Research

JAMA Cardiology | Original Investigation

Association of Coronary Artery Calcium Score

vs Age With Cardiovascular Risk in Older Adults
An Analysis of Pooled Population-Based Studies
Yuichiro Yano, MD, PhD; Christopher J. O’Donnell, MD, MPH; Lewis Kuller, MD, DrPh; Maryam Kavousi, MD, PhD;
Raimund Erbel, MD; Hongyan Ning, MD, MS; Ralph D’Agostino, PhD; Anne B. Newman, MD, MPH;
Khurram Nasir, MD; Albert Hofman, MD, PhD; Nils Lehmann, PhD; Klodian Dhana, MD, PhD; Ron Blankstein, MD;
Udo Hoffmann, MD, MPH; Stefan Möhlenkamp, MD; Joseph M. Massaro, PhD; Amir-Abbas Mahabadi, MD;
Joao A. C. Lima, MD; M. Arfan Ikram, MD, PhD; Karl-Heinz Jöckel, PhD; Oscar H. Franco, MD, PhD; Kiang Liu, PhD;
Donald Lloyd-Jones, MD, ScM; Philip Greenland, MD

Supplemental content
IMPORTANCE Besides age, other discriminators of atherosclerotic cardiovascular disease
(ASCVD) risk are needed in older adults.

OBJECTIVES To examine the predictive ability of coronary artery calcium (CAC) score vs age
for incident ASCVD and how risk prediction changes by adding CAC score and removing only
age from prediction models.

DESIGN, SETTING, AND PARTICIPANTS We conducted an analysis of pooled US

population-based studies, including the Framingham Heart Study, the Multi-Ethnic Study of
Atherosclerosis, and the Cardiovascular Health Study. Results were compared with 2
European cohorts, the Rotterdam Study and the Heinz Nixdorf Recall Study. Participants
underwent CAC scoring between 1998 and 2006 using cardiac computed tomography. The
participants included adults older than 60 years without known ASCVD at baseline.

EXPOSURES Coronary artery calcium scores.

MAIN OUTCOMES AND MEASURES Incident ASCVD events including coronary heart disease
(CHD) and stroke.

RESULTS The study included 4778 participants from 3 US cohorts, with a mean age of 70.1
years; 2582 (54.0%) were women, and 2431 (50.9%) were nonwhite. Over 11 years of
follow-up (44 152 person-years), 405 CHD and 228 stroke events occurred. Coronary artery
calcium score (vs age) had a greater association with incident CHD (C statistic, 0.733 vs
0.690; C statistics difference, 0.043; 95% CI of difference, 0.009-0.075) and modestly
improved prediction of incident stroke (C statistic, 0.695 vs 0.670; C statistics difference,
0.025; 95% CI of difference, −0.015 to 0.064). Adding CAC score to models including
traditional cardiovascular risk factors, with only age being removed, provided improved
discrimination for incident CHD (C statistic, 0.735 vs 0.703; C statistics difference, 0.032;
95% CI of difference, 0.002-0.062) but not for stroke. Coronary artery calcium score was
more likely than age to provide higher category-free net reclassification improvement among
participants who experienced an ASCVD event (0.390; 95% CI, 0.312-0.467 vs 0.08; 95% CI
−0.001 to 0.181) and to result in more accurate reclassification of risk for ASCVD events
among these individuals. The findings were similar in the 2 European cohorts (n = 4990).

CONCLUSIONS AND RELEVANCE Coronary artery calcium may be an alternative marker besides
age to better discriminate between lower and higher CHD risk in older adults. Whether CAC Author Affiliations: Author
score can assist in guiding the decision to initiate statin treatment for primary prevention in affiliations are listed at the end of this
older adults requires further investigation. article.
Corresponding Author: Philip
Greenland, MD, Northwestern
University, Department of Preventive
Medicine, 680 N Lake Shore Dr,
JAMA Cardiol. doi:10.1001/jamacardio.2017.2498 Ste 1400, Chicago, IL 60611
Published online July 26, 2017. (p-greenland@northwestern.edu).

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© 2017 American Medical Association. All rights reserved.

