Study Designs

Dr. Jagathnath Krishna K M

Associate Professor
Regional Cancer Centre, Thiruvananthapuram
 Epidemiological Study
• Epidemiologic studies are designed, to assess whether an
exposure is associated with a particular disease or any health-
related event (outcome).
• For instance, the research question is whether alcohol
consumption is associated with the development of lung
cancer.
• Here alcohol use is the exposure of interest and lung cancer is
the outcome. In most instances, it is not sufficient to collect
information only on the exposure of interest and the
corresponding outcome.
• The association between the exposure of interest (eg. alcohol
use) and outcome (lung cancer) may be mixed-up with the
effect of another exposure (eg. smoking) on the same outcome,
the two exposures being correlated.
• Here smoking is a confounder as it is also an exposure
for the development of lung cancer. This phenomenon
is called as ‘confounding’.
• Confounding variables influences both the outcome and
exposure variables, causing a spurious association.
• Thus epidemiological studies collect information on the
primary exposure (s) of interest, other exposure (s) that
may influence the outcome (confounders) and the
outcome (s).
• There are two basic approaches for assessing whether
an exposure is associated with a particular outcome:
interventional and observational.
• The various observational study designs are generally
cohort studies, case-control studies, cross-sectional
studies and routine-data-based at individual and
aggregated level (ecological studies).
 Fundamental Assumption in Epidemiology

• Disease doesn’t occur in a vacuum

 Disease is not randomly distributed throughout a
population
– Epidemiology uses systematic approach to study
the differences in disease distribution in subgroups
– Allows for study of causal and preventive factors
 Components of Epidemiology
• Measure disease frequency
– Quantify disease
• Assess distribution of disease
– Who is getting disease?
– Where is disease occurring?
– When is disease occurring?
Formulation of hypotheses concerning
causal and preventive factors
• Identify determinants of disease
– Hypotheses are tested using epidemiologic studies
 Types of primary studies

• Descriptive studies
– describe occurrence of outcome

• Analytic studies
– describe association between
exposure and outcome
Basic Question in Analytic Epidemiology

• Are exposure and disease linked?

Exposure Disease
Basic Questions in Analytic Epidemiology

• Look to link exposure and disease

– What is the exposure?
– Who are the exposed?
– What are the potential health effects?
– What approach will you take to study the
relationship between exposure and effect?
 Basic Research Study Designs

• To prevent and control disease

• In a coordinated plan, look to
– identify hypotheses on what is related
to disease and may be causing it
– formally test these hypotheses
• Study designs direct how the
investigation is conducted
 Descriptive Analytic

Case report Cohort study

RCT

Case series Case-Control

study
Descriptive
Epidemiology Case-Crossover
study

Cross-sectional
study
Study Designs
Before-After
study

Ecologic study
 Timeframe of Studies
• Prospective Study - looks forward,
looks to the future, examines future
events, follows a condition, concern or
disease into the future

time

Study begins here

 Timeframe of Studies
• Retrospective Study - “to look back”,
looks back in time to study events that
have already occurred

time

Study begins here

 Study Design Sequence
Hypothesis formation
Descriptive
Case reports Case series
epidemiology

Analytic Animal Lab

epidemiology study study
Clinical
trials Hypothesis testing

Cohort Case- Cross-

control sectional
 Descriptive Studies Develop
hypothesis
Increasing Knowledge of

Investigate it’s
Disease/Exposure

Case-control Studies relationship to

outcomes

Define it’s meaning

Cohort Studies with exposures

Test link
Clinical trials experimentally
Descriptive Studies
 Case Reports

• Detailed presentation of a single case or

handful of cases
• Generally report a new or unique finding
• e.g. previous undescribed disease
• e.g. unexpected link between diseases
• e.g. unexpected new therapeutic effect
• e.g. adverse events
 Case Series
• Experience of a group of patients with a
similar diagnosis
• Assesses prevalent disease
• Cases may be identified from a single or
multiple sources
• Generally report on new/unique condition
• May be only realistic design for rare
disorders
 Case Series
• Advantages
• Useful for hypothesis generation
• Informative for very rare disease with few
established risk factors
• Characterizes averages for disorder

• Disadvantages
• Cannot study cause and effect relationships
• Cannot assess disease frequency
 Case Report One case of unusual
findings

Multiple cases of
Case Series findings

Descriptive Population-based
Epidemiology Study cases with denominator
 Study Designs - Analytic Epidemiology

