What do case-control studies estimate?

Research meeting ISPM – July 16th 2007

Mirjam J. Knol, Jan P. Vandenbroucke, Pippa Scott, Matthias Egger

A survey of 150 published studies

Introduction

Case-control design

• 1 of 3 main epidemiological designs

• First use 1926

• Widely used about 348,000 in Medline

• Efficient design if:

- Outcome is rare

- Exposure is expensive to measure

- Results are quickly needed

Introduction

Definition case-control study

• Study of persons with the disease (or other outcome variable) of

interest (cases) and a suitable control group of persons without

the disease (controls), where the history of exposure to a

suspected risk or preventive factor is compared between cases

and controls

Introduction

Interpretation of estimated odds ratio depends on:

• Nature of cases

- Prevalent cases

- Incident cases

• Type of source population

- Fixed cohort

- Dynamic population (stable population)

• Sampling design for controls

- From population at risk end of study period

- From population at risk beginning of study period

- From person-time at risk

Introduction

Fixed cohort

• A cohort in which no additional membership is allowed and in

which immigration cannot occur, i.e. it is fixed by being present at

some defining event

Introduction

Fixed cohort

• A cohort in which no additional membership is allowed and in

which immigration cannot occur, i.e. it is fixed by being present at

some defining event

Dynamic population

• A population that gains and loses members, i.e. a population in

which emigration and immigration may occur over the risk period

Introduction

Fixed cohort

• A cohort in which no additional membership is allowed and in

which immigration cannot occur, i.e. it is fixed by being present at

some defining event

Dynamic population

• A population that gains and loses members, i.e. a population in

which emigration and immigration may occur over the risk period

Stable population

• A population in which the distributions of all variables of interest

including exposures are not changing over time

Introduction

End of study period (exclusive / traditional) – fixed cohort

• Controls are sampled from the population still at risk at the end of

the study period.

Introduction

End of study period (exclusive / traditional) – fixed cohort

• Controls are sampled from the population still at risk at the end of

the study period.

Beginning of study period (inclusive) – fixed cohort

• Controls are sampled from all individuals in the study population

at risk at the beginning of the study period.

Introduction

End of study period (exclusive/traditional) – fixed cohort

• Controls are sampled from the population still at risk at the end of the

study period.

Beginning of study period (inclusive) – fixed cohort

• Controls are sampled from all individuals in the study population at risk

at the beginning of the study period.

Person-time

• Concurrent / matched on time – fixed and dynamic cohort

- Controls are sampled from those at risk at the time each case is

diagnosed.

• Not matched on time – dynamic cohort

- Controls are sampled from those at risk at a certain point in time

Introduction

Fixed cohort

End of study period

Assumption:Rare disease

Risk ratio

Beginning of study period

Assumption:Censoring

unrelated to exposure

Risk ratio

Concurrent

Rate ratio

Dynamic population

Matched on time

Not matched on time

Assumption:Stable population

Rate ratio

Rate ratio

Incident cases

Prevalent cases

Prevalence odds ratio

Objective

To conduct a survey of published case-control studies to examine

what was estimated by the odds ratio

Methods

Literature search

• Combining journal names and Mesh term ‘Case-control studies’

• From March 2007 backwards in time

• Total of 150 articles

Methods

Literature search

• Combining journal names and Mesh term ‘Case-control studies’

• From March 2007 backwards in time

• Total of 150 articles

Selected journals

• 5 general medicine journals 10 articles each- Annals of internal medicine, BMJ, JAMA, Lancet, NEJM

• 5 general epidemiology journals 10 articles each- AJE, Epidemiology, IJE, JCE, JECH

• 10 clinical specialist journals 5 articles each- AJRCCM, AGP, Arthritis and rheumatism, Blood, Circulation, CID, Diabetes Care,

JAGS, JNCI, Pediatrics

Methods

Data extraction

• Standardized form

- General items: sample size, exposure, outcome

- Specific items: type of source population and sampling design

• Two reviewers (MK and PS)

Methods

Data extraction

• Standardized form

- General items: sample size, exposure, outcome

- Specific items: type of source population and sampling design

• Two reviewers (MK and PS)

Data-analysis

• Frequencies of general and specific items

• Fisher‘s Exact test

• Use of flow chart

Results

General medicine articles (n=50)

General epidemiologyarticles (n=50)

Clinical specialistarticles (n=50)

Number of cases 494 (26-13,556) 611 (42-22,225) 282 (18-21,169)

Number of controls 846 (27-135,386) 1204 (85-180,220) 585 (20-423,128)

