Resampling Fragility, Perturbation Fragility, and Why the Global Fragility Index Is Not a P-Value in Disguise

Authors

  • Thomas F. Heston Department of Family Medicine, University of Washington, Seattle, USA; Department of Medical Education and Clinical Sciences, Elson S. Floyd College of Medicine, Washington State University, Spokane, USA https://orcid.org/0000-0002-5655-2512

DOI:

https://doi.org/10.5281/zenodo.22059146

Keywords:

global fragility index, p-fr-nb, fragility quotient, statistical fragility, P-value, resampling, perturbation, clinical trials

Abstract

The charge that the fragility index is a P-value in disguise rests on a strong correlation between the two across trials, and it overlooks a distinction between two distinct constructs derived from the same observed result. Resampling fragility asks how often the significance verdict would change if the trial were drawn again at the same size; it is a probability, and because it is based on the same observed result and a specified replication model, it is often strongly associated with the P-value. Perturbation fragility asks how many recorded outcomes must change before the observed table crosses the significance threshold; it is a count, the global fragility index, or a proportion, the global fragility quotient, and it measures the geometric distance of the observed table from the decision boundary, a quantity the P-value does not encode. Worked examples from published trials show tables with similar P-values and widely different perturbation fragility. The redundancy critique, whether made by resampling or by machine-learning models that use the P-value as a predictor, is correct about resampling fragility but does not address the fragility index.

References

1. Carter RE, McKie PM, Storlie CB. The Fragility Index: a P-value in sheep’s clothing? Eur Heart J. 2017;38: 346–348. doi:10.1093/eurheartj/ehw495

2. Condon TM, Sexton RW, Wells AJ, To M-S. The weakness of fragility index exposed in an analysis of the traumatic brain injury management guidelines: A meta-epidemiological and simulation study. Pasin L, editor. PLOS ONE. 2020;15: e0237879. doi:10.1371/journal.pone.0237879

3. McHugh ML. The Chi-square test of independence. Biochem Medica. 2013; 143–149. doi:10.11613/BM.2013.018

4. Potter GE. Dismantling the Fragility Index: A demonstration of statistical reasoning. Stat Med. 2020;39: 3720–3731. doi:10.1002/sim.8689

5. Baer BR, Gaudino M, Charlson M, Fremes SE, Wells MT. Fragility indices for only sufficiently likely modifications. Proc Natl Acad Sci U S A. 2021;118: e2105254118. doi:10.1073/pnas.2105254118

6. Vivekanantha P, Son H, Kay J, Kotipalli S, Bouchard MD, Madden K, et al. Direct Comparison Between Loss‐to‐Follow‐Up and Statistical Fragility Is Methodologically Inappropriate, and Fragility Reflects the P Value, Not Trial Robustness: A Simulation Analysis of 300,000 Randomized Controlled Trials. Arthroscopy. 2026; arj.70457. doi:10.1002/arj.70457

7. Heston TF. Significance, Fragility, and Robustness in Clinical Trials: Stratifying Statistical Evidence. Cureus. 2025;17. doi:10.7759/cureus.100494

8. Heston TF. The Global Fragility Index: A Path-Independent Measure of Statistical Fragility. SSRN Electron J. 2025; 5709162. doi:10.2139/ssrn.5709162

9. Cid MC, Unizony SH, Blockmans D, Brouwer E, Dagna L, Dasgupta B, et al. Efficacy and safety of mavrilimumab in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 2022;81: 653–661. doi:10.1136/annrheumdis-2021-221865

10. Green JB, Everett BM, Ghosh A, Younes N, Krause-Steinrauf H, Barzilay J, et al. Cardiovascular Outcomes in GRADE (Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness Study). Circulation. 2024;149: 993–1003. doi:10.1161/CIRCULATIONAHA.123.066604

11. Lyles KW, Colón-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, et al. Zoledronic Acid and Clinical Fractures and Mortality after Hip Fracture. N Engl J Med. 2007;357: 1799–1809. doi:10.1056/NEJMoa074941

12. Tsze DS, Woodward HA, McLaren SH, Leu C-SS, Venn AMR, Hu NY, et al. Optimal Dose of Intranasal Midazolam for Procedural Sedation in Children: A Randomized Clinical Trial. JAMA Pediatr. 2025;179: 979. doi:10.1001/jamapediatrics.2025.2181

13. Taylor L, Many S, Jeanguenat H, Hattendorf J, Sayasone S, Keiser J. Efficacy and safety of ascending doses of emodepside in comparison with ivermectin in adults infected with Strongyloides stercoralis in Laos: a phase 2a, dose-ranging, randomised, parallel-group, placebo-controlled, single-blind clinical trial. Lancet Infect Dis. 2025;25: 1254–1264. doi:10.1016/S1473-3099(25)00255-5

14. Seror R, Baron G, Hachulla E, Debandt M, Larroche C, Puéchal X, et al. Adalimumab for steroid sparing in patients with giant-cell arteritis: results of a multicentre randomised controlled trial. Ann Rheum Dis. 2014;73: 2074–2081. doi:10.1136/annrheumdis-2013-203586

Downloads

Published

2026-08-22

How to Cite

Heston, T. F. (2026). Resampling Fragility, Perturbation Fragility, and Why the Global Fragility Index Is Not a P-Value in Disguise. Internet Medical Journal, 1(1), e22059146. https://doi.org/10.5281/zenodo.22059146

Issue

Section

Perspectives