Prevalence and implications of significance testing for baseline covariate imbalance in randomised cancer clinical trials: The Table 1 Fallacy.

Humans Prevalence Cross-Sectional Studies Neoplasms / epidemiology Randomized Controlled Trials as Topic
Covariate imbalance Oncology Phase III Randomised controlled trials Significance testing for baseline characteristics Table 1 Fallacy Testing for baseline differences

Journal

European journal of cancer (Oxford, England : 1990)
ISSN: 1879-0852
Titre abrégé: Eur J Cancer
Pays: England
ID NLM: 9005373

Informations de publication

Date de publication:
11 2023
Historique:
received: 01 08 2023
revised: 18 09 2023
accepted: 20 09 2023
medline: 20 11 2023
pubmed: 13 10 2023
entrez: 12 10 2023
Statut: ppublish

Résumé

The 'Table 1 Fallacy' refers to the unsound use of significance testing for comparing the distributions of baseline variables between randomised groups to draw erroneous conclusions about balance or imbalance. We performed a cross-sectional study of the Table 1 Fallacy in phase III oncology trials. From ClinicalTrials.gov, 1877 randomised trials were screened. Multivariable logistic regressions evaluated predictors of the Table 1 Fallacy. A total of 765 randomised controlled trials involving 553,405 patients were analysed. The Table 1 Fallacy was observed in 25% of trials (188 of 765), with 3% of comparisons deemed significant (59 of 2353), approximating the typical 5% type I error assertion probability. Application of trial-level multiplicity corrections reduced the rate of significant findings to 0.3% (six of 2345 tests). Factors associated with lower odds of the Table 1 Fallacy included industry sponsorship (adjusted odds ratio [aOR] 0.29, 95% confidence interval [CI] 0.18-0.47; multiplicity-corrected P < 0.0001), larger trial size (≥795 versus <280 patients; aOR 0.32, 95% CI 0.19-0.53; multiplicity-corrected P = 0.0008), and publication in a European versus American journal (aOR 0.06, 95% CI 0.03-0.13; multiplicity-corrected P < 0.0001). This study highlights the persistence of the Table 1 Fallacy in contemporary oncology randomised controlled trials, with one of every four trials testing for baseline differences after randomisation. Significance testing is a suboptimal method for identifying unsound randomisation procedures and may encourage misleading inferences. Journal-level enforcement is a possible strategy to help mitigate this fallacy.

Sections du résumé

BACKGROUND
The 'Table 1 Fallacy' refers to the unsound use of significance testing for comparing the distributions of baseline variables between randomised groups to draw erroneous conclusions about balance or imbalance. We performed a cross-sectional study of the Table 1 Fallacy in phase III oncology trials.
METHODS
From ClinicalTrials.gov, 1877 randomised trials were screened. Multivariable logistic regressions evaluated predictors of the Table 1 Fallacy.
RESULTS
A total of 765 randomised controlled trials involving 553,405 patients were analysed. The Table 1 Fallacy was observed in 25% of trials (188 of 765), with 3% of comparisons deemed significant (59 of 2353), approximating the typical 5% type I error assertion probability. Application of trial-level multiplicity corrections reduced the rate of significant findings to 0.3% (six of 2345 tests). Factors associated with lower odds of the Table 1 Fallacy included industry sponsorship (adjusted odds ratio [aOR] 0.29, 95% confidence interval [CI] 0.18-0.47; multiplicity-corrected P < 0.0001), larger trial size (≥795 versus <280 patients; aOR 0.32, 95% CI 0.19-0.53; multiplicity-corrected P = 0.0008), and publication in a European versus American journal (aOR 0.06, 95% CI 0.03-0.13; multiplicity-corrected P < 0.0001).
CONCLUSIONS
This study highlights the persistence of the Table 1 Fallacy in contemporary oncology randomised controlled trials, with one of every four trials testing for baseline differences after randomisation. Significance testing is a suboptimal method for identifying unsound randomisation procedures and may encourage misleading inferences. Journal-level enforcement is a possible strategy to help mitigate this fallacy.