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 Research Original Investigation
U
sing the 2013 American College of Cardiology/
American Heart Association cardiovascular disease
lipid treatment guidelines and the Pooled Cohort
Equation,1 nearly all individuals aged 60 years and older would
potentially qualify for statin treatment on the basis of a 10-
year atherosclerotic cardiovascular disease (ASCVD) risk of
greater than 7.5% simply by virtue of their age.2 However,
ASCVD events are unlikely to occur even in older adults if they
have few cardiovascular risk factors.3,4 In addition, even a small
increase in geriatric-specific adverse effects associated with
statins (eg, rhabdomyolysis) could offset the cardiovascular
benefit.5 Therefore, other discriminators of ASCVD risk be-
sides age are needed in older adults. The 2013 American Col-
lege of Cardiology/American Heart Association guideline pro-
posed using additional tests to assist with treatment decisions
in the presence of uncertainty or hesitation to use statins, and
1 marker that was suggested in the guideline for this purpose
was coronary artery calcium (CAC).1
Coronary artery calcium, a marker of atherosclerotic
burden,6,7 has a potential role as an alternative marker for age
for predicting ASCVD events. Coronary artery calcium score,
when added to models including traditional cardiovascular risk
factors (eg, age and blood pressure [BP]), was associated with
improved ASCVD risk prediction in older adults.8-13 However,
CAC score and age were considered jointly in risk prediction
models in these studies,8-13 and therefore, whether CAC score
can be an alternative marker for age as a predictor of ASCVD
events in older adults remained to be determined.
Using a pooled individual participant data analysis (≥60
years of age, without known cardiovascular diseases at base-
line) from 3 US cohorts (the Framingham Heart Study [FHS],
the Multi-Ethnic Study of Atherosclerosis [MESA], and the Car-
diovascular Health Study [CHS]), we sought to examine the pre-
dictive ability of CAC score vs age for ASCVD, including coro-
nary heart disease (CHD) and stroke. Our results were
confirmed by European cohorts, the Rotterdam Study (RS)14
and the Heinz Nixdorf Recall (HNR) Study.15
Methods
Study Participants
Original Cohorts: 3 US Cohorts
Adults older than 60 years without known cardiovascular dis-
eases (including CHD, stroke, and heart failure) at baseline were
recruited from the FHS, MESA, and the CHS. The rationale for
selecting age 60 years as the cutoff value of older adults in this
study is that most individuals 60 years or older may be eli-
gible for statins by US guidelines.5 Details of the study design
and methods of each cohort have been described previously
(eMethods in the Supplement).9,16-23
Briefly, the original FHS cohort began in 1948 and
enrolled 5209 participants.16 Five thousand one hundred
twenty-four children of the original FHS cohort and the chil-
dren’s spouses were enrolled in 1971 (the offspring
cohort),17,18 and 4095 children of the offspring cohort partici-
pants were also enrolled in 2002 (the third-generation
cohort).19 Between 2002 and 2005, 3529 participants (1422
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Association of Coronary Artery Calcium vs Age With Cardiovascular Risk
Key Points
Question Can coronary artery calcium score serve as an
alternative marker for age as a predictor of atherosclerotic
cardiovascular disease events in older adults?
Findings In this analysis of pooled US population-based studies,
coronary artery calcium score was more likely than age to provide
discrimination between lower and higher coronary heart disease
risk in older adults. Findings were similar in 2 European cohorts.
Meaning In older adults without known cardiovascular disease,
individual coronary artery calcium score provided better
discrimination than chronological age for incident atherosclerotic
cardiovascular disease (coronary heart disease in particular) during
an 11-year follow-up.
from the offspring cohort and 2093 from the third-generation
cohort) underwent CAC scoring using multidetector com-
puted tomography (CT).23
The MESA is a prospective, population-based cohort com-
prising 4 races/ethnicities (white, African American, His-
panic, and Chinese) and 6 US communities.20 The study re-
cruited 6809 participants aged 45 years to 84 years who did
not have cardiovascular diseases between 2000 and 2002.
Coronary artery calcium scoring was conducted at baseline
using either a cardiac-gated electron-beam CT scanner or mul-
tidetector CT.24
The CHS is a population-based, prospective cohort study
aimed at determining cardiovascular disease risk factors in
older adults. Community-dwelling adults 65 years and older
were recruited from 4 US field centers.21,22 Between 1998 and
2000, 614 participants in Pittsburgh underwent CAC scoring
using an electron-beam CT scanner.9
Confirmation Cohorts: 2 European Cohorts
Details of the study design and methods of the RS10,14 and
the HNR Study 1 5 , 2 5 have been desc ribed prev iously
(eMethods in the Supplement). The RS is a prospective
population-based cohort study that recruited participants 55
years and older from 1990 (RS-I).14 Starting in 2000, the
original cohort was extended with a second cohort of partici-
pants who reached 55 years of age and those who had moved
to the research area (RS-II). Assessment of CAC score was
performed with an electron-beam CT C-150 Imatron scanner
(GE-Imatron Inc) in the third examination of RS-I (n = 2063)
or with 16-slice or 64-slice multidetector CT scanners
(SOMATON Sensation 16 or 64; Siemens) in the second
examination of RS-II (n = 2524).10
The HNR Study is a population-based cohort study that re-
cruited 4814 participants aged 45 years to 75 years from the
metropolitan Ruhr area in Germany in 2000 to 2003.15 Elec-
tron-beam CT scans were performed with a C-100 or C-150
scanner (GE Imatron) at 2 sites in Bochum and Mülheim.25
The institutional review boards of all 5 studies provided
approval, and all participants gave written informed consent
before enrollment in each study. The protocol for this study
was approved by the institutional review board at Northwest-
ern University.
jamacardiology.com
 Association of Coronary Artery Calcium vs Age With Cardiovascular Risk
Risk Factor and CAC Score Measurements
The assessments of traditional cardiovascular risk factors26 and
CAC score in each cohort are described in the eMethods in the
Supplement.9,23,24 eTable 1 in the Supplement provides infor-
