Analytical

Epidemiological Study Designs

November 6, 2021
Goba, Ethiopia
11/6/2021 By: Fikadu (MPH-E) 1
 Objectives of the course
At the end of the session, students should be able to:

 Describe the basic concepts of different analytical

epidemiological study designs

 Describe how to conduct and analyze different analytical of

epidemiological study designs

 Compare and contrast different epidemiologic study

designs regarding subject selection, data collection, and
analysis

 Describe the strengths and limitations of each analytical

study design
11/6/2021 By: Fikadu (MPH-E) 2
 Brainstorming
 What type of analytical epidemiology study design do you
know?
 What are the purpose of analytical epidemiology study
designs?
 How do you compare and contrast analytical vs. descriptive
study?

11/6/2021 By: Fikadu (MPH-E) 3

 Study design
A study design is a specific plan or protocol for conducting
the study, which allows the investigator to translate the
conceptual hypothesis into an operational activity.
A framework which guides the researcher in the various
stages of the research process.
All studies involve some descriptive or analytic type of
comparison of exposure and disease status.
Analytical study design options include: observational or
interventional (based on the role of the investigator).

11/6/2021 By: Fikadu (MPH-E) 4

Epidemiologic Study Designs

 Case report/series
 Ecological/correlation
 Descriptive Cross-
sectional

11/6/2021 By: Fikadu (MPH-E) 5

 Epidemiologic Study.....
• Specific epidemiological study designs can be used to reveal
etiologic (causal) relationships,
• First, using observational analytical studies :
Determine whether there is an association between a factor
or a characteristic and the development of disease,
• Second:
From these associations, derive appropriate inferences
regarding a possible causal relationship

11/6/2021 By: Fikadu (MPH-E) 6

 Analytical Studies
 Control and experimental comparison groups
 Randomized groups: data collected without bias
 Dependent and independent factors

11/6/2021 By: Fikadu (MPH-E) 7

 Observational Analytical Study Designs
Features Cohort Case-control Cross-sectional

Comparison Exposed vs Non Outcome vs Either by

Group exposed With out exposure or by
outcome outcome status

Object of Proportion who Proportion who Proportion with

Comparison were exposed were exposed out come or
exposure

Timing of group Before data Before data After data

formation collection collection collection

11/6/2021 By: Fikadu (MPH-E) 8

 Case-control study design
I. Design concept
Also known as Case-referent study
Starts with cases and comparative groups(controls)
Subjects are selected on the basis of whether they
do(cases) or do not (controls) have a particular disease
under study
We determine what proportion of cases were exposed and
what proportion were not,
We also determine what proportion of controls were
exposed and what proportion were not,
Groups are then compared with respect to the proportion
having a history of an exposure or characteristics of interest.
11/6/2021 By: Fikadu (MPH-E) 9
Case-control….

exposed
cases
Not exposed
Study pop

exposed
controls
Not exposed
Study begins here

By: Fikadu (MPH-E) 10

 Case-control….
After identifying cases & controls, investigators look
backward in time to assess their exposures

If all the cases of the disease have been diagnosed at the

time the investigators initiates the study, it is a retrospective
(prevalence) case-control study (most common)

If the study is begun and all new cases that are diagnosed
within the next period of time are included, the study is a
prospective (incidence) case-control study

11/6/2021 By: Fikadu (MPH-E) 11

 Case-control….
II. Selection of cases:
A/ Case definition- precise definition of cases(clinical
,laboratory and other criteria)
Establish strict diagnostic criteria for the disease.
Depending on the certainty of the diagnosis, and the amount
of information available, it is often useful to perform analyses
separately for cases classified as definite, probable, or
possible
B/ Inclusion and exclusion criteria
-Cases should be selected to improve validity(ex. by excluding
cases with coexisting disease)
-Cases should be restricted to limited time period and
geographic area, age range etc…
11/6/2021 By: Fikadu (MPH-E) 12
 Case-control….
C/ Incident or prevalent cases?
To the extent possible avoid prevalent cases.
Why?
 Chicken-egg dilemma on cause and effect
 Non-representative cases since long-time survivors
 Prevalent cases with long disease duration may not accurately
recall antecedent events,
 Difficult to distinguish prognostic factor and cause
-However, prevalent cases are commonly used in studies of
chronic conditions with ill-defined onset times (e.g. multiple
sclerosis)

