Challenges to the Epidemiology of Aging:

The REasons for Geographic And Racial Differences in Stroke Study

George Howard, DrPH

UAB School of Public HealthBirmingham, AL

… something that appears simple on the surface, that may be more complicated than one would think

Introduction• Goal: Examine how age influences associations of risk

factors with stroke events• Background:– Many studies have a restricted age range and can see “part of

the picture” regarding the impact of age– REGARDS has both broad age range, and a large sample size,

allowing assessment with age strata of risk factor associations with stroke events

• Approach:– There have been 715 strokes over 5.5 years of follow-up– Proportional hazards analysis to evaluate associations with

“traditional” (Framingham) stroke risk factors within age strata

Age Distribution and Stroke Events in REGARDS

45-64 65-74 75+0

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Age Strata

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190 Strokes(1.3%)

283 Strokes(3.2%)

242 Strokes(5.3%)

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“Univariate” Hazard Ratio of Incident Stroke for “Traditional” Stroke Risk Factors

(after adjustment for age)

Hypertension Diabetes Smoking Atrial Fib LVH Heart Dis

UniMulti UniMulti UniMulti UniMulti UniMulti UniMulti0.0

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“Univariate” & Multivariable Hazard Ratio of Incident Stroke for “Traditional” Stroke Risk Factors

(after adjustment, or additional adjustment, for age)

Hypertension Diabetes Smoking Atrial Fib LVH Heart Dis

Overall Analysis Conclusions

• After adjustment for age, these “traditional” risk factors:– Univariately:• All significantly (p ≤ 0.0002) associated with stroke risk• Univariately, each is associated with a hazard ratio of ≈

1.5 to 2.0– Multivariable adjustment had only modest impact

on the significance (p ≤ 0.0014) or magnitude of association (HR ≈ 1.4 to 2.0)

• But what of the association within age strata?

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Univariate Hazard Ratio of Incident Stroke for “Traditional” Stroke Risk FactorsShown for Young (45-64), Middle-Aged (65-74), and Old (75+) Participants

Hypertension Diabetes Smoking Atrial Fib LVH Heart Dis

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Univariate Hazard Ratio of Incident Stroke for “Traditional” Stroke Risk FactorsShown for Young (45-64), Middle-Aged (65-74), and Old (75+) Participants

Hypertension Diabetes Smoking Atrial Fib LVH Heart Dis

Observations• Univariately– Substantial declines in the impact of hypertension, diabetes,

smoking and heart disease with age– More modest decline for LVH– Initial decline, then increase, for atrial fibrillation– Hypertension, diabetes, smoking, and LVH all not even

significant in the oldest age strata

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Univariate Hazard Ratio of Incident Stroke for “Traditional” Stroke Risk FactorsShown for Young (45-64), Middle-Aged (65-74), and Old (75+) Participants

Hypertension Diabetes Smoking Atrial Fib LVH Heart Dis

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Multivariable Hazard Ratio of Incident Stroke for “Traditional” Stroke Risk Factors

Shown for Young (45-64), Middle-Aged (65-74), and Old (75+) Participants

Hypertension Diabetes Smoking Atrial Fib LVH Heart Dis

Observations• Univariately– Substantial declines in the impact of hypertension and

diabetes with age– More modest (but still substantial) decline for smoking,

heart disease and LVH– Initial decline, then increase, for atrial fibrillation– Hypertension, diabetes, smoking, and LVH all not even

significant in the oldest age strata• For hypertension, diabetes, atrial fibrillation, LVH and heart disease – multivariable adjustment had:– A substantial mediating impact on risk at young ages – Little impact at older ages

• Multivariable adjustment had little impact on smoking

Interpretation?• The small literature on age-related changes agrees …

risk factor effects are smaller in the elderly• Should we conclude that risk factors are less important

in the elderly?• … what little randomized trial data there is in the

elderly shows treatment is beneficial – For example, the Systolic Hypertension in the Elderly

Program (SHEP) showed a reduction from 8.2/100 participants to 5.2/100 participants for antihypertensive treatment (RR = 0.64; p = 0.0003)

– … but SHEP eligibility started at 60 years• Still, what else could be driving the smaller impact at

older ages?

An Alternative Explanation• Suppose the incorrect proportional hazards model is fit,

h(t) = g(t) eα(HYPER) rather than h(t) = g(t) eα(HYPER) + β(OTHER)

• Well … it depends– If OTHER is not correlated with HYPER … no worries … a confounder

must be associated with both the exposure (HYPER) and outcome (STROKE)

– However, if OTHER is correlated with HYPER ...• Then OTHER will be confounder if it is associated with stroke risk• The estimate for α will include the effect of HYPER and everything that is

correlated with it (in this case OTHER)

• But … this should be a constant bias if:– The impact of HYPER and OTHER is constant across age (no AGE-by-

OTHER interaction)– Correlation between HYPER and OTHER is constant across age

• So are these assumptions true?

Interesting … but what does this have to do with the epidemiology of aging?

