and events with an early or a gradual onset that cannot be detected until long after vaccination. For simplicity, all of these are denoted ”late onset.” These potential adverse events can also be either acute or chronic in nature.
The most suitable study designs and analysis methods are greatly dependent on whether the potential adverse event has an early or late onset, and in the description below, separate methods are proposed for the two outcome types. This is a little bit of a simplification, since there are, of course, also potential adverse events that fall somewhere in between on this spectrum. It should also be pointed out that an early-onset chronic condition can be studied by use of either of the methods described for early or late onset, but the early-onset methods are in most cases preferable.
Another key issue is whether there is a clear time at which the potential adverse event happened, as with, for example, a seizure, or whether the disease evolves more gradually, without a single clearly defined day of onset, as with, for example, narcolepsy or autism. This does not affect the study design as much as the time of onset, but it is an important consideration when defining and collecting the data.
For most potential adverse events, we are interested only in incident diagnoses, that is, the first time that a particular diagnosis has been made. For example, if a child is diagnosed with asthma at age 2 years and then has a follow-up visit for his/her asthma at age 4 years, we do not want to attribute the asthma to a vaccination given at age 3 years. Depending on the potential adverse event under study, one can define an incident diagnosis as a diagnosis that has not occurred during the previous D days. The value of D will depend on the adverse event, but a typical value is about 1 year.
The potential adverse event studied either can be very specific, such as febrile seizures or autism, or can be more general, such as all-cause outpatient physician visits, emergency department visits, or hospitalizations. The latter set of events may seem more desirable, as it includes the combined effect of the vaccine schedule on all important health events, but the opposite is true. Such general definitions are more prone to biases, and they are therefore more difficult to study. This is because people that follow the CDC-recommended vaccine schedule may be different from those that do not, in terms of their health care–seeking behavior. For example, parents that are more prone to take their children to the doctor when the child is sick may also be more prone to take their children to the well care visits during which most vaccines are given.
Data Sets for Postmarketing Vaccine Safety Studies
To facilitate the understanding of the study designs and methods described in subsequent sections, a brief background is first given concerning