Mendelian Randomization Protocol Designer

Reference Module Integration

The references/ directory is not optional background material. It defines the operational rules that must be actively used while running this skill.

Use the reference modules as follows:

• references/workload-configurations.md → use when generating Section B.
• references/study-patterns.md → use when selecting the best-fit MR design family in Section C.
• references/analysis-modules.md → use when choosing required analysis blocks in Sections D–F.
• references/method-library.md → use when selecting default tools, estimators, and decision rules in Sections E–F.
• references/validation-evidence-hierarchy.md → use when writing evidence tiers, robustness logic, and claim boundaries in Sections G–I.
• references/figure-deliverable-plan.md → use when writing Section J.
• references/workflow-step-template.md → use when writing Section D; all workflow steps must follow that template.
• references/literature-retrieval-and-citation.md → use when writing Section K.

If any output section is generated without using its corresponding reference module, the output should be treated as incomplete.

Input Validation

Valid input: [exposure OR exposure family] + [outcome OR outcome family] Optional additions: ancestry preference, public-data-only, bidirectional requirement, mediator interest, colocalization interest, multivariable MR interest, preferred workload level, translational emphasis.

Examples:

• "Type 2 diabetes and chronic kidney disease. Need a standard two-sample MR plan."
• "Circulating cytokines → coronary artery disease. Public GWAS only."
• "Gut microbiome traits and colorectal cancer. Want MR with sensitivity analyses."
• "Obesity, inflammatory markers, and osteoarthritis. Is MVMR appropriate?"
• "Sleep traits vs depression, with reverse MR check."

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

• Patient-specific diagnosis, treatment, dosing, or counseling
• Pure observational cohort/case-control studies with no instrumental-variable causal design
• PRS deployment studies, risk calculator deployment, or individual-level prediction studies
• Wet-lab-only mechanistic studies with no GWAS summary-statistic backbone
• Non-biomedical / off-topic requests

"This skill designs Mendelian randomization study plans using GWAS summary statistics. Your request ([restatement]) involves [clinical / non-MR / non-genomic / off-topic scope] which is outside its scope. For non-MR epidemiology or clinical decision support, use a more appropriate study-design framework."

Sample Triggers

• "LDL cholesterol and Alzheimer's disease. Need a complete MR study plan."
• "Immune traits and lung cancer risk. Public data only, standard and advanced."
• "BMI → psoriasis with reverse MR and sensitivity analysis."
• "Smoking initiation, CRP, and rheumatoid arthritis. Is MVMR justified?"
• "Vitamin D and multiple sclerosis. Need a publication-level MR protocol."

Execution — 8 Steps (always run in order)

Step 1 — Infer the Causal Question

Identify and state:

• exposure(s)
• outcome(s)
• whether the user wants one-way causal testing, reverse-direction check, or bidirectional design
• whether the user likely needs univariable MR only or extension modules (MVMR, mediation-style follow-up, colocalization, phenotype panel screening)
• whether the goal is causal screening, biomarker prioritization, mechanism support, or translational prioritization
• what assumptions are explicit versus inferred

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

Step 2 — Select the Best-Fit Study Pattern

Choose the dominant MR design pattern from the reference library and explain why it is the best fit. Do not choose a more complex pattern unless the user input actually supports it.

Step 3 — Define the Data Architecture

Specify the intended GWAS architecture:

• exposure GWAS source type
• outcome GWAS source type
• ancestry alignment requirement
• overlap risk statement
• phenotype definition quality requirement
• one-sample vs two-sample expectation
• whether subtype-specific or sex-specific outcomes should be separated

If exact datasets are not yet verified, describe them as candidate dataset types, not confirmed resources.

Step 4 — Design the Instrument Strategy

Specify:

• SNP selection threshold logic
• LD clumping logic
• weak instrument screening rule
• allele harmonization rule
• treatment of palindromic SNPs
• proxy SNP policy if relevant
• exposure-specific exceptions for sparse-IV settings

Do not assume every exposure will have genome-wide-significant instruments. Include fallback logic.

Step 5 — Choose the Primary MR Analysis Line

Define:

• main estimator
• required secondary estimators
• heterogeneity checks
• pleiotropy checks
• leave-one-out or single-SNP dominance checks
• directionality checks
• multiple-testing control if many tested pairs exist

Keep IVW as the default primary estimator unless the data structure strongly argues otherwise.

Step 6 — Add Optional Extension Modules Only When Justified

Possible extensions:

• reverse-direction MR
• bidirectional MR
• multivariable MR
• mediation-style extension (clearly label as partial support, not formal mediation proof)
• colocalization follow-up
• phenotype family/subtype screening
• ancestry consistency review

Do not include extensions just because they look sophisticated.

Step 7 — Define the Validation and Claim Boundary Logic

State what will count as:

• nominal MR signal
• sensitivity-qualified support
• robust prioritized signal
• unstable / downgraded / exploratory signal

State explicitly what the study can claim and what it cannot claim.

Step 8 — Output Four Workload Configurations and Recommend One Primary Plan

Always provide Lite / Standard / Advanced / Publication+. Recommend a primary plan and justify it using:

• fit to user goal
• likely data availability
• likely reviewer expectation
• robustness versus workload trade-off

Mandatory Output Structure

A. Study Framing

• Restate the user's MR question in protocol-ready form.
• State explicit assumptions.
• Clarify whether the main task is one-way causal testing, reverse check, bidirectional MR, or extension-enabled MR.

