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"ridge", "configurationId": 20, "configuration": { "alpha": 36746619.40736688 }, "innerValidationSpearman": 0.14710495966105383, "fitAndValidationSeconds": 0.026235208000002785 }, { "heldStudy": "NMDRHT", "family": "ridge", "configurationId": 21, "configuration": { "alpha": 110529514.11260243 }, "innerValidationSpearman": 0.14712194140595986, "fitAndValidationSeconds": 0.026198292000003676 }, { "heldStudy": "NMDRHT", "family": "ridge", "configurationId": 22, "configuration": { "alpha": 332459793.22709453 }, "innerValidationSpearman": 0.14710633295846925, "fitAndValidationSeconds": 0.026639000000002966 }, { "heldStudy": "NMDRHT", "family": "ridge", "configurationId": 23, "configuration": { "alpha": 1000000000.0 }, "innerValidationSpearman": 0.1471055335763916, "fitAndValidationSeconds": 0.02615191600000344 } ] } ], "protocol": { "createdUtc": "2026-10-13T13:34:49.948258+00:00", "status": "Frozen before v4 model fits", "evaluation": "Retrospective two-study transfer development. No fresh holdout.", "selection": "Identical existing aligned-v3 gene-hash inner 80/20 split; maximize validation Spearman. Outer-study targets never select configurations.", "candidate": "XGBoost 300 trees, learning_rate .03, max_depth 2/3/5, reg_lambda 10/100, min_child_weight 20/80, objective reg:squarederror/reg:pseudohubererror (24 combinations).", "ExtraTrees": "250 trees, min_samples_leaf 2/5/10/20, max_features .33/.67/1, max_depth 18/None (24 combinations).", "ridge": "24 logarithmically spaced alpha values from .01 to 1e9.", "seed": 2026101304, "threadLimit": 4, "primaryMetric": "Spearman; report MAE and R2 and training-median reference for all cohorts.", "uncertainty": "1000 paired gene bootstrap draws, Bonferroni across eight model/study/baseline comparisons. Development-only conditional intervals, not confirmatory evidence.", "M4": "Reuse v3 gene-aligned targets/features.", "M5": "Use separately labelled GEO counts; paired sample+assay+depletedRPF model for Aliouat. Preserve NMDRHT unpaired assay-by-condition model, as RNA and RPF came from separate experiments. No significant-response filtering.", "freshTestGate": "Qualify human matched endpoint and accessible data; audit sample lineage; freeze predictions and primary decision rule before numerical outcome access.", "promotion": "Research-only models. No promotion based on retrospective superiority.", "inputHashes": { "docs/validation/2026-10-13-response-reconciliation-v4/NMDRHT-te-estimator.json": "9e03401ba79ca8abe4c905a0e9197d963faaf57e2189c3ca3b4c91ef4e94da04", "docs/validation/2026-10-13-response-reconciliation-v4/reconciliation-R-session.txt": "3aefb1c58fb16bd6f8f6eacca44d503b47392d8589b9be8b84c3c1b4d9eb395f", "docs/validation/2026-10-13-response-reconciliation-v4/m4-aligned.parquet": "08527f163c57d28fc248a78eb7f9c262dafed686300727a4257df2e90d2ff68b", "docs/validation/2026-10-13-response-reconciliation-v4/RIBOSEQ-prior-TRUE-reconstructed.csv": "9b6b0e8a87bab2d534dabd38be0600147ab0e0a4304af4fe35f7add8ca902f6c", "docs/validation/2026-10-13-response-reconciliation-v4/RNASEQ-prior-FALSE-reconstructed.csv": "628862108895b7644a8aa8c9dcd88eadc9b88f2da8a8f00690691bd41a7949bc", "docs/validation/2026-10-13-response-reconciliation-v4/published-contrasts.csv": "0c7131eca9044ac4b0c0b09b7f40159fbc1991e09611772313e22b1df62112e5", "docs/validation/2026-10-13-response-reconciliation-v4/Aliouat2019-counts.csv": "37accdd334ebcafd73e819384b94a0de3e50bd78cfc629cf528691fdbbc1ce71", "docs/validation/2026-10-13-response-reconciliation-v4/GSE126385-source-metadata.soft.gz": "3e6f66b1e1acc7eb941b71ac4d6bc045c5e012a1a8461e76622e1468f46a0dd0", "docs/validation/2026-10-13-response-reconciliation-v4/RNASEQ-source-counts.csv": "ea53a7b11bb7f96fa5123b7da0029c3b14375c73b3fcb080d9a6e6f8d1ac35b1", "docs/validation/2026-10-13-response-reconciliation-v4/