A smoking gun?

Detecting
causes of disease
R. Fielding
Dept. Community Medicine,
HKU
http://www.commed.hku.hk/

Learning objectives
Critically review the concept of
causality in relation to disease.
Know Hills Criteria for Causality and
why such criteria are needed

Offer coherent arguments of nature

versus nurture on health and
disease.

Different levels of causality

Thinking about causality

What does the term cause imply?
That which produces an effect (Chambers
20th C)

Causality is the relation of cause and effect.

In health care, we usually talk of cause and
effect as etiological factor (cause) and
disease or pathological process (effect), e.g:
Strep. Pneumoniea causes pneumonia and
meningitis.
Arterial occlusion causes tissue necrosis

Is that what we mean?

However, what we really mean is:
infection with Strep. Pneumoniea, under a
limited range of conditions, can lead to the
development of pneumonia and meningitis.
Arterial occlusion leads to tissue necrosis.

Is this splitting hairs? No, because it

reflects our thinking about disease: what
it is, its causes, and, most importantly,
what strategies are used to tackle it.

Different levels of causality

Very few things have single, isolated
causes. Instead they reflect chains
or nets, temporal sequences of
events.
Proximal causes: close factors
Distal causes: distant factors
Predisposing factors

Genetic
Environmental
Lifestyle

Distinguishing cause and

determinants from chance
associations
Many factors influence the
development of disease in addition
to the direct cause.
Investigation of cause is complex;
nature of affected (and unaffected
individuals)
nature of their exposure

Koch's Postulates
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 microorganism should be isolated
from the diseased animal and grown in pure
culture on artificial laboratory media.
3. This freshly isolated microorganism, when
inoculated into a healthy laboratory animal, should
cause the same disease seen in the original
animal.
4. The microorganism should be reisolated in pure
culture from the experimental infection.

Hills criteria

Strength of association
Temporal relationship
Distribution of the disease
Gradient
Consistency
Specificity
Biological plausability
Experimental models
Preventive trials

Risk
Risk is the likelihood of an event
occurring. In health care events, we
usually consider a negative consequence
arising from exposure to a hazard.
Types of risk
Absolute: incidence of disease in any
population
Relative: ratio of the incidence rate in the
group exposed to the hazard to the incidence
rate in the non-exposed group
Attributable: Difference in incidence rates
between exposed and non-exposed groups.

How are different causal

levels often misconstrued?

Errors in thinking about

causality
The following reflect common
mistakes in thinking about causes of
disease
Genes cause disease
Disease is due to "Lifestyle
Environment accounts for most
variation in disease rates

Why are they problematic?

What do you think?

Family history
Family history of a disease, e.g.
cancer, is seen as indicating highrisk status.
But
those dying younger have less chance
to manifest disease, so offspring have
less family history
those living longer more likely to
develop disease, but longevity ignored
as benefit to offspring.

Problematic thinking:
disease-gene
All disease is a product of geneenvironment interaction.
Genes specify protein structures -ONLY

Only when genes come into contact

with an environment is their
advantage or disadvantage apparent:
environment could be cellular or
geographic.
Lifestyle, (includes ageing, nutrition,
infection, toxin exposure)

Do genes cause disease?

It all dependson whoyou ask
Differentiate
gene
a. genetic material instructing proteins that
confer relative advantage or disadvantage
(inherited polymorphisms): normal.
b. germ-line mutations: instructing proteins that
confer relative advantage or disadvantage
(sporadic/random polymorphisms) in germ
cells - inheritable
c. somatic mutation: instructing proteins that
confer relative advantage or disadvantage
(sporadic or random) limited to one cell.

...and other cellular levels

d. Transcription/repair errors: mistakes in reading
/repairing DNA, RNA, or ribosome control (see c.).
e. Cellular dysfunction in protein synthesis
f. Internal modification or modulation of cellular
responses to external factors

.However,
a, b, genetic disease, are really normal genetic
processes through which evolution occurs; only
the disadvantage is disease; advantage is
not.
c-f involve external factors
all translate into greater or lesser susceptibility
to incur problems in certain environments

How might they act?

Mono-genetic effects - e.g.
thalassemia (rare)
Complex effects - e.g. cancer and
almost every other disease
Variations in metabolism of
environmental toxins (e.g. via C450
polymorphs)
Behavioural (through polymorphs,
e.g. various sensitivity to certain
chemicals like adrenaline, dopamine)

To what extent is the burden

of disease due to different
components?

What proportion of cancer is due

to cancer-causing genes?
Can you see what is wrong with this
question?
Only ~10% of cancers are believed to be
related to specific cancer causing
genes, e.g. BRCA1;
Of these, most are interactive,
accounted for by e.g. Ca prostate (~40% of
risk due to heritable factors; Ca Br. 27%;
colorectal, 35%).
Very few, rare cancers, e.g. retinoblastoma

Epidemiological model for

disease evaluation
%

allocation of mortality

% of Cause of medical Life

deaths mortality
care
style
34.0 Heart dis.
12
54
14.9 Cancer
10
37
13.4 CVD
7
50
8.0
Accident
13
60
3.8
Influenza
18
23
pneumon
2.7
Respiratory 13
40

Enviro Biology
nment
9
28
24
29
22
21
25
2
20
39
24

24

Comparison of US Federal
expenditure to allocation of mortality
according to epidemiological model
Epidemiological Federal health
model
expenditure
1974-1976 (%)
90.2
System of
medical care
organization
1.3
Lifestyle

Allocation of
mortality (%)
11

43

Environment

1.6

19

Human biology

6.9

27

Interactions
Genes do not cause diseases. It is wrong
to claim they do. Genes instruct the
manufacture of proteins, which may or may
not advantage or disadvantage the
organism under certain conditions.
Similarly, no single disease can be
attributed to environment. Even poisoning
is influenced by phenotypical detoxification,
which is genetically modulated.
Lifestyle is even more complex that either
genes or environment.

Barkers Hypothesis
Barkers Hypothesis
Take a look at the above link for
further information.