{ "benchmark_id": "mr-twas-scipy-v1", "validation_set_id": "VAL-SET-019-MR-TWAS-12COHORT", "timestamp_utc": "2026-11-03T00:50:00Z", "native_engine": "bio-suite 4-Stage Allele-Oriented Multiplicative Random-Effects IVW, MR-Egger Pleiotropy & Weighted Median Engine", "reference_tool": "SciPy v1.18.1 (scipy.linalg.lstsq + WLS / Weighted Median)", "total_cohorts": 12, "dev_cohorts": 6, "reserve_cohorts": 6, "total_instruments_evaluated": 120, "mae_ivw_beta": 0.0, "mae_ivw_se": 0.0, "mae_cochran_q": 0.0, "mae_egger_slope": 0.0, "mae_egger_intercept": 0.0, "mae_weighted_median_beta": 0.0, "pearson_r_ivw_beta": 1.0, "pearson_r_egger_slope": 1.0, "pearson_r_weighted_median": 1.0, "regime_concordance_rate": 1.0, "native_runtime_ms": 0.3805, "scipy_runtime_ms": 7.2, "speedup_factor": 18.9225, "ascii_mr_forest_and_egger_plot": "============================================================================================================\n TWO-SAMPLE MENDELIAN RANDOMIZATION (IVW, MR-EGGER & WEIGHTED MEDIAN) CALIBRATION (VAL-SET-019)\n============================================================================================================\n Cohort Split Exposure -> Outcome beta_IVW beta_WM beta_Egg alpha_Egg Q_IVW Regime\n ----------------------------------------------------------------------------------------------------------\n DEV-01 DEV Genetically Proxied PCSK9 & HMG -0.4505 -0.4510 -0.4528 +0.0004 0.07 ConcordantProtectiveCausalEffect\n DEV-02 DEV IL6R Asp358Ala Down-Regulated T -0.3153 -0.3159 -0.3177 +0.0004 0.07 ConcordantProtectiveCausalEffect\n DEV-03 DEV Circulating Lipoprotein(a) Mass +0.3847 +0.3841 +0.3821 +0.0004 0.07 ConcordantRiskCausalEffect\n DEV-04 DEV Genetically Predicted Body Mass +0.5197 +0.5191 +0.5173 +0.0004 0.07 ConcordantRiskCausalEffect\n DEV-05 DEV ANGPTL3 & LPL Triglyceride-Rich -0.3603 -0.3609 -0.3628 +0.0004 0.07 ConcordantProtectiveCausalEffect\n DEV-06 DEV Circulating C-Reactive Protein +0.0017 +0.0012 -0.0007 +0.0004 0.07 NullNonCausalInstrumentSet\n RES-01 RESERVE TYK2 Pseudokinase & IL23R Cytok -0.4904 -0.4910 -0.4927 +0.0004 0.07 ConcordantProtectiveCausalEffect\n RES-02 RESERVE Genetically Predicted Systolic +0.4646 +0.4641 +0.4622 +0.0004 0.07 ConcordantRiskCausalEffect\n RES-03 RESERVE APOC3 Loss-of-Function Plasma T -0.3954 -0.3959 -0.3977 +0.0004 0.07 ConcordantProtectiveCausalEffect\n RES-04 RESERVE Circulating Macrophage Metalloe +0.2948 +0.2943 +0.2923 +0.0004 0.07 ConcordantRiskCausalEffect\n RES-05 RESERVE GLP1R Agonist Genetic Proxy (Al -0.3403 -0.3409 -0.3427 +0.0004 0.07 ConcordantProtectiveCausalEffect\n RES-06 RESERVE Pleiotropic HDL-Cholesterol Ins +0.0834 +0.0015 -0.5006 +0.1003 178.10 HorizontalPleiotropyConfoundedReject\n============================================================================================================\n", "cohorts": [ { "cohort_id": "DEV-01", "split": "Development", "exposure_trait": "Genetically Proxied PCSK9 & HMGCR LDL-C Lowering (SD)", "outcome_trait": "Coronary Artery Disease & Myocardial Infarction (CARDIoGRAMplusC4D)", "therapeutic_or_biological_anchor": "PCSK9 / HMGCR Inhibition (Evolocumab & Statin Target Validation)", "instrument_count": 10, "mean_f_statistic": 283.0249, "is_negative_control": false, "native_ivw_beta": -0.4505, "native_ivw_se_mre": 0.0272, "native_ivw_z": -16.592, "native_cochran_q": 0.0681, "native_i2_percent": 0.0, "native_egger_slope": -0.4528, "native_egger_slope_se": 0.0733, "native_egger_intercept": 0.0004, "native_egger_intercept_se": 0.0113, "native_egger_intercept_t": 0.0343, "native_rucker_q_prime": 0.0669, "native_weighted_median_beta": -0.451, "native_regime": "ConcordantProtectiveCausalEffect", "scipy_ivw_beta": -0.4505, "scipy_ivw_se_mre": 0.0272, "scipy_ivw_z": -16.592, "scipy_cochran_q": 0.0681, "scipy_i2_percent": 0.0, "scipy_egger_slope": -0.4528, "scipy_egger_slope_se": 0.0733, "scipy_egger_intercept": 0.0004, "scipy_egger_intercept_se": 0.0113, "scipy_egger_intercept_t": 0.0343, "scipy_rucker_q_prime": 0.0669, "scipy_weighted_median_beta": -0.451, "scipy_regime": "ConcordantProtectiveCausalEffect", "abs_diff_ivw_beta": 0.0, "abs_diff_ivw_se": 0.0, "abs_diff_cochran_q": 0.0, "abs_diff_egger_slope": 0.0, "abs_diff_egger_intercept": 0.0, "abs_diff_weighted_median": 0.0, "regime_concordant": true, "top_instruments": [ { "rsid": "rs1159101", "gene_locus": "PCSK9-R46L", "oriented_beta_exp": 0.065, "oriented_beta_out": -0.0281, "f_statistic": 66.0156, "wald_ratio": -0.4323, "wald_se": 0.1846, "ivw_normalized_weight": 0.0216 }, { "rsid": "rs1159102", "gene_locus": "PCSK9-E670G", "oriented_beta_exp": 0.082, "oriented_beta_out": -0.0384, "f_statistic": 83.0123, "wald_ratio": -0.4683, "wald_se": 0.1646, "ivw_normalized_weight": 0.0272 }, { "rsid": "rs1159103", "gene_locus": "HMGCR-rs12916", "oriented_beta_exp": 0.095, "oriented_beta_out": -0.042, "f_statistic": 90.25, "wald_ratio": -0.4421, "wald_se": 0.1579, "ivw_normalized_weight": 0.0296 }, { "rsid": "rs1159104", "gene_locus": "LDLR-rs6511720", "oriented_beta_exp": 0.11, "oriented_beta_out": -0.0505, "f_statistic": 100.0, "wald_ratio": -0.4591, "wald_se": 0.1091, "ivw_normalized_weight": 0.0619 }, { "rsid": "rs1159105", "gene_locus": "APOB-rs515135", "oriented_beta_exp": 0.128, "oriented_beta_out": -0.0562, "f_statistic": 256.0, "wald_ratio": -0.4391, "wald_se": 0.1055, "ivw_normalized_weight": 0.0663 } ] }, { "cohort_id": "DEV-02", "split": "Development", "exposure_trait": "IL6R Asp358Ala Down-Regulated Trans-Signaling (cis-pQTL / sIL-6R)", "outcome_trait": "Coronary Heart Disease & Rheumatoid Arthritis Risk", "therapeutic_or_biological_anchor": "IL-6 Receptor Blockade (Tocilizumab / Sarilumab Mechanism)", "instrument_count": 10, "mean_f_statistic": 283.0249, "is_negative_control": false, "native_ivw_beta": -0.3153, "native_ivw_se_mre": 0.0272, "native_ivw_z": -11.6143, "native_cochran_q": 0.0698, "native_i2_percent": 0.0, "native_egger_slope": -0.3177, "native_egger_slope_se": 0.0733, "native_egger_intercept": 0.0004, "native_egger_intercept_se": 0.0113, "native_egger_intercept_t": 0.0353, "native_rucker_q_prime": 0.0685, "native_weighted_median_beta": -0.3159, "native_regime": "ConcordantProtectiveCausalEffect", "scipy_ivw_beta": -0.3153, "scipy_ivw_se_mre": 0.0272, "scipy_ivw_z": -11.6143, "scipy_cochran_q": 0.0698, "scipy_i2_percent": 0.0, "scipy_egger_slope": -0.3177, "scipy_egger_slope_se": 0.0733, "scipy_egger_intercept": 0.0004, "scipy_egger_intercept_se": 0.0113, "scipy_egger_intercept_t": 0.0353, "scipy_rucker_q_prime": 0.0685, "scipy_weighted_median_beta": -0.3159, "scipy_regime": "ConcordantProtectiveCausalEffect", "abs_diff_ivw_beta": 0.0, "abs_diff_ivw_se": 0.0, "abs_diff_cochran_q": 0.0, "abs_diff_egger_slope": 0.0, "abs_diff_egger_intercept": 0.0, "abs_diff_weighted_median": 0.0, "regime_concordant": true, "top_instruments": [ { "rsid": "rs2228101", "gene_locus": "IL6R-D358A", "oriented_beta_exp": 0.065, "oriented_beta_out": -0.0193, "f_statistic": 66.0156, "wald_ratio": -0.2969, "wald_se": 0.1846, "ivw_normalized_weight": 0.0216 }, { "rsid": "rs2228102", "gene_locus": "IL6R-intron1", "oriented_beta_exp": 0.082, "oriented_beta_out": -0.0273, "f_statistic": 83.0123, "wald_ratio": -0.3329, "wald_se": 0.1646, "ivw_normalized_weight": 0.0272 }, { "rsid": "rs2228103", "gene_locus": "IL6R-prom", "oriented_beta_exp": 0.095, "oriented_beta_out": -0.0291, "f_statistic": 90.25, "wald_ratio": -0.3063, "wald_se": 0.1579, "ivw_normalized_weight": 0.0296 }, { "rsid": "rs2228104", "gene_locus": "IL6R-3UTR", "oriented_beta_exp": 0.11, "oriented_beta_out": -0.0357, "f_statistic": 100.0, "wald_ratio": -0.3245, "wald_se": 0.1091, "ivw_normalized_weight": 0.0619 }, { "rsid": "rs2228105", "gene_locus": "IL6R-enh1", "oriented_beta_exp": 0.128, "oriented_beta_out": -0.0389, "f_statistic": 256.0, "wald_ratio": -0.3039, "wald_se": 0.1055, "ivw_normalized_weight": 0.0663 } ] }, { "cohort_id": "DEV-03", "split": "Development", "exposure_trait": "Circulating Lipoprotein(a) Mass Concentration (LPA cis-pQTL)", "outcome_trait": "Calcific Aortic Valve Stenosis & Coronary Heart Disease", "therapeutic_or_biological_anchor": "Hepatocyte LPA ASO / siRNA Target Validation (Pelacarsen / Olpasiran)", "instrument_count": 10, "mean_f_statistic": 283.0249, "is_negative_control": false, "native_ivw_beta": 0.3847, "native_ivw_se_mre": 0.0272, "native_ivw_z": 14.1702, "native_cochran_q": 0.0684, "native_i2_percent": 0.0, "native_egger_slope": 0.3821, "native_egger_slope_se": 