|The experimenter's view of the trees.|
- Causal pathway redundancy: redundancy in causal pathways may mitigate the agent's effects on the downstream outcome of interest - blocking one intermediary fails because another pathway remains active
- Causal factor redundancy: the factor affected by the agent has both beneficial and untoward effects in different causal pathways - that is, the agent's toxic effects may outweigh/counteract its beneficial ones through different pathways
- Time dependency of the causal pathway: the agent interferes with a factor in the causal pathway that is time dependent and thus the timing of administration is crucial for expression of the agent's effects
- Multiplicity of agent effects: the agent has multiple effects on multiple pathways - e.g., HMG-CoA reductase inhibitors both lower LDL cholesterol and have anti-inflammatory effects. In this case, the agent may influence the outcome favorably, but it's a trick of nature - it's doing so via a different mechanism than the one you think it is.
Next consider Figure 2. S. pneumoniae triggers a causal cascade that leads to death, but it also triggers several other sequences that do not lead to death, represented as A, B, C and J, K, L. (These factors could be cytokines or any other immunological molecules.) Suppose that investigators researching clinical illness with S. pneumoniae discover these nine molecules and further research shows that, compared to levels of these molecules in patients without disease, levels in patients with clinical infection are elevated and positively correlated with the probability of death. Naturally we hope that the molecules we have discovered and can measure are part of the causal pathway to death from the illness, but we have no way of knowing based on these correlations. In this simple example, only a third of the molecules discovered and correlated with death are causal intermediaries. The other two-thirds are epiphenomena, and their manipulation by any means will not affect the causal pathway to the outcome of interest.
(See also: Why Sepsis Trials Fail by Roger Bone, JAMA, 1996; and an editorial by Opal and LaRosa in AJRCCM June 1, 2013.)