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Published on: May 25, 2020
Assessing the Fragility of Statistically Significant Outcomes in Randomized Controlled Trials of Minimally Invasive
Abdus Samad Ansari1, Minsu Jung2, Amar Hamdan3
1From the Moorfields Eye Hospital NHS Foundation Trust (A.S.A., A. Hayre, P.T.K., G.G.), London, UK; Section of Academic Ophthalmology (A.S.A.), School of Life Course Sciences, FoLSM, King's College London, London, UK.
Topic:
Minimally invasive glaucoma surgery (MIGS) has been widely adopted as a surgical option for glaucoma, yet concerns remain regarding the robustness of the evidence supporting many procedures. The fragility index (FI) and fragility quotient (FQ) provide complementary measures to traditional p values by quantifying how dependent statistically significant results are on a small number of outcome events.
Clinical Relevance:
Understanding the statistical fragility of MIGS trials is important for clinicians, guideline developers, and policymakers when interpreting reported efficacy and safety outcomes, particularly in a field characterised by small trials, heterogeneous endpoints, and commercially sensitive interventions.
Methods:
A systematic review was conducted in accordance with PRISMA guidelines and registered on PROSPERO. Electronic databases were searched from inception to August 1, 2025, to identify randomized controlled trials evaluating MIGS procedures in patients with glaucoma. Trials reporting at least one statistically significant binary outcome with sufficient raw data were included. The FI was calculated using iterative Fisher exact testing, and the FQ was derived by normalizing FI to total sample size. Risk of bias was assessed using the Revised Cochrane Risk of Bias Tool (RoB 2.0).
Results:
Sixteen randomized controlled trials encompassing 4,562 participants met inclusion criteria. The median sample size was 236.5 (interquartile range [IQR], 88-511), with a median follow-up of 24 months. The mean FI was 9.4 ± 10.0 and the mean FQ was 0.031 ± 0.025, indicating that approximately 3% of participants would require a different outcome to render results non-significant. Three trials (18.8%) had an FI of zero. In six studies (37.5%), the FI was less than or equal to the number of participants lost to follow-up, suggesting vulnerability to attrition bias. Fragility varied across device categories, with larger multicenter trials demonstrating higher FI values but consistently low FQ values.
Conclusion:
Statistically significant outcomes in RCTs of MIGS exhibit variable statistical robustness when assessed using fragility metrics, often due to small numbers of events. These findings highlight the need for cautious interpretation of reported significance and support the incorporation of fragility metrics alongside conventional statistical measures when appraising the MIGS evidence base.
