1. Variants of the case- control design Katharina Alpers EPIET introductory course, Menorca (Spain), 10 October, 2011

2. 2 Overview Design of case-control studies Exclusive (traditional) Inclusive (case-cohort) Concurrent (density) Case-to-case Case-crossover

3. 3 Cohort study: incidence risk ExposureTotalCasesRisk (%)Risk ratio Exposed1004040%4 Unexposed1001010%Reference Total2005025% Cumulative incidence Number of cases/population initially at risk

4. 4 Cohort study: incidence rate ExposureTotal Time CasesRate per 100 p.y. Rate ratio Exposed1500 p.y402.7/100 p.y.2.7 Unexposed1000 p.y.101.0/100 p.y.Reference Total2500 p.y.502.0/100 p.y. Incidence density Number of cases/sum of times at risk

5. 5 Cohort study Currently at risk Cases exposed C e Start of study End of study Currently at risk Person years at risk of exposed (pyar e ) Person years at risk of unexposed (pyar 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 Time Rodrigues L et al. Int J Epidemiol. 1990;19:205-13.

6. 6 Case-control studies Efficient for rare diseases Compare exposure in cases to sample of population –sampled from source population that gives rise to cases –representative of exposure in source population Sampling independent of exposure status Different control sampling schemes

7. 7 Cohort study Cases exposed End of study Exposed population (E) Unexposed population (U) Cases unexposed Still at risk Still at risk Time Rodrigues L et al. Int J Epidemiol. 1990;19:205-13. Cases Sample of non cases Traditional case-control design (exclusive)

8. 8 Traditional design Controls sampled from population still at risk at the end of the study period Disease odds ratio = exposure odds ratio If disease is rare: OR good estimate of risk ratio and rate ratio

9. 9 Cohort study Cases exposed End of study Exposed population (E) Unexposed population (U) Cases unexposed Still at risk Still at risk Time Rodrigues L et al. Int J Epidemiol. 1990;19:205-13. Cases Sample of source population Inclusive design: Case cohort study

10. 10 Case-cohort design Control group estimates the proportion of the total population that is exposed Controls selected from all individuals at risk at the start of the study –sampled regardless whether or not they will fall ill Case may also be selected as a control and vice versa -> kept in both groups OR estimates relative risk

11. 11 Cohort study Cases exposed End of study Exposed population (E) Unexposed population (U) Cases unexposed Still at risk Still at risk Time Rodrigues L et al. Int J Epidemiol. 1990;19:205-13. Cases Sample of source population Still at risk Concurrent design: density case control

12. 12 Concurrent design: density case control Controls selected from those still at risk when a case occurs Control can later become a case Not vice versa -> cases no longer at risk Controls who later become cases kept in both groups Controls represent person years at risk experience among exposed and unexposed Matched analysis on time of selection OR estimates the rate ratio

13. 13 How to select controls to estimate the respective measure of association MeasureDesignFormulation Alternative formulation Controls to be sampled from Risk ratioInclusiveC e /N e C u /N u C e /C u N e /N u Rate ratio ConcurrentC e /pyar e C u /pyar u C e /C u pyar e /pyar u Odds ratio ExclusiveC e /(N e - C e ) C u /(N u - C u ) C e /C u (N e - C e ) /(N u - C u ) Rodrigues L et al. Int J Epidemiol. 1990;19:205-13. Total study population regardless of past or future disease status People currently at risk People disease-free throughout study period

14. 14 Rare diseases: all give similar results Non-recurrent disease with high incidence -> Case cohort design (inclusive): OR relative Risk Recurrent common disease -> Density case control design (concurrent): OR relative Rate Probability or effect of exposure changes along time -> Density case control design: OR relative Rate No need to quantify -> traditional design What design and when?