mation pertaining to when CT scans were performed and
whether the results were reported to participants and physi-
cians. A calcified lesion was defined as an area of at least 2 con-
nected pixels with CT attenuation of more than 130 Hounsfield
units. Agatston score was calculated,27 multiplying the area of
each lesion with a weighted attenuation score dependent on
the maximal attenuation within the lesion.
Ascertainment of Outcomes
Protocols and criteria for the ascertainment and diagnosis of
events have been reported previously (eMethods in the
Supplement)16-22; they were relatively similar across cohorts.
Incident ASCVD during follow-up, including CHD (nonfatal
myocardial infarctions and CHD deaths) and stroke (fatal or
nonfatal) events, were assessed as outcomes. Physician mem-
bers of the end points committee within each cohort indepen-
dently reviewed medical records to adjudicate each possible
cardiovascular outcomes, using specific definitions and a de-
tailed manual of operations (http://www.mesa-nhlbi.org/;
https://www.framinghamheartstudy.org/; https://chs-nhlbi
.org/; and http://www.epib.nl/research/ergo.htm). Participants
who did not have events and who did not drop out of the study
after the initial examination were censored.
Statistical Analyses
All statistical analyses were performed with Stata version 12.1
(StataCorp). Descriptive statistics are presented as mean (SD),
percentages of participants, and medians and quartiles.
Cox proportional hazards models were used to examine the
predictive ability of CAC score for cardiovascular outcomes. In-
cident ASCVD, CHD, and stroke were evaluated as outcomes sepa-
rately. The proportionality assumption for the Cox regression
analysis was confirmed graphically and with the inclusion of a
time by CAC score interaction. First, discordance in predictive
ability between age and CAC score was assessed based on indi-
vidual 10-year ASCVD risk. We defined 3 groups: age greater than
CAC score discordance, concordance, and age less than CAC score
discordance. Second, for assessing model fit, the likelihood ra-
tio χ2 test was used. Comparison of the discriminative ability of
each prediction model was conducted with C statistics (Harrell
C statistic).28 Coronary artery calcium score was tested as a strati-
fied variable (the similar cutoff points used in earlier MESA re-
port: 0, 1 to 100, 101 to 300, and >30029) and as a continuous vari-
able (log [Agatston score +1] transformation). Covariates included
age, sex, race/ethnicity (white, African American, Hispanic, and
Asian), study site (FHS, MESA, and CHS), and traditional cardio-
vascular risk factors26 (ie, smoking, systolic BP, diabetes, total
cholesterol, high-density lipoprotein cholesterol, and lipid-
lowering and antihypertensive medication use). These covari-
ates were selected a priori because they are included in the Ameri-
can College of Cardiology/American Heart Association 2013
cardiovascular risk equation.1 We examined (1) the predictive abil-
ity of CAC score vs age for specific cardiovascular outcomes; (2)
how risk prediction changes by adding CAC score and removing
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Original Investigation Research
only age from prediction models including covariates; and (3) how
risk prediction changes by replacing CAC score for cardiovascu-
lar risk factors (ie, smoking, systolic BP, diabetes, total choles-
terol level, high-density lipoprotein cholesterol, and lipid-
lowering and antihypertensive medication use) but retaining age
in prediction models. We evaluated category-based/category-free
net reclassification improvement (NRI) for events and nonevents
separately.30,31 We used cutoff values for 10-year ASCVD risk of
less than 7.5% and at least 7.5%, the statin therapy threshold rec-
ommended in the 2013 American College of Cardiology/American
Heart Association cholesterol guideline.1 We then calculated the
proportion of participants who were reclassified by the compari-
son model compared with the base model.
In sensitivity analyses, we examined analyses of the in-
teraction between CAC score and sex, race/ethnicity, or base-
line age (<75 years and ≥75 years) in association with specific
cardiovascular outcomes and sex-specific, race/ethnicity-
specific, and age-specific (<75 years and ≥75 years) C statistic
analyses. Statistical significance was defined as a P value < .05
using 2-sided t tests.
We first conducted a pooled individual participant analy-
sis using data from 3 US cohorts. The analyses were indepen-
dently repeated in 2 confirmation cohorts. Results from origi-
nal cohorts were compared with those cohorts respectively.
Results
Original Cohorts: 3 US Cohorts
In all cohorts, we excluded participants younger than 60 years;
those without CAC information; those with known CHD, stroke,
and heart failure at baseline; those who had any missing co-
variates required in the analysis; and those lost to follow-up.
As a result, 515 FHS participants, 3881 MESA participants, 387
CHS participants, 3089 RS participants, and 1901 HNR partici-
pants were included (total sample size in original cohorts,
n = 4778). Of the 4778 participants, 2582 (54.0%) were women
and 2347 (49.0%) were white, and the mean age was 70.1 years.
Table 1 shows overall and cohort-specific demographic and
clinical characteristics of the included participants. Coronary
artery calcium score was higher in men compared with women
(men: median, 97.8; interquartile range [IQR], 5.5-439.3; wom-
en: median, 14.8; IQR, 0-142.8; P < .001 by Mann-Whitney
U test) and white individuals compared with African Ameri-
can, Hispanic, and Asian individuals (white: median, 94.2; IQR,
2.1-395.8; African American: median, 15.7; IQR, 0-146.7; His-
panic: median, 17.2; IQR, 0-128.0; Asian: median, 22.0; IQR,
0-132.3; P < .001 by Kruskal-Wallis test). Thirty-one percent of
the study population had a CAC score of 0 at baseline (36.5%
of white individuals, 31.4% of African American individuals,
20.7% Hispanic individuals, and 11.2% Asian individuals;
eTable 2 in the Supplement). The proportion of participants
with a CAC score of 0 was smallest in white individuals com-
pared with other races/ethnicities (23% vs 35%-40%).
Baseline CAC Categories and Outcomes
During a median follow-up period of 10.7 years (IQR, 7.4-11.4
years; 44 152.4 person-years), 598 ASCVD events occurred (14.9
(Reprinted) JAMA Cardiology Published online July 26, 2017 E3
 Research Original Investigation Association of Coronary Artery Calcium vs Age With Cardiovascular Risk