11/6/2021 By: Fikadu (MPH-E) 13

 Case-control….
Sources of cases
A. Hospital or medical care facility
This approach is referred to as hospital-based case control
study
is more common because it is relatively easy & inexpensive to
conduct
B. General population
Referred as population-based case control study
Involves locating and obtaining data from all affected individuals
or a random sample from a defined population
It avoids bias arising from whatever selection factors lead,
But, are not routinely used because of the logistic and
cost considerations
11/6/2021 By: Fikadu (MPH-E) 14
 Case-control….
Sources of information for disease status
Review of death certificates, case registries that
maintain ongoing surveillance
Office records of physicians
Hospital admission or discharge records
Pathology department log books

11/6/2021 By: Fikadu (MPH-E) 15

 Case-control….
III. Selection of controls
Selection of an appropriate comparison group is the most
difficult and critical issue in the design of case-control studies.
Involves consideration of a number of issues including :
The characteristics and source of the cases
The need to obtain comparable information from cases and controls
Practical and economic considerations
The control subjects should be selected to be comparable to
the cases,

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 Case-control….
III. Selection of controls…
Controls should represent the population at risk of
becoming cases(controls and cases should came from the
same source population)
The prevalence of exposure among controls should
reflect the prevalence of exposure in the source
population.
The time during which a subject is eligible to be a control
should be the time in which the individual is also eligible
to be a case.
If the above three points are not fulfilled=Selection bias

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 Case-control….
Sources of Controls:
I. Hospital/Clinic-based controls: are patients who have been
admitted for conditions other than the disease being studied
Advantages:
Easily identified and readily available in sufficient numbers
Minimal cost and effort involved in their assembly
Likely to have been subject to the same intangible selection
factors that influenced the cases to come to this particular
physician or hospital,
More likely to be willing to cooperate than healthy individuals,
thus minimizing bias due to non-response
11/6/2021 By: Fikadu (MPH-E) 18
 Case-control….
I. Hospital/Clinic-based controls…
Disadvantages
They are ill and therefore differ from healthy individuals
Thus, the experience of these other patients may not
accurately represent the exposure distribution in the
population from which the cases derived(may not
representative)

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 Case-control….
II. General population controls
When the cases have been chosen from a hospitalized
population but the use of hospitalized controls is not
scientifically desirable or feasible, the comparison group may
be selected from the general population.
Should also be utilized when the cases have been selected to
represent affected individuals in a defined general population
The use of general population controls assures the greatest
level of comparability

11/6/2021 By: Fikadu (MPH-E) 20

 Case-control….
II. General population controls…
Disadvantages:-
More costly and time consuming
Population lists are not always available
It is difficult to contact healthy people with busy work and
leisure activity schedules
May not recall exposures with the same level of accuracy as
those who have developed the disease
Tend to be less motivated to participate

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 Case-control….
III. Special controls: are special groups such as friends,
neighbor, relatives, or spouses of cases,
Controls are often matched to cases from the same
friends, neighbor, relatives, or spouses of cases,
Advantage:
 More likely to be cooperative
 Offer a degree of control of important confounding factors
related to ethnic background, socioeconomic status, or
environment that is not otherwise easily achieved
Disadvantage
 If the study factor itself is one for which family members and
friends are likely to be similar to the cases, an underestimate
of the true effect of the exposure of interest may result.
11/6/2021 By: Fikadu (MPH-E) 22
 Case-control….
How many case-to- control groups?
When the number of available cases and controls is large and
the cost of obtaining information from both groups is
comparable, the optimal control-to-case ratio is 1:1.
when the number of cases is small, the sample size for the
study can be increased by using more than one control to
achieve the desired sample size.
e.g. 1:2 1:3 1:4
As the number of controls per case increases, the power of the
study also increases.
Not generally recommended that this ratio increase beyond
4:1
11/6/2021 By: Fikadu (MPH-E) 23
 Case-control…
IV. Ascertaining Exposure
 Sources of exposure data (cases and controls):
---Study subjects (self-report). Particularly vulnerable to recall
bias as cases may recall their exposure history more
thoroughly than controls.
---Records (preferably completed before the occurrence of
outcome events).
---Interviews with surrogates (spouses, siblings, etc.).
 How far back should exposure be assessed?
---Define a part of the person’s exposure history considered
relevant to the etiology of disease (e.g. the “empirical
induction” period).
---Code the exposure data in an etiologically-relevant manner
(e.g. magnitude of exposure, years of exposure, ever
exposed, etc.).
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 Case-control….
V. Analysis of case-control study
Compare between cases and controls with respect to the
frequency of an exposure,
This comparison is made primarily by estimating the RR as
computed by the OR.
If the case-control study is population based, or if estimates of
disease incidence are available from an outside source, rates of
disease for those exposed and non-exposed can be computed
and compared directly.
Evaluate the role of chance by testing the significance of this
measure of association and calculating confidence intervals .

