CAUSATION

Session Objectives
At the end of this session , participants will be
able to:

Explain the difference between the various models

of causation

State the relationship between association and

causation

List the Bradford-Hill causal criteria.

 Causation

How do we know that one thing causes another?

How do we know that a risk factor causes a disease?

 What causes MI?
Cigarette smoking
Cholesterol
Elevated blood pressure
Stress
Family history
Obesity

Which contributes the most risk?

What are the relationships among risk factors?

 What causes diarrhea?

Contaminated water

Undercooked meat and/or seafood

Raw fruit

Prescription medications

Stress

Fatty foods/change in diet

 Concept of Cause
Prescription Fatty foods/change
medications
in diet
Contaminated water

Undercoo
ked
meat
and/or Susceptible Infection Diarrheal disease
seafood
Host

Raw
fruit
Stress

Risk factors for diarrheal disease Mechanism for diarrheal

disease
 Causation
Cause (dictionary)– the producer of an effect,
result, or consequence

Cause (Rothman) – an antecedent event,

condition, or characteristic that was necessary for
the occurrence of the disease at the moment it
occurred, given that the other conditions are fixed.

Cause (Rothman, lay terms) – an event, condition,

or characteristic that preceded the disease event
and without which the disease event either would not
have occurred at all or would not have occurred until
some later time
 Association vs. Causation
Association is simply an identifiable relationship
between an exposure and a disease

Implies that exposure might cause disease

Exposures associated with a difference in disease

risk are often called “risk factors”
 Association vs. Causation
Causation implies that there is a true mechanism
that leads from exposure to disease

e.g., long-term heavy smoking causes

myocardial infarction
 
Finding an association does not make it causal

e.g., hospital stays are associated with an

increased mortality rate, but this does not
mean they cause death
 Causal Inference: Introduction
Why be concerned with cause?
so that can intervene and prevent disease

Basic definition of “cause”:

exposure that leads to new cases of disease

remove exposure ,some cases do not occur

(disease rate drops)
do not need to understand all casual factors to
prevent disease
 Models of causation

• Issue is not as simple as first appears

• Need a framework of causation
–Necessary and Sufficient
–Multicausality
 Models of causation:
Necessary and Sufficient
• Sufficient Cause
– If the cause is present, the disease
always occurs
• Necessary Cause
– If the cause is absent, the disease cannot
occur
• Multicausality
– Several ways to cause disease
4 Models of Causal Relationships
 Necessary and Sufficient

Only Factor X Disease

Genetic Factors Sickle Cell

Necessary but not Sufficient
Factor X
+

Factor B Disease
+

Factor C
Necessary but not Sufficient
Initiation

Cancer

Promoter
Sufficient but not Necessary

Factor A

Factor B Disease

Factor C
 Sufficient but not Necessary
Ionizing
Radiation

Benzene Leukemia

Electromagnetic
Fields
Neither Sufficient nor Necessary -
Multicausality

Factor A +/- Factor B

+/- +/-

Factor C +/- Factor D Disease

+/- +/-

Factor E +/- Factor F

Neither Sufficient nor Necessary -
Multicausality
Smoking +/- Cholesterol
+/- +/-
Family Myocardial
HBP +/-
History Infarction
+/- +/-

Stress +/- Obesity

 Necessary and Sufficient

Variable A may cause B

A is necessary A is sufficient
+ +
+ -
- +
- -
 Multicausality - Rothman
Three sufficient causes of disease

I II III

A A A
B E B H C J

C D F G F I
 Multicausality - Rothman
Three sufficient causes of disease

I II III

A A A
B E B H C J

C D F G F I
 Multicausality - Rothman
Three sufficient causes of disease

I II III

A A A
B E B H C J

C D F G F I

Single Component Cause

 How do we assess whether risk
factor is indeed causal?

• Does exposure A cause disease B?

• Find out if variables are statistically associated
• A preponderance of evidence
Bradford Hill: Considerations for
Causal Inference
• Strength of association
• Consistency of findings
• Specificity
• Temporality
• Biological gradient (dose-response)
• Biological plausibility
• Coherence with established facts
• Experiment
• Analogy
 Strength of Association

• Strong associations (ratio of

incidence rates) are less likely to be
caused by chance or by bias
• The stronger the association, the
more likely it is to be causal
Strength of Association

Relative risk Interpretation

1.1-1.3 Weak
1.4-1.7 Modest
1.8-3.0 Moderate
3-8 Strong
8-16 Very strong
16-40 Dramatic
40+ Overwhelming
 Coherence and Consistency
of Findings
• Relationships that are demonstrated
in multiple studies are more likely to
be causal; i.e. consistent results are
found
– In different populations,
– In different circumstances, and
– With different study designs.
 Coherence and Consistency
of Findings
• Cigarette smoking and Lung cancer
Consistent results are found
– Numerous studies (case-control,
retrospective cohort, prospective cohort)
have been done show an association
between cigarette smoking and lung cancer
Coherence and Consistency of
Findings
– Doll R, Hill AB. Smoking and carcinoma of the
lung. Brit Med J. 1950; 2:739-748
• Case control study conducted in London from April 1948 to Feb 1952
– Yaun J et al. Morbidity and mortality in relation
to cigarette smoking in Shanghai, China. A
prospective male cohort study
• Prospective cohort study conducted in Shanghai from Jan 1986 to Sept. 1989
– Fritschi et al. Mortality and cancer incidence in a
cohort of meatworkers
• Retrospective cohort study conducted in Australia from 1982 and 1999.

