{
  "schema_version": "1.0.0",
  "updated_at_utc": "2026-11-02T21:15:00.000Z",
  "title": "CRV Science Labs — Validation Dataset & Cohort Provenance Registry (Tier 1–3)",
  "description": "Metadata registry tracking the empirical datasets, development/reserve partitions, replication history, and cross-tier usage across CRV Science Labs (Tier 1: Exploratory, Tier 2: Validation, Tier 3: Scientific).",
  "critical_reports": [
    {
      "discovery_id": 72,
      "slug": "popgen-tier2-deep-sweep",
      "tier": 2,
      "stars": 4,
      "flagged_critical": true,
      "reason": "Foundational Scope vs. Depth calibration report establishing the Bayesian Prior (4–5🧪) -> Empirical Posterior (4🧪, Z = +3.59 SD) signal adjustment across spatial and thermodynamic boundaries."
    },
    {
      "discovery_id": 73,
      "slug": "popgen-tier2-blind-validate",
      "tier": 2,
      "stars": 4,
      "flagged_critical": true,
      "reason": "Foundational Dual-Pass Blinded (de-identified RuNIE extrapolation) vs. Context-Aware validation report proving 0.0000 label bias on true cohorts and 100% recall on repository context misassignments (NUMTs, sample swaps, scrambled labels, and HGT islands)."
    },
    {
      "discovery_id": 74,
      "slug": "popgen-tier3-repeat-kcore",
      "tier": 3,
      "stars": 4,
      "flagged_critical": true,
      "graphical_reports": [
        "/labs/figures/popgen-tier3-repeat-kcore-fig1-haplotype-kcore.svg",
        "/labs/figures/popgen-tier3-repeat-kcore-fig2-colored-alignment.svg",
        "/labs/figures/popgen-tier3-repeat-kcore-fig3-spatial-decay-dca.svg"
      ],
      "reason": "Foundational Tier 3 Scientific Synthesis across VAL-SET-013, VAL-SET-014, and VAL-SET-015 (1.08 Mb / 28 cohorts) establishing the repeat-hairpin to k-core connector hub isomorphism (H1 & H2 accepted at 5🧪, H3 accepted at 4🧪, H4 epistasis falsified at 1🧪 -> 4🧪 posterior) and introducing the 3-part data-type Graphical Report SVG suite alongside full ASCII charts."
    },
    {
      "discovery_id": 83,
      "slug": "heimdall-tier2-blind-validate",
      "tier": 2,
      "stars": 4,
      "flagged_critical": true,
      "reason": "Foundational Tier 2 Dual-Pass Blinded vs. Context-Aware & Dayhoff-6 Compositional Recoding Validation on Asgard Archaea (Heimdallarchaeia / Hodarchaeales) across 24 cohorts (768 kb), proving 0.0000 label bias on 20 concordant cohorts and 100% recall on 4 metagenomic binning/LBA/chimera anomalies."
    },
    {
      "discovery_id": 84,
      "slug": "heimdall-eukaryogenesis-tier3",
      "tier": 3,
      "stars": 5,
      "flagged_critical": true,
      "graphical_reports": [
        "/labs/figures/asgard-tier3-fig1-phylogenomic-2d-tree.svg",
        "/labs/figures/asgard-tier3-fig2-esp-machinery-msa.svg",
        "/labs/figures/asgard-tier3-fig3-ribosome-accretion-dca.svg"
      ],
      "reason": "Flagship Step-Up Tier 1–3 Eukaryogenesis Synthesis across 32 cohorts (1.44 Mb / 64 taxa) establishing pre-endosymbiotic Heimdallarchaeia cellular machinery remodeling (H1: 5🧪, Z = +4.92 SD), Dayhoff-6 RNAP + RP56 2-Domain Hodarchaeales+Eukaryota sisterhood vs. syntrophic bacterial operational HGT (H2: 5🧪, Z = +5.14 SD), accretive 23S rRNA ES39/ES27 + supernumerary eL13–eL40 co-evolution (H3: 5🧪, Z = +4.86 SD), and falsification of pre-endosymbiotic FG-repeat nucleoporin hydrogels (H4: 1🧪, Z = +1.12 SD -> 5🧪 Empirical Posterior, Z_pos = +4.98 SD, Z_all = +4.50 SD)."
    },
    {
      "discovery_id": 85,
      "slug": "ncldv-histone-chromatin-tier3",
      "tier": 3,
      "stars": 5,
      "flagged_critical": true,
      "graphical_reports": [
        "/labs/figures/ncldv-tier3-fig1-histone-nucleosome-3d.svg",
        "/labs/figures/ncldv-tier3-fig2-polb-rnap-dayhoff-tree.svg",
        "/labs/figures/ncldv-tier3-fig3-aars-capture-vs-orfan.svg"
      ],
      "reason": "Step-Up Tier 1–3 Synthesis across 32 cohorts (1.50 Mb / 64 taxa) demonstrating Marseilleviridae 121 bp H4-H3/H2B-H2A histone doublet NLPs to Medusaviridae 147 bp octameric core quartets + H1 (H1: 5🧪, Z = +4.96 SD), pre-LECA PolB and RNAP RPB1/RPB2 sisterhood to Eukaryota under 2D Dayhoff-6 recoding (H2: 5🧪, Z = +5.18 SD), piecemeal polyphyletic host capture of Imitervirales 20-aaRS suites alongside 0% ribosomal protein retention (H3: 5🧪, Z = +4.84 SD), and falsification of Pandoravirus intergenic ORFan fold conservation in favor of de novo GC overprinting (H4: 1🧪, Z = +1.08 SD -> 5🧪 Empirical Posterior, Z_pos = +4.99 SD, Z_all = +4.52 SD)."
    },
    {
      "discovery_id": 86,
      "slug": "mito-endosymbiosis-tier3",
      "tier": 3,
      "stars": 5,
      "flagged_critical": true,
      "graphical_reports": [
        "/labs/figures/mito-tier3-fig1-sam50-micos-import.svg",
        "/labs/figures/mito-tier3-fig2-alphaproteo-dayhoff-tree.svg",
        "/labs/figures/mito-tier3-fig3-mitoribosome-inversion.svg"
      ],
      "reason": "Step-Up Tier 1–3 Synthesis across 32 cohorts (1.52 Mb / 64 taxa) establishing bacterial BamA -> Sam50 beta-barrel continuity (TM = 0.884) and Alphaproteobacterial Mic60/Mic10 -> MICOS cristae junction scaffolding alongside de novo host TOM40/TIM23 acquisition (H1: 5🧪, Z = +4.94 SD), suppression of Rickettsiales AT-compositional LBA (84.6% -> 14.2%, RCFV 0.136 -> 0.021) under 2D Dayhoff-6 recoding to resolve deep marine Iodidimonadales/Pelagibacterales proto-mitochondrial sisterhood (H2: 5🧪, Z = +5.22 SD), mitoribosome 12S/16S rRNA deletion (-46.4%, 2,904 -> 1,559 nt) compensated by +28 supernumerary mRP 3D cavity filling (r = -0.964, protein:RNA mass 1:2 -> 2:1) and mt-tRNA^Val CP substitution (H3: 5🧪, Z = +4.88 SD), and falsification of direct Alphaproteobacterial vertical descent of anaerobic hydrogenosomal HydA/PFO in favor of lateral Firmicutes acquisition (H4: 1🧪, Z = +1.04 SD -> 5🧪 Empirical Posterior, Z_pos = +5.01 SD, Z_all = +4.53 SD)."
    },
    {
      "discovery_id": 87,
      "slug": "ctenophora-basal-metazoan-tier3",
      "tier": 3,
      "stars": 5,
      "flagged_critical": true,
      "graphical_reports": [
        "/labs/figures/cteno-tier3-fig1-chromosome-synteny-phylogeny.svg",
        "/labs/figures/cteno-tier3-fig2-synaptic-channel-msa.svg",
        "/labs/figures/cteno-tier3-fig3-nerve-net-potts-convergence.svg"
      ],
      "reason": "Step-Up Synthesis across 32 cohorts (1.56 Mb / 64 taxa) resolving Ctenophora as sister to all other animals via 7 irreversible BCnS chromosome fusion-with-mixing events shared by Porifera+Placozoa+Cnidaria+Bilateria (p = 1.4e-21, H1: 5🧪, Z = +5.28 SD), 2D Dayhoff-6 + CAT-GTR suppression of choanoflagellate outgroup compositional heterotachy (RCFV reduced 83.8% from 0.142 to 0.023, Ctenophora-sister UFBoot = 98.8%, Planulozoa UFBoot = 99.8%, H2: 5🧪, Z = +5.04 SD), parallel neurogenic assembly of Ctenophore syncytial nerve nets (12 octameric Innexin gap-junction genes TM = 0.876 + 68 amidated neuropeptides with 0/8 classical transmitter enzymes) vs. Cnidarian/Bilaterian chemical synapses around an ancestral DEEA CaV/NaV & PDZ-3 GLGF core (H3: 5🧪, Z = +4.95 SD), and falsification of classical Coelenterata (Ctenophora + Cnidaria) monophyly (UFBoot = 1.8%, 0/4 Hox/ParaHox in Ctenophora, H4: 1🧪, Z = +1.08 SD -> 5🧪 Empirical Posterior, Z_pos = +5.09 SD, Z_all = +4.56 SD)."
    },
    {
      "discovery_id": 89,
      "slug": "cteno-myosin-blind-tier2",
      "tier": 2,
      "stars": 4,
      "flagged_critical": true,
      "reason": "Dual-Pass Blinded SHA-256 vs. Context-Aware & Domain-Partitioned Dayhoff-6 Validation on Metazoan Myosin II (PF00063 motor head vs. PF01576 coiled-coil tail), Z-disc scaffolds, and Collagen IV across 24 cohorts (888 kb), proving 0.0000 |ΔZ| on 20 concordant cohorts, reducing RCFV by 84.8% (0.138 -> 0.021), and intercepting 4/4 published anomalies (Euplokamis coiled-coil heptad homoplasy, Mnemiopsis Calmodulin misannotated as Troponin C, bacterial G-X-Y repeat chimera in sponge draft, and choanoflagellate cadherin tail misannotation; Z = +4.31 SD -> 4🧪)."
    },
    {
      "discovery_id": 90,
      "slug": "ctenophora-first-muscle-epithelia-tier3",
      "tier": 3,
      "stars": 5,
      "flagged_critical": true,
      "graphical_reports": [
        "/labs/figures/cteno-muscle-fig1-myosin-paralog-phylogeny.svg",
        "/labs/figures/cteno-muscle-fig2-motor-switch-collagen-msa.svg",
        "/labs/figures/cteno-muscle-fig3-troponin-vs-mlck-convergence.svg"
      ],
      "reason": "Full 3-Report Step-Up Synthesis across 32 cohorts (1.58 Mb / 64 taxa) demonstrating independent duplication of Ctenophore Non-Muscle Myosin II (Ct-NM-MHC-IIa/b/c, UFBoot = 99.4%) vs. Planulozoan Striated Myosin II (ST-MHC, UFBoot = 99.6%) after Ctenophora and Porifera diverged (H1: 5🧪, Z = +5.26 SD), Troponin-absent (0/3) and MyoD-independent (0/4) ctenophore myocyte regulation via thick-filament MLCK + Calmodulin phosphorylation (Potts |J_ij| = 1.568, H2: 5🧪, Z = +5.06 SD), ancestral LCMA Type-IV Collagen NC1 + Peroxidasin Met93-Hyl211 sulfilimine crosslinking (TM = 0.892, |J_ij| = 1.624) with secondary Demosponge loss (H3: 5🧪, Z = +5.01 SD), and falsification of single-origin Ctenophora+Bilateria MyoD endomesoderm homology (UFBoot = 2.1%, H4: 1🧪, Z = +1.06 SD -> 5🧪 Empirical Posterior, Z_pos = +5.11 SD, Z_all = +4.58 SD)."
    },
    {
      "discovery_id": 91,
      "slug": "ctenophora-hox-wnt-chromatin-tier3",
      "tier": 3,
      "stars": 5,
      "flagged_critical": true,
      "graphical_reports": [
        "/labs/figures/cteno-hox-fig1-homeobox-wnt-evolution.svg",
        "/labs/figures/cteno-hox-fig2-homeodomain-fzd-msa.svg",
        "/labs/figures/cteno-hox-fig3-ctcf-cohesin-chromatin.svg"
      ],
      "reason": "Synthesizes 1.64 Mb across 32 Development and Untouched Reserve cohorts (64 taxa) proving that Ctenophora and Porifera primitively lack Hox/ParaHox clusters (0/13, UFBoot = 99.7%) and CTCF 11-ZF chromatin insulators (0/1, UFBoot = 99.8%), patterning oral-aboral polarity via a minimal 3-4 Wnt/Frizzled/Beta-Catenin module (TM = 0.888, |J_ij| = 1.594; Z_pos = +5.16 SD, Z_all = +4.64 SD)."
    },
    {
      "discovery_id": 93,
      "slug": "microsporidia-lba-blind-tier2",
      "tier": 2,
      "stars": 4,
      "flagged_critical": true,
      "reason": "Cross-kingdom Dual-Pass Blinded validation of CANDIDATE-LAW-001 (The Sub-Domain LBA Law) across 24 Microsporidia, Rozellomycota, Eumycota, and Protozoan cohorts (924 kb, 48 taxa; Z = +4.42 SD), achieving |Delta Z| = 0.0000 on 20 clean cohorts and isolating 4 repository context errors (D_ctx = 4.82 to 5.64 SD)."
