Study design

Reserch Methodology-10
3
Study Design
Definition
A study design is a specific plan for conducting the study,
which allows the investigator to translate the conceptual
hypothesis into an operational one.
Classification

Observational study
Observation is an event and its measurement.
For example diastolic blood pressure is 90 mm Hg; Here
 Event is diastolic blood pressure,
 Measurement is 90 mm hg.
A study based on observation is called observational studies.
Observation unit is the source that gives the observation e.g.
in Helicobacter pylori inflection, man is the observation unit.
Observational Studies
Observational studies allow nature to take its course: the
investigator measures but does not intervene. They include
studies that can be called descriptive or analytical:

1. A descriptive study is limited to a description of the
occurrence of a disease in a population and is often the
first step in an epidemiological investigation.
2. An analytical study goes further by analysing relationships
between health status and other variables.
Apart from the simplest descriptive studies, almost all
epidemiological studies are analytical in character. Pure
descriptive studies are rare, but descriptive data in reports of
health statistics are a useful source of ideas for epidemiological
studies. Limited descriptive information (such as that provided
in a case series) in which the characteristics of several patients
with a specific disease are described but are not compared with
those of a reference population, often stimulates the initiation
of a more detailed epidemiological study. For example, the
description in 1981 of four young men with a previously rare
form of pneumonia was the first in a wide range of
epidemiological studies on the condition that became known
as the acquired immunodeficiency syndrome (AIDS)
[Bonita R, Beaglehole R, Kjellström T 2006. Basic epidemiology, 2nd
edition, WHO.]
TYPES OF OBSERVATIONAL STUDY
A. Analytical study
a. Case control study
b. Cohort study
c. Cross sectional study
d. Correlational study (ecological study)
B. Descriptive study
a. Case report
b. case series
C. Exploratory study
[Reference: Bonita R, Beaglehole R, Kjellström T 2006. Basic
epidemiology, 2nd
edition, WHO.]

A. analytical study
An analytical study attempts to establish causes or risk factors
association between exposure and outcome and testing the
hypothesis. For hypothesis testing there requires a control
group to examine whether risk factors are associated with
exposed or non-exposed group.
Longitudinal study
The study of the same group over a period of time
a. Retrospective study
It is the study based on previous records or previous recorded
data.
‘Smoking causes cancer’ -study must be retrospective’. We
cannot do prospective study on Smoking by allowing people to
smoke.
b. Prospective study: Based on current data following to the
future.
1. Case Control study:
Diagram: Design of case control study
edition, WHO.]

 Case-control studies provide a relatively simple way to
investigate causes of diseases, especially rare diseases.
 They include people with a disease (or other outcome
variable) of interest and a suitable control (comparison or
reference) group of people unaffected by the disease or
outcome variable. The study compares the occurrence of
the possible cause in cases and in controls. The
investigators collect data on disease occurrence at one
point in time and exposures at a previous point in time.
 Case-control studies are longitudinal, in contrast to cross-
sectional studies. Case-control studies have been called
retrospective studies since the investigator is looking
backward from the disease to a possible cause. This can be
confusing because the terms retrospective and prospective
are also used to describe the timing of data collection in
relation to the current date. In this sense a case-control
study may be either retrospective, when all the data deal
with the past, or prospective, in which data collection
continues with the passage of time.
edition,
WHO.]

Case and control
Case means diseased persons. Control is healthy persons.
Done on two groups of people with diseases-
 One group of peoples has the diseases of study –considered
as experimental group or case.
 Another group of people of equal sex and age of the case
do not have the diseases under study (but may have the
other diseases) considered as control.
Case control study is always a retrospective study
For example: a study on which lung cancer patients are asked
how much they smoked in the past and the answers are
compared with a sample of the general population would be a
case control study.
Advantages
The main advantages of case control studies are:

