{
  "protocol": {
    "lockedAtUTC": "2026-10-13T18:05:28.109459+00:00",
    "development": "Only v1 MFASS development partition; exclude all external-study genes before CV. Do not use prior MFASS test partition.",
    "candidate": "Research M3 v2 combines published SpliceAI and Pangolin scores. Pangolin is an explicit dependency, not a newly trained neural model. Select additive logit spline or quadratic logit fusion by five-group-fold development Brier.",
    "primary": "External equal-study mean Brier across four minigene cohorts FAS, MST1R/RON, POU1F1, WT1. Cohort-size-weighted pooled Brier and ranking metrics secondary.",
    "external": "Smith & Kitzman 2023 supplementary Table S1, public Figshare 26991223.v1, file 49126486; four minigene sheets. No selection of external genes or variants using prediction success.",
    "exclusions": "MLH1 excluded: clinical ascertainment and assumed essential-site labels. BRCA1 excluded: combined protein-function/RNA label. Random500k lacks assay outcomes. FGFR2 lacks matched Pangolin/assay labels. Reject non-SNV, ambiguous/missing labels or scores, duplicates or reference mismatch.",
    "scoreContract": "Use unmasked SpliceAI delta max and absolute unmasked Pangolin delta max; no test calibration, clipping only probability outputs; missing scores stay missing. Source uses hg19 MANE and exon-length windows vs MFASS hg38 GENCODE44 window50. Qualifies only as shifted-assay transfer, not matched-protocol confirmation.",
    "successRule": "M3 must have lower equal-study Brier than every prespecified baseline, positive Bonferroni-adjusted paired gene-cluster bootstrap lower limits, and beat ET_joint and the strongest calibrated Pangolin baseline in all four studies. Four genes give weak uncertainty estimation; no general clinical or universal superiority claim.",
    "uncertainty": "10000 paired whole-gene bootstrap draws, seed20261014, Bonferroni across all evaluated baselines, all four cohorts retained. Per-study results always shown.",
    "disclosure": "During schema discovery one example row per sheet, including labels, and published aggregate article results were seen. No external outcome metrics used for development, selection or calibration. Full external labels are read only after checkpoint lock.",
    "excludedDevelopmentGenes": [
      "FAS",
      "MST1R",
      "RON",
      "POU1F1",
      "WT1",
      "BRCA1",
      "MLH1"
    ],
    "baseTrainingIndependence": "Not established for pretrained SpliceAI/Pangolin; local revision gene separation is not proof of base-network independence.",
    "trainingInputSHA256": "08557265d924fd384e97eaa7ccf22b77122777e7924ff1a85411c721d6e6b7bf",
    "trainingOutcomeSHA256": "1ad6ce084b69d601b2e4221efec95a57cfc3c193715092b2e35e3e26462ef013",
    "externalFileSHA256": "e376bbc302d1b4af4e1bdac384af1132827466be91c9c6969d7500040e8fcf9b",
    "serving": "No deployment or promotion; separate checkpoint."
  },
  "qualification": {
    "status": "Qualified for frozen cross-study transfer only; not matched-protocol or independent base-model validation",
    "source": "https://figshare.com/articles/dataset/26991223",
    "paper": "https://doi.org/10.1186/s13059-023-03144-z",
    "sourceRows": 2230,
    "eligibleRows": 2230,
    "rejectedRows": 0,
    "studies": {
      "FAS": 189,
      "MST1R": 598,
      "POU1F1": 941,
      "WT1": 502
    },
    "referenceChecks": [
      {
        "gene": "FAS",
        "url": "https://api.genome.ucsc.edu/getData/sequence?genome=hg19;chrom=chr10;start=90770509;end=90770572",
        "sha256": "7b2dbfb8b1785a676ee18c70fca67d770e96c00300bb685c7b8204b9f1cb1b31",
        "rows": 189,
        "matches": 189
      },
      {
        "gene": "MST1R",
        "url": "https://api.genome.ucsc.edu/getData/sequence?genome=hg19;chrom=chr3;start=49933352;end=49933584",
        "sha256": "0a292bea7e65f21a47c903e474a85289b751c6b9c9523beb8576e3e8c660f72a",
        "rows": 598,
        "matches": 598
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      {
        "gene": "POU1F1",
        "url": "https://api.genome.ucsc.edu/getData/sequence?genome=hg19;chrom=chr3;start=87322396;end=87322725",
        "sha256": "ebdb4470af02eed7f3f516ddb8830d10dfa819d73f732dc438f2a03e1321d044",
        "rows": 941,
        "matches": 941
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      {
        "gene": "WT1",
        "url": "https://api.genome.ucsc.edu/getData/sequence?genome=hg19;chrom=chr11;start=32413477;end=32413650",
        "sha256": "db24ac5970485e59bf3c8ad1bf57845de5b916d35261a178543af1a9d2245b0c",
        "rows": 502,
        "matches": 502
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    ],
    "publisherMD5Verified": true,
    "externalFileSHA256": "e376bbc302d1b4af4e1bdac384af1132827466be91c9c6969d7500040e8fcf9b",
    "developmentRows": 5801,
    "developmentGroups": 324,
    "developmentExcludedRows": 327,
    "developmentGeneOverlap": [],
    "hg19PositionOverlapIncludingAdjacentBases": 0,
    "overlapScope": "Successful v2 development rows only; same-build coordinate audit conservatively checks original MFASS positions plus/minus one. Gene exclusion applied before training; pretrained network exposure remains unknown.",
    "limitations": [
      "Different assay definitions: MFASS large exon-inclusion loss vs author-defined disruption including alternate isoform gains.",
      "External hg19 MANE/exon-length scoring differs from development hg38 GENCODE44/50nt. Unmasked score columns used for both. Neural scores are published, not rerun.",
