Design and Methods of Case Control Studies

Giancarlo Logroscino MD PhD

Department of Neurology and Psychiatry University of Bari. Italy

Neuroepidemiology Teaching Course: Non-Experimental NeuroepidemiologyChisinau MoldaviaSeptember 26 2012

When Did Lou Gehrig’s Personal Illness Begin?

Kasarskis et al, Neurology, 1989; 39:1243-1245

-10 -9 -8 -7 -6 -5 -4 -3 -2 R

Bat

ting

aver

age

0.400

0.350

0.300

0.250

0.200

0.150

0.100

Years

Yankee teammates(n=9)(x±SD)

Gehrig

ALS and Soccer

• Rare disease

• Neurodegenerative chronic

disease

• Induction period is unknown

probably some years before

disease onset

The Question: Is trauma a risk factor for ALS?

Population Survey

Case-Control

Cohort RandomizedClinical

Trial

Descriptive Studies

PopulationsFrequencyDistribution by

timePlacePerson

Analytic Studies

•Counting exposure and outcomes in individuals•Test causal hypotheses•Uncontrolled assignment

Experimental Studies

•Counting exposure and outcomes in individuals•Test causal hypotheses•Controlled assignment

Classification of Studies

Natural History of Disease and Case-control StudiesBhopal R. Concept of Epidemiology. An Integrated Introduction to the Ideas, Theories,

Principles and Methods of Epidemiology. 2002 Oxford University Press, Oxford

C

ALS

ALS ALS

ALS

ALS

C

C

C

C

C

Now

Disease is known

Exposure unknown

Past

C

C

C

C

Case Control Design: Advantages

• Useful for rare conditions

• Short duration

• Relatively inexpensive

• Relatively small

• Study more than one exposure

• Measure of effect is the odds ratio (OR)

What are the Odds?

• The odds in favor of an event or a proposition are the ratio of the probability that an event will happen to the probability that it will not happen.

• For example, the odds that a randomly chosen day of the week is a Sunday are one to six, which is sometimes written 1:6, or 1/6.[1]

• 'Odds' are an expression of relative probabilities. A bookmaker may use 'odds' of 'one-sixth', but a more common use is "odds against", of the form 6 to 1,

Case Control: Problems

• Bias from Sampling

• Does not establish sequence of events (Temporality)

• Potential Bias in Measuring Predictors

• Potential Survivors Bias

• Only one outcome ( disease)

• Does not estimate incidence and risk

Population Concept of a Case-control StudyBhopal R. Concept of Epidemiology. An Integrated Introduction to the Ideas, Theories, Principles and Methods of Epidemiology. 2002 Oxford University Press, Oxford

time

nowpast

future

Exposure?Exposure?

Find Cases (ALS)Define Controls (C)Base population C

ALS

ALS

ALS

ALS

ALS

C

C

C

CC

Selection of Controls

1. Given a set of cases is to select controls who aproximate the exposure prevalence of the population who generated the cases

2. Key Comparison is that of controls with the source population they are intended to approximate

3. Biased study originate because the controls do not reflect the exposure prevalence in the reference population

Goal of the Unexposed in Cohort Studies

• Tp provide an estimate of the disease rate that the exposed group would have had, had they not be exposed

• Counterfactual comparison

• trial

Who are the right controls? Who are the right controls?

Conceptual questionsConceptual questions Comparable to the cases ?Comparable to the cases ? Representative of all non Representative of all non

diseased peoplediseased people

Practical QuestionsPractical QuestionsResourcesResourcesTimeTimeSample sizeSample size

CasesExposed

Unexposed

Source population

Controls:• Sample of the denominator• Representative with regard to exposure

Controls

Sample

Target Population

Target Sample

Study Sample

Study Design

Study Implementation

Measurement

Difference in exposurePercentDrinkingCoffee

Cases Controls

Interpreting the results of a case-control study of coffee drinking and pancreatic cancer

Population Concept of a Case-control StudyBhopal R. Concept of Epidemiology. An Integrated Introduction to the Ideas, Theories, Principles and Methods of Epidemiology. 2002 Oxford University Press, Oxford

time

nowpast

future

Exposure?Exposure?

