1. Choosing a Reference Group Adriana Pistol EPIET introductory Course, Lazareto September 2011

2. Objectives of the presentation Define source population Understand importance of representativeness Understand the importance of a reference group in analytical studies Understand the advantages and disadvantages of different types of controls

3. Incidence in exposed and unexposed (cohort studies) Exposure in cases and controls Incidence over time (surveillance) Making comparisons fundamental to epidemiology

4. Purpose of the comparison group (concept of counterfactuality) Cohort study: The comparison group serves to provide an estimate of the expected disease incidence in the exposed group if the exposure had been absent. Case control study: The comparison group serves to provide an estimate of the exposure distribution in the source population from which the cases originate. Rothman KJ, 1986

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

6. Case control study Outbreak 24 cases of Salmonella Typhimurium Cornwall (population 500,000) onset through May 2004 age range 16 – 56 years 9 male, 6 female no recent travel abroad

7. Who are the right controls?

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

9. Control characteristics (1) If controls represent source population: be representative of exposures in source population (the same chance that they were exposed as cases) be identified as cases if they had disease under study have same exclusion and restriction criteria as cases

10. Control characteristics (2) Controls should ideally be similar to cases with respect to: – Demographic characteristics – Cultural background – Socio-economic group – Employment Failure to recruit cases and controls from the same population lead to a bias

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

12. Considerations when choosing controls Validity – Selection bias – Information bias – Confounding Efficiency (most information for least cost) – Resources – Time scale – Sample size (precision)

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

14. 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?

15. 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

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

17. Selecting controls (examples) 1.Population – random from register/list/directory – stratified (age/sex/general practice) 2.Friends 3.Family 4.Neighbourhood 5.Hospital

18. 1) 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

19. 1) Population controls e.g. random digit dialling using residential directories or mobile numbers quick and easy but may be bias in selection – telephone ownership – availability – geographical area – participation

20. 1) Population controls e.g. matching Matching = stratification in study design e.g. same age, same sex, same doctor Matching useful if – do not have full list of source population – only specific group affected – effect of matching variables is of no interest

21. Advantages good matching for social factors can be quick and efficient validity in food poisoning investigations 2) Friend controls

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

23. 3) Family controls are rarely used in field epidemiology as exposures in family controls are often so similar to those of the cases that the association of interest may not be shown at all.

24. 4) 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

25. 5) 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

26. Example of a set of controls belonging to the same study base Hospital-based study examining risk factors for cholera during an outbreak Controls: – Patients admitted with meningitis into the same hospital The two diseases are of equivalent severity The population bases can be expected to be identical

27. Example of a set of controls not belonging to the same study base Hospital-based study examining risk factors for cholera during an outbreak Controls: – Patients admitted with minor complaints at the outpatient clinic in the same hospital The two diseases are not of equivalent severity The population bases can be expected to be different – Catchment areas will be larger for more severe diseases

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

29. Controls may not be easy to find

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

31. Some common questions A.Non-cases as controls B.Asymptomatic cases C.Immune populations D.100% exposure

32. A. 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

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

34. B. 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

35. B. 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

36. C. 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)

37. D. 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 What if 99% of population are cases? – Try to conduct a cohort study!

38. Characteristics of good controls Come from the same population as cases May be exposed like cases Can develop the disease Could be recruited as cases if diseased Have exposure windows identical to cases Are adapted to the study objectives

39. Dealing with imperfect control groups Examine the limitations of your control group with respect to each criteria Assess in which way the limitation will affect the odds ratio – Towards one – Away from one Interpret your results in light of this review of limitations Recruiting two control groups is an option

40. Be prepared to defend your choice…

41. …and do the study!

42. 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.