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EXPERIMENTAL STUDIES. Epidemiological studies are either observational or experimental. Observational studies are considered “natural” experiments while experimental studies are considered true experiments.
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Epidemiological studies are either observational or experimental. Observational studies are considered “natural” experiments while experimental studies are considered true experiments
1.Defining feature of experimental studies: Investigator assigns exposure to study subjects A) Experimental studies most closely resemble controlled laboratory experiments and serve as models for the conduct of observational studies. B) They are the gold standard of epidemiological research. They have high status and validity, and can pick up small and modest effects
2. Overall conduct A) Hypothesis formed B) Study subjects recruited based on specific criteria and their informed consent is sought C) Eligible and willing subjects randomly allocated to receive one of the two or more interventions being compared D) Study groups are monitored for outcome under study (recurrence of disease, first occurrence of disease, getting better, side effects) E) Rates of the outcome in the various groups are compared
3. Ways to categorize experimental studies Individual versus community – treatment allocated to individual OR entire community • Do women with stage I breast cancer given a lumpectomy alone survive as long without recurrence of disease as women given a lumpectomy plus radiation? • Does fluoride in the water supply decrease the frequency of dental caries in a community compared to a similar community without such water treatment?
3. Ways to categorize experimental studies Preventive versus therapeutic – prophylactic agent given to healthy or high-risk individual to prevent disease OR treatment given to diseased individual to reduce risk of recurrence, improve survival, quality of life • Does tamoxifen lower the incidence of breast cancer in women with high risk profile compared to high risk women not given tamoxifen? • Do combinations of two or three antiretroviral drugs prolong survival of AIDS patients as well as regimens of single drugs?
4. Selection of study population A) Reference population - general group to whom results of a trial should be applicable (all humans, or some restrictions may apply) B) Study or experimental population – people who are considered for enrollment in a trial, potential participants
Reference Population Experimental Population Non-Participants Participants Treatment Allocation Treatment Group Comparison Group Cooperators Cooperators Non-Cooperators Non-Cooperators Population Hierarchy
5. Issues to be considered A) Size, size, size - not just number of people in the trial, but how many endpoints (outcome under study) are expected B) Restrictions on who is eligible (eligibility criteria) • Substantive: What group are you interested in? • Logistics: What group is accessible? Who will comply with study protocol? How feasible is complete and accurate follow-up on the subjects? • Characteristics of volunteers - How does study population differ from total experimental population?
6. Allocation of treatment A) Should be random assignment • DEFINITION: Each individual has the same chance of receiving each possible “treatment” B) Some examples of random allocation • Random number table: as each subject enrolled, assigned a number from the random number table; assign even numbers to treatment A and odd to treatment B • Toss a coin for each subject: heads=A, tails=B C) Some examples of nonrandom allocation • Alternate assignment of treatments • Assignment by day of the week
6. Allocation of treatment D) Goal of randomization • To achieve baseline comparability between compared groups on factors related to outcome • Essence of good comparison between “treatments” is that the compared groups are the same EXCEPT for the “treatment.” • Any group of individuals will vary in response to a “treatment” based upon their sex, age, overall health, severity of illness - in short, any factor that is relevant to response to the treatment. The investigator knows some of these (like severity of illness), but there are many unknown factors that are also relevant.
6. Allocation of treatment D) Goal of randomization IV. The compared groups should have the same distribution of all of these characteristics. That is what randomization can accomplish: the equal distribution of known and unknown factors that are relevant to response to the treatment (confounders) V. The larger the groups, the better randomization works
7. Use of placebo and blinding A) Goals • Placebos are used to make the groups as comparable as possible (recall laboratory experiment) • Blinding: subjects do not know if they are receiving treatment or placebo (single blind); neither subjects nor investigators know who is receiving treatment or placebo (double blind). • Purpose of blinding: To avoid bias in ascertainment of outcome • Placebo allows study to be blind
8. Maintenance and assessment of compliance A) Study requires active participation and cooperation of participants but deviations from the protocol will occur related to side effects, illness, level of interest, and length of follow-up B) Noncompliance makes the compared groups more alike, which reduces the ability of the investigator to detect a difference between the groups (diminishes study power) C) Strategies to enhance compliance exist at the design phase (pick an interested group and design a simple protocol) and during the study itself (frequent contact with subjects, incentives to continue, such as free check-ups)
9. Ascertaining the outcome A) Goals • High follow-up rates: don’t lose people • Uniform follow-up for compared groups: must be equally vigilant in follow-up in all compared groups B) Penalty of non-uniform ascertainment of outcome is BIAS
10. Analysis of data from experimental studies Data set up: familiar 2 x 2 table Measure of treatment effect: RR or RD
11. Important issues in experimental studies • Ethical considerations • Equipoise: Must be genuine doubt about efficacy of treatment yet sufficient belief that it may work • Stopping rules: What if it becomes apparent, before the trial is over, that the new treatment is beneficial (and should not be withheld from the placebo group) or is toxic (and treatment should be withdrawn)?
11. Important issues in experimental studies • Planning for an informative result. If the study finds no difference between compared treatments, do you believe it? Or was there a difference but the study was not powerful enough to detect it? Initial consideration is study size. • Analyzing by intention to treat: As the saying goes… once randomized, always analyzed.
