"""Week 1 exploratory run: build per-study DE + concordance for the whole-blood pair.

Read-only decision aid (NOT the final pipeline): downloads GSE35007 + GSE16728, runs DE on
each, collapses to HGNC symbols, computes concordance, and reports whether the sanity-gate
genes survive — so we can choose Tier A (concordance pair) vs Tier B (GSE35007 alone) with
real numbers. Intermediate DE tables are cached under data/raw/geo/.
"""

from __future__ import annotations

import sys
from pathlib import Path

import GEOparse
import numpy as np
import pandas as pd

sys.path.insert(0, str(Path(__file__).resolve().parent.parent))
from src.disease import (  # noqa: E402
    DISEASE_LABEL,
    HEALTHY_LABEL,
    collapse_probes_to_symbols,
    compute_differential_expression,
    concordance_filter,
)

GEO_DIR = Path("data/raw/geo")
GEO_DIR.mkdir(parents=True, exist_ok=True)

SANITY_GENES = ["HBG1", "HBG2", "ALAS2", "CA1", "AHSP", "SLC4A1", "HBB", "ERAF"]
SYMBOL_COL_CANDIDATES = [
    "Symbol", "ILMN_Gene", "Gene Symbol", "GENE_SYMBOL", "Gene symbol",
    "gene_assignment", "GeneSymbol",
]


def log(msg: str) -> None:
    print(msg, flush=True)


def get_symbol_map(gpl) -> pd.Series:
    tbl = gpl.table
    col = next((c for c in SYMBOL_COL_CANDIDATES if c in tbl.columns), None)
    if col is None:
        raise RuntimeError(f"No symbol column in GPL {gpl.name}; columns={list(tbl.columns)[:15]}")
    s = tbl.set_index("ID")[col].astype(str).str.strip()
    # gene_assignment fields are '// SYMBOL // ...'; take the first real token.
    if col == "gene_assignment":
        s = s.str.split("//").str[1].str.strip()
    s = s.replace({"": np.nan, "nan": np.nan, "---": np.nan})
    return s.dropna()


def build_expression(gse, sample_ids: list[str]) -> pd.DataFrame:
    cols = {}
    for gsm_id in sample_ids:
        tbl = gse.gsms[gsm_id].table
        cols[gsm_id] = tbl.set_index("ID_REF")["VALUE"]
    return pd.DataFrame(cols)


def char_value(gsm, key: str) -> str | None:
    for c in gsm.metadata.get("characteristics_ch1", []):
        if c.lower().startswith(key.lower()):
            return c.split(":", 1)[1].strip()
    return None


def run_study(gse, groups: dict[str, str], label: str) -> pd.DataFrame:
    """groups: gsm_id -> 'disease'/'healthy'. Returns symbol-level DE table."""
    sample_ids = list(groups.keys())
    log(f"[{label}] {len(sample_ids)} samples "
        f"({sum(v==DISEASE_LABEL for v in groups.values())} disease / "
        f"{sum(v==HEALTHY_LABEL for v in groups.values())} healthy)")
    expr = build_expression(gse, sample_ids).apply(pd.to_numeric, errors="coerce").dropna(how="all")
    sample_groups = pd.Series(groups)
    de = compute_differential_expression(expr, sample_groups, method="welch")
    gpl = list(gse.gpls.values())[0]
    sym = get_symbol_map(gpl)
    de_sym = collapse_probes_to_symbols(de, sym, expression_for_ranking=expr)
    log(f"[{label}] probes->symbols: {len(de)} probes -> {len(de_sym)} symbols; "
        f"sig q<0.05: {(de_sym['qvalue']<0.05).sum()}")
    de_sym.to_parquet(GEO_DIR / f"de_{label}.parquet")
    return de_sym


def main() -> None:
    # --- GSE35007: whole blood, hb phenotype SS (disease) vs AA (healthy) ---
    log("downloading GSE35007 ...")
    gse1 = GEOparse.get_GEO(geo="GSE35007", destdir=str(GEO_DIR), silent=True)
    g1 = {}
    for gsm_id, gsm in gse1.gsms.items():
        hb = char_value(gsm, "hb phenotype")
        if hb == "SS":
            g1[gsm_id] = DISEASE_LABEL
        elif hb == "AA":
            g1[gsm_id] = HEALTHY_LABEL
    de1 = run_study(gse1, g1, "GSE35007")

    # --- GSE16728: whole blood only (PAXgene preps; exclude PBMC), patient vs control ---
    log("downloading GSE16728 ...")
    gse2 = GEOparse.get_GEO(geo="GSE16728", destdir=str(GEO_DIR), silent=True)
    g2 = {}
    for gsm_id, gsm in gse2.gsms.items():
        prep = char_value(gsm, "rna prep") or ""
        subj = char_value(gsm, "subject") or ""
        if "PBMC" in prep:
            continue  # whole-blood only
        if subj.lower().startswith("sickle"):
            g2[gsm_id] = DISEASE_LABEL
        elif subj.lower().startswith("control"):
            g2[gsm_id] = HEALTHY_LABEL
    de2 = run_study(gse2, g2, "GSE16728")

    # --- Concordance ---
    keep, summary = concordance_filter(de1, de2)
    log("\n==== CONCORDANCE (whole-blood pair) ====")
    log(f"genes tested in both: {summary.n_genes_tested}")
    log(f"concordant (q<0.05 both + same sign): {summary.n_concordant} "
        f"(up={summary.n_up}, down={summary.n_down})")
    keep.to_parquet(GEO_DIR / "concordant_genes.parquet")

    log("\n==== SANITY-GATE GENES ====")
    for g in SANITY_GENES:
        in1 = g in de1.index
        in2 = g in de2.index
        row1 = de1.loc[g] if in1 else None
        row2 = de2.loc[g] if in2 else None
        concord = "YES" if g in keep.index else "no"
        d1 = f"lfc={row1['log_fc']:+.2f},q={row1['qvalue']:.1e}" if in1 else "absent"
        d2 = f"lfc={row2['log_fc']:+.2f},q={row2['qvalue']:.1e}" if in2 else "absent"
        log(f"  {g:7s} | GSE35007 {d1:28s} | GSE16728 {d2:28s} | concordant={concord}")

    log("\n==== TOP 15 CONCORDANT (by worst-case q) ====")
    log(keep.head(15).to_string())


if __name__ == "__main__":
    main()