Strengthening the reporting of observational studies in epidemiology using mendelian randomisation (STROBE-MR): explanation and elaboration

Skrivankova, Veronika; Richmond, Rebecca C; Woolf, Benjamin; Davies, Neil M; Swanson, Sonja A; VanderWeele, Tyler J.; Timpson, Nicholas J.; Higgins, Julian P T; Dimou, Niki; Langenberg, Claudia; Loder, Elizabeth; Golub, Robert M.; Egger, Matthias; Smith, George Davey; Richards, J. Brent

doi:10.1136/bmj.n2233

Cited by 551 publications

(487 citation statements)

References 130 publications

(308 reference statements)

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“…In our study, there was no overlap between the datasets contributing toward the gene-exposure association and gene-outcome associations, which could otherwise introduce sampling bias [ 11 ]. We reported our findings in line with the MR-STROBE guidance [ 12 ].…”

Section: Methodssupporting

confidence: 85%

Morning Cortisol and Circulating Inflammatory Cytokine Levels: A Mendelian Randomisation Study

Rajasundaram

Rahman

Woolf

et al. 2022

Genes

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Cortisol exerts a broad anti-inflammatory effect on the immune system. Inflammatory cytokines contribute to the molecular signalling pathways implicated in various autoimmune and inflammatory conditions. However, the mechanisms by which cortisol modulates such signalling pathways remain uncertain. Leveraging summary-level data from the CORtisol NETwork (CORNET, n = 25,314) and FINRISK (n = 8293) genome-wide association studies, we used two-sample Mendelian randomisation to investigate the causal effect of genetically proxied increased morning cortisol levels on 42 circulating cytokines. We found that increased genetically proxied morning cortisol levels were associated with reduced levels of IL-8 and increased levels of MIF. These results provide mechanistic insight into the immunomodulatory effects of endogenous cortisol and the therapeutic effects of exogenous corticosteroids. Clinically, our findings underline the therapeutic importance of steroids in inflammatory conditions where IL-8 and MIF play a central pathophysiological role in the onset and progression of disease.

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Section: Methodssupporting

confidence: 85%

Morning Cortisol and Circulating Inflammatory Cytokine Levels: A Mendelian Randomisation Study

Rajasundaram

Rahman

Woolf

et al. 2022

Genes

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“…The study was conducted using publicly available genome-wide association studies (GWAS) summary data. The study was reported based on recommendations by STROBE-MR and "Guidelines for performing Mendelian randomization investigations" (Burgess et al, 2020;Skrivankova et al, 2021). The study protocol and details were not pre-registered.…”

Section: Methodsmentioning

confidence: 99%

Understanding the consequences of educational inequalities on periodontitis: A Mendelian randomization study

Baumeister

Freuer

Baurecht

et al. 2022

J Clinic Periodontology

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Materials and Methods: Using summary data from genetic association studies from up to 1.1 million participants of European descent, univariable and multivariable Mendelian randomization analyses were performed to infer the total effect of educational attainment on periodontitis and to estimate the degree to which income, smoking, alcohol consumption, and body mass index mediate the association. Results:The odds ratio of periodontitis per 1 standard deviation increment in genetically predicted education was 0.78 (95% CI: 0.68-0.89). The proportions mediated of the total effect of genetically predicted education on periodontitis were 64%, 35%, 15%, and 46% for income, smoking, alcohol consumption, and body mass index, respectively.Conclusions: Using a genetic instrumental variable approach, this study triangulated evidence from existing observational epidemiological studies and suggested that higher educational attainment lowers periodontitis risk. Measures to reduce the burden of educational disparities in periodontitis risk may tackle downstream risk factors, particularly income, smoking, and obesity.

