{ "schema": "nmd-vcell-candidate-pathway-cascade/1.0", "analysis_release": "PCN-v0.1-20260802", "scientific_release": "v1.1.0-cascade-resource", "interface_build": "EA-20260803-47", "generated": "2026-08-03", "counts": { "candidate_perturbations": 21, "measured_hepg2_response_genes": 9623, "reactome_pathway_nodes": 1360, "reactome_topology_edges": 11336, "provisional_cross_context_priorities": 3, "measured_dmd_candidate_replications": 0 }, "validation": { "reactome_graph_median_heldout_pathway_spearman": 0.766629, "reactome_graph_mean_heldout_pathway_spearman": 0.763299, "permuted_graph_mean_heldout_pathway_spearman": 0.018015, "cross_candidate_mean_heldout_pathway_spearman": 0.08835, "interpretation": "Topology reconstruction diagnostic. Pathways overlap in member genes, so this is not independent biological validation." }, "external_dmd_stress_test": { "result": "heterogeneous_not_replication_success", "metrics": [ { "scope": "GENE", "left_axis": "DMD1_minus_WT", "right_axis": "GSE233606_CRISPR_DMD", "ideal_relation": "same", "n_overlap": 14221, "pearson_to_ideal": -0.0162, "spearman_to_ideal": -0.02, "cosine_to_ideal": -0.0067, "direction_agreement_to_ideal": 0.4898, "inference_warning": "genes_are_not_independent_and_one_shared_WT_reference" }, { "scope": "GENE", "left_axis": "DMD1_minus_WT", "right_axis": "GSE233606_PATIENT_DMD", "ideal_relation": "same", "n_overlap": 14221, "pearson_to_ideal": 0.0114, "spearman_to_ideal": 0.027, "cosine_to_ideal": 0.0081, "direction_agreement_to_ideal": 0.4803, "inference_warning": "genes_are_not_independent_and_one_shared_WT_reference" }, { "scope": "GENE", "left_axis": "DMD1_minus_WT", "right_axis": "GSE272233_DISEASE_MEDIAN", "ideal_relation": "same", "n_overlap": 12745, "pearson_to_ideal": 0.046, "spearman_to_ideal": 0.0804, "cosine_to_ideal": 0.0431, "direction_agreement_to_ideal": 0.5602, "inference_warning": "genes_are_not_independent_and_one_shared_WT_reference" }, { "scope": "GENE", "left_axis": "DMD1_minus_WT", "right_axis": "GSE272233_CORRECTION_MEDIAN", "ideal_relation": "opposite", "n_overlap": 12745, "pearson_to_ideal": -0.0585, "spearman_to_ideal": -0.0755, "cosine_to_ideal": -0.0844, "direction_agreement_to_ideal": 0.4743, "inference_warning": "genes_are_not_independent_and_one_shared_WT_reference" }, { "scope": "GENE", "left_axis": "DMD2_minus_WT", "right_axis": "GSE233606_CRISPR_DMD", "ideal_relation": "same", "n_overlap": 14221, "pearson_to_ideal": 0.0081, "spearman_to_ideal": 0.0126, "cosine_to_ideal": 0.0143, "direction_agreement_to_ideal": 0.5009, "inference_warning": "genes_are_not_independent_and_one_shared_WT_reference" }, { "scope": "GENE", "left_axis": "DMD2_minus_WT", "right_axis": "GSE233606_PATIENT_DMD", "ideal_relation": "same", "n_overlap": 14221, "pearson_to_ideal": 0.0567, "spearman_to_ideal": 0.0598, "cosine_to_ideal": 0.0523, "direction_agreement_to_ideal": 