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Case-control designs in the

study of common diseases

& alternative designs

JC Desenclos, F Simn, A Moren

EPIET, Menorca, Spain, October 9, 2006


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Case-control studies

Objective: compare exposure in cases and inpopulation 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


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Cohort populations origin of cases and controls

Currently at risk

Cases exposed

CE

Start of study End of study

Currently at risk

Person years at risk

(pyrsE)

Occurrence of

New case

Person years at risk

(pyrsU)

Initially

at

Risk

NE

Initially

at

Risk

Nu

Exposed population (E)

Unexposed population (U)Cases unexposed

CU

Still at risk

NE- CE

Still at risk

Nu- Cu

Rodrigues L et al. Int J Epidemiol. 1990;19:20


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Origin of controls and measures of association

Inclusive (case-coh

Concurrent (densit

ExcIusive (traditionNo cases at the end

of the study period

People at risk when

the case appears

Total Study Cohort

origin of cases

Origin of SampledControls

AlternativeFormulation

Formulation

Odds Ratio

Relative Rate

Density Incidence Ratio

Relative Risk

Cumulative

Incidence Ratio

EstimatedMeasure of Association

UU

EE

NC

NC

UU

EE

pyrsC

pyrsC

UUU

EEE

CNC

CNC

EU

UE

NC

NC

EU

UE

pyrsC

pyrsC

)CN(C

)CN(C

EEU

UUE


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Inclusive design (case-cohort): OR estimates R

Controls representative proportion of total population atrisk 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 thesame time period (ex: OB of gastro-enteritis)


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Concurrent design: OR estimates Relative Rate

Controls representative proportion of population at riskwhen the case appears (concurrent selection)

Represent person-time at risk in exposed and unexpose

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 unitselecting 3 controls per case among those at risk of

infection at the same time as the case occurs


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Traditional design (exclusive)

Controls sampled from population still at risk at the endof the study period

OREof cases to controls = ORDof exposed to non

exposed

OR good estimate of relative risk and relative rate if

disease is rare


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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 = 0,2

RR = 3,04

Case

(n = 50)

Control

(n = 50)

Yes 37 19

No 13 31

OR = 4,64 (CI 95%: 1.811.9)

Case

(n = 50)

Control

(n = 50)

Yes 37 24

No 13 26

OR = 3,08 (CI 95%: 1.27.8)

Exclusive design Case cohort design (inclusive)


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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


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Alternative designs

Case to Case

Case - Crossover

Case-time-control


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Case to case design


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Two listeriosis outbreaks of 2 distinct PFGE

patterns, France, 1999-2000

0

1

2

3

4

5

6

7

8

9

10

40 42 44 46 48 50 52 2 4 6 8

Outbreak 2 (32 cases)


October November December January February March

1999 2000

Cases

de Valk H et al.Am J Epidemiol2001;154:944

Li t i i tb k d di b


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Listeriosis outbreak and sporadic cases by

routine PFGE pattern, France, 1999-2000

0

2

4

6

8

10

12

14

40 42 44 46 48 50 52 2 4 6 8

Sporadic cases




1999 2000

Cases


C l l d di f


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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

40 42 44 46 48 50 52 2 4 6 8

Other sporadic cases

Sporadic cases used as controls (N = 32)

Outbreak 2 (N = 32)

Outbreak 1 (N = 10)


1999 2000

Cases

de Valk H et al.Am J Epidemiol2001;154:944-5


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Food consumption multivariate analysis on 29 case-patients

and 32 control-patients. Outbreak of listeriosis

France, December 1999 - February 2000.

Food consumed

AdjustedOdds 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



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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


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Case-Crossover design


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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


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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,

F d f i f ti i th i k d


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Food exposures from menu information in the risk and

control periods and matched OR for 17 nosocomial case

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 - 46,9Ham

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 bleu0 (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


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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


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Case-time control design


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Between period confounding

ORa/ORb= OR of exposure adjusted for time trend

Cyclical variation of exposure

Control period

Risk period

onset

Cases : ORa

for the

exposure and the

time trend

Controls: ORbfor the tim

trend

Folic acid antagonists (FAA) in pregnancy and


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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 2nd& 3rd month of pregnancy

Case-crossover study for cases and controls independently

OR=1.0 (0.5-2

OR= 0.3 (0.2-0

Case-time control

OR = 1/0.3 = 2.9 (1.2-7.2

-2 -1 1 2 3 4 5 6 7 8 9Cases:

-2 -1 1 2 3 4 5 6 7 8 9Controls:

ORcrude=2.3 (1.4-3.9)

Control

period

Risk

period

Delivery

Hernandez-Diaz S.Am J Epidemiol 2003;158:385-39


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Conclusions

If you do not need that OR estimates correctly the RRthen: 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


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Find the foot fitting the glass slipper


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References

1. Rodrigues L et al. Int J Epidemiol1990;19:205-13

2. de Valk H et al.Am J Epidemiol2001;154:944-50

3. Haegebaert S et al. Epidemiol infect2003;131,809-813

4. Hernandez-Diaz S et al.Am J Epidemiol2003;158:385-39

5. Rothman KJ; Epidemiology: an introduction. Oxford

University Press 2002, 73-93

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