The committee has noted, moreover, that the term biological plausibility is a source of confusion on at least two fronts. First, it is associated with guidelines (sometimes referred to as the Bradford Hill criteria) for causal inference from epidemiological evidence (Hill, 1965). In that context, an assessment of the biological plausibility of an association demonstrated by epidemiological analysis is meant to ensure that such an association is consistent with current biological knowledge. Evidence regarding biological plausibility can never prove causality. Therefore, it is also meant to guard against attributions of causality to biologically implausible statistical associations that might result from studies that have not adequately accounted for important variables.

For example, although a strong statistical relationship might exist between a woman’s risk of breast cancer and the number of bathrooms in her home, there is no mechanism based on knowledge of cancer biology that could indicate the relationship is causal. Rather, the number of bathrooms is associated with socioeconomic status, which is associated with such factors as diet that can be linked mechanistically to cancer biology. The biological implausibility of an association between the number of bathrooms in a house and the risk of breast cancer weakens the argument for a causal relationship. In other cases, a review of the biological plausibility of an association might add reassurance that the epidemiological findings point toward or reflect causality. Occasionally an epidemiological observation has been explained by a reasonable biological mechanism that, on further investigation, appeared not to be relevant for the pathophysiology.

This committee, however, is often faced with a set of circumstances in which the epidemiological evidence is judged inadequate to accept or reject a causal association between a vaccine exposure and an adverse event of concern. It is then left with the task of examining proposed or conceivable biological mechanisms that might be operating if an epidemiologically sound association could be shown between vaccine exposure and an adverse event. Identification of sound mechanisms could influence the development of an appropriate research agenda and give support for policymakers, as decisions frequently must be made in situations of incomplete information regarding causality. Finally, there is often value in understanding and pursuing possible biological mechanisms even if the epidemiological evidence suggests a lack of a causal association. New epidemiological studies could question that existing causality assessment and the biological data would gain prominence in the new assessments. Also, a review of biological data could give support to the negative causality assessment or could cause one to reconsider or pursue the epidemiological findings further.

Second, the committee understands that some readers of its reports are confused by what are perceived as contradictory findings. Although the committee has previously stated that biological plausibility can range across a spectrum, readers sometimes regard the term with a degree of certainty or precision the committee never intended. When other evidence of causality is available, bio-



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