1. Statistical significance: Might chance—that is, sampling variation—be responsible for the observed vaccine-adverse event association? The magnitude of the P (probability) value (or the width of the confidence interval) associated with an effect measure such as the relative risk or risk difference is generally used to estimate the role of chance in producing the observed association. This type of quantitative estimation is firmly founded in statistical theory on the basis of repeated sampling. No similar quantitative approach is usually possible, however, for assessing nonrandom errors (bias) in estimating the strength of the association.

  2. Consistency: Can It? causality is strengthened if the vaccine-adverse event association has been detected in more than one study, particularly if the studies employed different designs and were undertaken in different populations.

  3. Biologic plausibility and coherence: The vaccine-adverse event association should be plausible and coherent with current knowledge about the biology of the vaccine and the adverse event. Such information includes experience with the naturally occurring infection against which the vaccine is given, particularly if the vaccine is a live attenuated virus. Animal experiments and in vitro studies can also provide biologic plausibility, either by demonstrating adverse events in other animals that are similar to the ones in humans or by indicating pathophysiologic mechanisms by which the adverse event might be caused by receipt of the vaccine.

Although Can It? causality is usually addressed from epidemiologic studies, an affirmative answer can occasionally be obtained from individual case reports. Thus, if one or more cases have clearly been shown to be caused by a vaccine (i.e., Did It? can be answered strongly in the affirmative), then Can It? is also answered, even in the absence of epidemiologic data. In several circumstances, for example, the committee based its judgment favoring acceptance of a causal relation solely on the basis of one or more convincing case reports.

In this regard, however, it must also be added that the absence of convincing case reports cannot be relied upon to answer Can It? in the negative. If a given vaccine has an extremely long history of use and no cases of occurrence of a particular adverse event have been reported following its administration, doubt is inevitably cast on a possible causal relation. Given an extremely rare adverse event and the notorious problems of underreporting in passive surveillance systems, however, the absence of such reports is insufficient to reject a causal relation. The committee acknowledges that that which has not been reported might indeed have occurred.

Instead, the committee relied on epidemiologic studies to reject a causal relation. On the basis of the combined evidence from one or more con-



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