"""
Intake-based trial matching — accepts raw clinical data (SI units) and scores
it against Trial nodes in the graph. No patient ID required.

SI unit reference:
  Hemoglobin:   g/dL   (×10 → g/L)
  WBC:          ×10⁹/L
  ANC:          ×10⁹/L
  Platelets:    ×10⁹/L
  Creatinine:   μmol/L (÷88.4 → mg/dL)
  eGFR:         mL/min/1.73m²
  Bilirubin:    μmol/L (÷17.1 → mg/dL)
  ALT/AST:      U/L
  Albumin:      g/dL
"""
import re
import uuid
from typing import Optional
from neo4j_setup import neo4j_conn


# ── Biomarker registry ────────────────────────────────────────────────────────
# Maps graph node id → human label → search terms found in eligibility text
BIOMARKER_REGISTRY = {
    "HER2_POS":  ("HER2 Positive",   ["HER2-positive", "HER2+", "HER2 amplified", "HER2/neu positive"]),
    "HER2_NEG":  ("HER2 Negative",   ["HER2-negative", "HER2-"]),
    "ER_POS":    ("ER Positive",      ["ER-positive", "ER+", "estrogen receptor positive"]),
    "PR_POS":    ("PR Positive",      ["PR-positive", "PR+", "progesterone receptor positive"]),
    "BRCA1_MUT": ("BRCA1 Mutation",   ["BRCA1", "BRCA1 mutation", "BRCA1-mutated"]),
    "BRCA2_MUT": ("BRCA2 Mutation",   ["BRCA2", "BRCA2 mutation", "BRCA2-mutated"]),
    "EGFR_MUT":  ("EGFR Mutation",    ["EGFR mutation", "EGFR-mutated", "EGFR exon 19", "EGFR exon 21"]),
    "ALK_POS":   ("ALK Rearrangement",["ALK rearrangement", "ALK-positive", "ALK fusion"]),
    "ROS1_POS":  ("ROS1 Rearrangement",["ROS1 rearrangement", "ROS1-positive", "ROS1 fusion"]),
    "PD_L1_POS": ("PD-L1 Positive",  ["PD-L1", "PD-L1 positive", "PDL1"]),
    "KRAS_WT":   ("KRAS Wild-type",   ["KRAS wild-type", "KRAS WT", "KRAS-wildtype"]),
    "BRAF_MUT":  ("BRAF V600E",       ["BRAF V600E", "BRAF mutation", "BRAF-mutated"]),
    "MSI_H":     ("MSI-High",         ["MSI-H", "microsatellite instability-high", "MSI high", "dMMR"]),
    "NRAS_MUT":  ("NRAS Mutation",     ["NRAS mutation", "NRAS-mutated"]),
    "FLT3_MUT":  ("FLT3 Mutation",    ["FLT3 mutation", "FLT3-mutated", "FLT3-ITD"]),
    "IDH1_MUT":  ("IDH1 Mutation",    ["IDH1 mutation", "IDH1-mutated"]),
    "IDH2_MUT":  ("IDH2 Mutation",    ["IDH2 mutation", "IDH2-mutated"]),
    "BCR_ABL":   ("BCR-ABL",          ["BCR-ABL", "Philadelphia chromosome", "Ph-positive"]),
    "TRIPLE_NEG":("Triple Negative",  ["triple-negative", "TNBC", "triple negative breast"]),
}


# ── Age parsing ───────────────────────────────────────────────────────────────

def _parse_age_years(age_str: str) -> Optional[int]:
    """'45 Years' → 45, '6 Months' → 0, '' → None"""
    if not age_str:
        return None
    m = re.search(r"(\d+)\s*year", age_str, re.I)
    if m:
        return int(m.group(1))
    m = re.search(r"(\d+)\s*month", age_str, re.I)
    if m:
        return 0
    m = re.search(r"(\d+)", age_str)
    if m:
        return int(m.group(1))
    return None


