V2 CN validation: Pi tuning rounds, CYTO-041 effect, common-CNV sensitivity limit (K-027)

docs/validation/V2_cn.md

@@ -53,11 +53,34 @@ BAF-supported "mosaic" events are 0–2 % in truth and rarely reproduced: shifte
 mismatched cluster file mimic allelic imbalance). Small BAF-supported mosaic gains are often real germline
 duplications labelled mosaic (43 % in truth).
 
+## Pi tuning rounds (2026-09-29), 40 arrays (20 individuals × replicates 1, 2), reference = replicate 3 of all 120
+
+`scripts/v2/cn_tune.sh TAG [options]`; truth as above, QUAL ≥ 20, PASS only (after the K-027 noise-gate fix).
+
+| Round | DEL calls / in truth | DUP | mosaic loss PASS / in truth | mosaic gain PASS / in truth | LOH replicated |
+|---|---|---|---|---|---|
+| base (per-probe reference het BAF spread in the emissions) | 22 / 100 % | 3 / 67 % | 29 / 11 % | 24 / 38 % | 80 % |
+| `--mosaic-prior 0.0005` | 25 / 96 % | 4 / 75 % | 27 / 12 % | 22 / 36 % | 80 % |
+| `--mosaic-prior 0.0005 --switch-distance 1e8` | 24 / 96 % | 4 / 75 % | 25 / 14 % | 23 / 35 % | 80 % |
+| CYTO-041 (noise-normalised BAF split, complete-loss promotion) | 27 / 93 % | 4 / 75 % | **19** / 5 % | **19** / 42 % | 80 % |
+
+* The mosaic prior and switch distance barely matter. CYTO-041 moves heterozygote-free "mosaic" losses (compressed
+  constitutional deletions) to DEL (`HIGHFRACTION`) and sends noise-driven mosaic calls to `LowFraction`
+  (MDEL 29 → 19 PASS, MDUP 24 → 19). On the implanted set (`data/v2cn/syn3`) MF estimates stay unbiased
+  (15 % → 0.16, 20 % → 0.21, 30 % → 0.30), detection is unchanged (126/216) and the CYTO-022 gate still passes.
+* Remaining mosaic-loss false positives are long, low-amplitude LRR dips (−0.05 … −0.1) with a heterozygous BAF
+  spread only 1.0–1.3 × the probe's reference spread, or short events with < 20 heterozygous probes (MF from LRR).
+  Without phasing a < 20 % mosaic loss cannot be separated from regional BAF noise (K-027).
+* **Sensitivity is limited by common CNVs.** Detected truth DEL by carrier frequency among the 120 individuals:
+  < 5 %: 24/64 (38 %), 5–20 %: 1/20, 20–50 %: 1/80, > 50 %: 0/156 (DUP 10/66, 0/2, 1/24, 0/40). The batch
+  reference is the per-probe median LRR, so an event carried by most reference samples is normalised away (and the
+  cluster file, trained on the population, already absorbs part of it). Array CN calling targets rare events; the
+  headline sensitivity figures above are dominated by common polymorphic deletions.
+
 ## Next steps
 
-1. Mosaic calling: require consistent BAF imbalance with a per-probe reference of heterozygous BAF spread, raise the
-   evidence for mosaic states (prior/size), and relabel compressed germline gains/losses as constitutional; tune on
-   GSE165845 and re-measure (replicate reproducibility is the cheapest check).
-2. Sensitivity for 25–500 kb events: lower switch cost for short events with strong LRR, per-probe LRR SD from the
-   reference.
-3. Re-run the truth comparison; document the final numbers.
+1. Report sensitivity for rare events (carrier frequency < 5 %) as the primary metric in `cn_validate_truth.py`.
+2. Mosaic losses: phasing-based BAF (MoChA-style) is the principled fix for low fractions; until then consider a
+   minimum heterozygous-probe count for mosaic PASS calls.
+3. Sensitivity for 25–500 kb events: per-probe LRR SD from the reference.
+4. A final full-cohort run (cloud, ~$0.10, needs approval) once the above settle.