PGx CN: pgx copy-number train|call (CLI-031/032, PCN-001..017, IN-050), region BED v1, demo identities (K-028)
- simurg/pgx/cn.py: per-region CN mixture, mu_c = delta + gamma*log2((c+1)/3), free lower CN-0 component, Hardy-Weinberg-constrained weights over haplotype copy numbers, EM from a grid of label starts. - pipeline/pgx_cn.py: model file (.simurg-pgxcn), batch rules (PCN-004), per-sample CN VCF + tbi, batch and sample summaries. - The GSA v4 PGx demo arrays are 30 CEPH/1000G individuals (scripts/pgx/demo36_identity.tsv); against NYGC 30x SV RD_CN 224/240 region calls agree (GSTM1, UGT2B17 30/30), in-sample (docs/validation/V2_pgx_cn.md). Co-Authored-By: Claude Opus 5.5 <[email protected]> Claude-Session: https://claude.ai/code/session_01814GKVzZVL3FuF3DeiZXhv
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"""Targeted PGx copy number — spec PCN-001, PCN-009. Pure functions, no I/O.
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Region value x = median over the region's unmasked probes of (sample-centred LRR − the probe's training reference),
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minus the sample's scale (median of the same quantity over non-target autosomal probes).
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CN mixture [OURS; array intensity compression as in cnvPartition/PennCNV, LIT: Wang et al. 2007 Genome Res 17:1665]:
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component means µ_c = δ_r + γ_r · log2((c + 1) / 3) for CN c = 0 … 5 — a probe signal proportional to (c + β) with
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a background β = 1 copy-equivalent, compressed by γ_r. δ_r (the region's CN-2 location), γ_r, σ_r and the weights
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π_r are per region; γ_r has a Gaussian prior N(0.25, 0.08²). CN 0 may sit lower than the template (its own shift
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ε₀ ≤ 0 and SD): GSTT1 probes drop by ~2 at CN 0, GSTM1 probes by ~0.3. The weights are constrained to Hardy–Weinberg
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proportions of haplotype copy numbers (0 … 3 copies per haplotype, Dirichlet prior favouring one copy). Fitted by
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EM from a grid of starts (each observed cluster labelled CN 0 … 4, CN 0 on the template or on the lowest values).
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HWE and the template's spacing ratios identify the labels in multi-cluster regions (GSTM1 0/1/2 rather than 1/2/3,
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which would imply unobserved CN-0 samples). On GSA v4 PGx CNV probes γ_r ≈ 0.19–0.56 (K-028).
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"""
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from __future__ import annotations
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import math
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from dataclasses import dataclass
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import numpy as np
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import numpy.typing as npt
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F64 = npt.NDArray[np.float64]
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CN_MAX = 5 # "5 or more"
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CNS = np.arange(CN_MAX + 1)
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TEMPLATE = np.log2((CNS + 1) / 3.0)
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HAP_ALPHA = np.array([1.2, 3.0, 1.2, 1.05]) # Dirichlet prior on haplotype copy frequencies f_0..f_3 (f_1 favoured)
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SIGMA_FLOOR = 0.012
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GAMMA_PRIOR = (0.25, 0.08) # mean, SD
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GAMMA_RANGE = (0.15, 0.80)
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PI_FLOOR = 0.002
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CN0_PRIOR_N = 2.0
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@dataclass(frozen=True)
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class Region:
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chrom: str
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start0: int
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end: int
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name: str
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gene: str
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def parse_regions(text: str) -> list[Region]:
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"""PCN-001 BED: ``chrom start0 end region gene``; ``#`` comments."""
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out = []
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for ln in text.splitlines():
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if not ln.strip() or ln.startswith("#"):
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continue
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c, s, e, r, g = ln.split("\t")[:5]
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out.append(Region(c, int(s), int(e), r, g))
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return out
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@dataclass
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class RegionFit:
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delta: float
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gamma: float
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sigma: float
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weights: list[float]
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n: int
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cn0_shift: float = 0.0 # ≤ 0: extra drop of the CN-0 component below the template (probe-specific background)
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cn0_sigma: float = 0.0 # SD of the CN-0 component (≥ sigma; 0 = sigma)
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def means(self) -> F64:
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m = self.delta + self.gamma * TEMPLATE
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m[0] += self.cn0_shift
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return m
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def sds(self) -> F64:
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s = np.full(len(CNS), self.sigma)
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s[0] = max(self.sigma, self.cn0_sigma)
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return s
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def hwe_weights(f: F64) -> F64:
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"""CN weights under Hardy–Weinberg from haplotype copy-number frequencies f_k (k = 0 … 3 copies):
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π_c = Σ_{i+j=c} f_i f_j, CN ≥ 5 pooled into 5 [LIT: HWE; OURS: use as the CN mixture prior]."""
