1. A smoking gun? Detecting causes of disease R. Fielding Dept. Community Medicine, HKU http://www.commed.hku.hk/

2. Learning objectives Critically review the concept of causality in relation to disease. Know Hill’s Criteria for Causality and why such criteria are needed Offer coherent arguments of nature versus nurture on health and disease.

3. Different levels of causality

4. 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

5. 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.

6. 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

7. 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

8. 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.

9. Hill’s criteria Strength of association Temporal relationship Distribution of the disease Gradient Consistency Specificity Biological plausability Experimental models Preventive trials

10. 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.

11. How are different causal levels often misconstrued?

12. 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?

13. 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.

14. 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)

15. Do genes cause disease? It all depends…on who…you askIt 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.

16. ...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

17. 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)

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

19. 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

20. Epidemiological model for disease evaluation

21. Comparison of US Federal expenditure to allocation of mortality according to epidemiological model

22. 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.

23. Barker’s Hypothesis Take a look at the above link for further information.