Evaluation of Epidemiological

Associations

2024
 Presentation Outline
1. Definitions of a cause
2. Types of associations
3. Steps to assess the relationship between
a possible cause and an outcome
4. Criteria to judge the causal significance
of the association between a factor
(attribute or event) and an effect
(outcome, disease ..)
 A cause of a disease is an
event, condition, characteristic
or a combination of these
factors, which plays an
important role in producing the
disease
 Other Definitions of “Cause”
• A cause is a factor (characteristic behavior,
event) that influences the occurrence of disease
(the effect).

• A cause is an act or event or a state of nature

(factor) which initiates or permits, alone or in
conjunction with other causes, a sequence of
events resulting in an effect (disease or health
problem).

• A cause is a factor or habit whose reduction or

removal leads to reduction of the incidence of
the disease or health problem.
 Henle-Koch postulates (1882)
1- The agent (microbial agent) must be shown
to be present in every case by isolation in
culture.
2- The agent must not be found in cases of
other diseases.
3- The agent isolated must be capable of
producing disease in experimental animals, and
must be recovered (re-cultured) from
experimental disease produced.
Conditions not satisfying Koch postulates
1- Many diseases are multi-factorial with
several contributing causes (heart disease,
diabetes, cancer).
2- One exposure can cause several diseases
(smoking).
3- Disease is usually the result of interaction
between host, agent and environmental
factors (e.g., genetic susceptibility, immunity,
agent virulence, malnutrition…etc.).
 Sufficient and/or Necessary Cause
A cause is termed sufficient when it inevitably
produces or initiates a disease.
A sufficient cause is usually not a single factor, but often
consists of several components, e.g., genetic factors,
overeating and lack of physical activity in causing diabetes.

A cause is termed necessary if the disease cannot

develop in its absence, e.g. infectious agents that
cause infectious diseases.

A causal factor may neither be necessary nor sufficient,

e.g. Tuberculosis and poor living conditions.
The table is explained more in your module manual
Not every association is
causation

(Association is not equal to

causation)
 Epidemiological association can be
*Apparent, but incorrect (artefactual), association due to
1. Bias (systematic error)
2. Confounding variables
3. Chance (random error)

**True association other than the proposed causal link may

result from a- Reverse causality (e.g. being obese and
working in a restaurant),
b- common or shared cause (e.g. chronic bronchitis and lung
cancer, both are due to smoking).

***True association with the proposed causal link

(e.g., smoking leads to lung cancer).
Steps to assess the relationship between
a possible cause and an outcome

1. Could the association be due to bias?

Bias is a systematic error.

One should evaluate how the study groups
were selected, how the information about
exposure and disease was collected, and how
the data were analyzed.
Bias: is deviation of the results or
inferences from the truth, or processes
leading to such deviation. It arises during
process of collection, analysis,
interpretation, publication or review of
data that are different from the truth.

Examples of bias
a- Selection bias
b- Information bias (e.g. recall,
measurement bias)
2. Could other confounding variables have
accounted for the observed relationship?
A situation in which the effect of an exposure on
risk of an outcome is distorted because of the
association of the exposure with other factors that
influence the outcome under study.

?associated
Coffee consumption Cancer of the Pancreas
(exposure) (outcome)
Associated Causally Associated
Cigarette smoking
(Confounder)
 Common confounders
• Age -- e.g., exposed persons are older
• Sex -- e.g., more exposure in men
• Risk factors - more exposed persons (or
unexposed) smoke (-), exercise (+), eat
vegetables (+), use of drugs (-) .
3. Could the association have been
observed by chance?

Chance can be excluded by statistical tests

through measuring
a- P-value (random error).
b- 95% confidence interval.
4. Does the association represent a
Cause-and-Effect relationship?

