Methodological challenges in mendelian randomization
- PMID: 24681576
- PMCID: PMC3981897
- DOI: 10.1097/EDE.0000000000000081
Methodological challenges in mendelian randomization
Abstract
We give critical attention to the assumptions underlying Mendelian randomization analysis and their biological plausibility. Several scenarios violating the Mendelian randomization assumptions are described, including settings with inadequate phenotype definition, the setting of time-varying exposures, the presence of gene-environment interaction, the existence of measurement error, the possibility of reverse causation, and the presence of linkage disequilibrium. Data analysis examples are given, illustrating that the inappropriate use of instrumental variable techniques when the Mendelian randomization assumptions are violated can lead to biases of enormous magnitude. To help address some of the strong assumptions being made, three possible approaches are suggested. First, the original proposal of Katan (Lancet. 1986;1:507-508) for Mendelian randomization was not to use instrumental variable techniques to obtain estimates but merely to examine genotype-outcome associations to test for the presence of an effect of the exposure on the outcome. We show that this more modest goal and approach can circumvent many, though not all, the potential biases described. Second, we discuss the use of sensitivity analysis in evaluating the consequences of violations in the assumptions and in attempting to correct for those violations. Third, we suggest that a focus on negative, rather than positive, Mendelian randomization results may turn out to be more reliable.
Figures
![Figure 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3981897/bin/nihms-560669-f0001.gif)
![Figure 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3981897/bin/nihms-560669-f0002.gif)
![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3981897/bin/nihms-560669-f0003.gif)
![Figure 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3981897/bin/nihms-560669-f0004.gif)
![Figure 5](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3981897/bin/nihms-560669-f0005.gif)
![Figure 6](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3981897/bin/nihms-560669-f0006.gif)
![Figure 7](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3981897/bin/nihms-560669-f0007.gif)
![Figure 8](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3981897/bin/nihms-560669-f0008.gif)
![Figure 9](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3981897/bin/nihms-560669-f0009.gif)
![Figure 10](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3981897/bin/nihms-560669-f0010.gif)
Similar articles
-
Interpreting findings from Mendelian randomization using the MR-Egger method.Eur J Epidemiol. 2017 May;32(5):377-389. doi: 10.1007/s10654-017-0255-x. Epub 2017 May 19. Eur J Epidemiol. 2017. PMID: 28527048 Free PMC article.
-
Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression.Int J Epidemiol. 2015 Apr;44(2):512-25. doi: 10.1093/ije/dyv080. Epub 2015 Jun 6. Int J Epidemiol. 2015. PMID: 26050253 Free PMC article.
-
Mendelian randomization studies: a review of the approaches used and the quality of reporting.Int J Epidemiol. 2015 Apr;44(2):496-511. doi: 10.1093/ije/dyv071. Epub 2015 May 6. Int J Epidemiol. 2015. PMID: 25953784 Review.
-
Use of allele scores as instrumental variables for Mendelian randomization.Int J Epidemiol. 2013 Aug;42(4):1134-44. doi: 10.1093/ije/dyt093. Int J Epidemiol. 2013. PMID: 24062299 Free PMC article.
-
Avoiding bias from weak instruments in Mendelian randomization studies.Int J Epidemiol. 2011 Jun;40(3):755-64. doi: 10.1093/ije/dyr036. Epub 2011 Mar 16. Int J Epidemiol. 2011. PMID: 21414999 Review.
Cited by
-
Gastroesophageal reflux disease and non-alcoholic fatty liver disease: a two-sample Mendelian randomization combined with meta-analysis.Sci Rep. 2024 Jun 2;14(1):12633. doi: 10.1038/s41598-024-63646-z. Sci Rep. 2024. PMID: 38824176 Free PMC article.
-
The healthcare costs of increased body mass index-evidence from The Trøndelag Health Study.Health Econ Rev. 2024 Jun 1;14(1):36. doi: 10.1186/s13561-024-00512-8. Health Econ Rev. 2024. PMID: 38822866 Free PMC article.
-
The association between three prevalent autoimmune disorders and the likelihood of developing prostate cancer: a Mendelian randomization study.Sci Rep. 2024 May 23;14(1):11755. doi: 10.1038/s41598-024-62716-6. Sci Rep. 2024. PMID: 38783043 Free PMC article.
-
Association among attention-deficit hyperactivity disorder, restless legs syndrome, and peripheral iron status: a two-sample Mendelian randomization study.Front Psychiatry. 2024 May 8;15:1310259. doi: 10.3389/fpsyt.2024.1310259. eCollection 2024. Front Psychiatry. 2024. PMID: 38779543 Free PMC article.
-
Association between basal metabolic rate and cardio-metabolic risk factors: Evidence from a Mendelian Randomization study.Heliyon. 2024 Mar 23;10(7):e28154. doi: 10.1016/j.heliyon.2024.e28154. eCollection 2024 Apr 15. Heliyon. 2024. PMID: 38590845 Free PMC article.
References
-
- Katan MB. Apolipoprotein E isoforms, serum cholesterol, and cancer. Lancet. 1986;1:507–508. - PubMed
-
- Little J, Khoury MJ. Mendelian randomisation: a new spin or real progress? Lancet. 2003;362:930–931. - PubMed
-
- Davey Smith G, Ebrahim S. Mendelian randomization: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol. 2003;32:1–22. - PubMed
-
- Davey Smith G, Ebrahim S. Mendelian randomization: prospects, potentials, and limitations. Int J Epidemiol. 2004;33:30–42. - PubMed
-
- Thomas DC, Conti DV. Commentary: the concept of ‘Mendelian Randomization’. Int J Epidemiol. 2004;33:21–25. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources