is not reasonably convincing in either the causal or non-causal direction, it is placed in the category “inadequate to accept or reject a causal relationship.” Evidence that is sparse, conflicting, of weak quality, or just suggestive falls into this category.

The sources of evidence considered by the committee in its scientific assessment of causality include epidemiological and clinical studies directly addressing the question at hand. That is, the data relate to the effects of the vaccine(s) under review and the specific adverse health outcome(s) under review— in the case of this report, the effects of multiple immunizations on developing immune system function. Epidemiological studies carry the most weight in a causality assessment; these studies measure health-related exposures or outcomes in a defined sample of subjects and make inferences about the nature and strength of associations between exposures and outcomes in the overall population from which the study sample was drawn. Epidemiological studies can be categorized as observational or experimental (clinical trial), and as uncontrolled (descriptive) or controlled (analytic). Among these various study designs, experimental studies generally have the advantage of random assignment to exposures and therefore carry the most weight in assessing causality. Uncontrolled observational studies are important but are generally considered less definitive than controlled studies. In uncontrolled observational studies where observations are made over time, confounding (e.g., changing case definitions and improving case detection) may influence the incidence and prevalence of the adverse outcomes studied.

Case reports and case series are generally inadequate by themselves to establish causality. Despite the limitations of case reports, the causality argument for at least one vaccine-related adverse event (the relationship between vaccines containing tetanus toxoid and Guillain-Barré syndrome) was strengthened most by a single, well-documented case report on recurrence of the adverse event following re-administration of the vaccine, a situation referred to as a “rechallenge” (IOM, 1994).

Biological Mechanisms

Evidence considered in the scientific assessment of biological mechanisms includes human, animal, and in vitro studies related to biological or pathophysiological processes by which immunizations could cause immune system dysfunction. This kind of review has been referred to in previous reports of this committee (IOM, 2001a, 2001b) and others (IOM, 1991, 1994) as an assessment of the “biological plausibility” of a causal relationship. The committee has previously described biological plausibility as existing on a spectrum, ranging from not plausible to established. An agreed upon hierarchy of evidence required for assessments of biological plausibility does not exist, nor does an associated terminology (Weed and Hursting, 1998).

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