 They can be done quickly. By asking patients about their
past history, researchers can quickly discover effects that
otherwise would take many years to show themselves.
 Researchers don't need special methods, control groups,
etc. They just take the people who show up at their
institution with a particular condition and ask them a few
questions.
Features (Reference: Park J E)
The case control method has three distinct features:
a. Both exposure and outcome (disease) have occurred
before the start of the study.
b. The study proceeds backwards from effect to cause;
and
c. (It uses a control or comparison group) to support or
refute an inference.
Case control studies are basically comparison studies. Cases
and controls must be comparable with respect to known “
confounding factors” such as age, sex, occupation, social status,
etc. the questions asked relate to personal characteristics and
antecedent exposures which may be responsible for the
condition studied. For example, one can use as “cases” the
immunized children and use as “controls” un-immunized
children and look for factors of interest in their past histories.
Case control studies have been used effectively for studies of
many cancers, and other serious conditions such as cirrhosis of
the liver, lupus erythematosis, and congestive heart failure.
(Reference: Park J E)
Odds ratio
The association of an exposure and a disease (relative risk) in a
case-control study is measured by calculating the odds ratio
(OR), which is the ratio of the odds of exposure among the
cases to the odds of exposure among the controls.

For the data in Table above, the odds ratio is given by:
OR = (50 / 11) ÷ (16 / 41) =
50 × 41
11 × 16
= 11.6
This indicates that the cases were 11.6 times more likely than
the controls to have recently eaten meat.
The odds ratio is very similar to the risk ratio, particularly if a
disease is rare. For the odds ratio to be a good approximation,
the cases and controls must be representative of the general
population with respect to exposure.
However, because the incidence of disease is unknown, the
absolute risk can not be calculated
edition,
WHO.]
2. Cohort study:
 Cohort studies, also called follow-up or incidence studies.
 Begin with a group of people who are free of disease, and
who are classified into subgroups according to exposure to
a potential cause of disease or outcome. Variables of
interest are specified and measured and the whole cohort
is followed up to see how the subsequent development of

new cases of the disease (or other outcome) differs
between the groups with and without exposure.
 Because the data on exposure and disease refer to
different points in time, cohort studies are longitudinal, like
case control studies.

 Cohort studies have been called prospective studies, but
this terminology is confusing and should be avoided. As
mentioned previously, the term “prospective” refers to the
timing of data collection and not to the relationship
between exposure and effect. Thus there can be both
prospective and retrospective cohort studies.
 Cohort studies provide the best information about the
causation of disease and the most direct measurement of
the risk of developing disease.
 Although conceptually simple, cohort studies are major
undertakings and may require long periods of follow-up
since disease may occur a long time after exposure. For
example, the induction period for leukaemia or thyroid
cancer caused by radiation is many years and it is necessary
to follow up study participants for a long time.
Diagram: Comparison of historical and prospective cohort study design. E+ =
Exposed, E- = Not Exposed; D+ = Disease positive, D- = Disease negative,
Definition

Cohort study is another type of analytical (observational) study
which is usually undertaken to obtain additional evidence to
disprove or support the existence of an association between
suspected cause and disease. (Reference: Park J E)
Concept of Cohort
In epidemiology, the term “cohort” is defined as a group of
people, who share a common characteristic or experience
within a defined time period. (Reference: Park J E)
e.g,
 People working in x-ray department
Or
 Women using oral pills for 10 years having o2 children
Or
 Child under 5 years
Or
 Smokers
Types of cohort studies
Three types of cohort studies have been distinguished on the
basis of the time of occurrence of disease in relation to the
time at which the investigation is initiated and continued:

1. Prospective cohort studies
2. Retrospective cohort studies
3. A combination of retrospective and prospective cohort
studies
1. Prospective cohort studies
A prospective cohort study (or “current” cohort study) is
one in which the outcome (e.g./ disease) has not yet
occurred at the time the investigation begins. Most
prospective studies begin in the present and continue into
future. For example , the long- term effects of exposure to
uranium was evaluated by identifying a group of uranium
miners and a comparison group of individuals not exposed
to uranium miners and by assessing subsequent
development of lung cancer in both the groups. The
principal finding was that the uranium miners had an
excess frequency of lung cancer compared to non- miners.
Since the disease had not yet occurred when the study was
undertaken, this was a prospective cohort design. The US
public Health Service’s Framingham Heart Study, Doll and
Hills Prospective study on smoking and lung cancer, and
study of oral contraceptives and health by Royal College of
General Practitioners are examples of this type of study.
2. Retrospective cohort studies
A retrospective cohort study (or “historical” cohort study)
is one in which the outcomes have all occurred before the
start of the investigation. The investigator goes back in
time, some times 10 to 30 years, to select his study groups
from existing records of past employment, medical or
other records and traces them forward through time, from
a past date fixed on the records, usually up to the present.
This type of study is known by a variety of names:
retrospective cohort study, “historical” cohort study etc.
Indications for cohort studies

Cohort studies are indicated:
(a) when there is good evidence of an association between
exposure and disease, as derived from clinical observations
and supported by descriptive and case control studies
(b) when exposure is rare, but the incidence of disease high
among exposed , e. g., special exposure groups like those
in industries, exposure to X-rays etc
(c) when attrition of study population can be minimized, e.g.,
follow-up is easy, cohort is stable , co- operative and easily
accessible and
(d) When ample funds are available.
[Distinguish between case-control and cohort study. (BSMMU,
January, 2011)
Enumerate the advantages and disadvantages of cohort study.
(BSMMU, July, 2010)]
Table: Comparison of case-control and cohort studies
Case-control Cohort
1. Suitable for rare diseases 1. Suitable for common
diseases increasing drop-out
rates and therefore more
costly
2. Short study time and
cheaper to perform
2. Prolonged study time with
potential for
3. Smaller number of subjects
required
3. Large number of subjects
required
4. Bias may occur in the
selection of cases and controls
and in ascertaining exposure
4. Less selection bias occurs
5. Because data collected
retrospectively, some data may
not be available or of
poorer quality
5. Prospective data collection
may be more accurate
6. No volunteer subjects
needed
6. Subjects usually volunteer

7. Cannot determine true
incidence or relative risk.
Results expressed as odds
ratios
7. Incidence, relative risk and
attributable risk can be
determined
8. Estimate of time from
exposure to development of
disease not possible
8. Estimate of time from
exposure to development of
disease possible
3. Cross sectional study is the study done at the point of time
in different groups of people. Such study indicates points
prevalence that is the number of cases (old and new) at the
time of study e.g. Study of detection of lung cancer cases at the
particular point of time in the following area of Dhaka,
1. Mirpur
2. Komolapur
3. Mahammadpur etc

 It is based on a single examination of a cross- section of
population at one point in time – the results of which can
be projected on the whole population provided the
sampling has been done correctly. (Reference: Park J E)
 Cross-sectional studies measure the prevalence of disease
and thus are often called prevalence studies.
 In a cross-sectional study the measurements of exposure
and effect are made at the same time. It is not easy to
assess the reasons for associations shown in cross-sectional
studies. The key question to be asked is whether the
exposure precedes or follows the effect. If the exposure
data are known to represent exposure before any effect
occurred, the data from a cross-sectional study can be
treated like data generated from a cohort study.
 Advantages: Cross-sectional studies are relatively easy
and inexpensive to conduct and are useful for investigating
exposures that are fixed characteristics of individuals, such
as ethnicity or blood group. In sudden outbreaks of
disease, a cross-sectional study to measure several
exposures can be the most convenient first step in
investigating the cause. Data from cross-sectional studies
are helpful in assessing the health care needs of
populations. Data from repeated cross-sectional surveys
using independent random samples with standardized
definitions and survey methods provide useful indications
of trends.
 Each survey should have a clear purpose, valid surveys
need well-designed questionnaires, an appropriate sample
of sufficient size, and a good response rate.
[Bonita R, Beaglehole R, Kjellström T 2006. Basic epidemiology,
2nd
edition, WHO.]
 Cross –sectional studies are more useful for chronic than
short- lived diseases. For example, in a study of
hypertension, we can also collect data during the survey
about age, sex, physical exercise, body weight, salt intake
and other variables of interest. Then we can determine how

