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CONTROL CONFOUNDING

etiologic or causal, associations between disease and exposure.

In controlling for confounding, we attempt to obtain an

undistorted estimate of the strength of the hypothesized

relationship.

populations, i.e. , membership in the population is the

exposure, standardization of summary rates is carried out in

order to take into account differences in characteristics

between the two populations, such as age, gender, etc.

Standardized rates are useful in a public health context, and

are used for descriptive as well as analytical purposes.

factor (or multiple other factors) with the primary association

of interest.

Standardization of rates is commonly used when comparing

mortality rates or incidence rates across populations.

census tracts, etc.

recently white collar occupations studies), members of HMOs,

groups categorized by race/ethnicity, etc.

overall risk of disease or death, which can be compared across

populations. Similar to stratification procedures, however, a

summary rate sometimes masks differences within stratum

that may be relevant for public health or etiologic purposes.

An age adjusted summary rate, for example, will not reveal if

the age specific relative risks for two populations are

homogeneous.

Since age is positively correlated with most chronic diseases

and risk of death, and since most populations have different

age structures, age meets the definition of a confounder, and

age adjusted rates are generated in order to make comparisons

across different populations.

Population A has 12% of population over age of 65

Population B has 6% of population over age of 65

Higher crude death rates would be expected in

population A on the basis of age difference alone.

to know if there are factors other than age that

contribute to the difference in CHD rates that are

amenable to interventions.

What distinguishes standardization of rates from other

stratified methods of controlling for confounding, is use

of an external standard as the basis for comparison.

For example, when adjusting for age using direct

standardization, the external standard is an age

distribution. This can be the World age distribution,

state or nation age distribution, or can be one of the

populations being compared, or a combination of the

two populations being compared.

a set of age specific rates applied to the study age

distribution.

Direct standardization applies the stratum specific rates

(i.e. age specific rates) of each study population to the

number of individuals in the corresponding stratum in

the standard population. An expected number of

cases/deaths is generated for each stratum, and the total

expected is used in the numerator of the adjusted rate.

The denominator is the total number of individuals in

the standard population. Adjusted rates can then be

compared for different populations using Relative

Risks, or Attributable Risk differences.

adjusted rates

have experienced if they had the same distribution on

the confounding factor. Age adjusted risks, for

example, are the rates the different populations would

have had if they all had the same age distribution. Age

adjusted rates mean nothing by themselvesthey are

only used in comparison with other age adjusted rates.

Assumptions

populations, adjusted RR or AR assume that the effects

are homogeneous across strata of the confounding

variable. The adjusted RR or AR is a weighted average

that should reasonably represent stratum specific RR

or AR.

model (AR), or multiplicative model (RR). If there is

no additive interaction, it is appropriate to use adjusted

AR. If there is no multiplicative interaction, it is

appropriate to use adjusted RR.

EXAMPLE

Table 7-4 in Szklo

homogeneous

Study Group A Study Group B

Age N Cases Rate N Cases Rate

(%) (%)

<40 100 20 20 400 40 10

>=40 200 100 50 200 80 40

Total 300 120 40 600 120 20

< 40 20-10=10 < 40 20/10=2.00

>40 50-40=10 >40 50/40=1.25

Age N Expected Expected N Expected Expected

cases cases Cases cases using

using A using B using A B rates

rates rates rates

<40 500 100 50 100 20 10

>=40 100 50 40 500 250 200

Total 600 150 90 600 270 210

Adjusted rate A: 150/600= 25% Adjusted Rate A: 270/600=45%

Adjusted rate B: 90/600=15% Adjusted Rate B: 210/600=35%

AR=25-15=10% AR=45-35=10%

RR A/B=.25/.15= 1.67 RR A/B=.45/.35=1.29

using younger population as standard, results in higher relative risk.

Adjusted AR are same, regardless of standard

population because AR are homogeneous within

stratum. Adjusted RR are different due to lack of

homogeneity across stratum.

choice of standard population will affect the adjusted

AR or RR. It may be preferable in this situation, to use

stratum specific AR or RR.

Example when stratum specific RR are homogeneous,

but AR are not homogeneous.