0.0733, "native_egger_intercept": 0.0004, "native_egger_intercept_se": 0.0113, "native_egger_intercept_t": 0.0379, "native_rucker_q_prime": 0.067, "native_weighted_median_beta": 0.3841, "native_regime": "ConcordantRiskCausalEffect", "scipy_ivw_beta": 0.3847, "scipy_ivw_se_mre": 0.0272, "scipy_ivw_z": 14.1702, "scipy_cochran_q": 0.0684, "scipy_i2_percent": 0.0, "scipy_egger_slope": 0.3821, "scipy_egger_slope_se": 0.0733, "scipy_egger_intercept": 0.0004, "scipy_egger_intercept_se": 0.0113, "scipy_egger_intercept_t": 0.0379, "scipy_rucker_q_prime": 0.067, "scipy_weighted_median_beta": 0.3841, "scipy_regime": "ConcordantRiskCausalEffect", "abs_diff_ivw_beta": 0.0, "abs_diff_ivw_se": 0.0, "abs_diff_cochran_q": 0.0, "abs_diff_egger_slope": 0.0, "abs_diff_egger_intercept": 0.0, "abs_diff_weighted_median": 0.0, "regime_concordant": true, "top_instruments": [ { "rsid": "rs1045501", "gene_locus": "LPA-I4399M", "oriented_beta_exp": 0.065, "oriented_beta_out": 0.0262, "f_statistic": 66.0156, "wald_ratio": 0.4031, "wald_se": 0.1846, "ivw_normalized_weight": 0.0216 }, { "rsid": "rs1045502", "gene_locus": "LPA-M2989T", "oriented_beta_exp": 0.082, "oriented_beta_out": 0.0301, "f_statistic": 83.0123, "wald_ratio": 0.3671, "wald_se": 0.1646, "ivw_normalized_weight": 0.0272 }, { "rsid": "rs1045503", "gene_locus": "LPA-KIV2-tag1", "oriented_beta_exp": 0.095, "oriented_beta_out": 0.0374, "f_statistic": 90.25, "wald_ratio": 0.3937, "wald_se": 0.1579, "ivw_normalized_weight": 0.0296 }, { "rsid": "rs1045504", "gene_locus": "LPA-KIV2-tag2", "oriented_beta_exp": 0.11, "oriented_beta_out": 0.0414, "f_statistic": 100.0, "wald_ratio": 0.3764, "wald_se": 0.1091, "ivw_normalized_weight": 0.0619 }, { "rsid": "rs1045505", "gene_locus": "LPA-prom1", "oriented_beta_exp": 0.128, "oriented_beta_out": 0.0507, "f_statistic": 256.0, "wald_ratio": 0.3961, "wald_se": 0.1055, "ivw_normalized_weight": 0.0663 } ] }, { "cohort_id": "DEV-04", "split": "Development", "exposure_trait": "Genetically Predicted Body Mass Index (GIANT Adult BMI SD)", "outcome_trait": "Type 2 Diabetes Mellitus Incidence (DIAGRAM)", "therapeutic_or_biological_anchor": "Hypothalamic Adiposity & Systemic Insulin Resistance Axis", "instrument_count": 10, "mean_f_statistic": 283.0249, "is_negative_control": false, "native_ivw_beta": 0.5197, "native_ivw_se_mre": 0.0272, "native_ivw_z": 19.1399, "native_cochran_q": 0.0686, "native_i2_percent": 0.0, "native_egger_slope": 0.5173, "native_egger_slope_se": 0.0733, "native_egger_intercept": 0.0004, "native_egger_intercept_se": 0.0113, "native_egger_intercept_t": 0.035, "native_rucker_q_prime": 0.0674, "native_weighted_median_beta": 0.5191, "native_regime": "ConcordantRiskCausalEffect", "scipy_ivw_beta": 0.5197, "scipy_ivw_se_mre": 0.0272, "scipy_ivw_z": 19.1399, "scipy_cochran_q": 0.0686, "scipy_i2_percent": 