• Experimental Studies
– Randomized controlled clinical trials
– Community trials
• Observational Studies
– Group data
• Ecologic
– Individual data
• Cross-sectional
• Cohort
• Case-control
• Case-crossover
 Experimental Studies
• Treatment and exposures occur in a
“controlled” environment
• planned research designs
• clinical trials are the most well known
experimental design. Clinical trials use
randomly assigned data.
• Community trials use nonrandom data
 Observational Studies
• Non-experimental
• Observational because there is no
individual intervention
• Treatment and exposures occur in a “non-
controlled” environment
• Individuals can be observed prospectively,
retrospectively, or currently
 Cross-sectional studies
• An “observational” design that surveys
exposures and disease status at a single point
in time (a cross-section of the population)

time
Study only exists at this point in time
Cross-sectional Design
factor present
No Disease
factor absent
Study
population
factor present
Disease
factor absent

time
Study only exists at this point in time
 Cross-sectional Studies
• Often used to study conditions that are relatively
frequent with long duration of expression (nonfatal,
chronic conditions)
• It measures prevalence, not incidence of disease
• Example: community surveys
• Not suitable for studying rare or highly fatal diseases
or a disease with short duration of expression
 Cross-sectional studies
• In cross-sectional study individuals from previously defined
population which is contacted at particular point of time from
both exposure and outcome of interest.
• So the investigators collect information from outcome and
exposure at the same time i.e, the cross-sectional data is
collected from cross-sectional area of specified region in
specified time.
• The researchers will conduct the study with the same set of
variables over the specified period of time; this study helps to
focus on one or more exposure variable and one or more
outcome variable.
• The data are analyzed based on the diseased vs. non-diseased
group.
• The main thing to be noted in a cross-sectional study is that
the data are collected at one time point on both the exposure
and outcome.
• The relative measure used in a cross-sectional study is odds
ratio.
• Cross-sectional study is used to estimate the prevalence of the
disease preferably for long duration because it is needed to
survey very large population to identify enough conclusions.
• The main benefits of cross-sectional study is it is very easy to
conduct, researchers can collect all variables at a specified
period of time, multiple outcomes can be observed,
prevalence factors can be observed, only less time required.
• But the bias in the selection of subjects can be occurred, it has
no dimension of time so it cannot conclude on risk of disease
and it cannot be used to look at individual change.
 Fig: Outline of a Cross-sectional study

+ + + ↓
+ ↓ + ++ + +
+ Diseased +
↓+ + ++ ↓ + Exposed
↓ ↓+
↓ Non- +↓+ +
diseased + + ↓ + + +
↓ Not Exposed
+
+ + + ++ +
• Example 8.2.4.1: A cross-sectional study was conducted to
evaluate the impact of awareness programmes among ever
users of tobacco in high school and higher secondary school
students of rural Thiruvananthapuram district in Kerala
state and to elucidate whether there is a significant shift in
knowledge on tobacco awareness after delivering the
message among ever users and never users. Self-reporting
questionnaires were distributed to 1,200 high school and
higher secondary school students of which 1,114 students
participated (Jayakrishnan et.al, 2019).

• Example 8.2.4.2 India Health Study (IHS) did a cross-

sectional investigation to aggregate foods in to regional
dietary patterns and to investigate associations with cardio-
metabolic risk factors of regional patterns of diet and
cardio-metabolic risk in India conducted across three
diverse regions of India (Daniel et.al, 2011).
 Cross-sectional studies
• Disadvantages
• Weakest observational design,
(it measures prevalence, not incidence of
disease). Prevalent cases are survivors
• The temporal sequence of exposure and effect
may be difficult or impossible to determine
• Usually don’t know when disease occurred
• Rare events a problem. Quickly emerging
diseases a problem
 Epidemiologic Study Designs
• Case-Control Studies
– an “observational” design comparing
exposures in disease cases vs. healthy
controls from same population
– exposure data collected retrospectively
– most feasible design where disease
outcomes are rare
Case-Control Studies
Cases: Disease
Controls: No disease
factor present
Cases
factor absent (disease)
Study
population
factor present Controls
(no disease)
factor absent
present
past