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pi = np.zeros(len(CNS))
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for i in range(len(f)):
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for j in range(len(f)):
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pi[min(i + j, CN_MAX)] += f[i] * f[j]
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return pi
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def _hap_update(r: F64, f: F64) -> F64:
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"""M-step for f: split each sample's CN responsibilities over the haplotype pairs (i, j) with i + j = c."""
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counts = HAP_ALPHA - 1.0
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counts = counts.astype(np.float64).copy()
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pi = hwe_weights(f)
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for i in range(len(f)):
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for j in range(len(f)):
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c = min(i + j, CN_MAX)
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share = f[i] * f[j] / max(pi[c], 1e-300)
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w = float(r[:, c].sum()) * share
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counts[i] += w
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counts[j] += w
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counts = np.maximum(counts, 1e-9)
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out: F64 = counts / counts.sum()
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return out
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def _norm_pdf(x: F64, mu: F64, sd: float | F64) -> F64:
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sd_ = np.broadcast_to(np.asarray(sd, dtype=np.float64), mu.shape)[None, :]
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return np.exp(-0.5 * ((x[:, None] - mu[None, :]) / sd_) ** 2) / (sd_ * math.sqrt(2 * math.pi))
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def _em_region(x: F64, gamma: float, delta: float, iters: int, eps0: float = 0.0) -> tuple[RegionFit, float]:
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"""EM for one region; returns the fit and its penalised log-likelihood (HWE weights from haplotype copy
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frequencies with a Dirichlet prior, Gaussian prior on γ).
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CN 0 has its own shift ε₀ ≤ 0 below the template and its own SD, both shrunk towards the template with a prior
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weight of ``CN0_PRIOR_N`` samples (on some probe sets CN 0 is far lower than the compressed template, GSTT1)."""
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n = len(x)
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f = np.array([0.1, 0.8, 0.07, 0.03])
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pi = hwe_weights(f)
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sd = max(SIGMA_FLOOR, float(np.std(x)) if n > 1 else 0.05)
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sd0 = sd
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if eps0 < 0: # a start with a far CN-0 cluster: the other components get the spread of the rest
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rest = x[x > delta + gamma * TEMPLATE[0] + eps0 / 2]
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sd = max(SIGMA_FLOOR, float(np.std(rest)) if len(rest) > 1 else 0.05)
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sd0 = sd
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g0, gs = GAMMA_PRIOR
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ll = -math.inf
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for _ in range(iters):
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mu = delta + gamma * TEMPLATE
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mu[0] += eps0
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sds = np.full(len(CNS), sd)
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sds[0] = sd0
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dens = pi[None, :] * _norm_pdf(x, mu, sds) + 1e-300
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tot = dens.sum(axis=1, keepdims=True)
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ll = float(np.log(tot).sum() + ((HAP_ALPHA - 1) * np.log(np.maximum(f, 1e-12))).sum()
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- 0.5 * ((gamma - g0) / gs) ** 2) # fmt: skip
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r = dens / tot
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f = _hap_update(r, f)
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pi = hwe_weights(f)
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# δ and γ: weighted least squares of x on (1, t_c) over CN ≥ 1, γ shrunk towards its prior
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rr = r.copy()
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rr[:, 0] = 0.0
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w = rr.sum(axis=0)
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sw, st, stt = float(w.sum()), float((w * TEMPLATE).sum()), float((w * TEMPLATE**2).sum())
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sx, stx = float((rr * x[:, None]).sum()), float((rr * x[:, None] * TEMPLATE[None, :]).sum())
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lam = sd**2 / gs**2
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det = sw * (stt + lam) - st * st
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if det > 0:
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delta = (sx * (stt + lam) - st * (stx + lam * g0)) / det
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gamma = float(np.clip((sw * (stx + lam * g0) - st * sx) / det, *GAMMA_RANGE))
