"""Finalize the Week 1 sickle cell signature (Tier A, whole-blood concordance pair).

Reads the cached concordant gene table, maps symbols -> Entrez/Ensembl via mygene, attaches
two-study provenance + concordance summary, and persists
data/processed/sickle_cell_signature_v1.json.

Tier note: GSE16728 is exactly 10/group, which fails assign_tier()'s strict n>10. Tier A is
assigned explicitly here on the basis of cross-study, cross-platform, cross-population
concordance (the founder's decision), with the n=10 / prep-merge caveat documented in the
tier rationale and limitations.
"""

from __future__ import annotations

import sys
from pathlib import Path

import mygene
import pandas as pd

sys.path.insert(0, str(Path(__file__).resolve().parent.parent))
from src.disease import (  # noqa: E402
    ConcordanceSummary,
    SignatureProvenance,
    StudyProvenance,
    build_signature,
    persist_signature,
)
from src.provenance import ConfidenceTier  # noqa: E402

CREATED_DATE = "2026-06-23"
GEO_DIR = Path("data/raw/geo")


def map_ids(symbols: list[str]) -> pd.DataFrame:
    mg = mygene.MyGeneInfo()
    res = mg.querymany(
        symbols, scopes="symbol", fields="entrezgene,ensembl.gene",
        species="human", as_dataframe=True, verbose=False,
    )
    res = res[~res.index.duplicated(keep="first")]

    def _ensembl(v):
        if isinstance(v, list) and v:
            v = v[0]
        if isinstance(v, dict):
            return v.get("gene")
        return v

    id_map = pd.DataFrame(index=res.index)
    id_map["entrez_id"] = res["entrezgene"] if "entrezgene" in res.columns else None
    ens_col = "ensembl.gene" if "ensembl.gene" in res.columns else ("ensembl" if "ensembl" in res.columns else None)
    id_map["ensembl_id"] = res[ens_col].map(_ensembl) if ens_col else None
    return id_map


def main() -> None:
    concordant = pd.read_parquet(GEO_DIR / "concordant_genes.parquet")
    print(f"loaded {len(concordant)} concordant genes "
          f"({(concordant['log_fc']>0).sum()} up / {(concordant['log_fc']<0).sum()} down)")

    id_map = map_ids(list(concordant.index))
    print(f"mygene mapped {id_map['entrez_id'].notna().sum()}/{len(id_map)} symbols to Entrez")

    provenance = SignatureProvenance(
        studies=[
            StudyProvenance(
                geo_accession="GSE35007", n_disease=190, n_healthy=12,
                platform="Illumina HumanHT-12 V4 (GPL10558)",
                tissue="whole blood", method="welch",
            ),
            StudyProvenance(
                geo_accession="GSE16728", n_disease=10, n_healthy=10,
                platform="Affymetrix HG-U133 Plus 2.0 (GPL570)",
                tissue="whole blood (PAXgene; globin-reduced + total RNA preps merged)",
                method="welch",
            ),
        ],
        concordance=ConcordanceSummary(
            n_genes_tested=16208, n_concordant=671, n_up=444, n_down=227,
        ),
        created_date=CREATED_DATE,
    )

    tier_rationale = (
        "Measured RNA expression concordant across two independent peer-reviewed whole-blood "
        "studies on different platforms (Illumina GPL10558, Affymetrix GPL570) and populations "
        "(pediatric West-African GSE35007; adult GSE16728). Tier A rests on cross-study / "
        "cross-platform concordance. Caveat: GSE16728 is exactly 10/group (two PAXgene preps "
        "merged), which does not meet the strict n>10 per-study threshold on its own."
    )
    limitations = [
        "Whole-blood expression is partly driven by cell-composition differences "
        "(reticulocytosis in sickle patients), not pure disease-state regulation; the "
        "signature is dominated by erythroid markers (CA1, AHSP, SLC4A1). v2 needs cell-type "
        "deconvolution.",
        "Fetal-hemoglobin genes (HBG1/HBG2) are NOT captured: flat in GSE35007 and removed by "
        "GSE16728's globin-depleted RNA prep. The signature therefore does not directly encode "
        "the HbF axis that hydroxyurea acts on, which may weaken the hydroxyurea recovery test.",
        "GSE35007 is highly imbalanced (SS n=190 vs AA n=12); the healthy arm is small.",
        "GSE16728 whole-blood arm is small (10/group) and merges two RNA-prep batches.",
        "Cross-platform probe->symbol collapse (keep max-mean-expression probe) loses "
        "isoform-level resolution and drops genes absent from either platform.",
    ]

    signature = build_signature(
        concordant, provenance,
        tier=ConfidenceTier.A,
        tier_rationale=tier_rationale,
        limitations=limitations,
        id_map=id_map,
        top_n=250,
    )
    path = persist_signature(signature)
    print(f"wrote {path}")
    print(f"signature: {len(signature.up_regulated)} up / {len(signature.down_regulated)} down, "
          f"tier {signature.confidence_tier.value}")


if __name__ == "__main__":
    main()