Find Cases (ALS)Define Controls (C)Base population C

ALS

ALS

ALS

ALS

ALS

C

C

C

CC

Registers and RegistriesLast JM A Dictionary of Epidemiology Oxford 1987: 112

• Ongoing registration of all cases of a particular disease or other health relevant condition in a geographically defined population. With this information incidence rates can be calculated.

• If the case are regularly followed up, information on remission, exacerbation, prevalence and survival can also be obtained

• Register is the document and registry is the ongoing registration system

The Amyotrophic

Lateral Sclerosis

Incidence in Puglia,

Southern Italy

SLAP Registry

ALS Center

• Strengths :– Multiple sources of case-

ascertainment – Defined geographic area– Prospective collection of data– Same diagnostic criteria:

EEC

• Limitations– only 60-80 cases per

registry/year

EURALSPopulation-Based Registries in Europe

2• Catchment pop.: 24 million

Sources of Cases

• Departments of Neurology

• Neurophysiologic Units

• Area Neurologists

• ALS Association

• National Centers for ALS quaternary referral

Advantages of Case-Controls Using Registries

• Clear definition of population-time experience that produces the ALS cases– Geographic boundaries– Calendar periods

• Full roster of the cases

Target Population

Target Sample

Study Sample

Study Design

Study Implementation

Measurement

Who are the cases in my study?

Who would have became a ALS case in our study ?

1. Whether symptoms came to attention

2. Whether subjects in that population seek

diagnosis for those symptoms

3. Whether they have access to medical care

4. Who they chose as their health care provider

5. Willingness to participate to the study

EURALS: The Incident Cases

N=1028Piemonte

Lombardia

PugliaScotland

Ireland

Lancashire

231

15454265

194

130

Population Concept of a Case-control StudyBhopal R. Concept of Epidemiology. An Integrated Introduction to the Ideas, Theories, Principles and Methods of Epidemiology. 2002 Oxford University Press, Oxford

time

nowpast

future

Exposure?Exposure?

Find Cases (ALS)Define Controls (C)Base population C

ALS

ALS

ALS

ALS

ALS

C

C

C

CC

Target Population

Target Sample

Study Sample

Study Design

Study Implementation

Measurement

Who are the controls in my study?

EURALS: The Reference Population

N=23.869.485

Piemonte

Lombardia

PugliaScotland

Ireland

Lancashire

5.1

3.71.74.44.4

4.9

4.0

Possible Controls

• Neighborhood controls

• Random digit dialing

• Best friend controls / spouses

• Hospitalized controls

European CC ALS Study: Issues to be considered in Controls Selection • Large area with NHS but not homogenous levels of

access to care and to ALS care• Very different habits for physical activity and access to

professional sports especially in the age groups of ALS cases

• Physical activity and type of physical activity is a social behavior strongly conditioned by SES and cultural characteristics (broad range across bas population)

Possible Definition of Control

• Those who had been resident in the same area at the time of case diagnosis for one year.

• Source of sampling: the roster of the GP who referred the case

• Matched for age and gender

Physician refusal of access to the patient

• Perceived vulnerability of the patient

• Perceived hostility of the patient

• GP attitude toward patient autonomy

Population Concept of a Case-control StudyBhopal R. Concept of Epidemiology. An Integrated Introduction to the Ideas, Theories, Principles and Methods of Epidemiology. 2002 Oxford University Press, Oxford

time

nowpast

future

Exposure?Exposure?

