Fig. 4: Comparison of different cis MR methods through effect size analysis, the true and false causal link datasets used for a comparison of discriminative ability of the metabolites in this study. | Nature Communications

Fig. 4: Comparison of different cis MR methods through effect size analysis, the true and false causal link datasets used for a comparison of discriminative ability of the metabolites in this study.

From: MR-link-2: pleiotropy robust cis Mendelian randomization validated in three independent reference datasets of causality

Fig. 4: Comparison of different cis MR methods through effect size analysis, the true and false causal link datasets used for a comparison of discriminative ability of the metabolites in this study.

Causal effects are estimated for an exposure for each associated exposure region, testing single region results for each region. a–d The causal effect estimates of the Mendelian randomization (MR) methods tested in this study, when comparing nominally significant (\(P\le 0.05\)) estimates between a metabolite on itself using two different mQTL datasets, when they are not included in the true positive dataset. The mean (\(\mu\)) of a self-estimate is expected to be 1.0. panels represent different methods: a MR-link-2 (79 comparisons), b MR-IVW (80 comparisons), c MR-IVW LD (82 comparisons) and (d) MR-PCA (80 comparisons). e–h Distribution of Bonferroni significant (\(P\le \,2.1\cdot {10}^{-7}\)) regional causal effect estimates. We report percentage positive effect size estimates, these likely represent direct metabolic reactions, as substrate to product reactions should have positive effect. e MR-link-2 (1242 combinations), f MR-IVW (3218 combinations), g MR-IVW (3373 combinations) and (h) MR-PCA (3229 combinations). i A Venn diagram representing the number of true causal link combinations used for the regional results in this study per pathway definition. True positives are metabolites (one for each associated exposure region) that are one reaction apart. j Negatives used in this study. We define the link between two metabolites as a negative when separated by at least m reactions in the full metabolite graphs created from the databases (combinations with more than 10 links). k–p The area under the receiver operator characteristic curve (AUC) of cis-MR and colocalization methods benchmarked against different databases (k–m) and database combinations (n–p). Only considering comparisons with more than 10 negatives (same as panel j) per positive definition (same as panel i). When there is no SuSIE coloc estimate available for a region, the original coloc estimate is used. True causality and false causality: k from the KEGG pathway, l from the MetaCyc pathway, m from the WikiPathways pathway, n present in any pathway definition, o present in at least two pathway definitions, p shared in all pathways.

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