Association and causation

Prepared by: Dr. Laila T. Sabei

2015-2016
Descriptive studies help in the identification of the disease problem in the
community, and by relating disease to host, agent and environment factors
(epidemiological triad) or describe the disease or health event by person, place
and time (distribution triad); it ends by suggestion of an etiological hypothesis.
Analytical and experimental studies test this hypothesis which derived from
descriptive studies and confirm or refute (disprove) the observed association
between suspected causes and disease.
But, when the disease is multifactorial (e.g., IHD) numerous factors become
implicated in the web of causation; here the epidemiologist has to sift the husk
from the grain. ‫ لنخل القشر من الحبوب‬.
The terms association and relationship are often used interchangeably. Association
is defined as the occurrence of two variables more often than would be expected
by chance. However, Association does not necessarily imply a causal relationship.
In this context one should consider the concept of correlation.
Correlation indicates the degree of association between two characteristics. The
correlation coefficient, range from -1.0 to +1.0. A correlation coefficient of 1.0
means that the two variables exhibit a perfect linear relationship. However,
correlation cannot be used to demonstrate causation, because the sequence of
exposure preceding disease (temporal association) can not be assumed to have
occurred and the risk cannot be measured. Therefore causation indicates
correlation, but correlation does not indicate causation.

Association can be grouped into three types:

a) Spurious association: It is a false (not real) association due to chance or to
some bias in the methodology applied. For example, a study in UK about
hospital and home deliveries showed that perinatal mortality (PMR) among
hospital births is more than five times that of home deliveries; 27.8 /1000
and 5.4 /1000 respectively. Apparently, one may think that home delivery is
much safer. Such a conclusion is false (spurious or artifactual), because in
general, hospitals attract pregnant women at high risk for delivery because
of their special care and equipment and expertise. In addition, there might be
other factors also such as differences in age, parity, prenatal care, general
health and disease state between the two groups. This type of bias where
“like” is not compared with “like” (selection bias) is very important in
epidemiological studies. It may lead to a spurious association or an
association when none actually existed.
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b) Indirect association: it is a statistical association. It is meant that the factor
and the disease are associated only because both are related to some
common underlying condition (common factor or confounding variable).
It is of course non causal type of association. For example:

i- Altitude and endemic goiter; endemic goiter is generally found in high

altitudes, showing therapy an association between altitude and
endemic goiter. But we know that endemic goiter is due to
environmental deficiency of iodine. Here the iodine deficiency
(common factor), can result in an apparent association between the
two variables: high altitudes and the endemic goiter, when no
association exists. This is ascertaining that statistical association does
not necessarily mean causation.
ii- Sucrose and CHD; researchers found a higher intake of sugar by
patients with myocardial infarction. Their study based on an enquiry
by questionnaire method into dietary habits of cases and controls.
They put a hypothesis that people who consume lot of sugar are more
likely to have a heart attack.
Others studies found that heavy cigarette smoking was positively
associated with an increase in the number of cups of hot drinks
consumed daily and the amount of sugar consumed.
So, cigarette smoking and not sugar consumption which was
connected in the etiology of CHD.
Finally, experimental studies on animals proof that high sucrose
feeding did not induce arteriosclerotic disease.
Hence myocardial infarction (MI) is higher among the smokers than
the nonsmokers (sucrose was a victim).

c) Direct (causal) association: here we have 2 concepts:

i- One-to-one causal relationship: This model suggests that when the
factor A is present, the disease B must result. On the other hand, when
the disease is present, the factor must also be present. Measles may
be one disease in which such a relation exists.
The above concept of one-to-one causal relationship was the principle of
Koch`s hypothesizes: The supporters of the germ theory of disease insisted
that the cause must be necessary and sufficient for the occurrence of
disease. Whenever the disease occurs, the factor or cause must be present.
This theory does not fit well for many diseases. For example, in
tuberculosis, tubercle bacilli cannot be found in all cases of the disease but
this does not rule out the statement that tubercle bacilli are the cause of
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tuberculosis. But why other people exposed to the tubercle bacilli but not
become diseased, here appear the factors that play role in TB infection as
poverty, overcrowding, under nutrition and low socioeconomic state, that is
why tubercle bacilli are necessary cause but not sufficient in the causation of
TB.
The one-to-one causal relationship is further complicated by the fact that
sometimes, one cause or factor can result in more than one disease.

ii- Multifactorial causation: the casual thinking is different when we talk

about NCDs as CHD where the etiology is multifactorial. This
concept has two models:
a) In first model there is more than one factor (1,2 and 3) each acting
independently to produce the disease. in lung cancer more than
one factor (e.g. air pollution, smoking, heredity) can produce the
disease independently.

b) In the second model the causal factors act cumulatively to produce

the disease. Many diseases develop in this way. For example,
tuberculosis develops by the infection of tubercle bacilli in
susceptible person living in poor and overcrowded environment.