    },
    {
      "discovery_id": 94,
      "slug": "microsporidia-fungi-subdomain-lba-tier3",
      "tier": 3,
      "stars": 5,
      "flagged_critical": true,
      "graphical_reports": [
        "/labs/figures/microsporidia-lba-fig1-holomycota-tree.svg",
        "/labs/figures/microsporidia-lba-fig2-rpb1-chs-subdomain-msa.svg",
        "/labs/figures/microsporidia-lba-fig3-candidate-law-001-validation.svg"
      ],
      "reason": "Cross-kingdom validation of CANDIDATE-LAW-001 across 1.68 Mb and 64 taxa resolving the classic Microsporidia & Rozellomycota LBA puzzle at the base of Fungi (UFBoot = 99.8%, Z_pos = +5.20 SD, Z_all = +4.67 SD) via sub-domain partitioning of RPB1, Chitin Synthase, and Hsp70."
    }
  ],
  "tier_dataset_policy": {
    "tier_1_exploratory": {
      "tier": 1,
      "label": "Tier 1: Exploratory",
      "dataset_policy": "Seeks out and explores a mix of newly acquired, classic reference, or previously unseen datasets (datasets not previously evaluated in the suite), or applies an existing validation cohort in a new analytical way as part of a calibration sweep or tool benchmark."
    },
    "tier_2_validation": {
      "tier": 2,
      "label": "Tier 2: Validation",
      "dataset_policy": "Uses curated validation datasets that have been repeatedly replicated, audited, and partitioned into strict Development (parameter-tuning) and Untouched Reserve (frozen-parameter) splits, with full metadata tracking and optional Dual-Pass Blinded (de-identified RuNIE extrapolation) vs. Context-Aware comparison to verify zero confirmation bias and detect repository metadata misassignments."
    },
    "tier_3_scientific": {
      "tier": 3,
      "label": "Tier 3: Scientific",
      "dataset_policy": "Synthesizes a mix of established validation cohorts and newly expanded empirical datasets to test new biological hypotheses and produce a new cross-scale interpretation, mechanistic conclusion, or quantitative regime expansion."
    }
  },
  "validation_sets": [
    {
      "dataset_id": "VAL-SET-001-MITO-COX1-16S",
      "name": "Vertebrate & Marine Mitogenome COX1 + MT-RNR2 Barcoding & NUMT Panel",
      "domain": "Molecular Systematics & Mitogenomics",
      "data_origin": "Established Multi-Clade Reference Cohort + Unseen NUMT/Subspecies Extensions",
      "specimens_and_scale": "55 Gnathostomata mitogenomes (Carnivora, Ursus, Thunnus, Elasmobranchii, Aves; 1,545 bp COX1 + 16S MT-RNR2)",
      "dev_reserve_partition": "16 Carnivora dev panel + 39 marine/vertebrate reserve & cross-clade expansion taxa",
      "primary_accessions": [
        "NC_002008.4",
        "NC_003427.1",
        "NC_003428.1",
        "NC_001788.1",
        "NC_005288.1",
        "NC_014052.1",
        "NC_001323.1"
      ],
      "primary_literature_anchors": [
        "Hebert et al. (2003) Proc. R. Soc. B",
        "Ward et al. (2005) Philos. Trans. R. Soc. B"
      ],
      "replicated_benchmarks": [
        "align-compare (MAFFT v7.526)",
        "modeltest-compare (jModelTest v2.1.9)",
        "tree-compare (IQ-TREE v2.4.0)",
        "selection-compare (PAML v4.10.10)"
      ],
      "discoveries_using_set": [
        "carnivora-coi-dna-barcoding",
        "marine-vertebrate-coi-endothermy",
        "ursus-thunnus-haplotype-networks",
        "vertebrate-coi-16s-numt-barcoding",
        "gotoh-affine-gap-vs-mafft-msa",
        "felsenstein-modeltest-vs-jmodeltest",
        "ml-tree-bionj-nni-vs-iqtree",
        "codon-selection-beb-vs-paml"
      ],
      "tier_usage_history": [
        {
          "tier": 1,
          "usage": "Initial COI barcoding, haplotype network clustering, and native-vs-external aligner/tree-builder benchmarks."
        },
        {
          "tier": 2,
          "usage": "Repeatedly replicated baseline for K2P/TN93 distance, 24-model BIC selection, and 60-state mitochondrial codon dN/dS parity."
        }
      ]
    },
    {
      "dataset_id": "VAL-SET-002-RRNA-16S-18S-23S-ITS",
      "name": "Cross-Domain Ribosomal RNA (16S rrnA–rrnH, 23S PTC, 18S, 28S & Fungal ITS1–5.8S–ITS2) Panel",
      "domain": "Ribosomal Systematics & RNA Secondary Structure",
      "data_origin": "Established Multi-Kingdom Reference Panel + Intragenomic Paralog Stress Tests",
      "specimens_and_scale": "48 prokaryotic and eukaryotic rRNA operons and cistrons (E. coli K-12 rrsA–rrsH, S. enterica, Aspergillus/Candida ITS, Avian 4-locus rRNA)",
      "dev_reserve_partition": "24 core bacterial/fungal rRNA dev loci + 24 avian/eukaryotic reserve & partitioned supermatrix loci",
      "primary_accessions": [
        "NC_000913.3",
        "NC_003197.2",
        "NR_111256.1",
        "NR_130680.1",
        "KT445934.2",
        "NR_033238.1"
      ],
      "primary_literature_anchors": [
        "Woese & Fox (1977) PNAS",
        "Schoch et al. (2012) PNAS",
        "Coleman (2007) Nucleic Acids Res."
      ],
      "replicated_benchmarks": [
        "align-compare (MAFFT L-INS-i)",
        "rna-fold-compare (ViennaRNA v2.7.2)",
        "na-1d2d3d-compare (US-align v20261019)"
      ],
      "discoveries_using_set": [
        "bacterial-16s-operon-haplotypes",
        "fungal-its-58s-cbc-barcoding",
        "ribosomal-rna-23s-ptc-epistasis",
        "bacterial-rpob-gyrb-vs-16s",
        "avian-4locus-rrna-partitioned-tree",
        "rna-folding-mfe-vs-viennarna"
      ],
      "tier_usage_history": [
        {
          "tier": 1,
          "usage": "Marker diagnostic horizon mapping (16S paralog collapse vs. rpoB/gyrB rescue; ITS1 unanchored collapse vs. 5.8S-anchored ITS2 CBCs)."
        },
        {
          "tier": 2,
          "usage": "Secondary-structure MFE and McCaskill partition function replication against ViennaRNA v2.7.2."
        }
      ]
    },
    {
      "dataset_id": "VAL-SET-003-GRCH38-NONB-APOE-HTT",
      "name": "Human GRCh38 Subtelomeric Non-B DNA, APOE Chr19q13.32 & HTT Chr4p16.3 Repeat Expansion Panel",
      "domain": "Human Structural Genomics, Chromatin & Neurogenetics",
      "data_origin": "Mix of Established GRCh38 Reference Windows + Newly Explored Single-Cell Somatic Repeat Cohorts",
      "specimens_and_scale": "5 subtelomeric windows (60–100 kb each: Chr1p36.33, Chr7p22.1, Chr11p15.5, Chr16p13.3, Chr19p13.3), Chr19q13.32 APOE locus, and Chr4p16.3 HTT Exon 1 CAG/CAA tract (2,400 single-nucleus profiles)",
      "dev_reserve_partition": "Chr1p36.33 / APOE dev windows + 4 subtelomeric reserve windows & 12-subclone HTT somatic expansion panel",
      "primary_accessions": [
        "NC_000001.11",
        "NC_000004.12",
        "NC_000019.10",
        "NM_002111.8",
        "NM_000041.4"
      ],
      "primary_literature_anchors": [
        "Bedrat et al. (2016) Nucleic Acids Res.",
        "Handsaker et al. (2025) Cell",
        "Pangenome Reference Consortium (2023) Nature"
      ],
      "replicated_benchmarks": [
        "nonb-dna-compare (G4Hunter / Z-Hunt-II)",
        "synteny-compare (Minimap2 v2.31)",
        "htt-repeat-sc (RuNIE Tier-1 Exploratory)"
      ],
      "discoveries_using_set": [
        "chr1p36-non-b-dna-agrn",
        "subtelomeric-non-b-dna-chromatin",
        "apoe-christchurch-epistatic-shield",
        "nonb-dna-g4hunter-zhunt-benchmark",
        "huntington-somatic-cag-slippage-threshold"
      ],
      "tier_usage_history": [
        {
          "tier": 1,
          "usage": "Unbiased sliding-window G4/Z-DNA anomaly scans and exploratory single-cell Huntington's disease somatic CAG slippage modeling."
        },
        {
          "tier": 2,
          "usage": "Exact G4Hunter score and 65,536-state Z-DNA Boltzmann partition function calibration."
        }
      ]
    },
    {
      "dataset_id": "VAL-SET-004-ESKAPE-AMR-BGC-MICROBIAL",
      "name": "ESKAPE Resistome, Plasmid HGT Islands & 36-Genome Bacterial/Fungal BGC Validation Cohort",
      "domain": "Microbial Genomics, Antimicrobial Resistance & Natural Products",
      "data_origin": "Multi-Round Calibrated Validation Set (10 Dev + 6 Reserve-1 + 9 Reserve-2 + 11 Negative Controls)",
      "specimens_and_scale": "10 ESKAPE clinical resistome assemblies + 36 complete/draft bacterial & fungal genomes (182.8 Mb total, 128 MIBiG-anchored BGCs)",
      "dev_reserve_partition": "10 Development genomes (91 BGCs) + 6 Round-1 Reserve + 9 Round-2 Untouched Reserve genomes (24 bacterial + 13 fungal BGCs) + 11 negative controls",
      "primary_accessions": [
        "NC_002516.2",
        "NC_003888.3",
        "NC_000964.3",
        "NC_000962.3",
        "NC_002951.2",
        "NC_003197.2"
      ],
      "primary_literature_anchors": [
        "Feldgarden et al. (2021) Microb. Genom.",
        "Carroll et al. (2021) Nucleic Acids Res.",
        "Terlouw et al. (2023) Nucleic Acids Res. (MIBiG 3.0/4.0)"
      ],
      "replicated_benchmarks": [
        "amr-compare (AMRFinderPlus v4.2.7)",
        "bgc-compare / bgc-round4 (GECCO v0.11.0)",
        "hmm-compare (HMMER v3.4)",
        "gene-compare (Prodigal v2.6.3)"
      ],
      "discoveries_using_set": [
        "pseudomonas-blandm1-hgt-island",
        "streptomyces-cryptic-bgc-gyrb-amp",
        "amr-hgt-vs-amrfinderplus",
        "bgc-rule-caller-vs-gecco",
        "bgc-reserve-genomes"
      ],
      "tier_usage_history": [
        {
          "tier": 1,
          "usage": "Initial HGT tetranucleotide KL-divergence scans and GECCO vs. native BGC rule-caller comparisons."
        },
        {
          "tier": 2,
          "usage": "Multi-round reserve-genome generalization audit (Discoveries #58–#60) tracking false-positive suppression across 11 negative controls."
        }
      ]
    },
    {
      "dataset_id": "VAL-SET-005-PSEUDO-LOSS-MACSE-RELAX",
      "name": "Mammalian & Cave/Aquatic Lineage-Specific Pseudogenization & Homopolymer Indel Cohort (12 Loci)",
      "domain": "Comparative Genomics, Codon Selection & Human Target Validation",
      "data_origin": "Two-Stage Development + Untouched Reserve Validation Cohort",
      "specimens_and_scale": "12 multi-species coding alignments (72 sequences: GULO, UOX, PCSK9, ANGPTL3,ABCA4, OCA2, CRYAA, MMP20, ENAM,ACTN3, HBB, MYBPC3)",
      "dev_reserve_partition": "6 Development Cohorts (DEV-01..DEV-06) + 6 Untouched Reserve Cohorts (RES-01..RES-06) including 4 homopolymer repeat artifact controls",
      "primary_accessions": [
        "NM_000187.3",
        "NM_174936.4",
        "NM_014495.4",
        "NM_000350.3",
        "NM_000273.3",
        "NM_000518.5"
      ],
      "primary_literature_anchors": [
        "Wertheim et al. (2015) Mol. Biol. Evol. (RELAX)",
        "Ranwez et al. (2018) Mol. Biol. Evol. (MACSE v2)",
        "Sharma et al. (2020) Nature"
      ],
      "replicated_benchmarks": [
        "relax-compare (MACSE v2.07 + PAML v4.10.10 codeml)"
      ],
      "discoveries_using_set": [
        "mammalian-pseudogene-knockout-targets",
        "vertebrate-trait-loss-drug-targets",
        "pseudogene-relax-macse-paml"
      ],
      "tier_usage_history": [
        {
          "tier": 1,
          "usage": "Exploratory trait-loss target screening and 3-frame codon/frameshift calibration against MACSE v2.07 and PAML v4.10.10."
        },
        {
          "tier": 2,
          "usage": "Registered 12-cohort Dev/Reserve benchmark for distinguishing true relaxed purifying selection (k < 0.25) from sequencing homopolymer indels (k ~ 1.0)."
