PGx star alleles: pgx star-allele call (PGX-011..021), probe masks vs 1000G, GeT-RM validation (K-029)

- simurg/pgx/star.py: solver-free diplotype enumeration incl. CN forms (deletion, xN), wildcards, array-equivalence classes, raw_score/score with CPIC frequency priors; calibrated error model (spec PGX-012 amended). - pipeline/pgx_star.py: DB gene models, SNV + PGx CN VCF evidence, masks, diplotype_summary.tsv + pgx_calls.json. - scripts/pgx: derive_masks.py (array vs 1000G 30x over HTTPS, GS calibration), getrm_truth.py, validate_star_getrm.py. - GSA v4 PGx demo vs GeT-RM (16 CEPH): 100/109 gene calls; CYP2D6/2C19/2C9 41/45 (docs/validation/V2_pgx_star.md). Co-Authored-By: Claude Opus 5.5 <[email protected]> Claude-Session: https://claude.ai/code/session_01814GKVzZVL3FuF3DeiZXhv
2026-09-29 14:08:03 +01:00
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+# V2 — PGx DB and star-allele calling (PGX-001 … PGX-021)
+
+Status: **implemented for CPIC star-allele genes, interim validation** (2026-09-29).
+
+* `scripts/pgx/fetch_sources.sh` → CPIC API tables (CC0, data version 2026-08-03).
+* `simurg pgx db build` → deterministic SQLite: 22 genes, 1354 alleles, 1897 normalised variant rows; GSA v4 PGx
+  probe map 5002 links; two builds byte-identical.
+* `simurg pgx star-allele call` → `diplotype_summary.tsv`, `pgx_calls.json` (11 star-allele genes).
+* Unit tests: `tests/unit/test_pgx_db.py`, `tests/unit/test_pgx_star.py`.
+
+## Data and truth
+
+* Arrays: the GSA v4 PGx demo (36 arrays = 30 CEPH/1000G individuals, `scripts/pgx/demo36_identity.tsv`), SNV VCFs
+  and PGx CN VCFs from SimurgArray.
+* Star-allele truth: GeT-RM consolidated PGx/HLA table (CDC, 2025 V4) — 16 of the 30 individuals
+  (`scripts/pgx/getrm_truth.py`).
+* Probe mask (PGX-010): array vs 1000G 30x (NYGC phased panel, fetched per gene over HTTPS) for the **other 14
+  individuals** (`scripts/pgx/derive_masks.py`), so the mask is independent of the GeT-RM validation set: 8 of 658
+  assessed records (23 probe names) below 95 % concordance — e.g. CYP2C19 rs367543002 and CYP2D6 rs1135836 called
+  homozygous ALT in every sample, the UGT1A1 `C>CATAT` TA-repeat probe. Regenerate with the command in the script
+  header (the mask lists vendor probe names and is not committed).
+
+## Result (16 individuals; replicate arrays counted once)
+
+| Gene | Top solution = GeT-RM | Truth among array-equivalent feasible solutions |
+|---|---|---|
+| CYP2C9 | **15/15** | 15/15 |
+| CYP2C19 | **14/15** | 15/15 |
+| CYP2D6 | **12/15** | 14/15 |
+| CYP3A5 | 15/15 | 15/15 |
+| TPMT | 15/16 | 15/16 |
+| CYP2B6 | 12/14 | 12/14 |
+| CYP4F2 | 8/9 | 8/9 |
+| NAT2 | 8/9 | 8/9 |
+| NUDT15 | 1/1 | 1/1 |
+| **total** | **100/109 (91.7 %)** | **103/109 (94.5 %)** |
+
+PGX-032 target (≥ 90 % for CYP2D6/CYP2C19/CYP2C9 against truth): **41/45 = 91 %** (top solution).
+Details and every discordant call: `V2_pgx_star_getrm16.json`.
