Experimental Studies in Epidemiology (ch8)
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Observational Study (209)
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Researchers observe events for individuals in the study without altering them. Past experience, lifestyle, personal behaviors, training, immunization levels, exposure to risk factors, and environmental factors all impact the state of health and susceptibility to illness of individuals in groups and are beyond the influence of the investigator. Associations are observed, not manipulated. On the other hand, the experimental (also called intervention) study design involves the science and planning of how an experiment will be conducted in order to obtain valid and reliable results.
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Experimental Study (209-10)
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Researchers evaluate the effects of an assigned intervention on an outcome, the investigators intervene in the study by influencing the exposure of the study subjects. With the exception of the experimental study, all study designs are observational.
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Experimental Study Designs (210)
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No particular study design is always better than another. Each design has its unique strengths and weaknesses. Also has an important place in epidemiology. It involves a comparison or control group. The study includes randomization of participants to the intervention and control groups and participants and evaluators are blinded, confounding and bias may be effectively controlled. This is also a powerful study design because the investigator has more control over the level of exposure. The randomized blinded experimental study is considered to be the \"GOLD STANDARD\" in epidemiology for basing conclusions about casual relationships.
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Case Studies (210)
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Provide clues for identifying a new disease or adverse health outcome resulting from an exposure or experience.
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Cross-sectional Surveys (210)
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Useful for estimating prevalence an measuring several associations between variables at a give time.
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Ecologic Studies (210)
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Allow for estimation of effects not easily measured on individuals.
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Case-Control Studies (210)
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Are effective for measuring associations between exposure and outcome variables when the outcome is rare and the latency period is long.
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Cohort Studies (210)
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Are useful for establishing a time sequence of events and allows epidemiologist to estimate incidence (risk).
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Experimental Studies (210)
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Resemble controlled experiments performed in scientific research. They are the most useful for establishing cause-effect relationships and for evaluating the efficacy of prevention and therapeutic interventions.
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Between-Group Design (210)
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The strongest methodological design, where outcomes are compared between two or more groups of people receiving different levels of the intervention.
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Within-Group Design (210)
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May also be used where the outcome in a single group is compared before and after the assignment of an intervention. An important strength of this design is that individual characteristics that might confound an association (gender, race, genetic susceptibility) are controlled, however the within group design is susceptible to confounding from time- related factors such as the media but may be adjusted for in the analysis.
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Community Trial (210)
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In an experimental study, the unite of analysis may be on the individual or community level, in the latter case. In this case, the intervention is applied to individuals on the group level (school, classroom, or city).
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Clinical Trial (210)
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Is called when a experimental study is performed in a clinical setting.
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Natural Experiment (210)
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in some rare situations in nature, unplanned events produce a natural experiment. An unplanned typer of experimental study where the level of exposure to a presumed cause differ among a population in a way that is relatively unaffected by extraneous factors so that the situation resembles a planned experiment. ex...screening and treatment for prostate cancer in the Seattle-Puget Sound are differed considerably from screening and treatment in Connecticut during the period from 1987 to 1990.
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Applying the Experimental Study Design (211)
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May be readily apparent, for assessing physical, chemical, biological, and psychosocial environments poses ethical challenges. The outcome of interest may be too rare to feasibly perform an experimental study. For this reason, some of the other study designs presented in the outset of this section may be preferable. Variations of the experimental study involving randomization and blinding (running design, factorial design, matched-pair design, and the group-randomized design) are addressed later in this chapter.
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Random Assignment (211)
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When the study group is determined in an ideal situation the participants are then assigned to the intervention and control groups. Makes intervention and control groups look as similar as possible, thereby minimizing the potential influence of confounding factors. Chance is the only factor that determines group assignment, thus allowing the application of inferential statistical tests of probability and determination of the levels of significance.
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Randomized Controlled Trials (211)
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Most common in clinical settings.
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Subjects (211)
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Can be randomly assigned to more than just two groups when the efficacy of various levels of a treatment or combinations of treatments is being investigated. As with the other research designs, inferential statistical tests of probability are applied and levels of significance determined.