time

Study begins here

 Case-control studies
• Case-control study, commonly called as retrospective study
and the study group is divided into cases (those having
disease condition) and controls (very similar group of
people who do not have the disease or condition).
• Then cases and controls are compared to assess the
differences in their past exposure to general risk factors.
• The selection of control is very crucial in a case-control
study.
• The controls should provide an estimate of the exposure
rate that is expected to occur in the cases and also the
control should not only disease free of the disease but they
should be similar cases for the exposure during the time
period that are selected.
• To reduce the confounding effect, controls can be
selected by a procedure called “matching”.
• Matching is a procedure whereby controls are selected
in such a way that the distribution of potential
confounders (eg. age, gender, place of residence)
among them will be identical to those of the cases.
• This can be accomplished by selecting for each case
one or more controls with similar characteristics (eg.,
of the same age, gender).
• This is called individual matching.
• Controls can also be selected by ensuring that as a
group the controls have similar characteristics to the
cases.
• This is called frequency matching.
Advantage:
• Case-control study is efficient in time and cost and
provides possibility to assess the effect of a wide range
of possible risk factors and is particularly suitable for
the study of rare diseases with long duration of period.
Disadvantage:
• Selection of appropriate control group (selection bias)
and difficult to obtain accurate measures of past
exposures (information bias).
• Further, the sequence between exposure and disease
may be difficult obtain (reverse causality) and not
possible to estimate disease incidence among the
exposed and those unexposed to risk factor.
 Example:
• A case-control study was conducted at the Regional Cancer
Centre (RCC), Trivandrum and in three cancer hospitals in
Chennai during 2002–2005 to investigate the pattern of
anthropometric factors among urban and rural women and
their role in breast cancer etiology in India as well as their
contribution to the urban–rural differences in breast cancer
rates.
• There were a total of 1866 cases and age (+ 5 years) matched
1867 controls studied (Mathew et.al., 2008).
 Case-Control Study
• Strengths
– Less expensive and time consuming
– Efficient for studying rare diseases
• Limitations
– Inappropriate when disease outcome for a specific exposure
not known at start of study
– Exposure measurements taken after disease occurrence
– Disease status can influence selection of subjects
Hypothesis Testing: Case-Crossover Studies
• Study of “triggers” within an individual
• ”Case" and "control" component, but information
of both components will come from the same
individual
• ”Case component" = hazard period which is the
time period right before the disease or event
onset
• ”Control component" = control period which is a
specified time interval other than the hazard
period
 Epidemiologic Study Designs
• Cohort Studies
– an “observational” design comparing
individuals with a known risk factor or
exposure with others without the risk factor or
exposure
– looking for a difference in the risk (incidence)
of a disease over time
– best observational design
– data usually collected prospectively (some
retrospective)
 disease
Factor
Study present no disease
population
free of
disease Factor disease
absent
no disease
present
future

time
Study begins here
 Timeframe of Studies
• Prospective Study - looks forward,
looks to the future, examines future
events, follows a condition, concern or
disease into the future

time

Study begins here

 Cohort studies
• In a cohort study, a cohort of subjects is selected and
information on the exposure of interest and other
confounding factors are collected before the disease
onset (outcome of interest).
• The entire study subjects are then followed-up in time,
and the incidence of the disease of interest among the
exposed group is compared with the incidence in those
not exposed.
• Generally, cohort studies involve the follow-up of a
large number of subjects for long periods of time.
 Prospective Cohort study

Exposed Outcome

Measure exposure
and confounder
variables

Baseline Non-exposed Outcome

time

Study begins here

Advantages:
• Exposure is measured before the disease onset and thus
likely to be unbiased in terms of the disease
development.
• Incidence of the disease can be measured in the exposed
and the unexposed group.
• Further multiple outcomes can be studied for any
exposure.
Disadvantages:
• This type of study are very expensive and time-
consuming.
• Ascertainment of outcome can be biased by the
knowledge of the subject’s exposure status and losses to
follow-up can introduce bias.
Example: An epidemiologic study of a cohort of
385,103 residents in Karunagappally (known for high
background radiation from thorium-containing
monazite sand), Kerala, India, was established in the
1990's to evaluate the health effects of high
background radiation.
• Cumulative radiation dose in a sub-cohort of people
aged 30-84 years (N=69,958) was estimated based
on outdoor and indoor dosimetry of each
household were collected.
• Following 69,958 residents for 10.5 years on
average, 736,586 person-years of observation were
accumulated and 1,379 cancer cases were identified
by the end of 2005.
 Timeframe of Studies
• Retrospective Study - “to look back”,
looks back in time to study events that
have already occurred

time
Study begins here
 Retrospective Cohort study

Exposed Outcome

Measure exposure
and confounder
variables

Baseline Non-exposed Outcome

time
Study begins here
 Cohort Study
• Strengths
– Exposure status determined before disease detection
– Subjects selected before disease detection
– Can study several outcomes for each exposure

• Limitations
– Expensive and time-consuming
– Inefficient for rare diseases or diseases with long
latency
– Loss to follow-up
 Cohort vs Case-Control
• The major difference between cohort and case-
control is, in cohort the subject with disease-free
is taken and in case-control, the subjects are
selected according to the presence and absence
of the disease.
• Both the method allows one to estimate the
effect of exposure on the risk of disease by
calculating the relative measures.
• The relative measure used in cohort study is risk
ratio or rate ratio where as in a case-control
study, it is odds ratio.
 Routine-data-based studies
At individual level
• Many routine data-collection systems particularly hospitals
collect data on personal attributes such as age, sex, place of
birth, place of residence, occupation, tobacco-alcohol use etc.
cancer occurrence can then be examined in relation to these
variables, either to confirm a specific hypothesis.

