track1_scoring.py

"""
Track 1 (Variant Prediction) automated scoring.

Adapted from the CAGI6 Rare Genomes Project Challenge assessment methodology
(Stenton et al., 2024), simplified for a single proband ("N-of-1") with a
clinically validated compound-heterozygous answer key.

Submission format (CSV):
    proband_id,chrom_1,pos_1,ref_1,alt_1,chrom_2,pos_2,ref_2,alt_2,epcr

    - One row per proposed causal variant (or compound-het variant pair).
    - chrom_2/pos_2/ref_2/alt_2 are left blank for single-variant proposals.
    - epcr = Estimated Probability of Causal Relationship, in (0, 1].
    - Up to 10 rows per proband. Rows do NOT need to be pre-sorted by the
      submitter; this script sorts by epcr descending before scoring
      (but will warn if the file wasn't already sorted, since real CAGI
      submissions are expected to be pre-ranked).

Two metrics are computed, matching CAGI's two numeric metrics:
    1. Rank points  — weighted score based on the rank position of the
       true causal variant(s) in the submission.
    2. F-max        — the maximum F-measure (harmonic mean of precision
       and recall) for causal-variant identification, swept across all
       unique EPCR thresholds present in the submission.

Because there is only one proband, "mean rank points across probands"
collapses to a single score, and F-max is computed by treating each
individual variant (not each row) as a classifiable unit — this keeps
the metric meaningful even at N=1, since a compound-het true answer
still has two independent variants to be recovered.
"""

from __future__ import annotations
import csv
from dataclasses import dataclass, field
from typing import Optional


Variant = tuple[str, int, str, str]  # (chrom, pos, ref, alt)

# Rank-point scale, compressed from CAGI's RGP weighting to fit a single
# proband with a max of 10 submitted candidates (rather than CAGI's
# multi-family, up-to-100-candidate benchmark).
RANK_POINT_TIERS = [
    (1, 100),
    (3, 50),
    (5, 25),
    (10, 10),
]


@dataclass
class SubmissionRow:
    variants: frozenset[Variant]  # 1 element = single variant, 2 = compound het
    epcr: float
    rank: int  # 1-indexed position after sorting by epcr descending
    finding_type: str = "primary"  # "primary" or "secondary" — informational only,
                                    # does not affect the automated score


@dataclass
class ScoreResult:
    proband_id: str
    full_match_rank: Optional[int]
    partial_match_rank: Optional[int]
    rank_points: float
    f_max: float
    f_max_threshold: Optional[float]
    n_predictions_at_f_max: int


def _parse_variant(chrom: str, pos: str, ref: str, alt: str) -> Optional[Variant]:
    if not chrom or not pos:
        return None
    return (chrom.strip(), int(pos), ref.strip().upper(), alt.strip().upper())


def load_submission(csv_path: str) -> dict[str, list[SubmissionRow]]:
    """Load a Track 1 submission CSV and group rows by proband, sorted by EPCR desc."""
    by_proband: dict[str, list[tuple[frozenset[Variant], float, str]]] = {}

    with open(csv_path, newline="") as f:
        reader = csv.DictReader(f)
        for row in reader:
            pid = row["proband_id"].strip()
            v1 = _parse_variant(row["chrom_1"], row["pos_1"], row["ref_1"], row["alt_1"])
            v2 = _parse_variant(row.get("chrom_2", ""), row.get("pos_2", ""),
                                 row.get("ref_2", ""), row.get("alt_2", ""))
            if v1 is None:
                raise ValueError(f"Row missing primary variant for proband {pid}")
            variants = frozenset([v1, v2]) if v2 else frozenset([v1])
            epcr = float(row["epcr"])
            if not (0 < epcr <= 1):
                raise ValueError(f"EPCR {epcr} out of range (0,1] for proband {pid}")
            finding_type = (row.get("finding_type") or "primary").strip().lower()
            if finding_type not in ("primary", "secondary"):
                raise ValueError(
                    f"finding_type must be 'primary' or 'secondary' for proband {pid}, "
                    f"got '{finding_type}'"
                )
            by_proband.setdefault(pid, []).append((variants, epcr, finding_type))

    result: dict[str, list[SubmissionRow]] = {}
    for pid, rows in by_proband.items():
        if len(rows) > 10:
            raise ValueError(f"Proband {pid} has {len(rows)} rows; max is 10")
        # Sort descending by EPCR (ties broken by original order)
        rows_sorted = sorted(enumerate(rows), key=lambda x: (-x[1][1], x[0]))
        result[pid] = [
            SubmissionRow(variants=v, epcr=e, rank=i + 1, finding_type=ft)
            for i, (_, (v, e, ft)) in enumerate(rows_sorted)
        ]
    return result


def _rank_to_points(rank: int) -> int:
    for max_rank, points in RANK_POINT_TIERS:
        if rank <= max_rank:
            return points
    return 0


def score_proband(
    proband_id: str,
    submission_rows: list[SubmissionRow],
    true_variants: frozenset[Variant],
) -> ScoreResult:
    """
    Score a single proband's submission against its known causal variant(s).

