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

Incidence is most relevant clinically

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
100 80 60 40 20 0

Excess Risk

Risk among risk AR = factor positives Risk among risk factor negatives
+ -

Risk Factor

Attributable Fraction

AF =

Risk among risk factor positives

Risk among risk factor negatives

Risk among risk factor positives

X 100%

Major Epidemiology Study Designs

Case Control (retrospective)

Cohort (prospective) Cross sectional (one point in time)

Case Control/Retrospective Studies

Risk factor + Risk factor Risk factor + Risk factor -

Identify affected and unaffected individuals

Risk factor data is collected retrospectively

No Disease Disease

Disease

No Disease

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 + Risk factor -

Identify unaffected individuals Risk factor data collected at baseline

Follow until occurrence of disease

Disease

No Disease

No Disease Disease

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
Risk factor?

Future
Disease?

Cohort Studies

Risk factor?

Disease?

Case-Control Studies

Cross Sectional Studies

Defined Population

Risk Factor +
No disease

Risk Factor No disease

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

30 25

per 100,000/yr

20 15 10 5 0 5 10 15 20 Age in Years

WM NWM WF NWF

Type 1 Diabetes Incidence Allegheny County, PA

20 15 10 5 0 Jan-Mar Apr-Jun Season Jul-Sep Oct-Dec

Type 1 Diabetes Incidence Allegheny County, PA

25 20 15 10 5 0 1975-79 1980-84 1985-89 WM NWM WF NWF

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 risk for 1st degree relatives

Risk for siblings ~6%

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

DRBQ-DQB1 haplotypes

Rate/100,000/yr
40 35 30 25 20 15 10 5 0

Fi nl Sa rd in ia Sw ed en N or w ay U SA -W I U SA -P A I ta ly Is ra el Ja pa n M ex ic o an d

Type 1 Diabetes Incidence 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
*0405 -*0301- *0302 *0301 - *0501- *0201 *0701 - *0301- *0201 *0901 - *0301- *0303 *0405 - *0301- *0401

Ethnicity
W, B, H, C W, B, H, C B J 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

a c e

b d f

Odds Ratios for T1D

Cases Controls

2S
1S 0S

a c e

b d f
Baseline

OR2S = af / be OR1S = cf / de OR0S = 1.0

Odds Ratios for T1D

Population Finland PA-W PA-B AL-B Mexico Japan China 2S 51.8* 15.9* >230* 14.6* 57.6* 14.9* >75.0* 1S 10.2* 5.6* 8.4* 5.6* 3.0* 5.4* 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 R1S, R0S

Genotype proportions among controls Genotypespecific incidence

R2S,

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 Finland PA-W PA-B AL-B Mexico Japan China 2S 7.1% 2.6% 28.7% 1.7% 1.0% 0.3% 0.7% 1S 2.3% 0.9% 1.2% 0.6% 0.1% 0.1% 0.1%

Attributable Fraction for T1D Public Health Implications

Population Finland PA-W PA-B AL-B Mexico Japan China 2S 29% 33% 55% 31% 44% 26% 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 theory-based 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

T1D ~42 yrs

Translation research

T1D Risk Algorithm

Age-specific probability estimates for GIFT-D
riskvar Years 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Positive Family History 2 1 0 0.5838 0.5780 0.5721 0.5341 0.4912 0.4758 0.4705 0.4651 0.4596 0.4512 0.4426 0.3879 0.3783 0.3683 0.3480 0.3412 0.3342 0.3270 0.2828 0.1848 0.1783 0.1717 0.1649 0.1581 0.1442 0.1299 0.1003 0.0900 0.0794 0.0687 <0.0687 0.2652 0.2616 0.2580 0.2355 0.2114 0.2031 0.2003 0.1974 0.1945 0.1902 0.1857 0.1585 0.1538 0.1491 0.1396 0.1364 0.1332 0.1300 0.1103 0.0693 0.0667 0.0640 0.0614 0.0587 0.0533 0.0477 0.0365 0.0326 0.0287 0.0247 <0.0247 0.1453 0.1431 0.1410 0.1278 0.1140 0.1092 0.1076 0.1060 0.1043 0.1019 0.0994 0.0841 0.0816 0.0790 0.0737 0.0720 0.0702 0.0685 0.0578 0.0359 0.0345 0.0331 0.0317 0.0303 0.0275 0.0246 0.0187 0.0167 0.0147 0.0127 <0.0127 Negative Family History 2 1 0 0.1321 0.1302 0.1283 0.1162 0.1035 0.0992 0.0977 0.0962 0.0947 0.0925 0.0902 0.0763 0.0740 0.0716 0.0668 0.0652 0.0636 0.0620 0.0523 0.0325 0.0312 0.0300 0.0287 0.0274 0.0249 0.0223 0.0169 0.0151 0.0133 0.0114 <0.0114 0.0486 0.0479 0.0471 0.0425 0.0377 0.0360 0.0355 0.0349 0.0344 0.0335 0.0327 0.0275 0.0266 0.0258 0.0240 0.0234 0.0229 0.0223 0.0187 0.0115 0.0111 0.0106 0.0102 0.0097 0.0088 0.0079 0.0060 0.0053 0.0047 0.0040 <0.0040 0.0251 0.0247 0.0243 0.0219 0.0194 0.0185 0.0182 0.0180 0.0177 0.0172 0.0168 0.0141 0.0137 0.0132 0.0123 0.0120 0.0117 0.0114 0.0096 0.0059 0.0057 0.0054 0.0052 0.0050 0.0045 0.0040 0.0031 0.0027 0.0024 0.0021 <0.0021

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.