Measures of Disease Association

• Measuring occurrence of new outcome

events can be an aim by itself, but usually
we want to look at the relationship between
an exposure (risk factor, predictor) and the
outcome
• The type of measure showing an association
between an exposure and an outcome event
is linked to the study design
 Main points to be covered
• Measures of association compare measures of
disease between levels of a predictor variable
• Prevalence ratio versus risk ratio
• Probability and odds
• The 2 X 2 table
• Properties of the odds ratio
• Absolute risk versus relative risk
• Disease incidence and risk in a cohort study
Cross-Sectional Study Design: A Prevalent Sample
 Measures of Association in a
Cross-Sectional Study
• Simplest case is to have a dichotomous
outcome and dichotomous exposure variable
• Everyone in the sample is classified as
diseased or not and having the exposure or
not, making a 2 x 2 table
• The proportions with disease are compared
among those with and without the exposure
• NB: Exposure=risk factor=predictor
 2 x 2 table for association of disease and exposure
Disease
Yes No

Yes
a b a+b
Exposure

No c d c+d

a+c b+d N = a+b+c+d

Note: data may not always come to you arranged as above.
STATA puts exposure across the top, disease on the side.
 Prevalence ratio of disease in exposed and unexposed
Disease
Yes No

Yes a b a
a+b
Exposure

PR =
c
No c d c+d
 Prevalence Ratio

• Text refers to Point Prevalence Rate Ratio

in setting of cross-sectional studies

• We like to keep the concepts of rate and

prevalence separate, and so prefer to use
prevalence ratio
 Prevalence ratio (STATA output)
Exposed Unexposed | Total
---------------------------------------------------
Cases | 14 388 | 402
Noncases | 17 248 | 265
---------------------------------------------------
Total | 31 636 | 667
| |
Risk | .4516129 .6100629 | .6026987

Point estimate [95% Conf. Interval]

---------------------------------------------
Risk ratio .7402727 | .4997794 1.096491
-----------------------------------------------
chi2(1) = 3.10 Pr>chi2 = 0.0783
STATA calls it a risk ratio by default
 Prevalence ratio of disease in exposed and unexposed
Disease
Yes No

Yes a b a
a+b
Exposure

PR =
c
No c d c+d

So a/a+b and c/c+d = probabilities of disease

and PR is ratio of two probabilities
 Probability and Odds
• Odds another way to express probability of
an event
• Odds = # events
# non-events
• Probability = # events
# events + # non-events
= # events
# subjects
 Probability and Odds
• Probability = # events
# subjects
• Odds = # events
# subjects = probability
# non-events (1 – probability)
# subjects
• Odds = p / (1 - p)
[ratio of two probabilities]
 Probability and Odds

• If event occurs 1 of 5 times, probability = 0.2.

• Out of the 5 times, 1 time will be the event and 4

times will be the non-event, odds = 0.25

• To calculate probability given the odds:

probability = odds / 1+ odds
 Odds versus Probability
• Less intuitive than probability (probably wouldn’t
say “my odds of dying are 1/4”)
• No less legitimate mathematically, just not so easily
understood
• Used in epidemiology because the measure of
association available in case-control design is the
odds ratio
• Also important because the log odds of the outcome
is given by the coefficient of a predictor in a logistic
regression
 Odds ratio
• As odds are just an alternative way of
expressing the probability of an outcome,
odds ratio (OR), is an alternative to the
ratio of two probabilities (prevalence or risk
ratios)

• Odds ratio = ratio of two odds

 Probability and odds in a 2 x 2 table
Disease
Yes No
What is p of
disease
Yes 2 3 5 in exposed?
Exposure

What are odds of

disease in exposed?

No 1 4 5
And the same for
the un-exposed?

3 7 10
 Probability and odds ratios in a 2 x 2 table
Disease
Yes No
PR = 2/5 1/5 
=2
Yes 2 3 5
Exposure


0R = 2/3 1/4
= 2.67
No 1 4 5

3 7 10
 Odds ratio of disease in exposed and unexposed
Disease
Yes No a
a+b
Yes a b a
1-
a+b
Exposure

OR =
c
No c d c+d
c
1-
c+d
Formula of p / 1-p in exposed / p / 1-p in unexposed
 Odds ratio of disease in exposed and unexposed
a a
a+b a+b
b
1- a a
a+b a+b b ad
OR = c = = =
c c bc
c+d
c c+d d
1-
c+d d
c+d
Important Property of Odds Ratio #1

• The odds ratio of disease in the exposed and

unexposed equals the odds ratio of exposure
in the diseased and the not diseased
– Important in case-control design
 Odds ratio of exposure in diseased and not diseased
Disease
Yes No a
a+c
Yes a b a
1-
a+c
Exposure

