Table 138–2 lists the different study formats discussed below.
TABLE 138–2.Epidemiologic Study Designs: Types, Measurements, and Advantages ||Download (.pdf) TABLE 138–2. Epidemiologic Study Designs: Types, Measurements, and Advantages
|Study Designa ||Main Measurement ||Advantages |
|Clinical trial ||Efficacy ||Gold standard for drug development |
|Noninferiority trial ||Safety ||Noninferior drugs may be better tolerated, cheaper, or easier to use |
|Cohort ||Incidence, Risk Factors ||Provides more robust evidence of association |
| || ||Reduced bias in exposure data |
| || ||Can study many outcomes simultaneously |
| || ||Allows direct calculation of incidence |
| || ||Allows direct calculation of relative risk |
|Case control ||Association ||Smaller sample required when outcome is rare |
| || ||Reduced bias in outcome data |
| || ||Can study many exposures simultaneously |
| || ||Allows estimation of relative risk |
| || ||May obviate need for long follow-up period |
|Analysis of secular trends ||Population ||Examine trends in disease events over time |
| ||Trends ||Study across different geographic locations |
| || ||Can correlate them with trends in putative exposures |
|Cross-sectional ||Prevalence ||Uncover relationships for future study |
| || ||Highly feasible |
|Case series ||Descriptive ||Characterize new syndromes or exposures |
|Case report ||Descriptive ||Identify signals for hypothesis generation |
Observational Design: Descriptive
A staggering array of xenobiotics are able to injure people, necessitating reliance of toxicologists on good descriptive data regarding toxic outcomes. Through 2011, the National Poison Data System (NPDS) of the American Association of Poison Control Centers (AAPCC) has amassed a database of more than 50 million human exposures (Chap. 136). Descriptive case reporting serves a valuable purpose in describing the characteristics of a medical condition or procedure and remains a fundamental tool of epidemiological investigation. A case report is a clinical description of a single patient or procedure in a unique context. Case reports are most useful for hypothesis generation. However, single case reports are not always generalizable, as the reported situation 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. In 1966, a case series of two patients with acute liver necrosis following overdose of acetaminophen (APAP)12 was accompanied by a case report of liver damage and impaired glucose tolerance after APAP overdose,40 which led to further study and the eventual creation of the Rumack-Matthew nomogram (Chap. 35). Similarly, a 1979 case report of “hypertension and cerebral hemorrhage after trimolets ingestion”24 led to subsequent animal studies, experimental human studies, and epidemiologic studies culminating in the decision by the US Food and Drug administration to remove phenylpropanolamine from nonprescription cold remedies and appetite suppressants (Chap. 42). The important role for descriptive data in guiding clinical research, focusing educational efforts, and formulating public policy are often underappreciated.
Cross-sectional studies assess a population for the presence or absence of an exposure and condition simultaneously. Such data often provide estimates of prevalence—the fraction of individuals in a population sharing a characteristic or condition at a point in time. These studies are particularly helpful in public health planning and have been 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. The US National Health and Nutrition Examination Survey demonstrated that the percentage of children with blood lead concentration greater than 10 μg/dL decreased from 88.2% to 4.4% between 1976 and 1991, with the highest rates of plumbism among African American, low-income, or urban children.5
An analysis of secular trend is a study type that compares changes in illness over time or geography to changes in risk factors (ecological). These analyses often lend circumstantial support to a hypothesis; however, because of the ecologic nature of their design, individual data on risk factors are not available to allow exclusion of alternative hypotheses also consistent with the data. A prime example of an analysis of secular trends is the finding that reports of Reye syndrome declined between 1980 and 1985, coincident with a fall in sales of, or physician recommendations of, children’s salicylate products.4 This investigation suggested an etiologic role of salicylate in the development of Reye syndrome but could not exclude alternative hypotheses such as a change in viral epidemic patterns.
Observational Design: Analytical
Hypotheses that are generated by theoretical reasoning or anecdotal association require analytical testing. Case-control studies and cohort studies are analytical techniques that use observational data, and each technique has its own advantages and disadvantages (Table 138–2). Case-control studies compare affected, treated, or diseased patients (cases) to nonaffected patients (controls) and evaluate for a difference in prior risk factors or exposures (Fig. 138–1A). Because participants 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 studied is rare, and they enable the investigation of any number of potential etiologies for a single disease.
(A) Schematic representation of the case-control study design. Participants with an outcome or condition of interest are selected, along with control participants, and then are evaluated for previous exposure to a risk factor of interest. (B) Schematic representation of the cohort study design. Participants are recruited based on the presence or absence of a risk factor or exposure, then followed to see if they develop an outcome.
