Case-control designs in the study of common diseases & alternative designs

JC Desenclos, F Simón, 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 Exposed population (E) Initially at Risk N E

Person years at risk (pyrs E )

Currently at risk

Cases exposed C E Still at risk N E - C E Unexposed population (U) Initially at Risk N u

Person years at risk (pyrs U )

Currently at risk

Cases unexposed C U Still at risk N u - C u Start of study Occurrence of New case End of study

Rodrigues L et al. Int J Epidemiol. 1990;19:205-13.

Origin of controls and measures of association Origin of Sampled Controls Total Study Cohort origin of cases People at risk when the case appears No cases at the end of the study period Formulation C E N E C

U

N U C E C U pyrs E pyrs U Alternative Formulation C E C U



N U



N E Estimated Measure of Association Relative Risk Cumulative Incidence Ratio Inclusive (case-cohort) C E C U

 

pyrs pyrs U E Relative Rate Density Incidence Ratio Concurrent (density) C C E U N E N U

-

C E C U C E C U



( N U



( N E

-

C U C E ) ) Odds Ratio ExcIusive (traditional)

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 exposed of exposed to non • OR good estimate of relative risk and relative rate if disease is rare

Example: waterborne OB of gastro-enteritis Water consumption Yes No Total Exclusive design Yes Case (n = 50) 37 Control (n = 50) 19 No 13 31 Ill 148 54 202 OR = 4,64 (CI 95%: 1.8 – 11.9) Not ill Total 188 319 507 336 373 709 Attack rate = 0,29 RR = 3,04 Case cohort design (inclusive) Yes Case (n = 50) 37 Control (n = 50) 24 No 13 26 OR = 3,08 (CI 95%: 1.2 – 7.8)

Which design is best?

• Rear diseases: similar results • Common diseases: • Non-recurrent disease with high incidence – Inclusive design (case-cohort): OR  RR • 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: OR  RRate

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 Cases 10 4 3 2 1 0 9 8 7 6 5 Outbreak 2 (32 cases) Outbreak 1 (10 cases) 40 42 44 46 48 50 52 2 4 6 8 October November December January February March 1999 2000

de Valk H et al.

Am J Epidemiol

2001;154:944-50

Cases Listeriosis outbreak and sporadic cases by routine PFGE pattern, France, 1999-2000 14 Sporadic cases 12 Outbreak 2 (32 cases) 10 Outbreak 1 (10 cases) 8 6 4 2 0 40 42 44 46 48 50 52 2 4 6 8 October November December January February March 1999 2000

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) Cases 14 Other sporadic cases Sporadic cases used as controls (N = 32) 12 Outbreak 2 (N = 32) 10 Outbreak 1 (N = 10) 8 6 4 2 0 40 42 44 46 48 50 52 2 4 6 8 October November December January February March 1999 2000

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 Pork tongue in jelly Cooked ham Pâté de campagne Adjusted Odds ratio* 75,5 7,1 8,9 95% CI 4,7 – 1216,0 0,7 – 71,8 1,7 – 46,1 p 0,002 0,1 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 »

Hospital and community OB of S. Typhimurium 7 6 5 4 3 2 1 8 Cases Alert Community cases Hospital 1 Hospital 2 Hospital 3 Hospital 4 Hospital 5 Nursing home 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 01 September October November December Week January

Haegebaert S et al.

Epidemiol infect

2003;130,1-5

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 Onset Discordant pair ( 0,1 ) Discordant pair ( 1,0 ) Concordant pair ( 1,1 ) Concordant pair ( 0,0 ) Exposure

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 Veal Pork Hamburgers Ham Pâté Chicken Turkey “Cordon bleu” Lamb sausages Poultry sausages Risk period Exposed (%) 5 (29) 4 (23) 13 (77) 6 (35) 2 (12) 2 (12) 11 (65) 0 (0) 2 (12) 2 (12) Control period Exposed (%) Matched OR 95% C.I.

1 (6) 6 (35) 5 (29) 5 (29) 2 (12) 3 (18) 6 (35) 2 (12) 0 (0) 0 (0) 5 0,6 5 1,5 1 1 2,67 undefined undefined undefined 0,6 - 236,5 0,1 - 3,1 1,1 - 46,9 0,2 - 17,9 0,01 - 78,5 0,01 - 78,5 0,7 - 15,6 -

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 Cyclical variation of exposure Controls: OR b trend for the time Cases : OR a for the exposure and the time trend Control period Risk period onset OR a /OR b = OR of exposure adjusted for 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 Delivery Cases: -2 -1 1 2 3 4 5 6 7 8 9 OR=1.0 (0.5-2.0) Controls: Control period Risk period Case-time control OR = 1/0.3 = 2.9 (1.2-7.2) -2 -1 1 2 3 4 5 6 7 8 9 OR= 0.3 (0.2-0.6) OR crude =2.3 (1.4-3.9)

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  design for each situation RR, identify the best • 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