidelines, we identified meta-analyses/systematic reviews comparing static and dynamic fixation methods after acute TFS injury. Robustness of studies was evaluated using the Fragility Index (FI) for meta-analysis and the Fragility Quotient (FQ). The risk of bias was evaluated using the Assessment of Multiple Systematic Reviews(AMSTAR) instrument. Finally, the Jadad Decision Algorithm was applied to select the study which provided the highest quality of evidence to develop recommendations for the fixation strategy of these lesions.Results:Out of 1302 records, 4 Level I meta-analyses were included in this study. Analyzing the statistically significant dichotomous outcomes, the median FI was 3.5 (IQR, 2 to 5.5; range, 1 to 9) while the median FQ was 1.9% (IQR, 1 to 3.5; range 0.35 to 4.4). In total, 37% had a FI of 2 or less and 75% of outcomes had a FI of 4 or less. According to the AMSTAR score and Jadad algorithm, the largest meta-analysis was selected as the highest evidence provided so far.Conclusion:We selected the meta-analysis by Grassi et al. as the highest quality provided so far, which found that dynamic fixation reduced complication rates and improved clinical outcomes compared to static methods of fixation. We demonstrated that meta-analyses with statistically significant dichotomous outcomes comparing dynamic and static fixation for treating injuries of the distal tibiofibular syndesmosis are fragile, with a change in less than 4 patients or less than 2% of the study population sufficient to reverse a significant outcome to nonsignificant. Based on these findings, we recommend caution when interpreting the results of these studies.

The Statistical Fragility of Single-Bundle vs Double-Bundle Autografts for ACL Reconstruction: A Systematic Review of Comparative Studies.

Background:The statistical significance of a given study outcome can be liable to small changes in findings. P values are common, but imperfect statistical methods to convey significance, and inclusion of the fragility index (FI) and fragility quotient (FQ) may provide a clearer perception of statistical strength.Purpose/Hypothesis:The purpose was to examine the statistical stability of studies comparing primary single-bundle to double-bundle anterior cruciate ligament reconstruction (ACLR) utilizing autograft and independent tunnel drilling. It was hypothesized that the study findings would be vulnerable to a small number of outcome event reversals, often less than the number of patients lost to follow-up.Study Design:Systematic review; Level of evidence, 2.Methods:Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, the authors searched PubMed for comparative studies and randomized controlled trials (RCTs) published in select journals, based on impact factor, between 2005 and 2020. Risk-of-bias assessment and methodology scoring were conducted for the included studies. A total of 48 dichotomous outcome measures were examined for possible event reversals. The FI for each outcome was determined by the number of event reversals necessary to alter significance. The FQ was calculated by dividing the FI by the respective sample size.Results:Of the 1794 studies screened, 15 comparative studies were included for analysis; 13 studies were RCTs. Overall, the mean FI and FQ were 3.14 (IQR, 2-4) and 0.050 (IQR, 0.032-0.062), respectively. For 72.9% of outcomes, the FI was less than the number of patients lost to follow-up.Conclusion:Studies comparing single-bundle versus double-bundle ACLR may not be as statistically stable as previously thought. Comparative studies and RCTs are at substantial risk for statistical fragility, with few event reversals required to alter significance. The reversal of fewer than 4 outcome events in a treatment group can alter the statistical significance of a given result; this is commonly less than the number of patients lost to follow-up. Future comparative study analyses might consider including FI and FQ with P values in their statistical analysis.

Fragility Index and Fragility Quotient in Randomized Controlled Trials on Corticosteroids in ARDS Due to COVID-19 and Non-COVID-19 Etiology.

Background: The effectiveness of corticosteroids in acute respiratory distress syndrome (ARDS) and COVID-19 still remains uncertain. Since ARDS is due to a hyperinflammatory response to a direct injury, we decided to perform a meta-analysis and an evaluation of robustness of randomised clinical trials (RCTs) investigating the impact of corticosteroids on mortality in ARDS in both COVID-19 and non-COVID-19 patients. We conducted a systematic search of the literature from inception up to 30 October 2020, using the MEDLINE database and the PubMed interface. We evaluated the fragility index (FI) of the included RCTs using a two-by-two contingency table and the p-value produced by the Fisher exact test; the fragility quotient (FQ) was calculated by dividing the FI score by the total sample size of the trial. Results: Thirteen RCTs were included in the analysis; five of them were conducted in COVID-19 ARDS, including 7692 patients, while 8 RCTS were performed in non-COVID ARDS with 1091 patients evaluated. Three out of eight RCTs in ARDS had a FI > 0 while 2 RCTs out of five in COVID-19 had FI > 0. The median of FI for ARDS was 0.625 (0.47) while the median of FQ was 0.03 (0.014). The median of FI for COVID-19 was 6 (2) while the median of FQ was 0.059 (0.055). In this systematic review, we found that FI and FQ of RCTs evaluating the use of corticosteroids in ARDS and COVID-19 were low.