0.0, "scipy_egger_slope": 0.5173, "scipy_egger_slope_se": 0.0733, "scipy_egger_intercept": 0.0004, "scipy_egger_intercept_se": 0.0113, "scipy_egger_intercept_t": 0.035, "scipy_rucker_q_prime": 0.0674, "scipy_weighted_median_beta": 0.5191, "scipy_regime": "ConcordantRiskCausalEffect", "abs_diff_ivw_beta": 0.0, "abs_diff_ivw_se": 0.0, "abs_diff_cochran_q": 0.0, "abs_diff_egger_slope": 0.0, "abs_diff_egger_intercept": 0.0, "abs_diff_weighted_median": 0.0, "regime_concordant": true, "top_instruments": [ { "rsid": "rs9939601", "gene_locus": "FTO-intron1", "oriented_beta_exp": 0.065, "oriented_beta_out": 0.035, "f_statistic": 66.0156, "wald_ratio": 0.5385, "wald_se": 0.1846, "ivw_normalized_weight": 0.0216 }, { "rsid": "rs9939602", "gene_locus": "MC4R-distal", "oriented_beta_exp": 0.082, "oriented_beta_out": 0.0411, "f_statistic": 83.0123, "wald_ratio": 0.5012, "wald_se": 0.1646, "ivw_normalized_weight": 0.0272 }, { "rsid": "rs9939603", "gene_locus": "TMEM18-5p", "oriented_beta_exp": 0.095, "oriented_beta_out": 0.0502, "f_statistic": 90.25, "wald_ratio": 0.5284, "wald_se": 0.1579, "ivw_normalized_weight": 0.0296 }, { "rsid": "rs9939604", "gene_locus": "BDNF-Val66Met", "oriented_beta_exp": 0.11, "oriented_beta_out": 0.0562, "f_statistic": 100.0, "wald_ratio": 0.5109, "wald_se": 0.1091, "ivw_normalized_weight": 0.0619 }, { "rsid": "rs9939605", "gene_locus": "GNPDA2-prom", "oriented_beta_exp": 0.128, "oriented_beta_out": 0.068, "f_statistic": 256.0, "wald_ratio": 0.5313, "wald_se": 0.1055, "ivw_normalized_weight": 0.0663 } ] }, { "cohort_id": "DEV-05", "split": "Development", "exposure_trait": "ANGPTL3 & LPL Triglyceride-Rich Lipoprotein Clearance", "outcome_trait": "Ischemic Coronary Artery Disease Protection", "therapeutic_or_biological_anchor": "ANGPTL3 Monoclonal Antibody / siRNA Inhibition (Evinacumab)", "instrument_count": 10, "mean_f_statistic": 283.0249, "is_negative_control": false, "native_ivw_beta": -0.3603, "native_ivw_se_mre": 0.0272, "native_ivw_z": -13.2709, "native_cochran_q": 0.0676, "native_i2_percent": 0.0, "native_egger_slope": -0.3628, "native_egger_slope_se": 0.0733, "native_egger_intercept": 0.0004, "native_egger_intercept_se": 0.0113, "native_egger_intercept_t": 0.0361, "native_rucker_q_prime": 0.0663, "native_weighted_median_beta": -0.3609, "native_regime": "ConcordantProtectiveCausalEffect", "scipy_ivw_beta": -0.3603, "scipy_ivw_se_mre": 0.0272, "scipy_ivw_z": -13.2709, "scipy_cochran_q": 0.0676, "scipy_i2_percent": 0.0, "scipy_egger_slope": -0.3628, "scipy_egger_slope_se": 0.0733, "scipy_egger_intercept": 0.0004, "scipy_egger_intercept_se": 0.0113, "scipy_egger_intercept_t": 0.0361, "scipy_rucker_q_prime": 0.0663, "scipy_weighted_median_beta": -0.3609, "scipy_regime": "ConcordantProtectiveCausalEffect", "abs_diff_ivw_beta": 0.0, "abs_diff_ivw_se": 0.0, "abs_diff_cochran_q": 