        }
      ]
    },
    {
      "dataset_id": "VAL-SET-006-PALEOBIO-MK-MORPHO-12CLADE",
      "name": "Twelve-Clade Paleobiological Morphological (Mk+ASC), Stratigraphic Tip-Dating & Allometric PIC Cohort",
      "domain": "Paleobiology, Total-Evidence Systematics & Comparative Methods",
      "data_origin": "Two-Stage Replicated Literature Validation Cohort (6 Dev + 6 Reserve Clades)",
      "specimens_and_scale": "12 clades, 101 extant and fossil taxa (48 fossil tips, 0.05–518.0 Ma), 340 osteological, dental, floral, and behavioral characters",
      "dev_reserve_partition": "6 Development Clades (Canidae, Theropoda-Aves, Tetrapodomorpha, Cetartiodactyla, Hominidae, Panarthropoda) + 6 Untouched Reserve Clades (Ursidae, Sphenisciformes, Equidae, Proboscidea, Crocodylomorpha, Angiospermae)",
      "primary_accessions": [
        "PBDB:Canidae_Zrzavy2018",
        "PBDB:Theropoda_Brusatte2014",
        "PBDB:Tetrapoda_Daeschler2006",
        "PBDB:Cetacea_Thewissen2007",
        "PBDB:Equidae_MacFadden2005",
        "PBDB:Crocodylomorpha_Pierce2017"
      ],
      "primary_literature_anchors": [
        "Lewis (2001) Syst. Biol.",
        "Zrzavy et al. (2018) Zool. Scr.",
        "Thewissen et al. (2007) Nature",
        "Chang (2025) Evol. Biol."
      ],
      "replicated_benchmarks": [
        "mk-compare (IQ-TREE v2.4.0 -st MORPH -m MK & MK+ASC)",
        "runie (Studies #1 & #2)"
      ],
      "discoveries_using_set": [
        "bayesian-markov-pipeline-inference",
        "mk-morpho-iqtree-tip-dating"
      ],
      "tier_usage_history": [
        {
          "tier": 2,
          "usage": "Strict replication of published morphological matrices, FBD tip-dating horizons, and PIC encephalization scaling across 6 Dev and 6 Reserve clades."
        }
      ]
    },
    {
      "dataset_id": "VAL-SET-007-PDB-ANM-KAIABC-12COHORT",
      "name": "Twelve-Cohort Experimental PDB Elastic Network Allostery & KaiABC Circadian Oscillator Benchmark Set",
      "domain": "Structural Biophysics, Normal-Mode Allostery & Nonlinear Biochemical Kinetics",
      "data_origin": "Mix of Established Pocket-Docking PDB Targets Reused for Spectral Normal-Mode Calibration + Unseen Reserve Allosteric Gates",
      "specimens_and_scale": "12 experimental RCSB PDB cohorts (700 C-alpha nodes + 72-hour four-state phosphorylation trajectories: 1UYD, 1ORC, 6X3P, 1RX2, 4ZAM, 5RGF, 4BDF, 1G50, 4URL, 1XAV, NC02)",
      "dev_reserve_partition": "6 Development Cohorts (DEV-01..DEV-06 including 1ORC locked-KaiB negative control) + 6 Untouched Reserve Cohorts (RES-01..RES-06 including 40 C Q10 compensation and Hill n = 2 sub-critical control)",
      "primary_accessions": [
        "PDB:1UYD",
        "PDB:1ORC",
        "PDB:6X3P",
        "PDB:1RX2",
        "PDB:4ZAM",
        "PDB:5RGF",
        "PDB:4BDF",
        "PDB:1G50",
        "PDB:4URL",
        "PDB:1XAV"
      ],
      "primary_literature_anchors": [
        "Bahar et al. (1997) Fold. Des.",
        "Rust et al. (2007) Science",
        "Chang et al. (2015) Science",
        "Nussinov et al. (2023) Structure"
      ],
      "replicated_benchmarks": [
        "anm-compare (SciPy v1.18.1 eigh + solve_ivp RK45)",
        "pocket-dock-compare (fpocket v4.2.3 + AutoDock Vina v1.2.7)"
      ],
      "discoveries_using_set": [
        "protein-pocket-docking-vs-fpocket-vina",
        "bayesian-markov-pipeline-inference",
        "kaiabc-allostery-scipy"
      ],
      "tier_usage_history": [
        {
          "tier": 1,
          "usage": "Reused PDB structural targets in a new way (spectral Kirchhoff normal-mode B-factors and coupled Goodwin-Hopf RK4 limit-cycle calibration against SciPy v1.18.1)."
        },
        {
          "tier": 2,
          "usage": "Replicated 9-study RuNIE validation for KaiABC circadian period stability and allosteric pocket coupling."
        }
      ]
    },
    {
      "dataset_id": "VAL-SET-008-RP16-DEEP-PHYLOGENOMICS-12COHORT",
      "name": "Twelve-Cohort Universal 16-Ribosomal-Protein (RP16) Deep-Time Compositional LBA & Auxotrophy Set",
      "domain": "Deep-Time Phylogenomics, Compositional Recoding & Symbiont Metabolic Reconstruction",
      "data_origin": "Mix of Classic Deep-Branching Phylogenomic Benchmarks (Hug et al. 2016; Spang et al. 2015) + Unseen Reserve Endosymbiont/Metazoan LBA Stress Cohorts",
      "specimens_and_scale": "12 multi-taxon syntenic RP16 supermatrices (98 taxa across Asgard/Eukaryota, CPR/Patescibacteria, DPANN, Aquifex/Thermotoga, Rickettsiales/Mitochondria, Gloeomargarita/Plastids, Microsporidia, Buchnera/Wigglesworthia, Basal Metazoa, and TACK Archaea)",
      "dev_reserve_partition": "6 Development Cohorts (DEV-01..DEV-06 including within-class compositional drift control) + 6 Untouched Reserve Cohorts (RES-01..RES-06 including reserve compositional decoy)",
      "primary_accessions": [
        "NC_000913.3",
        "NC_000964.3",
        "NC_000918.1",
        "NC_000854.2",
        "NC_003103.1",
        "NC_001807.4",
        "NC_002528.1",
        "NC_000908.2",
        "CP010426.1"
      ],
      "primary_literature_anchors": [
        "Hug et al. (2016) Nat. Microbiol.",
        "Spang et al. (2015) Nature",
        "Susko & Roger (2007) Mol. Biol. Evol.",
        "Williams et al. (2020) Nat. Ecol. Evol."
      ],
      "replicated_benchmarks": [
        "rp16-compare (IQ-TREE v2.4.0 -st AA POISSON+FQ & -st MORPH MK -keep-ident)",
        "runie (Study #3: Hug et al. 2016)"
      ],
      "discoveries_using_set": [
        "bayesian-markov-pipeline-inference",
        "rp16-dayhoff-recoding-iqtree"
      ],
      "tier_usage_history": [
        {
          "tier": 1,
          "usage": "Exploratory head-to-head calibration of AA-20 vs. Dayhoff-6 and SR4 compositional recoding against IQ-TREE v2.4.0 across 6 seen dev clades and 6 unseen reserve LBA clades."
        },
        {
          "tier": 2,
          "usage": "Baseline validation of CPR/DPANN monophyly and metabolic auxotrophy completeness in RuNIE Study #3."
        }
      ]
    },
    {
      "validation_set_id": "VAL-SET-009-CODON-OPT-VIENNARNA-12COHORT",
      "name": "mRNA Synonymous Codon Adaptation & Secondary-Structure MFE / Partition-Function Benchmark Set (12 Coding Sequences)",
      "domain": "RNA Biophysics, Synonymous Codon Optimization & Thermodynamic Folding",
      "status": "Active Validation Set (Calibrated & Reserve-Verified)",
      "replication_count": 2,
      "specimens_and_scale": "12 coding sequences (1,620 nt across SARS-CoV-2 Spike RBD, Influenza HA, Human EPO, Human Insulin, RSV Fusion F0, Rabies GP, Human Factor IX, Human GLA, VZV gE, Human G6PD, plus AUG-UGG non-degenerate and pre-saturated optimal negative controls)",
      "dev_reserve_partition": "6 Development Cohorts (DEV-01..DEV-06 including non-degenerate AUG-UGG negative control) + 6 Untouched Reserve Cohorts (RES-01..RES-06 including pre-saturated optimal negative control)",
      "primary_accessions": [
        "NC_045512.2",
        "NC_007362.1",
        "NM_000799.4",
        "NM_000207.3",
        "NC_001803.1",
        "NC_001542.1",
        "NM_000133.4",
        "NM_000169.3",
        "NC_001348.1",
        "NM_001042351.3"
      ],
      "primary_literature_anchors": [
        "Sharp & Li (1987) Nucleic Acids Res.",
        "McCaskill (1990) Biopolymers",
        "Mathews et al. (2004) PNAS",
        "Zhang et al. (2023) Nature"
      ],
      "replicated_benchmarks": [
        "codon-opt-compare (ViennaRNA v2.7.2 RNAfold -p --noPS)"
      ],
      "discoveries_using_set": [
        "bayesian-markov-pipeline-inference",
        "codon-opt-viennarna"
      ],
      "tier_usage_history": [
        {
          "tier": 1,
          "usage": "Exploratory head-to-head calibration of synonymous codon optimization (CAI, GC3%, U%) and Turner-2004 MFE / McCaskill ensemble folding against ViennaRNA v2.7.2 across 6 Dev and 6 Untouched Reserve coding sequences."
        }
      ]
    },
    {
      "validation_set_id": "VAL-SET-010-REPEAT-MOTIF-BIOMECHANICS-12COHORT",
      "name": "Repetitive Structural Protein Motif Grammar (Poly-Ala / GPGXX / GGX / GAGAGS) & Biomechanics Benchmark Set (12 Cohorts)",
      "domain": "Protein Motif Grammar, Structural Biomaterials & Sequence-to-Mechanics Regression",
      "status": "Active Validation Set (Calibrated & Reserve-Verified)",
      "replication_count": 2,
      "specimens_and_scale": "12 structural protein sequences across spider dragline/capture/tubuliform spidroins (Caerostris darwini, Caerostris extrusa, Trichonephila clavipes, Araneus diadematus, Araneus ventricosus, Latrodectus hesperus, Argiope aurantia), Bombyx mori fibroin heavy chain, and 2 negative controls (human lysozyme globular control & shuffled block-disrupted decoy)",
      "dev_reserve_partition": "6 Development Cohorts (DEV-01..DEV-06 including globular non-repetitive control) + 6 Untouched Reserve Cohorts (RES-01..RES-06 including shuffled block-disrupted decoy)",
      "primary_accessions": [
        "PRD23988.1",
        "P19837.3",
        "Q16987.1",
        "AF027973.1",
        "NP_001106733.1",
        "NP_000230.1",
        "PRD24102.1",
        "GBN88412.1",
        "ABR68856.1",
        "AF350266.1",
        "AY953070.1"
      ],
      "primary_literature_anchors": [
        "Arakawa et al. (2022) Sci. Adv.",
        "Agnarsson et al. (2010) PLoS ONE",
        "Hayashi et al. (1999) J. Mol. Biol.",
        "Gosline et al. (1999) J. Exp. Biol."
      ],
      "replicated_benchmarks": [
        "repeat-motif-compare (SciPy v1.18.1 scipy.linalg.solve & NumPy v2.5.4)"
      ],
      "discoveries_using_set": [
        "bayesian-markov-pipeline-inference",
        "repeat-motif-scipy"
      ],
      "tier_usage_history": [
        {
          "tier": 1,
          "usage": "Exploratory head-to-head calibration of tandem repeat motif extraction (poly-Ala block length, GPGXX spiral density, GGX helix density) and candle-core ridge regression against SciPy v1.18.1 across 6 Dev and 6 Untouched Reserve cohorts."
        }
      ]
    },
    {
      "validation_set_id": "VAL-SET-011-KABSCH-TMSCORE-PDB-12COHORT",
      "name": "3D Protein Backbone Kabsch SO(3) Superposition, Active-Site Motif RMSD & Zhang-Skolnick TM-Score Benchmark Set (12 PDB Cohorts)",
      "domain": "3D Structural Bioinformatics, Active-Site Motif Superposition & Fold Similarity",
      "status": "Active Validation Set (Calibrated & Reserve-Verified)",
      "replication_count": 2,
      "specimens_and_scale": "12 experimental PDB 3D coordinate sets (1UYD, 6X3P, 1RX2, 4ZAM, 5RGF, 1ORC, 4BDF, 1G50, 4URL, 1XAV, plus unfolded random-walk steric decoy and mirror-image chiral reflection control)",
      "dev_reserve_partition": "6 Development Cohorts (DEV-01..DEV-06 including unfolded random-walk control) + 6 Untouched Reserve Cohorts (RES-01..RES-06 including mirror-image chiral reflection control)",
      "primary_accessions": [
        "1UYD",
        "6X3P",
        "1RX2",
        "4ZAM",
        "5RGF",
        "1ORC",
        "4BDF",
        "1G50",
        "4URL",
        "1XAV"
      ],
      "primary_literature_anchors": [
        "Kabsch (1976) Acta Crystallogr. A",
        "Zhang & Skolnick (2004) Proteins",
        "Watson et al. (2023) Nature"
      ],
      "replicated_benchmarks": [
        "kabsch-tm-compare (SciPy v1.18.1 scipy.linalg.svd & NumPy v2.5.4)"
      ],
      "discoveries_using_set": [
        "bayesian-markov-pipeline-inference",
        "kabsch-tm-scipy"
      ],
      "tier_usage_history": [
        {
          "tier": 1,
          "usage": "Exploratory head-to-head calibration of Kabsch SO(3) SVD superposition (with det(R)=+1 chirality guard), active-site motif RMSD, and Zhang-Skolnick TM-score against SciPy v1.18.1 across 6 Dev and 6 Untouched Reserve PDB cohorts."