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Randomization (211-12)
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An important feature is that it balances out the effect of confounding. Assuming that smoking is a confounding factor, randomization of a sufficiently large number of subjects will produce a similar distribution of smokers (in terms of age started, duration, and intensity of smoking) between the intervention and control groups. Has the advantage of controlling for both known and unknown confounders. Sufficiently large number of subjects produces groups that are alike on average. Some situation, a physician may strongly believe in an intervention and place patients with more severe health problems in that group. Patients with more serious health problems may self select the intervention. Has the advantage of eliminating conscious bias resulting from physician or patient selection and averages out unconscious bias from unknown factors.
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Confounding Factors (211)
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Although it is possible to adjust for confounding factors at the analysis phase of a study, this assumes that data on the suspected confounders were collected at the outset of the study.
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Blinding (212)
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Used in experimental studies to minimize potential bias from the placebo effect.
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Placebo (212)
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An inactive substance or treatment given to satisfy a patients expectation of treatment. In some experimental studies that involve drug treatments, the placebos given of the control group are virtually indistinguishable ( to blind the patients and providers, when possible) from the true intervention, providing a comparative basis for determining the effect of the treatment being investigated.
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Placebo Effect (212)
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The effect on patient outcomes (improved or worsened) that may occur because of the expectation by a patient (or provider) that a particular intervention will have an effect. Is independent of the true effect (pharmacologic, surgical, etc) of a particular intervention. An assessing investigator, albeit honest, may believe in a certain intervention, and unconscious bias may arise in the way the researcher evaluates those subjects who receive the intervention.
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Blinding Patients (212)
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Controlled clinical trials in order to minimize the placebo effect dates back about 100 years.
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Double-Blind Placebo-Controlled Trial (212)
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In 1907, was conducted by W.H.R. Rivers to explore the association between alcohol and other substances and fatigue.
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Harry Gold (212)
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Advanced the Double-Bling Placebo-Controlled design in the 1940s and 1950s in several lectures and publications.
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Henry Beecher 1950s (212)
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Estimated that in over two dozens studies that he assessed the placebo effect was responsible for about one third of those who showed improvement. The contributions of these and other researchers led the Food and Drug Administration to recommend (in the 1970s) but not require that new drug trials be double blinded.
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Single-Blinded (212)
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Placebo-controlled study, the subjects are blinded, but investigation are aware of who is receiving the active treatment.
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Double-Blind Study (212)
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Neither the subjects nor the investigators know who is receiving the active treatment.
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Triple-Blind Study (212)
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Not only are the treatment and research approaches kept a secret from the subjects and investigators, but the analyses are completed in a way that is removed from the investigators.
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Drug Studies (212)
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Placebo is a pill of the same size, color, and shape as the treatment, however for nondrug studies, such as those involving behavior changes or surgery, it may be impossible or unethical to blind. It may also be problematic to blind in drug studies where a treatment has characteristic side effects. Building side effects into a placebo, which has no potential therapeutic advantages, may be unethical.
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Need for Blinding (212)
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Related to whether the outcome is subjectively determined. Ex...if the outcome measure is pain relief, a placebo would be highly desirable, whereas if the outcome measure was based on a urine sample or blood test, blinding the patient would be unnecessary.
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Drug Studies (212)
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Where placebos are used, compliance and retention in the study may be much better because patients will think they are benefiting from a given medication.
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Nonrandomization (213)
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Several reasons exist for not using random assignment. 1st, large research populations ar not always available, especially in clinical settings. Research is expensive, and funds may be adequate for the research procedures, follow-up treatments, and testing of large study and control groups. Another restraint is the lack of subjects with the disease or condition or desire to participate. If large population is to be treated with a preventive measure such as immunization, the epidemiologist would not purposely have half the population assigned at random to a control group and leave them at risk of getting the disease because they were not immunized.
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Randomization (213)
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Cannot be applied if an entire population is to be affected or subjected to the treatment. If fluoride is added to the water supply of a city, there is not way to include or exclude certain individuals.
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Seat Belt Laws (213)
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Implemented, control groups are not selected, and randomization is not used in the enforcement of the law. If randomly selected control groups are available, a comparison group may be selected from individuals with traits similar to those of the subjects in the treatment group. A pre-test/post-test approach will allow the treatment group to serve as its own control. The changes from the pre-test results to the post-test results often show a statistically significant cause-effect relationship.