reconciliation.log": "d613430705b7b8a3a8111d1de7dd6f2140adf1b154472a5709b05796c26b3baf", "docs/validation/2026-10-13-response-reconciliation-v4/NMDRHT-te-targets.csv": "0354af35151579d37fee71e81712783f8c185f01f7ef3fa040a032455d5ed4ed", "docs/validation/2026-10-13-response-reconciliation-v4/aliouat-count-mapping.json": "f648ed92556adf5dba0c48107536f376722dd84896dcb1976bb610da71f6226e", "docs/validation/2026-10-13-response-reconciliation-v4/m4-alignment.json": "832ed0228bbf528208657b7b1549c27961646e77a09864ce58408c88f59d7b99", "docs/validation/2026-10-13-response-reconciliation-v4/RIBOSEQ-source-counts.csv": "3ba059841f70ea6afe79cd09126fb832bbe1ee477a1732b00a80772e0779da06", "docs/validation/2026-10-13-response-reconciliation-v4/RNASEQ-prior-TRUE-reconstructed.csv": "c22e4a7e80489aafc2f711268056a394c254950936531aad1a3d1cfc2f8c7848", "docs/validation/2026-10-13-response-reconciliation-v4/UPF1_NMDRHT_Translation.R": "83ed68e7213c6efe14dad8d975adb6b0e6832cba6329b165e7d139e01210f0bd", "docs/validation/2026-10-13-response-reconciliation-v4/reconstruction-metrics.json": "64d832568825dd5818e5b80a24124ff8f8b4130c7f915caeedd95d85f760f93a", "docs/validation/2026-10-13-response-reconciliation-v4/RIBOSEQ-prior-FALSE-reconstructed.csv": "9e88be327613c26e38a89165c355c43386496c609cb77d93c38c83e12b8291bf" } }, "reconciliation": { "status": "Operational target discrepancy reconciled; source-label conflict requires author/raw-read confirmation", "finding": "Supplement S1 RNA-labelled contrasts closely match deposited RIBOSEQ-derived contrasts, not deposited RNASEQ contrasts. Prior S1 RPF-minus-RNA differences are therefore not a reliable TE reference.", "evidence": [ { "assay": "RNASEQ", "contrast": "UPF1", "genes": 13098, "spearman": 0.3718539719958795, "medianAbsoluteLfcDifference": 0.1755467566750965, "withinHalfRoundingUnit": 21, "fractionWithinHalfRoundingUnit": 0.001603298213467705 }, { "assay": "RNASEQ", "contrast": "eRF3", "genes": 13098, "spearman": 0.7152484978299215, "medianAbsoluteLfcDifference": 0.14855182660774713, "withinHalfRoundingUnit": 22, "fractionWithinHalfRoundingUnit": 0.0016796457474423576 }, { "assay": "RIBOSEQ", "contrast": "UPF1", "genes": 13136, "spearman": 0.9980845613692342, "medianAbsoluteLfcDifference": 0.0002621865047909844, "withinHalfRoundingUnit": 11642, "fractionWithinHalfRoundingUnit": 0.886266747868453 }, { "assay": "RIBOSEQ", "contrast": "eRF3", "genes": 13136, "spearman": 0.9992161042843137, "medianAbsoluteLfcDifference": 0.0002709137960385244, "withinHalfRoundingUnit": 11184, "fractionWithinHalfRoundingUnit": 0.8514007308160779 } ], "reconstruction": [ { "assay": "RNASEQ", "betaPrior": "FALSE", "publishedColumn": "labelled_RNA_UPF1", "n": 13098, "rho": 0.33425049370191695, "medianAbsoluteLfcDifference": 0.20248651331226453, "baseMeanRelativeMedianError": 0.7748514070094864 }, { "assay": "RNASEQ", "betaPrior": "FALSE", "publishedColumn": "labelled_RPF_UPF1", "n": 12997, "rho": 0.31948757624054536, "medianAbsoluteLfcDifference": 0.21108705320095, "baseMeanRelativeMedianError": 0.6837726878142245 }, { "assay": "RNASEQ", "betaPrior": "TRUE", "publishedColumn": "labelled_RNA_UPF1", "n": 13098, "rho": 0.3718539719958795, "medianAbsoluteLfcDifference": 0.1755467566750965, "baseMeanRelativeMedianError": 0.7748514070094864 }, { "assay": "RNASEQ", "betaPrior": "TRUE", "publishedColumn": "labelled_RPF_UPF1", "n": 12997, "rho": 0.3540397412902092, "medianAbsoluteLfcDifference": 0.1806861204704004, "baseMeanRelativeMedianError": 0.6837726878142245 }, { "assay": "RIBOSEQ", "betaPrior": "FALSE", "publishedColumn": "labelled_RNA_UPF1", "n": 13136, "rho": 0.9941233141901308, "medianAbsoluteLfcDifference": 0.018883094042390497, "baseMeanRelativeMedianError": 2.5344129282391033e-05 }, { "assay": "RIBOSEQ", "betaPrior": "FALSE", "publishedColumn": "labelled_RPF_UPF1", "n": 13025, "rho": 