11/6/2021 By: Fikadu (MPH-E) 25

 Case-control…
VI. Strengths of case-control study
It is relatively quick and inexpensive compared with other
analytic designs
Well suited to the evaluation of diseases with long latent
periods
Optimal for the evaluation of rare diseases
Can examine multiple etiologic factors for a single disease

11/6/2021 By: Fikadu (MPH-E) 26

 Case-control…
VII. Limitations of case control study
Inefficient for the evaluation of rare exposures
Can not directly compute incidence rates of disease in
exposed and non-exposed individuals, unless study is
population based,
i.e. Inability to provide a direct estimate of risk (measure of
association in case control study is Odds Ratio)
In some situations, the temporal relationship between
exposure and disease may be difficult to establish,
i.e. Uncertainty of exposure-disease time relationship
Is particularly prone to bias compared with other analytic
designs, in particular selection and recall bias
11/6/2021 By: Fikadu (MPH-E) 27
 Reading Assignment
1. Nested Case-Control study
2. Dynamic case-control study/Risk-set sampling,
3. Case-cohort studies,
4. Case-Only Studies,

11/6/2021 By: Fikadu (MPH-E) 28

 Cohort study design
I. Design concept
Also called follow up study, longitudinal study or incidence
study.
 ‘Cohort’ a group of people who share a common experience.
E.g. A Birth cohort, a cohort of smokers, a cohort of MPH 2014 students,
etc.
Groups of individuals are defined on the basis of presence or
absence of exposure to the suspected risk factor,
Eligible participants are then followed over a period of time to
assess occurrence of outcome/disease,
At the time the exposure status is defined, all potential subjects
must be free from the out come/disease and yet are at risk.
The exposure of interest is determined for each member of the
cohort and the group is followed to document
11/6/2021 By: Fikadu (MPH-E)incidence in the
29
 Cohort study…

1. FIRST subjects are defined on the basis of exposure status

2. NEXT subjects are followed over time to assess disease development
 Cohort study…
III. Types of Cohort Studies:
- Depending on the temporal relationship between the
initiation of the study and the occurrence of the disease;
1. Prospective (concurrent)
2. Retrospective (historical)
Other classification:
1. Closed cohort
 Members of the cohort will be followed without adding
others.
◦ E.g. 1000 children followed for 2 or 3 years
2. Open (dynamic) cohort study
◦ Other than initially chosen study group others could be
added (birth, in-migrants)or be lost (death, out-migrants).
◦ People at risk are measured using person-time.
11/6/2021 By: Fikadu (MPH-E) 31
 Prospective vs. Retrospective Cohort

Selection of
Exposed & Unexposed Follow - Up
Participants
2025 PROSPECTIVE
2021 COHORT
STUDY
End of Follow Up
Investigator
begins the study

2015 2021
RETROSPECTIVE
2011 COHORT
STUDY
End of Follow Up
Investigator
begins the study
 Cohort study…
1. Prospective cohort
The relevant exposures may or may not have occurred at the
time the study is begun,
Participants must be followed into the future to assess
incidence rates of the disease.
More reliable and informative compared to the retrospective
cohort
Unless specified, cohort study refers to prospective cohort

