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Cited by 3,485Genetic Associations and EpidemiologyAdvanced Causal Inference TechniquesMeta-analysis and systematic reviews

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Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption

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Hartwig, Fernando Pires, Davey Smith, George, Bowden, Jack·2017·International Journal of Epidemiology
DOI 10.1093/ije/dyx102PMC PMC5837715

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Abstract

Background: Mendelian randomization (MR) is being increasingly used to strengthen causal inference in observational studies. Availability of summary data of genetic associations for a variety of phenotypes from large genome-wide association studies (GWAS) allows straightforward application of MR using summary data methods, typically in a two-sample design. In addition to the conventional inverse variance weighting (IVW) method, recently developed summary data MR methods, such as the MR-Egger and weighted median approaches, allow a relaxation of the instrumental variable assumptions. Methods: Here, a new method - the mode-based estimate (MBE) - is proposed to obtain a single causal effect estimate from multiple genetic instruments. The MBE is consistent when the largest number of similar (identical in infinite samples) individual-instrument causal effect estimates comes from valid instruments, even if the majority of instruments are invalid. We evaluate the performance of the method in simulations designed to mimic the two-sample summary data setting, and demonstrate its use by investigating the causal effect of plasma lipid fractions and urate levels on coronary heart disease risk. Results: The MBE presented less bias and lower type-I error rates than other methods under the null in many situations. Its power to detect a causal effect was smaller compared with the IVW and weighted median methods, but was larger than that of MR-Egger regression, with sample size requirements typically smaller than those available from GWAS consortia. Conclusions: The MBE relaxes the instrumental variable assumptions, and should be used in combination with other approaches in sensitivity analyses.

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Figure 1 Illustration of the ZEro Modal Pleiotropy Assumption (ZEMPA) in the simple (i.e. unweighted) mode-based estimate (MBE). βM is the simple MBE causal effect and β is the true causal effect; nldenotes the number of variants with a given horizontal pleiotropic effect (n0 denotes the number of valid instruments). Panel A: ZEMPA is satisfied. Panel B: ZEMPA is violated. SNP, single nucleotide polymorphism.
Figure 1 Illustration of the ZEro Modal Pleiotropy Assumption (ZEMPA) in the simple (i.e. unweighted) mode-based estimate (MBE). βM is the simple MBE causal effect and β is the true causal effect; nldenotes the number of variants with a given horizontal pleiotropic effect (n0 denotes the number of valid instruments). Panel A: ZEMPA is satisfied. Panel B: ZEMPA is violated. SNP, single nucleotide polymorphism.CC BY · PubMed Central
Figure 2 Weighteda empirical density function of all individual-instrument ratio causal effect estimates (β^Rj) of plasma LDL-C (panel A), HDL-C (panel B), triglycerides (panel C) and urate (panel D) levels on ln(odds ratio) of coronary heart disease for different values of the tuning parameter ϕ. LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol. The dashed line indicates the zero value. aWeights were calculated without making the NOME assumption.
Figure 2 Weighteda empirical density function of all individual-instrument ratio causal effect estimates (β^Rj) of plasma LDL-C (panel A), HDL-C (panel B), triglycerides (panel C) and urate (panel D) levels on ln(odds ratio) of coronary heart disease for different values of the tuning parameter ϕ. LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol. The dashed line indicates the zero value. aWeights were calculated without making the NOME assumption.CC BY · PubMed Central

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Metadata

Authors
Hartwig, F. P., Davey Smith, G., & Bowden, J.
Affiliations
  • Universidade Federal de Pelotas (BR)
  • MRC Integrative Epidemiology Unit and
  • University of Bristol (GB)
Corresponding author
Hartwig, Fernando Pires
ORCID
Venue
International Journal of Epidemiology
Publisher
Oxford University Press (OUP)
Published
2017-07-12
Volume
46
Issue
6
Pages
1985-1998
ISSN
  • 0300-5771 (ISSN-L)
  • 1464-3685
DOI
10.1093/ije/dyx102
PMC
PMC5837715
OpenAlex
W2613603864
Cited by
3,485
References
28
Citations by year
2026: 387 · 2025: 798 · 2024: 1094 · 2023: 475 · 2022: 231 · 2021: 226 · 2020: 119 · 2019: 88 · 2018: 53 · 2017: 12
FWCI
49.57
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • International Journal of Epidemiology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Bristol Research (University of Bristol) (submittedVersion, cc-by)
  • Explore Bristol Research (submittedVersion, cc-by)
Funders
  • University of Bristol (MC_UU_12013/9)
  • Medical Research Council (MC_UU_12013, MR/N501906/1, MC_UU_12013/9)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Physical Sciences › Mathematics › Statistics and Probability › Advanced Causal Inference Techniques
  • Social Sciences › Decision Sciences › Statistics, Probability and Uncertainty › Meta-analysis and systematic reviews
Keywords
Mendelian randomization, summary data, invalid instruments, causal effect estimation, MR-Egger, weighted median, inverse variance weighting, plasma lipids, uric acid, coronary artery disease, sensitivity analysis
MeSH terms
Humans, Models, Statistical, Causality, Sample Size, Genome-Wide Association Study, Mendelian Randomization Analysis, Genetic Pleiotropy

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