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Epidemiology and Biostats Chapter 8

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Objectives
Discuss the role of randomization in controlled trials, Discuss the role of blinding in controlled trials, Identify the general strengths and weaknesses of controlled trials,Identify the advantages to using a run-in design, a factorial design, a randomized matched pair design, or a group-randomized design, Discuss some of the ethical issues associated with experimental studies
Epidemiologic Experimental Studies
Resemble controlled experiments performed in scientific research
Best reserved for relatively mature questions
Best for establishing cause-effect relationships and for evaluating the efficacy of prevention and therapeutic interventions
Experimental Studies
-intervention studies
-Investigators influence the exposure of the study subjects
Two types of experimental trials
Controlled trials
Community trials
Between-Group Design
The strongest methodological design is a between-group design, where outcomes are compared between two or more groups of people receiving different levels of the intervention
Within-Group Design
May be used where the outcome in a single group is compared before and after the assignment of an intervention
Strength - Individual characteristics that might confound an association (e.g., gender, race, genetic susceptibility) are controlled
Weakness - Susceptible to confounding from time-related factors such as the media but may be adjusted for in the analysis
Controlled Trial
Unit of analysis is the individual

Randomized control trail in a clinical setting is referred to as a clinical trial
Community Trial
The unit of analysis is the group or community
An experimental epidemiologic study where one group of people, or one community, receives an intervention and another does not is a community trial
Natural Experiment
In some rare situations in nature, unplanned events produce a natural experiment

Levels 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
Example Of Natural Experiment
Screening and treatment for prostate cancer Seattle-Puget Sound area differed considerably from that in Connecticut during 1987-90
Example Of Natural Experiment
Ten-year cumulative incidences of radical prostatectomy and external beam radiation up to 1996 were
2.7% and 3.9% for those in Seattle
0.5% and 3.1% for those in Connecticut
Example Of Natural Experiment cont.
Did mortality from prostate cancer from 1987 to 1997 differ between Seattle and Connecticut?
The adjusted rate ratio of prostate cancer mortality during the study period for Seattle vs. Connecticut was 1.03 (0.95 to 1.11)
In other words, the 11-year follow-up data showed no difference in prostate cancer mortality between the two areas, despite much more intensive screening and treatment in Seattle
Experimental Studies
Experimental studies may be
Between-group designs
Within-group designs
Between Group Design
Comparison is made between outcomes observed by two or more groups of subjects that receive different levels of the intervention... BETWEEN-GROUP DESIGN.
Within Group Design
Comparing outcomes observed in a single group before/after the intervention
Random Assignment
-makes intervention and control groups look as similar as possible

Chance is the only factor that determines group assignment
Neither the patient or the physician know in advance which prevention program or therapy will be assigned
Confounding and sample size
Non-Randomized Study
AKA convenience sample

Concurrent comparison group is allocated by a non-random process
Assignment
Problems
Not effective at controlling unmeasured confounding variables
Measured confounding variables; however, may be adjusted through analytic methods
Advantages of randomized controlled clinical trials
Advantages of randomization
Eliminates conscious bias due to physician or patient selection
Averages out unconscious bias due to unknown factors
Groups are "alike on average"
Disadvantages of randomized controlled clinical trials
Ethical issues
Interferes with the doctor-patient relationship
Blinding
Three levels of blinding
Single blind - Subjects
Double blind - Investigators
Triple blind - Analyses
Single-Blinded Study
In a single-blinded placebo-controlled study, the subjects are blinded but investigators are aware of who is receiving the active treatment
Double-Blinded Study
neither the subjects nor the investigators know who is receiving the active treatment
Triple-Blinded Study
Kept secret from subjects and investigators.
analyses are completed and removed from investigators
Blinding Patients
Why blind patients?
Patients try to get well/please physicians
Minimize potential bias from a placebo effect
Placebo Effect
Effect on patient outcomes

