{
  "date": "2026-10-13",
  "status": "New M4 lead found; neither endpoint has a qualified fresh holdout yet.",
  "finalStudy": null,
  "newTrainingRun": true,
  "scope": "Targeted public-source qualification, not an exhaustive proof that no suitable dataset exists. Article narratives and assay metadata were reviewed; new candidate outcome tables were not downloaded or scored. No blind third-party custody has been established.",
  "studies": [
    {
      "name": "PRJDB2542 / DRP000622",
      "model": "M4",
      "status": "Already-used Tani 2012 study family",
      "reason": "The project title matches the Tani 2012 BRIC-seq study already used through its reprocessed results. The archive contains 25 runs, including siUPF1 and control time courses. Its later archive release date does not establish a new experiment.",
      "source": "https://www.ebi.ac.uk/ena/browser/view/PRJDB2542"
    },
    {
      "name": "PRJEB80386 / E-MTAB-13837_2",
      "model": "M5",
      "status": "Already-used NMDRHT study family",
      "reason": "The ENA project record explicitly maps this human UPF1 Ribo-Seq deposit to E-MTAB-13837_2. Its project description and publication lineage identify the Boehm NMDRHT experiments already used in model development. A different archive accession does not make a fresh study.",
      "source": "https://www.ebi.ac.uk/ena/browser/view/PRJEB80386"
    },
    {
      "name": "GSE143301 \u00b7 UPF1 RNA without UPF1 RPF",
      "model": "M5",
      "status": "Excluded from UPF1 TE-response benchmark",
      "reason": "All 21 sample metadata records were checked. The 12 RPF entries cover control and ABCE1 depletion; three UPF1-depleted entries are total RNA only. Sequencing lanes are not additional biological replicates.",
      "source": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE143301"
    },
    {
      "name": "GSE276918 \u00b7 newly identified human decay time course",
      "model": "M4",
      "status": "Promising alternative; metadata conflict blocks qualification",
      "reason": "A separate Yunnan University deposit lists human HCT116 control/UPF1 time courses at 0, 4, 8 and 12 hours with three replicates. Six UPF1 samples have conflicting time labels: 4h titles versus I8 file descriptions, and 8h titles versus I4 descriptions. The series summary names alpha-amanitin, whereas its design names actinomycin D. Exact depletion duration and matched control assignment also need clarification.",
      "source": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE276918"
    },
    {
      "name": "Jackson-Jones 2021 \u00b7 missing nascent RNA",
      "model": "M4",
      "status": "Not located in the checked public repositories",
      "reason": "The thesis repository contains one original attachment: the thesis PDF. Its metadata and file inventory expose no count matrix. Edinburgh DataShare returned no matches for the author/NMD query. The six GEO author-name matches include GSE152435/6/7 and three unrelated mouse studies; the relevant deposit lists total and subcellular RNA, not the missing nascent fraction.",
      "source": "https://era.ed.ac.uk/handle/1842/37947"
    },
    {
      "name": "GSE245551 \u00b7 Shin 2024",
      "model": "M5",
      "status": "Excluded \u00b7 perturbation mismatch",
      "reason": "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"
    },
    {
      "name": "GSE152437 \u00b7 Longman 2020",
      "model": "M4",
      "status": "Not a qualified decay holdout",
      "reason": "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": "Jackson-Jones 2021 \u00b7 human HeLa nascent RNA",
      "model": "M4",
      "status": "Promising endpoint; required data not located",
      "reason": "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": "NMDRHT 2025",
      "model": "M4 + M5",
      "status": "Development only",
      "reason": "Used for development. This revision aligns M4 to gene-level same-time decay contrasts and re-estimates M5 from counts. Assay, cell, perturbation and M5 control-timing differences remain.",
      "source": "https://github.com/boehmv/2025_UPF1_NMDRHT",
      "previouslyUsed": true,
      "qualifiedFinal": false
    },
    {
      "name": "Tani 2012 / Imamachi 2017 \u00b7 DRA000591",
      "model": "M4",
      "status": "Previously tested",
      "reason": "These papers share the same BRIC-seq measurements and count as one study family. Previously tested; now explicitly admitted to retrospective development for aligned v3. Never a fresh final holdout again.",
      "source": "https://pmc.ncbi.nlm.nih.gov/articles/PMC5340968/",
      "previouslyUsed": true,
      "qualifiedFinal": false
    },
    {
      "name": "Aliouat 2019 \u00b7 GSE126385",
      "model": "M5",
      "status": "Previously tested",
      "reason": "Previously tested and used for development. V4 traced the supplement/count source conflict and superseded the earlier TE interpretation. The corrected-count model still transfers negatively; this study cannot be a fresh holdout.",
      "source": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE126385",
      "previouslyUsed": true,
      "qualifiedFinal": false
    },
    {
      "name": "Musaev 2024 \u00b7 GSE153258 basal half-lives",
      "model": "M4",
      "status": "Endpoint mismatch",
