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Testing for non-linear causal effects using a binary genotype in a Mendelian randomization study: application to alcohol and cardiovascular traits

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Testing for non-linear causal effects using a binary genotype in a Mendelian randomization study : application to alcohol and cardiovascular traits. / Silverwood, Richard J.; Holmes, Michael V.; Dale, Caroline E.; Lawlor, Debbie A.; Whittaker, John C.; Smith, George Davey; Leon, David A.; Palmer, Tom; Keating, Brendan J.; Zuccolo, Luisa; Casas, Juan P.; Dudbridge, Frank; Alcohol-ADH1B Consortium.

In: International Journal of Epidemiology, Vol. 43, No. 6, 12.2014, p. 1781-1790.

Research output: Contribution to journalJournal articlepeer-review

Harvard

Silverwood, RJ, Holmes, MV, Dale, CE, Lawlor, DA, Whittaker, JC, Smith, GD, Leon, DA, Palmer, T, Keating, BJ, Zuccolo, L, Casas, JP, Dudbridge, F & Alcohol-ADH1B Consortium 2014, 'Testing for non-linear causal effects using a binary genotype in a Mendelian randomization study: application to alcohol and cardiovascular traits', International Journal of Epidemiology, vol. 43, no. 6, pp. 1781-1790. https://doi.org/10.1093/ije/dyu187

APA

Silverwood, R. J., Holmes, M. V., Dale, C. E., Lawlor, D. A., Whittaker, J. C., Smith, G. D., Leon, D. A., Palmer, T., Keating, B. J., Zuccolo, L., Casas, J. P., Dudbridge, F., & Alcohol-ADH1B Consortium (2014). Testing for non-linear causal effects using a binary genotype in a Mendelian randomization study: application to alcohol and cardiovascular traits. International Journal of Epidemiology, 43(6), 1781-1790. https://doi.org/10.1093/ije/dyu187

Vancouver

Silverwood RJ, Holmes MV, Dale CE, Lawlor DA, Whittaker JC, Smith GD et al. Testing for non-linear causal effects using a binary genotype in a Mendelian randomization study: application to alcohol and cardiovascular traits. International Journal of Epidemiology. 2014 Dec;43(6):1781-1790. https://doi.org/10.1093/ije/dyu187

Author

Silverwood, Richard J. ; Holmes, Michael V. ; Dale, Caroline E. ; Lawlor, Debbie A. ; Whittaker, John C. ; Smith, George Davey ; Leon, David A. ; Palmer, Tom ; Keating, Brendan J. ; Zuccolo, Luisa ; Casas, Juan P. ; Dudbridge, Frank ; Alcohol-ADH1B Consortium. / Testing for non-linear causal effects using a binary genotype in a Mendelian randomization study : application to alcohol and cardiovascular traits. In: International Journal of Epidemiology. 2014 ; Vol. 43, No. 6. pp. 1781-1790.

Bibtex

@article{237a16d8e49a4218b2d058ba2b45aa94,
title = "Testing for non-linear causal effects using a binary genotype in a Mendelian randomization study: application to alcohol and cardiovascular traits",
abstract = "BACKGROUND: Mendelian randomization studies have so far restricted attention to linear associations relating the genetic instrument to the exposure, and the exposure to the outcome. In some cases, however, observational data suggest a non-linear association between exposure and outcome. For example, alcohol consumption is consistently reported as having a U-shaped association with cardiovascular events. In principle, Mendelian randomization could address concerns that the apparent protective effect of light-to-moderate drinking might reflect 'sick-quitters' and confounding.METHODS: The Alcohol-ADH1B Consortium was established to study the causal effects of alcohol consumption on cardiovascular events and biomarkers, using the single nucleotide polymorphism rs1229984 in ADH1B as a genetic instrument. To assess non-linear causal effects in this study, we propose a novel method based on estimating local average treatment effects for discrete levels of the exposure range, then testing for a linear trend in those effects. Our method requires an assumption that the instrument has the same effect on exposure in all individuals. We conduct simulations examining the robustness of the method to violations of this assumption, and apply the method to the Alcohol-ADH1B Consortium data.RESULTS: Our method gave a conservative test for non-linearity under realistic violations of the key assumption. We found evidence for a non-linear causal effect of alcohol intake on several cardiovascular traits.CONCLUSIONS: We believe our method is useful for inferring departure from linearity when only a binary instrument is available. We estimated non-linear causal effects of alcohol intake which could not have been estimated through standard instrumental variable approaches.",
keywords = "Mendelian randomization, instrumental variables, causal inference, local average treatment effects, alcohol consumption, cardiovascular disease",
author = "Silverwood, {Richard J.} and Holmes, {Michael V.} and Dale, {Caroline E.} and Lawlor, {Debbie A.} and Whittaker, {John C.} and Smith, {George Davey} and Leon, {David A.} and Tom Palmer and Keating, {Brendan J.} and Luisa Zuccolo and Casas, {Juan P.} and Frank Dudbridge and {Alcohol-ADH1B Consortium}",
note = "{\textcopyright} The Author 2014; Published by Oxford University Press on behalf of the International Epidemiological Association.",
year = "2014",
month = dec,
doi = "10.1093/ije/dyu187",
language = "English",
volume = "43",
pages = "1781--1790",
journal = "International Journal of Epidemiology",
issn = "0300-5771",
publisher = "NLM (Medline)",
number = "6",

