A strong association as measured by a high (or low) risk or ratio, an association that is found in a number of studies, and an increased risk of disease with increasing exposure or a decline in risk after cessation of exposure all strengthen the likelihood that an association seen in epidemiologic studies is causal. With deployment to a war-zone, there can be substantial uncertainty in the assessment of possible exposures in theater. To assess whether explanations other than causality (such as random or systematic error) are responsible for an observed association, one must bring together evidence from different studies and take into account the considerations presented by Hill and others (Evans, 1976; Hill, 1965; Susser, 1973, 1977, 1988, 1991; Wegman et al., 1997). For a recent review of those criteria, see the 2004 report of the US Surgeon General (Office of the Surgeon General, 2004).

TYPES OF EPIDEMIOLOGIC STUDIES

The committee focused on epidemiologic studies because epidemiology deals with the determinants, frequency, and distribution of disease in human populations. A focus on populations distinguishes epidemiology from medical disciplines that focus on the individual. Epidemiologic studies examine the relationship between exposures to agents of interest and health outcomes in a population (in this review, deployment is the exposure). Such studies can be used to generate hypotheses for study or to test hypotheses posed by investigators. This section describes the major types of epidemiologic studies considered by the committee.

Cohort Studies

A cohort study is an epidemiologic design that follows a defined group, or cohort, over a period of time. Using data from a cohort study, investigators can test hypotheses about whether exposure to a specific agent is related to the development of disease and can examine multiple health outcomes that might be associated with exposure to a given agent (for example, to deployment). A cohort study starts with people who are free of a disease (or other outcome) and classifies them according to whether they have been exposed to the agent of interest. It compares health outcomes in people who have been exposed to the agent in question with those who have not.

Cohort studies can collect data prospectively (such as in repeated follow-ups) or retrospectively (when exposure and outcome records exist). Generally, investigators select a group of subjects free of the health outcome at baseline (start of study follow-up) and determine who is exposed and not exposed to a given agent (independent variable) during follow-up while also determining the occurrence of the health outcome in both exposed and unexposed cohort members over time. In a retrospective (or historical) cohort study, investigators usually rely on records to determine past exposures for the cohort and another record system to ascertain the rate of disease. In a prospective cohort study both the exposure and disease assessment methods can be designed by the investigator rather than having to rely on existing records as is necessary for a retrospective cohort study. However, a prospective cohort study will not be able to provide sufficient data on chronic disease risk factors until a number of years, if not decades, of follow-up time have accrued. That is, many diseases have a lengthy latency period, for some health outcomes such as some cancers and cardiovascular disease, this can be 20 years or more.

Cohort studies can be used to estimate a risk difference or a relative risk, two statistics that measure association between the exposure groups. The risk difference, or attributable risk, is



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