        }
      ]
    },
    {
      "validation_set_id": "VAL-SET-012-DCA-COEVOLUTION-12COHORT",
      "name": "Mean-Field Direct Coupling Analysis (mfDCA) & Epistatic Contact Disentanglement Benchmark Set (12 Cohorts)",
      "domain": "Co-Evolutionary Epistasis, Direct Coupling Analysis & 3D Contact Prediction",
      "status": "Active Validation Set (Calibrated, Reserve-Verified & Tier 3 Synthesized)",
      "replication_count": 3,
      "specimens_and_scale": "12 multiple sequence alignment cohorts (160 sequences x 12 columns each across 23S rRNA PTC, SHV-1 beta-lactamase, E. coli DHFR, 16S rRNA Helix 44, Human HSP90A, Fungal ITS2 Helix III, Human MT-RNR2, S. aureus ParE, Human BTK, Human ESR1, plus column-permuted and clonal neutral-drift negative controls)",
      "dev_reserve_partition": "6 Development Cohorts (DEV-01..DEV-06 including column-permuted negative control) + 6 Untouched Reserve Cohorts (RES-01..RES-06 including clonal neutral-drift negative control)",
      "primary_accessions": [
        "NC_000913.3",
        "4ZAM",
        "1RX2",
        "4V5D",
        "1UYD",
        "NR_111007.1",
        "NC_012920.1",
        "4URL",
        "6X3P",
        "1G50"
      ],
      "primary_literature_anchors": [
        "Morcos et al. (2011) PNAS",
        "Dunn et al. (2008) Bioinformatics",
        "Weigt et al. (2009) PNAS",
        "Marks et al. (2011) PLoS ONE"
      ],
      "replicated_benchmarks": [
        "dca-compare (SciPy v1.18.1 scipy.linalg.inv & NumPy v2.5.4)",
        "popgen-tier3-synthesis (Hypothesis H4 Flanking Epistasis Falsification)"
      ],
      "discoveries_using_set": [
        "bayesian-markov-pipeline-inference",
        "dca-coevo-scipy",
        "popgen-tier3-repeat-kcore"
      ],
      "tier_usage_history": [
        {
          "tier": 1,
          "usage": "Exploratory head-to-head calibration of Mean-Field Direct Coupling Analysis (mfDCA precision matrix inversion + zero-sum gauge Frobenius norm + APC) against SciPy v1.18.1 across 6 Dev and 6 Untouched Reserve co-evolutionary cohorts."
        },
        {
          "tier": 3,
          "usage": "Tier 3 scientific synthesis testing Hypothesis H4 (whether repeat-flanking W1 substitutions co-evolve via pairwise mfDCA epistasis), falsifying H4 at DCA_APC = 0.044 (Z = +0.84 SD, 1🧪) vs. 0.482 in paired 3D structural stems."
        }
      ]
    },
    {
      "validation_set_id": "VAL-SET-013-POPGEN-HAPLO-MSN-12COHORT",
      "name": "Minimum Spanning Haplotype Network (MSN), Hudson F_ST, Nucleotide Diversity (pi) & Tajima's D Benchmark Set (12 Cohorts)",
      "domain": "Population Genetics, Haplotype Network Graph Topology & Demographic Neutrality Tests",
      "status": "Active Validation Set (Calibrated, Reserve-Verified, Blind-Validated & Tier 3 Synthesized)",
      "replication_count": 5,
      "specimens_and_scale": "12 population-genetic alignment cohorts (24 sequences x 60 bp each across Ursus maritimus/U. arctos COX1, Human HBB rs334, SARS-CoV-2 Spike, Drosophila melanogaster Adh, Plasmodium falciparum pfcrt, Thunnus thynnus/T. orientalis COX1, Human HLA-DRB1, Mycobacterium tuberculosis rpoB/katG, Arabidopsis thaliana FRI, Salmo salar ND1, plus monomorphic clonal, panmictic label-permuted, and NUMT/scrambled-label audit controls)",
      "dev_reserve_partition": "6 Development Cohorts (DEV-01..DEV-06 including monomorphic S=0 control) + 6 Untouched Reserve Cohorts (RES-01..RES-06 including panmictic label-permuted F_ST=0 control)",
      "primary_accessions": [
        "NC_003428.1",
        "NC_003427.1",
        "NG_000007.3",
        "NC_045512.2",
        "M17833.1",
        "XM_001348968.1",
        "NC_014052.1",
        "NC_008455.1",
        "NG_002392.2",
        "NC_000962.3",
        "NM_116232.3",
        "NC_001960.1"
      ],
      "primary_literature_anchors": [
        "Tajima (1989) Genetics",
        "Hudson, Slatkin & Maddison (1992) Genetics",
        "Nei (1987) Molecular Evolutionary Genetics",
        "Watterson (1975) Theor. Popul. Biol.",
        "Bandelt, Forster & Röhl (1999) Mol. Biol. Evol."
      ],
      "replicated_benchmarks": [
        "popgen-compare (SciPy v1.18.1 scipy.sparse.csgraph.minimum_spanning_tree & NumPy v2.5.4)",
        "popgen-tier2-deep-sweep (24-Cohort Chained Tier 2 Deep Sweep)",
        "popgen-tier2-blind-validate (Dual-Pass Blinded vs. Context-Aware Validation)",
        "popgen-tier3-synthesis (28-Cohort / 1.08 Mb Cross-Study Scientific Synthesis)"
      ],
      "discoveries_using_set": [
        "haplotype-network-clustering",
        "popgen-haplo-scipy",
        "popgen-tier2-deep-sweep",
        "popgen-tier2-blind-validate",
        "popgen-tier3-repeat-kcore"
      ],
      "tier_usage_history": [
        {
          "tier": 1,
          "usage": "Exploratory head-to-head calibration of Prim Minimum Spanning Haplotype Network (MSN), Nei Hd, nucleotide diversity pi, Watterson's theta_W, Tajima's D, and Hudson F_ST against SciPy v1.18.1 across 6 Dev and 6 Untouched Reserve cohorts."
        },
        {
          "tier": 2,
          "usage": "Tier 2 deep 24-cohort (312 kb) calibration sweep integrating Haplotype MSN, Hudson F_ST, and Tajima's D with McDonald (2011) repeat-indel decay and Hagmann (2008) k-core hub centrality (Bayesian Prior 4–5🧪 -> Empirical Posterior 4🧪, Z_posterior = +3.59 SD)."
        },
        {
          "tier": 2,
          "usage": "Tier 2 Dual-Pass Blinded vs. Context-Aware validation verifying 100% de-identified biotype extrapolation and catching cryptic nuclear NUMT paralogs (H_pos2 = 0.418 bits) and scrambled subpopulation labels (latent MST F_ST = 0.762 vs. labeled 0.042)."
        },
        {
          "tier": 3,
          "usage": "Tier 3 scientific synthesis (28 cohorts / 1.08 Mb) demonstrating pipeline isomorphism with VAL-SET-014 and VAL-SET-015: Repeat+/Indel- haplotypes form k=5–6 MSN connector hubs (H1 Accepted, 5🧪) and blinded H_pos2 + D_KL pre-filtering removes 100% of NUMT/HGT network bridge artifacts (H3 Accepted, 4🧪)."
        }
      ]
    },
    {
      "validation_set_id": "VAL-SET-014-MCDONALD-2011-REPEAT-INDEL-SNP-CLUSTERS",
      "name": "Repeat-Driven Substitution & Indel Mutation Clustering Validation Set (McDonald et al. 2011 PLoS Biology)",
      "domain": "Population Genomics, Repeat-Induced Polymerase Stalling & Flanking Nucleotide Diversity Decay",
      "status": "Active Tier 2 & Tier 3 Validation Set (Primary Literature Replicated, Deep-Sweep, Blind-Validated & Tier 3 Synthesized)",
      "replication_count": 5,
      "specimens_and_scale": "6 core cohorts + 24-cohort deep spatial expansion + 28-cohort Tier 3 cross-study synthesis (1.08 Mb across Saccharomyces paradoxus URA3/CAN1, S. cerevisiae CAN1/FLO1/HIS4, Escherichia coli lacZ-mhpR/tolC, Drosophila melanogaster Chr2L/Notch, Homo sapiens HTT/ATXN1/DMPK/FMR1/HBB, Plasmodium falciparum pfcrt, and Arabidopsis FRI)",
      "dev_reserve_partition": "14 Development Cohorts + 14 Untouched Reserve Cohorts in Tier 3 Synthesis",
      "primary_accessions": [
        "NC_001137.3",
        "NC_001133.9",
        "NC_000913.3",
        "NT_033779.5",
        "NC_000004.12",
        "NC_000006.12",
        "NC_000019.10",
        "NC_000023.11",
        "XM_001348968.1"
      ],
      "primary_literature_anchors": [
        "McDonald, Wang, Huang & Leu (2011) PLoS Biology 9(6): e1000622 (https://doi.org/10.1371/journal.pbio.1000622)"
      ],
      "replicated_benchmarks": [
        "popgen-tier2-validate (Windowed Proximal W1 vs. Distal W3 pi Decay & Haplotype MSN)",
        "popgen-tier2-deep-sweep (5-Window Spatial Decay W1..W5, Turner-2004 Hairpin MFE, mfDCA & Pol-zeta Horizon)",
        "popgen-tier2-blind-validate (Dual-Pass Blinded vs. Context-Aware Validation)",
        "popgen-tier3-synthesis (28-Cohort / 1.08 Mb Cross-Study Scientific Synthesis)"
      ],
      "discoveries_using_set": [
        "popgen-haplomap-tier2",
        "popgen-tier2-deep-sweep",
        "popgen-tier2-blind-validate",
        "popgen-tier3-repeat-kcore"
      ],
      "tier_usage_history": [
        {
          "tier": 2,
          "usage": "Tier 2 validation confirming that tandem repeat sequences—even in indel-free haplotypes (Repeat+/Indel-)—drive ~3.75x proximal flanking substitution clustering via translesion repair polymerase recruitment, whereas non-repeat indels (Repeat-/Indel+) remain at 1.00x baseline."
        },
        {
          "tier": 2,
          "usage": "Tier 2 deep 24-cohort (312 kb) Bayesian calibration sweep mapping 5-window flanking decay (lambda_decay ~ 118 bp), identifying three biological attenuation boundaries (n<=3 proto-repeat threshold at Z=+2.21 SD, >350 bp Pol-zeta processivity horizon at Z=+1.12 SD, and recombination erosion at Z=+3.09 SD), and adjusting the 4–5🧪 prior to a 4🧪 posterior (Z_posterior = +3.59 SD)."
        },
        {
          "tier": 2,
          "usage": "Tier 2 Dual-Pass Blinded vs. Context-Aware validation verifying 0.0000 |ΔZ| on true-labeled repeat flanks while catching sample-swapped rev3Δ Pol-zeta knockouts (|ΔZ| = 4.42 SD) and exogenous bacterial tRNA HGT islands mislabelled as housekeeping DNA (7.6x D_KL = 0.486 bits)."
        },
        {
          "tier": 3,
          "usage": "Tier 3 scientific synthesis (28 cohorts / 1.08 Mb) proving that Repeat+/Indel- alleles act as the k=5–6 network connector hubs (H1 Accepted, Z=+4.84 SD, 5🧪) and that 1–2 CAA/CAT/AGG triplet interruptions destabilize slip-out hairpins (+4.8 kcal/mol) and abolish flanking hypermutability (H2 Accepted, Z=+4.74 SD, 5🧪)."
        }
      ]
    },
    {
      "validation_set_id": "VAL-SET-015-HAGMANN-2008-NETWORK-CORE-TOPOLOGY",
      "name": "Multi-Module Network Structural Core, k-Core Decomposition & Connector Hub Centrality Validation Set (Hagmann et al. 2008 PLoS Biology)",
      "domain": "Network Graph Topology, k-Core Peeling Decomposition, Connector Hub Betweenness Centrality & Minimum Spanning Backbones",
      "status": "Active Tier 2 & Tier 3 Validation Set (Primary Literature Replicated, Deep-Sweep, Blind-Validated & Tier 3 Synthesized)",
      "replication_count": 5,
      "specimens_and_scale": "6 core cohorts + 24-cohort deep multi-module haplotype/connectome graph sweep + 28-cohort Tier 3 synthesis (1.08 Mb linking repeat-flanking haplotype networks directly to k-core connector hub centrality)",
      "dev_reserve_partition": "14 Development Cohorts + 14 Untouched Reserve Cohorts in Tier 3 Synthesis",
      "primary_accessions": [
        "DSI-66ROI-6MOD",
        "DSI-POSTMEDIAL-RES04",
        "HAPLO-6MOD-CORE-DEV05",
        "HAPLO-5BASIN-CORE-RES05",
        "NG_002392.2"
      ],
      "primary_literature_anchors": [
        "Hagmann, Cammoun, Gigandet, Meuli, Honey, Wedeen & Sporns (2008) PLoS Biology 6(7): e159 (https://doi.org/10.1371/journal.pbio.0060159)"
      ],
      "replicated_benchmarks": [
        "popgen-tier2-validate (k-Core Peeling, Shortest-Path Betweenness Centrality C_B & Kruskal MST Backbone)",
        "popgen-tier2-deep-sweep (24-Cohort k-Core Peeling, Connector Hub C_B, Prim/Kruskal MST vs. SciPy v1.18.1)",
        "popgen-tier2-blind-validate (Dual-Pass Blinded vs. Context-Aware Validation)",
        "popgen-tier3-synthesis (28-Cohort / 1.08 Mb Cross-Study Scientific Synthesis)"
      ],
      "discoveries_using_set": [
        "popgen-haplomap-tier2",
        "popgen-tier2-deep-sweep",
        "popgen-tier2-blind-validate",
        "popgen-tier3-repeat-kcore"
      ],
      "tier_usage_history": [
        {
          "tier": 2,
          "usage": "Tier 2 validation of iterative k-core peeling decomposition (k_max = 5-6 vs. k_max = 1 in peripheral tree/chain controls), connector hub shortest-path betweenness centrality (C_B), and Minimum Spanning Tree backbone weights."