Table 1. Participant Characteristics From Original Cohorts (N = 4778) and Confirmation Cohorts (N = 4990)a

No. (%)
Original Cohorts (n = 4778) Confirmation Cohorts (n = 4990)
Total MESA FHS CHS Rotterdam Study HNR Study
Descriptive Variable (n = 4778) (n = 3876) (n = 515) (n = 387) (n = 3089) (n = 1901)
Age, y
Mean (SD) 70.1 (6.5) 69.6 (6.2) 67.4 (5.0) 78.8 (3.9) 68.7 (6.0) 65.8 (4.4)
Median (range) 69.1 (60.0-96.0) 69.0 (60.0-84.0) 66.9 (60.0-83.5) 78.0 (71.0-96.0) 67.2 (60.0-98.0) 65.0 (60.0-76.0)
Men 2196 (46.0) 1835 (47.3) 221 (42.9) 140 (36.2) 1317 (42.6) 868 (45.7)
Race/ethnicity
Non-Hispanic white 2347 (49.1) 1532 (39.6) 515 (100) 300 (77.5) 3089 (100) 1901 (100)
African American 1158 (24.2) 1072 (27.7) 0 86 (22.2) 0 0
Hispanic 463 (17.0) 463 (11.9) 0 0 0 0
Asian 810 (9.7) 809 (20.9) 0 1 (0.3) 0 0
Current smoking 412 (8.6) 356 (9.2) 25 (4.9) 31 (8.0) 501 (16.2) 274 (14.4)
Systolic BP, 132.3 (21.5) 132.4 (22.0) 131.7 (18.6) 132.6 (20.1) 143.8 (20.0) 137.4 (20.8)
mean (SD), mm Hg
Total cholesterol, 195.2 (35.8) 193.6 (35.4) 201.2 (34.7) 203.3 (39.4) 225.7 (36.2) 235.8 (38.7)
mean (SD), mg/dL
HDL cholesterol, 52.4 (15.2) 52.0 (15.1) 53.8 (16.2) 54.7 (14.7) 55.7 (15.5) 59.5 (16.9)
mean (SD), mg/dL
Diabetes 682 (14.3) 585 (15.1) 52 (10.1) 45 (11.6) 351 (11.4) 269 (14.2)
Antihypertensive 1990 (41.7) 1615 (41.7) 186 (36.1) 189 (48.8) 994 (32.2) 760 (40.0)
medication use
Lipid-lowering 911 (19.1) 750 (19.4) 103 (20.0) 58 (15.0) 447 (14.5) 237 (12.5)
medication use
CAC score
Agatston score, 265.7 (560.0) 224.9 (513.5) 380.7 (703.3) 521.0 (689.3) 296.7 (663.3) 243.2 (584.1)
mean (SD)
Agatston score, 42.3 (0-255.1) 27.3 (0-197.2) 102.2 (7.6-414.1) 249.1 (45.0-716.4) 61.37 (4.00-289.8) 38.9 (1.5-200.9)
median (IQR)
Agatston score = 0 1478 (30.9) 1359 (35.1) 92 (17.9) 27 (7.0) 461 (14.9) 417 (21.9)
Agatston 1439 (30.1) 1171 (30.2) 164 (31.8) 104 (26.9) 1333 (43.2) 780 (41.0)
score = 1-100
Agatston 781 (16.4) 602 (15.5) 106 (20.6) 73 (18.9) 535 (17.3) 346 (18.2)
score = 101-300
Agatston score >300 1080 (22.6) 744 (19.2) 153 (29.7) 183 (47.3) 760 (24.6) 358 (18.8)
a
Abbreviations: CAC, coronary artery calcium; BP, blood pressure; Original cohorts include MESA, FHS, and CHS, and individual participant data
FHS, Framingham Heart Study; CHS, Cardiovascular Health Study; meta-analysis was conducted. Confirmation cohorts include the Rotterdam
HDL, high-density lipoprotein; HNR, Heinz Nixdorf Recall; IQR, interquartile Study and the HNR Study, and the analyses were independently conducted
range; MESA, Multi-Ethnic Study of Atherosclerosis. within each study.
SI conversion factor: To convert HDL cholesterol to millimoles per liter, multiply
by 0.0259; to convert total cholesterol to millimoles per liter, multiply by
0.0259.

per 1000 person-years), including 405 CHD events (9.0 per 1000
person-years) and 228 stroke events (5.0 per 1000 person-years).
eTable 3 in the Supplement shows the frequency of cardiovas-
cular outcomes and corresponding event rates (per 1000 person-
years) by CAC categories, and those within each cohort are shown
in eTable 4 in the Supplement. The event rates for total ASCVD
and for each outcome increased across CAC strata. Eleven per-
cent of all ASCVD events (8% of CHD and 16% of stroke) occurred
in those with a CAC score of 0, whereas 42% of all ASCVD events
(45% of CHD and 38% of stroke) occurred in participants with a
CAC score of at least 300 (eTable 3 in the Supplement). Figure 1
shows the Kaplan-Meier cumulative probability of remaining free
of an ASCVD event during 12-year follow-up, stratified by CAC
categories; the probability progressively reduced with increas-
ing CAC categories. The probability remains high (>90%) in those
with a CAC score of 0 during the follow-up.
Predictive Ability of CAC Score vs Age for Outcomes
Discordance in predictive ability of ASCVD events between age
and CAC score is shown in original cohorts in eTable 5 in the
Supplement. The proportion of participants in each group was
as follows: age greater than CAC score discordance group,
23.0%; concordance group, 62.9%; and age less than CAC score
discordance group, 14.1%.
Results from Cox models suggest that both CAC score and
age were positively associated with risk for ASCVD, CHD, and
stroke (eTable 6 in the Supplement, models 1-3). When CAC score
and age were analyzed jointly, their risks were attenuated but re-
tained statistical significance (models 4-5). Differences in C sta-
tistics for outcomes between CAC score vs age are shown in eFig-
ure 1 in the Supplement. Coronary artery calcium score (vs age)
had a greater association with incident CHD (C statistic, 0.733 vs
0.690; C statistics difference, +0.043; 95% CI of difference,

