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 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 epidemiology articles (n=50) Clinical specialist articles (n=50) Number of cases494 (26-13,556)611 (42-22,225)282 (18-21,169) Number of controls846 (27-135,386)1204 (85-180,220)585 (20-423,128) Source of cases Population based31 26 Hospital based Both110 Unclear633 Source of controls Population based36 29 Hospital based8810 Both222 Unclear449

Results General medicine articles (n=50) General epidemiology articles (n=50) Clinical specialist articles (n=50) Number of cases494 (26-13,556)611 (42-22,225)282 (18-21,169) Number of controls846 (27-135,386)1204 (85-180,220)585 (20-423,128) Source of cases Population based31 26 Hospital based Both110 Unclear633 Source of controls Population based36 29 Hospital based8810 Both222 Unclear449

Results General medicine articles (n=50) General epidemiology articles (n=50) Clinical specialist articles (n=50) Number of cases494 (26-13,556)611 (42-22,225)282 (18-21,169) Number of controls846 (27-135,386)1204 (85-180,220)585 (20-423,128) Source of cases Population based31 26 Hospital based Both110 Unclear633 Source of controls Population based36 29 Hospital based8810 Both222 Unclear449

Results General medicine articles (n=50) General epidemiology articles (n=50) Clinical specialist articles (n=50) Incident cases Fixed cohort10311 End416 Beginning001 Concurrent312 Unclear312 Dynamic population Matched on time983 Not matched on time743 Unclear Unclear 213 Prevalent cases226 Unclear2310

Results General medicine articles (n=50) General epidemiology articles (n=50) Clinical specialist articles (n=50) Incident cases Fixed cohort10311 End416 Beginning001 Concurrent312 Unclear312 Dynamic population Matched on time983 Not matched on time743 Unclear Unclear 213 Prevalent cases226 Unclear2310

Results General medicine articles (n=50) General epidemiology articles (n=50) Clinical specialist articles (n=50) Incident cases Fixed cohort10311 End416 Beginning001 Concurrent312 Unclear312 Dynamic population Matched on time983 Not matched on time743 Unclear Unclear 213 Prevalent cases226 Unclear2310

Results General medicine articles (n=50) General epidemiology articles (n=50) Clinical specialist articles (n=50) Incident cases Fixed cohort10311 End416 Beginning001 Concurrent312 Unclear312 Dynamic population Matched on time983 Not matched on time743 Unclear Unclear 213 Prevalent cases226 Unclear2310

Results General medicine articles (n=50) General epidemiology articles (n=50) Clinical specialist articles (n=50) Incident cases Fixed cohort10311 End416 Beginning001 Concurrent312 Unclear312 Dynamic population Matched on time983 Not matched on time753 Unclear Unclear 213 Prevalent cases226 Unclear2310

Results What does the odds ratio estimate? Risk ratio if rare disease 11 (4/1/6) Risk ratio if exposure unrelated to censoring1 (0/0/1) Rate ratio 26 (12/9/5) Rate ratio if stable population 75 (25/33/17) Prevalence odds ratio10 (2/2/6) Unclear27 (7/5/15) Total150 (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!