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Criteria for Causation

2. Nice to Know:

Sadly, there is no sufficient way to prove that an association between a factor and a disease is a causal relationship. But there may be some indications, such as those identified by the philosopher John Stuart Mill in "A System of Logic" in 1843.

In 1965 Austin Bradford Hill adapted these (with input from other sources) into a set of criteria for assessing epidemiological relationships (Bradford-Hill A. The environment and disease: association or causation? Proc R Soc Med 1965;58:295-300).  These are very widely quoted, but have also been disputed, so to illustrate I have added comments after each one.  Please note that many authors have revised these criteria, so you will find different versions; sometimes 9 are listed and sometimes 7; please do not stress unduly over details.

Criteria:
Comments:
1. Chronological relationship: Exposure to the presumed cause must predate the onset of the disease This is widely accepted. But beware of the difficulty in knowing when some diseases actually began, if they have long latent periods.
2. Strength of association: If all those with the disease were exposed to the presumed causal agent, but very few in the comparison group were exposed, the association is a strong one. In quantitative terms, the larger the relative risk, the more likely the association is causal.  This criterion can be disputed: the strength depends very much on how many other factors are also considered, and how these are controlled in a study.  A strong relationship may also still be a confounded result. An example is the strong link between birth order and risk of Down's syndrome. This is actually due to maternal age at the child's birth. 
3. Intensity or duration of exposure (also called biological gradient, or dose-response relationship): If those with the most intense, or longest, exposure to the agent have the greatest frequency or severity of illness, while those with less exposure are not as sick, then it is more likely that the association is causal. A reasonable criterion if present, but may not apply if there are threshold relationships. Hence the absence of a dose response does not disprove causality
4. Specificity of association: If an agent or risk factor is found that consistently relates only to this disease, then it appears more likely that it plays a causal role. This is a weak criterion, and was derived from thinking about infectious diseases. Factors such as smoking or obesity are causally associated with several diseases; the absence of specificity does not undermine a causal interpretation
5. Consistency of findings: An association is consistent if it is confirmed by different studies; it is even more persuasive if these are in different populations. A good criterion, although it may lead us to miss causal relationships that apply to only a minority of people
6. Coherent, or plausible findings: Do we have a biological (or behavioural, etc.) explanation for the observed association?  Evidence from experimental animals, analogous effects created by analogous agents, and information from other experimental systems and forms of observation are among the kinds of evidence to be considered. A good criterion, but can be subjective: post hoc one can often supply an explanation for an unexpected result
7. Cessation of exposure. If the causal factor is removed from a population, then the incidence of disease should decline. This may work for a population, but for an individual the pathology is not always reversible

The more of these criteria are met in a given instance, the stronger the presumption that the association is causal.

For example, the lawyer asks you whether this patient's exposure to asbestos fibres cause lung cancer:

  1. Can we prove that the exposure predated the cancer?
  2. Did occupational groups most exposed to asbestos show the highest rates of cancer?
  3. Were those with the longest work history the most likely to get sick?
  4. Did they just get lung cancer?
  5. Have similar findings been reported from different countries?
  6. Does it make biological sense?
  7. When laws were passed banning asbestos, did lung cancer rates decline in those occupations?

Links: Confounding