Study Group A Study Group B

Age N Cases Rate N Cases Rate

(%) (%)

<40 100 6 6 400 12 3

>=40 200 60 30 200 30 15

Total 300 66 22 600 42 7

< 40 6-3=3% < 40 6/3=2.00

>40 30-15=15% >40 30/15=2.00

Age N Expected Expected N Expected Expected

cases cases Cases cases using

using A using B using A B rates

rates rates rates

<40 500 30 15 100 6 3

>=40 100 30 15 500 150 75

Total 600 60 30 600 156 78

Adjusted rate A: 60/600= 10% Adjusted Rate A: 156/600=26%

Adjusted rate B: 30/600= 5% Adjusted Rate B: 78/600=13%

AR=10-5=5% AR=26-13=13%

RR A/B=.10/.5= 2.00 RR A/B=.26/.13=2.00

attributable risk is greater in older than younger stratum (15 vs 3%)

Issues in Direct Adjustment

value of an adjusted rate will vary depending on the

standard population, so the absolute rate is not usually

of interest.

Standard population. World standard is often used in

comparison of mortality rates by country.

For local rates (i.e. county or cities) can use the state

standard population. For example, Illinois State

Cancer Registry publishes age adjusted rates by county

using Illinois standard population.

metropolitan area, can use metropolitan area as

standard.

Other standard populations:

stratum)

comparison of two counties, can add number of subjects

in each stratum from each county)

groups. Eliminates the need to calculate age adjusted

rate for that group, because the crude=adjusted for that

group. If one study group is relatively small, use that

population as the standard, because the age specific

rates will be unstable due to small numbers.

sizes are smallproduces statistically stable adjusted

estimates using population sizes from both study

samples. (Alternatively can use indirect method if

sample sizes are small).

Can adjust for more than one confounder in direct or

indirect adjustment

However, for public health purposes, rates are also

often calculated separately by sex, race. Illinois State

Cancer Registry calculates rates separately by

race/ethnicity, sex, so that health disparity issues can be

addressed. Calendar time is also used as a confounder,

because rates can vary over time.

rate may not be appropriate, particularly if intervention

is planned.

sparse, rates will be unstable. Indirect adjustment can

be used instead.

Adjustment for more than one confounder:

Male

White Black

1990-1994 1995-1999 1990-94 1995-999

Age 0-4

5-9

10-14

.

.

.

.

85+

population, can get age, race, gender, calendar year

adjusted rate.

separately by race and gender.

EXAMPLE USING DIRST in PEPE

population

(no SE or confidence interval calculated)

8 age groups

DIRST - Direct Standardization

Thursday, 19th September 2002.

DATA

Weights expressed as proportions:

Stratum Weight

1 0.28492

2 0.17440

3 0.12257

4 0.11362

5 0.11426

6 0.09148

120

8 0.03755

2 Numerator = 4747 Denominator = 3558000

3 Numerator = 4036 Denominator = 2677000

4 Numerator = 6701 Denominator = 2359000

5 Numerator = 2330 Denominator = 15675000

6 Numerator = 1704 Denominator = 26276

7 Numerator = 1105 Denominator = 36259

1 Numerator = 8751 Denominator = 5524000

2 Numerator = 4747 Denominator = 3558000

3 Numerator = 4036 Denominator = 2677000

4 Numerator = 6701 Denominator = 2359000

5 Numerator = 15675 Denominator = 2330000

6 Numerator = 26276 Denominator = 1704000

7 Numerator = 36259 Denominator = 1105000

8 Numerator = 63840 Denominator = 696000

95% confidence interval = 8.782 to 8.864 per 1000

99% confidence interval = 8.769 to 8.877 per 1000

DATA

1 Numerator = 535 Denominator = 286000

2 Numerator = 192 Denominator = 168000

3 Numerator = 152 Denominator = 110000

4 Numerator = 313 Denominator = 109000

5 Numerator = 759 Denominator = 110000

6 Numerator = 1622 Denominator = 94000

7 Numerator = 2690 Denominator = 69000

8 Numerator = 4788 Denominator = 46000

95% confidence interval = 9.708 to 10.069 per 1000

99% confidence interval = 9.652 to 10.126 per 1000

Crude rate for California: 8.3

Crude rate for Maine: 11.1

Relative risk crude: Maine/California= 1.34

AR Maine-California=2.8

Age adjusted rate for Maine: 9.89

RR adjusted for age: 1.12

AR Adjusted for age: 1.07

Maine still has higher mortality rate than California after

adjusting for age. Some other factor explains this difference.

