Table 2.

Causal guidelines

Criterion	Definition	Notes
Temporality	Causes must precede effects, including any delay that may be expected between them.	This is necessary for all posited causal effects, even speculative ones.
Analogy	A proposed causal relationship should have some similarity to a known process or circumstance.	Analogs can make substitutions in one or more organisms, settings, specific exposures, or outcomes.
Mechanism	A modification of Hill’s original “Plausibility.” Causal relationships should have a plausible theoretical explanation.	This can be in terms of physiology, cellular processes, ‘omics, and more.
Reproducibility	The attribution of causation is strengthened when results can be replicated by different investigators across different times and places with different study subjects.
Specificity	Causal explanations are stronger when the causal relationship is observed in specific contexts, with specific persons, exposures, and outcomes.	This is the classic Person/Place/Time of epidemiology.
Coherence	The agreement between all evidence, especially when it validates proposed mechanisms.	This is translational science.

Causal guidelines employed by the HSRB for the level of evidence assessment (adapted from Sir A. Bradford Hill)^6,35.