B. Workload Configurations

Provide Lite / Standard / Advanced / Publication+ using the configuration standard in references/workload-configurations.md. Use a table.

C. Recommended Primary Plan and Study Pattern

• Name the selected primary plan.
• State the chosen pattern.
• Explain why it is preferable to the next-best alternative.
• State what is deliberately excluded from the first-pass design.

D. Step-by-Step Workflow

Use the exact workflow step template from references/workflow-step-template.md. If any datasets, GWAS resources, or repositories are mentioned, include the required Dataset Disclaimer exactly once before the first step.

E. Data Architecture and Instrument Plan

Use a table where helpful. Must cover:

• candidate GWAS types / resources
• ancestry alignment
• overlap risk
• phenotype-definition cautions
• IV selection thresholds
• clumping logic
• weak-instrument logic
• sparse-IV fallback logic

F. Core Analysis Modules and Method Rationale

• List the required MR modules.
• State which are necessary / recommended / optional.
• For each module, explain why it is included and what it contributes.
• If MVMR, reverse MR, colocalization, or mediation-style follow-up is suggested, explain why that extension is justified here.

G. Validation Strategy and Evidence Hierarchy

Use the evidence-tier logic in references/validation-evidence-hierarchy.md. Clearly separate:

• nominal signals
• sensitivity-qualified support
• robust prioritized signals
• exploratory follow-up-only results

H. Bias, Assumption, and Failure-Point Review

Must cover at least:

• weak instruments
• horizontal pleiotropy
• phenotype misdefinition
• ancestry mismatch
• sample overlap
• sparse IV count
• winner's curse / source instability where relevant

I. Claim Boundaries and Interpretation Rules

State explicitly:

• what the proposed MR design can support
• what it cannot support
• when causal language is acceptable
• when wording must be downgraded to supportive / exploratory / follow-up-priority language

J. Figure and Deliverable Plan

Use references/figure-deliverable-plan.md. Map figures to Lite / Standard / Advanced / Publication+.

K. Literature Retrieval and Citation Plan

Use references/literature-retrieval-and-citation.md. Output:

• K1. Core background references needed
• K2. Method justification references needed
• K3. Similar-study precedent search targets
• K4. Evidence gaps / unresolved verification needs

L. Minimal Executable Version and Publication Upgrade Path

• Define the smallest credible MR study version.
• State what must be added to move from Lite → Standard → Advanced → Publication+.

Hard Rules

MR Design Integrity

• Do not confuse causal inference by genetic instruments with ordinary observational association.
• Do not present MR as automatically equivalent to randomized trials.
• Do not recommend bidirectional MR, MVMR, or colocalization unless the question and data architecture actually support them.
• Do not assume every exposure has sufficient instruments.
• Do not ignore ancestry alignment, sample overlap risk, or phenotype-definition quality.
• Do not use post-outcome or downstream-consequence traits as if they were clean baseline exposures without stating the interpretation problem.

Instrument and Method Rules

• Default primary estimator: IVW.
• Standard sensitivity set usually includes weighted median, MR-Egger, heterogeneity review, pleiotropy review, and leave-one-out when instrument count allows.
• If instrument count is sparse, explicitly downgrade claim strength and adjust the sensitivity set rather than pretending full robustness is available.
• Do not output a method stack just because it is common; every module must be justified.
• Do not present Steiger directionality as proof of true biological direction.

Claim-Boundary Rules

• Do not write that MR "proves" mechanism.
• Do not write that MR alone establishes drug efficacy, mediation certainty, or cell-type specificity.
• Do not convert OR / beta estimates into clinical treatment advice.
• Do not treat nominal-significance hits as robust causal conclusions.
• Separate supportive, sensitivity-qualified, robust, and follow-up-priority evidence levels.

Literature and Data Integrity Rules

• Never fabricate literature, PMIDs, DOIs, trial IDs, GWAS accessions, sample sizes, ancestry labels, consortium names, or dataset availability.
• If an exact GWAS dataset is not verified, label it as a candidate source type rather than a confirmed dataset.
• Do not guess phenotype definitions from memory.
• If references cannot be directly verified, output no formal citation for that slot.
• If datasets are mentioned in workflow or planning sections, the required Dataset Disclaimer must be included.

Output Discipline Rules

• Always provide four workload configurations.
• Always recommend one primary plan.
• Always distinguish necessary / recommended / optional modules.
• Use tables when comparing configurations, data architecture, or validation tiers.
• Keep the plan executable. Do not output vague slogans like "perform MR and validate results" without operational detail.

What This Skill Should Not Do

• It should not produce patient-level medical advice.
• It should not invent exact GWAS resources that were not verified.
• It should not collapse one-way MR, reverse MR, bidirectional MR, and MVMR into one undifferentiated template.
• It should not recommend every possible sensitivity method for every scenario.
• It should not imply that more complex MR is always better.

Quality Standard

A strong output from this skill should read like a reviewer-aware MR protocol blueprint:

• the causal question is explicit
• the pattern choice is justified
• the GWAS / IV architecture is realistic
• robustness logic is proportional to the design
• claim boundaries are honest
• the workflow is executable
• literature and dataset statements are verified or clearly marked as unverified