Choosing a reference group

James Stuart

EPIET, Mahon

September 2006

Epidemiology

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

• Incidence in exposed and unexposed

• Exposure in cases and controls

• Incidence over time

Making comparisons

fundamental to epidemiology

• Can be difficult to select reference group

• Especially in case control studies

• Constraints of time and resource

Field epidemiology

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

Who are the right controls?

Controls

Controls should be representative

of population from which cases arise

(source population)

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

CasesExposed

Unexposed

Source population

Controls:Sample of the denominator Representative with regard to exposure

Controls

Sample

Who is source population?

Start with your case definition

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?

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

Q2. How to select controls?

• Aim for random sample of source population

• Not always feasible

Selecting controls (examples)

• Population

random from register/list/directory

stratified (age/sex/general practice) • Friends • Neighbourhood • Hospital

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

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

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

Friend controls

Advantages

• good matching for social factors

• can be quick and efficient

• validity in food poisoning investigations

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

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

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

Sample size

• Often limited by number of cases available

• Unusual to select more than 2-3 controls/case

• Little extra power beyond this number

Controls may not be easy to find

Source population

Residents of Cornwall aged above 15 years

during May 2004

who have not recently travelled abroad

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

Some common questions

• Non-cases as controls

• Asymptomatic cases

• Immune populations

• 100% exposure

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

Non-cases as controls

High attack rate

Cases

Non- cases

start end

Sourcepopn

Low attack rate

Asymptomatic cases

• Does it matter if we fail to identify mild cases? • Analogous to non-response• Example: 40 cases, 40 controls

  Cases Controls

Exposed 20 10

Not exposed 20 30

OR = 20.30/20.10 = 3.0

Asymptomatic cases

• If we only identify half the cases and % exposure is the same

  Cases Controls

Exposed 10 10

Not exposed 10 30

OR = 30.10/10.10= 3.0

No bias

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)

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)

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

Be prepared to defend your choice…

…and

do the study!

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.

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, Sweden3000 employees 200 cases of gastroenteritis