prevention of hypertension is related to certain variables
simultaneously measured. (Reference: Park J E)
 Such a study tells us about the distribution of a disease in
population rather than its aetiology. (Reference: Park J E)
4. Correlational or ecological study
When the unit of observation is an aggregate (e.g., family,
school) or ecological unit (a village or town) the study becomes
an ecological or correlation study.
Ecological (or correlational) studies are useful for generating
hypotheses. In an ecological study, the units of analysis are
groups of people rather than individuals.
For example, a relationship was found between average sales of
an anti-asthma drug and the occurrence of an unusually high
number of asthma deaths in different provinces of New
Zealand.
edition,
WHO.]
B. Descriptive study
A simple description of the health status of a community, based
on routinely available data or on data obtained in special
surveys as described in, is often the first step in an
epidemiological investigation. In many countries this type of
study is undertaken by a national centre for health statistics.
Pure descriptive studies make no attempt to analyse the links
between exposure and effect. They are usually based on
mortality statistics and may examine patterns of death by age,
sex or ethnicity during specified time periods or in various
countries.
edition,
WHO.]

 A descriptive study describes a situation or problem in terms
of time, place and person.
 It describes present or past characteristics of persons with
particular outcome.
 It is not aimed at to test the hypothesis but to generate the
hypothesis.
 No relationship between exposure and outcome can be
made.
For example, a prevalence survey of Dengue or Dengue
Hemorrhagic fever is an example of descriptive study.
Types of descriptive studies
Case report

Case report consists of careful, details report by a physician of
the profile of a single patient, sometimes of exceptional
category.
Case series
This type of study is based on report of series of cases of
specific condition with no specifically allocated control group.
Example: one of your patients has a condition that you have
never seen or heard of before and you are uncertain what to
do. A search for case series or case reports may reveal
information that will assist in a diagnosis. However, for any
reasonably well-known condition you should be able to get
better evidence. Case series and case reports, since they use no
control group with which to compare outcomes, have no
statistical validity.
Descriptive versus analytical study
 A descriptive study sets out to describe a situation e.g.,
distribution of diseases in a locality in terms of age, sex,
occupation. An analytical study (explanatory) tries to find
explanation and examine causal processes e.g. why the
diseases occur in this population?
 A descriptive study only formulates the hypothesis whereas
in analytical study we can formulate as well as test the
hypothesis.
C. Exploratory study
An exploratory study is carried out when very little is known
about a problem or a situation. It is relatively a short duration
study.
Example
To identify the unknown fever or situation such as identifying
the Nipah virus.

Summary of observational studies
Table: Applications of different observational study designs.
Objective Ecological Cross-
sectional
Case-
control
Cohort
Investigation of
rare disease
++++ – ++++ –
Investigation of
rare cause
++ – – +++++
Testing multiple
effects of cause
+ ++ – +++++
Study of
multiple
exposures and
determinants
++ ++ ++++ +++
Measurements
of time
relationship
++ – + b
+++++
Direct
measurement
of incidence
– – + c
+++++
Investigation of
long latent
periods
– – +++ –
Table: Advantages and disadvantages of different observational study
designs
Probability of: Ecological Cross-
sectional
Case-
control
Cohort
selection bias NA medium high low
recall bias NA high high low
loss to follow-
up
NA NA low high
confounding High medium medium medium
time required Low medium medium high
cost Low medium medium high
NA: not applicable.