0.5032, "inference_warning": "genes_are_not_independent_and_one_shared_WT_reference" }, { "scope": "GENE", "left_axis": "DMD2_minus_WT", "right_axis": "GSE272233_DISEASE_MEDIAN", "ideal_relation": "same", "n_overlap": 12745, "pearson_to_ideal": -0.1041, "spearman_to_ideal": -0.1541, "cosine_to_ideal": -0.0991, "direction_agreement_to_ideal": 0.4577, "inference_warning": "genes_are_not_independent_and_one_shared_WT_reference" }, { "scope": "GENE", "left_axis": "DMD2_minus_WT", "right_axis": "GSE272233_CORRECTION_MEDIAN", "ideal_relation": "opposite", "n_overlap": 12745, "pearson_to_ideal": -0.0046, "spearman_to_ideal": 0.0326, "cosine_to_ideal": -0.0261, "direction_agreement_to_ideal": 0.5133, "inference_warning": "genes_are_not_independent_and_one_shared_WT_reference" }, { "scope": "GENE", "left_axis": "DMD3_minus_WT", "right_axis": "GSE233606_CRISPR_DMD", "ideal_relation": "same", "n_overlap": 14221, "pearson_to_ideal": -0.0216, "spearman_to_ideal": -0.0234, "cosine_to_ideal": -0.0206, "direction_agreement_to_ideal": 0.4918, "inference_warning": "genes_are_not_independent_and_one_shared_WT_reference" }, { "scope": "GENE", "left_axis": "DMD3_minus_WT", "right_axis": "GSE233606_PATIENT_DMD", "ideal_relation": "same", "n_overlap": 14221, "pearson_to_ideal": -0.0139, "spearman_to_ideal": 0.0012, "cosine_to_ideal": -0.0142, "direction_agreement_to_ideal": 0.4917, "inference_warning": "genes_are_not_independent_and_one_shared_WT_reference" }, { "scope": "GENE", "left_axis": "DMD3_minus_WT", "right_axis": "GSE272233_DISEASE_MEDIAN", "ideal_relation": "same", "n_overlap": 12745, "pearson_to_ideal": 0.0825, "spearman_to_ideal": 0.1252, "cosine_to_ideal": 0.0826, "direction_agreement_to_ideal": 0.5537, "inference_warning": "genes_are_not_independent_and_one_shared_WT_reference" }, { "scope": "GENE", "left_axis": "DMD3_minus_WT", "right_axis": "GSE272233_CORRECTION_MEDIAN", "ideal_relation": "opposite", "n_overlap": 12745, "pearson_to_ideal": -0.0832, "spearman_to_ideal": -0.1132, "cosine_to_ideal": -0.0864, "direction_agreement_to_ideal": 0.4579, "inference_warning": "genes_are_not_independent_and_one_shared_WT_reference" }, { "scope": "GENE", "left_axis": "median_DMD_minus_WT", "right_axis": "GSE233606_CRISPR_DMD", "ideal_relation": "same", "n_overlap": 14221, "pearson_to_ideal": -0.0081, "spearman_to_ideal": -0.0207, "cosine_to_ideal": -0.0, "direction_agreement_to_ideal": 0.4911, "inference_warning": "genes_are_not_independent_and_one_shared_WT_reference" }, { "scope": "GENE", "left_axis": "median_DMD_minus_WT", "right_axis": "GSE233606_PATIENT_DMD", "ideal_relation": "same", "n_overlap": 14221, "pearson_to_ideal": 0.0222, "spearman_to_ideal": 0.0375, "cosine_to_ideal": 0.0186, "direction_agreement_to_ideal": 0.4867, "inference_warning": "genes_are_not_independent_and_one_shared_WT_reference" }, { "scope": "GENE", "left_axis": "median_DMD_minus_WT", "right_axis": "GSE272233_DISEASE_MEDIAN", "ideal_relation": "same", "n_overlap": 12745, "pearson_to_ideal": 0.0283, "spearman_to_ideal": 0.0351, "cosine_to_ideal": 