A smoking gun Detecting causes of disease

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A smoking gun? Detecting causes of disease

• R. Fielding
• Dept. Community Medicine,
• HKU
• http//www.commed.hku.hk/

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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.

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Different levels of causality
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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

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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.

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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

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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

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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 s
hould be isolated from the diseased animal and
grown in pure culture on artificial laboratory
media. 3. This freshly isolated microorganism, w
hen 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.
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Hills criteria

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

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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.

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How are different causal levels often
misconstrued?
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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?

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Family history

• Family history of a disease, e.g. cancer, is seen
  as indicating high-risk 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.

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Problematic thinking disease-gene

• All disease is a product of gene-environment
  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)

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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.

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• ...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

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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)

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To what extent is the burden of disease due to
different components?
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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

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Epidemiological model for disease evaluation
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Comparison of US Federal expenditure to
allocation of mortality according to
epidemiological model
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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.

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Barkers Hypothesis

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