Table 1.

Factors Relevant to Causal Inference Regarding the Risk of Mortality and Malignancy in the Setting of Immunosuppressive Therapy Given for Eye Diseases^*

Factor Suggesting Causality	Explanation	Supportive Observation(s)	Alternative Explanations of the Supportive Observation(s)
Strength of Association	A stronger association of the putative risk factor (“exposure”) with disease is more likely to reflect a causal relationship than a weaker association	Large (or small) risk ratios	Strong counfounding or bias
Consistency	A real effect, particularly one that is of wide generalizability, often will be observed consistently across many different circumstances	The association is observed in different populations under different circumstances	Repetition of a bias in study design or patterns of confounding across several studies
Temporality	A cause must precede an effect	Exposure precedes the purported effect	Not applicable
Biologic Gradient	The effect of exposure increases with increased exposure	Dose-reponse effects	Strong relationship of dose with a strong confounder
Biologic Plausibility	A reasonable biological explanation of the association can be made	A conclusion of causality is consistent with plausible theories of pathogenesis	Existing theories of pathogenesis are erroneous or are incorrectly question
Experimental Evidence	An experiment appropriately designed to test the relationship between exposure and disease is likely to affirm or refute the hypothesis of causation	Clinical trial/experiment randomizing to exposure or no exposure finds increased risk of mortality or malignancy	Random error

^*Adapted from Hill AB. The environment and disease: association or causation? Proc R Soc Med 1965; 16:1667–1670.