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 Association of Coronary Artery Calcium vs Age With Cardiovascular Risk
Figure 1. Kaplan-Meier Curves of the Cumulative Probability
of Atherosclerotic Cardiovascular Disease (ASCVD) Event–Free
by Coronary Artery Calcium (CAC) Categories in Original Cohorts
100
Cumulative Probability of
90
ASCVD Event Free, %
80
70
60
Log-rank test: P <.001
40
0 4
Follow-up Time, y
No. at risk
CAC 0 1470 1379
CAC 1-100 1471 1306
CAC 101-300 1472 693
CAC >300 1077 888
The cumulative probability of free of ASCVD events by CAC categories is shown;
ASCVD included coronary heart disease and stroke. The log-rank was used to
calculate P values. CHD indicates coronary heart disease.
0.009-0.075) and modestly improved prediction for stroke
(C statistic, 0.695 vs 0.670; C statistics difference, +0.025; 95%
CI of difference, −0.015 to 0.064). When we compared the C sta-
tistics between CAC score alone and age alone, results were gen-
erally similar (eTable 7 in the Supplement).
Adding CAC Score and Removing Only Age
From Prediction Models
In CHD prediction models, model fit assessed by likelihood ra-
tio χ2 change was improved when we added CAC score to mod-
els including cardiovascular risk factors, with only age being
removed (eTable 8 in the Supplement). C statistics also sig-
nificantly increased after adding log CAC (Agatston score +1)
to the CHD prediction model including cardiovascular risk fac-
tors with only age being removed (C statistic, 0.735 vs 0.703;
C statistics difference, +0.032; 95% CI of difference, 0.002-
0.062) but modestly in stroke prediction models (C statistic,
0.733 vs 0.717; C statistics difference, +0.017; 95% CI of dif-
ference, −0.011 to 0.045) (Figure 2).
Replacing CAC Score for Cardiovascular Risk Factors
but Retaining Age in Prediction Models
Replacing CAC score for risk factors but retaining age im-
proved model fit and discrimination for CHD (C statistic, 0.740
vs 0.703; C statistics difference, +0.037; 95% CI of difference,
0.012-0.062), whereas it reduced the discrimination of inci-
dent stroke (eTable 9 in the Supplement).
Repeated Cox analysis including CAC score and all risk fac-
tors including age, with the inclusion of an interaction term,
suggested that there were no significant interactions be-
tween CAC score and sex, race/ethnicity, or age in association
with all cardiovascular outcomes. Sex-specific, race/ethnicity–
specific, and age-specific (<75 years and ≥75 years) C statis-
tics analyses showed similar results (eFigures 2-17 in the
Supplement).
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Original Investigation Research
Coronary artery calcium score was more likely than age
to provide higher category-free NRI among participants who
experienced an ASCVD event and to result in more accurate
reclassification of risk for ASCVD events among these indi-
viduals (Table 2). In participants who did not experience an
CAC 0 ASCVD event, adjusting the model of category-based NRI by
adding CAC score to the other cardiovascular risk factors
CAC 1-100 resulted in a greater improvement in risk reclassification
CAC 101-300 compared with the model adjusted by adding age.
CAC >300
Confirmation Cohorts: 2 European Cohorts
Demographic and clinical characteristics of the included
p a r t i c i p a nt s a re s h ow n i n Ta b l e 1 . e Ta b l e 4 i n t h e
8 12 Supplement shows the frequency of cardiovascular out-
comes and corresponding event rates (per 1000 person-
1228 148 years). Discordance in predictive ability of ASCVD events
1056 145
between age and CAC score is shown in eTable 10 and
525 61
618 84 eTable 11 in the Supplement. The proportion of participants
in each group was as follows: age greater than CAC score
discordance group, 15% to 18%; concordance group, 64% to
79%; and age less than CAC score discordance group, 2% to
20%. Coronary artery calcium score had a greater associa-
tion with incident CHD compared with age, whereas age
performed better than CAC score for predicting stroke
(Figure 3 and eFigures 18-21 in the Supplement). Cardiovas-
cular risk factor covariates with CAC score and without age
provided improved discrimination for incident CHD but not
for stroke (eFigures 20-21 in the Supplement). Replacing
CAC score for risk factors but retaining age improved model
fit and discrimination for CHD, whereas it reduced the dis-
crimination of incident stroke (eTable 12 in the Supple-
ment). In the RS, CAC score was more likely than age to pro-
vide higher category-free NRI and total number of correctly
reclassified participants for ASCVD events (eTable 13 in the
Supplement). In contrast, a difference in the categorical NRI
between age and CAC score was modest in the HNR Study
(eTable 14 in the Supplement).
Discussion
Our study, based on results from a pooled individual participant
data analysis from 3 US cohorts comprising older adults (≥60
years) without known cardiovascular diseases at baseline (n =
4778; mean age, 70.1 years; and 51% nonwhite), demonstrated
that (1) 1478 participants (30.9%) had a CAC score of 0 and their
probability of remaining ASCVD event–free over 12-year follow-
up remains high (>90%); (2) CAC score instead of age had a greater
association with incident CHD and a modest association with
stroke; (3) traditional cardiovascular risk factor with CAC score
and without age provided improved discrimination for incident
CHD and modest discrimination for stroke; (4) age plus CAC score
without cardiovascular risk factors provided improved discrimi-
nation for incident CHD but not for stroke; and (5) CAC score im-
proved risk reclassification for incident ASCVD better than age.
The superior ability of CAC score vs age for predicting CHD events
was confirmed in 2 well-described European cohorts showing
similar results.
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 Research Original Investigation Association of Coronary Artery Calcium vs Age With Cardiovascular Risk

Figure 2. Predictive Ability of Risk Factor Covariates With Coronary Artery Calcium (CAC) and Without Age for Cardiovascular Outcomes
in Original Cohorts

C Statistic C Statistic Change vs

Study (95% CI) Base Model (95% CI)
ASCVD event (n = 598)
Base model 0.699 (0.669-0.728) 1 [Reference]
Base model minus age + CAC categories 0.724 (0.696-0.753) 0.027 (0.005-0.048)
Base model minus age + CAC (continuous) 0.725 (0.697-0.753) 0.025 (0.004-0.047)
CHD event (n = 405)
Base model 0.703 (0.666-0.741) 1 [Reference]
Base model minus age + CAC categories 0.733 (0.698-0.767) 0.030 (–0.0004-0.060)
Base model minus age + CAC (continuous) 0.735 (0.700-0.769) 0.032 (0.002-0.062)
Stroke event (n = 228)
Base model 0.717 (0.671-0.762) 1 [Reference]
Base model minus age + CAC categories 0.729 (0.686-0.772) 0.013 (–0.015-0.041)
Base model minus age + CAC (continuous) 0.733 (0.691-0.776) 0.017 (–0.011-0.045)

