Real-World Evidence Study Designer

This skill must not confuse RWE study design with simple retrospective chart review, cross-sectional database description, randomized trial design, or unsupported causal inference.

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/rwe-question-fit-rules.md → use when judging whether an RWE design is appropriate in Section B.
• references/data-source-and-capture-framework.md → use when selecting among EHR, claims, and registry structures and clarifying capture limits in Section C.
• references/time-zero-exposure-followup-rules.md → use when defining index date, baseline window, exposure episode logic, outcome windows, and censoring in Sections D–F.
• references/target-trial-emulation-rules.md → use when the question implies comparative effectiveness, treatment strategy evaluation, or causal language in Section G.
• references/confounding-and-bias-control-rules.md → use when building confounder control logic and validity review in Sections H–I.
• references/analysis-line-framework.md → use when specifying the primary statistical analysis line in Section J.
• references/output-section-guidance.md → use to keep the final report sectioned, bounded, and decision-oriented across Sections A–L.
• references/literature-integrity-rules.md → use whenever referring to prior RWE precedents, coding algorithms, linked-data availability, validation status, event rates, guideline support, or published evidence.
• references/workflow-step-template.md → use to keep the workflow sequencing explicit and consistent.

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

Input Validation

Valid input usually includes one or more of the following:

• a comparative effectiveness or safety question using routine-care data
• a treatment pattern, adherence, switching, utilization, or outcome question suitable for EHR / claims / registry analysis
• a prognostic or outcome-association question that requires longitudinal real-world follow-up
• a request to design an observational study with time-zero, exposure, outcome, and censoring logic
• a request to emulate part of a target trial using available real-world data

Examples:

• “Design an EHR-based RWE study on whether early steroid exposure changes infection risk in autoimmune disease.”
• “Help me build a claims-based comparative effectiveness study of first-line anticoagulants.”
• “I want a registry-based RWE design for device failure and reintervention.”
• “Can you structure a target-trial-emulation-style study of GLP-1RA initiation and kidney outcomes?”
• “We have linked claims and mortality data and want to study treatment discontinuation and hospitalization.”

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

• direct patient-specific diagnosis or treatment advice
• a request that is truly a randomized trial protocol
• a question better answered by case-control, purely cross-sectional, diagnostic accuracy, mechanistic experimental, or qualitative design without longitudinal RWD logic
• pure literature review requests with no study-design purpose

“This skill is designed to build real-world evidence study designs using EHR, claims, or registry data. Your request ([restatement]) is outside that scope because it requires [patient-specific medical advice / a different study design family / a completed evidence answer rather than RWE study design].”

Sample Triggers

• “Design an RWE study using EHR data.”
• “Help me define time zero and exposure windows for a claims analysis.”
• “I want a registry-based comparative effectiveness protocol skeleton.”
• “Can you structure this as a target trial emulation?”
• “Build the main design logic for a real-world safety study.”

Core Function

When given a clinical or translational question, this skill must produce a real-world evidence study blueprint that clarifies:

1. whether an RWE design is appropriate;
2. which real-world data source structure best fits the question;
3. the implied target population and source population;
4. eligibility, baseline, and index-date logic;
5. exposure definition and treatment episode construction;
6. outcome definitions and measurement windows;
7. follow-up, censoring, competing events, and data truncation logic;
8. whether target trial emulation is justified, and at what level;
9. the main confounding, selection, misclassification, and missingness risks;
10. the primary analysis line;
11. what is available, potentially obtainable, or currently unsupported in the proposed data environment;
12. what design choices would make the study uninterpretable.

Workflow Standard

Follow this sequence:

1. Determine whether the question is suitable for RWE design at all.
2. Identify the implied estimand and whether it is descriptive, associative, or causal-leaning.
3. Select the best-fit data source type and explicitly state capture strengths and weaknesses.
4. Define source population, eligibility, baseline window, and time zero.
5. Define exposure strategy, comparator, outcome windows, and censoring structure.
6. Decide whether target trial emulation should be used, approximated, or explicitly rejected.
7. Build the confounder-control line and major bias review.
8. Propose the primary analysis line and key sensitivity structure.
9. Separate what is known, assumed, potentially obtainable, and currently unsupported.
10. End with a primary recommendation and the most important design cautions.

Do not skip time-zero logic. Do not treat convenience variables as valid confounders without temporal discipline. Do not imply causal validity without design support.

Mandatory Output Structure

Use the section structure below.

A. Study Intent and RWE Fit

State the user’s apparent objective, the likely RWE use case, and whether this is truly suitable for EHR / claims / registry design.

B. Question Type and Estimand Framing

Classify the question as mainly descriptive, utilization, prognostic, comparative effectiveness, safety, adherence, treatment-pattern, or causal-leaning. State the implied estimand in plain language.

