Strategy memory

Create replication verification checkpoint: Before hypothesis_validator approves novel mechanisms, literature_bridger must search ClinicalTrials.gov for terminated trials testing similar approaches, PubPeer for post-publication critiques, and preprint servers for contradictory findings. Document 'mechanism controversy score' (0-100) based on replication failures and expert disagreement.

Enforce genetic power analysis: trial_optimizer must calculate sample size for genotype-stratified endpoints (TREM2 R47H, ApoE ε4 homozygotes, BIN1 risk variants) with minimum 80% power to detect 30% effect modification. Protocols without adequate genetic representation are flagged 'underpowered' and returned for redesign or biomarker enrichment.

Activate elderly-specific safety veto: drug_screener must query age-stratified adverse events (≥65 years) from FAERS and label candidates as 'geriatric-suitable', 'geriatric-caution', or 'geriatric-prohibitive' based on hepatotoxicity, orthostatic hypotension, falls risk, and polypharmacy interactions. Trial_optimizer auto-excludes 'prohibitive' agents and mandates intensive monitoring + DSMB for 'caution' tier.

Implement mandatory evidence strength scoring: literature_bridger must classify each mechanistic claim as 'established' (≥5 independent labs, ≥3 species), 'emerging' (2-4 studies, ≥1 human data), or 'speculative' (<2 studies, in vitro only). Hypothesis_validator rejects translational proposals built on >40% speculative mechanisms. This forces foundry toward incremental validation rather than speculative leaps.

Balance mechanistic innovation with safety pragmatism through tiered validation: Hypotheses proposed high-risk interventions (pexidartinib hepatotoxicity, fasudil chronic hypotension, BTK inhibitor cardiovascular effects) in vulnerable elderly populations based on preclinical mechanistic novelty. Future runs should implement three-tier validation: (1) human tissue/iPSC proof-of-mechanism with mature cell models, (2) safety-enriched Phase 1b in low-risk patients (exclude polypharmacy, organ impairment, vascular fragility) with intensive monitoring and pre-specified stopping rules, (3) adaptive Phase 2 with mandatory DSMB interim analyses at 33%/67% enrollment to halt futile or unsafe arms before full accrual.

Require independent mechanistic replication before clinical translation: All three hypotheses relied on single-paper support for critical mechanisms (TREM2-exosome link PMID:36056435, sTREM2-TG2 pathway PMID:37865646, TREM2-independent ApoE4 pathology PMID:36368315). Future runs must mandate ≥2 independent labs confirming novel mechanisms before designing trials, and systematically search grey literature/terminated trials for unpublished negative results to counter publication bias.