feat: confidence-gap safeguards before wet-lab synthesis

[cschanhniem]

Summary

Three safeguards added to close critical confidence gaps before committing to the $10k wet-lab synthesis budget.

Gap 1 — Safety scorer v0.4: hydrophobic moment as hemolysis signal

Pilot-panel SEED-005 variants had μH 0.69–0.87 but were trivially scored safety=1.0 because their hydrophobic fraction sat below the old 0.65 threshold. Amphipathicity (μH) is the primary predictor of non-selective membrane disruption per Dathe & Wieprecht (1999).

• Added: if mu_h > 0.55: risk += (mu_h - 0.55) * 1.5
• Effect: SEED-005 variants drop to safety 0.52–0.77; SEED-003 variants (shorter, highly charged, moderate μH ≈ 0.59) stay at 0.94
• Known blind spot documented: melittin-like peptides (bent-helix hemolytic character) are not captured by 1D μH

Gap 2 — Retrospective AUROC benchmark (critical gate)

Compares 44 known AMPs against 44 composition-identical shuffled decoys. Since all composition features (charge, hydrophobic fraction, Boman, GRAVY, length) are identical per pair, only order-dependent features (hydrophobic_moment) can separate them. This tests whether the scoring signal is real.

Result: AUROC = 0.5305 (gate: >0.70 proceed, 0.55–0.70 caution, <0.55 STOP)

This is a hard finding. The model sits in the POOR zone — it is near-random at discriminating known AMPs from their composition-matched shuffles. Root cause: hydrophobic_moment contributes only ~15% of the activity score; the remaining ~85% is composition-based (identical for each AMP/decoy pair).

Implication: the current scoring model's order-sensitive discriminative power is weak. Run make validate-scoring for the full report.

Gap 3 — External predictor checklist

Generates a pilot FASTA + structured markdown table for manual submission to three independent published tools:

• CAMPR4 (SVM+RF+ANN+DT ensemble)
• AMPScanner v2.0 (LSTM)
• dbAMP 2.0 (Random Forest)

Decision gate: ≥12/20 agree → synthesise; 6–11 → wave-1 only; <6 → STOP. Run make external-predict.

New CLI commands

make validate-scoring     # retrospective AUROC (must run before synthesis)
make external-predict     # FASTA + submission checklist
make pilot-confident KEEP=ID1,ID2,...  # filter to externally confirmed candidates

What to do next (honest)

The AUROC=0.5305 result means the scoring model is not sufficiently discriminative in order-sensitive features. Before spending $10k:

1. Mandatory: Submit pilot FASTA to all 3 external tools (make external-predict). If ≥12/20 agree, the external consensus overrides the weak internal signal.
2. Recommended: Improve the model by increasing weight of hydrophobic_moment or adding position-specific features (N-terminal charge patch, motif detection).
3. Alternative: Use a published QSAR/ML AMP classifier (CAMPR4 offline, iAMPpred) as a primary scorer rather than purely physicochemical heuristics.

Test plan

• 364 tests pass (all green)
• 23 new tests: test_safety_moment.py (7 tests), test_retrospective.py (16 tests)
• Pre-push CI hook ran and passed
• make validate-scoring runs cleanly and outputs AUROC=0.5305 with interpretation
• Human: submit outputs/pilot_panel.fasta to CAMPR4, AMPScanner v2, dbAMP 2.0 and record results in checklist

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