Examining the causal association between 25-hydroxyvitamin D and caries in children and adults: a two-sample Mendelian randomization approach

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Abstract

Background: Prior observational studies have reported that higher levels of vitamin D are associated with decreased caries risk in children. However, these studies are prone to bias and confounding so do not provide causal inference. Genetic variants associated with a risk factor of interest can be used as proxies, in a Mendelian randomization (MR) analysis, to test for causal association with an outcome. The objective was to estimate the causal association between serum 25-hydroxyvitamin D (25(OH)D) (the commonly measured vitamin D metabolite in blood) and dental caries using a two-sample MR approach which estimates the causal effect of an exposure on an outcome.

Methods: A total of 79 genetic variants reliably associated with 25(OH)D were identified from genome-wide association studies and used as a proxy measure of 25(OH)D. The association of this proxy measure with three outcome measures was tested; specifically: caries in primary teeth (n=17,035, aged 3-12 years), caries in permanent teeth in childhood and adolescence (n=13,386, aged 6-18 years), and caries severity in adulthood proxied by decayed, missing and filled tooth surfaces (DMFS) counts (n=26,792, aged 18-93 years).

Results: The estimated causal effect of a one standard deviation increase in natural log-transformed 25(OH)D could be summarized as an odds ratio of 1.06 (95%CI: 0.81, 1.31; P=0.66) for caries in primary teeth and 1.00 (95%CI: 0.76, 1.23; P=0.97) for caries in permanent teeth in childhood and adolescence. In adults, the estimated casual effect of a one standard deviation increase in natural log-transformed 25(OH)D was 0.31 fewer affected tooth surfaces (95%CI: from 1.81 fewer DMFS to 1.19 more DMFS; P=0.68)

Conclusions: The MR-derived effect estimates for these three measures are small in magnitude with wide confidence intervals and do not provide evidence for a causal relationship between 25(OH)D and dental caries.

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Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression

Jack Bowden, George Davey Smith, Stephen Burgess (2016)

Background: The number of Mendelian randomization analyses including large numbers of genetic variants is rapidly increasing. This is due to the proliferation of genome-wide association studies, and the desire to obtain more precise estimates of causal effects. However, some genetic variants may not be valid instrumental variables, in particular due to them having more than one proximal phenotypic correlate (pleiotropy). Methods: We view Mendelian randomization with multiple instruments as a meta-analysis, and show that bias caused by pleiotropy can be regarded as analogous to small study bias. Causal estimates using each instrument can be displayed visually by a funnel plot to assess potential asymmetry. Egger regression, a tool to detect small study bias in meta-analysis, can be adapted to test for bias from pleiotropy, and the slope coefficient from Egger regression provides an estimate of the causal effect. Under the assumption that the association of each genetic variant with the exposure is independent of the pleiotropic effect of the variant (not via the exposure), Egger’s test gives a valid test of the null causal hypothesis and a consistent causal effect estimate even when all the genetic variants are invalid instrumental variables. Results: We illustrate the use of this approach by re-analysing two published Mendelian randomization studies of the causal effect of height on lung function, and the causal effect of blood pressure on coronary artery disease risk. The conservative nature of this approach is illustrated with these examples. Conclusions: An adaption of Egger regression (which we call MR-Egger) can detect some violations of the standard instrumental variable assumptions, and provide an effect estimate which is not subject to these violations. The approach provides a sensitivity analysis for the robustness of the findings from a Mendelian randomization investigation.

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Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator

Jack Bowden, George Davey Smith, Philip C. Haycock … (2017)

ABSTRACT Developments in genome‐wide association studies and the increasing availability of summary genetic association data have made application of Mendelian randomization relatively straightforward. However, obtaining reliable results from a Mendelian randomization investigation remains problematic, as the conventional inverse‐variance weighted method only gives consistent estimates if all of the genetic variants in the analysis are valid instrumental variables. We present a novel weighted median estimator for combining data on multiple genetic variants into a single causal estimate. This estimator is consistent even when up to 50% of the information comes from invalid instrumental variables. In a simulation analysis, it is shown to have better finite‐sample Type 1 error rates than the inverse‐variance weighted method, and is complementary to the recently proposed MR‐Egger (Mendelian randomization‐Egger) regression method. In analyses of the causal effects of low‐density lipoprotein cholesterol and high‐density lipoprotein cholesterol on coronary artery disease risk, the inverse‐variance weighted method suggests a causal effect of both lipid fractions, whereas the weighted median and MR‐Egger regression methods suggest a null effect of high‐density lipoprotein cholesterol that corresponds with the experimental evidence. Both median‐based and MR‐Egger regression methods should be considered as sensitivity analyses for Mendelian randomization investigations with multiple genetic variants.