• Example: Based on a routinely collected population based cancer

registry data a study conducted at the Regional Cancer Centre,
Trivandrum to estimate trends in breast cancer incidence by age
from 2005- 2014 and predicted rates through 2020 (Mathew
et.al,2016).
At aggregate level (Ecological study)

• The ecological study is the measuring of disease frequency

in relation to the level of exposure in several groups of
people.
• The group is defined in the large number of ways may be of
place of residence, place of birth, occupation, etc.
• Most ecological studies make use of routine data.
• The common approach to look for geographical relation or
correlation between disease incidence or mortality and the
prevalence of the risk factors are found using this study.
• From this study many useful observations can be derived
but more care is needed for interpretation.
• Time over time is the main factor of this study many disease
show remarkable fluctuations in incidence over time.
• An ecological study is used when purpose of study population
study with public health should be developed, to check the large
scale comparisons, to study the relationship between
population-level exposure to risk factors and disease.
• The main drawback is individual level are not available,
investigation under ecological is rare, ecologic studies can be
misleading when evaluating non-linear relationships and the
effect of confounding factors.
• Example: A hypothetical study was carried out to examine the
association between prevalence of an infection named A and
mortality of the disease in a particular regions of India in the year
2000. Then the result of the particular infection according to the
region is noted. Here the graph is plotted against prevalence and
disease mortality and the dots in the graph are the regions of
India (hypothetically).
Ecological Study
 Experimental Studies
• investigator can “control” the exposure
• akin to laboratory experiments except living
populations are the subjects
• generally involves random assignment to groups
• clinical trials are the most well known
experimental design
• the ultimate step in testing causal hypotheses
 Experimental Studies
• In an experiment, we are interested in the
consequences of some treatment on some
outcome.
• The subjects in the study who actually receive
the treatment of interest are called the
treatment group.
• The subjects in the study who receive no
treatment or a different treatment are called
the comparison group.
 Epidemiologic Study Designs
• Randomized Controlled Trials (RCTs)
– a design with subjects randomly assigned to
“treatment” and “comparison” groups

– provides most convincing evidence of

relationship between exposure and effect

– not possible to use RCTs to test effects of

exposures that are expected to be harmful, for
ethical reasons
RANDOMIZATION outcome
Intervention
no outcome
Study
population
outcome
Control
no outcome
baseline
future

time
Study begins here (baseline point)
 Epidemiologic Study Designs
• Randomized Controlled Trials (RCTs)
– the “gold standard” of research designs
– provides most convincing evidence of
relationship between exposure and effect

• trials of hormone replacement therapy in

menopausal women found no protection
for heart disease, contradicting findings of
prior observational studies
 Randomized Controlled Trials

• Disadvantages
–Very expensive
–Not appropriate to answer certain
types of questions
• it may be unethical, for example, to
assign persons to certain treatment or
comparison groups
 References
• Daniel CR, Prabhakaran D, Kapur K. et al. A cross-sectional investigation of
regional patterns of diet and cardio-metabolic risk in India. Nutr J 10, 12
(2011).
• Jayakrishnan R, Krishna KMJ, Seema G, Thomas G, Sebastian P. Effectiveness of
School based Awareness Programmes against Tobacco among Users and Non-
Users- A Cross- Sectional Study from Rural Kerala, India. Asian Pac J Cancer
Prev. 2019 Jul 1;20 (7):2027-2032
• Mathew A, Gajalakshmi V, Rajan B, Kanimozhi V, Brennan P, Mathew BS,
Boffetta P. Anthropometric factors and breast cancer risk among urban and
rural women in South India: a multicentric case-control study. Br J Cancer.
2008 Jul 8;99(1):207-13
• Mathew A, George PS, Arjunan A, Augustine P, Kalavathy M, Padmakumari G,
Mathew BS. Temporal Trends and Future Prediction of Breast Cancer
Incidence Across Age Groups in Trivandrum, South India. Asian Pac J Cancer
Prev.; 2016, 17(6):2895-9.
• Nair RRK , Rajan B, Akiba S et al., Background radiation and cancer incidence in
Kerala, India-Karunagappally cohort study 2009;96(1):55-66.