For individuals, the question refers to the probability that a given vaccine recipient will experience the adverse event because of the vaccine. For populations, Will It? refers to the proportion of vaccinees who will experience the adverse event as a result of the vaccine. For either individuals or populations, the answer to Will It? is best estimated by the magnitude of the risk difference (attributable risk): the incidence of the adverse event among vaccine recipients minus the incidence of the adverse event among other otherwise similar nonrecipients. This entity is often confused with the etiologic fraction, probably because the latter is also referred to as the population attributable risk.

The risk difference depends on both the background incidence of the adverse event (i.e., among nonrecipients of the vaccine) and the relative risk of its occurrence in vaccine recipients versus nonrecipients. Thus, even when the relative risk is high, the risk difference will be low if the event is extremely rare.

Will It? causality assessments are essential for risk-benefit considerations, because the risk difference expresses the probability of the risk of an adverse event caused by the vaccine. But Will It? depends on Can It?; if the evidence is insufficient to conclude whether a vaccine can cause a given adverse event, then it is also insufficient to conclude whether it will. Moreover, when an affirmative answer to the Can It? question is based only on case reports rather than epidemiologic studies, no quantitative estimate of Will It? is possible.

Even though the Will It? question was not part of the committee's specific mandate, estimates of the risk difference (attributable risk) are provided, whenever possible, for those associations for which the committee judged the evidence to favor acceptance of a (Can It?) causal relation and for which epidemiologic data provide information on the incidence of the adverse event among nonvaccinees and the relative risk of its occurrence among vaccinees.

SOURCES OF EVIDENCE FOR CAUSALITY

The sources of evidence for causality examined by the committee include demonstrated biologic plausibility, reports of individual cases or series of cases, and epidemiologic studies. In an epidemiologic study, the investigators measure one or more health-related attributes (exposures, outcomes, or both) in a defined sample of human subjects and make inferences about the values of those attributes or the associations among them (or about both the values and associations) in the source population from which the study sample originates. Epidemiologic studies can be either uncontrolled (descriptive) or controlled (analytic), observational (survey) or experimental (clinical trial). These sources of evidence are discussed in greater



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