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Goldfrank's Manual of Toxicologic Emergencies

Goldfrank's Manual of Toxicologic Emergencies

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Published by Kang Kyu Choi
Goldfrank's Manual of Toxicologic Emergencies
Goldfrank's Manual of Toxicologic Emergencies

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Published by: Kang Kyu Choi on Jul 10, 2011
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Advances in clinical medicine are usually achieved through a typical scientific
method. First, astute clinicians make interesting observations. These observa-
tions lead to the generation of hypotheses. Research questions are analyzed with
an epidemiologic investigation, and initial studies are examined with method-
ologic scrutiny. Initial analytic techniques are improved, and confirmatory stud-
ies are performed. Ultimately, models relating cause to effect are formulated.
The field of medical toxicology is rapidly transitioning from a descriptive
discipline to one of rigorous scientific exploration. New associations between
toxic xenobiotics and diseases are being explored every year. An understand-
ing of basic principles of research design and epidemiology is required to in-
terpret published studies and to lay the groundwork for future investigation in
toxicology.

EPIDEMIOLOGIC TECHNIQUES AVAILABLE TO INVESTIGATE
CLINICAL PROBLEMS

Table 132–1 lists the different study formats.

Study Designs

Descriptive case reporting serves a valuable purpose in describing the characteris-
tics of a medical condition or procedure and remains a fundamental tool of epide-
miologic investigation. A case report is a clinical description of a single patient or
procedure with respect to a situation. Case reports are most useful for hypothesis
generation. However, single case reports are not generalizable, as the reported sit-
uation may be atypical. A number of case reports can be grouped, on the basis of
similarities, into a case series.Case series can be used to characterize an illness or
syndrome, but without a control group they are severely limited in proving cause
and effect. Cross-sectional studies assess a population for the presence or absence
of an exposure and condition simultaneously. Such data often provide estimates
ofprevalence—the fraction of individuals in a population sharing a characteristic
or condition at a point in time. These studies, particularly helpful in public health
planning, are extremely useful in monitoring common environmental exposures,
such as childhood lead poisoning, or population-wide drug use, such as occurs
with tobacco, marijuana, and alcohol. An analysis of secular trendsis a study
type that compares changes in illness over time or geography to changes in risk
factors. These analyses often lend circumstantial support to a hypothesis; how-
ever, because of the ecologic nature of their design, individual data on risk factors
are not available to allow exclusion of alternative hypotheses that are also consis-
tent with the data. Case-control studies compare affected, treated, or diseased pa-
tients (cases) to nonaffected patients (controls) and look for a difference in prior
risk factors or exposures. Because subjects are recruited into the study based on
prior presence or absence of a particular outcome, case-control studies are always
retrospective in nature. They are especially useful when the outcome being stud-
ied is rare, and they enable the investigation of any number of potential etiologies
for a single disease. Cohort studiescompare patients with certain risk factors or
exposures to those patients without the exposure, then follow these cohorts to see

Copyright © 2007 by The McGraw-Hill Companies, Inc. Click here for terms of use.

1048

PART C THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

which subjects develop the outcome of interest. In this respect, they allow the
comparison of incidence(the number of new outcomes occurring within a popu-
lation initially free of disease over a period of time) between populations that
share an exposure and populations that do not. They are particularly well suited to
investigations in which the outcome of interest is relatively common.
Experimental studies are those in which the treatment, risk factor, or expo-
sure of interest can be controlled by the investigator to study differences in
outcome between the groups. The prototype is the randomized, blinded, con-
trolled clinical trial. Among epidemiologic study types, these provide the
most convincing demonstration of causality. Unfortunately, interventional
studies are the most complex to perform, and several questions must be ad-
dressed by investigators before performing a clinical trial. Human clinical tri-
als have been especially difficult to apply to the practice of toxicology. Table
132–2 lists the characteristics of poisoned patients that hamper attempts at
clinical trials.

MEASURES USED TO QUANTIFY THE STRENGTH OF AN
EPIDEMIOLOGIC ASSOCIATION

Therelative riskcan be defined as the incidence of outcome in exposed indi-
viduals compared to the incidence of outcome in unexposed individuals, and
can be calculated directly from cohort or interventional studies. However, in a
case-control study, an investigator chooses the numbers of cases and controls
to be studied, so true incidence data are not obtained. In case-control studies
anodds ratio can be calculated, and the odds ratio will provide an estimate
for relative risk in situations where the outcome is rare, such as when the out-

TABLE 132–1.Types of Epidemiologic Study Designsa

Experimental
Clinical trial
Observational: Analytic
Cohort
Case-control
Observational: Descriptive
Analysis of secular trends
Cross-sectional
Case series
Case report

a

Study designs are listed in descending order from the design that offers the
best epidemiologic evidence for association to that which offers the least.

TABLE 132–2.Difficulties in Applying Clinical Trials to Human Poisoning

•It is unethical to intentionally “poison” subjects.
•Poisoned patients represent a broad spectrum of demographic patterns.
•A wide variety of poisons exist.
•Exposures to any single poison are usually limited.
•A limited number of poisoned patients are available at any one study site.
•Uncertainty often exists as to type, quantity, and timing of most poison expo-

sures.

•Poisoning typically results in a relatively short course of illness.

132PRINCIPLES OF EPIDEMIOLOGY AND RESEARCH DESIGN

1049

come occurs in fewer than 10% of exposed individuals. A relative risk of 1.0
signifies that an outcome is equally likely to occur whether an individual is
exposed or not and implies that no association exists between the exposure
and the outcome. A relative risk approaching 0 suggests that an exposure is a
marker of protection with regard to the outcome, and a relative risk approach-
ing infinity suggests the exposure predicts a tendency toward the outcome.