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mu = delta + gamma * TEMPLATE
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n1 = float(w.sum())
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if n1 > 0:
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sd = max(SIGMA_FLOOR, math.sqrt(float((rr * (x[:, None] - mu[None, :]) ** 2).sum() / n1)))
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r0 = r[:, 0]
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n0 = float(r0.sum())
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eps0 = min(0.0, float((r0 * (x - mu[0])).sum()) / (n0 + CN0_PRIOR_N))
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v0 = float((r0 * (x - mu[0] - eps0) ** 2).sum())
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sd0 = max(sd, math.sqrt((v0 + CN0_PRIOR_N * sd**2) / (n0 + CN0_PRIOR_N)))
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return RegionFit(float(delta), float(gamma), sd, pi.tolist(), n, float(eps0), float(sd0)), ll
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def fit_region(x: F64, iters: int = 200) -> RegionFit:
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"""PCN-009 step 4 for one region: the best of EM runs started with each observed cluster labelled CN 0 … 4, each
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with CN 0 on the template or on the lowest values."""
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g0 = GAMMA_PRIOR[0]
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cands = sorted({round(float(q) - g0 * float(t), 4) for q in np.quantile(x, [0.1, 0.3, 0.5, 0.7, 0.9])
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for t in TEMPLATE[:5]}) # fmt: skip
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lo = float(np.quantile(x, 0.02))
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best: tuple[float, float, float] | None = None
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for d0 in cands:
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for e0 in sorted({0.0, round(min(0.0, lo - (d0 + g0 * float(TEMPLATE[0]))), 4)}):
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_, ll = _em_region(x, g0, d0, 80, e0)
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if best is None or ll > best[0] + 1e-9:
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best = (ll, d0, e0)
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assert best is not None
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return _em_region(x, g0, best[1], iters, best[2])[0]
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def fit_mixture(values: dict[str, F64], iters: int = 200) -> dict[str, RegionFit]:
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"""Per-region fits for every region with ≥ 3 finite values."""
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out = {}
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for name, x in values.items():
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x = x[np.isfinite(x)]
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if len(x) >= 3:
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out[name] = fit_region(x, iters)
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return out
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def posterior(x: float, fit: RegionFit) -> F64:
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"""P(CN = c | x) for c = 0 … 5, with the training weights (floored) as prior."""
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pi = np.maximum(np.asarray(fit.weights), PI_FLOOR)
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pi = pi / pi.sum()
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d = pi * _norm_pdf(np.array([x]), fit.means(), fit.sds())[0]
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s = float(d.sum())
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out: F64 = d / s if s > 0 else pi
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return out
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def call_cn(x: float, fit: RegionFit) -> tuple[int, int, F64]:
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"""PCN-009 steps 5–6: (CN, QUAL, posterior)."""
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p = posterior(x, fit)
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cn = int(np.argmax(p))
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pmax = float(p[cn])
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qual = 60 if pmax >= 1.0 else int(min(60, max(0, round(-10 * math.log10(max(1e-300, 1 - pmax))))))
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return cn, qual, p
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@@ -0,0 +1,11 @@
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# simurg PGx CN regions v1, GRCh38, from UCSC ncbiRefSeq (PCN-001)
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chr1 109687816 109693745 GSTM1 GSTM1
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chr4 68537172 68576322 UGT2B17 UGT2B17
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chr10 133527362 133539123 CYP2E1 CYP2E1
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chr16 28605257 28610044 SULT1A1 SULT1A1
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chr19 40844772 40845293 CYP2A6.intron.7 CYP2A6
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chr19 40849746 40850947 CYP2A6.exon.1 CYP2A6
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chr22 42126498 42126752 CYP2D6.exon.9 CYP2D6
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chr22 42129185 42129737 CYP2D6.intron.2 CYP2D6
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chr22 42130810 42132810 CYP2D6.p5 CYP2D6
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chr22_KI270879v1_alt 270313 278446 GSTT1 GSTT1
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