Identifiants

DOI: 10.1016/j.ejca.2023.113357 PMID: 37827064
pubmed: 37827064
pii: S0959-8049(23)00659-7
doi: 10.1016/j.ejca.2023.113357
pii:
doi:

Types de publication

Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

113357

Subventions

Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States

Informations de copyright

Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Msaouel reported honoraria for scientific advisory board membership for Mirati Therapeutics, Bristol-Myers Squibb, and Exelixis; consulting fees from Axiom Healthcare; non-branded educational programmes supported by Exelixis and Pfizer; leadership or fiduciary roles as a Medical Steering Committee Member for the Kidney Cancer Association and a Kidney Cancer Scientific Advisory Board Member for KCCure; and research funding from Takeda, Bristol-Myers Squibb, Mirati Therapeutics, and Gateway for Cancer Research (all unrelated to this manuscript’s content). Dr. McCaw reported employment at Insitro (unrelated to this manuscript’s content). Dr. Tang reported grants from the Cancer Prevention & Research Institute of Texas (CPRIT) and the Andrew Sabin Family Foundation and being an Andrew Sabin Scholar and royalties from Wolters Kluwer and consulting fees and honoraria from Bayer, Diffusion Pharmaceuticals, and The Osler Institute Lecture Series (unrelated to this manuscript’s content). Dr. Taniguchi reports consulting fees from Phebry and Xerient and holds a patent related to radioprotection of the upper gastrointestinal tract. Dr. Rödel reported receiving research funding from German Cancer Aid (unrelated to this manuscript’s content). Dr. Fuller reported unrelated funding and salary support from: NIH NIBIB Research Education Programmes for Residents and Clinical Fellows Grant (R25EB025787-01); NIDCR Academic Industrial Partnership Grant (R01DE028290); NCI Parent Research Project Grant (R01CA258827) an NIH/NCI Cancer Centre Support Grant (CCSG); and an NSF Division of Civil, Mechanical, and Manufacturing Innovation (CMMI) grant (NSF 1933369). Dr. Fuller reported direct industry grant support, honoraria, and travel funding from Elekta AB unrelated to this project and reported direct infrastructure support from the multidisciplinary Radiation Oncology/Cancer Imaging Programme (P30CA016672-44) of the MD Anderson Cancer Centre Support (Core) Grant (P30CA016672) and the MD Anderson Programme in Image-guided Cancer Therapy. Dr. Sun reported personal fees from Boehringer Ingelheim (unrelated to this manuscript’s content). Dr. Meirson reported receiving personal fees from Purple Biotech (unrelated to this manuscript’s content). No other authors reported any conflicts of interest.

Auteurs

Alexander D Sherry (AD)

Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Pavlos Msaouel (P)

Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Translational Molecular Pathology, Division of Pathology/Lab Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Zachary R McCaw (ZR)

Insitro, South San Francisco, CA, USA; Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Joseph Abi Jaoude (J)

Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Radiation Oncology, Stanford University, Stanford, CA, USA.

Eric J Hsu (EJ)

Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Ramez Kouzy (R)

Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Roshal Patel (R)

Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

Yumeng Yang (Y)

Department of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, USA.

Timothy A Lin (TA)

Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Cullen M Taniguchi (CM)

Department of Gastrointestinal Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Experimental Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Claus Rödel (C)

Department of Radiotherapy and Oncology, University of Frankfurt, Frankfurt, Germany; Frankfurt Cancer Institute, Frankfurt, Germany; German Cancer Research Center (DKFZ), Heidelberg, German Cancer Consortium (DKTK), Partner Site Frankfurt am Main, Frankfurt, Germany.

Emmanouil Fokas (E)

Department of Radiotherapy and Oncology, University of Frankfurt, Frankfurt, Germany; Frankfurt Cancer Institute, Frankfurt, Germany; German Cancer Research Center (DKFZ), Heidelberg, German Cancer Consortium (DKTK), Partner Site Frankfurt am Main, Frankfurt, Germany.

Chad Tang (C)

Department of Translational Molecular Pathology, Division of Pathology/Lab Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genitourinary Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Clifton David Fuller (CD)

Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Bruce Minsky (B)

Department of Gastrointestinal Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Tomer Meirson (T)

Davidoff Cancer Center, Rabin Medical Center, Petach Tikva, Israel.

Ryan Sun (R)

Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Ethan B Ludmir (EB)

Department of Gastrointestinal Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: ebludmir@mdanderson.org.

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