# ── ECOG parsing from eligibility text ────────────────────────────────────────

def _max_ecog_from_text(text: str) -> Optional[int]:
    """Extract maximum allowed ECOG from eligibility criteria text."""
    patterns = [
        r"ECOG\s+(?:performance\s+status\s+)?(?:of\s+)?(?:0\s*(?:or|-)\s*)?([0-4])",
        r"performance\s+status\s+(?:of\s+)?(?:0\s*(?:or|-)\s*)?([0-4])",
        r"Karnofsky\s+.*?(\d{2,3})\s*%",  # convert KPS to ECOG approximately
    ]
    for pat in patterns:
        m = re.search(pat, text, re.I)
        if m:
            val = int(m.group(1))
            if "Karnofsky" in pat:
                # KPS 80-100 ≈ ECOG 0-1, 60-70 ≈ 2, 40-50 ≈ 3
                kps = val
                val = 0 if kps >= 80 else 1 if kps >= 70 else 2 if kps >= 60 else 3
            return val
    return None


# ── Lab value checking against eligibility text ───────────────────────────────

def _check_labs(labs: dict, eligibility_text: str) -> list[dict]:
    """
    Parse common lab thresholds from eligibility text and check patient values.
    Returns list of {criterion, patient_value, threshold, met}.
    """
    results = []
    text = eligibility_text or ""

    def _find_threshold(patterns):
        for pat in patterns:
            m = re.search(pat, text, re.I)
            if m:
                return float(m.group(1))
        return None

    # Hemoglobin ≥ threshold (g/dL in text; patient value in g/dL)
    hgb = labs.get("hemoglobin")
    if hgb is not None:
        # Try to find "hemoglobin >= X" or "Hgb >= X g/dL"
        thresh = _find_threshold([
            r"hemoglobin\s*[≥>=]+\s*([\d.]+)\s*g/dL",
            r"Hgb\s*[≥>=]+\s*([\d.]+)",
            r"hemoglobin\s+of\s+at\s+least\s+([\d.]+)",
        ])
        if thresh:
            results.append({"criterion": f"Hemoglobin ≥ {thresh} g/dL", "patient_value": f"{hgb} g/dL", "met": hgb >= thresh})

    # Platelets ≥ threshold (×10⁹/L)
    plt = labs.get("platelets")
    if plt is not None:
        thresh = _find_threshold([
            r"platelet[s]?\s*[≥>=]+\s*([\d,]+)\s*[×x]?\s*10[⁹9]/L",
            r"platelet[s]?\s+count\s*[≥>=]+\s*([\d,]+)",
            r"platelet[s]?\s+of\s+at\s+least\s+([\d,]+)",
        ])
        if thresh:
            thresh_val = thresh / 1000 if thresh > 1000 else thresh  # normalise if stored as /µL
            results.append({"criterion": f"Platelets ≥ {thresh_val} ×10⁹/L", "patient_value": f"{plt} ×10⁹/L", "met": plt >= thresh_val})

    # Creatinine ≤ threshold (μmol/L patient; text may be mg/dL or μmol/L)
    cr = labs.get("creatinine")  # patient value in μmol/L
    if cr is not None:
        # Most trial text uses mg/dL; convert patient value for comparison
        cr_mgdl = cr / 88.4
        thresh = _find_threshold([
            r"creatinine\s*[≤<=]+\s*([\d.]+)\s*mg/dL",
            r"serum\s+creatinine\s*[≤<=]+\s*([\d.]+)",
        ])
        if thresh:
            results.append({"criterion": f"Creatinine ≤ {thresh} mg/dL ({round(thresh*88.4)} μmol/L)", "patient_value": f"{cr} μmol/L ({round(cr_mgdl, 2)} mg/dL)", "met": cr_mgdl <= thresh})

    # eGFR ≥ threshold
    egfr = labs.get("egfr")
    if egfr is not None:
        thresh = _find_threshold([
            r"(?:eGFR|GFR|creatinine\s+clearance)\s*[≥>=]+\s*([\d.]+)",
            r"glomerular\s+filtration\s+rate\s*[≥>=]+\s*([\d.]+)",
        ])
        if thresh:
            results.append({"criterion": f"eGFR ≥ {thresh} mL/min/1.73m²", "patient_value": f"{egfr} mL/min", "met": egfr >= thresh})