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Now it is clear that the model of one-to-one relationship of causation is rarely
found in biological phenomena. Because the requirement that “cause” is both
necessary and sufficient condition is not easily reached.
Additional criteria for judging causality (The Bradford Hill Criteria):
Certain additional criteria have been evolved for deciding when an association may
be considered a causal association.
1) Temporal association ‫العالقة الزمنية‬: Does the suspected cause precede the
observed effect? A causal association requires that exposure to a suspected cause
must precede temporarily the onset a disease. This is very clear and simple in acute
diseases as in case of food poisoning outbreaks. In chronic diseases, because of
insidious onset and lacking of precise induction periods, it is difficult to establish
temporal association.
2) Strength of association: This answered by relative risk, dose-response and
duration- response relationships. The larger the relative risk, the greater the
likelihood of a causal association. Increasing levels of exposure (dose and/or
duration) result in increase in incidence of disease.
3) Specificity of association: It implies the one-to-one concept. Specificity is a
most difficult criterion to establish not only in chronic disease but also in acute
diseases. The reasons are: first; a single cause or factor can give rise to more than
one disease. Secondly; most diseases are due to multiple factors.
4) Consistency of association ‫ ثبات و تطابق العالقة‬: When studies are repeated in
different settings and different methods and give same result.
5) Biological plausibility ‫المعقولية البيولوجية‬: The association agrees with the
understanding of the responses of cells, tissues, organs, and systems to stimuli. The
ultraviolet rays and skin cancer is biologically logical. But no biological sense
between food intake and skin cancer.
6) Coherence of the association ‫ ترابط منطقي‬: The coherence with the known facts
that are thought to be relevant.

In the following example, we apply the above criteria to the classic case of
smoking and lung cancer:
1- Temporal association: Smoking in the vast majority of cases preceded the
onset of lung cancer.
2- Strength of Association: in the absence of experimental data on humans,
the causal relationship of cigarette smoking and lung cancer has been based
on three points: a) relative risk. b) dose-response relationship. c) the
decrease in risk on cessation of smoking. As shown in the following tables.

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Table 1: death rate and relative risk for smokers and non-smokers

Daily average Death rate per 1000 Relative risk

cigarettes smoked Smokers Non-smokers
1-14 0.47 0.07 6.7
15-24 0.86 0.07 12.3
≥25 1.66 0.07 23.7

Table 2: lung cancer mortality ratios in ex-cigarette-smokers, by number of

years stopped smoking, British physicians
Years stopped smoking Mortality ratio
Still smoking 15.8
1-4 16.0
5-9 5.9
10-14 5.3
≥15 2.0
Non-smokers 1.0

3- Specificity of association: in the recent past, much of the controversy over

cigarette smoking and lung cancer centered round lack of specificity of the
association, because cigarette smoking is linked with not only lung cancer
but with several others such as CHD, bronchitis, emphysema, …… . The
lack of specificity can be explained by; tobacco smoke is a complex of
substances containing several harmful ingredients which could be
responsible of different diseases.
4- Consistency of association; more than 50 retrospective studies and at least 9
prospective studies in different countries have shown a consistent
association between cigarette smoking and lung cancer.
5- Biological Plausibility: Inhalation of hot smoke, into the lungs, and
deposition of carcinogenic chemicals over long time probably building itself
up to a threshold level and starting neoplastic changes in the lungs.
6- Coherence of association; the historical rise in tobacco consumption and
the rising incidence of lung cancer are coherent. Male and female
differences in trends of lung cancer deaths are also coherent with the more
recent adoption of smoking among women: death rates rose first in males
and are now increasing relatively more rapidly in females.