OR =
b
No c d b+d
b
1-
b+d
 Important characteristic of odds ratio
a a
a+c a+c
a c a
1-
a+c a+c c ad
ORexp = = = =
b b b bc
b+d b+d
b d
1-
b+d d
b+d

OR for disease = OR for exposure

 Measures of Association Using
Disease Incidence
• With cross-sectional data we can calculate a
ratio of the probability or of the odds of
prevalent disease in two groups, but we
cannot measure incidence
• A cohort study allows us to calculate the
incidence of disease in two groups
 Measuring Association in a Cohort
Following two groups by exposure status within a
cohort:
Equivalent to following two cohorts defined by exposure
 Analysis of Disease Incidence in a
Cohort
• Measure occurrence of new disease
separately in a sub-cohort of exposed and a
sub-cohort of unexposed individuals

• Compare incidence in each sub-cohort

• How compare incidence in the sub-cohorts?

 Relative Risk vs. Relative Rate
• Risk is based on proportion of persons with
disease = cumulative incidence
• Risk ratio = ratio of 2 cumulative incidence
estimates = relative risk
• Rate is based on events per person-time =
incidence rate
• Rate ratio = ratio of 2 incidence rates =
relative rate
• We prefer risk ratio, rate ratio, odds ratio
A Note on RR or “Relative Risk”
• Relative risk or RR is very common in the
literature, but may represent a risk ratio, a rate
ratio, a prevalence ratio, or even an odds ratio
• We will try to be explicit about the measure and
distinguish the different types of ratios
• There can be substantial difference in the
association of a risk factor with prevalent
versus incident disease
 Difference vs. Ratio Measures
• Two basic ways to compare measures:
– difference: subtract one from the other
– ratio: form a ratio of one over the other
• Can take the difference of either an
incidence or a prevalence measure but rare
with prevalence
• Example using incidence: cumulative
incidence 26% in exposed and 15% in
unexposed,
– risk difference = 26% - 15% = 11%
– risk ratio = 0.26 / 0.15 = 1.7
 Summary of Measures of
Association
Ratio Difference
Cross-sectional prevalence ratio prevalence difference

odds ratio odds difference

Cohort risk ratio risk difference
rate ratio rate difference
odds ratio odds difference
 Why use difference vs. ratio?
• Risk difference gives an absolute measure of the
association between exposure and disease occurrence
– public health implication is clearer with absolute measure:
how much disease might eliminating the exposure
prevent?
• Risk ratio gives a relative measure
– relative measure gives better sense of strength of an
association between exposure and disease for inferences
about causes of disease
 Relative Measures and Strength of
Association with a Risk Factor
• In practice many risk factors have a relative
measure (prevalence, risk, rate, or odds ratio)
in the range of 2 to 5
• Some very strong risk factors may have a
relative measure in the range of 10 or more
– Asbestos and lung cancer
• Relative measures < 2.0 may still be valid
but are more likely to be the result of bias
– Second-hand smoke relative risk < 1.5
Example of Absolute vs. Relative
Measure of Risk
TB No TB Total
recurrence recurrence
Treated
> 6 mos 14 986 1000
Treated
< 3 mos 40 960 1000
Risk ratio = 0.04/0.014 = 2.9
Risk difference = 0.04 – 0.014 = 2.6%
If incidence is very low, relative measure
can be large but difference measure small
 Reciprocal of Absolute
Difference ( 1/difference)
• Number needed to treat to prevent one case
of disease
• Number needed to treat to harm one person
• Number needed to protect from exposure to
prevent one case of disease
• TB rifampin example: 1/0.026 = 38.5,
means that you have to treat 38.5 persons
for 6 mos vs. 3 mos. to prevent one case of
TB recurrence
Example of study reporting risk difference
Table 2. Survival and Functional
Outcomes from the Two Study Phases
Return of Risk
Spontaneous Difference
Study Phase Circulation p-value
(95% CI)
Rapid
Defibrillation --
12.9% --
(N=1391)
Advanced
Life Support 18.0% 5.1% (3.0-7.2) <0.001
(N=4247)

Risk difference = 0.051; number needed to treat = 1/0.051 = 20

Stiel et al., NEJM, 2004

 Risk Ratio
Diarrheal Disease
Yes No Total
Ate potato salad 54 16 70

Did not eat potato 2 26 28

salad
Total 56 42 98

Probability of disease, ate salad = 54/70 = 0.77

Probability of disease, no salad = 2/28 = 0.07
Risk ratio = 0.77/0.07 = 11
Illustrates risk ratio in cohort with complete follow-up
Risk Ratio in a Cohort with Censoring

