Dr. Mehrnaz Nikouyeh
Emergency physician
Definitions of Research

 The study of the distribution and determinants of
health-related states or events in specified populations
and the application of this study to the control of health
problems
PURPOSE OF EPIDEMIOLOGY

 To describe the frequency and extent of health conditions and disease.
 To determine the burden of disease in a community, including
socioeconomic impact of disease occurrence in specific populations.
 To identify the causes and risk factors of specific diseases. This is the
basis of disease prevention.
 To evaluate medical interventions, including both preventive and
therapeutic measures, and evaluate the delivery of these measures in
health care settings.
 To study the natural history and prognosis of disease.
 To provide the foundation for developing public policy and regulatory
decisions relating to health.
Where to Start?

 A good clinical study starts with
a good question based on good hypothesis that is based on
good and comprehensive review of the available evidence
from pre-clinical and clinical data
 Type of design depends on the question to be
answered
Formulating a Research Question

 Focused and specific
 Supported by available data
 Not a replication of already established evidence
 Ethical
 Answerable
 Methods, resources ….etc.
Objectives

 Specific aims
 Clear and detailed
 End point(s)
 Primary
 The main answer to the research question
 Secondary
 Answer other related questions
Study Design

Your
question
Your
resources
Community
• Describe
• Analyze
• Retrospective
• Prospective
• Acceptance of research
• Observational
• Interventional
Clinical Study Types

Descriptive
Case repot
Case series
Analytic
Survey
Observational
Experimental
Cross sectinal
Case control
Cohort
RCT
Types of primary studies

 Descriptive studies
 describe occurrence of outcome
 Analytic studies
 describe association between
exposure and outcome
Observational study  Clinical trial
describe as
occurring in nature
observational
study
exposed
outcome
allocate
randomly
non exposed
Clinical
Trial
10
Ethics!
Hierarchy of Epidemiologic Study
Design

Important issues in Study Design

Validity: Truth
 External Validity:
Can the study be generalized to the
population
 Internal Validity:
 Results will not be due to chance, bias or
confounding factors
 Symmetry Principle: Groups are similar
Important issues in Study Design

 Confounding: distortion of the effect of one risk factor by
the presence of another
 Bias: Any effect from design, execution, & interpretation
that shifts or influences results
 Confounding bias: failure to account for the effect of one or
more variables that are not distributed equally
 Measurement bias: measurement methods differ between
groups
 Sampling (selection) bias: design and execution errors
in sampling
13
Descriptive studies

 Cannot establish causal relationships
 Still play an important role in describing
trends and generating hypotheses about
novel association
 Describing a novel phenomena
Analytic Studies

 Attempt to establish a causal link between a
predictor/risk factor and an outcome.
 You are doing an analytic study if you have any
of the following words in your research
question:
 greater than, less than, causes, leads to, compared with,
more likely than, associated with, related to, similar to,
correlated with
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
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
Case Series
Multiple cases of
findings
Descriptive
Epidemiology Study
Population-based
cases with denominator
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
 Possibility of confounding
 No control over study units
 need to clearly describe study individuals
 Can study risk factors that have serious consequences
 Study individuals in their natural environment (>>
extrapolation)
Types of observational studies

cohort
Case control
Cross sectional
Aims of observational studies

Evaluate the effect of a suspected risk factor
(exposure) on an outcome (e.g. disease)
 define “exposure” and “disease”
Describe the impact of the risk factor on the
frequency of disease in a population
Temporal relations of observational
studies

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
Study
population
factor absent
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.
Comparison of prevalence among exposed and nonexposed.
 Not suitable for studying rare or highly fatal diseases or a
disease with short duration of expression
Cross - Sectional Study

 Random sample from population
 i.e. results reflect reference population
 Estimates the frequencies of both exposure
and outcome in the population
 Measuring both exposure and outcome at
one point in time
 Typically a survey
Cross - Sectional Study advantages

 Can study several exposure factors and outcomes
simultaneously
 Determines disease prevalence
 Helpful in public health administration & planning
 Quick
 Low cost (e.g. mail survey)
 Very useful for public health planning
 Disease etiology. Conduct this by obtaining data on risk
factors for a disease.
 Hypothesis generating
Cross-sectional studies disadvantages

observational design,
Weakest
(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
Does not determine causal relationship
Cross-Sectional: Pediatrician-to-Child Ratio
Pediatricians per
1000 Children

40
35
30
25
20
15
10
5
0
1981
1986
1991
1996
Rural
Urban
Greg et al. (2001) Pediatrics.107(2):e18
Case-Control Study Design

Exposed
Cases
Unexposed
Exposed
Controls
Unexposed
Time
Q: What
happened?
Direction of
inquiry
Data
collection
Case control studies

 Determines the strength of the association between
each predictor variable and the presence or absence
of disease
 Cannot yield estimates of incidence or prevalence
of disease in the population (why?)
 Odds Ratio is statistics
Case-Control Study