      "reason": "Paper methods describe basal HEK293 half-lives and separate UPF1-depletion RNA abundance. A genome-wide paired UPF1/control decay-rate endpoint has not been established from the reviewed material.",
      "source": "https://pmc.ncbi.nlm.nih.gov/articles/PMC11259039/",
      "previouslyUsed": false,
      "qualifiedFinal": false
    },
    {
      "name": "Karousis 2020",
      "model": "M5",
      "status": "Matched arm not established",
      "reason": "Published methods list HeLa ribosome profiling and separate UPF1-knockdown total RNA used to identify NMD-sensitive isoforms. Matched depleted/control ribosome profiling is not established. GEO sample verification was limited by access errors.",
      "source": "https://pmc.ncbi.nlm.nih.gov/articles/PMC7431590/",
      "previouslyUsed": false,
      "qualifiedFinal": false
    },
    {
      "name": "Hurt 2013 \u00b7 GSE41785",
      "model": "M5",
      "status": "Secondary candidate only",
      "reason": "Mouse embryonic stem cells with paired RNA/RPF conditions. GEO lists only one control-depleted and one Upf1-depleted RPF sample. Species shift and no replicated RPF contrast prevent qualification for the primary human benchmark. Outcome tables remain unread in this audit.",
      "source": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE41785",
      "previouslyUsed": false,
      "qualifiedFinal": false
    },
    {
      "name": "GSE102113 \u00b7 NAT10",
      "model": "M4 + M5",
      "status": "Perturbation mismatch",
      "reason": "RNA, ribosome profiling and decay measurements exist, but the perturbation is NAT10 rather than UPF1. It cannot answer the declared response question.",
      "source": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE102113",
      "previouslyUsed": false,
      "qualifiedFinal": false
    },
    {
      "name": "GSE7009",
      "model": "M4",
      "status": "Endpoint mismatch",
      "reason": "Human UPF1-depletion expression arrays measure abundance rather than paired decay rates.",
      "source": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE7009",
      "previouslyUsed": false,
      "qualifiedFinal": false
    }
  ],
  "endpoints": [
    {
      "model": "M4",
      "target": "Human gene-level log2(kdecay UPF1-depleted / kdecay control), equivalently log2(control half-life / depleted half-life).",
      "alignment": "Use directly estimated gene-level decay targets in each study; do not silently substitute the median of transcript predictions or steady-state RNA abundance. Audit control timing, mapping, units and decay-fit uncertainty before admitting a study."
    },
    {
      "model": "M5",
      "target": "Human gene-level UPF1-associated change in translation efficiency.",
      "alignment": "Use a common replicate-aware RNA/RPF condition-interaction estimator. Keep perturbation duration and cell context explicit. Separate-normalization contrasts and basal TE are not interchangeable endpoints."
    }
  ],
  "nextSteps": [
    "Completed: v4 alignment, source reconciliation and equal-budget development comparisons. Neither model establishes superiority over both strong baselines. Latest qualification audit found a new M4 time-course lead with unresolved sample labels.",
    "Qualify a third, untouched human study per endpoint: matched control/UPF1 response, compatible measurements, replicate metadata, identifier coverage and accession/sample lineage. No final study is reserved yet.",
    "Completed: two study-held-out development directions with equal tuning budgets. With only two study families, these are retrospective diagnostics rather than independent confirmation.",
    "Freeze the model, preprocessing, inclusion rules and analysis protocol before opening final outcomes. Publish one final evaluation including all failures and missing rows."
  ],
  "passCriteria": [
    "Primary accuracy: positive multiplicity-adjusted paired confidence bounds for Spearman improvement over both tuned ExtraTrees and ridge. Declare all model/baseline comparisons together before evaluation.",
    "Absolute error: demonstrate lower MAE than the training-only median baseline using a paired interval. Report MAE, R\u00b2, coverage and missingness for every method.",
    "Power and relevance: specify a meaningful minimum gain and assess sample size using development evidence before accepting a final cohort. No significance guarantee or post-hoc winning subgroup.",
    "Runtime: measure the same complete input-to-output path for all models on fixed hardware and thread settings. Separate cold startup, warm median/p95, preprocessing, memory and batch sizes; report accuracy/runtime trade-offs.",
    "Claim scope: a single-study win supports that cohort and endpoint only. Gene-level intervals do not establish across-study certainty, therapeutic efficacy or patentability."
  ],
  "limitations": [
    "No new superiority result was produced by this qualification step.",
    "The current v2 results and checkpoints remain unchanged.",
    "An independent study may share genes with development; report study independence and gene independence separately.",
    "Raw-read identity deduplication and complete accession lineage audits remain required for any admitted final study."
  ],
  "currentStage": "Qualification audit complete for this search; no new accuracy benchmark run. See the latest human-holdout search above for source metadata and unresolved requirements."
}