–0.03 0 0.03 0.06 0.09

C Statistics Difference (95% CI)

Figure shows differences in C statistics and 95% CIs for individual
cardiovascular outcome after CAC score was added to base models, with only
age being removed. The base model includes age and the following covariates:
sex, race/ethnicity, study site, current smoking, systolic blood pressure, total
cholesterol, high-density lipoprotein cholesterol, diabetes, and use of
antihypertensive drugs and lipid-lowering drugs. Coronary artery calcium score
was tested as a categorical variable (0, 1 to 100, 101 to 300, and >300) and as a
continuous variable (log [Agatston score +1] transformation). ASCVD indicates
atherosclerotic cardiovascular disease; CHD, coronary heart disease.

Table 2. Change in ASCVD Risk Stratification by CAC Score and Age in Original Cohorts (N = 4778)a

Base Model + Log CAC (Predicted Risk)

Base Model (Predicted Risk) <7.5% ≥7.5% Total Category-Based NRI (SE), % Category-Free NRI (95% CI), %
Model 1: ASCVD risk stratification by CAC score
Participants who experienced
ASCVD events, %
<7.5 27 41 68
≥7.5 53 477 530 -0.024 (-0.054 to 0.013) 0.390 (0.312 to 0.469)
Total 80 518 598
Participants who did not
experience ASCVD events, %
<7.5 971 347 1318
≥7.5 862 2000 2862 0.122 (0.107 to 0.141) 0.105 (0.08 to 0.137)
Total 1833 2347 4180
Model 2: ASCVD risk stratification by age
Participants who experienced
ASCVD events, %
<7.5 32 36 68
≥7.5 48 482 530 -0.025 (-0.050 to 0.011) 0.098 (-0.001 to 0.181)
Total 80 518 598
Participants who did not
experience ASCVD events, %
<7.5 975 343 1318
≥7.5 627 2235 2862 0.067 (0.051 to 0.081) 0.199 (0.171 to 0.225)
Total 1602 2578 4180
Abbreviations: ASCVD, atherosclerotic cardiovascular disease; CAC, coronary (model 1) or age (model 2) to the base model. The base model included sex,
artery calcium; NRI, net reclassification improvement. race/ethnicity, study site, current smoking, systolic blood pressure, total
a
Reclassification tables are separated for cases and noncases, with rows cholesterol, high-density lipoprotein cholesterol, diabetes, and use of
indicating the risk categories based on the base model and columns indicating antihypertensive drugs and lipid-lowering drugs. The cells note the number of
the new risk stratification after the addition of Log CAC (Agatston score +1) participants reclassified by predicted risk.

Predictive Ability of CAC Score vs Chronological Age
for Outcomes
Aging is the most consistent and robust contributor to inci-
dent ASCVD.32,33 However, arterial aging is a complex and
heterogeneous process across individuals.34 Even at old age,
31% of our study population had a CAC score of 0; however,
the results require careful interpretation because the propor-
tion differed by race/ethnicity (23% in white individuals vs
35%-40% in other races/ethnicities). Atherosclerotic cardio-
vascular disease risk was low in participants with a CAC score

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 Association of Coronary Artery Calcium vs Age With Cardiovascular Risk
Figure 3. Predictive Ability of Risk Factor Covariates With Coronary Artery Calcium (CAC) and Without Age
for Cardiovascular Outcomes in Confirmation Cohorts
C Statistic
Study (95% CI)
Rotterdam Study
ASCVD event (n = 395)
Base model 0.657 (0.628-0.686)
Base model minus age + CAC categories 0.683 (0.652-0.715)
Base model minus age + CAC (continuous) 0.690 (0.664-0.716)
CHD event (n = 229)
Base model 0.666 (0.626-0.706)
Base model minus age + CAC categories 0.714 (0.676-0.753)
Base model minus age + CAC (continuous) 0.727 (0.691-0.762)
Heinz Nixdorf Recall Study
ASCVD event (n = 173)
Base model 0.682 (0.625-0.739)
Base model minus age + CAC categories 0.693 (0.638-0.748)
Base model minus age + CAC (continuous) 0.710 (0.658-0.762)
CHD event (n = 106)
Base model 0.677 (0.596-0.758)
Base model minus age + CAC categories 0.723 (0.648-0.799)
Base model minus age + CAC (continuous) 0.723 (0.686-0.817)
of 0 (4.5 per 1000 person-years). This suggests that age per se
does not necessarily pose an invariant risk for ASCVD events
among older adults.32-34 The US Preventive Services Task Force
recommended statin use in primary prevention of ASCVD
events in adults in 2016.35 Doubts remain as to using statins
for primary prevention in older adults, especially individuals
older than 75 years. Our data illustrate that older adults with
a CAC score of zero may consider avoiding long-term statin use.
Coronary artery calcium score provided superior predic-
tion for incident CHD compared with chronological age in both
US and European cohorts. Conversely, we observed a nonsig-
nificant trend for improved stroke prediction with CAC score
compared with age in US cohorts, whereas age performed bet-
ter than CAC score in European cohorts. Potential mecha-
nisms behind the discrepancy include (1) intraindividual
heterogeneity of disease severity across distinct vascular beds
(ie, CAC represents the disease substrate of the coronary
artery)6,7; (2) various causes of stroke in older adults (eg, em-
bolisms from cardiac arrhythmia and small vessel diseases)36;
and the proportion may vary by race/ethnicity.37-39 In US co-
horts, although there was no significant interaction between
CAC score and race/ethnicity in association with stroke risk,
the predictive ability of CAC score for incident stroke appear
to vary across race/ethnicity; and (3) stroke is an age-
associated disease, ie, the incidence rate of stroke doubles for
each successive decade after age 55 years.40
Age Plus CAC Score Without Measuring Cardiovascular Risk
Factors in Predicting Outcomes
Replacing CAC score for cardiovascular risk factors but retain-
ing age provided improved prediction of incident CHD in both
US and European cohorts. The CHD prediction with risk factors
(cholesterol in particular) decreases with age, partly because of
selective survival and the influence of comorbidities on risk fac-
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Original Investigation Research
C Statistic Change vs
Base Model (95% CI)
1 [Reference]
0.026 (-0.009-0.061) Figure shows differences in C
0.033 (0.004-0.062) statistics and 95% CIs for individual
cardiovascular outcome after CAC
1 [Reference] score was added to base models,
0.049 (0.024-0.074) with only age being removed. The
0.061 (0.014-0.109) base model includes age and the
following covariates: sex, current
smoking, systolic blood pressure,
total cholesterol, high-density
1 [Reference] lipoprotein cholesterol, diabetes, and
0.010 (–0.019-0.041) use of antihypertensive drugs and
0.028 (–0.005-0.061) lipid-lowering drugs. Coronary artery
calcium score was tested as a
1 [Reference] categorical variable (0, 1 to 100, 101
0.046 (–0.004-0.097) to 300, and >300) and as a
continuous variable (log [Agatston
0.074 (0.031-0.018)
score +1] transformation). ASCVD
–0.03 0 0.03 0.06 0.09 0.12 indicates atherosclerotic
C Statistics Difference (95% CI) cardiovascular disease; CHD,
coronary heart disease.
tor levels.41,42 In addition, one-time measurement of risk factors
in late life is unlikely to reflect individual cumulative exposure
to risk factor during a lifetime. Coronary artery calcium reflects
exposure not only to measured (eg, cholesterol and BP) but also
unmeasured (eg, environmental and sociopsychological factors)
risk factors over a lifetime.6,7 Therefore, measuring CAC score (ie,
disease-based prediction) instead of assessing cardiovascular risk
factors (ie, risk-based prediction) may lead to an optimization of
CHD prediction in older adults.43 In contrast, replacing CAC score
for cardiovascular risk factors reduced the discrimination for in-
cident stroke in both US and European cohorts. This suggests that
a certain risk factor (eg, BP)44 is associated with and predictive
of incident stroke at older age. Stroke is common in older adults,40
and therefore, CAC scoring may be limited as a sole risk estima-
tor for ASCVD (ie, CHD and stroke) in older adults. Given smaller
effect of statins on stroke prevention compared with CHD pre-
vention in older adults,45 CAC scoring may be beneficial to guide
statin therapy for preventing incident CHD in older adults.
Limitations and Strengths
Strengths of this study include the large, community-based mul-
tiethnic cohorts and external confirmation in 2 well-described
European cohorts.14,15 However, there are limitations. First, par-
ticipants receiving statins were included from all cohorts, and
CAC score was reported to participants and their physicians in
the FHS, MESA, CHS, and RS. This might lead to risk factor modi-
fication for participants, which potentially leads to an underes-
timation of the true association between CAC score and ASCVD
risk. Second, assessments of CAC score, cardiovascular risk fac-
tors, and outcomes were relatively similar but not identical across
cohorts. In aggregate, these factors would tend to underestimate
the true associations between CAC score or cardiovascular risk
factors and outcomes. Third, CAC score was more likely than age
to improve risk reclassification for incident ASCVD. However, the
(Reprinted) JAMA Cardiology Published online July 26, 2017 E7
 Research Original Investigation Association of Coronary Artery Calcium vs Age With Cardiovascular Risk