Choose a time point for comparing two cumulative incidences:

At 6 years, % dead in low CD4 group = 0.70 and in high CD4
group = 0.26. Risk ratio at 6 years = 0.70/0.26 = 2.69
 Comparing two K-M Curves

Risk ratio would be different for different follow-up

Times. Entire curves are compared using log rank test
(or other similar tests).
 OR compared to Risk Ratio

If Risk Ratio = 1.0, OR = 1.0;

otherwise OR farther from 1.0

0 1 ∞
Stronger effect Stronger effect

OR Risk Ratio Risk Ratio OR

 Risk ratio and Odds ratio
If Risk Ratio > 1, then OR farther
from 1 than Risk Ratio:

RR = 0.4 = 2
0.2

OR = 0.4
0.6 = 0.67 = 2.7
0.2 0.25
0.8
 Risk ratio and Odds ratio
If Risk Ratio < 1, then OR farther
from 1 than RR:

RR = 0.2 = 0.67
0.3

OR = 0.2
0.8 = 0.25 = 0.58
0.3 0.43
0.7
 Odds ratio (STATA output)
Exposed Unexposed | Total
---------------------------------------------------
Cases | 14 388 | 402
Noncases | 17 248 | 265
---------------------------------------------------
Total | 31 636 | 667
| |
Risk | .4516129 .6100629 | .6026987

Point estimate [95% Conf. Interval]

---------------------------------------------
Risk ratio .7402727 | .4997794 1.096491
Odds ratio .5263796 | .2583209 1.072801
-----------------------------------------------
chi2(1) = 3.10 Pr>chi2 = 0.0783
Important property of odds ratio #2

• OR approximates Risk Ratio only if

disease incidence is low in both the
exposed and the unexposed group
 Risk ratio and Odds ratio

If risk of disease is low in both exposed and

unexposed, RR and OR approximately equal.

Text example: incidence of MI risk in high bp

group is 0.018 and in low bp group is 0.003:

Risk Ratio = 0.018/0.003 = 6.0

OR = 0.01833/0.00301 = 6.09
 Risk ratio and Odds ratio
If risk of disease is high in either or both exposed
and unexposed, Risk Ratio and OR differ

Example, if risk in exposed is 0.6

and 0.1 in unexposed:
RR = 0.6/0.1 = 6.0

OR = 0.6/0.4 / 0.1/0.9 = 13.5

OR approximates Risk Ratio only if incidence

is low in both exposed and unexposed group
 “Bias” in OR as estimate of RR
• Text refers to “bias” in OR as estimate of RR
(OR = RR x (1-incid.unexp)/(1-incid.exp))
– not “bias” in usual sense because both OR and
RR are mathematically valid and use the same
numbers
• Simply that OR cannot be thought of as a
surrogate for the RR unless incidence is low
Important property of odds ratio #3

• Unlike Risk Ratio, OR is symmetrical:

OR of event = 1 / OR of non-event
 Symmetry of odds ratio versus
non-symmetry of risk ratio
OR of non-event is 1/OR of event
RR of non-event = 1/RR of event
Example:
If cum. inc. in exp. = 0.25 and
cum. inc. in unexp. = 0.07, then
RR (event) = 0.25 / 0.07 = 3.6
RR (non-event) = 0.75 / 0.93 = 0.8
Not reciprocal: 1/3.6 = 0.28 = 0.8
 Symmetry of OR
Example continued:
OR(event) = 0.25
(1- 0.25) = 4.4
0.07
(1- 0.07)
OR(non-event) = 0.07
(1- 0.07) = 0.23
0.25
(1- 0.25)
Reciprocal: 1/4.46 = 0.23
Important property of odds ratio #4

• Coefficient of a predictor variable in

logistic regression is the log odds of the
outcome (e to the power of the
coefficient = OR)

– Logistic regression is the method of

multivariable analysis used most often in
cross-sectional and case-control studies
 3 Useful Properties of Odds
Ratios
• Odds ratio of disease equals odds ratio of
exposure
– Important in case-control studies
• Odds ratio of non-event is the reciprocal of
the odds ratio of the event (symmetrical)
• Regression coefficient in logistic regression
equals the log of the odds ratio
 Summary points
• Cross-sectional study gives a prevalence ratio
• Risk ratio should refer to incident disease
• Relative ratios show strength of association
• Risk difference gives absolute difference
indicating number to treat/prevent exposure
• Properties of the OR important in case-control
studies
– OR for disease = OR for exposure
– Logistic regression coefficient gives OR