    true_variants: frozenset of 1 variant (simple dominant/de novo case) or
                   2 variants (compound heterozygous recessive case).
    """
    is_compound_het = len(true_variants) == 2

    full_match_rank = None
    partial_match_rank = None

    for row in submission_rows:
        if row.variants == true_variants:
            full_match_rank = row.rank
            break  # first (best) full match is what counts

    if is_compound_het and full_match_rank is None:
        # Look for a row containing exactly one of the two true variants —
        # either proposed alone, or paired with an incorrect second variant.
        for row in submission_rows:
            if row.variants & true_variants:
                partial_match_rank = row.rank
                break

    # --- Rank points (metric 1) ---
    if full_match_rank is not None:
        rank_points = float(_rank_to_points(full_match_rank))
    elif partial_match_rank is not None:
        # CAGI-style partial credit: half weight for recovering only one
        # of two causal variants in a compound-het pair.
        rank_points = 0.5 * _rank_to_points(partial_match_rank)
    else:
        rank_points = 0.0

    # --- F-max (metric 2), computed at the individual-variant level ---
    thresholds = sorted({row.epcr for row in submission_rows}, reverse=True)
    best_f = 0.0
    best_threshold = None
    best_n = 0

    for t in thresholds:
        predicted_variants: set[Variant] = set()
        n_rows_at_threshold = 0
        for row in submission_rows:
            if row.epcr >= t:
                predicted_variants |= row.variants
                n_rows_at_threshold += 1

        tp = len(predicted_variants & true_variants)
        fp = len(predicted_variants - true_variants)
        fn = len(true_variants - predicted_variants)

        precision = tp / (tp + fp) if (tp + fp) > 0 else 0.0
        recall = tp / (tp + fn) if (tp + fn) > 0 else 0.0
        f = (2 * precision * recall / (precision + recall)) if (precision + recall) > 0 else 0.0

        if f > best_f:
            best_f = f
            best_threshold = t
            best_n = n_rows_at_threshold

    return ScoreResult(
        proband_id=proband_id,
        full_match_rank=full_match_rank,
        partial_match_rank=partial_match_rank,
        rank_points=rank_points,
        f_max=best_f,
        f_max_threshold=best_threshold,
        n_predictions_at_f_max=best_n,
    )


# ─────────────────────────────────────────────────────────────────────────
# Example usage / self-test
# ─────────────────────────────────────────────────────────────────────────
if __name__ == "__main__":
    # The known, NHS-validated compound-heterozygous BUB1B answer key.
    # Source: Royal Devon and Exeter NHS Foundation Trust genomic laboratory
    # report (issued 31/08/2023). Coordinates are GRCh38, matching the build
    # required by the submission schema.
    #
    # Variant 1 (maternal): NM_001211.6:c.2210T>G, p.(Leu737*) — Pathogenic
    # Variant 2 (paternal): NM_001211.6:c.3006T>G, p.(Asn1002Lys) — Likely Pathogenic
    #
    # Note: only the proband ID and variant coordinates are used here — the
    # patient's name, date of birth, and NHS number from the source report
    # are deliberately excluded, consistent with the Hackathon's
    # de-identification requirements.
    ANSWER_KEY: dict[str, frozenset[Variant]] = {
        "PROBAND01": frozenset([
            ("chr15", 40209701, "T", "G"),
            ("chr15", 40220612, "T", "G"),
        ]),
    }

    submissions = load_submission("track1_submission_template.csv")

    for proband_id, rows in submissions.items():
        true_variants = ANSWER_KEY[proband_id]
        result = score_proband(proband_id, rows, true_variants)
        print(f"Proband: {result.proband_id}")
        print(f"  Full match rank:      {result.full_match_rank}")
        print(f"  Partial match rank:   {result.partial_match_rank}")
        print(f"  Rank points:          {result.rank_points}")
        print(f"  F-max:                {result.f_max:.3f}")
        print(f"  F-max EPCR threshold: {result.f_max_threshold}")
        print(f"  # predictions at that threshold: {result.n_predictions_at_f_max}")