Nested case-control study
Can we sample a cohort efficiently at the times cases occur?
When to use this project
Use a nested case-control study when a defined cohort and event dates are available but measuring exposures or biomarkers for everyone is costly. For the incidence-density starter, sample controls from those still at risk when each incident case occurs.
How it differs
Unlike a general case-control study, the source cohort and risk-set membership are explicit. Unlike a case-cohort design, controls are selected at event times rather than as a baseline subcohort. A person can be a control more than once and later become a case.
Decisions before you start
- Define cohort entry, incident events and eligibility at each case time.
- Retain risk-set identifiers, sampling probabilities and any matching variables.
- Anchor exposure look-back to the case’s event time for all members of a sampled set.
How the flows work together
Each flow below links to its diagram, steps and tables. Flow order organizes the project; it does not imply that all work is strictly sequential. Data assessment, analysis planning and protocol refinement may inform one another.
1. Nested study overview
Overview · Question through sampled cohort analysis
Use this overview to state the purpose and link to detailed decisions. Keep a versioned protocol and decision register, and add evidence references for the rationale.
2. Source cohort construction
Selection · Define cohort entry and follow-up
Define time zero and the population at risk before counting events. Distinguish unique people from episodes and person-time. Death can be a competing event rather than ordinary loss to follow-up, depending on the outcome.
3. Risk-set control sampling
Selection · Sample eligible controls at events
At each incident event, eligible controls are members of the cohort still at risk. Repeated control selection and later case status are allowed by incidence-density sampling. Unique-person counts and sampling appearances must not be added as disjoint groups.
4. Exposure and covariate ascertainment
Data · Anchor measurements to index times
Anchor all members of a matched set to the case event time. Store person and set identifiers separately and preserve the date of specimens or measurements used to reconstruct prior exposure.
5. Matched analysis and sensitivity
Statistics · Respect sampled sets and assumptions
The analysis must respect risk-set sampling and matching. State any sampling weights or corrections and how repeated appearances enter uncertainty estimation. Conditional likelihood notation alone does not specify every sampling design.
Equations and statistical interpretation
These explanations describe notation and assumptions. Flow does not calculate these values.
Conditional likelihood contribution
Sⱼ is a sampled matched set containing one case c and its controls; x is a scalar exposure. A model combines contributions across sets. Under appropriate incidence-density sampling, exp(β) estimates a relative rate or hazard.
This illustrative form assumes sampling compatible with the conditional likelihood. Unequal sampling probabilities, additional covariates, repeated sampling and uncertainty need explicit treatment; the rare-disease approximation is not required for the rate-ratio interpretation.
Published example
Inspect the QResearch source population, case index dates, matching and exposure look-back. Separate unique participants from their contribution to matched comparisons.
This publication illustrates a study design, not an endorsement of every method or a reproduction of its results. Follow its protocol, supplement and update history when studying the example.
Hypothetical scenario
A biobank wants to study a stored blood biomarker and incident stroke but can assay only a subset of stored samples.
- Nested study overview: Define the source cohort, stroke outcome and biomarker question.
- Source cohort construction: Specify cohort entry and observation until stroke, competing events or censoring.
- Risk-set control sampling: Sample eligible controls at each stroke time, retaining repeated appearances.
- Exposure and covariate ascertainment: Assay pre-event specimens using consistent methods and index dates.
- Matched analysis and sensitivity: Use matched risk-set analysis and report the number of unique people separately from sampled appearances.
Deliver a populated protocol, decision log, data specification, and planned outputs. Enter numerical findings only after analysis and verification. Keep decisions made before seeing results distinguishable from later amendments.
Sources
- STROBE checklist for case-control studies
- STROBE checklist for cohort studies
- RECORD checklist for studies using routinely collected health data
- HMA–EMA Catalogue of RWD studies: registration and protocol guidance
- Pearce (2016): Analysis of matched case-control studies
- Rodrigues and Kirkwood (1990): case-control sampling and measures of relative incidence
Source check: 2026-09-17. Record the version of each reporting or appraisal tool used in your actual protocol.
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