Choosing a reference group

Louise Coole

Sources:EPIET courses (from 1995 to 2011)J Stewart, A Moren

Objectives

• Define “source population”

• Explore the meaning of representativeness

• Understand the importance of a reference group in analytical studies

• Describe advantages and disadvantages of selecting different types of controls

• Compare – disease incidence in exposed and

unexposed (cohort studies)

– exposure in cases and controls

– disease incidence in different time-periods in a population

Epidemiologists .... compare

Measure and compare

Comparison / Reference group

• Unexposed in cohort studies• Controls in case control studies

Focus on controls since selection of controls

can be an important source of bias.

Cohort study:Purpose of the comparison group

• “The comparison group serves to

provide an estimate of the

expected disease incidence

in the exposed group

if the exposure had been absent.”

Rothman KJ, 1986

Cohort study - Challenge

• To identify a population similar to the exposed populationand only differing by the absence of exposure

Cohort - Well defined population

• Nursing home, school, weddinge.g. food borne outbreak

Retrospectively identify

have eaten % disease

did not eat % disease

Does HIV infection increase risk of developing TB among a population of

drug users?

Population TB Cases

HIV + 215 8

HIV - 289 1

Source: Selwyn et al., New York, 1989

Reference group in case control studies

Reference group in a case control study= control group

“The comparison group serves to providean estimate of the

exposure distribution in the source population

from which the cases originate.”

Rothman KJ, 1986

Controls

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

Exposed

Unexposed

Source population

CasesExposed

Unexposed

Source population

CasesExposed

Unexposed

Source population

Sample

ControlsRothman KJ, Oxfort Univ Press, 2002

CasesExposed

Unexposed

Source population

Controls:Sample of the denominator Representative with regard to exposure

Controls

Sample

Case control studies

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

Case control study

Outbreak

• 32 cases of Salmonella Enteritidis • North Yorkshire(population 500,000)• onset through April 2012• age range 15 – 48 years• 19 male, 13 female • no recent travel abroad

Who are the right controls?

Who is source population?

Start with your case definition

Case definition

Resident of North Yorkshire aged above 14 years with isolate of Salmonella Enteritidis in faecal sample during April 2012 Exclusion: Travel abroad in week before illness

What is source population?

Source population

Residents of North Yorkshire aged above 14 yearsduring April 2012 who have not recently travelled abroad

Controls should then be representative of this population

How to select controls?

• Aim for random sample of source population

• Not always feasible

Case control studies

Selecting controls (examples)

• Populationrandom from register/list/directory stratified (age/sex/general practice)

• Friends • Neighbourhood • Hospital

Population / community 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

or... random digit dialling

• using residential directories or mobile numbers (e.g. add 5 to case number)

• quick and easy • but may be biased in selection

– telephone ownership– availability– geographical area– participation

Friends / family controls

AdvantagesGood matching for social and

genetic factors

Can be quick and easy

DisadvantagesEffectively link the cases and controls

May not be able to detect a diference

in exposure of importance

Co-operation may be limited

Neighbourhood controls

Advantages – no need for population register– similar socio-economic status and environmental exposure

Disadvantages– might be too similar to cases

– low co-operation

– may be time consuming, expensive

Hospital controls

• Advantages– useful if all cases identified from hospital register– easily identified – cost and time efficient

• Disadvantages– different catchments for different diseases – May not be representative of source population – overmatching on exposures for other diseases

• Tobacco / lung cancer and controls with CVD

Controls may not be easy to find

Case control study

Outbreak

• 32 cases of Salmonella Enteritidis • North Yorkshire(population 500,000)• onset through April 2012• age range 15 – 48 years• 19 male, 13 female • no recent travel abroad

Source population

Residents of North Yorkshire aged above 14 yearsduring April 2012 who have not recently travelled abroad

Controls should then be representative of this population

Which reference group ?

You are in charge of the case control study!

How would you select controls ?

No population register or list is available

Please discuss with a person next to you (2 minutes!)

Some common questions

• Immune populations

• 100% exposure

• 100% ill

• Non-cases as controls

Immune subjects

• Not eligible as cases – so not in source population

• Difficult to identify • May have been cases in the past • May have similar level of exposure

to risk factor as current cases in study • May introduce bias and under-estimation of

effect.

What if 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

Which control group if 100% ill ?

• What if close to 100% of population ill?

• Try to have severity

– Cases: severe cases

– Control group: less severe cases

Outbreak of S. enteritidis in a Kebab restaurant, North East London February 2005

Food specific attack rates of severe case (AR), relatives risks (RR), 95% confidence intervals (95%) amongst cases.

Food eaten Food not eaten

Severe Total AR% Severe Total AR% RR 95% CI

Salad 10 12 83.3 32 71 45.11.9

1.3-2.7

Chips 11 14 78.5 31 69 44.91.8

1.2-2.6

Sauce 31 59 52.5 11 24 45.81.2

0.7-1.9

Salad 31 57 54.4 11 26 42.31.3

0.8-2.1

Giraudon I et al, EPIET, London HPA

Controls are non cases

Low attack rate: non-cases likely to represent exposure in source pop

Non- casesSourcepopn

High attack rate: non-cases unlikely to represent

exposure in source population

Cases

Cases

Non- cases

endstart

endstart

Non- cases as controls

• If attack rate high – non-cases unlikely to represent exposure in source

population

• If attack rate low – non-cases likely to represent exposures

in source population – can use as controls

Cases

E

E 4

SourcePopulation

60

40

36

ARe = 60% ARue = 10%RR = 6

24

36

Non cases

Cohort

Outbreak of food borne disease in a nursing home. 100 residents, 40 cases

Cases

E

E 4

SourcePopulation

60

40

Outbreak of food borne disease in a nursing Home. 100 residents, 40 cases

36

RR = 6

24

36

Non cases

Cohort

Sample Non cases

12

18

OR = 13.5

Potential control groups

CasesSampleNon cases

E

E

12

4 18

SourcePopulation

60

40

Outbreak of food borne disease in a nursing home. 100 residents, 40 cases

36

Sample SourcePopulation

30

20

RR = 6 OR = 13.5 OR = 6

24

36

Non cases

Potential control groupsCohort

A member of the source populationis a suitable control

What if: Only non-cases as controls?

If attack rate is low non-cases likely to represent exposures in source

population can use them as controls

If attack rate is high, non-cases unlikely to represent exposure in source

population OR may be over-estimated

More accurate not to exclude cases from control group

Concept of case-cohort studies!

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

• No need to document disease status among controls

• OR estimates relative risk

Key points in choosing controls

• Define source population– Think of the cohort you could have done

• Aim for representative sample

• Review pros and cons of available options

Characteristics of good controls

• Come from the same population as the cases• May be exposed like cases• Can develop the disease• Could be recruited as cases if diseased• Have exposure window identical to cases• Are adapted to study objectives

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

• Interpret your results in light of this review

Conclusions

• No control group is perfect

• Consider the advantages and disadvantages of the available options

• Aim to minimise error within constraints of resources and urgency of study

Be prepared to defend your choice…

References

• Rothmann KJ, Greenland S. Modern epidemiology. Lippincott-Raven 1998.

• Hennekens CH, Epidemiology in Medicine. Lippincott-Williams and Wilkins 1987.