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condition? For example, can rubella vaccine cause chronic arthritis? If the conclusion is affirmative, a second question becomes pertinent: How frequently does it cause that condition? Or, how frequently is arthritis a result of rubella vaccination? The third question, which applies to a particular instance or case of an adverse event, is did it cause that specific event? Or, did rubella vaccine cause this particular individual to develop arthritis? Discussion of each of these three types of questions will help to indicate the committee's view of its task.

(1) Can vaccine cause the adverse event?

While the nature of causation has a deep philosophical underpinning, the work of the committee necessarily focused on a pragmatic question: What is the nature of the evidence relevant to drawing its conclusion about causation? In pursuing this question, the committee recognized that an absolute conclusion about the absence of causation may never be attained. As in science generally, studies of adverse events following vaccination are not capable of demonstrating a zero effect, that is, that the purported effect is impossible or could not ever occur. Any instrument of observation has a limit to its resolving power, and this is true as well of randomized clinical trials and epidemiologic studies. Hence, the committee could not prove the absence of any possibility of an adverse event caused by vaccine. Rather, in the absence of evidence suggesting an effect, and especially in the presence of evidence not consistent with causation, the committee could only conclude that the evidence fails to demonstrate an effect.

The evidentiary base that the committee found to be most helpful derived from epidemiologic studies of populations. Here, the primary question is whether an association exists between the exposure (immunization) and the event. To determine whether an association exists, epidemiologists estimate the magnitude of an appropriate quantitative measure (such as the relative risk or the odds ratio1) that describes the joint occurrence of exposures and events in defined populations or groups. Values of relative risk greater than 1 may indicate a positive, or direct (harmful), association and are emphasized in this discussion; values between 1 and 0 may indicate a negative, or inverse (protective), association. The observed relative risk in the study population must be sufficiently distant from unity to meet a stated criterion of significance before an association is said to be apparent.

1 Usage of "relative risk," "odds ratio," or "estimate of relative risk" is not consistent in the literature reviewed and cited in this report. In its own usage, the committee intends that ''relative risk" be used to refer to the results of cohort studies and "estimates of relative risk" or "odds ratio" be used to refer to the results of case-comparison studies (see Glossary of Terms for definitions).



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