Inadequate/Insufficient Evidence to Determine Whether an Association Exists

Evidence is of insufficient quantity, quality, consistency, or statistical power to permit a conclusion regarding the existence of an association between sustaining a TBI and a specific health outcome in humans.

Limited/Suggestive Evidence of No Association

Evidence from several adequate studies, covering the full range of severity of TBIs that humans are known to encounter, is consistent in not showing a positive association between sustaining a TBI and a specific health outcome. A conclusion of no association is inevitably limited to the conditions, magnitudes of exposure (types of TBI—mild, moderate, and severe or penetrating), and length of observation in the available studies. The possibility of a very small increase in risk of the health outcome after sustaining a TBI cannot be excluded.


Many of the studies reviewed by the committee presented substantial obstacles to determining associations between TBI and long-term health outcomes because they were beset by limitations that are commonly encountered in epidemiologic studies, including lack of representative sample, selection bias, lack of control for potential confounding factors, self-reports of exposure and health outcomes, and outcome misclassification.

A study’s representativeness, even if it is population-based, can be compromised by low participation rates and loss to followup. Low participation rates can introduce selection bias, for example, if people who are symptomatic choose to participate more frequently in studies than those who are not symptomatic. Similarly, loss to followup can result in attrition bias, a form of selection bias, particularly if attrition is associated with disease status. Researchers not only try to measure selection bias by comparing baseline characteristics of participants with nonparticipants or characteristics of those lost to followup with those followed but can make adjustments to estimate the magnitude and direction of its effects.

Some of the studies reviewed by the committee did not specify the time between the injury and the followup period, so the committee could not determine whether the outcome lasted longer than 6 months. Many studies involved populations in rehabilitation centers where subjects might have had multiple injuries that included TBI, but the initial TBI might have been due to a stroke or a brain tumor. Those studies presented several problems, such as lack of representativeness of the younger veteran population and an inherent selection bias; for example, they might include only people who have health insurance.

Most cohort studies rely on self-reporting of symptoms on questionnaires. Symptom self-reporting potentially introduces reporting or recall bias, which occurs when the group being studied reports what it remembers more frequently than a comparison group. Reporting bias can lead to overestimation of the prevalence of symptoms or diagnoses in the TBI population. Symptom self-reporting might sometimes introduce another type of bias known as outcome misclassification, which leads to errors in how symptoms are classified into outcomes and analyzed.

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