Canonical Edge Stress-Test

Edge of Knowledge · Canonical · Non-Actionable · Version 1.0

Epistemic Failure in Computational & Preclinical Medical Discovery

I. Scope & Non-Claims

This stress-test governs epistemic exposure, not practice or application. It does not propose treatments, mechanisms, experiments, compounds, or institutional actions. No biological efficacy or readiness is asserted. Its sole purpose is to expose how certainty can remain high while correctness collapses.

II. Stress-Test Invocation

This stress-test SHOULD be invoked when:

• Multiple models converge with high confidence
• Validation appears strong but remains internally bounded
• Programs advance despite weak external grounding
• Institutional momentum resists reassessment

This stress-test MUST NOT be used to select interventions, decide next steps, or justify action.

III. Phase A — Hidden Assumptions Audit

Objective: Identify the minimum assumption set whose falsity invalidates dominant narratives while confidence remains elevated.

Assumption Classes

• Causal validity of biomarkers
• Fidelity of preclinical models to human pathology
• Representativeness of training datasets
• Accuracy of phenotypic labels
• Integrity of proxy and engineered features
• Generalizability of internal validation
• Concordance interpreted as correctness
• Predictive performance equated with mechanism

Pass condition: Assumptions are explicit.
Fail condition: Assumptions remain implicit or are collapsed into confidence.

IV. Phase B — Counterfactual Consistency Analysis

Objective: Describe internally consistent biological realities in which current models mislead while appearing rigorous.

• Latent confounding producing reproducible but spurious signals
• Phenotypic concordance without shared causality
• Dataset artifact reinforcement across the field
• Surrogate endpoints disconnected from disease trajectory
• Technical overfitting to batch or instrument signatures
• Suppressed biological heterogeneity
• Entrenched literature-driven pathway narratives

Pass condition: Counterfactuals remain plausible.
Fail condition: Analysis drifts toward fixes or prescriptions.

V. Phase C — Error Persistence Mechanisms

Objective: Explain why error survives replication, peer review, and validation.

• Confirmation bias aligned with dominant narratives
• Institutional incentive structures
• Data availability bottlenecks
• Standard pipeline propagation

Pass condition: Persistence is structural, not personal.
Fail condition: Responsibility is individualized.

VI. Phase D — Downstream Revelation

Objective: Show how epistemic failure collides with reality late, indirectly, and ambiguously.

• Marginal efficacy decay and non-linear dose responses
• Late-emerging toxicology contradictions
• Regulatory ambiguity and indefinite data requests
• Post hoc rationalization of subgroup variability

Pass condition: Failure appears delayed and non-categorical.
Fail condition: Early, clean invalidation is implied.

VII. Phase E — Misattribution & Lock-In

Objective: Identify how institutions misread failure and entrench loss.

Misattribution Patterns

• Operational attribution replacing premise review
• Blame drift toward contextual variables
• Sunk-cost preservation through re-optimization

Irreversible Signals

• Late-stage marginal efficacy plateaus
• Class-effect toxicity recognized at scale
• Regulatory deadlock after resource exhaustion
• Ethical harm recognized retrospectively
• Loss of strategic optionality

Pass condition: Lock-in precedes recognition.
Fail condition: Easy redirection is suggested.

VIII. Output Constraints

• No treatments, mechanisms, experiments, or recommendations
• No claims of efficacy or readiness
• Uncertainty is explicit and primary
• Analysis remains non-actionable

IX. Canonical Close

This stress-test is complete when it demonstrates how confidence can remain high until correction is no longer possible. Further depth would require action and is therefore out of scope.

Version 1.0 · Canonical · Edge of Knowledge · Updated only by revision