Disease Mechanism Evidence Map

A disease-focused mechanism evidence mapping skill that organizes evidence into layered chains from molecular drivers to pathways, cell types, tissue pathology, biological consequences, and clinical phenotypes. It is designed to support mechanism hypothesis building while making evidence strength, evidence type, and chain completeness explicit.

Skill Goal

Systematically map the mechanism evidence chain of a disease from molecules to clinical phenotypes. The skill should help the user see which mechanism axes are dominant, which links are direct versus indirect, which layers are well-supported versus weakly connected, and where a mechanistic hypothesis can be built without overstating causality.

Core Function

This skill should:

1. Define the disease mechanism scope before mapping.
2. Identify the major mechanism axes rather than listing every possible pathway.
3. Organize evidence into layered chains from molecule to phenotype.
4. Distinguish direct evidence, indirect evidence, and inference.
5. Distinguish human evidence, animal evidence, cell-line evidence, omics inference, and review-level synthesis.
6. Label evidence strength and chain completeness.
7. Identify weak links without prematurely converting them into formal research gaps.
8. Support mechanism hypothesis building and downstream routing.
9. When literature is cited, require real, verifiable references with working links and DOI when available.

This skill should not:

• behave like a flat literature summary,
• behave like a generic pathway list,
• behave like a formal gap-finder,
• behave like a completed protocol writer,
• fabricate papers, DOI numbers, author names, PMIDs, journal names, or evidence links.

Primary Use Cases

• Rapid understanding of disease mechanism architecture.
• Mechanism hypothesis building before study design.
• Disease introduction / discussion framework construction.
• Mechanism-oriented evidence synthesis before gap analysis.
• Mechanism-chain inspection for translational thinking.

Supported Mapping Styles

• Whole-disease mechanism landscape.
• Stage-specific mechanism mapping.
• Organ- or tissue-focused mechanism mapping.
• Cell-type-centered mechanism mapping.
• Pathway-centered disease mapping.
• Translational molecule-to-phenotype mapping.
• Clinical-phenotype-linked mechanism mapping.

Expected User Inputs

The user may provide:

• a disease or condition,
• an optional stage or subtype,
• an optional tissue or organ focus,
• an optional mechanism of interest,
• an optional cell-type focus,
• an optional phenotype or clinical outcome focus,
• an optional evidence window or evidence-type preference.

Examples:

• "sepsis immune paralysis"
• "lupus nephritis tubulointerstitial injury"
• "gastric precancerous lesion progression"
• "ferroptosis in diabetic nephropathy"
• "HCC immunosuppressive microenvironment"

Output Requirements

Outputs must be structured as layered mechanism evidence chains, not just topic summaries. The output must explicitly distinguish:

• major mechanism axes,
• molecular drivers,
• pathways / programs,
• key cell types or cell states,
• tissue / histopathology changes,
• biological consequences,
• clinical phenotype links,
• evidence type,
• evidence strength,
• chain completeness,
• weak links,
• mechanism hypothesis entry points.

When formal literature citations are provided, every cited paper must be real and verifiable. Each formal citation should include, whenever available:

• title,
• first author,
• year,
• journal or venue,
• DOI,
• stable link.

If DOI is unavailable or not verified, state that explicitly. If a paper cannot be verified, do not present it as a formal supporting citation.

Reference Module Integration

The skill must explicitly use the following reference modules during reasoning and output construction:

• Use references/mechanism-scope-rules.md to define disease scope and boundary.
• Use references/mechanism-axis-identification-rules.md to identify dominant mechanism axes.
• Use references/layered-evidence-chain-rules.md to build molecule-to-phenotype evidence chains.
• Use references/cell-tissue-phenotype-link-rules.md to connect cell context, tissue pathology, and phenotype.
• Use references/direct-vs-indirect-evidence-rules.md to label evidence type correctly.
• Use references/evidence-strength-and-chain-completeness-rules.md to grade evidence and chain continuity.
• Use references/mechanism-hypothesis-entry-rules.md to suggest hypothesis-building entry points.
• Use references/literature-verification-and-citation-rules.md whenever formal literature evidence is cited.
• Use references/downstream-routing-rules.md to recommend the next best workflow step.
• Use references/workflow-step-template.md to structure the workflow explanation.
• Use references/output-section-guidance.md to enforce the final output format.

If a relevant output section is produced without using the corresponding reference module, the output should be treated as incomplete.

Input Validation

Valid input: one or more of the following:

• a disease topic
• a mechanism / pathway / biomarker / intervention theme
• a disease stage or subtype focus
• an optional population or tissue focus
• an optional outcome or phenotype focus
• an optional evidence or method angle

Out-of-scope — respond with the redirect below and stop:

• direct patient-specific treatment advice
• requests for final medical decisions
• requests for a completed protocol instead of evidence mapping
• non-biomedical mapping requests

"This skill is designed to build a structured evidence map around a biomedical topic. Your request ([restatement]) is outside that scope because it requires [patient-specific medical advice / a completed protocol / non-biomedical support]."

Sample Triggers

• "Map the evidence landscape around this topic first."
• "Show me the main streams, populations, endpoints, and methods in this field."
• "I want a mechanism evidence map for this disease."
• "Help me see the main mechanism chains before I decide what to study."
• "Do not jump to gaps yet—first show me the evidence map."

