Case-control designs in the

study of common diseases

& alternative designs
JC Desenclos, F Simn, A Moren

EPIET, Menorca, Spain, October 9, 2006
Case-control studies
Objective: compare exposure in cases and in
population origin of cases
Sample of that population as controls
Representative as for the exposure of interest
Random sampling, regardless exposure or disease
status
Meaning of OR differs according to different control
sampling schemes

Cohort populations origin of cases and controls
Currently at risk
Cases exposed
C
E
Start of study
End of study
Currently at risk
Person years at risk
(pyrs
E
)
Occurrence of
New case
Person years at risk
(pyrs
U
)

Initially
at
Risk
N
E
Initially
at
Risk
N
u
Exposed population (E)
Unexposed population (U)
Cases unexposed
C
U
Still at risk
N
E
- C
E
Still at risk
N
u
- C
u
Rodrigues L et al. Int J Epidemiol. 1990;19:205-13.
Origin of controls and measures of association
Inclusive (case-cohort)
Concurrent (density)
ExcIusive (traditional)
No cases at the end
of the study period
People at risk when
the case appears
Total Study Cohort
origin of cases
Origin of Sampled
Controls
Alternative
Formulation



Formulation
Odds Ratio
Relative Rate
Density Incidence Ratio
Relative Risk
Cumulative
Incidence Ratio
Estimated
Measure of Association
U U
E E
N C
N C
U U
E E
pyrs C
pyrs C
U U U
E E E
C N C
C N C
-
-
E U
U E
N C
N
C


E U
U E
pyrs C
pyrs C


) C N ( C
) C N ( C
E E U
U U E
-
-
Inclusive design (case-cohort): OR estimates RR
Controls representative proportion of total population at
risk at the beginning of the study period
including cases
Sampling independent of the exposure and outcome
A case may also be a control
No need to asses disease status among controls
Reasonable if source population is followed up for the
same time period (ex: OB of gastro-enteritis)
Concurrent design: OR estimates Relative Rates
Controls representative proportion of population at risk
when the case appears (concurrent selection)
Represent person-time at risk in exposed and unexposed
A control can be a case later
A person can be a control for several cases
Matched analysis because of time matching
Example: Prolonged OB of hepatitis C in a dialysis unit
selecting 3 controls per case among those at risk of
infection at the same time as the case occurs
Traditional design (exclusive)
Controls sampled from population still at risk at the end
of the study period
OR
E
of cases to controls = OR
D
of exposed to non
exposed
OR good estimate of relative risk and relative rate if
disease is rare

Example: waterborne OB of gastro-enteritis
Water
consumption
Ill Not ill Total
Yes 148 188 336
No 54 319 373
Total 202 507 709
Attack rate = 0,29
RR = 3,04

Case
(n = 50)
Control
(n = 50)
Yes 37 19
No 13 31
OR = 4,64 (CI 95%: 1.8 11.9)
Case
(n = 50)
Control
(n = 50)
Yes 37 24
No 13 26
OR = 3,08 (CI 95%: 1.2 7.8)
Exclusive design Case cohort design (inclusive)
Which design is best?
Rear diseases: similar results
Common diseases:
Non-recurrent disease with high incidence
Inclusive design (case-cohort): ORRR
Highly incident and recurrent disease or when probability
of exposure changes along time or when the effect of
exposure may change along time
Concurrent design: ORRRate
Alternative designs
Case to Case

Case - Crossover



Case-time-control
Case to case design
Two listeriosis outbreaks of 2 distinct PFGE
patterns, France, 1999-2000
0
1
2
3
4
5
6
7
8
9
10
4
0
4
2
4
4
4
6
4
8
5
0
5
2 2 4 6 8
Outbreak 2 (32 cases)
Outbreak 1 (10 cases)
October November December January February March
1999 2000
Cases
de Valk H et al. Am J Epidemiol 2001;154:944-50
Listeriosis outbreak and sporadic cases by
routine PFGE pattern, France, 1999-2000
0
2
4
6
8
10
12
14
4
0
4
2
4
4
4
6
4
8
5
0
5
2 2 4 6 8
Sporadic cases
Outbreak 2 (32 cases)
Outbreak 1 (10 cases)
October November December January February March
1999 2000
Cases
de Valk H et al. Am J Epidemiol 2001;154:944-50
Controls selected among sporadic cases for
the study of outbreak 2, France, 1999-2000
(Source: InVS-CNR)
0
2
4
6
8
10
12
14
4
0
4
2
4
4
4
6
4
8
5
0
5
2 2 4 6 8
Other sporadic cases
Sporadic cases used as controls (N = 32)
Outbreak 2 (N = 32)
Outbreak 1 (N = 10)
October November December January February March
1999 2000
Cases
de Valk H et al. Am J Epidemiol 2001;154:944-50
Food consumption multivariate analysis on 29 case-patients
and 32 control-patients. Outbreak of listeriosis
France, December 1999 - February 2000.