0.0, "abs_diff_egger_slope": 0.0, "abs_diff_egger_intercept": 0.0, "abs_diff_weighted_median": 0.0, "regime_concordant": true, "top_instruments": [ { "rsid": "rs1120701", "gene_locus": "ANGPTL3-S17X", "oriented_beta_exp": 0.065, "oriented_beta_out": -0.0222, "f_statistic": 66.0156, "wald_ratio": -0.3415, "wald_se": 0.1846, "ivw_normalized_weight": 0.0216 }, { "rsid": "rs1120702", "gene_locus": "ANGPTL3-E129X", "oriented_beta_exp": 0.082, "oriented_beta_out": -0.031, "f_statistic": 83.0123, "wald_ratio": -0.378, "wald_se": 0.1646, "ivw_normalized_weight": 0.0272 }, { "rsid": "rs1120703", "gene_locus": "ANGPTL3-prom", "oriented_beta_exp": 0.095, "oriented_beta_out": -0.0334, "f_statistic": 90.25, "wald_ratio": -0.3516, "wald_se": 0.1579, "ivw_normalized_weight": 0.0296 }, { "rsid": "rs1120704", "gene_locus": "LPL-S447X", "oriented_beta_exp": 0.11, "oriented_beta_out": -0.0406, "f_statistic": 100.0, "wald_ratio": -0.3691, "wald_se": 0.1091, "ivw_normalized_weight": 0.0619 }, { "rsid": "rs1120705", "gene_locus": "LPL-N291S", "oriented_beta_exp": 0.128, "oriented_beta_out": -0.0447, "f_statistic": 256.0, "wald_ratio": -0.3492, "wald_se": 0.1055, "ivw_normalized_weight": 0.0663 } ] }, { "cohort_id": "DEV-06", "split": "Development", "exposure_trait": "Circulating C-Reactive Protein (CRP cis-pQTLs — Null Control)", "outcome_trait": "Coronary Heart Disease (Non-Causal Observational Confounder)", "therapeutic_or_biological_anchor": "Classic Negative Control: CRP Is a Downstream Inflammatory Marker, Not a Causal Driver of CHD", "instrument_count": 10, "mean_f_statistic": 283.0249, "is_negative_control": true, "native_ivw_beta": 0.0017, "native_ivw_se_mre": 0.0272, "native_ivw_z": 0.0627, "native_cochran_q": 0.0669, "native_i2_percent": 0.0, "native_egger_slope": -0.0007, "native_egger_slope_se": 0.0733, "native_egger_intercept": 0.0004, "native_egger_intercept_se": 0.0113, "native_egger_intercept_t": 0.0354, "native_rucker_q_prime": 0.0656, "native_weighted_median_beta": 0.0012, "native_regime": "NullNonCausalInstrumentSet", "scipy_ivw_beta": 0.0017, "scipy_ivw_se_mre": 0.0272, "scipy_ivw_z": 0.0627, "scipy_cochran_q": 0.0669, "scipy_i2_percent": 0.0, "scipy_egger_slope": -0.0007, "scipy_egger_slope_se": 0.0733, "scipy_egger_intercept": 0.0004, "scipy_egger_intercept_se": 0.0113, "scipy_egger_intercept_t": 0.0354, "scipy_rucker_q_prime": 0.0656, "scipy_weighted_median_beta": 0.0012, "scipy_regime": "NullNonCausalInstrumentSet", "abs_diff_ivw_beta": 0.0, "abs_diff_ivw_se": 0.0, "abs_diff_cochran_q": 0.0, "abs_diff_egger_slope": 0.0, "abs_diff_egger_intercept": 0.0, "abs_diff_weighted_median": 0.0, "regime_concordant": true, "top_instruments": [ { "rsid": "rs1205001", "gene_locus": "CRP-rs1205", "oriented_beta_exp": 0.065, 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