+
+Not in the total (GeT-RM uses pre-2023 names the CPIC definitions no longer carry): UGT1A1 (GeT-RM `*60`;
+0/9 top) and SLCO1B1 (`*1B/*17/*21` vs CPIC `*37/*15/*20`; 9/15 top).
+
+Remaining discordances: CYP2D6 `*3/(*68)+*4` (NA12878; *68 hybrids not modelled, *3 frameshift probe), CYP2D6 *2 vs
+*1 where the array cannot separate them (prior picks *1), CYP2C19 *8, TPMT *21, CYP2B6 *27, CYP4F2 *2 — rare
+alleles whose defining variants are absent or masked on this array.
+
+## Error model (K-029)
+
+After masking, 0 of 9 740 array calls at DB variants disagreed with 1000G 30x in any GenCall-score bin (0.15–1.0),
+so the per-call error is 1e-3 (GS ≥ 0.15) and errors are handled by the probe mask. The first model,
+ε = 0.5·(1 − GS)², let correct low-GS calls lose to the prior (CYP2C9 7/15 → 15/15 after the change).
+
+## Caveats
+
+* 16 individuals, one array type, European (CEPH) only; masks from 14 individuals (spec: ≥ 100 samples).
+* Not yet: named-haplotype (G6PD), variant-based and tagging genes; CYP2D6 hybrids (*13, *36, *68); PharmVar-only
+  genes (CYP2A6, CYP3A4, CYP1A2, …); phenotype annotation (PGX-025) and the JSON schema (PGX-028).
@@ -0,0 +1,240 @@
+{
+ "individuals": 30,
+ "genes": {
+  "CYP2B6": {
+   "n": 14,
+   "top": 12,
+   "equivalent": 12,
+   "not_comparable": 1
+  },
+  "CYP2C19": {
+   "n": 15,
+   "top": 14,
+   "equivalent": 15
+  },
+  "CYP2C9": {
+   "n": 15,
+   "top": 15,
+   "equivalent": 15
+  },
+  "CYP2D6": {
+   "n": 15,
+   "top": 12,
+   "equivalent": 14
+  },
+  "CYP3A5": {
+   "n": 15,
+   "top": 15,
+   "equivalent": 15
+  },
+  "CYP4F2": {
+   "n": 9,
+   "top": 8,
+   "equivalent": 8
+  },
+  "NAT2": {
+   "n": 9,
+   "top": 8,
+   "equivalent": 8
+  },
+  "NUDT15": {
+   "n": 1,
+   "top": 1,
+   "equivalent": 1
+  },
+  "SLCO1B1": {
+   "n": 15,
+   "top": 9,
+   "equivalent": 9
+  },
+  "TPMT": {
+   "n": 16,
+   "top": 15,
+   "equivalent": 15
+  },
+  "UGT1A1": {
+   "n": 9,
+   "top": 0,
+   "equivalent": 1
+  }
+ },
+ "legacy_nomenclature_genes": [
+  "SLCO1B1",
+  "UGT1A1"
+ ],
+ "total": {
+  "n": 109,
+  "top": 100,
+  "equivalent": 103
+ },
+ "discordant": [
+  {
+   "individual": "NA12156",
+   "gene": "CYP4F2",
+   "truth": "(*2)/*3",
+   "call": "*1/*3",
+   "within_equivalents": false
+  },
+  {
+   "individual": "NA12156",
+   "gene": "SLCO1B1",
+   "truth": "*1/*21",
+   "call": "*1/*37",
+   "within_equivalents": false
+  },
+  {
+   "individual": "NA12156",
+   "gene": "UGT1A1",
+   "truth": "*60/*28",
+   "call": "*28/*80",
+   "within_equivalents": false
+  },
+  {
+   "individual": "NA12044",
+   "gene": "TPMT",
+   "truth": "*1/*21",
+   "call": "*1/*1",
+   "within_equivalents": false
+  },
+  {
+   "individual": "NA07019",
+   "gene": "UGT1A1",
+   "truth": "*1/*60",