This can be determined by the criteria of

causality
Bradford Hill Criteria to judge the causal
significance of the association between the
factor (attribute or event) and an effect
(outcome, disease ..) are:

1. Time sequence (temporal association)

2. Strength of the association
3. Specificity of association
4. Consistency of the association
5. Coherence of explanation and biological plausibility
6. Biologic gradient (dose response)
7. Experiment (reversibility)
8. Analogy
9. Overall judgement.
1- Time sequence (temporal association):
Exposure must precede occurrence of
disease. This cannot be proved by cross-
sectional or case-control studies.
The shorter the duration between exposure
to an agent and development of disease,
the more certain is the causal effect, e.g.,
exposure to acute infectious agents, or to
chemical poisons.
2- Strength of association:
Incidence rate ratio (or relative risk) is the most direct
measure of strength of association.
A strong association, as measured by the relative
risk, is unlikely to result from bias.

⚫ Does exposure to the cause, change

disease incidence?
⚫ If not, there is no epidemiological basis for a
conclusion on cause and effect.
⚫ Failure to demonstrate this does not, however,
disprove a causal role.
⚫ The usual measure of the increase in incidence, is
the incidence rate ratio (or relative risk).
3- Specificity:
Here, the association is limited to specific exposure and to
particular disease with no other association between the
exposure and other types of disease.
This may be difficult to demonstrate, e.g., smoking and lack
physical activity lead to several health problems.

4- Consistency upon repetition:

This is when the association between an agent and
health effects has been observed by different
researchers in different places, circumstances, and
times, e.g., the Surgeon General report (1964) cited
many prospective and retrospective studies that found
association between smoking and lung cancer.
5- Coherence of explanation and biological
plausibility:
The association must be supported with what is already
known about the natural history and biology of the
disease, e.g., the association between tobacco and
lung cancer is coherent with the experimentally known
ability of tobacco extract to cause skin cancer in mice.
However, lack of biological plausibility may reflect lack of
current knowledge about plausible biological
explanation, which may become available in the future.
6- Dose-response
Does the disease incidence vary with the level of
exposure? If yes, the case for causality is
advanced.
The dose-response relation is also measured using
the incidence rate ratio (or relative risk), e.g., for
mild, moderate and heavy smokers.
7- Experiment (reversibility):
Presence of natural or planned experiment

⚫ Does changing exposure (reducing or removing the

supposed cause) change disease incidence?
⚫ Often there have been natural or nonmedical
experiments.
⚫ Deliberate experimentation may be necessary.
⚫ Human experiments or trials are sometimes ethically
impossible.
⚫ Causal understanding can be greatly enhanced by
laboratory and experimental observations.
8- Analogy:
When such associations have already been
demonstrated, e.g., the association between
thalidomide (analgesic used in 1950-1960s) and
congenital malformations. This will support
causality, if one finds similar association when
using a new analgesic drug.

9- Overall judgement: The more criteria are

met and the stronger studies were designed, the
higher is likelihood that the association is causal.
 Coherence
Specificity
Analogy

are
the weakest criteria
 Example of judging causality: smoking and lung cancer
Question

• Does the supposed cause precede the disease • Yes, clearly so

(effect)

(Temporal association)

• By how much does exposure to the cause raise • Greatly and as much as 20 to 30 fold in
the incidence of disease? smokers of 20 or more cigarettes per day

(Strength)

• Does varying exposure lead to varying disease? • Yes, there is clear relationship and more
smoking causes more disease
(Does-response)

• Does the cause lead to a rise in a few relevant • No. Numerous diseases show an association
diseases? with smoking

(Specificity)
 Causality: lung cancer
• Is the association consistent across
different studies and between groups?
(Consistency)
• Is the way that the cause exerts its effect
on disease understood?
(Biological plausibility)
• Does manipulating the level of exposure
to the cause change disease experience?
(Experimental confirmation)
• Overall judgement
• Yes. The association is
demonstrable in men and women,
and across social groups.
• Only partly. The tar in cigarettes
contains important carcinogens
• Yes. Reducing consumption of
cigarettes reduces risk. Persuading
people to smoke more would be
unethical. Tobacco is carcinogenic
to animals
Originally, bitterly contested, now
accepted as causal.
Thank You