Risk Epidemiology

Absolute, Relative and
Attributable Risks
International Society for Nurses in Genetics
May 2007
Jan Dorman, PhD
University of Pittsburgh
Pittsburgh, PA USA
Objectives
Define measures of absolute, relative and

attributable risk
Identify major epidemiology study designs
Estimate absolute, relative and attributable

risks from studies in the epidemiology
literature
Interpret risk estimates for patients and

apply them in clinical practice
Clinical Epidemiology is
Science of making predictions about individual

patients by counting clinical events in similar
patients, using strong scientific methods for
studies of groups of patients to ensure that
predictions are accurate
Important approach to obtaining the kind of

information clinicians need to make good
decisions in the care of their patients
Sounds like evidence based practice!

Fletcher, Fletcher & Wagner, 1996
Considerations
Patients prognosis is expressed as

probabilities estimated by past
experience
Individual clinical observations can be

subjective and affected by variables that
can cause misleading conclusions
Clinicians should rely on observations based

on investigations using sound scientific
principles, including ways to reduce bias
Fletcher, Fletcher & Wagner, 1996
Epidemiology is
Process by which public health problems

are detected, investigated, and analyzed
Risk estimates
Based on large populations, not patients or

their caregivers
Potential bias and confounding are major
issues to be considered
Scientific basis of public health
Objectives of Epidemiology
To determine the rates of disease by person,

place and time
Absolute risk (incidence, prevalence)
To identify the risk factors for the disease

Relative risk (or odds ratio)
To develop approaches for disease prevention

Attributable risk/fraction
To determine the rates of

disease by person, place, & time
Absolute
risk (incidence, prevalence)
Incidence = number of new cases of a

disease occurring in a specified time
period divided by the number of
individuals at risk of developing the
disease during the same time
Prevalence = total number of affected

individuals in a population at a specified
time period divided by the number of
individuals in the population at the time
To identify the risk factors for

the disease
Relative
risk (RR), odds ratio (OR)
RR = ratio of incidence of disease in exposed

individuals to the incidence of disease in
non-exposed individuals (from a
cohort/prospective study)
If RR > 1, there is a positive association
If RR < 1, there is a negative association
OR = ratio of the odds that cases were

exposed to the odds that the controls were
exposed (from a case control/retrospective
study) is an estimate of the RR
Interpretation is the same as the RR
To identify the risk factors for

the disease
Relative
risk (RR), odds ratio (OR)
RR = ratio of incidence of disease in exposed

individuals to the incidence of disease in
non-exposed individuals (from a
cohort/prospective study)
If RR > 1, there is a positive association
If RR < 1, there is a negative association
OR = ratio of the odds that cases were

exposed to the odds that the controls were
exposed (from a case control/retrospective
study) is an estimate of the RR
Interpretation is the same as the RR
To develop approaches for

disease prevention
Attributable risk (AR)/fraction (AF)

AR = the amount of disease incidence that
can be attributed to a specific exposure
Difference in incidence of disease between
exposed and non-exposed individuals
Incidence in non-exposed = background risk
Amount of risk that can be prevented
AF = the proportion of disease incidence

that can be attributed to a specific
exposure (among those who were exposed)
AR divided by incidence in the exposed X 100%
Attributable Risk
Risk
Excess
Risk
Risk among risk

AR = factor positives
Risk among risk
factor negatives
Risk Factor
Attributable Fraction
AF =
Risk among
risk factor
positives
among
- Risk
risk factor
negatives
Risk among
risk factor
positives
X 100%
Major Epidemiology Study

Designs
Case
Control (retrospective)
Cohort
Cross
(prospective)
sectional (one point in time)
Case Control/Retrospective
Studies
Risk
factor
+
Risk
factor -
Risk
factor
+
No
Diseas
e
Diseas
e
Identify
affected and
unaffected
individuals
Risk factor
data is
collected
retrospectively
Risk
factor -
No
Diseas
e
Diseas
e
Case Control/Retrospective
Studies
Advantages
Inexpensive
Relatively short
Good for rare
disorders
Measures of risk
Odds ratio
Attributable risk
(if incidence is
known)
Disadvantages
Selection of
controls can be
difficult
May have biased
assessment of
exposure
Cannot establish
cause and effect
Cohort/Prospective Studies
Risk
factor
+
Risk
factor -
Risk
factor
+
No
Diseas
e
Diseas
e
Identify
unaffected
individuals
Risk factor
data collected
at baseline
Follow until
occurrence of
disease
Risk
factor -
No
Diseas
e
Diseas
e
Cohort/Prospective Studies
Advantages
Establishes cause
and effect
Good when disease
is frequent
Unbiased
assessment of
exposure
Measures of risk
Absolute risk
(incidence)
Relative risk
Attributable risk
Disadvantages
Expensive
Large
Requires lengthy
follow-up
Criteria/methods
may change over
time
Cohort and Case Control

Studies
Past
Present
Future
Risk factor?
Disease
?
Cohort Studies
Risk factor?
Disease
?
Case-Control Studies
Cross Sectional Studies