MEASURES USED TO QUANTIFY THE SIGNIFICANCE OF AN
EPIDEMIOLOGIC ASSOCIATION

The goal of statistical analysis is to determine the degree to which chance can
be excluded as the true reason the results of the study were obtained. By con-
vention, statistical analysis typically tests the null hypothesis—the hypothesis
that there is no association between exposure and outcome. Because analytic
studies involve only a sample of the total population, they contain 2 types of
inherent error. Type I error, also referred to as alpha (α) error, is the likeli-
hood that an investigator may conclude that an association exists when none
truly does. Type II error,or beta (β) error, is the possibility that an investiga-
tor will be unable to find an association when one is really present.

DIFFERENTIATION BETWEEN CLINICAL SIGNIFICANCE AND
STATISTICAL SIGNIFICANCE

The finding of a low pvalue indicates a statistically high level of confidence
that a difference between study groups exists, but offers no indication that the
difference is clinically important. Small actual differences between two
groups can become statistically significant if large numbers of subjects are
studied. Likewise, impressive associations of cause and effect can seem triv-
ial if few subjects are in a study. The clinical significance of an association is
left to the judgment of the individual interpreting a study. Ideally, a working
definition of clinical significance is developed before a study is performed.

METHODOLOGIC PROBLEMS FOUND WITHIN CLINICAL STUDIES

Clinical research involving patients is particularly susceptible to bias, which can
be defined as systematic error in the collection or interpretation of data. Because
such error can lead to an inappropriate estimate of the association between an ex-
posure and an outcome, careful evaluation of potential biases affecting a clinical
study is of paramount importance. Selection biasrefers to error introduced into a
study by the manner in which subjects are selected for inclusion in the study. In-

formation bias refers to error introduced into a study as a result of systematic dif-
ferences in the quality of data obtained between exposed and unexposed groups,
or between those with and without the outcome of interest. The potential for

recall biasis frequently cited as criticism of retrospective case-control studies.
Simply, exposed subjects may have a different capacity to remember than the un-
exposed. Similarly, interviewer biasmay occur if study personnel differ in how
they solicit, record, or interpret information as a result of knowledge of the sub-
jects’ status with regard to exposures or outcomes. Misclassification biasoccurs
when investigators incorrectly categorize subjects with respect to exposure or
outcome. Bias is best minimized through careful study design.
Unlike selection and information biases, which are errors introduced into
studies primarily by the investigators or subjects, confounding is a special
type of problem that may occur within a study as a result of interrelationships

1050

PART C THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

between the exposure of interest and another exposure. Confoundingis a bias
wherein an observed association is not a product of cause and effect but in-
stead results from linking of the exposure of interest to another associated ex-
posure. For example, studies pertaining to adverse effects of drugs of abuse
are especially prone to confounding by variables such as concomitant caf-
feine use, alcohol use, tobacco use, nutritional deficiency, and/or psychiatric
illness. Randomization is an important method to assure that unsuspected
confounding factors are equally distributed between treatment groups within
interventional studies.

EVIDENTIARY CRITERIA USED TO LINK CAUSE AND EFFECT

Association of an exposure to an illness does not necessarily equate to cause
and effect. In assessing causation, it must be determined if bias is present in
the selection or measurement of exposure or outcome. Table 132–3 provides
a list of evidentiary criteria that are often used to support causation. Because
in medical toxicology it is virtually impossible to prove causal relationships
beyond any doubt, the goal is to build empiric evidence so that associations
can be confirmed or refuted with conviction.

EVALUATION OF DIAGNOSTIC TESTS AND CRITERIA

In clinical practice it is often useful to have a test, which may be a laboratory
result or clinical paradigm, to help arrive at a diagnosis or predict an outcome.
The usefulness of diagnostic testing is often described in terms of sensitivity,
specificity, predictive value of a positive test (PPV), and predictive value of a
negative test (NPV). A cross-sectional design is often used to study diagnostic
tests, as we seek to determine the prevalence of positive tests among the dis-
eased (sensitivity), and the prevalence of negative tests among the healthy
(specificity). A perfect test would be highly sensitive and specific, but this is sel-
dom possible in medical toxicology. A highly sensitive test is often used in
screening programs because they rarely lead to false-negative diagnoses. Spe-
cific tests are typically used to confirm a diagnosis, as they rarely yield false-
positive results. Whereas sensitivity and specificity are inherent properties of a
diagnostic test applied to a given population; the probability of disease, based
on the results of a test, is highly dependent on the prevalence of disease within
the population being tested. The PPV is the probability of having disease in a
patient with a positive test; the NPV is the probability of not having disease
when the test result is negative. Figure 132–1 illustrates the calculation of the

TABLE 132–3.Criteria Supporting Causation

Study design

Was the association demonstrated in a well-designed study?

Temporality

Does the cause precede the effect?

Strength

What degree of relative risk was demonstrated in the analysis?

Dose
response

Does an increased presence of risk factor correlate to
greater or more frequent effect?

Consistency

Does the cause and effect hold true in different studies,
locations, and populations?

Plausibility

Is the association in accordance with current scientific
knowledge?

Specificity

Does the effect occur without the cause in question, or vice
versa?

132PRINCIPLES OF EPIDEMIOLOGY AND RESEARCH DESIGN

1051

sensitivity, specificity, PPV, and NPV. It is important to remember that these
calculations, too, are subject to bias and that these calculations are best pre-
sented with confidence intervals.

FIG. 132–1.Possible results of diagnostic testing and the statistical charac-
teristics used to describe the usefulness of diagnostic tests. The letters a, b, c,
and d represent the numbers of tested individuals with or without the disease of
interest.

1052

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