Epidemiology

Analytic Epidemiological Designs

Basic Question in Analytic Epidemiology
E
D
Exposure
Disease

Cohort Study

Cohort is an ancient Roman military unit of 300 – 600 men.

A group of soldiers marching forward in battle

In epidemiology, cohort is a group of people who share a common characteristic or experience within a defined period (e.g., are born, are exposed to a drug or a vaccine, etc.).
Thus a group of people who were born on a day or in a particular period, say 1980, form a birth cohort.


A study design that follows over time one or more populations (called cohorts) to determine which patient characteristics (risk factors) are associated with the development of a disease or outcome.

Key Point:

Presence or absence of risk factor is determined before outcome occurs.

General consideration while selection of cohorts

Both the cohorts are free of the disease.
Both the groups should equally susceptible to disease
Both the groups should be comparable
Diagnostic and eligibility criteria for the disease should be defined well in advance.

ANALYSIS

Calculation of incidence rates among exposed and non exposed groups

Estimation of risk

Incidence rates of outcome


N

d
c
b
a
Yes
No
Disease Status
Yes
No
Exposure
Status
a+b
c+d
b+d
a+c

Total

Exposed
Non Exposed

Relative Risk

• = 1 No association
• < 1 Negative association
•

Risk estimation

AR: Attributable Risk
Excess risk attributed to exposure
AR%: Attributable Risk percent
Express the gain or the benefit if the exposure removed


Incidence
I. among
exposed

A R%

A R

Base-line risk

I. among non exposed

• Smoking

• Lung cancer

• Total

• YES
• NO
• YES
• 70
• 6930
• 7000
• NO
• 3
• 2997
• 3000
• 73
• 9927
• 10000
Find out RR and AR for above data


Incidence of lung cancer among smokers
70/7000 = 10 per 1000
Incidence of lung cancer among non-smokers
3/3000 = 1 per thousand
RR = 10 / 1 = 10
(lung cancer is 10 times more common among smokers than non smokers)
AR = 10 – 1 / 10 X 100
= 90 %
(90% of the cases of lung cancer among smokers are attributed to their habit of smoking)

Timeframe of Studies

Prospective Study - Outcomes have not yet occurred as study begins. 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 - Outcomes have already occurred as the study begins. “to look back”, looks back in time to study events that have already occurred

time

Study begins here

Strengths

We can find out incidence rate and risk
More than one disease related to single exposure
can establish cause - effect
good when exposure is rare
minimizes selection and information bias

Weaknesses

losses to follow-up
often requires large sample
Ineffective for rare diseases
long time to complete
Expensive
Ethical issues






…... several famous large cohort studies continue to provide important information …..
Framingham Heart Study

Case Control study

Why case-control study?
In a cohort study, you need a large number of the subjects to obtain a sufficient number of case, especially if you are interested in a rare disease.
Gastric cancer incidence in Japanese male:
128.5 / 100,000 person year

A case-control study is more efficient in terms of study operation, time, and cost.

Case Control

Definition….

The case-control study is an analytic epidemiologic research design in which the study population consists of 2 groups who either have (cases) or do not have a particular health problem or outcome (controls).

The investigator looks back in time to measure exposure of the study subjects. The exposure is then compared among cases and controls to determine if the exposure could account for the health condition of the cases.
Case Control

Case-Control Studies

Cases: Disease
Controls: No disease


Case Control

Case-control study - Sequence of determining exposure and outcome status

Step1: Determine and select cases of your research interest

Step2: Selection of appropriate controls

Step3: Determine exposure status in both cases and controls

Case Control

Design of Case Control Study

• cases with the disease
Should have clear case definition i.e. clear criteria for defining the disease of interest
May be taken from clinics, hospitals, disease registries
Preferred newly diagnosed

Case Control

Design of Case Control Study
• Appropriate controls without the disease
Should comes from the same study base or population as cases
Can come from geographical sample, medical inistitution, neighbors, friends,….
Can have multiple control groups
May be matched
•


Case Control

１）a population-based case-control study

Both cases and controls are recruited from the population.

２）a case-control study nested in a cohort

Both case and controls are members of the cohort.