11/6/2021 By: Fikadu (MPH-E) 33

 Cohort study……
2. Retrospective cohort:-
 Both exposure and outcome of interest have already occurred
when the study is initiated,
E.g. Oral contraceptives (OCs) 10 years ago and developing heart disease,
Advantages of retrospective cohort
Conducted much more quickly and cheaply
Efficient for diseases with long latency requiring many years
Don’t have to wait for the outcome to occur, as in prospective design
Disadvantage of retrospective cohort
Reliance on available information:-result in incomplete and
possibly non-comparable information,
More sensitive to confounding and bias;-

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Cohort study……
III. Selection of the exposed population:
Choice depend on a variety of scientific and feasibility
considerations including:
The frequency of exposure (finding sufficient exposed
individuals within reasonable period of time).
 Common exposures cigarette, coffee drinking.
 Rare exposures  Occupational hazards.
Completeness and accuracy of exposure and follow up
information on all participants (easy to collect & follow ).
The nature of particular research question being evaluated,
 Presence of records or within institution Retrospective cohort.
 For common risk factors with common outcome  general popn.

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 Cohort study…
Selection of the comparison group:
 Comparison groups (non-exposed) should be as similar as possible
with respect to all other factors that may be related to the disease EXCEPT
the exposure under investigation,
Ensure that the information obtained from non-exposed group is
adequate for comparison with the exposed group,
1.Internal comparison group
- When a sample of the population is classified as exposed or unexposed
through a survey or examination,
Example: mortality among smokers vs. nonsmokers in a defined population
2.External comparison group
- For a special exposure group, often a sample of general population of
the area in which the exposed individuals reside is used as
comparison
- Example: mortality among rubber workers vs. mortality in general
population
- Comparison with general population, has limitation (‘Healthy Worker
Effect bias’). 11/6/2021 By: Fikadu (MPH-E) 36
 Cohort study…
IV. Sources of exposure information
Pre-existing records: Records from institutions,
In some circumstances, this may in fact be the only way to
obtain such data,
Advantage:-
Information is usually available for a high proportion of the
cohort & is relatively inexpensive to obtain,
Allow objective and unbiased classification of exposure status,
Disadvantage
Records may be insufficient to address specific research
question adequately,
May incomplete information/ do not contain data on potential
confounding variables.
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 Cohort study…
IV. Sources of exposure information…
Information by the study subjects
 Interviews and questionnaires are completed by study subjects
 Particularly useful for collecting information on exposures that
are not routinely recorded
 A potential for bias may exists (recall bias).
Direct physical examination or testing
 For some exposures such as blood pressure or cholesterol
level,
 Provide an objective and unbiased means of classifying study
subjects with respect to exposure

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 Cohort study…
V. Sources of outcome data
Depend on the specific resources available as well as the particular
disease under investigation,
 Death certificates: are completely acceptable when total
mortality is the end point of interest,
 Records: For nonfatal end points,
 Autopsies: For cause specific deaths
 Directly from the study participants:
 Periodic direct medical examinations: Allows for the
collection of objective information using standardized diagnostic
procedures for all subjects,
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 Cohort study…
VI. Analysis of cohort study
Calculation of incidence rates of the outcome among exposed
and non-exposed groups (RR).
Incidences could also be compared among various levels of
exposure and combinations.
 Denominators could be number of individuals or person-time
units. (RR, AR)
 Role of bias:
◦ Misclassification of exposure status or outcome status occurs in
most cohort studies.
 Selection bias is less concern in cohort (prospective) studies, but if
knowledge of disease affects selection of exposed and non
exposed (retrospective), selection bias may result.
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 Cohort study…
VI. Analysis of cohort study…
 Effect of loss to follow up:-
◦ Follow up is major challenge both cost-wisely and timely
◦ Length of follow up depends on the latency period disease.
◦ Loss to follow up is the major source of bias in cohort
studies.
◦ If this proportion of lost to follow up is large, > 20- 40 %,
difficult to validate.
 To reduce the effect of losses to follow up:
◦ Try to find outcome measures from possible sources.
◦ Compare presence of difference between loss to follow up
and follow up ascertained.
◦ Indirect estimation of their effect (1. assuming losses
developed the outcome, 2 assuming losses without
developing the outcome)
11/6/2021 By: Fikadu (MPH-E) 41
 Cohort study…
VII. Strengths of cohort studies
Valuable for rare exposure,
Can examine multiple effects of a single/rare exposure,
- E.g- Smoking  lung cancer, heart disease, diabetes, asthma, etc.
Can elucidate temporal relationship between exposure and
disease,
If prospective, minimizes bias in the ascertainment of exposure,
Allows direct measurement of incidence of disease in the
exposed and non-exposed groups,
 Study new or unusual exposures (primary method)
◦ Newly licensed drugs, technology, behaviors, etc.
Provides complete description of experience subsequent to
exposure,
rate of progression, staging and natural history of the disease
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 Cohort study…
VIII. Limitations of cohort studies
Inefficient for the evaluation of rare diseases
◦ Large study populations required: not easy to find subjects
If prospective, can be extremely expensive/logistically demanding,
If prospective, time consuming/results are delayed
If retrospective, requires the availability of adequate records,
Validity of the results can be seriously affected by loses to follow-
up bias, (subjects move, change jobs, lose interest in study)
Must anticipate secular trends in technology to detect sub-clinical
cases,
◦ Possible that some participants were not truly “disease-free” at the beginning
of the study,
 Classify people according to exposure at beginning of study, but
they can change throughout the study,
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 Summary of observational analytical study in
relation to exposure and outcome.
Case control
Exposure Disease
?
?

