design penelitian alternatif
TRANSCRIPT
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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)
Outbreak 1 (10 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
Outbreak 2 (32 cases)
Outbreak 1 (10 cases)
October November December January February March
1999 2000
Cases
de Valk H et al.Am J Epidemiol2001;154:944
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)
October November December January February March
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
de Valk H et al.Am J Epidemiol2001;154:944
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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