0.8904533787572467, "medianAbsoluteLfcDifference": 0.04835906252675798, "baseMeanRelativeMedianError": 0.5025664135027127 }, { "assay": "RIBOSEQ", "betaPrior": "TRUE", "publishedColumn": "labelled_RNA_UPF1", "n": 13136, "rho": 0.9980845613692342, "medianAbsoluteLfcDifference": 0.0002621865047909844, "baseMeanRelativeMedianError": 2.5344129282391033e-05 }, { "assay": "RIBOSEQ", "betaPrior": "TRUE", "publishedColumn": "labelled_RPF_UPF1", "n": 13025, "rho": 0.9005995525424743, "medianAbsoluteLfcDifference": 0.040051599729363, "baseMeanRelativeMedianError": 0.5025664135027127 } ], "source": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE126385", "paper": "https://pmc.ncbi.nlm.nih.gov/articles/PMC6973328/", "action": "Supersede the earlier M5 v2 TE superiority interpretation. Retain historical results unchanged. V4 uses separately deposited assay counts and paired Aliouat libraries.", "limits": [ "Strong numerical fingerprint is not author confirmation of a publication error. Raw reads were not re-quantified.", "Deposited assay labels are supported by GEO sample metadata; transcript/CDS count regions and upstream quantification may still differ.", "M5 cross-study biology and target transportability remain unresolved." ] }, "holdoutSearch": { "date": "2026-10-13", "qualifiedFreshHoldouts": 0, "searchScope": "Primary-source methods and sample metadata were inspected; candidate numerical outcomes were not opened. This is a bounded search, not proof that no eligible dataset exists.", "candidates": [ { "name": "Jackson-Jones 2021 \u00b7 human HeLa nascent RNA", "model": "M4", "status": "Promising endpoint; required data not located", "evidence": "The thesis describes nascent/total RNA stability estimates after UPF1 depletion. Its deposited-data section (printed p94 / PDF p127) specifies only total, membrane and cytoplasmic RNA under GSE152437. All 39 GEO sample titles/metadata were checked; no nascent fraction is listed. Obtain the nascent count matrix and sample metadata, then audit lineage before qualification.", "source": "https://era.ed.ac.uk/handle/1842/37947" }, { "name": "GSE152437 \u00b7 Longman 2020", "model": "M4", "status": "Not a qualified decay holdout", "evidence": "Deposited RNA abundance/fractionation does not supply the required nascent comparison. Longman2020 RNA libraries also appear in the upstream NMDRHT annotation metadata. Any later nascent release requires a sample-level overlap audit.", "source": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE152437" }, { "name": "GSE245551 \u00b7 Shin 2024", "model": "M5", "status": "Excluded \u00b7 perturbation mismatch", "evidence": "RNA and ribosome libraries are present, but all six sample metadata records describe control or SR-alpha depletion and immunoprecipitation; no UPF1-depleted RNA/RPF arm. This cannot test the fixed UPF1 TE-response endpoint.", "source": "https://www.ncbi.nlm.nih.gov/bioproject/PRJNA1028964" } ], "nextDecision": "Prioritize obtaining the Jackson-Jones nascent-RNA matrix and its sample lineage for M4. For M5, another matched human control/UPF1 RNA-plus-RPF study is required. Freeze a final model and predictions before reading any new holdout outcomes; do not relabel reused studies as fresh." }, "nextDecision": "Prioritize obtaining the Jackson-Jones nascent-RNA matrix and its sample lineage for M4. For M5, another matched human control/UPF1 RNA-plus-RPF study is required. Freeze a final model and predictions before reading any new holdout outcomes; do not relabel reused studies as fresh.", "modelSummaries": { "m4": "M4 improves its NMDRHT transfer correlation from 0.434 to 0.450, but falls from 0.442 to 0.435 on Tani. Tuned ExtraTrees still leads both directions.", "m5": "The corrected, paired-count M5 candidate still transfers negatively in both directions and loses to ridge. The earlier supplement-derived M5 TE advantage is superseded." } }