Veterans and Agent Orange Health Effects of Herbicides Used in Vietnam (1994) / Chapter Skim
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5 Methodologic Considerations in Evaluating the Evidence
5 Methodologic Considerations in Evaluating the Evidence
Pages 221-249
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From page 221... ...
whether a statistical association with herbicide exposure exists, taking into account the strength of the scientific evidence and the appropriateness of the statistical and epidemiologic methods used to detect the association; 2. the increased risk of each disease in question among those exposed to herbicides during Vietnam service; and 3.
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From page 222... ...
Conditions such as soft tissue sarcoma that are ill defined, birth defects that are known to occur in the absence of herbicide exposure, or conditions that generally have unknown causes or mechanisms of development are also inherently difficult to investigate. When the actual intensity or duration of exposure to a potential diseasecausing agent is difficult to measure, as is generally true for herbicide exposure in Vietnam, comparisons between presumably exposed and presumably nonexposed persons become clouded.
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From page 223... ...
When the groups differ with respect to factors that are also associated with the risk of the outcome of interest, a simple comparison of the groups may either exaggerate or hide the true difference in disease rates that is due to the exposure of interest. In the example of higher prevalence of smoking in the exposed workers, a simple comparison of lung cancer rates in the exposed and unexposed would exaggerate an apparent difference in lung cancer rates, since smoking is known to cause lung cancer.
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From page 224... ...
The evidentiary base that the committee found to be most helpful derived from epidemiologic studies of populations, that is, investigations in which large groups of people are studied to determine the association between the occurrence of particular diseases and exposure to the substances at issue. To determine whether an association exists, epidemiologists estimate the magnitude of an appropriate quantitative measure (such as the relative risk or the odds ratio)
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From page 225... ...
When those Vietnam veterans who are actually exposed have not been identified properly, as has generally been the case in existing studies, this question becomes difficult to answer. By considering the magnitude of the association observed in other cohorts, the quality and results of existing studies of veterans related to a particular outcome, and
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From page 226... ...
That is, it may be assumed that an exposure is harmful unless sufficient evidence of safety is present; alternatively, it may be assumed that an exposure is safe unless convincing evidence of harmful effects is present. In either case, it is sometimes argued that a burden of proof must be fulfilled before the presumed position is rejected.
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From page 227... ...
CATEGORIES OF EVIDENCE Experiments in Humans: Randomized Controlled Trials Theoretically, the ideal method for assessment of causal relations (and thereby associations) between treatments and health outcomes is the randomized controlled trial because, when appropriate and feasible, it is the most scientifically rigorous method for testing such hypotheses.
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From page 228... ...
In contrast to randomized controlled trials and other experimental studies in humans, most epidemiologic investigations are "observational." This means simply that the occurrences of herbicide exposure and particular diseases are studied as they arise in the usual course of life and not under the conditions of a planned experiment. Observational studies in populations are often "controlled," however, through various strategies of formal comparative investigation.
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From page 229... ...
In the second case, which typically depends on the availability of records of past exposures and health outcomes, the entire study may relate to experience prior to the start of the investigation. Such studies are termed historical or retrospective cohort studies.
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From page 230... ...
It seems reasonable to imagine that health status at the time of enlistment was comparable in these two groups, so the healthy worker effect is not likely to introduce serious bias. There were 1,261 Ranch Hands who were compared
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From page 231... ...
Even if the nearly 20-year period of observation for some individuals in the Ranch Hand study is considered, not even one case of STS would be expected among the 1,261 Ranch Hands. Because the outcomes in question are generally rare, the case-comparison or case-control design has more often been used in the investigation of health outcomes considered .
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From page 232... ...
Proportionate Mortality Studies In some cohort studies, investigators have no accurate data on the composition of the cohort, but they do have access to sets of death records. The proportion of deaths due to each cause in a particular cohort is available, but not the actual mortality rates.
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From page 233... ...
If a chemical is thought to cause lung cancer, for example, lung cancer deaths should be excluded from a proportionate mortality study of the association between that chemical and other cancers. An extreme ex ample would be an exposure that elevates the risk of every cause of death.