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“…This study was reported following the recommendations of the STROBE-MR guidelines (27) ( Supplementary material ).…”

Section: Methodsmentioning

confidence: 99%

The relationship between BMI and COVID-19: exploring misclassification and selection bias in a two-sample Mendelian randomisation study

Clayton

Soares

Goulding

et al. 2022

Preprint

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ObjectiveTo use the example of the effect of body mass index (BMI) on COVID-19 susceptibility and severity to illustrate methods to explore potential selection and misclassification bias in Mendelian randomisation (MR) of COVID-19 determinants.DesignTwo-sample MR analysis.SettingSummary statistics from the Genetic Investigation of ANthropometric Traits (GIANT) and COVID-19 Host Genetics Initiative (HGI) consortia.Participants681,275 participants in GIANT and more than 2.5 million people from the COVID-19 HGI consortia.ExposureGenetically instrumented BMI.Main outcome measuresSeven case/control definitions for SARS-CoV-2 infection and COVID-19 severity: very severe respiratory confirmed COVID-19 vs not hospitalised COVID-19 (A1) and vs population (those who were never tested, tested negative or had unknown testing status (A2)); hospitalised COVID-19 vs not hospitalised COVID-19 (B1) and vs population (B2); COVID-19 vs lab/self-reported negative (C1) and vs population (C2); and predicted COVID-19 from self-reported symptoms vs predicted or self-reported non-COVID-19 (D1).ResultsWith the exception of A1 comparison, genetically higher BMI was associated with higher odds of COVID-19 in all comparison groups, with odds ratios (OR) ranging from 1.11 (95%CI: 0.94, 1.32) for D1 to 1.57 (95%CI: 1.57 (1.39, 1.78) for A2. As a method to assess selection bias, we found no strong evidence of an effect of COVID-19 on BMI in a ‘no-relevance’ analysis, in which COVID-19 was considered the exposure, although measured after BMI. We found evidence of genetic correlation between COVID-19 outcomes and potential predictors of selection determined a priori (smoking, education, and income), which could either indicate selection bias or a causal pathway to infection. Results from multivariable MR adjusting for these predictors of selection yielded similar results to the main analysis, suggesting the latter.ConclusionsWe have proposed a set of analyses for exploring potential selection and misclassification bias in MR studies of risk factors for SARS-CoV-2 infection and COVID-19 and demonstrated this with an illustrative example. Although selection by socioeconomic position and arelated traits is present, MR results are not substantially affected by selection/misclassification bias in our example. We recommend the methods we demonstrate, and provide detailed analytic code for their use, are used in MR studies assessing risk factors for COVID-19, and other MR studies where such biases are likely in the available data.SummaryWhat is already known on this topic-Mendelian randomisation (MR) studies have been conducted to investigate the potential causal relationship between body mass index (BMI) and COVID-19 susceptibility and severity.-There are several sources of selection (e.g. when only subgroups with specific characteristics are tested or respond to study questionnaires) and misclassification (e.g. those not tested are assumed not to have COVID-19) that could bias MR studies of risk factors for COVID-19.-Previous MR studies have not explored how selection and misclassification bias in the underlying genome-wide association studies could bias MR results.What this study adds-Using the most recent release of the COVID-19 Host Genetics Initiative data (with data up to June 2021), we demonstrate a potential causal effect of BMI on susceptibility to detected SARS-CoV-2 infection and on severe COVID-19 disease, and that these results are unlikely to be substantially biased due to selection and misclassification.-This conclusion is based on no evidence of an effect of COVID-19 on BMI (a ‘no-relevance control’ study, as BMI was measured before the COVID-19 pandemic) and finding genetic correlation between predictors of selection (e.g. socioeconomic position) and COVID-19 for which multivariable MR supported a role in causing susceptibility to infection.-We recommend studies use the set of analyses demonstrated here in future MR studies of COVID-19 risk factors, or other examples where selection bias is likely.

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Strengthening the reporting of observational studies in epidemiology using mendelian randomisation (STROBE-MR): explanation and elaboration

Cited by 551 publications

References 130 publications

Morning Cortisol and Circulating Inflammatory Cytokine Levels: A Mendelian Randomisation Study

Morning Cortisol and Circulating Inflammatory Cytokine Levels: A Mendelian Randomisation Study

Understanding the consequences of educational inequalities on periodontitis: A Mendelian randomization study

The relationship between BMI and COVID-19: exploring misclassification and selection bias in a two-sample Mendelian randomisation study

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