0.0274, "direction_agreement_to_ideal": 0.5373, "inference_warning": "genes_are_not_independent_and_one_shared_WT_reference" }, { "scope": "GENE", "left_axis": "median_DMD_minus_WT", "right_axis": "GSE272233_CORRECTION_MEDIAN", "ideal_relation": "opposite", "n_overlap": 12745, "pearson_to_ideal": -0.0699, "spearman_to_ideal": -0.0732, "cosine_to_ideal": -0.0923, "direction_agreement_to_ideal": 0.4745, "inference_warning": "genes_are_not_independent_and_one_shared_WT_reference" }, { "scope": "REACTOME_PATHWAY", "left_axis": "DMD1_minus_WT", "right_axis": "GSE233606_CRISPR_DMD", "ideal_relation": "same", "n_overlap": 1531, "pearson_to_ideal": -0.1389, "spearman_to_ideal": -0.1136, "cosine_to_ideal": 0.2095, "direction_agreement_to_ideal": 0.6558, "inference_warning": "overlapping_pathways_are_not_independent_and_one_shared_WT_reference" }, { "scope": "REACTOME_PATHWAY", "left_axis": "DMD1_minus_WT", "right_axis": "GSE233606_PATIENT_DMD", "ideal_relation": "same", "n_overlap": 1531, "pearson_to_ideal": -0.0588, "spearman_to_ideal": 0.0498, "cosine_to_ideal": 0.0286, "direction_agreement_to_ideal": 0.4997, "inference_warning": "overlapping_pathways_are_not_independent_and_one_shared_WT_reference" }, { "scope": "REACTOME_PATHWAY", "left_axis": "DMD1_minus_WT", "right_axis": "GSE272233_DISEASE_MEDIAN", "ideal_relation": "same", "n_overlap": 1511, "pearson_to_ideal": 0.1678, "spearman_to_ideal": 0.1399, "cosine_to_ideal": 0.2842, "direction_agreement_to_ideal": 0.6803, "inference_warning": "overlapping_pathways_are_not_independent_and_one_shared_WT_reference" }, { "scope": "REACTOME_PATHWAY", "left_axis": "DMD1_minus_WT", "right_axis": "GSE272233_CORRECTION_MEDIAN", "ideal_relation": "opposite", "n_overlap": 1511, "pearson_to_ideal": -0.1151, "spearman_to_ideal": -0.0883, "cosine_to_ideal": -0.4587, "direction_agreement_to_ideal": 0.2502, "inference_warning": "overlapping_pathways_are_not_independent_and_one_shared_WT_reference" }, { "scope": "REACTOME_PATHWAY", "left_axis": "DMD2_minus_WT", "right_axis": "GSE233606_CRISPR_DMD", "ideal_relation": "same", "n_overlap": 1531, "pearson_to_ideal": -0.215, "spearman_to_ideal": -0.2061, "cosine_to_ideal": 0.0887, "direction_agreement_to_ideal": 0.6414, "inference_warning": "overlapping_pathways_are_not_independent_and_one_shared_WT_reference" }, { "scope": "REACTOME_PATHWAY", "left_axis": "DMD2_minus_WT", "right_axis": "GSE233606_PATIENT_DMD", "ideal_relation": "same", "n_overlap": 1531, "pearson_to_ideal": 0.1359, "spearman_to_ideal": 0.0418, "cosine_to_ideal": 0.1316, "direction_agreement_to_ideal": 0.5153, "inference_warning": "overlapping_pathways_are_not_independent_and_one_shared_WT_reference" }, { "scope": "REACTOME_PATHWAY", "left_axis": "DMD2_minus_WT", "right_axis": "GSE272233_DISEASE_MEDIAN", "ideal_relation": "same", "n_overlap": 1511, "pearson_to_ideal": -0.0219, "spearman_to_ideal": -0.0379, "cosine_to_ideal": 0.1691, "direction_agreement_to_ideal": 