• Risk factors sometimes tend to be correlated (for example, the metabolic syndrome)

• For example, it is expected that hypertensives are more likely to be diabetic (and obese, and dyslipidemic, and …)

• Since hypertensive participants are more likely to be diabetic … omitting diabetes from the model will include part of the effect of diabetes

• … but what is the association of hypertension and diabetes as a function of age?

Diabetes

Agreement of Risk Factors with Hypertension

Implications?• If diabetes is uniformly associated with stroke over ages, then

omitting diabetes from a model assessing hypertension as a risk factor for stroke will:– For young ages, the effect of hypertension will be substantially

overestimated… but adjustment for diabetes will substantially attenuate the effect of hypertension– At older ages, the impact of hypertension at older ages will still be

overestimated (diabetes still positively correlated!), but to a much smaller effect

… but adjustment for diabetes will have a much smaller attenuating effect• Hmmm … that is exactly what we saw in the univariate, then the

multivariable, analyses of hypertension?• Omitting hypertension from the estimation of diabetes will have

precisely the same effects (again, what we saw)• What about other factors association with hypertension?

SmokingAtrial FibLVHHeart Dis

Agreement of Risk Factors with Hypertension

Smoking and atrial Fib have low correlation, and only minimal

declines

LVH and Heart Disease have marginally higher correlations ,

and modest declines

… but what does this have to do with the declines of the impact of risk factors with age?• Not only does REGARDS show this declining impact

of risk factors with age … but so does nearly every study with data across a broad age range

• But if we adjust for the OTHER risk factors, we get the correct estimate for HYPER– But risk factors explain less than half of incident strokes– Even with residual confounding and measurement error

… there must be many unknown risk factors– Obviously, one cannot adjust for the unknown risk factors

… and they may be having the same impact as the known

Could There Be “Reflections” of OTHER Risk Factors Available?

• Consider the “General Health Question”Compared to others your age, how would you rate your health?

Excellent Very Good Good Fair Poor

Univar Stroke HR1.00 (ref)1.01 (0.80 – 1.28)1.47 (1.17 – 1.84)2.07 (1.61 – 2.66)3.00 (2.09 – 4.32)

Multi Stroke HR1.00 (ref)0.90 (0.71 – 1.15)1.11 (0.87 – 1.41)1.38 (1.05 – 1.81)1.71 (1.15 – 2.55)

… well join me on the thin ice … perhaps this is asking “How bad are your latent risk factors?”…but what are the agre-related associations of hypertension and general health?

Association of Hypertension with Self-Perceived General Health Status of Good, Fair or Poor

The “Latent” Risk Factors in the Elderly

• Hence, the associations of known and “latent” (or unobserved or unknown) risk factors could also be decreasing in the elderly

• Perhaps two forces are likely at work:– Elimination of those with multiple risk factors– Contamination of the control group with higher risk

participants• We could also speculate that other forces could be

active– Changes in the magnitude of associations with age– Synergies (interactions) between risk factors

Elimination of those with multiple risk factors• Suppose – There are only two risk factors (HYPER and OTHER)– Each is 50% prevalent and there is no correlation– 20% event rate in those without either risk factor– Each with a HR of 2.0 for both

At Age 45

OTHER Absent Present

HYPER Absent 100 100 Present 100 100

At Age 75

OTHER Absent Present

HYPER Absent 51 26 Present 26 7

50%50%

34%20%

• Put simply, it is a lot easier to be a 45 year old with hypertension and the latent factor, than it is to be a 75 year old with both risk factors

• As a corollary, at age 75, normotensive participants are more likely to also have OTHER than are hypertensives

Contamination of the control group with higher risk participants

• With the exception of cigarette smoking, the prevalence of most risk factors increases with age

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HypertensionDiabetesSmokingAtrial FibLVHHeart Dis

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• So … with the exception of cigarette smoking, the prevalence of most risk factors increases with age

• But this is happening while the associations between risk factors are decreasing

• These prevalences have to be increasing somewhere … and the only other place it can is in the control group

• A more difficult question … “Does the prevalence of the latent factor increase with age?”

• Again put simply– In the young, the impact of risk factors can be clearly seen– In the old, there is more “noise” in the system, and seeing the

impact of any one risk factor is more difficult

Age-Related Changes in the Prevalence of Risk Factors

Conclusions• In REGARDS (and in practically all other

studies with data) risk factors show a declining impact with aging

• This could be a true effect … or it could be a bias introduced through:– An age-related change in the correlation between risk

factors (particularly with latent factors)– Increasing “noise” making the identification of any singe

factor in the elderly more difficult• At some level, it may not make a difference … risk

differences of older individuals with/without risk are smaller

Potential Implications?• In study planning, anticipate smaller risk factor effects in

the elderly (and larger studies)• Interpret the absence of associations with caution

– The lack of an association may not imply that treatment does not reduce risk

– It is not clear whether studies in the young are overestimating associations, or studies in the elderly are underestimating effects … but it is clear one of these is true!

• Because the declining impact of risk factors may be attributable to biases– A more broad risk factor assessment may be warranted?– Perhaps heightened concern for precision in measurement?

• The link to randomized treatment trials is more tenuous