lecture 5 & 6 (slides) Research design II

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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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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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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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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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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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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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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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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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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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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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

lecture 5 & 6 (slides) Research design II

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