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Randomization Not Feasible (213)
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Concurrent comparison group in a nonrandom process (convenience sample) may be chosen. If one city has fluoridated water, another city without fluoridated water could serve as a control, and dental outcomes from both groups could be used to evaluate the efficacy of fluoridation. Ex....seat belt use., if one state requires seat belts use and another does not, the death rate from motor vehicle accidents or some other seat belt-related outcome measure between the two states could be compared in order to determined the efficacy of seat belt use.
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Designing a Randomized Controlled Trial (213)
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There are several steps involved with designing a randomized controlled trial. Six general steps are presented in this section. (1) selecting the intervention (2) assembling the study cohort (3) measuring baseline variable (4) choosing a comparison group (5) ensuring compliance (6) selecting the outcome--also called the end point.
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Selecting the Intervention (213)
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Begins with the research objective, whether it is to treat or prevent disease. Trials aimed at evaluating the efficacy of a treatment, the investigator must establish that the therapy is safe and active against the disease, provide evidence that the therapy is potentially better than another, and provide evidence that the therapy is likely to be implementable in the field.
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Different Stages for Testing New Therapies (213)
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Must occur before a drug is granted a license. labs testing and animal studies show that a new drug has potential to benefit patients, it is first evaluated as a phase 1 trial.
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Phase 1 Trial (213-4)
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An unblinded, uncontrolled study with typically less than 30 patients. The purpose of phase 1 trials is to determined the safety of a test in humans. Patients in phase 1 trials often have advanced disease and have already tried other options. They undergo intense monitoring that show promise advance to phase II trials.
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Phase II Trials (214)
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Relatively small (up to 50 people) randomized blinded trials that test tolerability, safe dosage, side effects, and how the body copes with the drug. If there is good evidence that the new treatment is at least as good as existing treatments, further testing in phase III trial is warranted. Also evaluate which types of disease a treatment is effective against, further assess side effects and how they can be managed, and reveal the most effective dosage level.
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Phase III Trials (214)
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Typically much larger and may involve thousands of patients. These trials typically involve random assignment and are used to evaluate the efficacy of a new treatment. Different dosages or methods of administration of the treatment are often part of the evaluation.
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Behavioral Interventions (214)
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Begin with an identified problem, such as relatively high levels of sexually transmitted diseases, is observed in a population through descriptive epidemiologic methods, tailored programs can be developed.
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Identifying High-Risk Behaviors for Disease (214)
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Where these risk behaviors are most common, and understanding why these behaviors are more readily adopted by this group and not by others are important in designing the intervention. Behavior interventions are often developed from behavior theory and refined with focus groups.
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New Interventions (214)
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Often develop from existing interventions shown to be efficacious in other settings. Evaluation of behavioral interventions often requires pilot testing in order to provide evidence that a larger scale assessment is worth doing.
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Assembling the Study Cohort (214)
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Before, inclusion and exclusion criteria must be established and an appropriate sample size determined. Inclusive and exclusion criteria influence the extent to which the results can be generalized.
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Compromise (214)
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Between the population most efficient for answering the research question and the population best for generalizing the study findings. If the outcome of interest is rare, it may be necessary to include in the cohort only those high risk for developing the outcome. Ex....coronary heart disease cohort study may restrict subjects to males who are at least 40 years of age. Generalization of the study results would be limited to a narrower group that the entire population. In a therapeutic trial, only persons with certain criteria may be included. In a prevention trial, only persons at risk of developing an outcome of interest should be included.
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Exclusion (214)
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Criteria are employed to help control error. Loss to follow-up is a primary concern in randomized controlled trials. Person may be excluded from a study if they are likely to be lost to follow-up (alcoholics, psychotic pts, homeless persons, and persons planning on moving out of the country). Those with rapidly fatal conditions who are unlikely to be alive at the end of the follow-up period may be also excluded.
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Sample Size Calculations (214)
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Employed to ensure that the number of participants is adequate to test the specific hypothesis or hypotheses motivating the study. Sample size calculation is based on (1) formulation of the null and one-or two-tailed research hypothesis (2) search for appropriate statistical test (3) effect size (and in some cases, variability) (4) desired level of statistical significance for a on or two tailed test and desired probability of failing to reject the null hypothesis when it is actually false (5) use of appropriate table or formula for estimating the sample size. These tables and formulas are available in most introductory biostatistics books.