    # Bilirubin ≤ threshold (μmol/L patient; text usually mg/dL)
    bili = labs.get("bilirubin")
    if bili is not None:
        bili_mgdl = bili / 17.1
        thresh = _find_threshold([
            r"(?:total\s+)?bilirubin\s*[≤<=]+\s*([\d.]+)\s*(?:×\s*)?ULN",
            r"(?:total\s+)?bilirubin\s*[≤<=]+\s*([\d.]+)\s*mg/dL",
        ])
        if thresh:
            # If "× ULN", ULN for bilirubin ≈ 1.0 mg/dL
            results.append({"criterion": f"Bilirubin ≤ {thresh} mg/dL ({round(thresh*17.1)} μmol/L)", "patient_value": f"{bili} μmol/L ({round(bili_mgdl, 2)} mg/dL)", "met": bili_mgdl <= thresh})

    # ANC ≥ threshold (×10⁹/L)
    anc = labs.get("anc")
    if anc is not None:
        thresh = _find_threshold([
            r"(?:ANC|absolute\s+neutrophil\s+count)\s*[≥>=]+\s*([\d.]+)\s*[×x]?\s*10[⁹9]/L",
            r"neutrophil[s]?\s*[≥>=]+\s*([\d.]+)",
        ])
        if thresh:
            results.append({"criterion": f"ANC ≥ {thresh} ×10⁹/L", "patient_value": f"{anc} ×10⁹/L", "met": anc >= thresh})

    return results


# ── Main scoring function ─────────────────────────────────────────────────────

def score_intake_against_trial(intake: dict, trial: dict) -> dict:
    """
    Score a clinical intake profile against a single trial.
    Returns {score, eligible, criteria_breakdown, risk_flags}.
    """
    breakdown = []
    risk_flags = []
    points = 0
    max_points = 0

    age = intake.get("age")
    sex = intake.get("sex", "").upper()
    ecog = intake.get("ecog")
    biomarkers = set(intake.get("biomarkers", []))
    labs = intake.get("labs", {})
    prior_chemo = intake.get("prior_chemo", False)
    eligibility_text = trial.get("eligibility_criteria", "")

    # ── Age (25 pts) ──────────────────────────────────────────────────────────
    max_points += 25
    min_age = _parse_age_years(trial.get("min_age", ""))
    max_age = _parse_age_years(trial.get("max_age", ""))
    if age is not None:
        age_ok = True
        note = ""
        if min_age and age < min_age:
            age_ok = False
            note = f"Trial requires ≥{min_age} years"
            risk_flags.append(f"Below minimum age ({age} < {min_age})")
        if max_age and age > max_age:
            age_ok = False
            note = f"Trial requires ≤{max_age} years"
            risk_flags.append(f"Above maximum age ({age} > {max_age})")
        if age_ok:
            points += 25
            note = f"Within range ({min_age or '≥18'}–{max_age or 'no max'})"
        breakdown.append({"criterion": "Age", "met": age_ok, "patient_value": f"{age} years", "note": note, "category": "demographics"})

    # ── Sex (15 pts) ──────────────────────────────────────────────────────────
    max_points += 15
    trial_sex = (trial.get("sex") or "ALL").upper()
    sex_ok = trial_sex in ("ALL", sex, "")
    if not sex_ok:
        risk_flags.append(f"Sex mismatch (trial requires {trial_sex})")
    else:
        points += 15
    breakdown.append({"criterion": "Sex", "met": sex_ok, "patient_value": sex or "Not specified", "note": f"Trial: {trial_sex}", "category": "demographics"})

    # ── ECOG (15 pts) ─────────────────────────────────────────────────────────
    max_points += 15
    max_ecog = _max_ecog_from_text(eligibility_text)
    if ecog is not None and max_ecog is not None:
        ecog_ok = ecog <= max_ecog
        if not ecog_ok:
            risk_flags.append(f"ECOG {ecog} exceeds trial max ({max_ecog})")
        else:
            points += 15
        breakdown.append({"criterion": "ECOG Performance Status", "met": ecog_ok, "patient_value": f"ECOG {ecog}", "note": f"Trial requires ≤{max_ecog}", "category": "performance"})
    elif ecog is not None:
        points += 10  # partial credit — can't verify from text
        breakdown.append({"criterion": "ECOG Performance Status", "met": None, "patient_value": f"ECOG {ecog}", "note": "Could not parse limit from trial text", "category": "performance"})

