Can a Mendelian Randomization Study Predict the Results of a Clinical Trial? Yes and No


  • Antonio Abbate VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA
  • Charles A. Dinarello Division of Infectious Diseases, Department of Medicine, University of Colorado, Denver, CO, USA
  • Mariangela Peruzzi Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
  • Sebastiano Sciarretta Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli, Italy
  • Giacomo Frati Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli, Italy
  • Giuseppe Biondi Zoccai Eleonora Lorillard Spencer Cenci Foundation, Rome, Italy



Adjustment, Confounding, Inference, Mendelian randomization study, Observational study, Prediction, Randomized controlled trial.


Randomized controlled trials are considered at the top of the evidence hierarchy. However, in several cases randomized trials cannot be conducted or have not yet been completed. In such settings observational studies may provide important inference, yet traditional statistical adjustment methods fall short of controlling for all potential confounders, as unknown confounders cannot be taken care of by even the most sophisticated statistical tools. The mendelian randomization study is a type of research design which simultaneously exploits random transmission of genes and genetic linkage to obtain inferential estimates from the association between specific genetic variants known to modulate given risk factors and the corresponding outcomes of interests. Despite several developments in this field, there remain several areas of further research, and discrepancies between mendelian randomization studies and the corresponding randomized trials have already been recognized. Nonetheless, it is likely that this novel type of study will be used more commonly in the future, and a working knowledge of its pros, cons, and range of validity is crucial for conscientious interpretation and application. We thus aimed to concisely yet poignantly introduce the scholarly reader to this novel type of research design, notwithstanding that complementarity prevails in most cases over overlap between mendelian randomization studies and randomized trials.


Biondi-Zoccai, G. In the kingdom of the blind, the one-eyed man is king: the case for the International Journal of Statistics in Medical Research. Int J Stats Med Res 2013; 2: i-iv.

Biondi-Zoccai, G, Lotrionte, M, Landoni, G, Modena, MG. The rough guide to systematic reviews and meta-analyses. HSR Proc Intensive Care Cardiovasc Anesth 2011; 3: 161-173.

Biondi-Zoccai, G, Ed. Network Meta-Analysis: Evidence Synthesis with Mixed Treatment Comparison. Hauppauge, NY: Nova Science Publishers; 2014.

Biondi-Zoccai, G, Abbate, A, Peruzzi, M, Frati, G. Commentary: observations, trials, and meta-analyses: the life cycle of evidence-based endovascular therapy. J Endovasc Ther 2014; 21: 693-696. DOI:

Jansen, H, Samani, NJ, Schunkert, H. Mendelian randomization studies in coronary artery disease. Eur Heart J 2014; 35: 1917-1924. DOI:

Greco, T, Biondi-Zoccai, G, Saleh, O, et al. The attractiveness of network meta-analysis: a comprehensive systematic and narrative review. Heart Lung Vessel 2015; 7: 133-142.

Gray, R, Wheatley, K. How to avoid bias when comparing bone marrow transplantation with chemotherapy. Bone Marrow Transplant 1991; 7 Suppl 3: 9-12.

Smith, GC, Pell, JP. Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials. BMJ 2003; 327: 1459-1461. DOI:

Lanini, S, Zumla, A, Ioannidis, JP, et al. Are adaptive randomised trials or non-randomised studies the best way to address the Ebola outbreak in west Africa? Lancet Infect Dis 2015; 15: 738-745. DOI:

Biondi-Zoccai, G, Romagnoli, E, Agostoni, P, et al. Are propensity scores really superior to standard multivariable analysis? Contemp Clin Trials 2011; 32: 731-740. DOI:

Dahabreh, IJ, Sheldrick, RC, Paulus, JK, et al. Do observational studies using propensity score methods agree with randomized trials? A systematic comparison of studies on acute coronary syndromes. Eur Heart J 2012; 33: 1893-1901. DOI:

Burgess, S, Timpson, NJ, Ebrahim, S, Davey Smith, G. Mendelian randomization: where are we now and where are we going? Int J Epidemiol 2015; 44: 379-388. DOI:

Bowden, J, Davey Smith, G, Burgess, S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol 2015; 44: 512-25. DOI:

Davey Smith, G, Lawlor, DA, Harbord, R, et al. Association of C-reactive protein with blood pressure and hypertension: life course confounding and mendelian randomization tests of causality. Arterioscler Thromb Vasc Biol 2005; 25: 1051-1056. DOI:

