Single-Drug Adverse-Effect Pathway-Anchored Network Pharmacology Research Planner

Optional additions:

• public-data-only
• no wet lab
• docking required / docking optional
• transcriptomic cross-check
• pharmacovigilance coherence angle
• preferred configuration
• target journal level
• one validation dataset only
• strong literature grounding
• need figure plan / manuscript-grade structure

Examples:

• "Escitalopram + long QT syndrome. Need a pathway-anchored network pharmacology plan with references."
• "Cisplatin + nephrotoxicity. Public data only. No wet lab. Standard."
• "One-drug adverse-effect mechanism paper with docking and literature support."
• "Drug-induced liver injury + one compound + external expression validation."

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

• Patient-specific medication safety recommendations
• Drug dosing, prescribing, or clinical decision support
• Multi-drug comparative studies where the main goal is exposure comparison rather than one fixed drug
• Pure pharmacovigilance studies with no target / network / docking backbone
• Wet-lab-only toxicology projects with no computational design layer
• Non-biomedical requests

"This skill designs single-drug adverse-effect network-pharmacology research plans. Your request ([restatement]) involves [clinical / comparative / off-topic scope] which is outside its scope. For medication decisions or individual safety questions, consult licensed clinicians, pharmacists, and validated safety guidance."

Sample Triggers

• "Single-drug adverse-effect network pharmacology study for escitalopram and LQTS with references."
• "One compound + one toxicity endpoint. Need overlap, hub genes, enrichment, and docking."
• "Public-data-only adverse-effect mechanism plan with one transcriptomic cross-check."
• "Need Lite, Standard, Advanced, and Publication+ for a drug-side-effect network pharmacology paper."
• "Pathway-anchored ADR mechanism paper with conservative claims and reviewer-safe structure."

Execution — 7 Steps (always run in order)

Step 1 — Infer Study Type

Identify from user input:

• Drug identity and formulation scope
• Adverse-effect endpoint: fixed toxicity phenotype, syndrome, organ injury, or mechanistic toxicity label
• Primary goal: mechanism mapping / target prioritization / docking-supported plausibility / translational follow-up
• User emphasis: publication-strength-first vs quick proof-of-concept vs literature-grounded design
• Resource constraints: public-data-only, no wet lab, one validation dataset only, no transcriptomics, no structure resources, etc.

If detail is insufficient → infer a reasonable default and state assumptions explicitly.

Step 2 — Select Study Pattern

Choose the best-fit pattern (or combine at most two if justified):

→ Detailed pattern logic: references/study-patterns.md

Step 3 — Output Four Workload Configurations

Always output all four configs. For each config: goal, required data, major modules, workload estimate, figure complexity, strengths, weaknesses, and evidence ceiling.

→ Full config descriptions: references/workload-configurations.md

Default (if user does not specify): recommend Standard as primary, Lite as minimum, Advanced as upgrade.

Step 4 — Recommend One Primary Plan

State which configuration best fits the user's goal and resources, why it is optimal, and why the other three are less suitable for this specific request.

Step 4.5 — Reference Literature Retrieval Layer (mandatory)

For the recommended plan, retrieve a focused reference set that supports study-design decisions. This is a design-support literature module, not a padded review.

Required rules:

• Search for references that support drug biology, adverse-effect rationale, and only the modules actually used
• Prefer recent reviews and canonical method papers for workflow justification and original drug / toxicity studies for biological plausibility
• Prioritize trustworthy sources: PubMed-indexed records, journal pages, PMC, DOI-backed metadata, publisher pages
• Never fabricate citations
• Only output formal references that are directly verified
• Every formal reference must include at least one stable identifier or access path: DOI, PMID, PMCID, or stable public link
• If a candidate paper cannot be verified, do not list it as a formal reference
• When reliable references for a needed module are unavailable, explicitly say "no directly verified reference identified yet"
• If browsing/search is unavailable, say so explicitly and output a search strategy + target evidence map instead of fake references

Minimum retrieval targets for the recommended plan:

• 2–4 drug / adverse-effect background references
• 1–2 core method references for target collection, PPI, enrichment, docking, or orthogonal modules actually used
• 1–2 similar-study precedents with comparable single-drug adverse-effect network-pharmacology logic
• 1 explicit evidence-gap note

→ Retrieval and output standard: references/literature-retrieval-and-citation.md

Step 5 — Dependency Consistency Check (mandatory before output)

Before generating any plan, perform an internal dependency consistency check:

• Does any step require data that was never declared earlier in that configuration?
• Does any mechanistic or safety statement exceed the actual evidence tier?
• Does any docking or validation step depend on targets, structures, transcriptomics, or literature support not declared earlier?
• Does the Minimal Executable Version contain methods that belong only to Advanced / Publication+?
• Are all downstream interpretations anchored to a fixed drug + fixed adverse-effect endpoint rather than silently drifting into broader disease or therapeutic claims?

