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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality
event occur in the absence of vaccine exposure? Does a similar event occur more frequently in animals exposed to the vaccine than in appropriate controls?
Alternative etiologic candidates: Can a preexisting or new illness explain the sudden appearance of the adverse event? Does the adverse event tend to occur spontaneously (i.e., in the absence of known cause)? Were drugs, other therapies, or diagnostic tests and procedures that can cause the adverse event administered?
Susceptibility of the vaccine recipient: Has he or she received the vaccine in the past? If so, how has he or she reacted? Does his or her genetic background or previous medical history affect the risk of developing the adverse event as a consequence of vaccination?
Timing of events: Is the timing of onset of the adverse event as expected if the vaccine is the cause? How does that timing differ from the timing that would occur given the alternative etiologic candidate(s)? How does the timing, given vaccine causation, depend on the suspected mechanism (e.g., immunoglobulin E versus T-cell-mediated)?
Characteristics of the adverse event: Are there any available laboratory tests that either support or undermine the hypothesis of vaccine causation? For live attenuated virus vaccines, has the vaccine virus (or a revertant) been isolated from the target organ(s) or otherwise identified? Was there a local reaction at the site at which the vaccine was administered? How long did the adverse event last?
Dechallenge: Did the adverse event diminish as would be expected if the vaccine caused the event? Is the adverse event of a type that tends to resolve rapidly regardless of cause (e.g., a febrile seizure)? Is it irreversible (e.g., death or a permanent neurologic deficit)? Did specific treatment of the adverse event cloud interpretation of the observed evolution of the adverse event?
Rechallenge: Was the vaccine readministered? If so, did the adverse event recur?
Three ways to assess Did It? causality from case reports could be applied to reports of adverse events following receipt of vaccines. The most common is global introspection (Lane, 1984). The assessor attempts to take the relevant aforementioned factors into account and to weigh them appropriately in arriving at an overall decision, which is usually expressed as "yes" or "no." Although causality in individual cases is occasionally obvious, it may be difficult or impossible to consider and properly weigh all the relevant facts simultaneously, let alone to possess those facts (Kramer, 1986).
A second method for assessing Did It? causality is based on the construction of algorithms (branched logic trees) (Venulet, 1982). Such algorithms have been shown not only to improve the reproducibility and validity