|Strength of Association
||A strong association is more likely to have a causal component than is a modest association. Strength of the association is determined by the types of existing studies. The highest-level studies from the evidence pyramid would represent the strongest associations, (i.e., Systematic Reviews with Meta-Analyses and RCTs). Results from these studies must demonstrate an Odds Ratio (OR) or Relative Risk (RR) of at least 2.0 or above in order to be meaningful. Anything between 1 and 2 is weak, while >2 is moderate and >4 is considered strong.
||A relationship is repeatedly observed in all available studies.
||A factor influences specifically a particular outcome or population. The more specific an association between a factor and an effect, the greater the probability that it is causal.
||The cause must precede the outcome it is assumed to affect, e.g., smoking before the appearance of lung cancer) Outcome measured over time (longitudinal study).
|Biological Gradient (Dose-Response)
||The outcome increases monotonically with increasing dose of exposure or according to a function predicted by a substantive theory, i.e., the more cigarettes one smokes, the greater the chance of the cancer occurring).
||The observed association can be plausibly explained by substantive matter, i.e., biologically possible.
||A causal conclusion should not fundamentally contradict present substantive knowledge. (Studies must not contradict each other).
||Causation is more likely if evidence is based on randomized experiments or a systematic review with a meta-analysis of randomized experiments. However, if RCT’s are not ethically possible then prospective cohort studies may provide the highest level of evidence.
||For analogous exposures and outcomes, an effect has already been shown, e.g., effects first demonstrated on animals or an effect previously occurring on humans such as the effects of thalidomide on a fetus during pregnancy.