Neuroepidemiology Teaching Course:
Non-Experimental Neuroepidemiology
Chisinau Moldavia
September 26 2012
Design and Methods of Cohort Studies
Giancarlo Logroscino MD PhD
Department of Neurology and Psychiatry
University of Bari. Italy
Veterans
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Veterans Gain U.S. Benefits for Lou Gehrig’s Disease
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By DENISE GRADY
September September
28, 2008 23, 2008
Published:
The federal government will provide disability pay,
lifetime health care and death benefits for all veterans with
Lou Gehrig’s disease, the Department of Veterans Affairs said Tuesday,
saying the disease was linked to military service.
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All veterans with the illness will be eligible, regardless of when or where
Some general statements
about epidemiology
Study Design: Two Steps
• We determine whether there is an association
between a factor or a characteristics and the
development of a disease
• We establish appropriate inferences regarding a
possible causal relationship based on the patterns
of the association that has been found
Goal of Epidemiology
• Quantification of causal relationship between exposure
and disease (K. Rothman 1986)
• Measurement of the association focuses on quantitative
index that characterizes the strength of the association
• Quantification of an association is a measure of state of
nature
Null
Effect
The Natural History of a Disease
Gordis L, Epidemiology 2000 W. B. Saunders Company Philadelphia, PA
Preclinical Phase
Clinical Phase
Outcome
(A)
Biological
Onset
(P)
(S)
Pathological
Evidence
Signs and
Symptoms
of Disease
time
(M)
Medical
Care
sought
(D)
Diagnosis
(T)
Treatment
Time and the Induction Period of Disease
Preclinical Phase
Clinical Phase
Exposure
Biological
Onset
time
Signs and
Symptoms
of Disease
Diagnosis
time
Classification of Studies
Descriptive
Studies
Populations
Frequency
Distribution by
time
Place
Person
Population
Survey
Analytic Studies
Experimental Studies
•Counting exposure and
outcomes in individuals
•Test causal hypotheses
•Uncontrolled assignment
•Counting exposure and
outcomes in individuals
•Test causal hypotheses
•Controlled assignment
CaseControl
Cohort
Randomized
Clinical
Trial
Anatomy of the Cohort Study
• Define the hypothesis
• Define the independent variable (risk factor)
-Exposed cohort
-Unexposed cohort
• Define the dependent variable (disease)
• Perform measures
-Initial study/baseline assessment
-Follow-up and detection of incident cases
• Statistical analysis
-Incidence and relative-risk
-Person-years, survival curves
• Interpretation of results (bias)
COHORT STUDIES
• Study design
Then follow to see whether
First
Select
Totals
Disease
Develop
Disease
Not develop
Exposed
a
b
a+b
Not exposed
c
d
c+d
Incidence Rates
of disease
a
a+b
c
c+d
COHORT STUDIES
• Results of a Hypothetical Cohort Study of Smoking and Coronary Heart Disease(CHD)
Then follow to see whether
Develop
CHD
First
Select
Smoke cigarettes
Do not smoke cigarettes
Totals
Do Not
develop CHD
Incidence per
1000 per year
84
2916
3000
28.0
87
4913
5000
17.4
RR= Ie/ Ine=
Do we need
observational studies?
Individuals and Populations
Observational epidemiolgy and Cohort Studies
Experimental Study (RCT)
Observational Study
POPULATION
OTHER-THAN
RANDOM
ALLOCATION
(e.g., Self Selection)
RANDOM
ALLOCATION
GROUP A
GROUP B
GROUP B
Animal Models
•Complete Control of Exposure
•Random Allocation
Individuals and Populations
Lost in translation:
treatment trials in the SOD1
mouse and in human ALS.
Benatar M Neurobiology of Disease 2007 Apr;26(1):1-13
Why did the US Government
take that decision about
Veterans and ALS?
Veterans
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Veterans Gain U.S. Benefits for Lou Gehrig’s Disease
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By DENISE GRADY
Published: September 23, 2008
The federal government will provide disability pay,
lifetime health care and death benefits for all veterans with
Lou Gehrig’s disease, the Department of Veterans Affairs said Tuesday,
September
28, 2008was linked to military service.
saying the disease
Skip to next paragraph
RSS Feed
•Get Health News From The New York Times »
All veterans with the illness will be eligible, regardless of when or where they
served.
The 10-year cost for death and disability benefits is projected at $505,839,000,
said Tom Pamperin, the deputy director of the compensation and pension service
at the Veterans Affairs Department. That figure does not include health care costs.