３）a hospital-based case-control study

Both case and controls are patients who are hospitalized or outpatients.
Controls with diseases associated with the exposure of interest should be avoided.
Types of case-control studies

Case Control

Case-Control Design
Study
population
Cases
(disease)
Controls
(no disease)
factor present
factor absent
factor present
factor absent


present
past

time

Study begins here
Case Control

31

Case-control Study – Design

Select subjects on the basis of disease status
Case Control

• Interpretation of (OR) odds ratio

• > 1 means the exposure is a risk factor.
• = 1 means the exposure is not associated with the disease.
• < 1 means the exposure is protective
Case Control


Lung cancer Controls
cases
N=100 N=100
Smokers (NOT recently started)
↓ ↓
70 40

An example of unmatched case-control study

Cases
Controls
smoker
70
40
Non-smoker
30
60

Odds ratio=

Case Control


Advantages
• Simple, not time consuming (quick) and inexpensive.
• Suitable for rare diseases.
• Can examine multiple exposures for a single disease.
• Support, but not provide causal association.
• Suitable for diseases of long latency period
• Dose response relationship can be assessed
• Small sample size
• No ethical problem
Case Control

Disadvantages

• Recall bias
• Selection bias
• Different diagnostic tools so “case groups” may be not homogenous.
• The chosen cases are selective survivors (the history of died cases may be different) thus the cases does not represent a universe of cases.
• The time sequence between the exposure and the disease is not clear.
• Control of confounding factors
• Not suitable for rare exposure
• Only one outcome


Case Control

36
Controlling extraneous variables (confounding)
Exposure of interest may be confounded by a factor that is associated with the exposure and the disease i.e., is an independent risk factor for the disease

A
B
C

Case Control

37
How to control for confounding
At the design phase
Randomization
Restriction
Matching
At the analysis phase
Age-adjustment
Stratification
Multivariable adjustment (logistic regression modeling, Cox regression modeling)


Case Control

Matching

• Selection of controls to match specific
• characteristics of cases
• Frequency matching
• Select controls to get same distribution of variable as cases (e.g. age group)
• Individual matching
• Select a specific control per case by matching variable (e.g. date of birth)
Case Control

Intervention or Experimental studies

Therapeutic
Study population
Patients with disease

Objectives

Cure patients
Diminish symptoms
Prevent recurrence of disease/risk of death
Preventive
Study Population
Population at risk


Objectives
Reduce the risk of developing disease
• Clinical trials are the most well known experimental design
Such 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.

RCT

Why Performed ?

• Provide stronger evidence of the effect (outcome) compared to observational designs, with maximum confidence and assurance
• Yield more valid results, as variation is minimized and bias controlled
• 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%)
RCT

Experimental Studies

A study in which a population is selected for a planned trial of a regimen, whose effects (consequences of some treatment on some outcome) are measured by comparing the outcome of the regimen between 2 groups.

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.
RCT


Experimental Design

time

Study begins here (baseline point)
Study
population
Intervention
Control
outcome
no outcome
outcome
no outcome

baseline

future

RANDOMIZATION

RCT


Types of trials
RCT

Design - conduct

Different phases

Enrollment (selection of study population)

Allocation of study regimes

Follow-up

Maintainence and assessment of adherence
High and uniform rates of ascertainment

Analysis and interpretation

RCT

Population hierarchy for intervention study

Reference population

Experimental population

Exclusion criteria
Informed consent


Excluded
Refused
Study population

Intervention group

Control group

Outcome

Losses to follow-up
Losses to follow-up

Random allocation

RCT

RCT Advantages (I)

the “gold standard” of research designs. They thus provide the most convincing evidence of relationship between exposure and effect. Example:
trials of hormone replacement therapy in menopausal women found no protection for heart disease, contradicting findings of prior observational studies
RCT

RCT Advantages (II)

Best evidence study design
No inclusion bias (using blinding)
Controlling for possible confounders
Comparable Groups (using randomization)

RCT

Disadvantages

Large trials (may affect statistical power)
Long term follow-up (possible losses)
Compliance
Expensive
Public health perspective ?
Possible ethical questions
RCT

Blinding

Hiding information about the allocated study regimes from key participants in a trial
• Depending on
outcome of interest
Ethics, feasibility, compromise
By Using Placebo which is Inert medication, i.e No effect, intended to give the patient the perception they are receiving treatment


Types:
• Single – blind :Observer or subject are kept ignorant about allocated study regime
• Double blind :Both observer and the subject are kept ignorant about allocated study regime

RCT

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