From association to
causation
1
Objectives of lecture:
• what is the cause
• concept of Association and Causation
• types of association
• does association implies causation
• what are the types of causal factors
• What are the Hill’s criteria for causation.
2
- Purpose of Epidemiology?
- Basic Question in Analytic Epidemiology
Exposure
Disease
Research Questions/Hypotheses
• Is there an association between Exposure (E)
& Disease (D)?
• Hypothesis: Do persons with exposure have
higher levels of disease than persons without
exposure?
Figure 13-4. Correlation between dietary fat intake and breast cancer
by country.
USA
250
Incidence Ratio per 100,000 Women
Switzerland
Canada
Fed. Repub.
Of Germany
Italy
200
Israel
UK
Sweden
France
Denmark
New Zealand
Australia
Norway
150
Finland
Yugoslavia
100
Spain
Poland
Romania
Hong Kong
Hungary
50
Japan
Per Capita Supply of Fat Calories
0
0
600
800
1000
1200
1400
1600
Prentice RL, Kakar F, Hursting S, et al: Aspects of the rationale for the Women’s Health Trial. J Natl Cancer Inst 80:802-814, 1988.)
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DOES CORRELATION IMPLY CAUSATION?
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Correlation: it indicates degree of association.
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Association……
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Do both invoke causation?
Types of Association:
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A real association (causal) is present if we
succeed in reducing the risk of disease by
lowering the exposure level.
Spurious associations refer to non-causal
associations due to chance, bias, failure to
control (confounding), etc. e.g;
Neonatal deaths at Home vs hosp delivery,
Interpreting Associations - Causal and Non-Causal
Non-Causal (due to confounding)
Causal
Characteristic Under Study
Characteristic Under Study
Factor X
Disease
Disease
Types of real association:
A) Negative Association (Inverse Relationship):
higher levels of the risk factor are protective against the outcome.
e.g. regular physical exercise and ischemic heart diseases
B) Positive Association:
The magnitudes of both variables appear to move together up or down.
e.g. hypertension and ischemic heart diseases
Pyramid of Associations
Causal
Non-causal
Confounded
Spurious / artefact
Chance
Association :
• the rate of disease in a persons with a specific
exposure.
• statistical dependence between two variables,
• • A causal association is one in which a change in the
frequency or quality of the exposure results in a
corresponding change in the frequency of the disease
or outcome of interest.
What is a Cause?
• An event, condition, or characteristic without which
the disease would not have occurred.
• Causative factor:
One pragmatic definition of a cause
of a disease is an exposure which
produces a regular and predictable
change in the risk of the disease.
A good epidemiologic exposure
variable should….
•
•
•
•
•
Have an impact on health
Be measureable
Differentiate populations
Generate testable hypotheses
Help to prevent or control disease
ASSOCIATION VS CAUSATION
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To decide whether exposure A
causes disease B,
we must first find out whether
the two variables are
associated?
Clinical observations
Available data
(Ecological or Cross-sectional Studies)
Case-control studies
Cohort studies
Randomized trials
(only used to confirm causation
Surgeon Alton Ochsner observed
that almost all lung cancer patients
were smokers
Ecologic study of per capita
smoking and lung cancer
incidence
Case-control study of lung cancer
patients versus those without lung
cancer
39 cohort studies ?
Types of causal pathway:
1. Direct causation (with out any intermediate
step).
disease
factor
2. Indirect causation (a factor causes a disease,
but only through an intermediate steps).
factor
Step 1
Step 2
disease
- Which one is always present in human
biology?
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Causal Factors in general:
Necessary cause: The cause must be
present for the outcome to happen.
Sufficient cause: If the cause is
present the outcome must occur.
Rare or Common?
Isolation/inclusion
Types of causal factors
1. Necessary and sufficient
–
–
Without factor, disease does not develop
Its presence is sufficient to initiate disease
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2. ‘necessary but not sufficient’:
Factor A
Factor B
Disease
Factor C
causative factor, and enabling factors required
Each factor is necessary but not sufficient
to cause the
Carcinogenesis
disease.
e.g: initiator + promoter
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3. “Sufficient but not necessary’:
Factor A
OR
Factor B
DISEASE
OR
Factor C
the factor alone can produce the disease, but
so can other factors that are acting alone.
