Dr. Zahid Ahmad Butt
“An antecedent event, condition, or characteristic that was
necessary for the occurrence of the disease at the moment it
occurred, given that other conditions are fixed”
 A cause of a disease occurrence is an event, condition, or
characteristic that preceded the disease onset and that, had the
event, condition, or characteristic been different in a specified
way, the disease either would not have occurred at all or would
not have occurred until some later time
Cause can also be defined as ‘something that brings
about an effect or a result’.
Cause may lead to an effect (disease) but, it is not
simple since several diseases are multifactorial.
Concepts of Cause
Smoking causes lung cancer, chronic obstructive pulmonary
disease, peptic ulcers, bladder cancer, coronary artery
Concepts of Cause contd..
Coronary Artery disease has multiple causes: cigarette
smoking, high levels of LDL, stress, hormonal effects,
hypertension, hypercholesterolemia, life style, lack of
physical activity, heredity etc.
Concepts of Cause contd..
Because of diseases being multifactorial, the influence of
peoples’ behaviours or characteristics of their environments
and life style are also important causes of diseases than the
pathogenic mechanisms.
Cardiovascular and cancer deaths can largely be traced to
behavioural and environmental factors.
The spread of AIDS is due primarily to sexual behaviours
and drug use.
Interpretations of causation
Mechanistic interpretation of causation (Lab
researcher)To be termed a cause an agent must be
both necessary and sufficient
e.g. Koch’s postulate
One must be mindful that although Koch’s postulate
was developed for infectious diseases, they are not
met for majority of these diseases e.g. polio virus,
Interpretations of causation
Mechanistic interpretations do not take into account
inter-individual differences in susceptibility or
interactions among causative agents.
Interpretations of causation
2. Probabilistic interpretation
Under this interpretation, a cause is something which
leads to an increased probability that disease will
This interpretation also allows for the concept of
interaction between causes. e.g. While it is believed
that HIV causes AIDS, there is evidence that the
probability of developing AIDS is lower in people
who are infection by certain strains of the HIV virus.
Interpretations of causation
3. Operational interpretation (public health based
A factor is a cause of if its elimination, or reduction in
the level of exposure, leads to a decrease in
occurrence of disease.
Types of Causal Relationships
 A causal pathway can be either direct or indirect.
 In direct causation, a factor directly causes a disease
without any intermediate step.
 In indirect causation, a factor causes a disease, but only
through an intermediate step or steps.
 In human biology, intermediate steps are virtually always
present in any causal process.
Types of Causal Relationships contd..
 If a relationship is causal, four types of causal
relationships are possible:
 (1) necessary and sufficient;
 (2) necessary, but not sufficient;
 (3) sufficient, but not necessary; and
 (4) neither sufficient nor necessary.
Figure 1. Direct versus indirect causes of disease.
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© 2005 Elsevier
Figure 2. Types of causal relationships: I. A factor is both
necessary and sufficient.
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© 2005 Elsevier
Figure 3. Types of causal relationships: II. Each factor is
necessary, but not sufficient.
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© 2005 Elsevier
Figure 4. Types of causal relationships: III. Each factor is
sufficient, but not necessary.
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© 2005 Elsevier
Figure 5. Types of causal relationships: IV. Each factor is
neither sufficient nor necessary.
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Criteria for causality
The following list is derived from an article by Sir
Austin Bradford Hill (1965). The criteria were
developed as a means to summarize scientific data on
a postulated cause-effect relationship
Today, with insights into disease manifestations as
well as our limited knowledge of certain emerging
diseases, not all criteria remain widely accepted, yet
some do remain important.
Criteria for causality
 Consistency of findings
 Strength of a relationship:
 Temporal sequence
 Dose response relationship
 Specificity:
 Biological plausibility
 Experimental evidence
 Reasoning by analogy
 Coherence of evidence
1. Consistency of findings
This refers to the repeated observations in other studies in
different populations, different places, different times and
under different circumstances.
2. Strength of a relationship:
Magnitude of OR or RR
Was OR or RR statistically significant
However, weak relationships can still be of importance to
public health if both exposure and disease are common.
3. Temporal sequence:
This refers to the temporal sequence of exposure and
outcome –is this sequence in the right direction
Did the exposure cause the disease?
Did the disease cause the exposure?
Best evidence is from RCT and prospective study
4. Dose response relationship (biological gradient):
Those who are exposed more heavily, have a higher risk
of disease than those exposed to lower doses.