***All of these (as well as many other studies)

show an association between smoking and lung
cancer
 Specificity of the Association

• An exposure leads to a single or

characteristic effect, or affects people with a
specific susceptibility (like the concept of a
“Necessary” cause)
– Easier to support causation when associations
are specific
• But, obviously not always true
•  Many exposures cause multiple diseases
• e.g., smoking causes many diseases including heart
disease, lung and other cancers, emphysema
 Specificity of the Association
Hepatitis A Botulism

Food OR Food OR

Sandwich 2.8
Bread 1.2
Fruit 3.2
Fruit 1.6
Salad 4.0 Tomato 4.0
Pastry 1.8 Tea 1.3
Milk 0.8 Cake 0.8
 Temporal Sequence

• Exposure must precede disease

• In disease with latency periods, exposures
must precede the latent period
• In chronic disease, often long-term
exposure for disease induction
 Temporal Sequence

Incubation
Period
1 to 12 days

0 5 10 15 20
Days
Date of Exposure
Cutaneous anthrax
 Biological Gradient

• “Dose- response”
• Changes in exposure are related to a trend in risk
• Risk of outcome increases with increasing exposure to
the suspected risk factor
 Biological Gradient

Age-standardized death rates, bronchogenic carcinoma (by smoking

history)
250

217.3

200

150 143.9
Mortality Rate per
100,000 Person-
Years
100
Adapted from
Hammond EC,
59.3 Horn D: JAMA
51.4
50 166:1294-1308,
1958.)
3.4
0
Never <1/2 1/2-1 1-2 2+
Smoked Pack/Day Pack/Day Packs/Days Packs/Day
 Biological Plausibility

• The proposed causal mechanism should be

biologically (etiologically) plausible
– The findings make biologic sense
– Results agree with current biological
knowledge of the disease
 Biological Plausibility

Plausible
– A disease shows a higher incidence in
individuals who are more sexually active
• The disease could be a sexually transmitted disease
Not Plausible
– HIV is caused by smoking
• This would go against the current knowledge on the
biological mechanism for HIV
 Experiment

• Experimental evidence seldom available for human

populations
• Experimental evidence shows an exposure-disease
relationship
– Human experiments
– Animal experiments
 Experiment
– In the 18th century, a famous English physician
named Edward Jenner made the observation that
milkmaids who became infected with cowpox did not
become infected with smallpox.
– In 1796 Jenner inoculated a young boy with cowpox,
then six weeks later exposed the boy to smallpox.
The boy did not become infected with smallpox.
– The experiment showed that those who had
previously developed cowpox were immune to
smallpox. This work paved the way for the modern
vaccination.
 Analogy
• Existence of other cause-effect relationship analogous
to the one studied supports causal relationship
• Other similar associations exist
– If a particular drug is a carcinogen, then other drugs
within the same class of drugs may be carcinogens
– From earlier example (Consistency and
Coherence), if an association is found between
smoking and lung cancer in people in England, it is
logical to expect a similar association among
people of China (or another nation)
 Causal Inference: Cautions
• No single study is sufficient for causal
inference
• Causal inference is not a simple process
– Consider “weight of evidence”, using Bradford Hill’s
criteria
– Always requires judgment and interpretation, no
cookbook method
– Some consider causal inference to be in the public
policy domain, rather than the scientific domain
• No way to prove causal associations
 Some notes from Bradford Hill
• A caveat:
“None of my … [guidelines] can bring indisputable
evidence for or against the cause-and-effect
hypothesis and none can be required as a sine
qua non”
• But also a need to act without “proof”:
“All scientific work is liable to be upset or modified
by advancing knowledge. That does not confer
upon us a freedom to ignore the knowledge we
already have, or to postpone the action that it
appears to demand at a given time.”
 Cigarette smoking and lung cancer
• There certainly is a strong association.
• Consistent across a wide range of researchers and studies.
• Smoking is not specific as it is associated with a wide range of
diseases
• Smoking precedes the diagnosis of cancer.
• There is a dose response relationship (heavy smokers are at
greater risk than light smokers).
• Mechanism: we know how certain chemicals can cause DNA
damage.
• Coherence: lung cancer rates are higher in countries where a lot
of people smoke.
• Experimental interventions: quitting smoking greatly reduce
cancer risk.
• Analogy: cigar and pipe smoking associated with cancers of the
mouth.
 Learning Objectives
Now you are able to:
– Explain the difference between the various
models of causation
– State the relationship between association
and causation
– List the Hill causal criteria.