{
  "date": "2026-10-13",
  "protocol": {
    "createdUtc": "2026-10-13T11:05:02.811423+00:00",
    "status": "pre-training, before independent numeric response inspection",
    "development": "Existing NMDRHT train/validation only; old chr8 test excluded from tuning",
    "candidates": {
      "M4": "Tani2012 BRIC-seq as reprocessed by Imamachi2017, independent UPF1-depleted HeLa versus control decay",
      "M5": "Aliouat2019 GSE126385 human UPF1 depletion paired RNA/ribosome response"
    },
    "primaryMetric": "Spearman response correlation",
    "secondaryMetrics": [
      "MAE",
      "R2"
    ],
    "superiority": "Paired gene bootstrap lower bound >0 versus BOTH tuned ExtraTrees and ridge, Bonferroni across four M4/M5 comparisons; report point estimates even when unsuccessful",
    "developmentBudget": "12 fits each LightGBM / ExtraTrees / ridge per endpoint. Select on existing validation Spearman; no external refit or selection. LightGBM shallow/regularized candidates and robust L1 loss.",
    "externalSelection": "All eligible mapped source rows, without significance/effect filtering. One-to-one stable gene or unique symbol joins; no fuzzy matching. M4 median prediction across mapped native isoforms for gene-level source; exact isoform mapping only if source supports it. No silent transcript equivalence.",
    "qualification": "Inspect source header/methods first. Only numeric decay rates or half-lives support M4; RNA abundance is not decay. M5 requires paired control/depletion TE or RNA+RPF measures. If unsupported report blocked, no substituted endpoint.",
    "direction": "M4 log2(kdeg depleted/control) = log2(halfLife control/depleted); M5 log2(TE depleted/control).",
    "freshness": "Study assays not used previously; input genes may overlap development. Report overlap and separate unseen-development-gene stratum without using it for selection. No independence-from-lab claim until source/sample audit.",
    "limitations": [
      "Cross-cell, assay, perturbation duration and annotation shift",
      "NMDRHT decay contrast UPF1 12h versus control0h has time confounding",
      "Native NMDRHT geometry may not match external isoforms",
      "No therapeutic efficacy or patentability conclusion"
    ],
    "seed": 2026101302,
    "bootstrapReplicates": 2000
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  "conclusion": "Historical v2 results: M4 did not beat both baselines. The earlier M5 TE interpretation is superseded by the source reconciliation below; it no longer supports TE superiority.",
  "qualification": [
    "Correction dated 2026-10-13: the M5 supplement-derived TE endpoint is unreliable; its earlier positive baseline comparison is superseded. See reconciled v4 for corrected-count results.",
    "Independent study measurements were excluded from fitting, tuning and checkpoint selection. Predictions were frozen before numerical response evaluation. These studies are now used test sets and cannot be reused as fresh holdouts.",
    "Most evaluated genes occur in NMDRHT development partitions. The primary test measures transfer between studies, not generalization to unseen genes. Unseen-development-gene results are reported separately and descriptively.",
    "M4 uses gene-level HeLa BRIC-seq outcomes and median native transcript predictions; this is a transfer stress test with isoform and assay mismatch. M5 uses exact stable gene/transcript pairs, but versions can differ.",
    "M5 TE changes are derived by subtracting two published DESeq2 contrasts. This is not the same joint TE estimator as NMDRHT; 72-hour knockdown and acute 12-hour depletion also differ.",
    "All v2 R\u00b2 values are negative and both models have worse MAE than the training-median baseline. A statistically detectable ranking difference is not strong absolute prediction.",
    "NMDRHT decay training compares UPF1 depletion at 12 hours with control at 0 hours. Time effects and source-annotation ascertainment remain potential confounders.",
    "The M5 candidate improves development correlation. M4 v2 does not beat its parent on development or external correlation. Existing defaults are preserved.",
    "Intervals resample genes within each published study; they do not quantify uncertainty across laboratories, perturbations or independently repeated studies. No therapeutic-efficacy or patentability conclusion follows."
  ],
  "sourceAudit": {
    "developmentAccessions": [
      "E-MTAB-13839",
      "E-MTAB-13788",
      "E-MTAB-13789",
      "E-MTAB-13787",
      "E-MTAB-13829",
      "E-MTAB-13836",
      "E-MTAB-14755",
      "E-MTAB-14725",
      "E-MTAB-13837"
    ],
    "externalM4": "DRA000591 (Tani2012), reprocessed in Imamachi2017; one external assay, not two independent studies",
    "externalM5": "GSE126385 (Aliouat2019)",
    "developmentPaper": "https://doi.org/10.1016/j.molcel.2025.08.015",
    "externalMetadataMatchInNmdrhtExperimentTable": false,
    "qualification": "Publication, accession and experiment-table audit; raw read identity deduplication was not performed."
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  "correction": {
    "date": "2026-10-13",
    "affectedModel": "m5",
    "status": "Superseded TE interpretation",
    "reason": "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.",
    "replacement": "/model-benchmark#reconciled-responses"
  }
}