Research Methods & Reporting

Use of Mendelian randomisation to assess potential benefit of clinical intervention

BMJ 2012; 345 doi: http://dx.doi.org/10.1136/bmj.e7325 (Published 06 November 2012) Cite this as: BMJ 2012;345:e7325

Re: Use of Mendelian randomisation to assess potential benefit of clinical intervention

In their article,[1] Burgess and al. rightly pointed out the limitations of studying the causal relationship between genetic variants and risk factors associated with diseases. As they suggest, when applied to humans, these studies remain observational. Strictly speaking, they therefore study associations and not causation.[2,3] Comparing these studies to randomised controlled trials can therefore be misleading.

In clinical trials, randomisation was designed to prevent bias from confounding effects without knowing their true nature. In other words, when using chance alone to allocate the factor of interest, potential confounders should be evenly distributed between intervention and control groups. This is only possible if the studied factor can be attributed randomly.

When studying genetic variants in humans, we have no means of controlling the attribution of a specific gene. Furthermore, genes are not transmitted across humans entirely randomly.[4] I therefore consider the term “Mendelian randomisation” as inappropriate and it should be replaced by “Mendelian attribution”.

In epidemiology, human studies on genetic variants cannot be classified as experimental designs and need to be considered as either cohort or case-control studies.

1. Burgess S, Butterworth A, Malarstig A, Thompson SG. Use of Mendelian randomisation to assess potential benefit of clinical intervention. BMJ 2012;345.
2. Hill AB. The Environment and Disease: Association or Causation? Proc R Soc Med 1965;58:295-300.
3. Parascandola M, Weed DL. Causation in epidemiology. Journal of Epidemiology and Community Health 2001;55(12):905-12.
4. Frank SA. Natural selection. III. Selection versus transmission and the levels of selection. Journal of evolutionary biology 2012;25(2):227-43.

Competing interests: No competing interests

12 November 2012
Paul Vaucher
DiO, MSc Clinical Trial, PhD student in neuroscience
Faculty of Medicine, University of Geneva
Michel-Servet 1, 1211 Geneva-4, Switzerland
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