    # ── Biomarkers (30 pts) ───────────────────────────────────────────────────
    max_points += 30
    if biomarkers:
        matched_bm = []
        for bm_id in biomarkers:
            info = BIOMARKER_REGISTRY.get(bm_id)
            if not info:
                continue
            label, search_terms = info
            found_in_text = any(term.lower() in eligibility_text.lower() for term in search_terms)
            matched_bm.append((label, found_in_text))

        relevant = [m for m in matched_bm if m[1]]
        if relevant:
            points += 30
            breakdown.append({
                "criterion": "Biomarker Profile",
                "met": True,
                "patient_value": ", ".join(l for l, _ in relevant),
                "note": f"{len(relevant)} of your biomarkers appear in trial criteria",
                "category": "molecular",
            })
        elif matched_bm:
            points += 5
            breakdown.append({
                "criterion": "Biomarker Profile",
                "met": None,
                "patient_value": ", ".join(l for l, _ in matched_bm),
                "note": "None of your biomarkers explicitly appear in criteria",
                "category": "molecular",
            })

    # ── Lab values (15 pts) ───────────────────────────────────────────────────
    if labs:
        max_points += 15
        lab_results = _check_labs(labs, eligibility_text)
        if lab_results:
            all_ok = all(r["met"] for r in lab_results)
            any_fail = any(not r["met"] for r in lab_results)
            if all_ok:
                points += 15
            elif not any_fail:
                points += 8
            for r in lab_results:
                if not r["met"]:
                    risk_flags.append(f"Lab out of range: {r['criterion']}")
            for r in lab_results:
                breakdown.append({
                    "criterion": r["criterion"],
                    "met": r["met"],
                    "patient_value": r["patient_value"],
                    "note": "",
                    "category": "labs",
                })
        else:
            points += 8  # no parseable lab criteria — give partial credit

    score = points / max_points if max_points > 0 else 0
    eligible = score >= 0.65 and not any("mismatch" in f or "exceeds" in f for f in risk_flags)

    return {
        "score": round(score, 3),
        "eligible": eligible,
        "criteria_breakdown": breakdown,
        "risk_flags": risk_flags,
        "points": points,
        "max_points": max_points,
    }


# ── Graph query + batch scoring ───────────────────────────────────────────────

def match_intake_to_trials(intake: dict, condition: str, limit: int = 10) -> list[dict]:
    """
    Query trials from the graph matching the condition, score each against intake,
    return ranked list.
    """
    rows = neo4j_conn.run_query(
        """
        MATCH (t:Trial)
        WHERE toLower(t.condition) CONTAINS toLower($condition)
          AND t.status IN ['RECRUITING', 'NOT_YET_RECRUITING']
        RETURN t.id AS nct_id, t.title AS title, t.phase AS phase,
               t.condition AS condition, t.min_age AS min_age, t.max_age AS max_age,
               t.sex AS sex, t.eligibility_criteria AS eligibility_criteria,
               t.sponsor AS sponsor, t.location_count AS location_count,
               t.last_updated AS last_updated, t.ctgov_url AS ctgov_url
        LIMIT $limit
        """,
        {"condition": condition, "limit": limit * 3},  # over-fetch, then rank
    )

    if not rows:
        return []

    scored = []
    for trial in rows:
        result = score_intake_against_trial(intake, trial)
        scored.append({
            **trial,
            **result,
        })

    scored.sort(key=lambda x: x["score"], reverse=True)
    return scored[:limit]


def save_intake_as_patient(intake: dict) -> str:
    """Optionally persist the intake as a Patient node for long-term graph enrichment."""
    pid = f"P_INTAKE_{uuid.uuid4().hex[:8].upper()}"
    neo4j_conn.run_query(
        """
        MERGE (p:Patient {id: $id})
        SET p += {
            age: $age, sex: $sex, ecog: $ecog, condition: $condition,
            source: 'intake_form', created_at: datetime()
        }
        """,
        {
            "id": pid,
            "age": intake.get("age"),
            "sex": intake.get("sex", ""),
            "ecog": intake.get("ecog"),
            "condition": intake.get("condition", ""),
        },
    )
    for bm_id in intake.get("biomarkers", []):
        neo4j_conn.run_query(
            """
            MATCH (p:Patient {id: $pid})
            MERGE (b:Biomarker {id: $bm_id})
            ON CREATE SET b.name = $name
            MERGE (p)-[:HAS_BIOMARKER]->(b)
            """,
            {"pid": pid, "bm_id": bm_id, "name": BIOMARKER_REGISTRY.get(bm_id, (bm_id,))[0]},
        )
    return pid