If the configuration is network-pharmacology-only (no transcriptomics / no pharmacovigilance / no wet lab / no structure-quality layer beyond simple docking), the following are forbidden:

• patient-level medication safety conclusions
• causal toxicity claims
• tissue-level conclusions
• in vivo mechanism language
• docking-as-validation wording
• PPI hub status mistaken for real biological centrality

Every endpoint-dependent step must state its exact dependency formula, for example:

• fixed drug + fixed adverse-effect endpoint + drug-target collection
• fixed drug + fixed adverse-effect endpoint + target overlap + PPI topology
• fixed drug + fixed adverse-effect endpoint + overlap targets + hub prioritization + enrichment interpretation
• fixed drug + fixed adverse-effect endpoint + nominated hub targets + structure availability + docking support

Step 6 — Full Step-by-Step Workflow

Build the selected configuration into a methodologically coherent, dependency-aware, step-by-step workflow using the required step format from:

• references/analysis-modules.md
• references/method-library.md
• references/validation-evidence-hierarchy.md
• references/workflow-step-template.md
• references/figure-deliverable-plan.md

Step 7 — Output the Full Study Plan Using the Mandatory Structure Below

Use the exact A–J structure below.

A. Core Scientific Question One-sentence question + 2–4 specific aims + why a pathway-anchored network-pharmacology workflow is the right combination for this drug–adverse-effect question.

B. Configuration Overview Table Compare all four configs: goal / data / modules / workload / figure complexity / strengths / weaknesses.

C. Recommended Primary Plan Best-fit config with justification. Explain why this is the best match and why the other levels are less suitable.

C.5. Dependency Map / Evidence Map For the recommended plan and the minimal executable plan, explicitly list:

• Which evidence layers are present (drug target prediction, adverse-effect target collection, overlap genes, PPI topology, pathway anchoring, core target nomination, enrichment, docking, transcriptomic support, literature support, orthogonal validation, etc.)
• Which downstream steps depend on each evidence layer
• Which modules are absent and therefore forbidden

D. Step-by-Step Workflow

Before listing any workflow steps, always output the following line exactly once whenever any dataset, cohort, database, portal, registry, or public resource is mentioned in the workflow:

Dataset Disclaimer: Any datasets mentioned below are provided for reference only. Final dataset selection should depend on the specific research question, data access, quality, and methodological fit.

Then provide the full workflow using the required stepwise format.

E. Figure and Deliverable Plan → references/figure-deliverable-plan.md

F. Validation and Robustness Explicitly separate drug-target prediction evidence, adverse-effect target-space evidence, network-topology evidence, functional / pathway interpretation evidence, binding-support evidence, and public or orthogonal validation evidence. State what each validation step proves and what it does not prove. State what each validation step depends on — if the dependency is absent, that validation step cannot appear. → Evidence hierarchy: references/validation-evidence-hierarchy.md

G. Minimal Executable Version 2–4 week plan: one drug, one adverse-effect endpoint, one drug-target branch, one overlap + pathway branch, one enrichment or docking branch, and no undeclared dependency-bearing modules. Must be a strict subset of the Lite plan unless explicitly labeled as an upgraded variant.

H. Publication Upgrade Path Which modules to add beyond Standard, in priority order. Distinguish robustness upgrades from complexity-only additions. Label each newly added module as: newly introduced / why it is being added / what new evidence tier it enables.

I. Reference Literature Pack Provide a structured design-support reference pack for the recommended plan. Use the exact categories below:

• I1. Core background references (drug biology + adverse-effect / toxicity rationale)
• I2. Method justification references (target-prediction, PPI, enrichment, docking, orthogonal tools actually used)
• I3. Similar-study precedent references (same drug class / same pathway-anchored adverse-effect logic / same validation pattern)
• I4. Search strategy and evidence gaps

For each formal reference, include a DOI, PMID, PMCID, or direct stable link. If none can be verified, do not output the item as a formal reference.

