People
tend to use the word “proof” without understanding what it means. When, in
respect of a proposition, someone says: “There is no proof”, the response
should be: “What do you mean by proof?”, a question that is usually met by a
puzzled silence.
“Proof”,
as originally defined in classical geometry, is the fulfillment of predefined
criteria. Someone who asks for proof should be asked: “What are your predefined
criteria of proof?”
This
was understood by the great German pathologist Robert Koch. His challenge was
to find the cause of tuberculosis, consumption or phthisis as it was known at
the time in the latter half of the nineteenth century. At the time it was
thought that tuberculosis was “constitutional” – it ran in families and, in the
days before genetics, it was considered to be somehow inherited. Koch felt that
the family clustering was the result of the transfer of a micro-organism.
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| Robert Koch 1943-1910 |
Much
laboratory work led him to define what became known as the Koch Bacillus, what
we now know as Mycobacterium tuberculosis. Although he felt that this
was the likely cause and had to be certain. He needed proof that would be
acceptable not only to himself but also to a scientific community that was
clearly sceptical.
Understanding
the concept of proof, Koch had to record his predefined criteria that, if
fulfilled, would lead to the acceptance of the micro-organism being the cause
of tuberculosis. His criteria were called “Koch’s Postulates”, and they are as
follows:
1. The specific organism should be shown to be present in all
cases of animals suffering from a specific disease but should not be found in
healthy animals.
2. The specific micro-organism should be isolated from the
diseased animal and grown in pure culture on artificial laboratory media.
3. This freshly grown micro-organism, when inoculated into a
healthy laboratory animal, should cause the same disease seen in the original
animal.
4. The micro-organism should be re-isolated in pure culture from
the experimental infection.
Koch’s
postulates were very demanding, and it can be seen that they required the
following reach requirements:
•
the postulated cause must be a
micro-organism;
•
the micro-organism must be isolated and grown in laboratory culture;
•
The micro-organism must be inoculated into a healthy animal and produce
disease.
Not
all micro-organisms can be isolated and grown, this applying to viruses and
many recently-discovered bacteria. Not every micro-organism causing human
disease will produce that disease in laboratory animals. Is inoculation into
human, volunteers or in ignorance, acceptable? The answer to this is an
emphatic “No!”
Koch’s
Postulates have major limitations and in practice they are only of historic
interest. They cannot be applied to non-biological likely causes of disease and
a different approach became necessary.
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| Sir Austin Bradford Hill 1897-1991 |
The
eminent British statistician Sir Austin Bradford Hill felt that proof of
causation could be made using different criteria than Koch’s postulates, and he
felt these to be necessary in the case of the inanimate causes of disease, for
example cigarette smoking as the cause of carcinoma of the lung. He
identified the following criteria as being necessary for “proof” to be
established:
1. Strength of association
2. Consistency of association
3. Temporality
4. Biological gradient
5. Plausibility
6. Coherence
7. Experimentation
8. Analogy
It
is important to note that apart from Experimentation, all the criteria are part
of the observational process of scientific investigation. The observations
become increasingly controlled so as to avoid other factor. For example death
rate must be standardised for age.
It
is generally recognised that proof is pragmatic, the fulfillment of
predetermined criteria. There is no absolute proof; we are looking for the best
story that can be defined using existing knowledge. It might change with the
passage of time as new knowledge becomes available.
Koch’s
postulates identified absolutes; a bacterium did or did not grow. Hill’s
criteria are not absolute and all criteria can be regarded as judgmental.
The
strength of association is the association between the disease and the
proposed cause. The strength is determined by statistical method.
Consistency is important, being the
association being corroborated in several studies.
Temporality indicates that association at one
point in time does not indicate cause-effect relationship, but we must look at
the association over a time-line. The proposed cause must predate the disease.
The
biological gradient indicates that in general the greater the exposure
to the proposed cause, the great is the probability of disease (for example
number of cigarettes smoked and the development of lung cancer).
All
these add up to construct plausibility – does it make sense? Is there a coherent pattern – does it all
hang together?
Experimentation is limited by ethical
considerations. It might be possible to transmit the disease to others, if not
to experimental animals then to other human beings. Such research is not
tolerated today. However the effect of elimination of the proposed cause is
ethical and highly informative.
Finally
there is analogy. Does the proposed cause or something similar
(biological or chemical) cause similar diseases?
Hill’s
criteria of causation have been reviewed and refined by researchers at the US
National Institute of Health (NIH) to look at the possibility of a microbe
causing a disease, and in this particular case Crohn’s disease. The principles
are equally applicable to the investigation of a possible microbial cause of
coronary heart disease, for which there is no obvious cause at present
(cholesterol and diet theories are not sustainable when the evidence is
reviewed critically).
Hill’s
Criteria are very valuable but little known. Most if not all doctors are aware
of Koch’s Postulates, but Hill’s Criteria do not seem to be taught. We should
all be more aware of them.