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Measuring Baseline Variables (215)
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Such as identifying information (name, address, telephone number), demographic information (age, gender, race/ethnicity, marital status, education, income) variables that might be associated with the outcome (cigarette smoking) and clinical features (serum cholesterol, blood pressure, glucose level) allow the researcher to accomplish certain objectives.
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Choice of a Comparison Group (215)
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When the efficacy of a new drug for treating a given illness is under investigation and existing drugs are currently available, the new drug is compared with the current treatment. Aim to identify whether improvements can be made over the status quo. In a study assessing the efficacy of a dietary program for recovering heart attack patients, it would be unethical to not allow those who are not randomly assigned the program to assume special diets designed for heart attack patients.
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Ensuring Compliance (215)
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The power of study is directly influenced by compliance with the protocol. If study follow up involves visiting a clinic for medical assessment, adherence can be improved by contacting patients by telephone or mail shortly involves adhering to the intervention protocol, the investigator should select a drug or behavioral intervention that is well tolerated. Low compliance (more regular contact with patients and higher incentives. Can be monitored in drug studies by self report, pill counts, and urine and blood test. Behavioral interventions can be monitored by self report and direction evaluation.
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Selecting the Outcome-End Point (216)
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It is not always clear what outcome variable is best
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Surrogate (216)
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In order to minimize cost and increase feasibility, SURROGATE markers of the actual phenomenon of interest are often used. Ex...instead of considering the effect of and HIV/AIDS drug on death, investigators might select a major AIDS-defining event as a surrogate end point for death. (parasitic infections fungal infection, viral infection, HIV dementia, HiV wasting syndrome, a neoplasm). Colon cancer prevention program could use polyps as an end points become particularly useful in randomized controlled trials when the outcome phenomenon of interest is rare. (ex...CD4 counts versus the presence or absence of a bacterial infection is HIV/AIDS patients)
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Selected Special Types of Randomized Study Designs (216)
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Under certain conditions, variations of the randomized controlled trial may have some advantages. Four of these study designs are presented in this section. They include run-in design, factorial design, randomized matched pairs, and group randomization.
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Run-In Design (216)
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For Placebo-Controlled studies, can be useful for minimizing bias associated with loss to follow up. All subjects in the cohort are placed on placebo and followed for some period of time (usually a week or two).
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Factorial Design (217)
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Allows investigators to address the efficacy of two interventions in a single cohort of subjects, are randomly assigned to one of four groups which represent the different combinations of the two interventions. In a placebo-controlled drug study, groups could be (1) drug A and drug B.....
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Randomization of Matched Pairs (217)
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Matching is a procedure that aims to make study and comparison groups similar with respect to extraneous (or confounding) factors, improve covariate balance on potential confounding variables. Provides more accurate estimates than unmatched randomization and may involve matching on several potential confounder. (ex....study group....dietary program, a drug)...
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Group Randomization (217)
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Instead of individual being randomly assigned the intervention, group or naturally forming clusters are randomly assigned the intervention. group may involve practices, schools, hospitals, or communities. ex....the Who Health Organization (WHO) randomly assigned 66 factories in the United Kingdom, Belgium, Italy, and poland to intervention and control groups. Primary outcome variable was death from coronary heart disease.
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Strengths and Weaknesses of Double-Blind Randomized Clinical Trials (218)
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Best study design for establishing cause-effect relationships in the double-blind randomized clinical trial. This is because blinding minimized bias and randomization minimizes confounding. Control over exposure status allows investigators to evaluate the influence of precise dosages and amounts on the outcome of interest, however, ethical and practical consideration often make this study design impossible to administer.
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Ethics in Experimental Research (218)
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In the U.S. the PUBLIC HEALTH SERVICE ACT OF 1985 ratified the establishment of institutional review boards (IRBs) are charged with the protection of research subjects. in part, a result of the moral problems associated with the Tuskegee Syphilis Study, which assessed the natural course of syphilis in untreated black males from Macon County, Alabama.
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Table 8-1 Selected Strengths and Weaknesses of Blinded Randomized Controlled Studies (218-9)
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Listing of STRENGTHS and WEAKNESSES
