Assessing the suitability of summary data for two-sample Mendelian randomization analyses using MR-Egger regression: the role of the I2I2 statistic

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Title: Assessing the suitability of summary data for two-sample Mendelian randomization analyses using MR-Egger regression: the role of the I2I2 statistic
Authors: Bowden, J
Del Greco M, F
Minelli, C
Davey Smith, G
Sheehan, NA
Thompson, JR
Item Type: Journal Article
Abstract: BACKGROUND: MR-Egger regression has recently been proposed as a method for Mendelian randomization (MR) analyses incorporating summary data estimates of causal effect from multiple individual variants, which is robust to invalid instruments. It can be used to test for directional pleiotropy and provides an estimate of the causal effect adjusted for its presence. MR-Egger regression provides a useful additional sensitivity analysis to the standard inverse variance weighted (IVW) approach that assumes all variants are valid instruments. Both methods use weights that consider the single nucleotide polymorphism (SNP)-exposure associations to be known, rather than estimated. We call this the `NO Measurement Error' (NOME) assumption. Causal effect estimates from the IVW approach exhibit weak instrument bias whenever the genetic variants utilized violate the NOME assumption, which can be reliably measured using the F-statistic. The effect of NOME violation on MR-Egger regression has yet to be studied. METHODS: An adaptation of the [Formula: see text] statistic from the field of meta-analysis is proposed to quantify the strength of NOME violation for MR-Egger. It lies between 0 and 1, and indicates the expected relative bias (or dilution) of the MR-Egger causal estimate in the two-sample MR context. We call it [Formula: see text] The method of simulation extrapolation is also explored to counteract the dilution. Their joint utility is evaluated using simulated data and applied to a real MR example. RESULTS: In simulated two-sample MR analyses we show that, when a causal effect exists, the MR-Egger estimate of causal effect is biased towards the null when NOME is violated, and the stronger the violation (as indicated by lower values of [Formula: see text]), the stronger the dilution. When additionally all genetic variants are valid instruments, the type I error rate of the MR-Egger test for pleiotropy is inflated and the causal effect underestimated. Simulation extrapolation is shown to substantially mitigate these adverse effects. We demonstrate our proposed approach for a two-sample summary data MR analysis to estimate the causal effect of low-density lipoprotein on heart disease risk. A high value of [Formula: see text] close to 1 indicates that dilution does not materially affect the standard MR-Egger analyses for these data. CONCLUSIONS: Care must be taken to assess the NOME assumption via the [Formula: see text] statistic before implementing standard MR-Egger regression in the two-sample summary data context. If [Formula: see text] is sufficiently low (less than 90%), inferences from the method should be interpreted with caution and adjustment methods considered.
Issue Date: 11-Sep-2016
Date of Acceptance: 12-Jul-2016
ISSN: 1464-3685
Publisher: Oxford University Press
Start Page: 1961
End Page: 1974
Journal / Book Title: International Journal of Epidemiology
Volume: 45
Issue: 6
Copyright Statement: © The Author 2016. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Science & Technology
Life Sciences & Biomedicine
Public, Environmental & Occupational Health
Mendelian randomization
MR-Egger regression
measurement error
I-2 statistic
simulation extrapolation
I2 statistic
0104 Statistics
1117 Public Health And Health Services
Publication Status: Published
Open Access location:
Appears in Collections:Infectious Disease Epidemiology
National Heart and Lung Institute
Faculty of Medicine

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