0.6413, "inference_warning": "overlapping_pathways_are_not_independent_and_one_shared_WT_reference" }, { "scope": "REACTOME_PATHWAY", "left_axis": "DMD2_minus_WT", "right_axis": "GSE272233_CORRECTION_MEDIAN", "ideal_relation": "opposite", "n_overlap": 1511, "pearson_to_ideal": 0.0543, "spearman_to_ideal": 0.0355, "cosine_to_ideal": -0.3189, "direction_agreement_to_ideal": 0.2839, "inference_warning": "overlapping_pathways_are_not_independent_and_one_shared_WT_reference" }, { "scope": "REACTOME_PATHWAY", "left_axis": "DMD3_minus_WT", "right_axis": "GSE233606_CRISPR_DMD", "ideal_relation": "same", "n_overlap": 1531, "pearson_to_ideal": 0.0793, "spearman_to_ideal": 0.1298, "cosine_to_ideal": 0.1451, "direction_agreement_to_ideal": 0.6009, "inference_warning": "overlapping_pathways_are_not_independent_and_one_shared_WT_reference" }, { "scope": "REACTOME_PATHWAY", "left_axis": "DMD3_minus_WT", "right_axis": "GSE233606_PATIENT_DMD", "ideal_relation": "same", "n_overlap": 1531, "pearson_to_ideal": -0.1143, "spearman_to_ideal": -0.0435, "cosine_to_ideal": -0.0963, "direction_agreement_to_ideal": 0.4905, "inference_warning": "overlapping_pathways_are_not_independent_and_one_shared_WT_reference" }, { "scope": "REACTOME_PATHWAY", "left_axis": "DMD3_minus_WT", "right_axis": "GSE272233_DISEASE_MEDIAN", "ideal_relation": "same", "n_overlap": 1511, "pearson_to_ideal": 0.0529, "spearman_to_ideal": -0.0092, "cosine_to_ideal": 0.1089, "direction_agreement_to_ideal": 0.5533, "inference_warning": "overlapping_pathways_are_not_independent_and_one_shared_WT_reference" }, { "scope": "REACTOME_PATHWAY", "left_axis": "DMD3_minus_WT", "right_axis": "GSE272233_CORRECTION_MEDIAN", "ideal_relation": "opposite", "n_overlap": 1511, "pearson_to_ideal": -0.2456, "spearman_to_ideal": -0.1949, "cosine_to_ideal": -0.3249, "direction_agreement_to_ideal": 0.3627, "inference_warning": "overlapping_pathways_are_not_independent_and_one_shared_WT_reference" }, { "scope": "REACTOME_PATHWAY", "left_axis": "median_DMD_minus_WT", "right_axis": "GSE233606_CRISPR_DMD", "ideal_relation": "same", "n_overlap": 1531, "pearson_to_ideal": -0.1516, "spearman_to_ideal": -0.1283, "cosine_to_ideal": 0.1866, "direction_agreement_to_ideal": 0.6662, "inference_warning": "overlapping_pathways_are_not_independent_and_one_shared_WT_reference" }, { "scope": "REACTOME_PATHWAY", "left_axis": "median_DMD_minus_WT", "right_axis": "GSE233606_PATIENT_DMD", "ideal_relation": "same", "n_overlap": 1531, "pearson_to_ideal": -0.0644, "spearman_to_ideal": 0.0301, "cosine_to_ideal": 0.0206, "direction_agreement_to_ideal": 0.5167, "inference_warning": "overlapping_pathways_are_not_independent_and_one_shared_WT_reference" }, { "scope": "REACTOME_PATHWAY", "left_axis": "median_DMD_minus_WT", "right_axis": "GSE272233_DISEASE_MEDIAN", "ideal_relation": "same", "n_overlap": 1511, "pearson_to_ideal": 0.134, "spearman_to_ideal": 0.0977, "cosine_to_ideal": 0.2716, "direction_agreement_to_ideal": 