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"m5-v3-tuned-transfer/3", "seed": 20261013, "frozenBeforeTuningAndNewOutcomeRead": true, "development": "Reuse fixed HeLa training/validation gene partitions from v2; no BJ or K562 outcome used for selection", "holdout": "TE_K562 published aggregate, never previously evaluated here; metadata study indices and sample aliases must be disjoint from HeLa/BJ and legacy studies", "testSelection": "First 600 eligible genes by SHA256('m5-v3-test:'+stableGeneID), excluding ALL v2 feature-extracted genes, original 2500 development genes mapped through original GTF, and prior 1000 HeLa holdout IDs. Same canonical start and UTR<=1000 eligibility as v2. Missing K562 outcomes removed only after predictions freeze.", "tuningBudget": "Exactly six training-only fits per family; same training/validation genes, no test tuning, select highest validation Spearman, no post-selection refit", "M5Candidates": "400-tree LightGBM, lr .03, L2 10, four threads: full context, UTR-only (remove CDS/3UTR lengths), core context (remove k-mer features), each 15 or 31 leaves", "ExtraTreesCandidates": "400 trees, four threads: minimum leaf 2,5,10 crossed with max_features .5 or 1.0; full features", "ridgeCandidates": "StandardScaler plus Ridge alpha .1,1,10,100,1000,10000; full features", "primaryMetric": "Spearman on fresh K562 finite outcomes", "comparisonFamily": [ "tuned ExtraTrees", "tuned ridge", "M5 v2" ], "uncertainty": "2000 paired gene-bootstrap resamples; Bonferroni-adjusted two-sided intervals for three comparisons; superiority requires every lower bound >0", "runtime": "Same frozen real transcripts, batch sizes 1 and 16. First-use subprocess load+extract+predict+JSON serialization and 20 rotating-order warm full-pipeline rounds; folding recomputed for every method/call, no feature cache. Four threads for tree inference; single-thread BLAS for ridge. Report median/p95, paired speedup intervals and components. Also measure actual local HTTP scoring roundtrip including request/response serialization and server feature extraction after integration.", "preservation": "Separate m5-sequence-context-v3 model and versioned evidence; earlier models/checksums immutable", "limitations": [ "Known development validation reused; only new test is confirmatory within this protocol", "Same published compendium processing pipeline; metadata-index separation is not independent-lab execution", "Gene-bootstrap uncertainty conditional on aggregate, not per-study replication", "No therapeutic or patentability conclusion; negative strong-baseline comparisons retained" ] }, "sourceAudit": { "testCell": "K562", "testStudyIndices": [ "256", "273", "558", "594", "616", "710" ], "knownTestGeoStudies": [ "GSE85864", "GSE89183" ], "testSamples": [ "GSM2285912", "GSM2285913", "GSM2285914", "GSM2285915", "GSM2285916", "GSM2285917", "GSM2285918", "GSM2285919", "GSM2285920", "GSM2285921", "GSM2285922", "GSM2285923", "GSM2360175", "GSM2360176", "GSM2360177", "GSM2360178", "GSM2360179", "GSM2360180", "GSM3566410", "GSM3566411", "GSM3566412", "GSM3566420", "GSM3566421", "GSM3692340", "GSM3692341", "GSM4425998", "GSM4425999", "GSM4426000", "GSM4426001", "GSM4426002", "GSM4426003", "GSM4426004", "GSM4426005", "GSM4426006", "GSM4426007", "GSM4426008", "GSM4426009", "GSM4426010", "GSM4426011", "GSM4426012", "GSM4426013", "GSM4647809", "GSM4647810" ], "sharedDevelopmentStudyIndices": [], "sharedSampleAliases": [], "metadataSha256": "21446350b2c51c31838e6a733196be5de4c8418f28c8f39bf1a237a97718ec35", "scope": "Declared metadata study indices/sample aliases disjoint; some GEO names missing, shared compendium processing and broader ENCODE provenance remain limitations" }, "predictionFreeze": { "modelSha256": "406597cf5fc3047166f9a132619dc40d50095ecb68b89109b6d1c93d769c4bbf", "predictionsSha256": "d620bcf59d0748e9c7f71eabde84f41ea575e5a5d1ee172994120348ff8d96fc", "testFeaturesSha256": "af5044364d330864913cf3a369f6b8617462eb6ee904afbdaca29f2e4f8a127a", "K562OutcomesRead": false, "baselineArtifactSha256": { "selected-v3.joblib": "8534cd74372db938df611477ca47ad4f090042d307b9343ba82733d8907fa3c0", "ridge.joblib": "a1adca4be21c03405233ae95e0a21fa5b0943d03a1fca4518fd33070103112da", "extra-trees.joblib": "c2900d59386ca1351e1e017024bdf939a7c2314fdfd1d83021ecdcd8a364f509" } }, "nmd": { "records": [ { "title": "Rapid UPF1 depletion / NMDRHT", "source": "https://github.com/boehmv/2025_UPF1_NMDRHT", "publication": "https://doi.org/10.1016/j.molcel.2025.08.015", "status": "Processed experimental response tables downloaded and inspected", "endpoint": "SLAM-seq transcript degradation-rate