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4.Neither sufficient nor necessary
Factor A
Factor B
OR
Factor D
Factor C
DISEASE
OR
Factor E
Factor F
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CAUSAL INFERENCE
1. DETERMINISTIC CAUSALITY:
as in necessary and sufficient causes.
AR%= ?
2. PROBABILISTIC CAUSALITY :
the web of causation, or chain of
causation
Characteristics??
Web of Causation
Web of Causation - CHD
An attempt to discover WHICH THE
CAUSE, OR whether TWO VARIABLES
are associated, WE NEED:
• EPIDEMIOLOGICAL STUDIES, to??
• Statistics, to?
Does Statistical analysis alone can
constitute proof of a causal
relationship?
NO
MAKING CAUSAL
INFERENCES
The use of Hill’s causal
criteria in making inferences
from data.
Hill’s criteria for judging whether an
association is causal
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Temporal relationship

Strength of association
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Dose response
relationship
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Consistency of the
findings
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Biologic plausibility and
Coherence with other
knowledge
Consideration of
alternate explanations
Reversibility of exposure
Specificity of the
association
Study design
Temporal Sequence
• It means?
• The length of exposure is also important,
• Which study designs?
STRENGTH
• Is the association strong?
• Heavy smoking with lung cancer,
• Heavy smoking with CHD.
• The stronger the association the more
likely it is to be truly causal.
• WHY??
•
small associations can be causal?
dose-response relationship
• relative risk increases with higher exposure dose.
• Years of exposure?
• Not necessary. Why? … threshold effect…
unascertained exposure level … irrelevant to all
exposures.
Consistency of Findings of Effect
• Does mean exact replication?
• Look for consistent findings
•
•
•
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– across different populations
– in differing circumstances
– with different study designs
Relationships that are demonstrated in multiple
studies are more likely to be causal.
Why?
Smoking with lung cancer.
contraceptives and breast cancer.
Plausibility and Coherence (ie.,
biologic credibility)
• existence of biologic or social mechanistic model
to explain the association
e.g. Trinitrate → headache
• Fitness .
• does it a provision?
EXAMPLE:
•
Serological marker of hepatitis B
infection is associated with elevated
rates of liver cancer.
• Is supported by viral genome in
many liver cancers.
• So… Hepatitis B infection is a true
cause of liver cancer
•
•
•
•
By contrast,
Reserpine was thought to be a cause of
breast cancer.
But, no supporting biological mechanism.
Subsequent larger studies (no
consistancy).
So .. Causation not true.
• Consideration of alternate
explanations
- review of literatures for analogue.
- depend on depth of knowledge.
Reversibility (cessation of exposure) :
Removal of the exposure leads to decreased risk of
outcome.
e.g. . stop smoking leads to decreased risk of CHD.
• HOWEVER, in certain cases, the damage may be
irreversible.
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Specificity of the Association
• Is it a Provision?
- H. Pylori?
- smoking & lung cancer?
Study design :
• All of the study designs are important.
• The best evidence comes from?.
• Example: Smoking cessation programs result in
lower lung cancer rates.
To put the studies in order according to power:
Type of study
Ability to " prove causation
Randomized controlled trial
Strong
Other intervention study
strong
prospective cohort
Moderate
Retrospective cohort
moderate
Case-control
Moderate
Cross-sectional study
Poor
Ecological
Poor
Parametric study
Very Poor
Judging Causality
Weigh weaknesses
in data and other
explanations
Weigh quality
of science and
results of causal
models
Framework for the Interpretation of an Epidemiologic
Study
I. Is there a valid statistical association?
• Due to chance?
• Due to bias?
• Due to confounding?
II. Can this valid statistical association be judged to
be one of cause and effect?
• Is there a strong association?
• Is there consistency with other studies?
• Is the time sequence compatible?
• Is there biologic credibility to the hypothesis?
• Is there evidence of a dose-response relationship?
Why was it relatively easy to determine
that smoking was a cause of lung cancer?
• Measurable.
• Used to classify persons accordingly.
• Lung cancer incidence in smokers is much
greater than in nonsmokers.
Why will it be relatively hard to determine
if community air pollution is a cause of
lung cancer?