C. Data Source Strategy

Specify the best-fit data source type (EHR, claims, registry, or linked sources), why it fits, and what the likely capture gaps are. Use a compact comparison table if more than one source is plausible.

D. Target Population, Source Population, and Eligibility

Define who the study is trying to say something about, how the source population would actually be constructed, and the inclusion / exclusion logic.

E. Time Zero, Baseline Window, and Follow-Up Logic

Define index date, allowable baseline ascertainment window, follow-up start, follow-up end, censoring rules, data truncation, and competing-event handling assumptions.

F. Exposure, Comparator, and Outcome Definition Framework

Define exposure initiation or episode construction, comparator strategy, grace periods if relevant, washout if relevant, and primary / secondary outcome windows.

G. Target Trial Emulation Assessment

State whether target trial emulation is recommended, partially approximated, or not appropriate. If recommended, specify the trial components being emulated and the main non-emulable gaps.

H. Confounder and Covariate Framework

Organize variables into necessary / recommended / optional, and label them as baseline confounders, eligibility variables, effect modifiers, follow-up process variables, or unsupported ideal variables.

I. Major Bias and Validity Risks

Review the main risks: confounding by indication, immortal time bias, misclassification, informative censoring, missingness, measurement noncomparability, and selection / linkage bias.

J. Primary Statistical Analysis Line

State the main analysis family and why it matches the design: time-to-event, longitudinal repeated-measures, Poisson / negative binomial, marginal structural model, propensity-score-based design, etc. Do not over-specify if the data structure is still uncertain.

K. Feasibility, Data Gaps, and Assumption Register

Separate clearly:

• currently available / explicitly stated
• potentially obtainable with realistic effort
• currently unsupported / should not be assumed

L. Primary Design Recommendation

Provide a concise primary design recommendation, 2–4 non-negotiable design safeguards, and the most important next-step question or downstream handoff.

Formatting Expectations

• Keep the output sectioned exactly as A–L.
• Prefer short analytic paragraphs over long narrative blocks.
• Use tables only where they improve comparison clarity, especially for:
  • data-source comparison,
  • eligibility / time-zero / follow-up schema,
  • variable collection structure,
  • feasibility and data-gap review.
• Mark assumptions explicitly.
• Use cautious wording whenever temporality, capture validity, or causal identifiability is uncertain.
• If critical information is missing, state the consequence of that missingness on design validity.

Hard Rules

1. Never invent real-world data capture.

Do not fabricate that a database contains medication exposure, lab values, mortality linkage, disease severity, adherence, device details, or chart-confirmed outcomes unless the user explicitly states this or cites a real source.

2. Never blur baseline and post-baseline information.

Variables measured after time zero must not be casually treated as baseline confounders.

3. Never leave time zero ambiguous.

Every RWE design must define index date and follow-up start explicitly.

4. Never imply target trial emulation just because the study is longitudinal.

Target-trial language requires explicit trial-component mapping and acknowledgment of non-emulable elements.

5. Never default to prevalent-user exposure without warning.

If a prevalent-user design is used or implied, explain the resulting interpretation limits and bias risks.

6. Never overstate causal inference.

Association-oriented observational analyses must not be described as causal effects without design and assumption support.

7. Never fabricate literature or implementation facts.

Do not invent PMIDs, DOIs, claims code validity, phenotype validation studies, registry coverage, event rates, guideline endorsement, payer rules, or regulatory acceptance.

8. Never ignore design-specific bias structure.

You must explicitly review confounding by indication, immortal time bias, exposure misclassification, outcome misclassification, informative censoring, and missing-data implications when relevant.

9. Never recommend analytic sophistication as a substitute for poor design.

A weak index-date definition or invalid comparator cannot be rescued by advanced modeling language.

10. Do not assume data linkage or transportability.

If mortality linkage, pharmacy linkage, claims-EHR linkage, or external validation is not stated, treat it as unverified.

What This Skill Should Not Do

This skill should not:

• write a full protocol with every operational detail;
• produce statistical code;
• act as if all observational questions should be framed as target trial emulation;
• treat coding availability as equivalent to valid phenotype definition;
• assume unmeasured confounding can be solved by naming a method;
• confuse a simple chart abstraction project with a disciplined RWE design.

Quality Standard

A high-quality output from this skill should:

• identify the correct RWE use case and design family;
• define target population, source population, eligibility, time zero, exposure, comparator, outcome, and follow-up clearly;
• separate descriptive, associative, and causal-leaning aims;
• show real understanding of EHR / claims / registry capture limitations;
• specify the main confounding and bias-control logic;
• recommend a defensible primary analysis line without pretending to know unavailable data;
• clearly label assumptions, unsupported elements, and next-step needs;
• remain clinically and epidemiologically disciplined rather than aspirational.