However associations that do not show an apparent
trend of effect with an increase in dose, beware of
unknown confounder
Consider therefore:
1. Is a dose response relationship due to an unknown
2. There may be threshold effects
5. Specificity:
One cause one outcome, i.e. the cause should lead to an
effect not multiple effects
Exposure: A disease should be specifically caused by a
single exposure( not true in public health practice)
Disease: An exposure should specifically cause one
disease ( not true in public health practice)
Specificity belongs more to mechanistic interpretation of
cause rather than modern epidemiological interpretation.
6. Biological plausibility:
Does this association make sense?
What are the known facts about the disease?
7. Experimental evidence:
This refers to the quality of the chosen study type. You
should ask yourself:
Is the study type the strongest that could have been used
under the circumstances (feasible and ethical)?
8. Reasoning by analogy:
This refers to the kind of reasoning which states- if one
drug can cause birth defects then maybe another drug can
also produce similar outcomes.
9. Coherence of evidence:
This implies that a cause and effect interpretation of result
does not conflict with what is generally known about the
natural history and biology of disease.
Problems with the criterion
Strength depends on the prevalence of other causes and,
thus, is not a biologic characteristic; could be confounded
Exceptions are understood best with hindsight
A cause can have many effects
It may be difficult to establish the temporal sequence
between cause and effect
Biologic gradient
Could be confounded; threshold phenomena would not
show a progressive relation
Too subjective
How does it differ from consistency and plausibility?
Experimental evidence
Not always available
Analogies abound
Table. Causal criteria of Hill
Assessment of the Evidence suggesting
Helicobacter Pylori as a causative agent of
duodenal ulcers
 Temporal relationship. Helicobacter pylori is clearly
linked to chronic gastritis. About 11% of chronic gastritis
patients will go on to have duodenal ulcers over a 10-year
 In one study of 454 patients who underwent endoscopy 10
years earlier, 34 of 321 patients who had been positive for
Helicobacter pylori (11%) had duodenal ulcer compared
with 1 of 133 Helicobacter pylori-negative patients
Assessment of evidence contd..
 Strength of the relationship. Helicobacter pylori is found in
at least 90% of patients with duodenal ulcer. In at least one
population reported to lack duodenal ulcers, a northern
Australian aboriginal tribe that is isolated from other people, it
has never been found.
 Dose-response relationship. Density of Helicobacter pylori
per square millimeter of gastric mucosa is higher in patients
with duodenal ulcer than in patients without duodenal ulcer.
Also see item 2 above.
Assessment of evidence contd..
 Replication of the findings. Many of the observations
regarding Helicobacter pylori have been replicated repeatedly.
 Biologic plausibility. Although originally it was difficult to
envision a bacterium that infects the stomach antrum causing
ulcers in the duodenum, it is now recognized that Helicobacter
pylori has binding sites on antral cells and can follow these
cells into the duodenum.
 Helicobacter pylori also induces mediators of inflammation.
 Helicobacter pylori-infected mucosa is weakened and is
susceptible to the damaging effects of acid.
Assessment of evidence contd..
 Consideration of alternate explanations. Data suggest that
smoking can increase the risk of duodenal ulcer in Helicobacter
pylori-infected patients but is not a risk factor in patients in
whom Helicobacter pylori has been eradicated.
 Cessation of exposure. Eradication of Helicobacter pylori heals
duodenal ulcers at the same rate as histamine receptor
 Long-term ulcer recurrence rates were zero after Helicobacter
pylori was eradicated using triple-antimicrobial therapy,
compared with a 60% to 80% relapse rate often found in patients
with duodenal ulcers treated with histamine receptor antagonists.
Assessment of evidence contd..
 Specificity of the association. Prevalence of Helicobacter
pylori in patients with duodenal ulcers in 90% to 100%.
However, it is found in some patients with gastric ulcer and
even in asymptomatic individuals.
 Consistency
with other knowledge. Prevalence of
Helicobacter pylori infection is the same in men as in women.
The incidence of duodenal ulcer, which in earlier years was
believed to be higher in men than in women, has been equal in
recent years.
Assessment of evidence contd..
 The prevalence of ulcer disease is believed to have peaked in
the latter part of the 19th century, and the prevalence of
Helicobacter pylori may have been much higher at that time
because of poor living conditions. This reasoning is also based
on observations today that the prevalence of Helicobacter
pylori is much higher in developing countries.