}

RIS

TY - JOUR

T1 - Testing for non-linear causal effects using a binary genotype in a Mendelian randomization study

T2 - application to alcohol and cardiovascular traits

AU - Silverwood, Richard J.

AU - Holmes, Michael V.

AU - Dale, Caroline E.

AU - Lawlor, Debbie A.

AU - Whittaker, John C.

AU - Smith, George Davey

AU - Leon, David A.

AU - Palmer, Tom

AU - Keating, Brendan J.

AU - Zuccolo, Luisa

AU - Casas, Juan P.

AU - Dudbridge, Frank

AU - Alcohol-ADH1B Consortium

N1 - © The Author 2014; Published by Oxford University Press on behalf of the International Epidemiological Association.

PY - 2014/12

Y1 - 2014/12

N2 - BACKGROUND: Mendelian randomization studies have so far restricted attention to linear associations relating the genetic instrument to the exposure, and the exposure to the outcome. In some cases, however, observational data suggest a non-linear association between exposure and outcome. For example, alcohol consumption is consistently reported as having a U-shaped association with cardiovascular events. In principle, Mendelian randomization could address concerns that the apparent protective effect of light-to-moderate drinking might reflect 'sick-quitters' and confounding.METHODS: The Alcohol-ADH1B Consortium was established to study the causal effects of alcohol consumption on cardiovascular events and biomarkers, using the single nucleotide polymorphism rs1229984 in ADH1B as a genetic instrument. To assess non-linear causal effects in this study, we propose a novel method based on estimating local average treatment effects for discrete levels of the exposure range, then testing for a linear trend in those effects. Our method requires an assumption that the instrument has the same effect on exposure in all individuals. We conduct simulations examining the robustness of the method to violations of this assumption, and apply the method to the Alcohol-ADH1B Consortium data.RESULTS: Our method gave a conservative test for non-linearity under realistic violations of the key assumption. We found evidence for a non-linear causal effect of alcohol intake on several cardiovascular traits.CONCLUSIONS: We believe our method is useful for inferring departure from linearity when only a binary instrument is available. We estimated non-linear causal effects of alcohol intake which could not have been estimated through standard instrumental variable approaches.

AB - BACKGROUND: Mendelian randomization studies have so far restricted attention to linear associations relating the genetic instrument to the exposure, and the exposure to the outcome. In some cases, however, observational data suggest a non-linear association between exposure and outcome. For example, alcohol consumption is consistently reported as having a U-shaped association with cardiovascular events. In principle, Mendelian randomization could address concerns that the apparent protective effect of light-to-moderate drinking might reflect 'sick-quitters' and confounding.METHODS: The Alcohol-ADH1B Consortium was established to study the causal effects of alcohol consumption on cardiovascular events and biomarkers, using the single nucleotide polymorphism rs1229984 in ADH1B as a genetic instrument. To assess non-linear causal effects in this study, we propose a novel method based on estimating local average treatment effects for discrete levels of the exposure range, then testing for a linear trend in those effects. Our method requires an assumption that the instrument has the same effect on exposure in all individuals. We conduct simulations examining the robustness of the method to violations of this assumption, and apply the method to the Alcohol-ADH1B Consortium data.RESULTS: Our method gave a conservative test for non-linearity under realistic violations of the key assumption. We found evidence for a non-linear causal effect of alcohol intake on several cardiovascular traits.CONCLUSIONS: We believe our method is useful for inferring departure from linearity when only a binary instrument is available. We estimated non-linear causal effects of alcohol intake which could not have been estimated through standard instrumental variable approaches.

KW - Mendelian randomization

KW - instrumental variables

KW - causal inference

KW - local average treatment effects

KW - alcohol consumption

KW - cardiovascular disease

U2 - 10.1093/ije/dyu187

DO - 10.1093/ije/dyu187

M3 - Journal article

C2 - 25192829

VL - 43

SP - 1781

EP - 1790

JO - International Journal of Epidemiology

JF - International Journal of Epidemiology

SN - 0300-5771

IS - 6

ER -