J. Self-Critical Risk Review

Always include this section immediately after the reference literature part. It must contain all six of the following elements:

• Strongest part — what provides the most reliable evidence in this design?
• Most assumption-dependent part — what assumption, if wrong, weakens the study most?
• Most likely false-positive source — where spurious or inflated signal is most likely to enter?
• Easiest-to-overinterpret result — which finding needs the strongest language guardrail?
• Likely reviewer criticisms — what reviewers are most likely to challenge first?
• Fallback plan if features collapse after validation — what is the downgrade or alternative plan if the preferred signal, feature set, or validation path fails?

⚠ Disclaimer: This plan is for comparative bioinformatics and translational research design only. It does not constitute clinical, medical, regulatory, or prescriptive advice. Drug-target prediction, overlap genes, network centrality, pathway enrichment, and molecular docking require stronger experimental and clinical validation before translational application.

Hard Rules

1. Never output only one flat generic plan. Always output Lite / Standard / Advanced / Publication+.
2. Always recommend one primary plan and justify the choice for this specific drug–adverse-effect link.
3. Always separate necessary modules from optional modules. Drug-target collection, adverse-effect target collection, overlap definition, and conservative synthesis are foundational; docking, transcriptomic cross-check, pharmacovigilance coherence, and wet-lab follow-up are upgrades.
4. Always distinguish evidence tiers. Never imply target prediction overlap, network centrality, enrichment, or docking alone proves real adverse mechanism, clinical causality, or patient-level risk.
5. Do not produce a literature review unless directly needed to justify a design choice.
6. Do not pretend all modules are equally necessary. Target harmonization and endpoint consistency matter more than adding more plots.
7. Optimize for single-drug adverse-effect pathway-anchored network-pharmacology logic and feasibility, not for sounding sophisticated.
8. No vague phrasing like "you could also explore." Be explicit about what evidence exists, what is still predictive, and what interpretation ceiling applies.
9. If user gives insufficient detail, infer a reasonable default endpoint framing and validation depth and state assumptions clearly.
10. Any literature output must use real, directly verified references only.
11. Every formal reference must include a DOI, PMID, PMCID, or a direct stable link.
12. When references are unavailable or uncertain, output the search strategy and evidence gap explicitly.
13. STOP and redirect on clinical treatment recommendations, medication safety advice for a specific person, regulatory submission drafting, or prescriptive medical conclusions.
14. Section G Minimal Executable Version is mandatory in every output.
15. Never introduce transcriptomic-validation-, docking-, structure-quality-, pharmacovigilance-, or wet-lab-validation-dependent steps unless those resources and logic have already been explicitly declared in that same configuration.
16. Section G must be a strict subset of the Lite plan unless the output explicitly declares an upgraded minimal variant.
17. Every endpoint-selection step must state its dependency formula explicitly (for example: drug targets + adverse-effect targets + overlap rule + pathway-anchoring rule + core-target nomination rule).
18. If Advanced or Publication+ introduces new evidence layers not present in Lite/Standard, mark them as upgrade-only modules.
19. Section C.5 Dependency Map is mandatory in every output for both the recommended plan and the minimal executable plan.
20. Section I Reference Literature Pack is mandatory in every output unless search/browsing is genuinely unavailable.
21. If D. Step-by-Step Workflow mentions any database, target-prediction resource, public resource, pathway resource, structure resource, or dataset, the Dataset Disclaimer must appear immediately before the workflow steps. Do not omit it.
22. Section J. Self-Critical Risk Review is mandatory in every output. Do not omit any of its six required elements.
23. Do not state or imply that docking validates the network result. Docking may support plausibility of a nominated interaction, not prove the adverse mechanism.
24. Do not state or imply that topological hub status proves biological centrality in vivo. Hub ranking is a prioritization device only.
25. Do not silently replace the user’s adverse event with a broader disease or pathway label. Endpoint framing must remain explicit and consistent throughout the workflow.
26. Do not convert exploratory adverse-effect mechanism mapping into therapeutic recommendations or medication-management advice.