{
  "slug": "pku-phenylalanine",
  "completed": true,
  "provider_mode": "Consensus MCP keyword search and record fetch; independent reconciliation against the frozen primary-source ledger and its recorded abstract/full-text access",
  "cutoff": "2026-09-27 (frozen review cutoff)",
  "queries": [
    "phenylalanine neurotoxicity phenylketonuria adults maternal PKU treatment thresholds natural history primary studies",
    "high phenylalanine levels directly affect mood sustained attention adults PKU randomized double blind placebo crossover ten Hoedt 2011 Bickel early diet trial PMID"
  ],
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    "checks/pku-phenylalanine/consensus-search-03.json",
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  "source_counts_preserved": {
    "evidence_inventory_rows": 27,
    "claims": 35
  },
  "primary_comparisons": [
    {
      "pmid": "13098090",
      "doi": "10.1016/S0140-6736(53)90473-5",
      "review_source_n": 1,
      "source_type": "primary human intervention, single historical case",
      "access_depth": "Full two-page original read from scanned primary-paper copy; bibliographic metadata checked; PubMed has no abstract",
      "result_comparison": "Phe add-back changed neurologic/behavioral state in one case; does not prove developmental prevention/reversal; already present.",
      "already_present": true
    },
    {
      "pmid": "21153445",
      "doi": "10.1007/s10545-010-9253-9",
      "review_source_n": 9,
      "source_type": "primary randomized double-blind crossover adult challenge",
      "access_depth": "Original abstract and bibliographic/status metadata read in Europe PMC; Entrez/web cross-check",
      "result_comparison": "Phe supplementation affected adult mood and sustained attention; acute adult outcome is narrower than untreated childhood ID; already present.",
      "already_present": true
    },
    {
      "pmid": "38569786",
      "doi": "10.1016/j.ajcnut.2023.11.007",
      "review_source_n": 10,
      "source_type": "primary randomized crossover adult challenge",
      "access_depth": "Original abstract and bibliographic/status metadata read in Europe PMC; Entrez/web cross-check",
      "result_comparison": "In early-treated adults the 4-week higher-Phe arm was noninferior for primary working-memory accuracy; does not establish childhood/lifelong safety; already present.",
      "already_present": true
    },
    {
      "pmid": "4140266",
      "doi": "10.1016/S0140-6736(74)91873-X",
      "review_source_n": 2,
      "source_type": "primary observational/natural-history treatment-timing study",
      "access_depth": "Original-paper abstract and bibliographic/status metadata read in indexed records; Entrez/web cross-check",
      "result_comparison": "Early-versus-late treatment history supports the developmental importance of early control, bounded by historical and ascertainment confounding; already present.",
      "already_present": true
    }
  ],
  "score_before": {
    "hsef_level": "Θ",
    "hsef_descriptor": "High predictive accuracy, minimal unresolved exceptions",
    "confidence": "High",
    "confidence_rationale": "Historical human developmental evidence, specific exposure challenges, longitudinal replication and controlled/genetically targeted models converge. Confidence describes reproducibility of the causal pattern, not GRADE certainty for every effect size or precision of the Η/Θ boundary. Pass-02 adds maternal-PKU and meta-analytic replication; unchanged band.",
    "rests_on_non_peer_reviewed_work": false,
    "rationale": "SC1 Θ, SC2 Θ and SC3 Θ yield Θ by the preregistered weakest-link rule. Phe accumulation predicts untreated natural history, early-treatment rescue, dose-response on timing and control, and maternal-exposure injury in offspring without PAH deficiency. The rare protected untreated phenotype is unexplained and blocks Ω.",
    "merge_note": "Three independent gradings: A Θ, B Η, R2 (blind) Θ. Pass-01 posted Η; pass-02 raises SC2 and the aggregate to Θ and records B's and pass-01's Η case in full."
  },
  "score_after": {
    "hsef_level": "Θ",
    "hsef_descriptor": "High predictive accuracy, minimal unresolved exceptions",
    "confidence": "High",
    "confidence_rationale": "Historical human developmental evidence, specific exposure challenges, longitudinal replication and controlled/genetically targeted models converge. Confidence describes reproducibility of the causal pattern, not GRADE certainty for every effect size or precision of the Η/Θ boundary. Pass-02 adds maternal-PKU and meta-analytic replication; unchanged band.",
    "rests_on_non_peer_reviewed_work": false,
    "rationale": "SC1 Θ, SC2 Θ and SC3 Θ yield Θ by the preregistered weakest-link rule. Phe accumulation predicts untreated natural history, early-treatment rescue, dose-response on timing and control, and maternal-exposure injury in offspring without PAH deficiency. The rare protected untreated phenotype is unexplained and blocks Ω.",
    "merge_note": "Three independent gradings: A Θ, B Η, R2 (blind) Θ. Pass-01 posted Η; pass-02 raises SC2 and the aggregate to Θ and records B's and pass-01's Η case in full."
  },
  "grade_changed": false,
  "conclusion": "The checked adult challenge papers do not overturn the developmental PKU claim and do not resolve its rare untreated exception. Short-term adult sensitivity is not equivalent to childhood developmental injury. Consensus discovery changes neither grade nor original inventory.",
  "addendum_path": "deliverables\\consensus_consistency_audit_2026-10-09\\checks\\pku-phenylalanine\\consensus-addendum.md",
  "independent_blinded_audit": false,
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  "primary_comparison_count": 4,
  "status": "completed_retrospective_original_source_reconciliation",
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}