Nature as a Trialist?: Deconstructing the Analogy Between Mendelian Randomization and Randomized Trials
Open accessAbstract
Mendelian randomization (MR) studies are often described as naturally occurring randomized trials in which genetic factors are randomly assigned by nature. Conceptualizing MR studies as randomized trials has profound implications for their design, conduct, reporting, and interpretation. For example, analytic practices that are discouraged in randomized trials should also be discouraged in MR studies. Here, we deconstruct the oft-made analogy between MR and randomized trials. We describe four key threats to the analogy between MR studies and randomized trials: (1) exchangeability is not guaranteed; (2) time zero (and therefore the time for setting eligibility criteria) is unclear; (3) the treatment assignment is often measured with error; and (4) adherence is poorly defined. By precisely defining the causal effects being estimated, we underscore that MR estimates are often vaguely analogous to per-protocol effects in randomized trials, and that current MR methods for estimating analogues of per-protocol effects could be biased in practice. We conclude that the analogy between randomized trials and MR studies provides further perspective on both the strengths and the limitations of MR studies as currently implemented, as well as future directions for MR methodology development and application. In particular, the analogy highlights potential future directions for some MR studies to produce more interpretable and informative numerical estimates.
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MR was first proposed using family data where the difference in alleles between siblings is random, however data limitations mean most MR is conducted using data on unrelated individuals.
“MR was first proposed using the family data where the difference in alleles between siblings is random, however data limitations mean most MR is conducted using data on unrelated individuals.22”
From Mendelian randomization (2022) · cites this paper as [22]
If the effect of an exposure on an outcome is cumulative over many years, MR can overestimate the effect when compared to short term interventions.
“Likewise, if the effect of an exposure on an outcome is cumulative over many years, MR can overestimate the effect when compared to short term interventions.60 119”
From Strengthening the Reporting of Observational Studies in Epidemiology using Mendelian Randomisation (STROBE-MR): explanation and elaboration. (2021) · cites this paper as [60]
An important component of interpretation is defining the time period.
“Finally, an important component of interpretation is defining the time period.60”
From Strengthening the Reporting of Observational Studies in Epidemiology using Mendelian Randomisation (STROBE-MR): explanation and elaboration. (2021) · cites this paper as [60]
MR has been able to test whether particular elements in the inflammatory response cause or are caused by disease.
“For example, whilst inflammation in general has long been postulated to influence vascular disease 49,50 , MR has been able to test whether particular elements in the inflammatory response cause 20 or are caused by 51 disease.”
From Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development (2021) · cites this paper as [51]
Pharmacological modification of C-reactive protein is unlikely to be beneficial to coronary heart disease, whereas randomized evidence demonstrates the value of targeting biomarkers further upstream, for example interleukin-6 receptor or interleukin 1-beta.
“as pharmacological modification of C-reactive protein is unlikely to be beneficial to CHD 51 , whereas randomized evidence demonstrates the value of targeting biomarkers further upstream, e.g. interleukin-6 receptor 21,54 or interleukin 1-beta 52”
From Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development (2021) · cites this paper as [51]
A drug-target MR of haemoglobin selecting cis-acting variants from across discrete protein-encoding genes would be oligogenic, in contrast to a monogenic instrument for CRP, encoded for by a single locus.
“Thus a drug-target MR of haemoglobin selecting cis-acting variants from across discrete protein-encoding genes would be oligogenic, in contrast to a monogenic instrument for CRP 51 , encoded for by a single locus.”
From Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development (2021) · cites this paper as [51]
Mendelian randomization using variants in/around the gene encoding C-reactive protein (CRP) does not support the hypothesis that CRP causes CHD.
“Mendelian randomization using variants in/around the gene encoding C-reactive protein (CRP) does not support the hypothesis that CRP causes CHD 51 .”
From Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development (2021) · cites this paper as [51]
MR of CRP failed to demonstrate a causal role in CHD.
“MR of CRP 51 failed to demonstrate a causal role in CHD”
From Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development (2021) · cites this paper as [51]
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Self-citation
- Authors
- Swanson, S. A., Tiemeier, H., Ikram, M. A., & Hernán, M. A.
- Affiliations
- Harvard University (US)
- Erasmus MC (NL)
- Corresponding author
- Swanson, Sonja A.
- Venue
- Epidemiology
- Published
- 2017-09
- Volume
- 28
- Issue
- 5
- Pages
- 653-659
- ISSN
- 1044-3983 (ISSN-L)
- PMC
- PMC5552969
- OpenAlex
- W2622187097
- Cited by
- 202
- References
- 44
- Citations by year
- 2026: 21 · 2025: 34 · 2024: 52 · 2023: 31 · 2022: 19 · 2021: 9 · 2020: 9 · 2019: 14 · 2018: 11 · 2017: 2
- FWCI
- 6.85
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Epidemiology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R01AI102634)
- Topics
- Physical Sciences › Mathematics › Statistics and Probability › Advanced Causal Inference Techniques
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Social Sciences › Decision Sciences › Statistics, Probability and Uncertainty › Meta-analysis and systematic reviews
- Keywords
- Mendelian randomization, causal inference, exchangeability, medication adherence, eligibility criteria, causal effect estimation
- MeSH terms
- Humans, Genetic Variation, Randomized Controlled Trials as Topic, Treatment Outcome, Mendelian Randomization Analysis
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