difference might be partly owing to limited age distribution in
the study populations. Fourth, we cannot address all the com-
plex interplay balancing issues of CAC scoring, including cost-
effectiveness, access, utility (including potential adverse events),
and integration in shared decision-making approaches from
stakeholder perspective (ie, patients).46 These issues need to be
examined in future studies.
Conclusions
In older adults without known cardiovascular diseases, indi-
vidual CAC score instead of chronological age provided bet-
ter discrimination for incident ASCVD (CHD in particular) over
an 11-year follow-up. Besides age, CAC may be an alternative
marker to better discriminate between lower and higher CHD
risk in older adults. Given the absence of clear agreement on
risk thresholds to initiate stains for primary prevention of
ASCVD in older adults, clinical judgment and patient input are
critical components during the decision-making process. Coro-
nary artery calcium score may assist in such a shared decision-
making approach. Clinical trials are needed to assess whether
CAC score can help refine treatment decisions and subse-
quently reduce unnecessary medical expenditure and ad-
verse effects of statins and increase treatment efficiency in
older adults.

ARTICLE INFORMATION
Accepted for Publication: June 9, 2017.
Published Online: July 26, 2017.
doi:10.1001/jamacardio.2017.2498
Author Affiliations: Department of Preventive
Medicine, Northwestern University Feinberg School
of Medicine, Chicago, Illinois (Yano, Ning, Liu,
Lloyd-Jones, Greenland); Department of Preventive
Medicine, University of Mississippi Medical Center,
Jackson (Yano); National Heart, Lung, and Blood
Institute’s Framingham Heart Study, Framingham,
Massachusetts (O’Donnell); Associate Editor,
JAMA Cardiology (O’Donnell); Department of
Epidemiology, Graduate School of Public Health,
University of Pittsburgh, Pittsburgh, Pennsylvania
(Kuller, Newman); Department of Epidemiology,
Erasmus University Medical Center, Rotterdam,
the Netherlands (Kavousi, Hofman, Dhana, Franco);
Department of Cardiology, West German Heart and
Vascular Center, University Clinic Essen, University
of Duisburg-Essen, Essen, Germany (Erbel,
Mahabadi); Biostatistics, Boston University School
of Public Health, Boston, Massachusetts
(D’Agostino, Massaro); Center for Prevention and
Wellness Research, Baptist Health Medical Group,
Miami Beach, Florida (Nasir); Department of
Epidemiology, Harvard T. H. Chan School of Public
Health, Boston, Massachusetts (Hofman); Institute
of Medical Informatics, Biometry, and
Epidemiology, University Clinic Essen, University of
Duisburg-Essen, Essen, Germany (Lehmann,
Jöckel); Cardiovascular Division, Brigham and
Women’s Hospital, Boston, Massachusetts
(Blankstein); Cardiovascular Imaging, Cardiac MR
PET CT Program, Department of Radiology,
Massachusetts General Hospital, Harvard Medical
School, Boston, Massachusetts (Hoffmann); Clinic
of Cardiology and Intensive Care Medicine,
Bethanien Hospital Moers, Moers, Germany
(Möhlenkamp); Department of Cardiology, Johns
Hopkins University, Baltimore, Maryland (Lima);
Departments of Epidemiology, Radiology, and
Neurology, Erasmus University Medical Center,
Rotterdam, the Netherlands (Ikram).
Author Contributions: Dr Yano had full access to all
of the data in the study and takes responsibility for
the integrity of the data and the accuracy of the
data analysis.
Study concept and design: Yano, O’Donnell, Erbel,
Newman, Nasir, Hoffmann, Lima, Ikram,
Lloyd-Jones, Greenland.
Acquisition, analysis, or interpretation of data: Yano,
O’Donnell, Kuller, Kavousi, Ning, D’Agostino,
Newman, Hofman, Lehmann, Dhana, Blankstein,
Hoffmann, Mohlenkamp, Massaro, Mahabad, Lima,
Ikram, Jockel, Franco, Liu, Lloyd-Jones, Greenland.
Drafting of the manuscript: Yano.
Critical revision of the manuscript for important
intellectual content: O'Donnell, Kuller, Kavousi,
Erbel, Ning, D’Agostino, Newman, Nasir, Hofman,
Lehmann, Dhana, Blankstein, Hoffmann,
Mohlenkamp, Massaro, Mahabad, Lima, Ikram,
Jockel, Franco, Liu, Lloyd-Jones, Greenland.
Statistical analysis: Yano, Kavousi, Ning, D’Agostino,
Lehmann, Dhana, Massaro, Mahabad.
Obtained funding: O’Donnell, Erbel, Newman,
Mohlenkamp, Ikram, Franco, Greenland.
Administrative, technical, or material support:
Kuller, Erbel, Newman, Hoffmann, Mohlenkamp,
Lima, Jockel, Lloyd-Jones, Greenland.
Supervision: Erbel, Nasir, Mahabad, Lima, Ikram,
Jockel, Franco, Lloyd-Jones, Greenland.
Conflict of Interest Disclosures: All authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest and
none were reported.
Funding/Support: The Multi-Ethnic Study of
Atherosclerosis was supported by contracts
HHSN268201500003I, N01-HC-95159,
N01-HC-95160, N01-HC-95161, N01-HC-95162,
N01-HC-95163, N01-HC-95164, N01-HC-95165,
N01-HC-95166, N01-HC-95167, N01-HC-95168, and
N01-HC-95169 from the National Heart, Lung, and
Blood Institute and by grants UL1-TR-000040 and
UL1-TR-001079 from the National Center for
Research Resources. The Framingham Heart Study
was supported by contracts N01-HC-25195,
HL076784, AG028321, HL070100, HL060040,
HL080124, HL071039, HL077447, and HL107385
from the National Heart, Lung, and Blood Institute.
The Cardiovascular Health Study was supported by
contracts HHSN268201200036C,
HHSN268200800007C, N01HC55222,
N01HC85079, N01HC85080, N01HC85081,
N01HC85082, N01HC85083, N01HC85086, and
grant U01HL080295 from the National Heart,
Lung, and Blood Institute, with additional
contribution from the National Institute of
Neurological Disorders and Stroke. Additional
support was provided by R01AG023629 from the
National Institute on Aging. A full list of principal
Cardiovascular Health Study investigators and
institutions can be found at chs-nhlbi.org. The
Rotterdam Study is funded by Erasmus MC and
Erasmus University, Rotterdam, the Netherlands;
the Netherlands Organization for Scientific
Research ; the Netherlands Organization for the
Health Research and Development; the Research
Institute for Diseases in the Elderly; the Ministry of
Education, Culture and Science; the Ministry for
Health, Welfare and Sports; the European
Commission (DG XII); and the Municipality of
Rotterdam. Dr Kavousi is supported by the
Netherlands Organisation for Scientific Research
Innovational Research Incentives Scheme Veni
grant (NWO VENI, 91616079). Dr Franco works in
ErasmusAGE, a center for aging research across the
life course funded by Nestlé Nutrition (Nestec Ltd);
Metagenics Inc; and AXA.
Role of the Funder/Sponsor: The funding sources
had no role in design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review or
approval of the manuscript; and decision to submit
the manuscript for publication.
Disclaimer: The views expressed in this article are
those of the authors and do not necessarily
represent the views of the National Heart, Lung,
and Blood Institute; the National Institutes of
Health; or the US Department of Health and Human
Services. Additionally, Dr O’Donnell is an associate
editor of JAMA Cardiology. He was not involved in
the evaluation or decision to accept this article for
publication.
REFERENCES
1. Stone NJ, Robinson JG, Lichtenstein AH, et al;
American College of Cardiology/American Heart
Association Task Force on Practice Guidelines. 2013
ACC/AHA guideline on the treatment of blood
cholesterol to reduce atherosclerotic cardiovascular
risk in adults: a report of the American College of
Cardiology/American Heart Association Task Force
on Practice Guidelines. Circulation. 2014;129(25, suppl
2):S1-S45.
2. Pencina MJ, Navar-Boggan AM, D’Agostino RB
Sr, et al. Application of new cholesterol guidelines
to a population-based sample. N Engl J Med. 2014;
370(15):1422-1431.
3. Stamler J, Stamler R, Neaton JD, et al. Low
risk-factor profile and long-term cardiovascular and
noncardiovascular mortality and life expectancy:
findings for 5 large cohorts of young adult and
middle-aged men and women. JAMA. 1999;282
(21):2012-2018.
4. Lloyd-Jones DM, Dyer AR, Wang R, Daviglus ML,
Greenland P. Risk factor burden in middle age and
lifetime risks for cardiovascular and
non-cardiovascular death (Chicago Heart
Association Detection Project in Industry).
Am J Cardiol. 2007;99(4):535-540.

E8 JAMA Cardiology Published online July 26, 2017 (Reprinted) jamacardiology.com

© 2017 American Medical Association. All rights reserved.