outcomes (improved or worsened) that may occur due to the expectation by a patient (or provider) that a particular intervention will have an effect
Chronic Severe Itching Study
Forty-six patients randomly assigned to one of four groups
Treatment Itching Score
Cyproheptadine HCI 27.6
Trimeprazine tartrate 34.6
Placebo 30.4
Nothing 49.6
Blinding Patients cont.
Pill of same size, color, shape as treatment
Sham operation (anesthesia and incision) for angina relief (unethical)
Problems with Blinding patients
Problems
In non-drug studies may be impossible/unethical
In drug studies if treatment has characteristic side effects
Placebos Blinding Patients
Placebos improve comparability of treatment groups in terms of compliance and follow-up
For example, if patient perceives improvement because of medication, more likely to remain in study
Blinding physician or outcome assessing investigator
-Best way to avoid unconscious bias is to blind
-Physicians - don't know which patient is taking the placebo and which patient is taking the drug
-Assessors - of the outcome; are not the treating doctors, and are not told which treatment was used
Why is it problematic to blind drug studies?
A treatment has characterictic side effects.
Purpose Of Experimental Studies
To identify clinical and public health approaches to solving public health problems (how to prevent or treat)
What are the strengths of blinded randomized controlled clinical trials?
-Demonstrate cause-effect relationships
-Produces faster/cheaper answer than observational studies.
-Appropriate approach for some research questions
-Investigators controls exposure levels
What are the weaknesses of blinded randomized controlled clinical trials?
-Cost time/money
-Not suitable for experimental designs because of ethical barriers/rare outcomes.
-Might be different from common practice.
-Limited generalizability use of volunteers, eligibility, follow-up.
Designing A Clinical Trial
-Assembling study cohort
-Measuring baseline variables
-Choosing comparison group
-Assuring compliance
-Selecting treatment
-Selecting patient population
-Selecting outcome (endpoint)
-Ethical considerations
Assembling Study Cohort
Inclusion criteria
Broad vs. specific - related to the extent of generalization
Is the outcome rare (e.g., CHD incidence)? Then recruit from populations at high risk such as males
Assembling Study Cohort cont.
Exclusion criteria
Define exclusion criteria that will help control error.
Example: An advanced cancer that may be fatal before the end of the follow-up period in a subject entering a CHD-prevention study
Why do you exclude people that have difficulty complying?
-Problems with alcohol
-psychotic patients
-planning to move out of state
-sample size
Why measure baseline variables?
Characterize the study cohort.
-Identifying information (name, address, ID#)
-Demographics (age, race, gender, etc.)
-Clinical factors
What are outcome variables for Baseline Variables?
To assure disease is or is not present at baseline (appropriate for between-group design)
Measure various predictors of outcomes (e.g., smoking habits) to allow for statistical adjustment
Be parsimonious (i.e., keep simple)
Choosing Comparison Group
Not contaminated by treatment
Ideal - possible to blind, usually meaning placebo used
Status quo vs. new treatment
How do you Assure Compliance?
Calling the day before clinical visit
Providing reimbursement
Adhering to the intervention protocol
Drug or behavioral intervention should be well tolerated
Taking once a day vs. complex schedule
Measuring compliance (self-report, pill counts, urinary metabolite levels)
Select Treatment?
What is the research objective?
Are the therapies safe and active against the disease?
Is there evidence that one therapy is better than another?
Is the intervention likely to be implemented in a clinical practice?
Is the intervention "strong" enough to have a chance of producing a detectable effect?
Selecting Outcomes (Endpoints)
-Primary Endpoint
-Selection of the "best" endpoint is often complicated
-Surrogate endpoint
Phase I Trial
Unblinded, uncontrolled study with typically fewer than 30 patients
The purpose of phase I trials is to determine the safety of a test in humans
Patients in phase I trials often have advanced disease and have already tried other options
They often undergo intense monitoring
Phase II Trial
Up to 50 people
-Tolerability
-Safe dosage
-Side effects
-How the body copes with the drug
Phase III Trial
-Has thousands of patients
-Involve random assignments
-evaluates efficacy of new treatment.
-different dosages/methods of administration.
Phase IV Trial
Conducted after the therapy has been approved by the FDA.
-access serious side effects
-find more therapeutic uses
Selected special types of randomized designs
Basic randomized designs
Run-in designs
Factorial design
Randomization of matched pairs
Group randomization
Factorial Design
-Subjects are randomly assigned to one of four groups. -The groups represent the different combinations of the two interventions.
Randomization Of Matched Pairs
Improves covariate balance on potential confounding variables
Matched randomization provides more accurate estimates than unmatched randomization, and may involve matching on several potential confounders
Randomization Of Matched Pairs cont.
-Matched in pairs
-By age,sex,race/ethnicity
Group Randomization
-Groups or naturally forming clusters are randomly assigned the intervention
-Groups may involve
Practices
Schools
Hospitals
Communities.
Group Randomization cont.
Individuals or patients within a cluster are likely to be more similar to each other compared to those in other clusters
Summary Of Ethical Principles
Benefits - Maximize good
Risks - Avoid doing harm
Subject - Respect for all persons
Society - Fairness to all
Is consent necessary?
Tuskegee Syphilis Study
The Tuskegee study had nothing to do with medical experiments
No treatment was offered for syphilis
No new drugs were tested, nor were any efforts made to establish the efficacy of older chemical treatments