Systematic comparison of Mendelian randomisation studies and randomised controlled trials using electronic databases

Abstract

Objective: To scope the potential for (semi)-automated triangulation of Mendelian randomisation (MR) and randomised controlled trials (RCTs) evidence since the two methods have distinct assumptions that make comparisons between their results invaluable.

Methods: We mined ClinicalTrials.Gov, PubMed and EpigraphDB databases and carried out a series of 26 manual literature comparisons among 54 MR and 77 RCT publications.

Results: We found that only 13% of completed RCTs identified in ClinicalTrials.Gov submitted their results to the database. Similarly low coverage was revealed for Semantic Medline (SemMedDB) semantic triples derived from MR and RCT publications -36% and 12%, respectively. Among intervention types that can be mimicked by MR, only trials of pharmaceutical interventions could be automatically matched to MR results due to insufficient annotation with Medical Subject Headings ontology. A manual survey of the literature highlighted the potential for triangulation across a number of exposure/outcome pairs if these challenges can be addressed.

Conclusions: We conclude that careful triangulation of MR with RCT evidence should involve consideration of similarity of phenotypes across study designs, intervention intensity and duration, study population demography and health status, comparator group, intervention goal and quality of evidence.

Keywords: Clinical trials; EPIDEMIOLOGIC STUDIES; EPIDEMIOLOGY.

Figure 1

Comparison of Mendelian randomisation and randomised controlled trial design. After: Nitsch et al, Ebrahim and Smith and Ference.

Figure 2

(A) Filtering steps applied to ClinicalTrials.Gov database. Filtering was designed to identify RCTs whose final results statistics were uploaded to the database (main dataset). In addition, other RCTs which published their findings in scientific journals were identified (literature dataset). (B) Filtering steps applied to EpigraphDB database. Filtering was designed to identify protein QTL MR studies with intervention and exposure matching those of RCT published on ClinicalTrials.Gov. MR, Mendelian randomisation; QTL, quantitative trait loci; RCT, randomised controlled trial.

Figure 3

Popularity of MR and RCT studies over time. We compare counts of MR and RCT papers indexed by PubMed (solid lines) with number of semantic triples derived from them using SemMedDB (dashed lines). MR, Mendelian randomisation; RCT, randomised controlled trial.

Figure 4

Summary of case series of MR and RCT studies with matching exposures (interventions) and outcomes (conditions). The values correspond to the number of analysed studies in a given category, while the cell background colour indicates summary direction of effect on the outcome when exposure is increased—we report direction of effect found either in all analysed studies or their majority (>50%). MR, Mendelian randomisation; RCT, randomised controlled trial.