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Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians

Neil M. Davies, Michael V. Holmes, George Davey Smith (2019)

Mendelian randomisation uses genetic variation as a natural experiment to investigate the causal relations between potentially modifiable risk factors and health outcomes in observational data. As with all epidemiological approaches, findings from Mendelian randomisation studies depend on specific assumptions. We provide explanations of the information typically reported in Mendelian randomisation studies that can be used to assess the plausibility of these assumptions and guidance on how to interpret findings from Mendelian randomisation studies in the context of other sources of evidence

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Author and article information

Contributors

Serena A. Dodhia: Role: ConceptualizationRole: Data CurationRole: Formal AnalysisRole: Writing – Original Draft PreparationRole: Writing – Review & Editing

ORCID: https://orcid.org/0000-0002-1536-0012

Nicola X. West: Role: Writing – Review & Editing

Steven J. Thomas: Role: Writing – Review & Editing

Nicholas J. Timpson: Role: ConceptualizationRole: Writing – Review & Editing

ORCID: https://orcid.org/0000-0002-7141-9189

Ingegerd Johansson: Role: Writing – Review & Editing

ORCID: https://orcid.org/0000-0002-9227-8434

Pernilla Lif Holgerson: Role: Writing – Review & Editing

ORCID: https://orcid.org/0000-0002-2779-5865

Tom Dudding: Role: ConceptualizationRole: Data CurationRole: Formal AnalysisRole: SupervisionRole: Writing – Review & Editing

ORCID: https://orcid.org/0000-0003-3756-040X

Simon Haworth: Role: ConceptualizationRole: Data CurationRole: Formal AnalysisRole: SupervisionRole: Writing – Review & Editing

ORCID: https://orcid.org/0000-0001-7793-7326

Journal

Journal ID (nlm-ta): Wellcome Open Res

Journal ID (iso-abbrev): Wellcome Open Res

Title: Wellcome Open Research

Publisher: F1000 Research Limited (London, UK )

ISSN (Electronic): 2398-502X

Publication date (Electronic): 20 July 2021

Publication date Collection: 2020

Volume: 5

Electronic Location Identifier: 281

Affiliations

[1 ]Bristol Dental School, University of Bristol, Bristol, BS1 2LY, UK

[2 ]Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, BS8 2BN, UK

[3 ]Avon Longitudinal Study of Parents and Children, University of Bristol, Bristol, UK

[4 ]Department of Odontology, Section of Cariology, Umea University, Umeå, Sweden

[5 ]Department of Odontology, Section of Pedodontics, Umea University, Umeå, Sweden

[1 ]Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway

[2 ]Center for Oral Health Services and Research Mid-Norway (TkMidt), Trondheim, Norway

[1 ]Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada

University of Bristol, UK

[1 ]Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway

[2 ]Center for Oral Health Services and Research Mid-Norway (TkMidt), Trondheim, Norway

University of Bristol, UK

Author notes

[a ] Simon.Haworth@ 123456bristol.ac.uk

No competing interests were disclosed.

Competing interests: No competing interests were disclosed.

Competing interests: I had contacted two authors in the manuscript for potential collaboration in the future. I believe that this will not affect my ability to review the article impartially.

Competing interests: No competing interests were disclosed.

Author information

Serena A. Dodhia https://orcid.org/0000-0002-1536-0012

Nicholas J. Timpson https://orcid.org/0000-0002-7141-9189

Ingegerd Johansson https://orcid.org/0000-0002-9227-8434

Pernilla Lif Holgerson https://orcid.org/0000-0002-2779-5865

Tom Dudding https://orcid.org/0000-0003-3756-040X

Simon Haworth https://orcid.org/0000-0001-7793-7326

Article

DOI: 10.12688/wellcomeopenres.16369.2

PMC ID: 8327219

PubMed ID: 34386609

SO-VID: b7142bb0-d669-4f68-87f0-225bcb8c903b

License:

This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date accepted : 14 July 2021

Funding

Funded by: Medical Research Council

Award ID: MC_UU_12013/3

Funded by: Wellcome Trust

Award ID: 202802

Funded by: NIHR Bristol Biomedical Research Centre

Award ID: BRC-1215-20011

Funded by: Wellcome Trust

Award ID: 201237

Funded by: Cancer Research UK

Award ID: C18281/A19169

Funded by: Wellcome Trust

Award ID: 201268

This workw as supported by Wellcome [201237 to T.D. and 201268 to S.H.]. T.D. and S.H. are now supported by National Institute for Health Research Academic Clinical Fellowships. N.J.T. is a Wellcome Investigator (202802), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215-20011), the MRC Integrative Epidemiology Unit (MC_UU_12013/3) and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A19169). S.H. and T.D. work in a unit that receives funding from the University of Bristol and the UK Medical Research Council (Grant ref: MC_UU_12013/3). S.A.D is supported by INSPIRE, the Academy of Medical Sciences (AMS) and Wellcome.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Examining the causal association between 25-hydroxyvitamin D and caries in children and adults: a two-sample Mendelian randomization approach

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Most cited references 31

Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression

Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator

Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians

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