1. Choosing a reference group James Stuart EPIET, Mahon September 2006

2. Objectives Define source population Understand importance of representativeness Describe advantages and disadvantages of selecting different types of controls Apply public health principles to choice of reference groups in case-control studies

3. Incidence in exposed and unexposed Exposure in cases and controls Incidence over time Making comparisons fundamental to epidemiology

4. Can be difficult to select reference group Especially in case control studies Constraints of time and resource Field epidemiology

5. Case control study Outbreak 24 cases of Salmonella Typhimurium Cornwall (population 500,000) South West England not far from Wales long way from Scotland onset through May 2004 age range 16 – 56 years 9 male, 6 female no recent travel abroad

6. Who are the right controls?

7. Controls Controls should be representative of population from which cases arise (source population)

8. Control characteristics If controls represent source population be representative of exposures in source population be identified as cases if they had disease under study have same exclusion and restriction criteria as cases

9. Cases Exposed Unexposed Source population Controls: Sample of the denominator Representative with regard to exposure Controls Sample

10. Who is source population? Start with your case definition

11. Case definition Resident of Cornwall aged above 15 years with isolate of Salmonella Typhimurium in faecal sample during May 2004 Exclusion: Travel abroad in week before illness What is source population?

12. Source population Residents of Cornwall aged above 15 years during May 2004 who have not recently travelled abroad Controls should then be representative of this population

13. Q2. How to select controls? Aim for random sample of source population Not always feasible

14. Selecting controls (examples) Population random from register/list/directory stratified (age/sex/general practice) Friends Neighbourhood Hospital

15. Population controls Is there a list or register of source population? Such a list should –be complete –contain all cases –be readily accessible –identify specified characteristics e.g. age Take random sample

16. or... random digit dialling using residential directories or mobile numbers (e.g. add 5 to case number) quick and easy but may be bias in selection –telephone ownership –availability –geographical area –participation

17. or… stratification Stratification in study design = matching e.g. same age, same sex, same doctor Matching useful if –do not have full list of source population –do not want to measure effect of matching variables Presentation next week

18. Friend controls Advantages good matching for social factors can be quick and efficient validity in food poisoning investigations

19. Friends controls Disadvantages Co-operation may be limited (concern about giving out names) if exposure same as in cases, may not detect causal association = Overmatching

20. Neighbourhood controls Advantages no need for population register similar socio- economic status Disadvantages low co-operation may be time consuming and expensive might be too similar to cases

21. Hospital controls Advantages useful if all cases identified from hospital register easily identified cost and time efficient Disadvantages different catchments for different diseases overmatching on exposures for other diseases

22. Sample size Often limited by number of cases available Unusual to select more than 2-3 controls/case Little extra power beyond this number

23. Controls may not be easy to find

24. Source population Residents of Cornwall aged above 15 years during May 2004 who have not recently travelled abroad

25. Which reference group ? You are in charge of the case control study What is your control definition? How would you select them? No population register or list is available Please discuss with your neighbourhood control

26. Some common questions Non-cases as controls Asymptomatic cases Immune populations 100% exposure

27. Non-cases as controls If attack rate high high risk that non-cases do not represent exposures in source population If attack rate low low risk that non-cases do not represent exposures in source population can use as controls

28. Non-cases as controls High attack rate Cases Non- cases start end Source popn Low attack rate

29. Asymptomatic cases Does it matter if we fail to identify mild cases? Analogous to non-response Example: 40 cases, 40 controls CasesControls Exposed2010 Not exposed2030 OR = 20.30/20.10 = 3.0

30. Asymptomatic cases If we only identify half the cases and % exposure is the same CasesControls Exposed10 Not exposed1030 OR = 30.10/10.10= 3.0 No bias

31. Immune subjects Not eligible as cases So not in source population Difficult to identify May have been cases in past May have similar level of exposure to risk factor as current cases in study Bias in OR towards 1 (null value)

32. 100% exposure What if close to 100% of population exposed? e.g. foodborne disease outbreaks where little choice in menu Try to measure dose response Reference group lowest level of exposure (case study to come)

33. Key points in choosing controls Define source population Aim for representative sample Review pros and cons of available options Plan to minimise bias, taking account of resources and urgency

34. Be prepared to defend your choice…

35. …and do the study!

36. References Rothmann KJ, Greenland S. Modern epidemiology. Lippincott-Raven 1998. Hennekens CH, Epidemiology in Medicine. Lippincott- Williams and Wilkins 1987. Gregg MB. Field epidemiology. Oxford University Press 1996. Wacholder S, McLaughlin JK, Silverman DT, Mandel JS. Selection of controls in case control studies I-III. Am J Epidemiol 1992; 135: 1019-50.

38. Although preferable to do a cohort study, you are short of staff to do the investigation and you decide to do a case control study using 200 controls from the same factory How would you select the 200 controls? Volvo factory, Sweden 3000 employees 200 cases of gastroenteritis