variable. Other common sources of information bias are the inability of study subjects to recall accurately the circumstances of their exposure (recall bias) and the likelihood that one group more frequently reports what it remembers than another group (reporting bias). Information bias is especially harmful in interpreting study results when it affects one comparison group more than another.

  • Confounding occurs when a variable or characteristic otherwise known to be predictive of the outcome can account for part or all of an apparent association. A confounding variable is an uncontrolled variable that influences the outcome of a study to an unknown extent, making precise evaluation of the effects of the independent variable impossible. Carefully applied statistical adjustments can often control for or reduce the influence of a confounder.


Chance is a type of error that can lead to an apparent association between an exposure to an agent and a health effect when none is present. An apparent effect of an agent on a health outcome may be the result of random variation due to sampling in assembly of the study population rather than the result of exposure to the agent under study. Standard methods that use confidence intervals, for example, allow one to assess the role of chance variation due to sampling.

Thus, the committee’s final judgment is based on a balance between the strength of support of an association and the degree of exclusion of alternatives. The evaluation of evidence to reach conclusions about statistical associations goes beyond quantitative procedures, and several stages during the review required thoughtful consideration and judgment and could not always be accomplished by adherence to a prescribed formula.

The approach described here evolved throughout the process of review and was determined in important respects by the nature of the evidence, exposures, and health outcomes being examined. Both quantitative and qualitative aspects of the process were important to the overall review. Ultimately, the conclusions expressed in this report about causation are based on the committee’s collective judgment.


The committee classified the evidence of an association between exposure to a specific agent and a specific health outcome in five categories. The categories have been developed by previous IOM committees and also have been used to evaluate vaccine safety (IOM 1991 1994a), herbicides used in Vietnam (IOM 1994b, 1996, 1999, 2001, 2003b), and indoor pollutants related to asthma (IOM 2000a).

Sufficient Evidence of a Causal Association

Evidence is sufficient to conclude that there is a causal association between exposure to a specific agent and a specific health outcome in humans. The evidence is supported by experimental data and fulfills the guidelines for sufficient evidence of an association (below). The evidence must be biologically plausible and satisfy several of the guidelines used to assess causality, such as strength of association, dose-response relationship, consistency of association, and temporal relationship.

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