Downloaded From: http://jamanetwork.com/ by Jimmy T on 07/29/2017

 Association of Coronary Artery Calcium vs Age With Cardiovascular Risk
5. Odden MC, Pletcher MJ, Coxson PG, et al.
Cost-effectiveness and population impact of statins
for primary prevention in adults aged 75 years or
older in the United States. Ann Intern Med. 2015;162
(8):533-541.
6. Blaha MJ, Silverman MG, Budoff MJ. Is there a
role for coronary artery calcium scoring for
management of asymptomatic patients at risk for
coronary artery disease? clinical risk scores are not
sufficient to define primary prevention treatment
strategies among asymptomatic patients. Circ
Cardiovasc Imaging. 2014;7(2):398-408.
7. Alexopoulos N, Raggi P. Calcification in
atherosclerosis. Nat Rev Cardiol. 2009;6(11):681-688.
8. Vliegenthart R, Oudkerk M, Hofman A, et al.
Coronary calcification improves cardiovascular risk
prediction in the elderly. Circulation. 2005;112(4):
572-577.
9. Newman AB, Naydeck BL, Ives DG, et al.
Coronary artery calcium, carotid artery wall
thickness, and cardiovascular disease outcomes in
adults 70 to 99 years old. Am J Cardiol. 2008;101
(2):186-192.
10. Elias-Smale SE, Proença RV, Koller MT, et al.
Coronary calcium score improves classification of
coronary heart disease risk in the elderly: the
Rotterdam study. J Am Coll Cardiol. 2010;56(17):
1407-1414.
11. Tota-Maharaj R, Blaha MJ, Blankstein R, et al.
Association of coronary artery calcium and
coronary heart disease events in young and elderly
participants in the multi-ethnic study of
atherosclerosis: a secondary analysis of a
prospective, population-based cohort. Mayo Clin
Proc. 2014;89(10):1350-1359.
12. Tota-Maharaj R, Blaha MJ, McEvoy JW, et al.
Coronary artery calcium for the prediction of
mortality in young adults <45 years old and elderly
adults >75 years old. Eur Heart J. 2012;33(23):
2955-2962.
13. Leening MJ, Elias-Smale SE, Kavousi M, et al.
Coronary calcification and the risk of heart failure in
the elderly: the Rotterdam Study. JACC Cardiovasc
Imaging. 2012;5(9):874-880.
14. Hofman A, van Duijn CM, Franco OH, et al.
The Rotterdam Study: 2012 objectives and design
update. Eur J Epidemiol. 2011;26(8):657-686.
15. Schmermund A, Möhlenkamp S, Stang A, et al.
Assessment of clinically silent atherosclerotic
disease and established and novel risk factors for
predicting myocardial infarction and cardiac death
in healthy middle-aged subjects: rationale and
design of the Heinz Nixdorf RECALL Study: risk
factors, evaluation of coronary calcium and lifestyle.
Am Heart J. 2002;144(2):212-218.
16. Dawber TR, Kannel WB, Lyell LP. An approach
to longitudinal studies in a community: the
Framingham Study. Ann N Y Acad Sci. 1963;107:
539-556.
17. Kannel WB, Feinleib M, McNamara PM, Garrison
RJ, Castelli WP. An investigation of coronary heart
disease in families: the Framingham offspring study.
Am J Epidemiol. 1979;110(3):281-290.
18. Feinleib M, Kannel WB, Garrison RJ, McNamara
PM, Castelli WP. The Framingham Offspring Study:
design and preliminary data. Prev Med. 1975;4(4):
518-525.
jamacardiology.com
© 2017 American Medical Association. All rights reserved.
Downloaded From: http://jamanetwork.com/ by Jimmy T on 07/29/2017
19. Splansky GL, Corey D, Yang Q, et al. The Third
Generation Cohort of the National Heart, Lung, and
Blood Institute’s Framingham Heart Study: design,
recruitment, and initial examination. Am J Epidemiol.
2007;165(11):1328-1335.
20. Bild DE, Bluemke DA, Burke GL, et al.
Multi-Ethnic Study of Atherosclerosis: objectives
and design. Am J Epidemiol. 2002;156(9):871-881.
21. Fried LP, Borhani NO, Enright P, et al.
The Cardiovascular Health Study: design and
rationale. Ann Epidemiol. 1991;1(3):263-276.
22. Tell GS, Fried LP, Hermanson B, Manolio TA,
Newman AB, Borhani NO. Recruitment of adults 65
years and older as participants in the Cardiovascular
Health Study. Ann Epidemiol. 1993;3(4):358-366.
23. Hoffmann U, Massaro JM, Fox CS, Manders E,
O’Donnell CJ. Defining normal distributions of
coronary artery calcium in women and men (from
the Framingham Heart Study). Am J Cardiol.
2008;102(9):1136-1141, 1141.e1.
24. Carr JJ, Nelson JC, Wong ND, et al. Calcified
coronary artery plaque measurement with cardiac
CT in population-based studies: standardized
protocol of Multi-Ethnic Study of Atherosclerosis
(MESA) and Coronary Artery Risk Development in
Young Adults (CARDIA) study. Radiology. 2005;234
(1):35-43.
25. Schmermund A, Möhlenkamp S, Berenbein S,
et al. Population-based assessment of subclinical
coronary atherosclerosis using electron-beam
computed tomography. Atherosclerosis. 2006;185
(1):177-182.
26. D’Agostino RB Sr, Vasan RS, Pencina MJ, et al.
General cardiovascular risk profile for use in primary
care: the Framingham Heart Study. Circulation.
2008;117(6):743-753.
27. Agatston AS, Janowitz WR, Hildner FJ, Zusmer
NR, Viamonte M Jr, Detrano R. Quantification of
coronary artery calcium using ultrafast computed
tomography. J Am Coll Cardiol. 1990;15(4):827-832.
28. Newson RB. Comparing the predictive powers
of survival models using Harrell’s C or Somers’.
D Stata J. 2010;10:339-358.
29. Detrano R, Guerci AD, Carr JJ, et al. Coronary
calcium as a predictor of coronary events in four
racial or ethnic groups. N Engl J Med. 2008;358(13):
1336-1345.
30. Pencina MJ, D’Agostino RB Sr, D’Agostino RB Jr,
Vasan RS. Evaluating the added predictive ability of
a new marker: from area under the ROC curve to
reclassification and beyond. Stat Med. 2008;27(2):
157-172.
31. Kennedy KF, Pencina MJ. A SAS macro to
compute added predictive ability of new markers
predicting a dichotomous outcome.
http://analytics.ncsu.edu/sesug/2010/SDA07
.Kennedy.pdf. Accessed May 30, 2017.
32. Kannel WB, Vasan RS. Is age really a
non-modifiable cardiovascular risk factor? Am J
Cardiol. 2009;104(9):1307-1310.
33. Grundy SM. Coronary plaque as a replacement
for age as a risk factor in global risk assessment. Am
J Cardiol. 2001;88(2A):8E-11E.
34. Najjar SS, Scuteri A, Lakatta EG. Arterial aging:
is it an immutable cardiovascular risk factor?
Hypertension. 2005;46(3):454-462.
(Reprinted) JAMA Cardiology Published online July 26, 2017
Original Investigation Research
35. Chou R, Dana T, Blazina I, Daeges M, Jeanne TL.
Statins for prevention of cardiovascular disease in
adults: evidence report and systematic review for
the US Preventive Services Task Force. JAMA. 2016;
316(19):2008-2024.
36. Goldstein LB, Bushnell CD, Adams RJ, et al;
American Heart Association Stroke Council; Council
on Cardiovascular Nursing; Council on
Epidemiology and Prevention; Council for High
Blood Pressure Research; Council on Peripheral
Vascular Disease, and Interdisciplinary Council on
Quality of Care and Outcomes Research. Guidelines
for the primary prevention of stroke: a guideline for
healthcare professionals from the American Heart
Association/American Stroke Association. Stroke.
2011;42(2):517-584.
37. Sudlow CL, Warlow CP; International Stroke
Incidence Collaboration. Comparable studies of the
incidence of stroke and its pathological types:
results from an international collaboration. Stroke.
1997;28(3):491-499.
38. Ueshima H, Sekikawa A, Miura K, et al.
Cardiovascular disease and risk factors in Asia:
a selected review. Circulation. 2008;118(25):
2702-2709.
39. Kim AS, Johnston SC. Global variation in the
relative burden of stroke and ischemic heart
disease. Circulation. 2011;124(3):314-323.
40. Go AS, Mozaffarian D, Roger VL, et al;
American Heart Association Statistics Committee
and Stroke Statistics Subcommittee. Heart disease
and stroke statistics: 2013 update: a report from the
American Heart Association. Circulation. 2013;127
(1):e6-e245.
41. de Ruijter W, Westendorp RG, Assendelft WJ,
et al. Use of Framingham risk score and new
biomarkers to predict cardiovascular mortality in
older people: population based observational
cohort study. BMJ. 2009;338:a3083.
42. Störk S, Feelders RA, van den Beld AW, et al.
Prediction of mortality risk in the elderly. Am J Med.
2006;119(6):519-525.
43. Lloyd-Jones DM. Coronary artery calcium
scoring: are we there yet? J Am Coll Cardiol. 2015;
66(15):1654-1656.
44. Lewington S, Clarke R, Qizilbash N, Peto R,
Collins R; Prospective Studies Collaboration.
Age-specific relevance of usual blood pressure to
vascular mortality: a meta-analysis of individual
data for one million adults in 61 prospective studies.
Lancet. 2002;360(9349):1903-1913.
45. Shepherd J, Blauw GJ, Murphy MB, et al;
PROSPER study group. Pravastatin in elderly
individuals at risk of vascular disease (PROSPER):
a randomised controlled trial. Lancet. 2002;360
(9346):1623-1630.
46. Nasir K. Overhauling cardiovascular risk
prediction in primary prevention: difficult journey
worth the destination. Circ Cardiovasc Qual
Outcomes. 2015;8(5):466-468.
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