      "Only four genes/exons and selected disease-associated loci; whole-gene confidence intervals have limited resolution.",
      "SpliceAI/Pangolin training exposure to external genes was not ruled out. New local calibrators have no external gene or outcome training.",
      "Published study and example rows were inspected for qualification. No external numerical metrics were used to tune models.",
      "M3 v2 depends on Pangolin; this cannot demonstrate a standalone new sequence model is superior to Pangolin.",
      "Not a clinical pathogenicity test or patentability determination."
    ]
  },
  "selection": {
    "lockedAtUTC": "2026-10-13T18:06:22.381392+00:00",
    "candidate": "M3_spline_joint",
    "selected": {
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          "C": 10
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        "cvBrier": 0.027921755460218224
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        "cvBrier": 0.028198263929886926
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        "configuration": {
          "leaf": 10,
          "depth": null
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          "depth": 4
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        "cvBrier": 0.03060991119379074
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          "knots": 5,
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        "cvBrier": 0.028055205016385632
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      "Pangolin_Platt": {
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          "C": 100
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        "cvBrier": 0.02829510680771689
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      "Pangolin_isotonic": {
        "configuration": {},
        "cvBrier": 0.02816295509006235
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      "SpliceAI_spline": {
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        "cvBrier": 0.030503595092246875
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      "Ridge_joint": {
        "configuration": {
          "alpha": 0.01
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        "cvBrier": 0.03464749204117665
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    "checkpoint": "backend/models/m3-score-fusion-v2/calibrators.joblib",
    "checkpointSHA256": "cd193f39323ec0ed3bd4c45bf051876af01e8e665fb2b253cb08d9e8fa0cbb30",
    "developmentSHA256": "f10187a0a68a24341c24953b07de81c177d34fff61a2a774b3a5c50719133ebb",
    "developmentRows": 5801,
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    "developmentPositives": 224,
    "geneExclusions": 327,
    "fits": 420,
    "tuningAndFitSeconds": 14.386558083,
    "timings": {
      "M3_spline_joint": {
        "refitSeconds": 0.004079874999999955
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      "M3_interaction_joint": {
        "refitSeconds": 0.0031496249999998227
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      "ET_joint": {
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      "ET_SpliceAI": {
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      "Pangolin_spline": {
        "refitSeconds": 0.002520500000001036
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      "Pangolin_Platt": {
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      "Pangolin_isotonic": {
        "refitSeconds": 0.0005417919999999299
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      "SpliceAI_spline": {
        "refitSeconds": 0.0024711249999995744
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      "Ridge_joint": {
        "refitSeconds": 0.0005173750000011523
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    "externalNumericalEvaluationPerformed": false
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  "positives": 677,
  "studyCounts": {
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      "positives": 115
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    "MST1R": {
      "rows": 598,
      "positives": 409
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    "POU1F1": {
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      "positives": 96
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    "WT1": {
      "rows": 502,
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    "SpliceAI_spline": 0.2922415912278529,
    "Ridge_joint": 0.308037004916321,
    "Historical_ET_v1": 0.3052733559907162,
    "Historical_Pangolin_Platt_v1": 0.2673375316944794,
    "Historical_Pangolin_Isotonic_v1": 0.25512969273037356,
    "Raw_Pangolin": 0.26989469892748763,
    "Raw_SpliceAI": 0.2771868174547403,
    "Development_prevalence": 0.3493707670652018
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    "Historical_ET_v1": {
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    "Historical_Pangolin_Isotonic_v1": {
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    "Raw_Pangolin": {
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    "Raw_SpliceAI": {
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  "perStudy": {
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      "Historical_Pangolin_Isotonic_v1": {
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      "Raw_SpliceAI": {
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    "POU1F1": {
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      "Pangolin_spline": {
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      "Pangolin_Platt": {
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