0.6684, "inference_warning": "overlapping_pathways_are_not_independent_and_one_shared_WT_reference" }, { "scope": "REACTOME_PATHWAY", "left_axis": "median_DMD_minus_WT", "right_axis": "GSE272233_CORRECTION_MEDIAN", "ideal_relation": "opposite", "n_overlap": 1511, "pearson_to_ideal": -0.1217, "spearman_to_ideal": -0.1014, "cosine_to_ideal": -0.4544, "direction_agreement_to_ideal": 0.2422, "inference_warning": "overlapping_pathways_are_not_independent_and_one_shared_WT_reference" } ], "boundary": "GSE277637 has three DMD lines and one unrelated WT line. Line-level effects are descriptive and cannot support a formal donor-replicated disease test." }, "evidence_states": [ "MEASURED_HEPG2_CANDIDATE_CRISPRI_PATHWAY_DELTA", "REACTOME_TOPOLOGY_NETWORK_CASCADE_PREDICTION", "CROSS_CONTEXT_DMD_PATHWAY_PROJECTION_NOT_DMD_MEASUREMENT", "DMD_CANDIDATE_PERTURBATION_TRUTH_MISSING" ], "claim_boundary": "The release prioritizes prospective tests. It does not contain measured candidate perturbations in DMD muscle, calibrated treatment probabilities, or therapeutic recommendations.", "candidates": [ { "candidate": "ADAM10", "decision_state": "PROVISIONAL_CROSS_CONTEXT_PRIORITY_REQUIRES_DMD_PERTURB_SEQ", "claim_level": "L2_CROSS_CONTEXT_NETWORK_HYPOTHESIS_ONLY", "observed_hepg2_cells": 161, "pathway_split_half_spearman": 0.818, "network_cv_spearman": 0.86, "permuted_network_cv_spearman": 0.113, "disease_consensus_rescue_projection_spearman": 0.331, "gse272233_correction_alignment_spearman": 0.082, "target_gene_measured_delta": -0.3, "skeletal_muscle_median_tpm": 3.116, "abstention_reasons": [], "top_cross_context_pathways": [ { "pathway_id": "R-HSA-6809371", "pathway_name": "Formation of the cornified envelope", "measured_hepg2_direct_delta": 0.052, "network_cascade_score": 0.032, "dmd_rescue_projection_contribution": 9.037, "evidence_state": "CROSS_CONTEXT_DMD_PATHWAY_PROJECTION_NOT_DMD_MEASUREMENT" }, { "pathway_id": "R-HSA-6805567", "pathway_name": "Keratinization", "measured_hepg2_direct_delta": 0.052, "network_cascade_score": 0.032, "dmd_rescue_projection_contribution": 9.037, "evidence_state": "CROSS_CONTEXT_DMD_PATHWAY_PROJECTION_NOT_DMD_MEASUREMENT" }, { "pathway_id": "R-HSA-1566948", "pathway_name": "Elastic fibre formation", "measured_hepg2_direct_delta": 0.062, "network_cascade_score": 0.042, "dmd_rescue_projection_contribution": 5.819, "evidence_state": "CROSS_CONTEXT_DMD_PATHWAY_PROJECTION_NOT_DMD_MEASUREMENT" }, { "pathway_id": "R-HSA-2129379", "pathway_name": "Molecules associated with elastic fibres", "measured_hepg2_direct_delta": 0.073, "network_cascade_score": 0.046, "dmd_rescue_projection_contribution": 5.453, "evidence_state": "CROSS_CONTEXT_DMD_PATHWAY_PROJECTION_NOT_DMD_MEASUREMENT" }, { "pathway_id": "R-HSA-176974", "pathway_name": "Unwinding of DNA", "measured_hepg2_direct_delta": -0.074, "network_cascade_score": -0.035, "dmd_rescue_projection_contribution": 