Case Control Design - Sampling Controls at Follow-up

Lead Author(s): Jeff Martin, MD

Summary of Case-Control Sampling

Design Sampling Measure of Association
Case-cohort Entire cohort at baseline risk ratio
Incidence-density Non-cases at time of diagnosis rate ratio
Prevalent Case Control Non-cases at single point in time

odds ratio

Definition of Prevalent Controls

Sampling only non-cases in a primary or secondary study base

This case-control design uses prevalent controls at follow-up . Odds ratio approximates risk ratio only if disease occurrence is rare

This sampling is the classic instance of needing the rare disease assumption assumption that many text books discuss

Diagram Using Prevalent Controls at Follow-up

In the diagram below, one can see prevalent controls drawn from the non-diseased individuals at follow-up.


Problems with Using Prevalent Controls at Follow-up

This is the design that most neophytes are drawn to. It is the least desirable of the three types of control sampling but it used to be the most common. That may no longer be the case as researchers are becoming more sophisticated about case-control design.


Limitation of Study Controls-FIRST PROBLEM

So even if all the cases are captured as in the schematic, So unlike the case-cohort and the case-control with incidence density sampling designs, Because the cases are excluded,

Bias in Waiting until Follow-up- SECOND PROBLEM

As you can see one of the problems with this design is that there is an obvious source of potential bias in waiting until the end of follow-up to select controls Furthermore, losses to follow-up and deaths also make this group of controls not very representative of the population that gave rise to the cases. If those factors are associated with both your predictor variable and your outcome, the measure of association will be biased.

Inability to Calculate the Risk Ratio -THIRD PROBLEM

In case control design, Case Control Design: OR equals RR.

0527_1_a_cases.JPG ratio is known in all case-control designs

BUT sampling only non-cases cannot get unbiased estimate of 0527_1_b_N.JPG

The ratio of exposed to unexposed in the whole cohort

Example of Inability to Calculate the Risk Ratio

So using prevalent controls, you get:

Example Showing Incorrect Odds Ratio

If you look at the odds calculation:

ad/bc = OR
IN this example,

One quarter of the cohort has been diagnosed with disease during the cohort follow-up Since the original cohort was divided 50/50 by exposure and the In other words, the odds of exposure in the eligible controls will be 2/3 and the odds ratio will be 4 divided by 2/3 = 6.0.

These numbers use everyone in the cohort and the case-control study will only use a sample of 150 remaining without disease but as they will be sampled independently of exposure status the ratio of 2/3 also applies to any random sample of controls.

Thus the OR in this example is much larger than the risk ratio and cannot be considered even an approximation of it.

Prevalent Controls - Rare Disease Assumption-FOURTH PROBLEM

If controls are selected among those without disease at time of study (+/- prevalent cases), the OR approximates risk ratio only with the

Case Control with Low Incidence-PROBLEM


If the disease only removes a few persons from the original cohort, It follows that estimating N0/N1 by using prevalent controls

Example of Case Control with Low Incidence

IN this example, Assuming that the incidence of disease was 2.5% (5 out of 200 developed disease), The somewhat arbitrary rule of thumb of incidence below 10% is sometimes given as what is meant by a rare disease

If the incidence were 10% (16 exposed cases and 4 unexposed cases),

CAVEAT: Sampling Non-cases May Introduce Bias-PROBLEM

Disease may remove few from study base sampled for controls, but other sources of loss to* *loss to follow-up can bias control group.

Losses to follow-up and deaths among potential controls from the study base givingrise to the cases affect who is available at one point in time.