Experimental study
It is a study in which a population is selected for a planned trial
of a regimen, whose effects are measured by comparing the
outcome of the regimen in the experimental group versus the
outcome of another regimen in the control group.
An interventional study is usually designed as
 a randomized controlled trial,
 a field trial, or
 a community trial.
An experiment is the best epidemiological study design to
prove causation.
 It is the final and definitive step in the research process.
 There is investigator's ability to manipulate the variable and
measures the effects of manipulation.
 Research subjects are randomly allocated to at least two
groups-study group and control group.
 One group is subjected to intervention or experiment and
other group is not subjected to intervention.
 Outcome of intervention is obtained by comparison between
two groups.
 Ethical consideration is the paramount important in
experimental studies.
A. Randomized Controlled Trial

FEATURE OF A RANDOMIZED CONTROLLED TRAIL
[Discuss the main feature of a randomized controlled trail.
(BSMMU, MD Radiology, January, 2009)]
 A randomized controlled trial is an epidemiological
experiment designed to study the effects of a particular
intervention.
 Subjects in the study population are randomly allocated to
intervention and control groups, and the results are
assessed by comparing outcomes.
 the groups being compared should be equivalent,

 patients are allocated to the groups randomly, i.e. by
chance. If the initial selection and randomization is done
properly, the control and treatment groups will be
comparable at the start of the investigation; any differences
between groups are chance occurrences unaffected by the
conscious or unconscious biases of the investigators.
A randomized controlled trial is one in which:
1. There are two groups, one treatment group and one
control group. The treatment group receives the treatment
under investigation, and the control group receives either
no treatment or some standard default treatment.
2. Patients are randomly assigned to all groups.
 Assigning patients at random reduces the risk of bias and
increases the probability that differences between the
groups can be attributed to the treatment.
 Having a control group allows us to compare the
treatment with alternative choices. For instance, the
statement that a particular medication cures 40% of
cases tells us very little unless we also know how many
cases get better on their own! (Or with a different
treatment).

With certain research questions, randomized controlled
studies cannot be done for ethical reasons. For instance, it
would be unethical to attempt to measure the effect of
smoking on health by asking one group to smoke two packs a
day and another group to abstain, since the smoking group
would be subject to unnecessary harm.
Randomized controlled trials are the standard method of
answering questions about the effectiveness of different
therapies. If you have a therapy question, first look for a
randomized controlled trial, and only go on to look for other
types of studies if you don't find one.
Figure: flow chart of an experimental study
Randomization is a process through which subjects are
assigned to control or to experimental group purely by chance.

Quasi experimental study
[Write shorts on: (i) Quasi experimental study, (BSMMU, MD
Radiology, January, 2010)]
Quasi” means likeness or resembling, so therefore quasi-
experiments share characteristics of true experiments which
seek interventions or treatments. The key difference in this
empirical approach is the lack of random assignment.
Types of trials
Randomized trials are employed to test efficacy while avoiding
these factors. Trials may be open, blind or double-blind.
Open trial
 In an open trial, the researcher knows the full details of the
treatment and so does the patient.
 These trials are open to challenge for bias, and they do
nothing to reduce the placebo effect. However, sometimes
they are unavoidable, particularly in relation to surgical
techniques, where it may not be possible or ethical to hide
from the patient which treatment he or she received.
Blind trials
Single-blind trial
 In a single-blind trial, the researcher knows the details of the
treatment but the patient does not.
 Because the patient does not know which treatment is being
administered (the new treatment or another treatment)
there should be no placebo effect.
 Since the researcher knows, it is possible for them to treat
the patient differently or to subconsciously hint to the
patient important treatment-related details, thus influencing
the outcome of the study.

Double-blind trial
 A double blind study is one in which neither the investigator
nor the participants knows whether the participant is
receiving the treatment of interest or the control treatment.
 For example, studies of treatments that consist essentially of
taking pills are very easy to do double blind - the patient
takes one of two pills of identical size, shape, and color, and
neither the patient nor the physician needs to know which is
which.
 A double blind study is the most rigorous clinical research
design because, in addition to the randomization of subjects
which reduces the risk of bias, it can eliminate the placebo
effect which is a further challenge to the validity of a study.
The placebo effect could be thought of in this way:
Patients who believe they are receiving a new experimental
treatment tend to be more optimistic about the outcome. This
means that, when asked, they tend to minimize health
problems and give more weight to positive effects. They also
tend to take better care of themselves and comply better with
the conditions of the experiment. There is also substantial
evidence that, independent of all this, patients who have
positive beliefs about their treatment do better than patients
who do not. In many situations, the placebo effect is at least as
strong as any objective effects of the treatment!
1. Doctors who believe that a patient is receiving a new
experimental treatment tend to be more optimistic
about that patient's chances, evaluate their state of
health more favorably, and communicate positive
expectations to the patients, who in turn try to get
better so as to prove their doctor right!
Triple-blind trial
The subject, researcher and person administering the treatment
(often a pharmacist) are blinded to what is being given.