15. 15 Relationship between OR and RR, according to the primary attack rate (AR) Acknowledgements: Olivier le Polain, EPIET Cohort 15 HPA London Epidemiology Unit, UK

16. 16 Cases detected by surveillance systems Non-random selection process: –Host factors (eg. asymptomatic infections) –Different health care seeking behaviour –Incomplete lab investigation –Incomplete reporting Differential recall –Between reported and not reported cases –Between cases and controls

17. 17 Case-to-case approach Same disease, different subtypes/clones: –Serotypes –Phage types –Antibiotic resistance patterns Controls = cases with non epidemic subtypes –from same source population –same susceptibility (underlying diseases) –included as cases if they had the outbreak strain –readily available Reduces selection AND recall bias Food-exposure collected before status is known

18. 18 Two listeriosis outbreaks France, 1999-2000: two distinct PFGE patterns October November December January February March 1999 2000 Cases de Valk H et al. Am J Epidemiol 2001;154:944-50

19. 19 Listeriosis outbreak cases and sporadic cases distinguished by routine PFGE, France, 1999-2000 October November December January February March 1999 2000 Cases de Valk H et al. Am J Epidemiol 2001;154:944-50

20. 20 Case to case control study: controls selected among sporadic cases listeriosis outbreak, France, 1999-2000 October November December January February March 1999 2000 Cases de Valk H et al. Am J Epidemiol 2001;154:944-50

21. 21 Outbreak of listeriosis, France, December 1999 - February 2000 Results multivariable analysis (29 cases, 32 controls) *adjusted for underlying condition, pregnancy status and date of interview de Valk H et al. Am J Epidemiol 2001;154:944-50

22. 22 Case-crossover design Same person taken as its own control -> No between-persons confounding Matched design: –Compare exposure in a risk period to one or more control periods –Only pairs of discordant periods used in the analysis Acute diseases Exposure –must vary over time –short induction and transient effect sensitive to recall bias

23. Reference period Wash out period Current period Exposure Study CasesMatched pairs 1Discordant 0, 1 2Discordant 1, 0 3Concordant 1, 1 4Concordant 0,0 Case-crossover design

24. 24 Prolonged Salmonella Typhimurium outbreak, France Food exposures in the risk and control period and matched OR for 17 nosocomial cases Foods Risk period Control period Matched OR 95% C.I. Exposed (%) Veal5 (29)1 (6) 5 0,6 - 236,5 Pork4 (23)6 (35) 0,6 0,1 - 3,1 Hamburgers13 (77)5 (29) 5 1,1 - 46,9 Ham6 (35)5 (29) 1,5 0,2 - 17,9 Pâté2 (12) 1 0,01 - 78,5 Chicken2 (12)3 (18) 1 0,01 - 78,5 Turkey11 (65)6 (35) 2,67 0,7 - 15,6 Cordon bleu0 (0)2 (12) undefined - Lamb sausages2 (12)0 (0) - Poultry sausages2 (12)0 (0) - undefined Haegebaert S et al. Epidemiol infect 2003;130,1-5

25. 25 Time trend in exposure: Between period confounding Case-time control design OR a /OR b = OR of exposure adjusted for time trend Control periodRisk period onset Cases: OR a for the exposure and the time trend Case-time controls: OR b for the time trend

26. 26 Folic acid antagonists (FAA) in pregnancy and congenital cardiovascular defects (CCD) Case-crossover approach Case: Woman who had a child with CCD (N=3870) Exposure: FAA during 2 nd & 3 rd month of pregnancy Control: Woman who had a child without CCD (N=8387) 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: Control period Risk period Delivery Hernandez-Diaz S. Am J Epidemiol 2003;158:385-391

27. 27 Conclusions If you do not need that OR estimates correctly the RR -> traditional design Otherwise, if you need OR RR -> identify the best design for each situation If it is difficult to find appropriate controls –Case to case –Case-crossover

28. 28 References Rodrigues L et al. Int J Epidemiol 1990;19:205-13 Rothman KJ. Epidemiology: an introduction. Oxford University Press 2002, 73-93 Rothman KJ, Greenland S, Lash TL: Modern Epidemiology. 3. ed., Philadelphia: Lippincott Williams & Wilkins, 2008. Chapter 8: Case-Control Studies, 111-127 McCarthy N, Giesecke J. 1 Int J Epidemiology 1999; 28, 764-8 de Valk H et al. Am J Epidemiol 2001;154:944-50 Haegebaert S et al. Epidemiol infect 2003;130,1-5 Hernandez-Diaz S et al. Am J Epidemiol 2003;158:385-391 Further Reading Suissa S. The case-time-control design. Epidemiology 1995;6:248-253. Greenland S. Epidemiology. 1996; 7231-239. Mittleman, Maclure, Robins. Am J Epidemiol 1995;142;1:91-98. Karagiannis I et.al. Epidemiol Infect 2010;138, 1726-1734