        },
        {
          "tier": 2,
          "usage": "Tier 2 deep 24-cohort (312 kb) calibration sweep evaluating k-core peeling and connector hub centrality across repeat-driven haplotype networks and structural connectomes (100% MST & k_max parity vs. SciPy v1.18.1; Bayesian Prior 4–5🧪 -> Empirical Posterior 4🧪)."
        },
        {
          "tier": 2,
          "usage": "Tier 2 Dual-Pass Blinded vs. Context-Aware validation confirming that de-identified adjacency matrices autonomously extrapolate k_max = 5–6 connector cores vs. k_max = 1 acyclic peripheral controls with 0.0000 |ΔZ|."
        },
        {
          "tier": 3,
          "usage": "Tier 3 scientific synthesis establishing that Hagmann k-core connector hubs (C_B = 0.494, k_max = 5–6) in population haplotype networks correspond to ancestral Repeat+/Indel- alleles, and collapse to acyclic k_max = 1–2 trees when CAA/CAT interruptions break repeat hairpins."
        }
      ]
    },
    {
      "validation_set_id": "VAL-SET-016-CHROM-LAPLACIAN-TAD-12COHORT",
      "name": "3D Chromatin Contact Graph Laplacian, TAD Insulation Score & A/B Compartment Eigenvector Calibration Panel (SciPy v1.18.1 Benchmark)",
      "domain": "3D Genome Architecture, Graph Spectral Laplacian Connectivity, TAD Insulation & Biomolecular Condensates",
      "status": "Active Validation Set (Calibrated & Reserve-Verified vs. SciPy v1.18.1)",
      "replication_count": 1,
      "specimens_and_scale": "12 3D chromatin contact matrix & IDR sticker-spacer cohorts (16x16 Hi-C / Micro-C contact maps spanning 119.36 Mb across Human chr1p36.33 AGRN seRNA hub, chr12p13.33 CACNA1C Intron-30 VNTR hub, chr2q35-q36 EPHA4/PAX3 canonical & Del-B enhancer-hijacking TAD boundaries, chr14 & chr19 A/B macro-compartments, chr8q24.21 MYC/PVT1 condensate clique, chr17q24.3 SOX9/KCNJ2 canonical & Dup-C Cook syndrome neo-TAD boundaries, chr2q31.1 HOXD bimodal TAD switch, plus isotropic polymer s^-1 and RAD21-AID cohesin-depleted loop-free negative controls)",
      "dev_reserve_partition": "6 Development Cohorts (DEV-01..DEV-06 including isotropic s^-1 polymer decay control) + 6 Untouched Reserve Cohorts (RES-01..RES-06 including RAD21-AID cohesin-depleted loop-free control)",
      "primary_accessions": [
        "4DNFI2R1W3YW",
        "NC_000001.11",
        "NC_000012.12",
        "NC_000002.12",
        "NC_000014.9",
        "NC_000008.11",
        "NC_000017.11",
        "NC_000019.10"
      ],
      "primary_literature_anchors": [
        "Lieberman-Aiden et al. (2009) Science 326:289-293",
        "Crane et al. (2015) Nature 523:240-244",
        "Lupianez et al. (2015) Cell 161:1012-1025",
        "Franke et al. (2016) Nature 538:265-269",
        "Sabari et al. (2018) Science 361:eaar3958",
        "Rao et al. (2017) Cell 171:305-320"
      ],
      "replicated_benchmarks": [
        "chrom-compare (SciPy v1.18.1 scipy.sparse.csgraph.laplacian, scipy.linalg.eigh & NumPy v2.5.4 numpy.corrcoef)"
      ],
      "discoveries_using_set": [
        "chrom-condensate-scipy"
      ],
      "tier_usage_history": [
        {
          "tier": 1,
          "usage": "Exploratory head-to-head calibration of Combinatorial & Normalized 3D Chromatin Graph Laplacian Fiedler algebraic connectivity (lambda_2, norm_lambda_2), Von Neumann spectral entropy (S_VN), Crane sliding-diamond TAD insulation score (IS_min), and Lieberman-Aiden O/E A/B compartment eigenvector (E1) against SciPy v1.18.1 across 6 Dev and 6 Untouched Reserve cohorts (0.0000 MAE across all spectral & insulation metrics, 100% boundary & regime concordance, 10.94x speedup)."
        }
      ]
    },
    {
      "validation_set_id": "VAL-SET-017-CLONAL-96SBS-SYNTH-12COHORT",
      "name": "Somatic Clonal 96-Channel Mutational JSD, NNLS COSMIC Deconvolution & CRISPR Synthetic Lethality Calibration Panel (SciPy v1.18.1 Benchmark)",
      "domain": "Somatic Oncology, 96-Channel Trinucleotide Mutational Signatures, Non-Negative Least Squares Deconvolution & Paralog Synthetic Lethality",
      "status": "Active Validation Set (Calibrated & Reserve-Verified vs. SciPy v1.18.1)",
      "replication_count": 1,
      "specimens_and_scale": "12 somatic subclone & CRISPR dependency cohorts (12,930 single cells and 133,890 somatic SNVs across Ovarian ARID1A-null/ARID1B, Chr9p21.3 MTAP-del/PRMT5, Colorectal MLH1-MSI/WRN, NSCLC SMARCA4-null/SMARCA2, TNBC BRCA1-null/PARP1, Endometrial POLE-P286R/STAG1, Urothelial ENO1-del/ENO2, Gastric MSH2-MSI/WRN, Prostate BRCA2-del/POLQ, Melanoma VPS4B-del/VPS4A, plus polyclonal HSC clock and synonymous passenger negative controls)",
      "dev_reserve_partition": "6 Development Cohorts (DEV-01..DEV-06 including polyclonal normal HSC clock control) + 6 Untouched Reserve Cohorts (RES-01..RES-06 including indolent synonymous passenger control)",
      "primary_accessions": [
        "NG_009266.1",
        "NG_012336.2",
        "NG_007109.2",
        "NG_011556.3",
        "NG_005905.2",
        "NG_033840.1",
        "NG_012098.1",
        "NG_007110.2"
      ],
      "primary_literature_anchors": [
        "Alexandrov et al. (2020) Nature 578:94-101",
        "Helming et al. (2014) Nat Med 20:251-254",
        "Kryukov et al. (2016) Science 351:1214-1218",
        "Chan et al. (2019) Nature 568:551-556",
        "Behan et al. (2019) Nature 568:511-516",
        "Lawson & Hanson (1995) Solving Least Squares Problems"
      ],
      "replicated_benchmarks": [
        "clonal-compare (SciPy v1.18.1 scipy.stats.entropy, scipy.spatial.distance.jensenshannon, scipy.optimize.nnls & scipy.stats.ttest_ind)"
      ],
      "discoveries_using_set": [
        "clonal-synth-scipy"
      ],
      "tier_usage_history": [
        {
          "tier": 1,
          "usage": "Exploratory head-to-head calibration of 96-channel trinucleotide Shannon entropy (H_96), base-2 Jensen-Shannon divergence (JSD), Lawson-Hanson Non-Negative Least Squares (NNLS) COSMIC v3.4 signature deconvolution, and DepMap CRISPR synthetic lethality (Delta Chronos & Welch t-statistic) against SciPy v1.18.1 across 6 Dev and 6 Untouched Reserve cohorts (0.0000 MAE across all 5 metrics, 100% regime concordance, 15.71x speedup)."
        }
      ]
    },
    {
      "validation_set_id": "VAL-SET-018-FINEMAP-COLOC-12COHORT",
      "name": "Wakefield ABF Statistical Fine-Mapping, 95% Causal Credible Sets & Giambartolomei Bayesian eQTL/pQTL Colocalization Calibration Panel (SciPy v1.18.1 Benchmark)",
      "domain": "Human Statistical Genetics, Bayesian Fine-Mapping Credible Sets & Multi-Trait eQTL/pQTL Colocalization",
      "status": "Active Validation Set (Calibrated & Reserve-Verified vs. SciPy v1.18.1)",
      "replication_count": 1,
      "specimens_and_scale": "12 human GWAS x cis-eQTL/pQTL/sQTL colocalization & fine-mapping cohorts (240 variants across 1p13.3 SORT1/CELSR2 rs12740374, 1p31.3 IL23R R381Q, 19q13.32 APOE/TOMM40 rs429358, 9p21.3 CDKN2A/CDKN2B/ANRIL 4-SNP enhancer LD block, 10q11.23 MSMB rs10993994, 19p13.2 TYK2 P1104A, 1p32.3 PCSK9 R46L, 2q24.3 SCN1A 3-SNP promoter block, 16p11.2 SH2B1/TUFM 3-SNP block, 5q15 ERAP2 rs2248374 splice-site NMD, plus 12q21.2 H0 underpowered null and 17q21.31 MAPT vs. KANSL1 H3 distinct-causal linkage negative controls)",
      "dev_reserve_partition": "6 Development Cohorts (DEV-01..DEV-06 including 12q21.2 H0 underpowered null control) + 6 Untouched Reserve Cohorts (RES-01..RES-06 including 17q21.31 MAPT vs. KANSL1 H3 distinct-causal linkage decoy)",
      "primary_accessions": [
        "rs12740374",
        "rs11209026",
        "rs429358",
        "rs1333049",
        "rs10993994",
        "rs34536443",
        "rs11591147",
        "rs6732655",
        "rs7359397",
        "rs2248374"
      ],
      "primary_literature_anchors": [
        "Wakefield (2009) Genet Epidemiol 33:79-86",
        "Giambartolomei et al. (2014) PLoS Genet 10:e1004383",
        "Musunuru et al. (2010) Nature 466:714-719",
        "Dendrou et al. (2016) Sci Transl Med 8:363ra149",
        "Wallace (2021) PLoS Genet 17:e1009440"
      ],
      "replicated_benchmarks": [
        "finemap-compare (SciPy v1.18.1 scipy.special.logsumexp + Wakefield ABF & Giambartolomei coloc.abf)"
      ],
      "discoveries_using_set": [
        "finemap-coloc-scipy"
      ],
      "tier_usage_history": [
        {
          "tier": 1,
          "usage": "Exploratory head-to-head calibration of log-space Wakefield Approximate Bayes Factors (ln ABF), overflow-protected LogSumExp Posterior Inclusion Probabilities (PIP), 95% causal credible sets (CS_95 & Shannon entropy H_CS), and Giambartolomei 5-hypothesis Bayesian colocalization (PP.H0..PP.H4) against SciPy v1.18.1 across 6 Dev and 6 Untouched Reserve cohorts (0.0000 MAE across all metrics, 100% credible-set & regime concordance)."
        }
      ]
    },
    {
      "validation_set_id": "VAL-SET-019-MR-TWAS-12COHORT",
      "name": "Two-Sample Mendelian Randomization (IVW, MR-Egger Pleiotropy, Weighted Median & Cochran's Q) Calibration Panel (SciPy v1.18.1 Benchmark)",
      "domain": "Causal Genetic Epidemiology, Two-Sample Mendelian Randomization & Pleiotropy-Robust Target Validation",
      "status": "Active Validation Set (Calibrated & Reserve-Verified vs. SciPy v1.18.1)",
      "replication_count": 1,
      "specimens_and_scale": "12 human Two-Sample Mendelian Randomization exposure -> outcome cohorts (120 independent genetic instruments across PCSK9/HMGCR LDL-C -> CAD, IL6R Asp358Ala -> CHD/RA, LPA -> Calcific Aortic Stenosis, BMI -> T2D, ANGPTL3/LPL -> CAD, TYK2/IL23R -> Psoriasis/IBD, Systolic BP -> Ischemic Stroke, APOC3 -> CHD, MMP12 -> Large-Artery Stroke, GLP1R Ala316Thr -> T2D/Heart Failure, plus CRP -> CHD null causal control and HDL-C directional horizontal pleiotropy negative control)",
      "dev_reserve_partition": "6 Development Cohorts (DEV-01..DEV-06 including CRP -> CHD null causal control) + 6 Untouched Reserve Cohorts (RES-01..RES-06 including HDL-C directional horizontal pleiotropy decoy)",
      "primary_accessions": [
        "rs11591147",
        "rs2228145",
        "rs10455872",
        "rs9939609",
        "rs11207977",
        "rs1205",
        "rs34536443",
        "rs138326449",
        "rs2276109",
        "rs10305492"
      ],
      "primary_literature_anchors": [
        "Burgess et al. (2013) Genet Epidemiol 37:658-665",
        "Bowden et al. (2015) Int J Epidemiol 44:512-525",
        "Bowden et al. (2016) Genet Epidemiol 40:304-314",
        "Ference et al. (2016) NEJM 375:2144-2153",
        "CRP CHD Genetics Collaboration (2011) BMJ 342:d548",
        "Voight et al. (2012) Lancet 380:572-580"
      ],
      "replicated_benchmarks": [
        "mr-compare (SciPy v1.18.1 scipy.linalg.lstsq + Multiplicative Random-Effects IVW, MR-Egger & Weighted Median)"
      ],
      "discoveries_using_set": [
        "mr-twas-scipy"
      ],
      "tier_usage_history": [
        {
          "tier": 1,
          "usage": "Exploratory head-to-head calibration of allele-oriented Multiplicative Random-Effects Inverse-Variance Weighted (IVW) causal estimation, Cochran's Q heterogeneity, MR-Egger weighted linear regression (slope, directional pleiotropy intercept & Rucker's Q'), and 50%-invalid-IV robust Weighted Median estimation against SciPy v1.18.1 across 6 Dev and 6 Untouched Reserve cohorts (0.0000 MAE across all 6 metrics, 100% regime concordance)."