Food consumed
Adjusted
Odds ratio*

95% CI

p
Pork tongue in jelly 75,5 4,7 1216,0 0,002
Cooked ham 7,1 0,7 71,8 0,1
Pt de campagne 8,9 1,7 46,1 0,009

*adjusted for underlying condition, pregnancy status and date of interview
by logistic regression

de Valk H et al. Am J Epidemiol 2001;154:944-50
Case-to-case study design
Controls = patient with non epidemic subtypes
from same source population
same susceptibility (underlying diseases)
included as cases if they had the OB strain
Information readily available
Reduces the information (recall) bias
Food-exposure collected before status is known
Case-Crossover design
September October November December January
Community cases
Hospital 1
Cases Hospital 2
8 Hospital 3
7 Hospital 4
6 Hospital 5
5
Nursing home
4
3
2
1
37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 01
Week
Alert
Haegebaert S et al. Epidemiol infect 2003;130,1-5
Hospital and community OB of S. Typhimurium
Case-Crossover design
Same person taken as control (matched design)
Compare exposure in a risk period to a prior control
period of the same duration
Matched analysis (discordant periods)
Evaluates exposures that
vary from time to time within a person
triggering a short term effect, with abrupt onset
Key issue : the definition of the risk period

Case crossover design applied to a
prolonged S. Typhimurium outbreak
Control period
72 hours
Wash out
period
48 hours
Risk period
72 hours
Discordant pair ( 1,0 )
Concordant pair ( 1,1 )
Discordant pair ( 0,1 )
Concordant pair ( 0,0 )
Exposure
Onset
Haegebaert S et al. Epidemiol infect 2003;130,1-5
Food exposures from menu information in the risk and
control periods and matched OR for 17 nosocomial cases
Foods
Risk
period
Control
period
Matched
OR
95%
C.I.
Exposed (%) Exposed (%)
Veal 5 (29) 1 (6) 5 0,6 - 236,5
Pork 4 (23) 6 (35) 0,6 0,1 - 3,1
Hamburgers 13 (77) 5 (29) 5 1,1 - 46,9
Ham 6 (35) 5 (29) 1,5 0,2 - 17,9
Pt 2 (12) 2 (12) 1 0,01 - 78,5
Chicken 2 (12) 3 (18) 1 0,01 - 78,5
Turkey 11 (65) 6 (35) 2,67 0,7 - 15,6
Cordon bleu 0 (0) 2 (12) undefined -
Lamb sausages 2 (12) 0 (0) -
Poultry sausages 2 (12) 0 (0) -
undefined
undefined
Haegebaert S et al. Epidemiol infect 2003;130,1-5
Case-Crossover design
For extended source outbreaks
No need of a control group
One to several control-periods per risk period
Controls for between-persons confounding
Very sensitive to recall bias unless data have been
collected prior to onset (administrative databases)
May be biased by time trend in exposure: between-
period confounding
Case-time-control
Case-time control design
Between period confounding
OR
a
/OR
b
= OR of exposure adjusted for time trend
Cyclical variation of exposure
Control period Risk period
onset
Cases : OR
a
for the
exposure and the
time trend

Controls: OR
b
for the time
trend
Folic acid antagonists (FAA) in pregnancy and
congenital cardiovascular defects (CCD)
Case: Woman who had a child with CCD (N=3870)
Control: Woman who had a child without CCD (N=8387)
Exposure: FAA during 2
nd
& 3
rd
month of pregnancy
Case-crossover study for cases and controls independently
OR=1.0 (0.5-2.0)
OR= 0.3 (0.2-0.6)
Case-time control
OR = 1/0.3 = 2.9 (1.2-7.2)
-2 -1 1 2 3 4 5 6 7 8 9
Cases:
-2 -1 1 2 3 4 5 6 7 8 9
Controls:
OR
crude
=2.3 (1.4-3.9)
Control
period
Risk
period
Delivery
Hernandez-Diaz S. Am J Epidemiol 2003;158:385-391
Conclusions
If you do not need that OR estimates correctly the RR
then: traditional design
Otherwise, if you need OR RR, identify the best
design for each situation
If you can not find or want to avoid controls
Case to case
Case-crossover
Find the foot fitting the glass slipper
References
1. Rodrigues L et al. Int J Epidemiol 1990;19:205-13

2. de Valk H et al. Am J Epidemiol 2001;154:944-50

3. Haegebaert S et al. Epidemiol infect 2003;131,809-813

4. Hernandez-Diaz S et al. Am J Epidemiol 2003;158:385-391

5. Rothman KJ; Epidemiology: an introduction. Oxford
University Press 2002, 73-93