The hypothesis, derived from multiple case reports and case series, that phenylpropanolamine might increase risk for hemorrhagic stroke was well suited to case-control study. Exposure to ingested phenylpropanolamine, as an ingredient in cold remedies and appetite suppressants, was common; but hemorrhagic stroke is rare among children and young adults. Other putative risk factors such as tobacco use, hypertension history, family history, cocaine use, and contraceptive use were identifiable and could be studied simultaneously. In a case-control analysis of 702 participants with hemorrhagic stroke and 1376 controls, the use of appetite-suppressant doses of phenylpropanolamine were found to be independently associated with the occurrence of hemorrhagic stroke.23
Cohort studies compare patients with certain risk factors or exposures to those patients without the exposure, and then follow these cohorts to see which participants develop the outcome of interest (Fig. 138–1B). In this respect, they allow the comparison of incidence (the number of new outcomes occurring within a population initially free of disease over a period of time) between populations who share an exposure and populations who do not. They may be retrospective or prospective and enable the study of any number of outcomes from a single exposure. They are particularly well suited to investigations in which the outcome of interest is relatively common. In circumstances when an outcome of interest is very uncommon, such as the case with stroke after phenylpropanolamine use, the large number of study participants required might make a cohort study impractical. A cohort of 981 APAP overdose participants was used retrospectively to investigate whether administration of activated charcoal might be beneficial therapy for APAP poisoning.8 Participants were separated on the basis of whether or not they were treated with activated charcoal and were subsequently followed to see if they developed concentrations deemed toxic by the Rumack-Matthew nomogram. Perhaps the most famous cohort study was the Framingham Heart Study in which 5209 residents of Framingham, MA, aged 30 to 62 years, were followed for over 50 years. This study provided a useful tool for studying the incidence of lung cancer, stroke, and cardiovascular disease in those exposed to cigarette smoke and other hazardous xenobiotics.13
Experimental studies are those in which the treatment, risk factor, or exposure of interest can be controlled by the investigator to study differences in outcome between the groups (Fig. 138–2). The prototype is the randomized, blinded, controlled clinical trial. Among epidemiologic study types, these provide the most convincing demonstration of causality. Clinical trials are used to measure the efficacy (the treatment effect within a controlled experimental setting) of treatment regimens and to draw inferences about the effectiveness of a treatment applied to the general population. Sometimes a trial can be designed to study drug treatments that are hampered by nonresponders to therapy, expensive drugs, or poorly tolerated regimens. Such trials are termed noninferiority trials, and operate on the null hypothesis that the new (study) drug is worse than the control (standard) drug. Thus, finding a difference between groups in a noninferiority trial means that the alternative hypothesis can be accepted that the new drug is not worse than the standard treatment.
Schematic representation of the design of a randomized clinical trial.
Unfortunately, interventional studies are the most complex to perform, and several questions must be addressed by investigators before performing a clinical trial (Table 138–3). Human clinical trials have been especially difficult to apply to the practice of toxicology. Table 138–4 lists characteristics of poisoned patients, which hamper attempts at clinical trials. Volunteer studies, using nontoxic xenobiotics or nontoxic doses of toxic xenobiotics, are often used to circumvent many of the problems in controlling human poisoning studies; but it is typically difficult to apply results from these studies to the actual context of toxic overdoses. In an experimental, human volunteer study, activated charcoal reduced absorption of ampicillin by 57%.39 Taken out of this artificial setting, a trial of single-dose oral activated charcoal was unable to prove benefit to outcome among 1479 heterogenous participants presenting to an emergency department (ED) for possible poisoning.29 Neither study was able to answer whether activated charcoal reduces morbidity from ingestion of dangerous xenobiotics if given while the xenobiotic is still in the stomach and amenable to adsorption.
TABLE 138–3.Considerations in Designing a Clinical Trial ||Download (.pdf) TABLE 138–3. Considerations in Designing a Clinical Trial
|What is the question of interest? |
|What is the target patient population? |
|How will the safety of subjects be assured? |
|What is a suitable control group? |
|How will outcomes be measured? |
|What difference in outcomes between groups is considered important? |
|What is the analysis plan? |
|How many subjects will be required? |
|How will randomization and blinding be achieved and maintained? |
|How long a follow-up period will be required? |
|How will loss of study subjects be addressed? |
|How will treatment compliance be evaluated? |
TABLE 138–4.Difficulties in Utilizing Clinical Trials to Study Human Poisoning ||Download (.pdf) TABLE 138–4. Difficulties in Utilizing Clinical Trials to Study Human Poisoning
|It is unethical to intentionally “poison” subjects. |
|Poisoned patients represent a broad spectrum of demographic patterns. |
|A wide variety of xenobiotics exist. |
|Exposures to any single xenobiotic 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 xenobiotic exposures. |
|Poisoning typically results in a relatively short course of illness. |
As toxicologists strive to find evidence for, or against, the traditions of clinical practice, several important clinical trials have been published. Among them are many important examples and lessons in epidemiologic study design. One trial attempted to evaluate whether or not corticosteroids might be beneficial in preventing esophageal strictures secondary to circumferential caustic injury of the esophagus.3 Because of the inherent difficulty in recruiting eligible patients from a single institution, only a small sample of 60 patients with esophageal injury were recruited over an 18-year period. Another study randomized hyperbaric oxygen therapy versus sham (placebo) therapy, among 152 victims of carbon monoxide poisoning, to investigate its effect on the development of neurocognitive injury.42 Certain concerns with the methodology and analyses of clinical studies are examined later in this chapter to illustrate epidemiologic concepts, and must be carefully considered when trying to apply the results of any clinical trial into the patient care setting.