SE of rates

rates. However, if populations are large (i.e. states,

countries, cities, etc), statistical or sampling stability is

less of an issue than other potential errorsdata

collection errors, estimation of population

denominators, coding of cause of death etc.

significant difference between rates even for trivial

differences.

important. Can calculate SE to get a confidence

interval around adjusted rate. (Chiang 1961, other

estimates)

adjusted rates, use to get a z score for significant

differences between rates (Kahn and Sempos, 1989)

INDIRECTLY STANDARDIZED RATES

rates.

population(s).

Ex. 2 deaths, 20 people in one stratum, rate=.10

If only 1death instead of 2, rate is 1/20= .05

Difference of only one death changes rate by 50%!

Indirect AdjustmentSteps

Study population:

stratum to get expected number of events.

prevalence(not used very often)

SIR/SMR less than 1 (100)--Observed less than expected

SIR/SMR ---comparison is always to the external

reference population from which you obtained the rates

either:

stratification variable, i.e. age, OR

your study population (i.e. SIRs/SMRs for each age

group are similar)

because the healthy worker effect declines with age (as

workers age, their mortality experience mirrors that of

the general population, thus SMRs tend to get larger

with age)

to each other.

reference rates.

Hypothetical Example with two study groups with

identical age specific rates, but different age

distributionsTable 7-8 in Szklo

External

Reference

Study Group A Study Group B Rates

Age N Deaths Rate N Deaths Rate

< 40 100 10 10% 500 50 10% 12%

>=40 500 100 20% 100 20 20% 50%

Total 600 110 18.3% 600 70 11.7%

specific populations

>=40 .50 x 500=250 .50 x 100=50

Total Expected 262 110

Even though they have the same age specific rates, they have

different SMRs because they have different age distributions.

Group B: <40 SMR= 50/60=.83 >=40 SMR=20/50=.4

We can compare them to the external standard but not to each

other for these reasons.

external standard.

external standard.

standard, it is similar to the direct method, in that the study

population is the standard population (we are using the age

distribution of the study population). But we cannot compare

stratum specific SMRs to each other in one study population

unless they have the same stratum specific distribution or

stratum specific SMRs.

EXAMPLES FROM OCCUPATIONAL COHORT

STUDIES

occupational cohort studies.

compared to external rates

interest, particularly because of the healthy worker effect

that of the general population because working people are

usually healthier than non-working people)

diseases such as cancers, which have a long latency period.

The healthy worker effect also declines with age.

adjusted for age, time worked, exposure, calendar year, etc.

Thus, we have not just one SMR, but often a number of SMRs

for different categories.

and small observed number of events, particularly for rare

diseases (i.e. cancers). Can combine some cells if this is a

problem (i.e. can use larger age groups)

Stratum specific SMRs may provide more information

regarding associations between disease and exposure in this

case.

Example:

number of years employed, adjusted for age and calendar year

employed deaths) Interval

Less than one 2.27 (4) .62-5.82

1-4 0 (0)

5-9 0 (0)

10 or more 6.22* (4) 1.70-15.92

TOTAL 2.27*(9) 1.04-4.31

*p < .01

20 or more years latency, 10 or more years worked: SMR: 6.33* (4), 1.73-16.20

distributions by age and calendar year, or similar SMRs across

these categories.

Primary Liver/Biliary Cancer Standardized Mortality Ratios, White Females,

by Calendar Year and Duration of Employment

Duration of Employment Deaths Confidence

Intervals

Number of years worked,

1944-1951

1-3 quarters 3 2.28 .47-6.7

1-4 years 1 .91 .02-5.06

5 years or more 4 9.80** 2.67-25.07

Number of years worked,

1952-1956

1-3 quarters 0 - -

1-3 years 0 - -

3 years or more 4 7.30** 1.99-18.67

Number of years worked,

1957-1970

1-3 quarters 2 5.86 .71-21.17

1-3 years 0 - -

3 years or more 3 4.55 .94-13.30

Number of years worked,

1970-1977

1-3 quarters 0

1-3 years 0

3 years or more 0

PERSON YEARS ARE TABULATED FOR EACH

STRATUM, EXPECTED EVENTS CALCULATED

SUMMED OVER ALL STRATUM OR SUB GROUP

OF STRATUM

Example:

White Males

Years worked=less than one

Calendar Years

1970-74 1975-1979 . 1995-99

Age*

18-24 Number Number etc

of of

Person person

yrs yrs

25-29

85+

*Working populationexcludes under 18

Years worked=1-4

Calendar Years

1970-74 1975-1979 . 1995-99

Age*

18-24 Person Person

yrs yrs

25-29

85+

NIOSH LTAS SoftwareGenerates SMRs for 99 or 92

causes of death using US or State Rates

Adjusted for age, sex, race, calendar year, user provides

employment info (years worked, calendar years worked

etc).

