Etiologic research

Study of the causes of disease

 Lecture contents

• Characteristics etiologic research

• Study design
• Three forms of bias
• Advantages and disadvantages of cohort and
case control studies
 Etiologic research

The research question

• Is there a relation between a determinant
(risk factor) and a disease-outcome?

 Research question for causal relation!

 Etiologic research
Characteristics
• Explanatory research
– versus descriptive research
• To demonstrate causality (cause-effect)
• Cause comes before effect
– Exposure to determinant occurs before the
disease-outcome occurs
• Determinant-outcome relation is not
explained by other factors
 Etiologic research
What study design?
• Experimental
– Exposure to determinant assigned by investigator

versus
• Observational
– Exposure to determinant not assigned by
investigator
This lecture: observational research
 Etiologic research
What study design?

• Design of two observational studies to

distinguish between cause and effect:
1. Cohort study
2. Case-control study
 Cohort study

• Also called follow-up study

• Definition
– Study in which persons, based on their exposure
to a determinant and free of the disease outcome
at the start of the study, are followed in time to
assess the occurrence of the disease outcome.
 Cohort study

disease +
determinant +
cohort disease -
without
disease
outcome disease +
determinant -
disease -

time
start study disease-
outcome
 Framingham Heart Study

• 1948 – Framingham, MA
• 5200 persons 30-62 years old
• Aim: identification of risk factors for
cardiovascular diseases
• Remeasured every 2 years

Example of a research question:

Is hypertension a risk factor for MI?
 Framingham Heart Study

MI +
hypertension +
cohort MI -
without
myocardial
infarction MI +
hypertension -
MI -

time
1948 1998
 Cohort study
determinant-outcome relation

MI + MI -

a/a+b=probability of MI for
hypertension + a b hypertension + = Incidence+

c/c+d=probability of MI for
hypertension - c d hypertension - = Incidence -

relative risk = incidence + / incidence -

 Cohort study

How do you get a cohort?

 Cohort study

How do you get a cohort?

• Geographical (Framingham Heart Study)
• Birth cohort (British 1946 birth cohort)
• Dynamic cohort (Leidsche Rijn)
• Occupational cohort (Whitehall study)
 Cohort study
How do you follow the cohort?
How do you find the disease-outcome?
 Cohort study

How do you follow the cohort?

How do you find the disease-outcome?
• After a certain time interval, send out a
questionnaire or invite for interview or
medical examination
• Record disease outcomes via medical files
or registrations
 Cohort study
summary

determinant disease-outcome
 Case-control study
• Also called patient-control study
• Definition
– Study in which patients with the disease-outcome
and a control group without the disease-outcome
are selected and in which it is determined how
many people in both groups have been exposed
to the determinant
 Case-control study
determinant +
disease +
determinant - (patients)

determinant +
disease –
determinant - (controls)

time
start study
Creutzfeldt-Jakob’s Disease
 Creutzfeldt-Jakob’s Disease
• Fast, progressive form of
dementia
• In the 90s a new variant of
Creutzfeldt-Jakob was
discovered in Europe after
an epidemic of mad-cow
disease
• Caused by eating beef?
What research question?
Why case control?
 Creutzfeldt-Jakob’s Disease
beef +
patients
beef - with CJD

beef +
controls from
beef - hospital

time
start study
 Case-control study
determinant-outcome relation

CJD + CJD -

beef + a b

beef - c d Odds Ratio

a/c = odds b/d = odds

beef+ in beef+ in = axd/bxc
cases controls
 Case-control study

How do you find cases/patients?

How to selecet a control group?

 Case-control study

How do you find patients?

• GP; hospital; cancer registration
How to select a control group?
• GP; hospital; general population

 Patients and controls have to come

from the same ‘source’ population.
 Case-control study

How do you assess exposure to

determinant?
 Case-control study

How do you assess exposure to

determinant?
• Interview with participant
• Interview with proxy
• Medical file
 Case-control study
summary

determinant disease-outcome
 Validity and bias

• Validity:
– absence of systematic errors in design, conduct or
data-analysis of the research
• Bias:
– degree of disruption of the determinant–outcome
relation caused by systematic errors – leads to
reduced validity
• 3 types of bias in etiologic research:
– selection bias, information bias, confounding
 Selection bias
cohort study
• In cohort study is selection bias no issue,
because the disease has not yet occurred
when the determinant is measured
• However, loss to follow-up can lead to
selection bias

• How can this happen?

 Selection bias and selection

• Selection is not per definition selection bias

 Information bias
definition
• Distortion of the determinant-outcome relation
caused by systematic errors in the
measurement of the determinant and/or
outcome.

• Who knows an example?

 Information bias
examples
• Misclassification of determinant
– Self reporting more accurate for cases than
controls (or the other way around)
• Misclassification of outcome
– Disease better diagnosed in people with
determinant
• In what cases can this play a role?
• Can this also play a role in cohort research?
 Confounding
definition
• Determinant – disease outcome relation is
disturbed by the effect of another factor (the
confounder) (“mixing of effects”)

• Can you think of an example?

 Confounding
example
• Children with a higher birth order more often
have Down’s syndrome

What could be a
confounder?
 Confounding

determinant disease outcome

(birth order) (Down sydrome)

Confounder
(age mother)
1. Confounder is determinant of the disease outcome
2. Confounder is associated with the determinant
3. Confounder is no factor in the causal chain
 Confounding

determinant disease outcome

Confounder

Think of another example of confounding

 How to prevent bias?
• Confounding – cannot be prevented
– Measure and adjust in data analysis
• Information bias - prevent during design
– Disease status blind for determinant status
– Medical files instead of self-reporting
– Same way of reporting for cases and controls
• Selection bias - prevent during design
– Control selection independent of determinant
status
– Good definition of source population
 Cohort study
Advantages and disadvantages

• What are the advantages of a cohort study?

• What are the disadvantages of a cohort study?

 Cohort study
• Advantages
– Cause is measured before effect
– Not very sensitive to selection- and
information bias
– Appropriate for rare determinant
– Can study several outcomes
• Disadvantages
– Selective withdrawal / loss to follow-up
– Expensive and time consuming
– Not appropriate for rare outcome
 Case-control study
Advantages and disadvantages

• What are the advantages of a case-control

study?

• What are the disadvantages of a case-control

study?
 Case-control study
• Advantages
– Efficient and relatively cheap
– Appropriate for rare outcome
– Can study several determinants
• Disadvantages
– Cause is measured after effect
– Very sensitive to selection- and infobias
– Not appropriate to study several outcomes