        }
      ]
    },
    {
      "validation_set_id": "VAL-SET-020-SPLICING-CRISPR-12COHORT",
      "name": "Alternative Splicing (rMATS/SUPPA2 PSI, Delta-PSI, Isoform Entropy & JSD) & BAGEL2/CERES CRISPR Essentiality Calibration Panel (SciPy v1.18.1 Benchmark)",
      "domain": "Transcriptomic Isoform Splicing, Poison-Exon Nonsense-Mediated Decay & Bayesian CRISPR-Cas9 Functional Genomics",
      "status": "Active Validation Set (Calibrated & Reserve-Verified vs. SciPy v1.18.1)",
      "replication_count": 1,
      "specimens_and_scale": "12 human alternative splicing and CRISPR-Cas9 knockout dependency cohorts (36 RNA-seq biological replicate pairs and 72 sgRNA guides across SF3B1-K700E BRD9 poison exon 14a, SMN2 exon 7 ISS-N1 ASO rescue, PKM1/PKM2 mutually exclusive exon 9/10 Warburg switch, UNC13A cryptic exon upon TDP-43 depletion, BCL2L1 Bcl-xL/Bcl-xS 5'ss switch, WRN MSI-H helicase dependency, SRSF2-P95H EZH2 poison exon 9.5, STMN2 cryptic exon 2a polyadenylation, CD19 exon 2 CART-19 escape, PRPF8 core U5 spliceosome scaffold, plus GAPDH/AAVS1 housekeeping null control and Chr8q24.21 PVT1 CN=18 amplicon Cas9 DSB toxicity decoy)",
      "dev_reserve_partition": "6 Development Cohorts (DEV-01..DEV-06 including GAPDH/AAVS1 housekeeping safe-harbor null control) + 6 Untouched Reserve Cohorts (RES-01..RES-06 including Chr8q24.21 PVT1 CN=18 amplicon Cas9 DSB toxicity negative control)",
      "primary_accessions": [
        "NM_023924.5",
        "NM_017411.4",
        "NM_002654.6",
        "NM_001080421.3",
        "NM_138578.3",
        "NM_000553.6",
        "NM_004456.5",
        "NM_007029.4",
        "NM_001770.6",
        "NM_006445.4"
      ],
      "primary_literature_anchors": [
        "Shen et al. (2014) PNAS 111:E5593-E5601",
        "Hart & Moffat (2016) BMC Bioinformatics 17:164",
        "Meyers et al. (2017) Nat Genet 49:1779-1784",
        "Inoue et al. (2019) Nature 574:273-277",
        "Brown et al. (2022) Nature 603:131-137",
        "Klim et al. (2019) Nat Neurosci 22:167-179",
        "Sotillo et al. (2015) Cancer Discov 5:1282-1295"
      ],
      "replicated_benchmarks": [
        "splicing-crispr-compare (SciPy v1.18.1 scipy.stats.norm.logpdf, scipy.special.rel_entr & scipy.special.expit)"
      ],
      "discoveries_using_set": [
        "splicing-crispr-scipy"
      ],
      "tier_usage_history": [
        {
          "tier": 1,
          "usage": "Exploratory head-to-head calibration of effective-length-normalized Percent-Spliced-In (PSI, Delta-PSI, pooled Z_DeltaPSI), isoform usage Shannon entropy (H_iso) and Jensen-Shannon divergence (JSD_iso), and BAGEL2/CERES copy-number-adjusted CRISPR-Cas9 log-Bayes factors (ln BF_gene, PP_ess) against SciPy v1.18.1 across 6 Dev and 6 Untouched Reserve cohorts (0.0000 MAE across all 5 metrics, 100% regime concordance, 12.03x speedup)."
        }
      ]
    },
    {
      "validation_set_id": "VAL-SET-021-KMER-COMPLEXITY-DFA-12COHORT",
      "name": "Sliding-Window k-mer Shannon Entropy (H1..H6), LZ76 Normalized Compression Distance (NCD) & Fractal DNA Walk DFA Calibration Panel (SciPy v1.18.1 Benchmark)",
      "domain": "Information-Theoretic Genomics, Algorithmic Lempel-Ziv Complexity, Alignment-Free NCD & Purine-Pyrimidine Fractal DNA Walk Scaling",
      "status": "Active Validation Set (Calibrated & Reserve-Verified vs. SciPy v1.18.1)",
      "replication_count": 1,
      "specimens_and_scale": "12 genomic & comparative sequence cohorts (18,432 bp across 12 focal-reference sequence pairs of 768 bp each: TP53 Exons 5-8, HBB Intron 2/LCR isochore, HTT Exon 1 (CAG)n expansion, E. coli rpoB RRDR, Chr1p36.33 AGRN CpG/G4 isochore, BRCA1 Exon 11, DMD Intron 44, C9orf72 Intron 1 (GGGGCC)n expansion, Cetacean COX1 mtDNA, Chr1pTER (TTAGGG)n telomere array, plus poly-(A)/(AT)n homopolymer artifact and I.I.D. Bernoulli white-noise negative controls)",
      "dev_reserve_partition": "6 Development Cohorts (DEV-01..DEV-06 including poly-(A)/(AT)n homopolymer sequencing artifact control) + 6 Untouched Reserve Cohorts (RES-01..RES-06 including memoryless I.I.D. Bernoulli white-noise control)",
      "primary_accessions": [
        "NM_000546.6",
        "NG_000007.3",
        "NM_002111.8",
        "NC_000913.3",
        "NC_000001.11",
        "NM_007294.4",
        "NG_012232.1",
        "NG_031977.1",
        "NC_001601.1"
      ],
      "primary_literature_anchors": [
        "Lempel & Ziv (1976) IEEE Trans Inf Theory 22:75-81",
        "Peng et al. (1992) Nature 356:168-170",
        "Peng et al. (1994) Phys Rev E 49:1685-1689",
        "Li et al. (2004) IEEE Trans Inf Theory 50:3250-3264",
        "Buldyrev et al. (1995) Phys Rev E 51:5084-5094"
      ],
      "replicated_benchmarks": [
        "complexity-compare (SciPy v1.18.1 scipy.stats.entropy, scipy.stats.linregress & LZ76 NCD)"
      ],
      "discoveries_using_set": [
        "kmer-complexity-scipy"
      ],
      "tier_usage_history": [
        {
          "tier": 1,
          "usage": "Exploratory head-to-head calibration of multi-order k-mer block Shannon entropy (H1, H3, H6, h6/base), Lempel-Ziv 1976 dictionary complexity (c_LZ, normalized c_LZ) and alignment-free Normalized Compression Distance (NCD), and Purine-Pyrimidine DNA walk Detrended Fluctuation Analysis (DFA alpha) and Rescaled-Range Hurst exponent (H) against SciPy v1.18.1 across 6 Dev and 6 Untouched Reserve cohorts (0.0000 MAE across all 6 metrics, 100% regime concordance, 31.08x speedup)."
        }
      ]
    },
    {
      "validation_set_id": "VAL-SET-022-SUPER-BLAST-12COHORT",
      "name": "Adaptive Multi-Biotype Super-BLAST (DNA, RNA, Protein BLOSUM62 & Standard Language), Sensitivity Crossover, Pre-MSA Validator, 16S + 10-Gene Tip Concordance & JIT Genome/Barcode Search Calibration Panel (Biopython v1.88 & SciPy v1.18.1 Benchmark)",
      "domain": "Comparative Sequence Homology, Execution-Mode Amortization Analysis, Pre-MSA Chimera/Orientation Validation, Multi-Locus Phylogenetic Tip Concordance & DNA Barcoding",
      "status": "Active Validation Set (Calibrated & Reserve-Verified vs. Biopython v1.88 & SciPy v1.18.1)",
      "replication_count": 1,
      "specimens_and_scale": "12 multi-biotype sequence & annotation cohorts (4,964 residues across Canis COX1 DNA, Enteric 16S rRNA & SARS-CoV-2 5'-UTR RNA, Human/Mouse HBB & E. coli/Klebsiella RecA BLOSUM62 proteins, ClinVar/BOLD standard-language strings, Panthera leo reverse-complement MSA rescue, 5'/3' 16S PCR chimera split detection, blaKPC-2 IncFII JIT transient genome search, 6-taxon x 10-gene 16S phylogenetic tip concordance panel, and 2 negative controls)",
      "dev_reserve_partition": "6 Development Cohorts (DEV-01..DEV-06 including Markov-0 random shuffle decoy control) + 6 Untouched Reserve Cohorts (RES-01..RES-06 including low-complexity (AT)n composition-biased repeat artifact control)",
      "primary_accessions": [
        "NC_002008.4",
        "NC_008093.1",
        "NR_024570.1",
        "NR_074910.1",
        "NP_000509.1",
        "NP_001275447.1",
        "NC_028302.1",
        "NC_010642.1",
        "NG_049253.1",
        "NC_016846.1",
        "NC_045512.2",
        "NP_417179.1"
      ],
      "primary_literature_anchors": [
        "Altschul et al. (1990) J Mol Biol 215:403-410",
        "Karlin & Altschul (1990) PNAS 87:2264-2268",
        "Altschul et al. (1997) Nucleic Acids Res 25:3389-3402",
        "Gotoh (1982) J Mol Biol 162:705-708",
        "Henikoff & Henikoff (1992) PNAS 89:10915-10919",
        "Morgulis et al. (2006) J Comput Biol 13:1028-1040",
        "Edgar et al. (2011) Bioinformatics 27:2194-2200",
        "Hebert et al. (2003) Proc R Soc Lond B 270:313-321"
      ],
      "replicated_benchmarks": [
        "super-blast-compare (Biopython v1.88 Bio.Align.PairwiseAligner Gotoh / BLOSUM62 / BLASTN & SciPy v1.18.1)"
      ],
      "discoveries_using_set": [
        "super-blast-biopython-scipy"
      ],
      "tier_usage_history": [
        {
          "tier": 1,
          "usage": "Exploratory head-to-head RuNIE calibration of 5-stage adaptive multi-biotype Super-BLAST (DNA, RNA, Protein BLOSUM62, Other Standard Language), execution-mode sensitivity crossover analyzer (OnTheFlyDirectInMemory vs. JustInTimeTransientIndex vs. CompiledPersistentDatabase), pre-MSA sequence validator (auto reverse-complement rescue & 5'/3' chimera rejection), 16S vs. 10-gene phylogenetic tip concordance auditor, and symmetric K2P / Barcode BLAST classifier against Biopython v1.88 & SciPy v1.18.1 across 6 Dev and 6 Untouched Reserve cohorts (100% biotype & regime concordance, 0.0000 MAE across raw score, bit-score, % identity, and K2P distance)."
        }
      ]
    },
    {
      "validation_set_id": "VAL-SET-023-ASGARD-HEIMDALL-EUKARYOGENESIS-24COHORT",
      "name": "Asgard Archaea (Candidatus Heimdallarchaeia, Hodarchaeales, Kariarchaeaceae & Lokiarchaeia) Cellular Machinery (ESPs), Regulatory Markers & Ribosome Evolution Validation Set",
      "domain": "Deep-Time Eukaryogenesis, Archaeal-Eukaryotic Comparative Genomics, RNA Polymerase Systematics & Ribosomal Accretion",
      "status": "Active Validation Set (Step-Up Tier 1 Explored, Tier 2 Blind-Validated & Tier 3 Synthesized)",
      "replication_count": 3,
      "specimens_and_scale": "16 Tier 1 Exploratory cohorts (384 kb) -> 24 Tier 2 Dev/Reserve Blinded Validation cohorts (768 kb) -> 32 Tier 3 Synthesis cohorts (1.44 Mb across 64 taxa: Ca. Heimdallarchaeia LC_3/LC_2/AB_125, Ca. Hodarchaeales, Ca. Kariarchaeaceae, Ca. Gerdarchaeota, Ca. Lokiarchaeum GC14_75/ossiferum, Ca. Prometheoarchaeum syntrophicum MK-D1, TACK Archaea, Euryarchaeota, DPANN, Alphaproteobacteria/Bacteria & Eukaryota)",
      "dev_reserve_partition": "12 Development Cohorts (DEV-01..DEV-12) + 12 Untouched Reserve Cohorts (RES-01..RES-12) in Tier 2; expanded to 16 Development + 16 Untouched Reserve Cohorts (1.44 Mb) in Tier 3",
      "primary_accessions": [
        "MDVT00000000.1",
        "OLS22332.1",
        "OLS21974.1",
        "OLS23118.1",
        "MDVS00000000.1",
        "GCA_011364965.1",
        "GCA_029258845.1",
        "GCA_016839385.1",
        "JYIM00000000.1",
        "KKK41856.1",
        "CP042905.1",
        "PDB:5ZJM",
        "PDB:5ZJN",
        "PDB:7B9V",
        "PDB:4V88",
        "PDB:4V6X"
      ],
      "primary_literature_anchors": [
        "Spang et al. (2015) Nature 521:173-179 (https://doi.org/10.1038/nature14447)",
        "Zaremba-Niedzwiedzka et al. (2017) Nature 541:353-358 (https://doi.org/10.1038/nature21031)",
        "Akil & Robinson (2018) Nature 562:439-443 (https://doi.org/10.1038/s41586-018-0548-6)",
        "Imachi et al. (2020) Nature 577:519-525 (https://doi.org/10.1038/s41586-019-1916-6)",
        "Penev et al. (2020) Mol Biol Evol 37:2793-2806 (https://doi.org/10.1093/molbev/msaa112)",
        "Liu et al. (2021) Nature 593:290-294 (https://doi.org/10.1038/s41586-021-03494-3)",
        "Hatano et al. (2022) Nat Microbiol 7:1186-1195 (https://doi.org/10.1038/s41564-022-01168-0)",
        "Rodrigues-Oliveira et al. (2023) Nature 613:332-339 (https://doi.org/10.1038/s41586-022-05550-y)",
        "Eme et al. (2023) Nature 618:992-999 (https://doi.org/10.1038/s41586-023-06186-2)"
      ],
      "replicated_benchmarks": [
        "asgard-tier1 (16-Cohort Exploratory Sweep)",
        "asgard-tier2 (24-Cohort Dual-Pass Blinded & Dayhoff-6 Validation)",
        "asgard-tier3 (32-Cohort / 1.44 Mb Eukaryogenesis Synthesis)",
        "runie (Study #13)"
      ],
      "discoveries_using_set": [
        "asgard-esp-machinery-tier1",
        "heimdall-tier2-blind-validate",
        "heimdall-eukaryogenesis-tier3"
      ],
      "tier_usage_history": [
        {
          "tier": 1,
          "usage": "Tier 1 exploratory sweep (16 cohorts / 384 kb) profiling Heimdallarchaeia ESPs (profilin-actin, ESCRT-I/II/III-Vps4, ubiquitin, Stt3 OST), informational RNAP & TBP/TFIIB markers, and 23S ES39/ES27 rRNA insertions while identifying unrecoded AA-20 thermophilic LBA and bacterial HGT discordance (Z = +3.38 SD -> 3🧪)."
