diseases; for example, a study on cerebral malaria in children might be reviewed if it provided information about the disease in adults.


The committee’s goal was to use the evidence in the medical and scientific literature to determine the relationships between the infectious diseases of interest and specific adverse health outcomes that might appear months to years after primary infections. Those relationships, presented in Chapter 5, are conceived in terms of the “strength of association” between a primary infection and a specific long-term adverse health outcome. The committee ranks strength of association qualitatively using a five-tier system, presented below in full.

Origin and Evolution of the Categories

A brief historical overview of the committee’s categories of association will elucidate their scientific roots. The International Agency for Research on Cancer (IARC), part of WHO, established criteria in 1971 to evaluate the human carcinogenic risk posed by chemicals (IARC 1998). First published in 1972, IARC’s evaluations are scientific, qualitative judgments by ad hoc working groups about the evidence of carcinogenicity or noncarcinogenicity provided by the available data. The working groups express their qualitative judgments in terms of five categories of the relative strength of the evidence that a substance or exposure is carcinogenic (IARC 1999a). Agencies in 57 countries use IARC’s published evaluations—a reflection of the widespread acceptance of the categorization scheme as it has been updated and applied to about 900 agents, mixtures, and exposures (IARC 1999b; IARC 2005).

In the early 1990s, an IOM committee adopted IARC’s categories in evaluating the adverse health outcomes of pertussis and rubella vaccines (IOM 1991). Later IOM committees used the categories, with some modifications, in evaluating the safety of childhood vaccines (IOM 1994a), the health outcomes of herbicides used in Vietnam (IOM 1994b; IOM 1996; IOM 1999; IOM 2001; IOM 2003b), and the relationship between indoor pollutants and asthma (IOM 2000a). The present committee’s predecessors also adapted and used the categories in evaluating the health effects of outcomes given to US troops and of chemical exposures that may have occurred during the Gulf War (IOM 2000b; IOM 2003a; IOM 2004; IOM 2005).

The five categories of strength of association used in this report are presented and defined below.

Sufficient Evidence of a Causal Relationship

Evidence from available studies is sufficient to conclude that there is a causal relationship between exposure to a specific agent and a specific health outcome in humans. The evidence includes supporting experimental data and fulfills the guidelines for sufficient evidence of an association (see next category). The association is biologically plausible, and the evidence satisfies several of the guidelines used to assess causality, such as strength of association, dose-response relationship, consistency of association, and a temporal relationship.

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