lecture 5 & 6 (slides) research design ii
TRANSCRIPT
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8/3/2019 lecture 5 & 6 (slides) Research design II
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Designing a study II
Research Methods
Dent 313
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Types of randomized control
trials Simple randomized design
Crossover design
Factorial studies
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Simple randomized design Randomization to two or more groups
Simple and powerful
When enough subjects are available andcan be recruited
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Crossover design
Subjects randomized to one study group
After a specific period of time, the samesubjects are switched to the other group
Advantages Gives two subjects for the price of one Less variability and more power Each subject serves as his/her own control
Increase subject motivation All subjects will be in treatment group at some stage Good when you cannot recruit enough subjects
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Crossover design
Disadvantages Bias due to carryover effects leading to failure to
ascribe successes or failures to correct group
Carryover effects are due to the 1st
treatment but occurduring the 2nd treatment
E.g. subject receives antibiotic A for 3 month thenAntibiotic B for the next 3 months. Infection appeared inmonth 4. Is it because antibiotic B failed? or infectionappeared in the period of antibiotic A but did not
manifest itself until the period of antibiotic B To overcome carryover effect
Washout period: a time with no treatment
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Factorial studies
Designed to answer more than one questionby randomizing each subject to more than onecondition
Advantages Get two studies in the price of one Cost effective
Disadvantages Different conditions may affect one another (interact) E.g. 1st Q: Lack of oral hygiene on caries
2nd Q: Lack of oral hygiene on periodontal disease
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Methods of allocating subjects
within a randomized design
Randomization with equal allocation
Blocked randomization
Randomization with unequal allocation Stratified randomization
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Randomization with equal
allocation
Equal number of person to each treatmentgroup
Standard method with highest power
Needs enough number of subjects in eachgroup (>20) to minimize the effect of chance inhaving 2 equal groups in the sample when theyare not equal in the population
Conditions of subjects have to be similar aswell. Thus equal allocation in number is not byitself sufficient
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Blocked randomization
Only used
When exact number in each group is needed but thestudy is too small (4 or 6 subjects per block)
In larger studies when temporal changes affectingstudy enrollment are expected
Enrollment at different times of people with changingconditions
In large multicenter studies Assignment of subjects is randomized
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Blocked randomization
Disadvantages
Staff may figure out the assignment of a subject priorto enrollment (in non-blinded studies)
Esp., when all but the last subject of a block havebeen enrolled
E.g., 4-subject block in two groups A, B. 3 have beenrandomized as ABB, thus the last one is to be assigned(not randomized) to A for the two groups to be equal
Overcome by randomly choosing among different sizeblocks so that staff do not know the size of the blockwithin which the subjects are being randomized
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Randomization with unequal
allocation E.g., two-to-one randomization
Advantages
Subjects of serious diseases may benefit from unequal allocation >50% chance of receiving the new treatment when allocated to the
larger group
More knowledge about side effect when allocating >50% of subjectsto the treatment group
Disadvantages
Losing power Harder to reject the false Null hypothesis Inconsistency with equipoise principles
Investigator beliefs that the 2 groups are equal Investigators may believe that one group is superior to the other
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Stratified randomization
Preferred when an equal distribution ofbaseline prognostic factors is needed Baseline prognostic factors
Sex and age Unequal distribution of baseline factors may
lead to confounding
Avoided by randomizing persons within groupsof important baseline factors
Advantage: variability is decreased, thus powerincreased
Disadvantage: only possible with one or twoassociated baseline factors
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Types of observational studies
Cross-sectional studies
Prospective cohort studies
Case-control studies Nested case-control studies
Ecologic studies
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Cross-sectional studies
Easy and fast
Information is collected from subject at a singlepoint of time
Used to answer descriptive questions What is the prevalence of a disease? Prevalence is the proportion of individuals in a
population who have a specific disease or condition at
a particular moment of time Used to determine frequency of risk behavior
Useful in estimating sample size
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Cross-sectional studies
Not good in answering analytic questions
An association found may go in eitherdirections
Risk factor may cause the outcome or vice versa Effect-cause or reverse causality E.g., either direction: alcohol and depression
E.g., one direction: smoking & facial wrinkles
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Prospective cohort studies
Sample is assembled prior to development of theoutcome and followed over time
Subjects are evaluated to make sure that they do notalready have the outcome being studied