4.525, "evidence_state": "CROSS_CONTEXT_DMD_PATHWAY_PROJECTION_NOT_DMD_MEASUREMENT" }, { "pathway_id": "R-HSA-72689", "pathway_name": "Formation of a pool of free 40S subunits", "measured_hepg2_direct_delta": -0.077, "network_cascade_score": -0.069, "dmd_rescue_projection_contribution": 4.519, "evidence_state": "CROSS_CONTEXT_DMD_PATHWAY_PROJECTION_NOT_DMD_MEASUREMENT" }, { "pathway_id": "R-HSA-156842", "pathway_name": "Eukaryotic Translation Elongation", "measured_hepg2_direct_delta": -0.079, "network_cascade_score": -0.069, "dmd_rescue_projection_contribution": 4.493, "evidence_state": "CROSS_CONTEXT_DMD_PATHWAY_PROJECTION_NOT_DMD_MEASUREMENT" }, { "pathway_id": "R-HSA-156827", "pathway_name": "L13a-mediated translational silencing of Ceruloplasmin expression", "measured_hepg2_direct_delta": -0.076, "network_cascade_score": -0.068, "dmd_rescue_projection_contribution": 4.243, "evidence_state": "CROSS_CONTEXT_DMD_PATHWAY_PROJECTION_NOT_DMD_MEASUREMENT" } ] }, { "candidate": "CALR", "decision_state": "PROVISIONAL_CROSS_CONTEXT_PRIORITY_REQUIRES_DMD_PERTURB_SEQ", "claim_level": "L2_CROSS_CONTEXT_NETWORK_HYPOTHESIS_ONLY", "observed_hepg2_cells": 86, "pathway_split_half_spearman": 0.414, "network_cv_spearman": 0.766, "permuted_network_cv_spearman": 0.059, "disease_consensus_rescue_projection_spearman": 0.193, "gse272233_correction_alignment_spearman": 0.123, "target_gene_measured_delta": -2.162, "skeletal_muscle_median_tpm": 88.631, "abstention_reasons": [], "top_cross_context_pathways": [ { "pathway_id": "R-HSA-381183", "pathway_name": "ATF6 (ATF6-alpha) activates chaperone genes", "measured_hepg2_direct_delta": -0.139, "network_cascade_score": -0.061, "dmd_rescue_projection_contribution": -6.806, "evidence_state": "CROSS_CONTEXT_DMD_PATHWAY_PROJECTION_NOT_DMD_MEASUREMENT" }, { "pathway_id": "R-HSA-9969896", "pathway_name": "Lanosterol biosynthesis", "measured_hepg2_direct_delta": 0.083, "network_cascade_score": 0.041, "dmd_rescue_projection_contribution": 6.689, "evidence_state": "CROSS_CONTEXT_DMD_PATHWAY_PROJECTION_NOT_DMD_MEASUREMENT" }, { "pathway_id": "R-HSA-6785470", "pathway_name": "tRNA processing in the mitochondrion", "measured_hepg2_direct_delta": 0.023, "network_cascade_score": 0.008, "dmd_rescue_projection_contribution": -6.422, "evidence_state": "CROSS_CONTEXT_DMD_PATHWAY_PROJECTION_NOT_DMD_MEASUREMENT" }, { "pathway_id": "R-HSA-975634", "pathway_name": "Retinoid metabolism and transport", "measured_hepg2_direct_delta": 0.074, "network_cascade_score": 0.038, "dmd_rescue_projection_contribution": 6.326, "evidence_state": "CROSS_CONTEXT_DMD_PATHWAY_PROJECTION_NOT_DMD_MEASUREMENT" }, { "pathway_id": "R-HSA-8963889", "pathway_name": "Assembly of active LPL and LIPC lipase complexes", "measured_hepg2_direct_delta": 0.037, "network_cascade_score": 0.031, "dmd_rescue_projection_contribution": -5.286, "evidence_state": "CROSS_CONTEXT_DMD_PATHWAY_PROJECTION_NOT_DMD_MEASUREMENT" }, { "pathway_id": "R-HSA-6806667", "pathway_name": 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