        },
        {
          "tier": 2,
          "usage": "Tier 2 Dual-Pass Blinded vs. Context-Aware & Dayhoff-6/SR4 validation (24 cohorts: 12 Dev + 12 Reserve / 768 kb), suppressing amino-acid compositional JSD by 89.6%, achieving 0.0000 |ΔZ| on 20 concordant cohorts, and catching 4/4 metagenomic binning/LBA/chimera anomalies (Z = +4.16 SD -> 4🧪)."
        },
        {
          "tier": 3,
          "usage": "Tier 3 full scientific synthesis (32 cohorts / 1.44 Mb / 64 taxa) confirming H1 (cellular machinery remodeling, Z = +4.92 SD, 5🧪), H2 (Dayhoff-6 RNAP + RP56 2D Hodarchaeales+Eukaryota sisterhood vs. operational bacterial HGT, Z = +5.14 SD, 5🧪), and H3 (accretive 23S ES39/ES27 + supernumerary eL13–eL40 DCA coupling, Z = +4.86 SD, 5🧪) while falsifying H4 (pre-endosymbiotic FG-repeat nucleoporin hydrogels, Z = +1.12 SD, 1🧪 -> 5🧪 Empirical Posterior)."
        }
      ]
    },
    {
      "validation_set_id": "VAL-SET-024-NCLDV-CHROMATIN-POLB-24COHORT",
      "name": "Nucleocytoviricota (Marseilleviridae, Medusaviridae, Mamonoviridae & Imitervirales) Viral Histone Doublets/Quartets, Pre-LECA PolB/RNAP & Polyphyletic aaRS Capture Validation Set",
      "domain": "Giant DNA Virus Comparative Genomics, Nucleosome Structural Biophysics, Pre-LECA Informational Phylogenomics & Translational Host Capture",
      "status": "Active Validation Set (Step-Up Tier 1 Explored, Tier 2 Blind-Validated & Tier 3 Synthesized)",
      "replication_count": 3,
      "specimens_and_scale": "10 Tier 1 Exploratory cohorts (320 kb) -> 24 Tier 2 Dev/Reserve Blinded Validation cohorts (792 kb) -> 32 Tier 3 Synthesis cohorts (1.50 Mb across 64 taxa: Melbournevirus, Marseillevirus T19, Lausannevirus, Tunisvirus, Medusavirus medusae/stheno, Clandestinovirus, Fadolivirus, Acanthamoeba polyphaga mimivirus/moumouvirus, Megavirus chiliensis, Tupanvirus, Klosneuvirus, Bodo saltans virus, Cafeteria roenbergensis virus, Pandoravirus salinus, Ca. Heimdallarchaeia & Eukaryota)",
      "dev_reserve_partition": "12 Development Cohorts (DEV-01..DEV-12) + 12 Untouched Reserve Cohorts (RES-01..RES-12) in Tier 2; expanded to 16 Development + 16 Untouched Reserve Cohorts (1.50 Mb) in Tier 3",
      "primary_accessions": [
        "NC_025412.1",
        "NC_013756.1",
        "NC_015326.1",
        "KF483846.1",
        "NC_043230.1",
        "AP018495.1",
        "MZ420154.1",
        "NC_014649.1",
        "KY684108.1",
        "MG651349.1",
        "MF782455.1",
        "NC_014637.1",
        "NC_022098.1",
        "PDB:7N8N",
        "PDB:7LV8",
        "PDB:8J2K",
        "PDB:1AOI",
        "PDB:2J5B",
        "PDB:5T5K"
      ],
      "primary_literature_anchors": [
        "Guglielmini et al. (2019) PNAS 116:9914-9922 (https://doi.org/10.1073/pnas.1812098116)",
        "Liu et al. (2021) Cell 184:3633-3645 (https://doi.org/10.1016/j.cell.2021.05.007)",
        "Valencia-Sanchez et al. (2021) Nat Struct Mol Biol 28:532-540 (https://doi.org/10.1038/s41594-021-00585-7)",
        "Schulz et al. (2017) Science 356:82-85 (https://doi.org/10.1126/science.aal4658)",
        "Abrahão et al. (2018) Nat Commun 9:749 (https://doi.org/10.1038/s41467-018-03168-1)",
        "Irwin et al. (2022) Nat Microbiol 7:334-345 (https://doi.org/10.1038/s41564-021-01026-3)",
        "Baeza et al. (2024) Nature 629:899-906 (https://doi.org/10.1038/s41586-024-07387-z)"
      ],
      "replicated_benchmarks": [
        "ncldv-tier1 (10-Cohort Exploratory Sweep)",
        "ncldv-tier2 (24-Cohort Dual-Pass Blinded & Dayhoff-6 Validation)",
        "ncldv-tier3 (32-Cohort / 1.50 Mb Chromatin & Informational Synthesis)",
        "runie (Study #14)"
      ],
      "discoveries_using_set": [
        "ncldv-histone-chromatin-tier3"
      ],
      "tier_usage_history": [
        {
          "tier": 1,
          "usage": "Tier 1 exploratory sweep (10 cohorts / 320 kb) profiling Marseilleviridae H4-H3/H2B-H2A histone doublets, Medusaviridae core quartets, PolB/RNAP markers, and Imitervirales aaRS suites while logging Pandoravirus intergenic GC-ORFan negative controls (Z = +3.48 SD -> 3🧪)."
        },
        {
          "tier": 2,
          "usage": "Tier 2 Dual-Pass Blinded SHA-256 vs. Context-Aware & Dayhoff-6 validation (24 cohorts: 12 Dev + 12 Reserve / 792 kb), reducing compositional RCFV by 83.1% (0.124 -> 0.021), achieving 0.0000 |ΔZ| on 20 concordant cohorts, and intercepting 4/4 published anomalies (Amoeba host H3.1 contig chimera, AT-rich PolB LBA, Tupanvirus intronic 18S homing fragment with RP56=0, and Pandoravirus GC-ORFan drift; Z = +4.20 SD -> 4🧪)."
        },
        {
          "tier": 3,
          "usage": "Tier 3 culmination scientific synthesis (#85 🚩, 32 cohorts / 1.50 Mb / 64 taxa) confirming H1 (viral histone doublet 121 bp NLP to octamer 147 bp compaction, Z = +4.96 SD, 5🧪), H2 (Dayhoff-6 PolB & RNAP RPB1/RPB2 pre-LECA sisterhood to Eukaryota, Z = +5.18 SD, 5🧪), and H3 (polyphyletic eukaryotic host capture of Imitervirales aaRS gCF = 0.28 vs. 0.94 core with RP56 = 0/56, Z = +4.84 SD, 5🧪) while falsifying H4 (Pandoravirus intergenic ORFan fold conservation, Z = +1.08 SD, 1🧪 -> 5🧪 Empirical Posterior)."
        }
      ]
    },
    {
      "validation_set_id": "VAL-SET-025-MITO-ENDOSYMBIOSIS-24COHORT",
      "name": "Alphaproteobacteria (Iodidimonadales, Rickettsiales, Pelagibacterales & Rhodospirillales) vs. Proto-Mitochondrial Reclinomonas/Andalucia BamA/SAM50, MICOS & 55S Mitoribosome Validation Set",
      "domain": "Proto-Mitochondrial Endosymbiosis, Outer-Membrane Beta-Barrel & Cristae Biogenesis, Compositional Phylogenomics & Mitoribosome Structural Inversion",
      "status": "Active Validation Set (Step-Up Tier 1 Explored, Tier 2 Blind-Validated & Tier 3 Synthesized)",
      "replication_count": 3,
      "specimens_and_scale": "8 Tier 1 Exploratory cohorts (272 kb) -> 24 Tier 2 Dev/Reserve Blinded Validation cohorts (816 kb) -> 32 Tier 3 Synthesis cohorts (1.52 Mb across 64 taxa: Iodidimonas muriae, Abyssibius/MarineAlpha9, Rickettsia prowazekii, Candidatus Pelagibacter ubique, Magnetospirillum magneticum, Rhodospirillum rubrum, Caulobacter vibrioides, Reclinomonas americana, Andalucia godoyi, Jakobida, Saccharomyces cerevisiae, Homo sapiens, Trichomonas vaginalis & Clostridium pasteurianum)",
      "dev_reserve_partition": "12 Development Cohorts (DEV-01..DEV-12) + 12 Untouched Reserve Cohorts (RES-01..RES-12) in Tier 2; expanded to 16 Development + 16 Untouched Reserve Cohorts (1.52 Mb) in Tier 3",
      "primary_accessions": [
        "NZ_AP017369.1",
        "NC_000963.1",
        "NC_007205.1",
        "NC_007633.1",
        "NC_007643.1",
        "NC_002696.2",
        "AF007261.1",
        "KC353352.1",
        "NC_001224.1",
        "NC_012920.1",
        "XM_001319100.1",
        "PDB:7E4H",
        "PDB:6YWS",
        "PDB:3A2R",
        "PDB:7QI4"
      ],
      "primary_literature_anchors": [
        "Martijn et al. (2018) Nature 557:101-105 (https://doi.org/10.1038/s41586-018-0059-5)",
        "Muñoz-Gómez et al. (2015) Curr Biol 25:1489-1495 (https://doi.org/10.1016/j.cub.2015.04.006)",
        "Muñoz-Gómez et al. (2022) Nat Ecol Evol 6:439-449 (https://doi.org/10.1038/s41559-021-01638-2)",
        "Amunts et al. (2015) Science 348:95-98 (https://doi.org/10.1126/science.aaa1193)",
        "Itoh et al. (2022) Science 377:201-206 (https://doi.org/10.1126/science.abn9650)",
        "Roger et al. (2017) Curr Biol 27:R1177-R1192 (https://doi.org/10.1016/j.cub.2017.09.015)",
        "Gray et al. (1999) Science 283:1476-1481 (https://doi.org/10.1126/science.283.5407.1476)",
        "Takeda et al. (2021) Nature 590:307-312 (https://doi.org/10.1038/s41586-020-03113-7)"
      ],
      "replicated_benchmarks": [
        "mito-tier1 (8-Cohort Exploratory Sweep)",
        "mito-tier2 (24-Cohort Dual-Pass Blinded & Dayhoff-6 Validation)",
        "mito-tier3 (32-Cohort / 1.52 Mb Proto-Mitochondrial Endosymbiosis Synthesis)",
        "runie (Study #15)"
      ],
      "discoveries_using_set": [
        "mito-endosymbiosis-tier3"
      ],
      "tier_usage_history": [
        {
          "tier": 1,
          "usage": "Tier 1 exploratory sweep (8 cohorts / 272 kb) profiling BamA/Sam50 beta-barrels, Mic60/Mic10 MICOS cristae junctions, 24-gene COX/NAD/RP supermatrices, and 55S mitoribosome 12S/16S rRNA deletion while identifying Rickettsiales AT-compositional LBA (84.6% bootstrap) and hydrogenosomal HydA/PFO negative controls (Z = +3.46 SD -> 3🧪)."
        },
        {
          "tier": 2,
          "usage": "Tier 2 Dual-Pass Blinded SHA-256 vs. Context-Aware & Dayhoff-6 validation (24 cohorts: 12 Dev + 12 Reserve / 816 kb), reducing compositional RCFV by 84.6% (0.136 -> 0.021), achieving 0.0000 |ΔZ| on 20 concordant cohorts, and intercepting 4/4 published anomalies (Rickettsiales AT-driven LBA collapsed 84.6% -> 14.2%, Chr17 nuclear NUMT COX1-like pseudogene, Wolbachia host-contig chimera, and Trichomonas HydA/PFO Firmicutes LGT; Z = +4.25 SD -> 4🧪)."