Chen, L, Smith, GD, Harbord, RM, Lewis, SJ. Alcohol intake and blood pressure: a systematic review implementing a Mendelian randomization approach. PLoS Med 2008; 5: e52. DOI:

Xin, X, He J, Frontini, MG, Ogden, LG, Motsamai, OI, Whelton, PK. Effects of alcohol reduction on blood pressure: a meta-analysis of randomized controlled trials. Hypertension 2001; 38: 1112-1117. DOI:

Pfister, R, Sharp, S, Luben, R, et al. Mendelian randomization study of B-type natriuretic peptide and type 2 diabetes: evidence of causal association from population studies. PLoS Med 2011; 8: e1001112. DOI:

Yancy, CW, Saltzberg, MT, Berkowitz, RL, et al. Safety and feasibility of using serial infusions of nesiritide for heart failure in an outpatient setting (from the FUSION I trial). Am J Cardiol 2004; 94: 595-601. DOI:

Skaaby, T, Husemoen, LL, Martinussen, T, et al. Vitamin D status, filaggrin genotype, and cardiovascular risk factors: a Mendelian randomization approach. PLoS One 2013; 8: e57647. DOI:

Pilz, S, Gaksch, M, Kienreich, K, et al. Effects of vitamin D on blood pressure and cardiovascular risk factors: a randomized controlled trial. Hypertension 2015; 65: 1195-1201. DOI:

Trummer, O, Pilz, S, Hoffmann, MM, et al. Vitamin D and mortality: a Mendelian randomization study. Clin Chem 2013; 59: 793-797. DOI:

Chowdhury, R, Kunutsor, S, Vitezova, A, et al. Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies. BMJ 2014; 348: g1903. DOI:

The Interleukin-1 Genetics Consortium. Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomization analysis. Lancet Diabetes Endocrinol 2015; 3: 243-253. DOI:

Nitsch, D, Molokhia, M, Smeeth, L, DeStavola, BL, Whittaker, JC, Leon, DA. Limits to causal inference based on Mendelian

randomization: a comparison with randomized controlled trials. Am J Epidemiol 2006; 163: 397-403. DOI:

Waehre, T, Yndestad, A, Smith, C, et al. Increased expression of interleukin-1 in coronary artery disease with downregulatory effects of HMG-CoA reductase inhibitors. Circulation 2004; 109: 1966-1672. Epub 2004 Mar 29. DOI:

Van Tassell, BW, Toldo, S, Mezzaroma, E, Abbate, A. Targeting interleukin-1 in heart disease. Circulation 2013; 128: 1910-23. DOI:

Morton AC, Rothman AM, Greenwood JP, et al. The effect of interleukin-1 receptor antagonist therapy on markers of inflammation in non-ST elevation acute coronary syndromes: the MRC-ILA Heart Study. Eur Heart J 2015; 36: 377-84. DOI:

Abbate A, Kontos MC, Grizzard JD, et al. VCU-ART Investigators. Interleukin-1 blockade with anakinra to prevent adverse cardiac remodeling after acute myocardial infarction (Virginia Commonwealth University Anakinra Remodeling Trial [VCU-ART] Pilot study). Am J Cardiol 2010; 105: 1371-1377. DOI:

Abbate, A, Van Tassell, BW, Biondi-Zoccai, G, et al. Effects of interleukin-1 blockade with anakinra on adverse cardiac remodeling and heart failure after acute myocardial infarction [from the Virginia Commonwealth University-Anakinra Remodeling Trial (2) (VCU-ART2) pilot study]. Am J Cardiol 2013; 111: 1394-1400. DOI:

Ridker, PM, Thuren, T, Zalewski, A, Libby, P. Interleukin-1β inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am Heart J 2011; 162: 597-605. DOI:

Biondi-Zoccai, G, Ed. Umbrella Reviews. Evidence Synthesis with Overviews of Reviews and Meta-Epidemiologic Studies. Cham: Springer International Publishing; 2016. DOI:




How to Cite

Abbate, A., Dinarello, C. A. ., Peruzzi, M., Sciarretta, S., Frati, G., & Zoccai, G. B. (2016). Can a Mendelian Randomization Study Predict the Results of a Clinical Trial? Yes and No . International Journal of Statistics in Medical Research, 5(1), 56–61.



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