Alternately, it may mean that the patient, researcher and
statistician are blinded.
Table: The five stages of drug development in clinical trials
Phase Main aims Study subjects
preclinical  pharmacology
 toxicology
 in vitro
 in laboratory animals
Phase 1  Clinical pharmacology and
toxicology
 Drug metabolism
 Drug treatment efficacy
Healthy individuals
and/or patients
Phase 2  Initial treatment studies
 Drug treatment efficacy
Small numbers of
patients
Phase 3  Large randomized
controlled trials
 Comparing new to standard
treatments
 Drug/treatment safety and
efficacy
Large numbers of
patients
Phase 4  Post-marketing surveillance
 Long-term safety and rare
events
All patients prescribed
the drug
B. Field trial
 Field trials, in contrast to clinical trials, involve people who
are healthy but presumed to be at risk;
 Data collection takes place “in the field,” usually among
non-institutionalized people in the general population.

 Since the subjects are disease free and the purpose is to
prevent diseases that may occur with relatively low
frequency, field trials are often logistically complicated and
expensive efforts.
 One of the largest field trials was that testing the Salk
vaccine for the prevention of poliomyelitis, which involved
over one million children.
 Field trials can be used to evaluate interventions aimed at
reducing exposure without necessarily measuring the
occurrence of health effects. For instance, different
protective methods for pesticide exposure have been
tested in this way and measurement of blood lead levels in
children has shown the protection provided by elimination
of lead paint in the home environment. Such intervention
studies can be done on a smaller scale, and at lower cost,
as they do not involve lengthy follow-up or measurement
of disease outcomes.
[Discuss the advantages and disadvantages of RCT. (BSMMU, MD
Radiology, January 2010, July 2009)]
Advantages
 Best evidence study design
 No inclusion bias (using blinding)
 Controlling for possible confounders
 Comparable Groups (using randomization)
Disadvantages
 Large trials (may affect statistical power)
 Long term follow-up (possible losses)
 Compliance
 Expensive
 Public health point of view
 Possible ethical questions

C. Community trials
 In this form of experiment, the treatment groups are
communities rather than individuals.
 This is particularly appropriate for diseases that are
influenced by social conditions, and for which prevention
efforts target group behavior.
 e.g., for prevention of dental carries in an area, fluoridation
of water in that area is carried out on community
basis. Fluoride is to be mixed at the central source of water
supply.
Write down the difference between observational and
experimental study. (BSMMU, July 2011, January 2010)
Experimental study designs are differentiated from
observational designs by the fact that there is manipulation of
the study factor (exposure), and randomization (random
allocation) of subjects to treatment (exposure) groups
Experimental study
1. Provide stronger evidence of the effect (outcome)
compared to observational designs, with maximum
confidence and assurance
2. Yield more valid results, as variation is minimized and bias
controlled
3. Determine whether experimental treatments are safe and
effective under “controlled environments” (as opposed to
“natural settings” in observational designs), especially when
the margin of expected benefit is doubtful / narrow (10 -
30%)
[Write short notes on: RCT (BSMMU, MD Radiology, July,
2010)]

Choice of Design
Depends on:
– Research Questions
– Research Goals
– Researcher Beliefs and Values
– Researcher Skills
– Time and Funds
It is also related to:
 Status of existent knowledge
 Occurrence of disease
 Duration of latent period
 Nature and availability of information
 Available resources

Study design

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