Can a Mendelian Randomization Study Predict the Results of a Clinical Trial? Yes and No
DOI:
https://doi.org/10.6000/1929-6029.2016.05.01.6Keywords:
Adjustment, Confounding, Inference, Mendelian randomization study, Observational study, Prediction, Randomized controlled trial.Abstract
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.
References
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. http://dx.doi.org/10.1583/14-4713C.1 DOI: https://doi.org/10.1583/14-4713C.1
Jansen, H, Samani, NJ, Schunkert, H. Mendelian randomization studies in coronary artery disease. Eur Heart J 2014; 35: 1917-1924. http://dx.doi.org/10.1093/eurheartj/ehu208 DOI: https://doi.org/10.1093/eurheartj/ehu208
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. http://dx.doi.org/10.1136/bmj.327.7429.1459 DOI: https://doi.org/10.1136/bmj.327.7429.1459
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. http://dx.doi.org/10.1016/S1473-3099(15)70106-4 DOI: https://doi.org/10.1016/S1473-3099(15)70106-4
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. http://dx.doi.org/10.1016/j.cct.2011.05.006 DOI: https://doi.org/10.1016/j.cct.2011.05.006
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. http://dx.doi.org/10.1093/eurheartj/ehs114 DOI: https://doi.org/10.1093/eurheartj/ehs114
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. http://dx.doi.org/10.1093/ije/dyv108 DOI: https://doi.org/10.1093/ije/dyv108
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. http://dx.doi.org/10.1093/ije/dyv080 DOI: https://doi.org/10.1093/ije/dyv080
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. http://dx.doi.org/10.1161/01.ATV.0000160351.95181.d0 DOI: https://doi.org/10.1161/01.ATV.0000160351.95181.d0
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. http://dx.doi.org/10.1371/journal.pmed.0050052 DOI: https://doi.org/10.1371/journal.pmed.0050052
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. http://dx.doi.org/10.1161/hy1101.093424 DOI: https://doi.org/10.1161/hy1101.093424
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. http://dx.doi.org/10.1371/journal.pmed.1001112 DOI: https://doi.org/10.1371/journal.pmed.1001112
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. http://dx.doi.org/10.1016/j.amjcard.2004.05.022 DOI: https://doi.org/10.1016/j.amjcard.2004.05.022
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. http://dx.doi.org/10.1371/journal.pone.0057647 DOI: https://doi.org/10.1371/journal.pone.0057647
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. http://dx.doi.org/10.1161/HYPERTENSIONAHA.115.05319 DOI: https://doi.org/10.1161/HYPERTENSIONAHA.115.05319
Trummer, O, Pilz, S, Hoffmann, MM, et al. Vitamin D and mortality: a Mendelian randomization study. Clin Chem 2013; 59: 793-797. http://dx.doi.org/10.1373/clinchem.2012.193185 DOI: https://doi.org/10.1373/clinchem.2012.193185
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. http://dx.doi.org/10.1136/bmj.g1903 DOI: https://doi.org/10.1136/bmj.g1903
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. http://dx.doi.org/10.1016/S2213-8587(15)00034-0 DOI: https://doi.org/10.1016/S2213-8587(15)00034-0
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. http://dx.doi.org/10.1093/aje/kwj062 DOI: https://doi.org/10.1093/aje/kwj062
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: https://doi.org/10.1161/01.CIR.0000125700.33637.B1
Van Tassell, BW, Toldo, S, Mezzaroma, E, Abbate, A. Targeting interleukin-1 in heart disease. Circulation 2013; 128: 1910-23. http://dx.doi.org/10.1161/CIRCULATIONAHA.113.003199 DOI: https://doi.org/10.1161/CIRCULATIONAHA.113.003199
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. http://dx.doi.org/10.1093/eurheartj/ehu272 DOI: https://doi.org/10.1093/eurheartj/ehu272
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. http://dx.doi.org/10.1016/j.amjcard.2009.12.059 DOI: https://doi.org/10.1016/j.amjcard.2009.12.059
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. http://dx.doi.org/10.1016/j.amjcard.2013.01.287 DOI: https://doi.org/10.1016/j.amjcard.2013.01.287
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. http://dx.doi.org/10.1016/j.ahj.2011.06.012 DOI: https://doi.org/10.1016/j.ahj.2011.06.012
Biondi-Zoccai, G, Ed. Umbrella Reviews. Evidence Synthesis with Overviews of Reviews and Meta-Epidemiologic Studies. Cham: Springer International Publishing; 2016. DOI: https://doi.org/10.1007/978-3-319-25655-9
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Copyright (c) 2016 Antonio Abbate, Charles A. Dinarello, Mariangela Peruzzi, Sebastiano Sciarretta, Giacomo Frati, Giuseppe Biondi Zoccai
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