Defined Population
Risk Factor
+
No
disease
Disease
Risk Factor No
disease
Disease
Determine presence of disease and risk

factors at the same time snapshot
Cross Sectional Studies
Advantages
Assessment of
disease/risk
factors at same
time
Measures of risk
Absolute risk
(prevalence)
Odds ratio
Attributable risk
(if incidence is
known)
Disadvantages
May have biased
assessment of
exposure
Cannot establish
cause and effect
Interpreting Study Results
No such thing as a perfect study

Recognize the limitations and the
strengths of any one study
Critiquing the epidemiology literature:
Are they comparable in terms of demographic

and other characteristics?
Are they representative of the entire
population?
Are the measurement methods comparable
(e.g., eligibility and classification criteria, risk
factor assessment)?
Could associations be biased or confounded by
other factors that were not assessed?
Genetic Epidemiology
of Type 1 Diabetes
Example of assessing
absolute, relative and
attributable risks
Type 1 Diabetes
One of most frequent chronic childhood diseases

Prevalence ~ 2/1000 in Allegheny County
Incidence ~ 20/100,000/yr in Allegheny County
Due to autoimmune destruction of pancreatic cells

Etiology remains unknown
Epidemiologic research may provide clues

1979 began study at Pitt, GSPH
Type 1 Diabetes Registries
Childrens Hospital of Pittsburgh Registry

All T1D cases seen at CHP diabetes clinic
since 1950
May not be representative of all newly
diagnosed cases
Allegheny County Type 1 Diabetes Registry

All newly diagnosed (incident)T1D cases in
Allegheny County since 1965
Type 1 Diabetes Incidence

Allegheny County, PA


Evidence for Environmental

Risk Factors
Seasonality
at onset
Increase in incidence worldwide
Migrants assume the risk of host
country
Environmental risk factors
- May act as initiators or precipitators
- Viruses, infant nutrition, stress
Evidence for Genetic

Risk Factors
Increased
relatives
risk for 1st degree
Risk for siblings ~6%

Concordance
in MZ twins 20 - 50%
Strongly associated with genes in the
HLA region of chromosome 6
DRBQ-DQB1 haplotypes

Worldwide
WHO Collaborating Center
for Disease Monitoring, Telecommunications and

the Molecular Epidemiology of Diabetes Mellitus
University of Pittsburgh, GSPH
Directors, Drs. Ron LaPorte, Jan Dorman
WHO Multinational Project for

Childhood Diabetes (DiaMond)
Collect standardized international

information on:
Incidence (1990 2000)
Risk Factors
Mortality
Evaluate health care and economics of T1D

Establish international training programs
Coordinating Centers: Helsinki and
Pittsburgh
Type 1 Diabetes Registries 60+ Countries by

1989
What is Causing the Geographic

Difference in T1D Incidence
Environmental
risk factors
Susceptibility genes
More than 20 genes associated with T1D
HLA region chromosome 6 is most important
HLA-DQ Locus
Chromosome 1
Chromosome 2
DQA1 Gene
for the chain
DQB1 Gene
for the Chain
DQ haplotype determined from

patterns of linkage disequilibrium
WHO DiaMond Molecular

Epidemiology Sub-Project
Hypothesis
Geographic differences in T1D incidence
reflect population variation in the
frequencies of T1D susceptibility genes
Case control design - international
Focus on HLA-DQ genotypes
WHO DiaMond Molecular

Epidemiology Sub-Project
Within country analysis

Odds ratios
Absolute risks
Attributable risks
Across country analysis

Allele/haplotype frequencies
Absolute risks
Susceptibility Haplotypes
for Type 1 Diabetes
DRB1- DQA1- DQB1 Ethnicity
*0405 -*0301- *0302W, B, H, C
*0301 - *0501- *0201W, B, H, C
*0701 - *0301- *0201B
*0901 - *0301- *0303
J
*0405 - *0301- *0401
C, J
White, Black, Hispanic, Chinese, Japanese
Distribution of Genotypes
S = DQA1-DQB1
haplotypes that are
more prevalent in
cases vs. controls
(p < 0.05) for each
ethnic group
separately
Cases
Controls
2S
1S
0S
Odds Ratios for T1D

Cases
Controls
2S
OR2S = af / be
1S
OR1S = cf / de
0S
OR0S = 1.0
Baseline
Odds Ratios for T1D

Population
2S 1S
Finland 51.8*
10.2*
PA-W
15.9*
5.6*
PA-B
>230*
8.4*
AL-B
14.6*
5.6*
Mexico 57.6*
3.0*
Japan
14.9*
5.4*
China
>75.0*
6.9*
How to Estimate GenotypeSpecific Incidence from a

Case Control Study?
for individuals with 2S, 1S

and 0S genotypes
Overall Population Incidence

(R)
Is
an average of the genotype-specific

risks (R2S, R1S, R0S)
Weighted
by the genotype distribution

(proportion) among the controls
R = R2S P2S + R1S P1S + R0S P0S

R
Population
incidence
P2S,
P1S, P0S
R2S,
R1S, R0S
Genotype
proportions
among controls
Genotypespecific
incidence
Odds Ratios Approximate