Exposure
Prospective Cohort Disease
?
?

Retrospective Cohort
Exposure Disease
?
?

? To be determined
Exposure, (+) or (-)
Investigator at beginning of study
Summary of observational analytical study…

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Interventional (Experimental)design
 An experimental study investigates the role of some
agent/intervention in the prevention or treatment of an
outcome
The investigator assigns iindividuals into experiment or
control groups by the investigator
If done properly, interventional studies can produce high
quality data for proof of causation.
Two key features in an interventional study design:
1. The investigator/researcher manipulates the agent
(exposure) under study and
2. Interventional studies are always prospective

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 Interventional study…
 Depending on the trial, the comparison
group may receive:
◦ No treatment at all,
◦ An inactive treatment such as a placebo, or
◦ Another active treatment (positive control)

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 Interventional study…
Types of interventional studies
Different classifications can be considered depending on:
Effect of the intervention as:
1. Preventive trial. Example: trial on agents such as vitamins or
behavioral modifications.
2. Therapeutic or clinical trial: Treatments such as surgery
radiation,

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 Interventional study…

Improved
outcome
New
Treatment No improvement

Sick B
R
Individuals Improved
outcome
Existing
Treatment
No improvment

R=randomization B=double blinding

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 Interventional study…

With outcome

Vaccinated
Without
outcome

Healthy B
R
Individuals With outcome
Not-
Vaccinated
Without
outcome

R=randomization B=double blinding

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 Interventional study…
Types of interventional…
Based on the population studied
1. Clinical trial
Usually performed in clinical settings
The subjects are patients
2. Field trial
Used in testing medicine for preventive purpose in the field,
Subjects are healthy people e.g. vaccine trial
3. Community trial
Field trial using unit of the study group of people/community
e.g. fluoridation of water to prevent dental caries
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 Interventional study…
Types of interventional….
Based on design:-
1. Uncontrolled trial
No control group
2. Non-randomized controlled
There is control group but allocation to either group is not
randomized
3. Randomized controlled
There is control group
There is random allocation of subjects to either group

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 Interventional study…
Types of interventional…
Based on objective
Phase I
Trial on small subjects to test a new drug with small dosage
to determine the toxic effect, usually 20-80 healthy
volunteers needed.
Phase II
Trial on small group to determine the therapeutic effect
usually100-200 ill volunteers needed.
Phase III
Study on large population
Usually randomized controlled trial
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 Interventional study…
Challenges of intervention studies
1. Ethical considerations
Practices or substances already known to be harmful should not be
allocated by an investigator
Therapies known to be beneficial should not be withheld from any
affected individual
2. Feasibility
Difficult to find a sufficiently large study subjects
3. Cost
4. Non-compliance
 Reasons for not complying include toxic reactions to the
treatment, lack of interest, and desire to seek other
therapies.
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Non-compliance
Some of the measures which are used to enhance
compliance:
– Enrolling motivated participants,
– Presenting a realistic picture of the required tasks during the
consent process,
– Designing an experimental regimen that is simple and easy to
follow,
– Maintaining frequent contact with participants during the study,
– Conducting a run-in period before enrollment,
 Methods to assess compliance of the study subjects: Self
reporting ; Pills count; Lab tests
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Interventional study…
Characteristics of a true experiment
1. Researcher-manipulated exposure
2. Control group
3. Random assignment