 Retrospective
 Can use hospital or health register data
 First identify cases
 Then identify suitable controls
 Hardest part: who is suitable ??
 Critical that the exposure in the controls is representative of the
exposure in the population
 Ideal controls would have same/similar characteristics as the cases
 Matching cases to controls
 Then inquire or retrieve previous exposure
 By interview
 By databases (e.g. hospital, health insurance)
Case-Control Study

Strengths
 Less expensive and time consuming
 Efficient for studying rare diseases




Can study many risk factors at the same time
Smaller sample
Multiple etiologic factors evaluated for single disease
Good for diseases with long latency
Case-Control Study

Limitations
 Inappropriate when disease outcome for a specific exposure
is not known at start of study
 Exposure measurements taken after disease occurrence
 Disease status can influence selection of subjects




Confounding likely
difficulties in selection of controls
ascertainment of disease & exposure status
inefficient for rare exposures unless attributable risk is high
Case-control study-minuses

- Causality still difficult to establish
- Selection bias (appropriate controls)
-
Caffeine and Pancreatic cancer in the GI clinic
- Recall bias: sampling (retrospective)
-
Abortion and risk of breast cancer in Sweden
Case Selection
• Define source population
• Cases
– incident/prevalent
– diagnostic criteria (sensitivity + specificity)
• Controls
– selected from same population as cases
– select independent of exposure status
Control Selection
• Random selection from source population
• Hospital based controls:
– convenient selection
– controls from variety of diagnostic groups other
than case diagnosis
– avoid selection of diagnoses related to
particular risk factors
– limit number of diagnoses in individuals
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
Prospective Cohort Study

Exposed
with outcome
without
outcome
Cohort
with outcome
Unexposed
Onset
of study
without
outcome
Time
Direction of inquiry
Q: What will happen?
Prospective Cohort study

Exposed
Outcome
Non-exposed
Outcome
Measure exposure
and confounder
variables
Baseline
time
Study begins here
Retrospective Cohort study

Measure exposure
and confounder
variables
Baseline
Exposed
Outcome
Non-exposed
Outcome
time
Study begins here
Cohort studies

 Follow-up studies; subjects selected on
presence or absence of exposure & absence of
disease at one point in time. Disease is then
assessed for all subjects at another point in
time.
 Typically prospective but can be retrospective,
depending on temporal relationship between
study initiation & occurrence of disease.
Cohort studies

1. Prospective cohort study – outcome event of interest
occur after the study is initiated
2. Retrospective cohort study – outcome events of interest
have already occurred at study initiation
 Can be regarded as a reconstruction of a cohort study
which has already taken place
 Generally cheaper and faster than a prospective study
 Requires good historical exposure data on subjects
Cohort studies

 More clearly established temporal sequence between
exposure & disease
 Can establish population-based incidence
 Accurate relative risk (risk ratio) estimation
 Can examine rare exposures (asbestos > lung cancer)
 Can be used where randomization is not possible
 Allows direct measurement of incidence
 Examines multiple effects of a single exposure
 - Magnitude of a risk factor’s effect can be quantified
 Selection and information biases are decreased
Cohort Study

 Strengths
 Exposure status determined before disease detection
 Subjects selected before disease detection
 Can study several outcomes for each exposure
 Directly measure incidence of a disease outcome
 Limitations
 Expensive and time-consuming
 Inefficient for rare diseases or diseases with long latency
 Loss to follow-up and unavailability of data
 potential confounding factors
 Unexpected environmental changes may influence the association
Basic Question in Analytic
Epidemiology

Are exposure and disease linked?
Exposure
Disease
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
Clinical Trial: Study Design

 Uncontrolled
 Controlled




Before/after (cross-over)
Historical
Concurrent, not randomized
Randomized
Non-randomized Trials

May Be Appropriate
Early studies of new and untried therapies
Uncontrolled early phase studies where the standard
is relatively ineffective
Investigations which cannot be done within the
current climate of controversy
Truly dramatic response
Randomized controled trial

RANDOMIZATION
outcome
Intervention
Study
population
baseline
no outcome
outcome
Control
no outcome
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
Advantages of Randomized
Control Clinical Trial

advantages
Randomization tends to produce
comparable groups
Assure causal relationship
Randomization produces valid statistical
tests
62
Disadvantages of
Randomized Control Clinical Trial

1. Generalizable Results?
 Participants studied may not represent general
study population.
2. Recruitment
 Hard
3. Acceptability of Randomization Process
 Some physicians will refuse
 Some participants will refuse
4. Administrative Complexity
5. Very expensive
63
Clinical Trials-Phases

Phase I - Does it hurt the Patient?


Phase II - Does it help the Patient?


On patients to confirm the effectiveness of the drug
Phase III - Is it any better?


Usually in normal volunteers, small groups for safety testing
Large groups of patients for statistical confirmation of effect
and incidence of side-effects
Phase IV - Does it work in the community?

Post marketing studies. Fine tuning and new rare findings from a
very large population
64