Inference from Epidemiological Evidence
Savitz DA Oxford University Press 2003: 8
• Association between exposure and disease among
study participants
• Causal effect of exposure on disease in study
population
• Causal effect of exposure on disease in external
population
• Prevention of disease through elimination or reduction
of the exposure
• Public Health Impact from elimination or reduction of
the exposure
Gulf War Veterans: the ALS occurrence
• 2482333 individuals who
were on active duty or
activate reserve
• 696118 deployed to the
Gulf region
• 516 ALS cases from passive
and active ascertainment
• 96.2% successfully
contacted
Occurrence of ALS among Gulf War Veterans
Horner et al, Neurology, 2003; 61:742-749
DMDC-reported Deployment Status:
Population
EEC
Onset July 1991
(n=86)
Men only
(n=105)
Total
2.1(1.3-3.2)
1.8(1.2-2.8)
1.7(1.2-2.6)
Unit
Active
Reserves-National Guard
2.2(1.4-3.6)
3.4(1.0-11.3)
2.0(1.2-3.2)
2.7(0.9-8.4)
2.0(1.3-3.1)
2.2(0.7-6.3)
Service branch
Air Force
Army
Marine corps
Navy
3.1(1.4-6.7)
2.1(1.1-4.3)
0.9(1.2-4.9)
1.9(0.7-5.1)
2.1(0.9-4.9)
2.7(1.3-5.3)
1.1(0.3-4.8)
1.0(0.3-3.0)
2.6(1.2-5.6)
1.8(0.9-3.3)
1.1(0.3-4.6)
1.4(0.6-3.4)
Anatomy of the Cohort Study
1.Define the hypothesis
1.War RF for ALS
2.Define the independent variable (risk factor)
2.
Deployment in GW
-Exposed cohort
Lack of deployment in GW
-Unexposed cohort
3. Define the dependent variable (disease)
3.ALS
4.Perform measures
-Initial study/baseline assessment
-Follow-up and detection of incident cases
4.Deployment Status Ascertainment
Detection of ALS cases
5.Statistical analysis
-Incidence and relative-risk
-Person-years, survival curves
5 Measurement of RR
6. Interpretation of results (bias)
Population Concept of a Cohort Study
Bhopal R. Concept of Epidemiology. An Integrated Introduction to the Ideas, Theories, Principles
and Methods of Epidemiology. 2002 Oxford University Press, Oxford
Time 0/Now
NE
NE
E
NE
NE
NE
E
E
NE
ALS
E
Induction Period
now
NE
NE
E
E
ALS
NE
ALS
E
NE
NE
E
NE
NE
NE
ALS
ALS
E
E
E
E
Time 1/Future
E
E
NE
ALS
CHD
future
Excess of Incidence of ALS
in Young Gulf War Veterans
Haley, Neurology, 2003; 61:750-756
3.50
3.19
3.00
2.50
2.27
2.16
SMR (Ratio O:E)
2.03
2.00
1.67
1.55
1.50
1.07
0.94
0.91
1.00
0.50
0.00
0.00
1991
1992
1993
1994
1995
1996
1997
1998
1991-1994
1995-1998
ALS and The Gulf War Veterans: a
Possible Cluster
• Onset of disease in young age groups that have a
very low rate in the general population
• There is an increasing slope of the epidemic
curve: the excess of cases is still to come
• The excess in incidence probably triggered by
some environmental exposure
ALS mortality by military service and birth cohort
Weisskopf et al Neurology: 2005;64:32-37
Relative Risk of ALS by Service
During War Periods (1989-1998)
Weisskopf et al Neurology: 2005;64:32-37
10
1
1.0
1.7
1.9
1.97
1
1
No
N
2w
>
ars 2 wa
Mi o Wa war
l i ta
rs
ry rtime
Se
rvi
ce
p for trend
<0.004
What is the Cause of ALS excess of cases
among Gulf War veterans?
ALS and Military Service:
Hints for Causality
Exposure precedes the outcome
The risk peaks after a time period
(induction period)
The risk increase with increasing dose of exposure
Advantage and Disadvantages
Disdvantages
Advantages
• Measure relative risk
• Less misclassification
• Less measurement bias
• Changes in exposure and
gradation of exposure
• Multiple disease for the same
risk factor
• Non-respondent/volunteer
bias (selection)
• Diagnostic suspicion bias
(measurement)
• Attrition
•Time and expense (big sample)
•Difficult to study uncommon diseases
• Study may alter outcome
• Ethical problems
• Limited and fixed number of
hypotheses (risk factors)
Potential Contribution of Study Design
Bhopal R, Concepts of Epidemiology, Oxford 2002
Criteria
Cross-sectional
Case-control
Cohort
Trial
Temporality
Sometimes
Sometimes
Often
Usually
Strength or
Dose-response
Sometimes
Often
Always
Always
Experimental
confirmation
Sometimes
(repeated studies)
Seldom
Sometimes
(natural changes)
Always
Specificity
Sometimes
Yes
(disease)
Yes
(risk factor(s))
Biological
Plausibility
Not Directly
Not directly
Not directly
Consistency
Yes
Yes
Yes
Yes
(risk or preventive
factor(s))
Not directly
Yes