change with adjusted p-value; transcript expression responses also available", "evidence": "45,757 transcript rows; 16,515 finite turnover changes with adjusted p-values; 13,678 of those map to a named GENCODE transcript.", "blocker": "Match assay condition, assembly, transcript coordinates, complete CDS/stop geometry and replicate structure. Current M4 is an exon annotation classifier, not a turnover-response predictor. Annotation-derived NMD flags in the same table cannot be experimental gold labels.", "next": "Prefer measured turnover outcomes, reserve genes and study conditions before development, and define a separate experimental-response model.", "downloaded": true }, { "title": "NMDetective-AI public DMS tables", "source": "https://github.com/Vejni/NMDetectiveAI", "publication": "https://github.com/Vejni/NMDetectiveAI", "status": "Public numerical DMS files downloaded; assay/geometry qualification pending", "endpoint": "Reported variant-reporter fitness values and sigma uncertainty, with stop-position/context fields", "evidence": "PE 453, LE 981, SP 10,666 CSV rows. Counts are assay-table rows, not independent genes or biological replicates.", "blocker": "Resolve normalization, controls, transcript/genome mappings, gene overlap and shared construct families. These are variant-reporter outcomes, not current M4 exon annotation labels. Author README says raw TCGA/GTEx variant sets are not shared in this distribution.", "next": "Audit the reporter measurements and uncertainty; group splits by gene and construct family before any fitting.", "downloaded": true }, { "title": "French et al. HeLa UPF1-response isoforms", "source": "https://doi.org/10.6078/D1H019", "publication": "https://doi.org/10.1101/2020.07.01.183327", "status": "Public metadata verified; numerical download returned HTTP 401", "endpoint": "Transcript abundance responses to UPF1 knockdown, with combined transcript GTF and all-isoform response table listed", "evidence": "Repository lists a 16.3 MB all-isoform response table and a 223.6 MB combined GTF. Numeric response rows were not retrieved here.", "blocker": "Access to files and hg19-to-current transcript mapping. The preselected NMD-target list requires a 50-nt geometry rule, so treating that list as independent biological truth would be circular. UPF1 response can include indirect effects.", "next": "Obtain the unfiltered response measurements and replicates through normal repository access; define assay-based outcomes independently of geometry.", "downloaded": false } ], "authorBlobIdentityVerified": { "NMDRHT-Table-S2.xlsx": true, "NMDRHT-Table-S3.xlsx": true, "NMDetectiveAI-PE.csv": true, "NMDetectiveAI-LE.csv": true, "NMDetectiveAI-SP.csv": true }, "M4ExperimentalAccuracyMeasured": false, "note": "No experimental M4 scores are fabricated or inferred from annotation-derived flags." }, "defaultModelReplaced": false, "overallSuperiorityEstablished": false, "runtimeThreadProfile": { "scope": "Validation features only; 19 timed alternating-order inference rounds per thread setting; select faster median; no test outcome used", "policy": { "1": { "M5 v3": 1, "M5 v2": 1, "tuned ExtraTrees": 1, "tuned ridge": 1 }, "16": { "M5 v3": 4, "M5 v2": 4, "tuned ExtraTrees": 1, "tuned ridge": 1 } }, "ledger": [ { "batchSize": 1, "method": "M5 v3", "medianInferenceMs": { "1": 0.3251659999996548, "4": 0.3399590000001673 }, "selectedThreads": 1 }, { "batchSize": 1, "method": "M5 v2", "medianInferenceMs": { "1": 0.31520800000039984, "4": 0.33549999999982205 }, "selectedThreads": 1 }, { "batchSize": 1, "method": "tuned ExtraTrees", "medianInferenceMs": { "1": 16.64362499999994, "4": 37.709917000000374 }, "selectedThreads": 1 }, { "batchSize": 16, "method": "M5 v3", "medianInferenceMs": { "1": 0.945542000000188, "4": 0.7522920000000433 }, "selectedThreads": 4 }, { "batchSize": 16, "method": "M5 v2", "medianInferenceMs": { "1": 0.7289169999999956, "4": 0.6096669999999804 }, "selectedThreads": 4 }, { "batchSize": 16, "method": "tuned ExtraTrees", "medianInferenceMs": { "1": 18.185290999999992, "4": 38.64999999999963 }, "selectedThreads": 1 } ] }, "runtimeAmendment": { "reason": "Four-thread ExtraTrees overhead dominates small batches. Optimize all tree-method thread settings on development inputs before final full-runtime measurements.", "maxAllowedThreads": 4, "selectedOn": "v2 validation feature rows only", "modelWeightsAndAccuracySelectionChanged": false, "previousRuntimeFilesPreserved": true, "remainingLimit": "Thread policy chosen on development microbenchmarks; final timings on same reserved real test inputs. No new accuracy test or tuning." } }