Source of cases

Population based 31 31 26

Hospital based 12 15 21

Both 1 1 0

Unclear 6 3 3

Source of controls

Population based 36 36 29

Hospital based 8 8 10

Both 2 2 2

Unclear 4 4 9

Results

General medicine articles (n=50)

General epidemiologyarticles (n=50)

Clinical specialistarticles (n=50)

Number of cases 494 (26-13,556) 611 (42-22,225) 282 (18-21,169)

Number of controls 846 (27-135,386) 1204 (85-180,220) 585 (20-423,128)

Source of cases

Population based 31 31 26

Hospital based 12 15 21

Both 1 1 0

Unclear 6 3 3

Source of controls

Population based 36 36 29

Hospital based 8 8 10

Both 2 2 2

Unclear 4 4 9

Results

General medicine articles (n=50)

General epidemiologyarticles (n=50)

Clinical specialistarticles (n=50)

Number of cases 494 (26-13,556) 611 (42-22,225) 282 (18-21,169)

Number of controls 846 (27-135,386) 1204 (85-180,220) 585 (20-423,128)

Source of cases

Population based 31 31 26

Hospital based 12 15 21

Both 1 1 0

Unclear 6 3 3

Source of controls

Population based 36 36 29

Hospital based 8 8 10

Both 2 2 2

Unclear 4 4 9

Results

General medicine articles(n=50)

General epidemiologyarticles(n=50)

Clinical specialistarticles(n=50)

Incident cases 46 45 34

Fixed cohort 10 3 11

End 4 1 6

Beginning 0 0 1

Concurrent 3 1 2

Unclear 3 1 2

Dynamic population 34 41 20

Matched on time 9 8 3

Not matched on time 7 4 3

Unclear 18 28 14

Unclear 2 1 3

Prevalent cases 2 2 6

Unclear 2 3 10

Results

General medicine articles(n=50)

General epidemiologyarticles(n=50)

Clinical specialistarticles(n=50)

Incident cases 46 45 34

Fixed cohort 10 3 11

End 4 1 6

Beginning 0 0 1

Concurrent 3 1 2

Unclear 3 1 2

Dynamic population 34 41 20

Matched on time 9 8 3

Not matched on time 7 4 3

Unclear 18 28 14

Unclear 2 1 3

Prevalent cases 2 2 6

Unclear 2 3 10

Results

General medicine articles(n=50)

General epidemiologyarticles(n=50)

Clinical specialistarticles(n=50)

Incident cases 46 45 34

Fixed cohort 10 3 11

End 4 1 6

Beginning 0 0 1

Concurrent 3 1 2

Unclear 3 1 2

Dynamic population 34 41 20

Matched on time 9 8 3

Not matched on time 7 4 3

Unclear 18 28 14

Unclear 2 1 3

Prevalent cases 2 2 6

Unclear 2 3 10

Results

General medicine articles(n=50)

General epidemiologyarticles(n=50)

Clinical specialistarticles(n=50)

Incident cases 46 45 34

Fixed cohort 10 3 11

End 4 1 6

Beginning 0 0 1

Concurrent 3 1 2

Unclear 3 1 2

Dynamic population 34 41 20

Matched on time 9 8 3

Not matched on time 7 4 3

Unclear 18 28 14

Unclear 2 1 3

Prevalent cases 2 2 6

Unclear 2 3 10

Results

General medicine articles(n=50)

General epidemiologyarticles(n=50)

Clinical specialistarticles(n=50)

Incident cases 46 45 34

Fixed cohort 10 3 11

End 4 1 6

Beginning 0 0 1

Concurrent 3 1 2

Unclear 3 1 2

Dynamic population 34 41 20

Matched on time 9 8 3

Not matched on time 7 5 3

Unclear 18 28 14

Unclear 2 1 3

Prevalent cases 2 2 6

Unclear 2 3 10

Results

What does the odds ratio estimate?

• Risk ratio if rare disease 11 (4/1/6)

• Risk ratio if exposure unrelated to censoring 1 (0/0/1)

• Rate ratio 26 (12/9/5)

• Rate ratio if stable population 75 (25/33/17)

• Prevalence odds ratio 10 (2/2/6)

• Unclear 27 (7/5/15)

Total 150 (50/50/50)

Significant difference between type of journal

Conclusions

• Majority of studies uses dynamic population (63%)

• Many studies do not explicitly say when controls were sampled

• Most studies (50%) estimate rate ratio if stable population

• Authors do not discuss stability of exposure

• Rare disease assumption only needed in few studies (7%)

• Teaching should focus more on assumption of stability of exposure

• Authors do not report what odds ratio estimates are they aware

what their odds ratio estimates?

• Better reporting is needed STROBE

Thank you all

for the nice time!