used much anymore

specific population information

CHOICE OF REFERENCE POPULATION

another working population (NIOSH has been developing such

a population) to avoid Healthy Worker Effect

populations use rural reference rates, etc. This is a way to

control for exposures that may vary by geography.

urban study groups looking at breast cancer. (Late age at first

pregnancy is a major risk factor for breast cancer, which

varies according to urban/rural residence)

enough. Ex. Study of an occupational cohort in Chicago

could use Cook County incidence/mortality rates as the

reference.

state or urban rates), use rates local to your population. This is

a way of controlling for exposures that may vary by

geography. For example, skin cancer rates are higher in the

Southern US, so if skin cancer is an outcome of interest in your

study population, which is in the northern US, use reference

rates from northern US. Otherwise, you will overestimate the

number of expected cases and underestimate the SMR/SIR.

REFERENCE RATES, Continued

occupational cohorts, can use a non-exposed group--IF

non-exposed group exists, and size of non-exposed group

is large enoughnot always true. Can use Cox Proportional

Hazard Models, other methods.

Confidence Intervals and Statistical Tests for

Indirectly Standardized Rates

different formulas for the Confidence Interval

(Rothman and Boice, 1979)

3

1 z 1

Obs 1

9 Obs 3 Obs

Lower Limit =

Exp

Upper Limit=

3

1 z 1

1 +

9 ( Obs + 1) 3 Obs + 1

( Obs + 1)

Exp

Obs=Numerator of SMR\SIR

Exp=Denominator of SMR\SIR

Z=Standard Normal Deviate (1.96 for 95% Confidence

Interval)

If expected number is less than 5, use exact confidence

intervals --uses iterative procedures

3

1 1.96 1

15 1

9 15 3 15 = .65

Lower Limit=

12.9

Upper Limit=

3

1 1.96 1

1 +

9 (15 + 1) 3 15 + 1 = 1.80

(15 + 1)

12.9

EXACT LIMITS CAN ALSO BE OBTAINED FROM TABLE

in SECTION A.2 in Szklo (see section A.7) for 95 %

Confidence Limits

events on p. 435, multiply by observed number, divide each

result by expected number

For 15 events, limits for number of events are .560 and 1.65

Upper Limit: 15 x 1.65=22.90 22.90/12.9=1.78

approximate of .65-1.80

Statistical Tests for the SMR

Square Test (1 d.f.) (some authors use 2 or greater)

H0=SMR/SIR=1

Ha=SMR/SIR NE 1

( Obs Exp )

2

=

2

Exp

( Obs Exp .5 )

2

2 =

Exp

( 15 12.9 .5 )

2

12.9

Cannot reject Null Hypothesis, SMR not significantly

different from 1

For this example:

Tuesday, 24th September 2002.

Exact P = 0.270 by the mid-P method.

Exact Fisher:

90% conf. interval = 9.25 to 23.10 0.72 to 1.79

95% conf. interval = 8.40 to 24.74 0.65 to 1.92

99% conf. interval = 6.89 to 28.16 0.53 to 2.18

Another example:

USING PEPI INDIRST --4 age groups

INDIRST - Indirect Standardization

Thursday, 26th September 2002.

DATA

STANDARD RATES per 1000

Stratum 1 2.5

Stratum 2 6.1

Stratum 3 12.4

Stratum 4 25.0

DATA

No correction factor.

NOTEif your standardized rates are annual rates, but your study

population observed events are for more than one year, you need to

enter the correction factor for the number of years followed, otherwise

the number expected will be underestimated because it will be based on

only one year of follow up.

DATA

STUDY POPULATION

Stratum 1: Numerator: 6 Denominator: 1200

Stratum 2: Numerator: 27 Denominator: 2340

Stratum 3: Numerator: 98 Denominator: 3750

Stratum 4: Numerator: 48 Denominator: 975

person years in each stratum

Expected cases = 88.149

SMR = 203.07%

Standard error of SMR = 14.95%

Approx. 90% conf. interval = 178.8 to 229.9%

Approx. 95% conf. interval = 174.4 to 235.1%

Approx. 99% conf. interval = 166.1 to 245.5%

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