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 Main steps in an RCT
1. Identify new drug/intervention/prevention
2. Identify comparison – e.g. standard treatment versus placebo
(Control v intervention group)
3. Define eligible patient population/ exclusions (i.e. the sampling
frame)
4. Define the outcomes and how to assess them
5. Write the protocol
6. Obtain research ethics committee approval
7. Recruit & consent required sample of patients
8. Randomize to treatment, then treat
9. Follow-up & compare/analyze outcome data
10. Publish/disseminate findings
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 Selection of a study population
First it is essential to determine, population is sufficiently large.
Once the experimental population has been defined, subjects
must then be invited to participate after being fully informed,
Those willing to participate must then be screened for eligibility
according to predetermined criteria
Those who are eventually determined to be both willing and
eligible compose the actual study population
 The study pop must include an adequate number of individuals
in order to determine if there is a true difference b/n the
treatment and comparison groups.

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 Interventional study…
Allocation of study regimens
Randomization:-
Random assignment implies that each individual has the same chance
of receiving each of the possible treatments,
 is the best option since it is less prone to selection bias.
 Random assignment methods include flipping a coin, use of random
numbers table, and a computerized random number generator.
Advantages of randomization
The selection bias in allocation to study groups is removed,
Study subjects will tend to be comparable with respect to all variables
except for the interventions being studied.
When the sample size is sufficiently large, both known and unknown
confounding factors are distributed equally among treatment groups.

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 Interventional study…
 Treatment assignment usually requires ‘blinding’/’masking’: to
avoid ‘participant effect’, ‘observer effect’ and ‘analyst effect’
 Once treatment assignment is finalized, the treatments are
administered according to a specific protocol.
 For example, in a therapeutic trial participants may be asked
to take either an active drug or an inactive drug known as a
placebo.

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 Interventional study…
Ascertainment of outcome:-
 During the follow-up stage of an experimental study, the groups
are monitored for the outcomes under study.
 If the study’s goal is to prevent the occurrence of disease, the
outcome is usually the incidence of the disease.
 If the study is investigating a new treatment among individuals
who already have a disease, the outcomes may include disease
recurrence, severity of symptoms, length of survival, etc…
 The length of follow-up depends on the outcome under study.
 It can range from a few months to a few decades.

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 Interventional study…
Analysis of interventional study
Similar to cohort studies; that is compare the rates of the
outcome of interest in the treated group(s) and rates in the
comparison group(s).
The roles of chance, bias, and confounding must be evaluated
Compare the relevant characteristics of the randomized
treatment and comparison groups to assess balance is achieved.
Noncompliance may be related to factors that also affect the
risk of the outcome under study,
Intention to treat analysis vs per protocol analysis
Thus, analyze by intention to treat-in other words, “once
randomized, always analyzed.”
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 Interventional study…
The quality of “gold-standard” in interventional
studies can be achieved through:
 – Randomization
 – Use of placebo
 – Double blinding

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 Interventional study…
Some reasons why a trial might be terminated
 Treatments found to be convincingly different
 Treatments found to be convincingly not different
 Side effects are too severe
 Definitive information becomes available from an outside
source
 Adherence to treatment is unacceptably low
 Resources to perform study are lost
 Study integrity has been undermined

11/6/2021 By: Fikadu (MPH-E) 64

 Reading Assignment
 Cluster randomization trial
 Crossover trial
 Factorial experimental design
 Randomized block design
 Quasi-experimental design
 Superiority, equivalence, and non-inferiority trials
 Differences-in-differences estimation

11/6/2021 By: Fikadu (MPH-E) 65

Hierarchy of Epidemiologic Study Design

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 Reading Materials
1. Hennekens C. Epidemiology in Medicine.
2. Bonita R. Basic Epidemiology, 2nd ed.
3. Rothmans K. Modern Epidemiology 3rd ed.
4. Woodward M. Study Design and Data Analysis, 2nd ed.

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THANK YOU!

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