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From page 234... ...
When the disease of interest is uncommon, which is true for many of the diseases suspected of being related to herbicide exposure, the odds ratio will generally provide a reasonable estimate of the relative risk (Breslow and Day, 1980~. As such, the odds ratio is a measure of association that can contribute to answering whether exposure is associated with the disease under consideration.
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From page 235... ...
Most of the outcomes thought to be associated with herbicide exposure did not become apparent until years or decades after the veteran returned from Vietnam. Most are relatively common outcomes in a cohort of individuals who are now generally 40 years of age or older.
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From page 236... ...
Information from Death Certificates Data used in many studies involving mortality experience are obtained from death certificates; these studies tend to be conducted among occupational groups, and medical records are not always reviewed. Death certificates can provide occupation as well as cause of death information; the occupation as listed is used by investigators as a surrogate for potential exposures under investigation.
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From page 237... ...
No decisions as to the adequacy of evidence favoring or not favoring a positive association were made solely on the basis of a quantitative metaanalytic result. Nevertheless, the fact that, in several instances, the metaanalysis was consistent with the qualitative conclusion, served to reinforce that conclusion.
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From page 238... ...
As can be seen in Chapter 8, for instance, a number of the studies on cancer describe so few cases that large relative risks cannot be ruled out. When a number of sufficiently similar studies of the same health outcome are available, it is sometimes possible to pool statistical information from the studies to develop an estimate of the relative risk, or odds ratio, of the outcome in question that is more precise than estimates from individual studies.
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From page 239... ...
are not necessarily study specific and depend to varying degrees on prior knowledge. Strength of Association Strength of association is usually expressed in epidemiologic studies as the magnitude of the measure of effect, for example, relative risk or odds ratio.
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From page 240... ...
The committee, in addition, considered whether the disease occurred within a time interval following herbicide exposure that was consistent with current understanding of its natural history. The committee interpreted the lack of an appropriate time sequence as evidence against association, but recognized that insufficient knowledge about the natural history and pathogenesis of many of the diseases under review limited the utility of this consideration.
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From page 241... ...
Given the limitations of existing biological or medical knowledge, however, lack of specific biologic support for a given health outcome did not rule out a conclusion of .
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From page 242... ...
Resolution in epidemiologic studies concerns the capacity of a study to discriminate the frequencies of health outcomes or exposures between groups in order to determine the presence or absence of associations. By analogy, resolution in epidemiology also depends in a sense on magnification, that is, on the order of magnitude of the numbers of participants for example, from tens to hundreds of cases and controls in case-control studies, and from hundreds to thousands of exposed and unexposed subjects in cohort studies.
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From page 243... ...
For example, in CDC's Selected Cancers Study (199Ob) , the lack of a significant statistical association between soft tissue sarcoma and the Vietnam experience may reflect the small sample size (310 cases)
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From page 244... ...
For individual studies, confidence intervals around estimated results such as relative risks represent a quantitative measure of uncertainty. Confidence intervals present a range of results that, with a predetermined level of certainty, is consistent with the observed data.
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From page 245... ...
, the likelihood of publication seemed to depend on the author's perception of the importance of the work, and this perception was related to the statistical significance of the findings. The committee did not consider the risk of publication bias to be high among studies of herbicide exposure and health risks for several reasons: 1.
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From page 246... ...
whether there is a plausible biologic mechanism or other evidence of a causal relationship between herbicide exposure and a disease. The committee addressed the first part of this charge by categorizing each of the health outcomes under study into one of the four categories described below on the basis of the epidemiologic evidence that it reviewed.
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From page 247... ...
. Increased Risk in Vietnam Veterans The categories related to the association between exposure to chemicals and health outcomes, not to the likelihood that any individual's health problem is associated with or caused by the herbicides in question.
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From page 248... ...
1990. Proportionate mortality among U.S.
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From page 249... ...
1981. An alternative to the proportionate mortality ratio.
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