Decision Logic

Step 1 — Define the Mechanism Scope

Use references/mechanism-scope-rules.md. Determine whether the request concerns the whole disease, a disease stage, a subtype, an organ, a tissue compartment, a mechanism family, or a phenotype-linked subproblem. Narrow the scope if necessary.

Step 2 — Identify Major Mechanism Axes

Use references/mechanism-axis-identification-rules.md. Prioritize the dominant and best-supported mechanism axes rather than treating all candidate pathways equally.

Step 3 — Build Layered Evidence Chains

Use references/layered-evidence-chain-rules.md. For each axis, organize evidence into layers such as:

• molecular drivers,
• pathways / programs,
• cell types / states,
• tissue / pathology change,
• biological consequence,
• clinical phenotype.

Step 4 — Connect Cell, Tissue, and Phenotype Context

Use references/cell-tissue-phenotype-link-rules.md. Show how cell-level changes translate into tissue-level or pathology-level changes and how those connect to clinical phenotypes.

Step 5 — Label Directness of Evidence

Use references/direct-vs-indirect-evidence-rules.md. For each key link, specify whether the support is direct evidence, indirect evidence, or inference.

Step 6 — Assess Evidence Strength and Chain Completeness

Use references/evidence-strength-and-chain-completeness-rules.md. Distinguish strong, moderate, weak, emerging, or speculative segments, and state where chains are complete versus broken.

Step 7 — Support Hypothesis Entry Points

Use references/mechanism-hypothesis-entry-rules.md. Suggest where the user can most reasonably build a mechanism hypothesis without overclaiming causality.

Step 8 — Cite Only Verified Literature Evidence

Use references/literature-verification-and-citation-rules.md. If formal literature evidence is included, only cite real, verified papers. Include stable links and DOI whenever available. If verification is incomplete, say so explicitly instead of fabricating.

Step 9 — Route to the Most Appropriate Next Step

Use references/downstream-routing-rules.md. Recommend whether the user should next deepen reading, perform a gap analysis, or convert the mechanism chain into a study plan.

Mandatory Output Structure

Use references/output-section-guidance.md.

A. Disease Scope Definition

State exactly what disease scope, stage, tissue, or phenotype is being mapped.

B. Major Mechanism Axes

List the dominant mechanism axes relevant to the scoped disease problem.

C. Layered Mechanism Chain Map

For each axis, summarize the chain from molecular driver to phenotype.

D. Cell and Tissue Context Map

State the main cell types, cell states, tissue compartments, and pathology contexts involved.

E. Phenotype Link Map

Explain how the mechanism layers connect to clinical manifestations, severity, progression, prognosis, or treatment response.

F. Key Evidence Chain Table

Provide a structured table summarizing the main mechanism chains.

G. Evidence Strength and Chain Completeness

Label which chains are well-supported, partially supported, or weakly connected.

H. Weak Links and Mechanistic Uncertainty

Identify the weakest links and the parts most dependent on inference.

I. Mechanism Hypothesis Entry Points

Suggest reasonable hypothesis-building entry points.

J. Suggested Next Step

Recommend the next best skill or workflow action.

K. Verified Supporting Literature (when citations are included)

List only real, verifiable supporting papers with DOI and stable links whenever available. If no verified formal citation is available for a claimed link, state that clearly.

Workflow Standard

Use references/workflow-step-template.md. Each workflow step should describe:

• objective,
• mechanism layer addressed,
• expected output,
• evidence caution.

Hard Rules

1. Do not treat a disease mechanism topic as a flat literature summary.
2. Always distinguish molecular, pathway, cell, tissue, and clinical phenotype layers.
3. Do not present indirect associations as completed mechanism chains.
4. Always label whether a link is supported by direct evidence, indirect evidence, or inference.
5. Distinguish human evidence, animal-model evidence, cell-line evidence, and omics inference.
6. Do not confuse repeated citation of a mechanism with strong cross-layer validation.
7. Prioritize dominant and best-supported mechanism axes instead of listing everything equally.
8. Do not turn weak links into formal research gaps unless a dedicated gap-analysis step is performed.
9. State clearly when the mechanism chain is incomplete between layers.
10. Use the map to support hypothesis building, not to overclaim causality.
11. Never fabricate literature citations, DOI numbers, PMIDs, stable links, author names, years, or journals.
12. If a cited paper cannot be directly verified, do not present it as formal supporting evidence.
13. If DOI is unavailable or not verified, state that explicitly.
14. If no verified paper is available for a link in the chain, say so instead of inventing one.

What This Skill Should Not Do

• It should not become a generic pathway dump.
• It should not flatten all evidence levels into one narrative.
• It should not overclaim completed mechanism closure when only single-layer data exist.
• It should not confuse model evidence with human disease validation.
• It should not replace a dedicated gap-analysis or protocol-design skill.
• It should not produce invented supporting references.

Quality Standard

A strong output from this skill should let the user see the disease mechanism architecture as a layered evidence chain. The user should be able to identify the dominant axes, the main cell and tissue contexts, the phenotype links, the best-supported chain segments, the weakest chain segments, and at least one hypothesis-ready entry point. If formal citations are included, they should be real, verifiable, and transparently limited by what can actually be confirmed.