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. 2022 Dec 30;17(12):e0278839.
doi: 10.1371/journal.pone.0278839. eCollection 2022.

Publication bias in pharmacogenetics of adverse reaction to antiseizure drugs: An umbrella review and a meta-epidemiological study

S Bally  1 , J Cottin  2 , M C Gagnieu  3 , J C Lega  1   4 , C Verstuyft  5   6 , S Rheims  7 , G Lesca  8 , M Cucherat  1   2 , Guillaume Grenet  2
Affiliations

Publication bias in pharmacogenetics of adverse reaction to antiseizure drugs: An umbrella review and a meta-epidemiological study

S Bally et al. PLoS One. .

Abstract

Publication bias may lead to a misestimation in the association between pharmacogenetic biomarkers (PGx) and antiseizure drug's adverse effects (AEs). We aimed to assess its prevalence in this field. We searched for systematic reviews assessing PGx of antiseizure drug's AEs. For each unique association between a PGx, a drug and its AE, we used the available odds ratio (ORs) to generate corresponding funnel plots. We estimated the prevalence of publication bias using visual inspections and asymmetry tests. We explored the impact of publication bias using ORs adjusted for potential publication bias. Twenty-two associations were available. Our visual analysis suggested a publication bias in five out twenty-two funnel plots (23% [95%CI: 8; 45]). The Egger's test showed a significant publication bias in one (HLA-B*15:02 and phenytoin-induced Stevens-Johnson syndrome or toxic epidermal necrolysis, p = 0.03) out of nine (11% [95%CI: 0; 48]) and the Begg's test in one (HLA-B*15:02 and carbamazepine-induced serious cutaneous reactions, p = 0.02) out of ten (10% [95%CI: 0; 45]) assessable funnel plots. Adjusting for publication bias may reduce by half the ORs of the pharmacogenetics associations. Publication bias in the pharmacogenetic of antiseizure drug's AEs is not uncommon and may affect the estimation of the effect of such biomarkers. When conducting pharmacogenetic studies, it is critical to publish also the negative one.

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Conflict of interest statement

I have read the journal’s policy and the authors of this manuscript have the following competing interests: SB, JC, MGC, GG declare that they have no competing interest. JCL has received speaker fees and honoraria from Roche. CV has received consulting fees from Genzyme, Novartis and speaker honoraria from Galapagos. SR received speaker and/or consulting fees from UCB Pharma, EISAI, GW Pharma, Idorsia, LivaNova, and Arvelle Therapeutics. GL has received speaker honoraria from GWpharma, Eisai and Biomarin. MC has received consulting fees from Boehringer Ingelheim, SANOFI, AstraZeneca, EISAI and speaker honoraria from SANOFI. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Flow diagram of the bibliographic search.
Fig 2
Fig 2. Funnel plot of the association between [HLA-B*15:02- Carbamazepine- Serious Cutaneous Reactions (SCRs)].
Each point is a clinical studies. The white, dark, and light grey zones stand for a p value of the odds ratio i) non-significant, ii) between 0.05 and 0.01, and iii) <0.01, respectively. The dashed triangle stands for the estimation of the meta-analysis of the association, without adjusting for a potential publication bias.
Fig 3
Fig 3. Funnel plot of the association between [HLA-B*15:02- Phenytoin- SJS/TEN (SJS: Stevens—Johnson syndrome, TEN: Toxic Epidermal Necrolysis)].
Each point is a clinical studies. The white, dark, and light grey zones stand for a p value of the odds ratio i) non-significant, ii) between 0.05 and 0.01, and iii) <0.01, respectively. The dashed triangle stands for the estimation of the meta-analysis of the association, without adjusting for a potential publication bias.
See this image and copyright information in PMC

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