On clinical trial fragility due to patients lost to follow up

Benjamin R Baer; Stephen E Fremes; Mario Gaudino; Mary Charlson; Martin T Wells

doi:10.1186/s12874-021-01446-z

On clinical trial fragility due to patients lost to follow up

Benjamin R Baer^*, Stephen E Fremes, Mario Gaudino, Mary Charlson, Martin T Wells

^*Corresponding author for this work

Statistics

Research output: Contribution to journal › Article › peer-review

Abstract

Background
Clinical trials routinely have patients lost to follow up. We propose a methodology to understand their possible effect on the results of statistical tests by altering the concept of the fragility index to treat the outcomes of observed patients as fixed but incorporate the potential outcomes of patients lost to follow up as random and subject to modification.

Methods
We reanalyse the statistical results of three clinical trials on coronary artery bypass grafting (CABG) to study the possible effect of patients lost to follow up on the treatment effect statistical significance. To do so, we introduce the LTFU-aware fragility indices as a measure of the robustness of a clinical trial’s statistical results with respect to patients lost to follow up.

Results
The analyses illustrate that clinical trials can either be completely robust to the outcomes of patients lost to follow up, extremely sensitive to the outcomes of patients lost to follow up, or in an intermediate state. When a clinical trial is in an intermediate state, the LTFU-aware fragility indices provide an interpretable measure to quantify the degree of fragility or robustness.

Conclusions
The LTFU-aware fragility indices allow researchers to rigorously explore the outcomes of patients who are lost to follow up, when their data is the appropriate kind. The LTFU-aware fragility indices are sensitivity measures in a way that the original fragility index is not.

Original language	English
Article number	254
Number of pages	11
Journal	BMC Medical Research Methodology
Volume	21
Issue number	254
DOIs	https://doi.org/10.1186/s12874-021-01446-z
Publication status	Published - 20 Nov 2021

Keywords

Fragility index
Statistical significance
Research methods
Loss to follow up
Sensitivity analysis
CABG

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Baer_2021_BMC-MRM_ON-clinical-trial_CC
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On Clinical Trial Fragility Due to Patients Lost to Follow Up (code)
Baer, B. (Creator), GitHub, 2023
https://github.com/brb225/FragilityTools
Dataset: Software

Cite this

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title = "On clinical trial fragility due to patients lost to follow up",

abstract = "BackgroundClinical trials routinely have patients lost to follow up. We propose a methodology to understand their possible effect on the results of statistical tests by altering the concept of the fragility index to treat the outcomes of observed patients as fixed but incorporate the potential outcomes of patients lost to follow up as random and subject to modification.MethodsWe reanalyse the statistical results of three clinical trials on coronary artery bypass grafting (CABG) to study the possible effect of patients lost to follow up on the treatment effect statistical significance. To do so, we introduce the LTFU-aware fragility indices as a measure of the robustness of a clinical trial{\textquoteright}s statistical results with respect to patients lost to follow up.ResultsThe analyses illustrate that clinical trials can either be completely robust to the outcomes of patients lost to follow up, extremely sensitive to the outcomes of patients lost to follow up, or in an intermediate state. When a clinical trial is in an intermediate state, the LTFU-aware fragility indices provide an interpretable measure to quantify the degree of fragility or robustness.ConclusionsThe LTFU-aware fragility indices allow researchers to rigorously explore the outcomes of patients who are lost to follow up, when their data is the appropriate kind. The LTFU-aware fragility indices are sensitivity measures in a way that the original fragility index is not.",

keywords = "Fragility index, Statistical significance, Research methods, Loss to follow up, Sensitivity analysis, CABG",

author = "Baer, {Benjamin R} and Fremes, {Stephen E} and Mario Gaudino and Mary Charlson and Wells, {Martin T}",

note = "Wells ′ research was partially supported by NIH grant U19 AI111143, PCORI IHS-2017C3-8923, and Cornell{\textquoteright}s Center for the Social Sciences project on Algorithms, Big Data, and Inequality. ",

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doi = "10.1186/s12874-021-01446-z",

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AU - Baer, Benjamin R

AU - Fremes, Stephen E

AU - Gaudino, Mario

AU - Charlson, Mary

AU - Wells, Martin T

N1 - Wells ′ research was partially supported by NIH grant U19 AI111143, PCORI IHS-2017C3-8923, and Cornell’s Center for the Social Sciences project on Algorithms, Big Data, and Inequality.

PY - 2021/11/20

Y1 - 2021/11/20

N2 - BackgroundClinical trials routinely have patients lost to follow up. We propose a methodology to understand their possible effect on the results of statistical tests by altering the concept of the fragility index to treat the outcomes of observed patients as fixed but incorporate the potential outcomes of patients lost to follow up as random and subject to modification.MethodsWe reanalyse the statistical results of three clinical trials on coronary artery bypass grafting (CABG) to study the possible effect of patients lost to follow up on the treatment effect statistical significance. To do so, we introduce the LTFU-aware fragility indices as a measure of the robustness of a clinical trial’s statistical results with respect to patients lost to follow up.ResultsThe analyses illustrate that clinical trials can either be completely robust to the outcomes of patients lost to follow up, extremely sensitive to the outcomes of patients lost to follow up, or in an intermediate state. When a clinical trial is in an intermediate state, the LTFU-aware fragility indices provide an interpretable measure to quantify the degree of fragility or robustness.ConclusionsThe LTFU-aware fragility indices allow researchers to rigorously explore the outcomes of patients who are lost to follow up, when their data is the appropriate kind. The LTFU-aware fragility indices are sensitivity measures in a way that the original fragility index is not.

AB - BackgroundClinical trials routinely have patients lost to follow up. We propose a methodology to understand their possible effect on the results of statistical tests by altering the concept of the fragility index to treat the outcomes of observed patients as fixed but incorporate the potential outcomes of patients lost to follow up as random and subject to modification.MethodsWe reanalyse the statistical results of three clinical trials on coronary artery bypass grafting (CABG) to study the possible effect of patients lost to follow up on the treatment effect statistical significance. To do so, we introduce the LTFU-aware fragility indices as a measure of the robustness of a clinical trial’s statistical results with respect to patients lost to follow up.ResultsThe analyses illustrate that clinical trials can either be completely robust to the outcomes of patients lost to follow up, extremely sensitive to the outcomes of patients lost to follow up, or in an intermediate state. When a clinical trial is in an intermediate state, the LTFU-aware fragility indices provide an interpretable measure to quantify the degree of fragility or robustness.ConclusionsThe LTFU-aware fragility indices allow researchers to rigorously explore the outcomes of patients who are lost to follow up, when their data is the appropriate kind. The LTFU-aware fragility indices are sensitivity measures in a way that the original fragility index is not.

KW - Fragility index

KW - Statistical significance

KW - Research methods

KW - Loss to follow up

KW - Sensitivity analysis

KW - CABG

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DO - 10.1186/s12874-021-01446-z

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SN - 1471-2288

VL - 21

JO - BMC Medical Research Methodology

JF - BMC Medical Research Methodology

IS - 254

M1 - 254

ER -

On clinical trial fragility due to patients lost to follow up

Abstract

Keywords

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On Clinical Trial Fragility Due to Patients Lost to Follow Up (code)

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