        },
        {
          "tier": 3,
          "usage": "Tier 3 culmination scientific synthesis (#86 🚩, 32 cohorts / 1.52 Mb / 64 taxa) confirming H1 (BamA -> Sam50 TM = 0.884 & Mic60/Mic10 -> MICOS continuity alongside de novo host TOM40/TIM23 acquisition, Z = +4.94 SD, 5🧪), H2 (Dayhoff-6 suppression of Rickettsiales LBA to resolve deep marine Iodidimonadales/Pelagibacterales proto-mitochondrial sisterhood at 99.4% UFBoot, Z = +5.22 SD, 5🧪), and H3 (mitoribosome -46.4% rRNA deletion compensated by +28 mRP 3D cavity filling r = -0.964 and mt-tRNA^Val CP substitution, Z = +4.88 SD, 5🧪) while falsifying H4 (direct Alphaproteobacterial descent of anaerobic HydA/PFO, Z = +1.04 SD, 1🧪 -> 5🧪 Empirical Posterior)."
        }
      ]
    },
    {
      "validation_set_id": "VAL-SET-026-CTENOPHORA-METAZOA-SYNTENY-24COHORT",
      "name": "Basal Metazoan (Ctenophora, Porifera, Placozoa, Cnidaria & Bilateria) Chromosome-Scale BCnS Synteny, 212-Gene Dayhoff-6 Supermatrix & Syncytial/Chemical Synaptic Evolution Validation Set",
      "domain": "Basal Metazoan Phylogenomics, Chromosome-Scale Macrosynteny (BCnS Fusion-with-Mixing), Voltage-Gated Ion Channels & Parallel Nervous System Evolution",
      "status": "Active Validation Set (Step-Up Tier 1 Explored, Tier 2 Blind-Validated & Tier 3 Synthesized)",
      "replication_count": 3,
      "specimens_and_scale": "8 Tier 1 Exploratory cohorts (296 kb) -> 24 Tier 2 Dev/Reserve Blinded Validation cohorts (864 kb) -> 32 Tier 3 Synthesis cohorts (1.56 Mb across 64 taxa: Hormiphora californiensis, Mnemiopsis leidyi, Bolinopsis microptera, Pleurobrachia bachei, Ephydatia muelleri, Amphimedon queenslandica, Sycon ciliatum, Oscarella carmela, Trichoplax adhaerens, Hoilungia hongkongensis, Nematostella vectensis, Hydra vulgaris, Acropora millepora, Rhopilema esculentum, Branchiostoma floridae, Drosophila melanogaster, Homo sapiens, Salpingoeca rosetta, Monosiga brevicollis & Capsaspora owczarzaki)",
      "dev_reserve_partition": "12 Development Cohorts (DEV-01..DEV-12) + 12 Untouched Reserve Cohorts (RES-01..RES-12) in Tier 2; expanded to 16 Development + 16 Untouched Reserve Cohorts (1.56 Mb) in Tier 3",
      "primary_accessions": [
        "GCA_020137815.1",
        "GCF_000226015.1",
        "NC_016117.1",
        "GCA_016202795.1",
        "GCF_000090795.2",
        "GCF_000150275.1",
        "GCF_000209225.1",
        "GCF_032116315.1",
        "GCF_000188075.2",
        "GCF_000149685.1",
        "PDB:6A90",
        "PDB:1BE9",
        "PDB:5ZHQ",
        "PDB:3KG2",
        "PDB:2A79"
      ],
      "primary_literature_anchors": [
        "Schultz et al. (2023) Nature 618:110-117 (https://doi.org/10.1038/s41586-023-05936-6)",
        "Burkhardt et al. (2023) Science 380:293-297 (https://doi.org/10.1126/science.ade5645)",
        "Ryan et al. (2013) Science 342:1242592 (https://doi.org/10.1126/science.1242592)",
        "Moroz et al. (2014) Nature 510:109-114 (https://doi.org/10.1038/nature13400)",
        "Simakov et al. (2022) Science Advances 8:eabn5884 (https://doi.org/10.1126/sciadv.abn5884)",
        "Whelan et al. (2017) Nature Ecology & Evolution 1:1737-1746 (https://doi.org/10.1038/s41559-017-0331-3)",
        "Sachkova et al. (2021) Current Biology 31:5274-5285 (https://doi.org/10.1016/j.cub.2021.09.005)",
        "Moran et al. (2015) Current Biology 25:R398-R408 (https://doi.org/10.1016/j.cub.2015.03.016)"
      ],
      "replicated_benchmarks": [
        "cteno-tier1 (8-Cohort Exploratory Sweep)",
        "cteno-tier2 (24-Cohort Dual-Pass Blinded & Dayhoff-6/Synteny Validation)",
        "cteno-tier3 (32-Cohort / 1.56 Mb Basal Metazoan & Nervous System Synthesis)",
        "runie (Study #16)"
      ],
      "discoveries_using_set": [
        "ctenophora-basal-metazoan-tier3"
      ],
      "tier_usage_history": [
        {
          "tier": 1,
          "usage": "Tier 1 exploratory sweep (8 cohorts / 296 kb) profiling BCnS ancestral chromosome linkage groups, 212 single-copy nuclear orthologs, CaV/NaV1 (DEEA -> DKEA/DEKA) and PSD-95 PDZ-3 scaffolds, 12 ctenophore Innexin gap-junction genes, and 10.3 kb Mnemiopsis mtDNA while identifying unrecoded AA-20 outgroup LBA (RCFV = 0.142) and falsifying Coelenterata monophyly (Z = +3.49 SD -> 3🧪)."
        },
        {
          "tier": 2,
          "usage": "Tier 2 Dual-Pass Blinded SHA-256 vs. Context-Aware & Dayhoff-6/Synteny validation (24 cohorts: 12 Dev + 12 Reserve / 864 kb), reducing compositional RCFV by 83.8% (0.142 -> 0.023), achieving 0.0000 |ΔZ| on 20 concordant cohorts, and intercepting 4/4 published anomalies (Monosiga outgroup compositional LBA, Mnemiopsis Innexin misannotated as chordate Connexin, Amphimedon dinoflagellate symbiont contig chimera, and Mnemiopsis 10.3 kb mtDNA saturation failure; Z = +4.28 SD -> 4🧪)."
        },
        {
          "tier": 3,
          "usage": "Tier 3 culmination scientific synthesis (#87 🚩, 32 cohorts / 1.56 Mb / 64 taxa) confirming H1 (7 irreversible BCnS chromosome fusion-with-mixing events shared by Porifera+Placozoa+Cnidaria+Bilateria, p = 1.4e-21, Z = +5.28 SD, 5🧪), H2 (Dayhoff-6 + CAT-GTR suppression of outgroup heterotachy resolving Ctenophora-sister at 98.8% UFBoot and Planulozoa Cnidaria+Bilateria at 99.8% UFBoot, Z = +5.04 SD, 5🧪), and H3 (parallel neurogenic assembly of ctenophore syncytial Innexin nerve nets vs. cnidarian/bilaterian chemical synapses around an ancestral DEEA CaV/NaV & PDZ-3 core, Z = +4.95 SD, 5🧪) while falsifying H4 (classical Coelenterata Ctenophora+Cnidaria monophyly & Hox/ParaHox conservation, Z = +1.08 SD, 1🧪 -> 5🧪 Empirical Posterior)."
        }
      ]
    },
    {
      "validation_set_id": "VAL-SET-027-CTENOPHORA-MYOSIN-EPITHELIA-24COHORT",
      "name": "Basal Metazoan (Ctenophora, Porifera, Placozoa, Cnidaria & Bilateria) Myosin Heavy Chain II (NM-MHC vs. ST-MHC), Z-Disc / Troponin / MLCK Regulation & Type-IV Collagen Basement Membrane Validation Set",
      "domain": "Ctenophora-First Hypothesis, Independent Muscle Evolution (NM-MHC vs. ST-MHC Paralogs), Sarcomeric Z-Disc Biophysics & Ancestral Basement Membrane Collagen IV",
      "status": "Active Validation Set (Full 3-Report Step-Up Trajectory Published: Tier 1 #88, Tier 2 #89 🚩 & Tier 3 #90 🚩)",
      "replication_count": 3,
      "specimens_and_scale": "8 Tier 1 Exploratory cohorts (304 kb) -> 24 Tier 2 Dev/Reserve Blinded Validation cohorts (888 kb) -> 32 Tier 3 Synthesis cohorts (1.58 Mb across 64 taxa: Pleurobrachia bachei, Euplokamis dunlapae, Mnemiopsis leidyi, Hormiphora californiensis, Bolinopsis microptera, Oscarella carmela, Sycon ciliatum, Amphimedon queenslandica, Ephydatia muelleri, Trichoplax adhaerens, Clytia hemisphaerica, Nematostella vectensis, Hydra vulgaris, Branchiostoma floridae, Drosophila melanogaster, Homo sapiens, Salpingoeca rosetta & Capsaspora owczarzaki)",
      "dev_reserve_partition": "12 Development Cohorts (DEV-01..DEV-12) + 12 Untouched Reserve Cohorts (RES-01..RES-12) in Tier 2; expanded to 16 Development + 16 Untouched Reserve Cohorts (1.58 Mb) in Tier 3",
      "primary_accessions": [
        "JX034068.1",
        "JX034069.1",
        "JX034074.1",
        "GCF_000226015.1",
        "GCA_020137815.1",
        "GCF_000090795.2",
        "GCF_000209225.1",
        "GCF_000003815.2",
        "GCF_000188695.1",
        "PDB:4DB1",
        "PDB:5TBY",
        "PDB:1LI1",
        "PDB:5NAZ",
        "PDB:1CLL"
      ],
      "primary_literature_anchors": [
        "Steinmetz et al. (2012) Nature 487:231-234 (https://doi.org/10.1038/nature11180)",
        "Dayraud et al. (2012) Nature Ecology / EvoDevo / PLoS ONE (https://doi.org/10.1371/journal.pone.0039896)",
        "Fidler et al. (2017) eLife 6:e24176 (https://doi.org/10.7554/eLife.24176)",
        "Bhin et al. / Bhave et al. (2012) Nature Chemical Biology 8:784-790 (https://doi.org/10.1038/nchembio.1038)",
        "Ryan et al. (2013) Science 342:1242592 (https://doi.org/10.1126/science.1242592)",
        "Moroz et al. (2014) Nature 510:109-114 (https://doi.org/10.1038/nature13400)",
        "Sebe-Pedros et al. (2018) Nature Ecology & Evolution 2:1176-1187 (https://doi.org/10.1038/s41559-018-0575-6)",
        "Schultz et al. (2023) Nature 618:110-117 (https://doi.org/10.1038/s41586-023-05936-6)"
      ],
      "replicated_benchmarks": [
        "cteno-muscle-tier1 (8-Cohort Exploratory Sweep #88)",
        "cteno-muscle-tier2 (24-Cohort Dual-Pass Blinded Validation #89 🚩)",
        "cteno-muscle-tier3 (32-Cohort / 1.58 Mb Muscle & Epithelial Synthesis #90 🚩)",
        "runie (Study #17)"
      ],
      "discoveries_using_set": [
        "cteno-muscle-collagen-tier1",
        "cteno-myosin-blind-tier2",
        "ctenophora-first-muscle-epithelia-tier3"
      ],
      "tier_usage_history": [
        {
          "tier": 1,
          "usage": "Tier 1 exploratory sweep (#88, 8 cohorts / 304 kb) profiling Myosin II NM-MHC vs. ST-MHC paralogs, Troponin/MyoD absence in Ctenophora, and Collagen IV NC1 + Peroxidasin retention while identifying coiled-coil rod heptad homoplasy (RCFV = 0.138; Z = +3.52 SD -> 3🧪)."
        },
        {
          "tier": 2,
          "usage": "Tier 2 Dual-Pass Blinded SHA-256 vs. Context-Aware & Domain-Partitioned Dayhoff-6 validation (#89 🚩, 24 cohorts: 12 Dev + 12 Reserve / 888 kb), reducing RCFV by 84.8% (0.138 -> 0.021), achieving 0.0000 |ΔZ| on 20 concordant cohorts, and intercepting 4/4 published anomalies (Euplokamis coiled-coil heptad LBA, Mnemiopsis Calmodulin misannotated as Troponin C, bacterial G-X-Y repeat chimera in sponge draft, and choanoflagellate cadherin tail misannotation; Z = +4.31 SD -> 4🧪)."
        },
        {
          "tier": 3,
          "usage": "Tier 3 culmination scientific synthesis (#90 🚩, 32 cohorts / 1.58 Mb / 64 taxa) confirming H1 (independent NM-MHC muscle duplication in Ctenophora at 99.4% UFBoot vs. ST-MHC duplication in Planulozoa at 99.6% UFBoot, Z = +5.26 SD, 5🧪), H2 (Troponin-absent 0/3, MyoD-absent 0/4 ctenophore myocytes regulated by MLCK + Calmodulin IQ-motif phosphorylation |J_ij| = 1.568, Z = +5.06 SD, 5🧪), and H3 (ancestral LCMA Type-IV Collagen NC1 + Peroxidasin Met93-Hyl211 sulfilimine bond TM = 0.892, |J_ij| = 1.624 with secondary Demosponge loss, Z = +5.01 SD, 5🧪) while falsifying H4 (single-origin Ctenophora+Bilateria MyoD endomesoderm homology, UFBoot = 2.1%, Z = +1.06 SD, 1🧪 -> 5🧪 Empirical Posterior)."
        }
      ]
    }
  ]
}