severe TBIs or repeated injuries) show larger increases in risk, the pattern would be consistent with a dose–response relationship.

Biologic Plausibility

Biologic plausibility reflects knowledge of the biologic mechanism by which a TBI could lead to a health outcome. That knowledge comes through mechanism-of-action or other studies, typically in animals. Biologic plausibility provides a high level of confidence in drawing a conclusion of “sufficient evidence of a causal association” (see below). However, a biologically plausible mechanism might not be known when an association is first documented.

Types of Observational-Study Designs

Epidemiologic-study designs differ in their ability to provide evidence of an association (Ellwood, 1998). It must be noted that the studies reviewed by the committee were seldom designed specifically to answer the question in the committee’s charge, that is, whether sustaining a TBI during combat results in long-term adverse health outcomes. In examining the available epidemiologic studies, the committee addressed the question, Does the available evidence support a causal association between exposure (sustaining a TBI) and an outcome (a health effect)? Even a finding of a causal association between a TBI and a specific health effect does not mean that a TBI invariably results in the health effect or that all cases of the effect are the result of deployment. As discussed above, Hill’s criterion of specificity is not particularly applicable in studies of TBI given the diffuseness of the injury, or even in injury epidemiology in general, and in any event such complete correspondence between exposure and effect is the exception in large populations (IOM, 1994). The committee evaluated the data and based its conclusions on the strength and coherence of the data that resulted from the selected epidemiologic studies that met its inclusion criteria.

The major types of epidemiologic studies that the committee considered were cohort studies, case–control studies, and cross-sectional studies. In each case below, exposure, for purposes of this study, means sustaining a TBI.

Cohort Studies

A cohort, or longitudinal, study follows a defined group, or cohort, over some period. It can test hypotheses about whether a TBI is related to the development of a health effect and can examine multiple health effects that may be associated with a TBI. Our review looked for evidence in cohort studies that compared health effects in people who had a TBI with effects in those who did not. The committee gave substantially less weight to cohort studies that included only persons with TBI and measured outcomes as a function of factors other than TBI, such as age. Those types of studies are valuable for determining risk factors other than TBI for specific outcomes, but they do not provide information on whether a particular outcome, such as Parkinson disease, is associated with TBI.

Cohort studies can be used to estimate risk difference, RR, and hazards, all of which measure the strength of an association. The risk difference is the rate of disease or other health effect in exposed persons minus the rate in unexposed persons; a rate greater than zero implies that extra cases of the effect are associated with the exposure. Relative risk is determined by

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