Provide much stronger evidence in support of a causalrelationship
Reduce the possibility of reverse causality Minimizing recall bias
Information about risk factor is collected ahead ofdisease development Recall bias is a problem with case control studies
developing disease make subject remember anexposure
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Prospective cohort studies
Can be used to calculate incidence rate
Incidence rate is the number of new
cases of a particular condition in an at-risk population per unit time
Longitudinal study
Length of follow up time is based on howlong it takes to develop the disease
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Prospective cohort studies
Disadvantages Take a long time to perform esp., when the disease
develops slowly
Costly and inefficient for studying uncommon diseases(fewer persons will develop the disease) Bias due to loss of subjects to follow up Period of temporal changes may influence results
Introduction of new instruments
Change in clinical practice Answer of research question may become lessrelevant when the study is complete
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Case-control studies
Subjects are assembled based onwhether they have experienced the
outcome (cases) or not (controls) Frequencies of risk factors are compared
between cases and controls
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Case-control studies
Advantages
Efficient especially for studying uncommon diseases Cases and controls must originate from the same
population
Disadvantages
Cannot be used to determine prevalence and incidence Selection bias: loss of cases/controls prior to their selection
(a case died prior to assembly of cases, then the samplewouldnt be representative)
Recall bias Cases are more likely to remember exposures than controls E.g., cases with cancer may report previous exposures
because they have been more aware about their health andsubjected to many previous tests
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Case-control studies
Can be matched and unmatched
Matching Individual matching
Each case is individually matched with one or morecontrols E.g., 45 yrs old man as case matched with 45 yrs old
man as a control
Frequency matching Controls are matched to cases as a group
Similar distribution of cases and controls on eachmatched variable E.g., males with range of 20-40 yrs account for 30% in
both groups
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Case control studies
Advantage of matching
Eliminate confounding Disadvantage of matching
Increasing difficulty and cost of identifying controls esp.,with limited number of potential controls
E.g., 45 yrs old male with prostate cancer Matching for a variable will not enable to study its impact on
the outcome
E.g., matching for smoking to study the effect of diesel fumeson lung cancer
Best to avoid matching except in small studies where it isdifficult to adjust statistically for all possible confoundersunless if matching is used
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Case-control studies
How many controls per case to enroll
Greatest efficiency with equal number
Adding additional controls when enough cases cannot be obtained such as in rareconditions increase the power of the study
there are more than one variable/confounder tomatch on
Maximum: 4 controls per case
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Nested case-control studies
A case-control study where cases and controlsare drawn from the subjects enrolled in aprospective study
Cases and controls from same population Information on risk factors has been collected prior todevelopment of disease no recall bias
When the outcome is death (you cannot examine thedead)
Not viable unless information about risk factors iscollected at the beginning of the prospective study
Consider banking serum and cells at the beginning ofstudy
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Ecologic studies
Collect data at the aggregate rather than individuallevel
Aggregate levels
Neighborhood, city, state, country E.g., Water fluoridation on frequency of dental visits nodata were collected from individuals
Used
When data do not exist on individual level When the primary focus is the well-being of an entire
community
Best to generate hypothesis which can be tested by otherstudy design
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Specifying a hypothesis
What are you hoping to prove before datacollection
Hypothesis
Null form There is no difference Alternative form
There is a difference
Study hypothesis is stated in both the null andalternative forms Statistical analysis is based on inferential reasoning
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Inferential reasoning
Assessing the probability that anassociation found in a sample couldhave occurred by chance if there were
no true association in the population If the probability that the association
could have occurred by chance falls
below (p
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A study with more than one
question
Collecting data on more than one outcome Collecting data on additional risk factors for the same
outcome does not answer multiple questions
Multiple outcomes Different stages of the same disease process Smoking on angina, MI and death
Different disease processes influenced by the same riskfactor
Smoking on gingival health, lung cancer and heart disease Outcomes unrelated to one another
Smoking on health and cost
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Sample size
Depends on the statistical test used
Discussed later
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Ethical approval
Human research committees Protect the rights of subjects Insures that the subjects fully informed Insures that subjects have consented to
participate
Insures that the risks are reasonable an muchless than the new knowledge/ benefit that the
study will provide Insures that confidentiality is maintained