+   "call": "*1/*1",
+   "within_equivalents": false
+  },
+  {
+   "individual": "NA06991",
+   "gene": "UGT1A1",
+   "truth": "*60/*60",
+   "call": "*1/*1",
+   "within_equivalents": false
+  },
+  {
+   "individual": "NA12878",
+   "gene": "CYP2D6",
+   "truth": "*3/(*68)+*4",
+   "call": "*4x2/*1;*4x2/*82",
+   "within_equivalents": false
+  },
+  {
+   "individual": "NA12878",
+   "gene": "UGT1A1",
+   "truth": "*60/*28",
+   "call": "*28/*80",
+   "within_equivalents": false
+  },
+  {
+   "individual": "NA11993",
+   "gene": "SLCO1B1",
+   "truth": "*1/*17",
+   "call": "*1/*15",
+   "within_equivalents": false
+  },
+  {
+   "individual": "NA11993",
+   "gene": "UGT1A1",
+   "truth": "(*28 + *60)/*60",
+   "call": "*28/*80",
+   "within_equivalents": false
+  },
+  {
+   "individual": "NA12003",
+   "gene": "UGT1A1",
+   "truth": "*60/*28",
+   "call": "*28/*80",
+   "within_equivalents": false
+  },
+  {
+   "individual": "NA07029",
+   "gene": "CYP2B6",
+   "truth": "*6/(*27)",
+   "call": "*1/*6",
+   "within_equivalents": false
+  },
+  {
+   "individual": "NA07029",
+   "gene": "CYP2C19",
+   "truth": "*8/*17",
+   "call": "*1/*17",
+   "within_equivalents": true
+  },
+  {
+   "individual": "NA07029",
+   "gene": "UGT1A1",
+   "truth": "*1/*1",
+   "call": "*1/*28",
+   "within_equivalents": true
+  },
+  {
+   "individual": "NA12892",
+   "gene": "CYP2B6",
+   "truth": "*1/*1",
+   "call": "*1/*5",
+   "within_equivalents": false
+  },
+  {
+   "individual": "NA11832",
+   "gene": "NAT2",
+   "truth": "*5/(*12)",
+   "call": "*1/*5",
+   "within_equivalents": false
+  },
+  {
+   "individual": "NA11832",
+   "gene": "SLCO1B1",
+   "truth": "*1/*1",
+   "call": "*14/*20",
+   "within_equivalents": false
+  },
+  {
+   "individual": "NA11832",
+   "gene": "UGT1A1",
+   "truth": "(*28 + *60)/*60",
+   "call": "*28/*80",
+   "within_equivalents": false
+  },
+  {
+   "individual": "NA10838",
+   "gene": "CYP2D6",
+   "truth": "*2/*4",
+   "call": "*1/*4;*2/*4",
+   "within_equivalents": true
+  },
+  {
+   "individual": "NA10838",
+   "gene": "SLCO1B1",
+   "truth": "*1/*1",
+   "call": "*1/*14",
+   "within_equivalents": false
+  },
+  {
+   "individual": "NA12813",
+   "gene": "CYP2D6",
+   "truth": "*2/*4",
+   "call": "*1/*4;*2/*4",
+   "within_equivalents": true
+  },
+  {
+   "individual": "NA12813",
+   "gene": "SLCO1B1",
+   "truth": "*1/*21",
+   "call": "*1/*20",
+   "within_equivalents": false
+  },
+  {
+   "individual": "NA12813",
+   "gene": "UGT1A1",
+   "truth": "(*28 + *60)/(*28 + *60)",
+   "call": "*80/*80",
+   "within_equivalents": false
+  },
+  {
+   "individual": "NA11881",
+   "gene": "SLCO1B1",
+   "truth": "*1/(*15)",
+   "call": "*14/*15",
+   "within_equivalents": false
+  }
+ ]
+}