Relative Risks (RR)
OR2S
RR2S = R2S / R0S
OR1S
RR1S = R1S / R0S
OR0S
RR0S = R0S / R0S
R = R2SP2S + R1SP1S + R0SP0S

Can
be re-written as:
= R0S [(R2S/R0S)P2S + (R1S/R0S)P1S + P0S]
Substitute
OR for RR:
= R0S [OR2SP2S + OR1SP1S + P0S]
Solve
for R0S
R = R2SP2S + R1SP1S + R0SP0S
OR2S R2S / R0S

- OR2S and R0S are known,
Solve for R2S
OR1S R1S / R0S

- OR1S and R0S are known,
Solve for R1S
R was used to estimate cumulative incidence
rates through age 35 years (R x 35) so risk
estimates could be interpreted as percents
Absolute T1D Risks Through

Age 35 Yrs
Population
2S 1S
Finland 7.1% 2.3%
PA-W
2.6%
0.9%
PA-B
28.7%
1.2%
AL-B
1.7%
0.6%
Mexico 1.0%
0.1%
Japan
0.3%
0.1%
China
0.7%
0.1%
Attributable Fraction for

T1D Public Health Implications
Population
2S
Finland 29%
PA-W
33%
PA-B
55%
AL-B
31%
Mexico 44%
Japan
26%
China
31%
Absolute Risk (Incidence)
Does not indicate whether there is a

significant positive or negative association
May be more important than odds ratio,

particularly when they can be estimated as
a percent
Has important clinical implications for

individuals and practitioners
Genetic Information for

Testing Type 1 Diabetes
GIFT-D
Developing and
evaluating a
theorybased web education
and risk
communication
program for families
with T1D
T1D Risk Algorithm

Based on regression analysis from genetic
epidemiologic research conducted by our
research group
Age
Family history of T1D
Siblings HLA-DQ genotype
Similarity of genotype with
T1D probands genotype
Translation research
T1D
~42
yrs
T1D Risk Algorithm

A 12 year old child who
shares both DQ
haplotypes with her T1D
sister has a ~7% chance
of developing T1D by
age 30 years if neither
parent has T1D
Risk increases to ~38% if

both parents have T1D
Encourage you to use genetic

epidemiologic literature to
estimate absolute, relative and
attributable risk
Important for evidence

based nursing practice in
the post-genome era
Thank you!
References
Dorman JS and Bunker CH. HLA-DQ locus

of the Human Leukocyte Antigen Complex
and type 1 diabetes: A HuGE review.
Epidemiol Rev 2000; 22:218-227
Dorman JS, Charron-Prochownik, D,

Siminerio L, Ryan C, Poole C, Becker D,
Trucco M. Need for Genetic Education
for Type 1 Diabetics. Arch Pediatr
Adolesc Med 2003; 157:935-936
References
Fletcher RH, Fletcher SW, Wagner EH.

Clinical epidemiology: the essentials,
Lippincott Williams and Wilkins, 1996.
Gordis L. Epidemiology. WB Saunders Co.,

Philadelphia, 1996.

Risk Epidemiology

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Absolute, Relative and

Define measures of absolute, relative and

Identify major epidemiology study designs

Estimate absolute, relative and attributable

Interpret risk estimates for patients and

Science of making predictions about individual

Important approach to obtaining the kind of

Sounds like evidence based practice!

Patients prognosis is expressed as

Individual clinical observations can be

Clinicians should rely on observations based

Process by which public health problems

Based on large populations, not patients or

Scientific basis of public health

To determine the rates of disease by person,

To identify the risk factors for the disease

To develop approaches for disease prevention

To determine the rates of

risk (incidence, prevalence)

Incidence = number of new cases of a

Prevalence = total number of affected

To identify the risk factors for

risk (RR), odds ratio (OR)

RR = ratio of incidence of disease in exposed

OR = ratio of the odds that cases were

To identify the risk factors for

risk (RR), odds ratio (OR)

RR = ratio of incidence of disease in exposed

OR = ratio of the odds that cases were

To develop approaches for

Attributable risk (AR)/fraction (AF)

AF = the proportion of disease incidence

AR divided by incidence in the exposed X 100%

Risk among risk

Major Epidemiology Study

sectional (one point in time)

Cohort and Case Control

Cross Sectional Studies

Determine presence of disease and risk

Cross Sectional Studies

Interpreting Study Results

No such thing as a perfect study

Are they comparable in terms of demographic

One of most frequent chronic childhood diseases

Due to autoimmune destruction of pancreatic cells

Epidemiologic research may provide clues

Type 1 Diabetes Registries

Childrens Hospital of Pittsburgh Registry

Allegheny County Type 1 Diabetes Registry

Type 1 Diabetes Incidence

Type 1 Diabetes Incidence

Type 1 Diabetes Incidence

Evidence for Environmental

Evidence for Genetic

risk for 1st degree

Risk for siblings ~6%

Type 1 Diabetes Incidence

WHO Collaborating Center

for Disease Monitoring, Telecommunications and