Find Cases (ALS)Define Controls (C)Base population C

ALS

ALS

ALS

ALS

ALS

C

C

C

CC

RISK OF TRAUMA IN ALS PATIENTS AND RISK OF TRAUMA IN ALS PATIENTS AND CONTROLSCONTROLS

BY NUMBER OF EVENTS BY NUMBER OF EVENTS

No events

Cases Controls OR 95% CI

0 174 338 Ref -

1 141 192 1.43 1.07 – 1.89

2 63 90 1.36 0.94 – 1.97

3 27 28 1.87 1.07 – 3.28

4 + 15 9 3.24 1.39 – 7.55

Severity ALS Controls OR 95% CI

No trauma Ref -

Mild 89 129 1.34 0.95 – 1.88

Moderate

119 154 1.50 1.10 – 2.05

Severe 29 25 2.25 1.24 – 4.12

RISK OF ALS BY SEVERITY OF TRAUMA

ALS & COFFEEVariable ALS vs hosp

controlsOR (95% CI)

ALS vs GPs’ controls

OR (95% CI)

ALS vs cancer cohort

OR (95% CI)

CoffeeNeverEver

10.7 (0.5-1.1)

10.6 (0.4-0.8)

10.4 (0.2-0.9)

Intake (years)0<3031-50>50

10.7 (0.4-1.3)0.7 (0.5-1.1)0.8 (0.5-1.3)

10.7 (0.4-1.4)0.6 (0.4-0.9)0.5 (0.3-0.8)

10.4 (0.1-1.0)0.4 (0.2-0.7)0.8 (0.3-2.0)

ConsumerNeverFormerCurrent

11.1 (0.7-2.0)0.7 (0.5-1.0)

11.0 (0.6-1.7)0.5 (0.3-0.7)

11.2 (0.4-3.5)0.4 (0.2-0.8)

Beghi et al, unpublished

Natural History of Disease and Case-control StudiesBhopal R. Concept of Epidemiology. An Integrated Introduction to the Ideas, Theories,

Principles and Methods of Epidemiology. 2002 Oxford University Press, Oxford

C

AD

AD AD

AD

AD

C

C

C

C

C

Now

Disease is known

Exposure unknown

Past

C

C

C

C

Does Smoking Cause Dementia?

Selected Case-Control Studies of Alzheimer’s Disease and Smoking (as Rewied by Lee[1999])

Kukull W A. Biol Psychiary 2001;49:194-199

Authors Year Odds ratio 95% CIKatzman et al 1989

Grossberg et al 1989

Ferini-Strambi et al 1990

Brenner et al 1993

Chandra 1987

Frnech et al 1985

Amaducci et al 1986

Graves et al 1990, 1991

Dewey et al 1988

Broe et al 1990

Heyman et al 1984

Barclay and Khefets 1989

Shalat et al 1987

Summary estimate (Lee 1994)

1989

1989

1990

1993

1987

1985

1986

1990

1988

1990

1984

1989

1987

0.2

0.3

0.4

0.6

0.6

0.7

0.7

0.8

0.8

0.8

1.0

1.3

1.3

0.6

0.1-0.5

0.2-0.6

0.2-0.8

0.4-1.0

0.3-1.4

0.3-1.5

0.4-1.2

0.5-1.2

0.4-1.6

0.5-1.3

0.5-2.0

0.5-3.2

0.7-2.3

0.5-0.8

0.40 0.50 0.67 1.0 1.5 2,0 2.5

Protective effect Null Harmful effect

JuanMerchantLauner

Ott

BrayneBroeWang TyasDoll&Peto

Smoking and AD: Conflicting Results from Cohort Studies ?

Problems with case-control studies

• Retrospective assessment of exposure to smoking– Recall bias

• Prevalent cases of dementia– Incidence/prevalence bias

• Biased selection of controls– Smokers overrepresented in hospital controls

• These problems may result in downwardly biased estimates

Selection of CasesIn CC Design

Potential Contribution of Study Design Bhopal R, Concepts of Epidemiology, Oxford 2002

Strength orDose-response

Criteria

Temporality

Experimental confirmation

Specificity

BiologicalPlausibility

Consistency

Cross-sectional

Sometimes

Sometimes

Sometimes(repeated studies)

Sometimes

Not Directly

Yes

Case-control

Sometimes

Often

Seldom

Yes (disease)

Not directly

Yes

Cohort

Often

Always

Sometimes (natural changes)

Yes (risk factor(s))

Not directly

Yes

Trial

Usually

Always

Always

Yes (risk or preventive

factor(s))

Not directly

Yes