The Ellipse of Insignificance, a refined fragility indexfor ascertaining robustness of results indichotomous outcome trials

  1. David Robert Grimes  Is a corresponding author
  1. Dublin City University, Ireland

Abstract

There is increasing awareness throughout biomedical science that many results do not withstand the trials of repeat investigation. The growing abundance of medical literature has only increased the urgent need for tools to gauge the robustness and trustworthiness of published science. Dichotomous outcome designs are vital in randomized clinical trials, cohort studies, and observational data for ascertaining differences between experimental and control arms. It has however been shown with tools like the fragility index (FI) that many ostensibly impactful results fail to materialise when even small numbers of patients or subjects in either the control or experimental arms are recoded from event to non-event. Critics of this metric counter that there is no objective means to determine a meaningful FI. As currently used, FI is not multi-dimensional and is computationally expensive. In this work a conceptually similar geometrical approach is introduced, the ellipse of insignificance (EOI). This method yields precise deterministic values for the degree of manipulation or miscoding that can be tolerated simultaneously in both control and experimental arms, allowing for the derivation of objective measures of experimental robustness. More than this, the tool is intimately connected with sensitivity and specificity of the event / non-event tests, and is readily combined with knowledge of test parameters to reject unsound results. The method is outlined here, with illustrative clinical examples.

Data availability

The paper is a modelling study and methodology and contains no data, and code provided in the supplementary material allows reproduction of all methods.

Article and author information

Author details

  1. David Robert Grimes

    Dublin City University, Dublin, Ireland
    For correspondence
    davidrobert.grimes@dcu.ie
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3140-3278

Funding

Wellcome Trust (214461/A/18/Z)

  • David Robert Grimes

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Philip Boonstra, University of Michigan, United States

Version history

  1. Preprint posted: March 28, 2022 (view preprint)
  2. Received: April 19, 2022
  3. Accepted: September 13, 2022
  4. Accepted Manuscript published: September 20, 2022 (version 1)
  5. Version of Record published: October 21, 2022 (version 2)

Copyright

© 2022, Grimes

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. David Robert Grimes
(2022)
The Ellipse of Insignificance, a refined fragility indexfor ascertaining robustness of results indichotomous outcome trials
eLife 11:e79573.
https://doi.org/10.7554/eLife.79573

Further reading

    1. Epidemiology and Global Health
    Tianyi Huang
    Insight

    A large observational study has found that irregular sleep-wake patterns are associated with a higher risk of overall mortality, and also mortality from cancers and cardiovascular disease.

    1. Epidemiology and Global Health
    Lachlan Cribb, Ramon Sha ... Matthew P Pase
    Research Article

    Background:

    Irregular sleep-wake timing may cause circadian disruption leading to several chronic age-related diseases. We examined the relationship between sleep regularity and risk of all-cause, cardiovascular disease (CVD), and cancer mortality in 88,975 participants from the prospective UK Biobank cohort.

    Methods:

    The sleep regularity index (SRI) was calculated as the probability of an individual being in the same state (asleep or awake) at any two time points 24 hr apart, averaged over 7 days of accelerometry (range 0–100, with 100 being perfectly regular). The SRI was related to the risk of mortality in time-to-event models.

    Results:

    The mean sample age was 62 years (standard deviation [SD], 8), 56% were women, and the median SRI was 60 (SD, 10). There were 3010 deaths during a mean follow-up of 7.1 years. Following adjustments for demographic and clinical variables, we identified a non-linear relationship between the SRI and all-cause mortality hazard (p [global test of spline term]<0.001). Hazard ratios, relative to the median SRI, were 1.53 (95% confidence interval [CI]: 1.41, 1.66) for participants with SRI at the 5th percentile (SRI = 41) and 0.90 (95% CI: 0.81, 1.00) for those with SRI at the 95th percentile (SRI = 75), respectively. Findings for CVD mortality and cancer mortality followed a similar pattern.

    Conclusions:

    Irregular sleep-wake patterns are associated with higher mortality risk.

    Funding:

    National Health and Medical Research Council of Australia (GTN2009264; GTN1158384), National Institute on Aging (AG062531), Alzheimer’s Association (2018-AARG-591358), and the Banting Fellowship Program (#454104).