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

The DOI matches its Crossref record; 27 of the 28 references it cites were found in a registry or an index.

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

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

Published version of a preprint

Open this paper in CoChat — free accountOpen PDF

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.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1093/ije/dyx102

Cites

27 of 27 references verified0 citation errors · 0 not checkable

Statistics

Figures

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

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 28 references

Cited by

Sorted by citations

Items 901–1,000 of 1,004

Related

See all

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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review