IEEE TRANSACTIONS ON INFORMATION TECHNOLOGY IN BIOMEDICINE, VOL. 16, NO.

5, SEPTEMBER 2012 795

Investigation on Cardiovascular Risk Prediction

Using Genetic Information
Li-Na Pu, Ze Zhao, and Yuan-Ting Zhang, Fellow, IEEE

Abstract—Cardiovascular disease (CVD) has become the pri-

mary killer worldwide and is expected to cause more deaths in the
future. Prediction and prevention of CVD have therefore become
important social problems. Many groups have developed predic-
tion models for asymptomatic CVD by classifying its risk based on
established risk factors (e.g., age, sex, etc.). More recently, stud-
ies have uncovered that many genetic variants are associated with
CVD outcomes/traits. If treated as single or multiple risk factors,
the genetic information could improve the performance of predic-
tion models as well as promote the development of individually
tailored risk models. In this paper, eligible genome-wide associa-
tion studies for CVD outcomes/traits will be overviewed. Clinical
trials on CVD prediction using genetic information will be sum-
marized from overall aspects. As yet, most of the single or multiple
genetic markers, which have been evaluated in the follow-up clin-
ical studies, did not significantly improve discrimination of CVD. Fig. 1. Projected global deaths for selected causes of death, 2002–2030. Car-
However, the potential clinical utility of genetic information has diovascular diseases, principally heart disease and stroke, are the major causes
of death even than cancers now and decades later in the world. Reprinted with
been uncovered initially and is expected for further development. permission from World health statistics 2007 [3], Copyright 2007 World Health
Index Terms—Cardiovascular disease (CVD), genetic variants, Organization.
risk prediction.

I. INTRODUCTION ruptures in blood vessels, thereby inducing the occurrence of

ARDIOVASCULAR DISEASE (CVD) is the world’s
C number one cause of morbidity and mortality worldwide
leading to millions of deaths every year [1], and an increasing
number of deaths due to CVD are supposed to occur decades
later (see Fig. 1) [2]. Unexpected acute events have resulted in
much affliction as well as high treatment costs. The latter are now
reaching unsustainable levels and are becoming huge burdens
even for developed countries. Early prediction and intervention
would therefore be of huge benefit to society.
CVD usually refers to those diseases that are related to
atherosclerosis (arterial disease). Vulnerable plaque [4] easily
Manuscript received October 1, 2011; revised April 6, 2012; accepted June 6,
2012. Date of publication June 18, 2012; date of current version September 20,
2012. This work was supported by National Basic Research Program 973 under
Grant 2010CB732606 from the Ministry of Science and Technology, China;
the Guangdong Innovation Team LCHT Fund, China; the External Cooperation
Program of the Chinese Academy of Sciences under Grant GJHZ1212; and by
the Hong Kong Innovation and Technology Fund.
L.-N. Pu is with the Institute of Biomedical and Health Engineering, Shen-
zhen Institutes of Advanced Technology, Chinese Academy of Sciences, and
the Key Lab of Health Informatics of Chinese Academy of Sciences, Shenzhen
518055, China (e-mail: ln.pu@siat.ac.cn).
Z. Zhao was with the Institute of Biomedical and Health Engineering, Shen-
zhen Institutes of Advanced Technology, Chinese Academy of Sciences, and
the Key Lab of Health Informatics of Chinese Academy of Sciences, Shenzhen
518055, China (e-mail: neu.zhaoze@gmail.com).
Y.-T. Zhang is with the Key Lab of Health Informatics of Chinese
Academy of Sciences, Shenzhen 518055, China, and also with the Joint Re-
search Centre for Biomedical Engineering, Department of Electronic Engi-
neering, The Chinese University of Hong Kong, Shatin, Hong Kong (e-mail:
ytzhang@ee.cuhk.edu.hk).
Digital Object Identifier 10.1109/TITB.2012.2205009
1089-7771/$31.00 © 2012 IEEE
a stroke, heart attack, etc. At present, most interventions are
undertaken if certain conditions are met, i.e., if acute outcomes
have occurred or high risk factors have been detected. Risk pre-
diction is of utmost importance to allow early intervention and
treatment of complex CVD to prevent the occurrence of acute
events and decrease costs. It is for this reason that risk prediction
has become such an important field to study.
To date, some risk prediction models have been built, such
as Framingham [5], ATP-III [6], SCORE [7], PROCAM [8],
QRISK [9], and MUCA [10]. These current risk prediction mod-
els have had some initial success in CVD prediction. However,
they did not have good performance in predicting the endpoint
of individuals who were assessed to have an intermediate risk of
developing CVD. The traditional risk factors are focused on age,
sex, smoking, diabetes, total cholesterol, systolic blood pres-
sure, low-density lipoprotein (LDL) cholesterol, high-density
lipoprotein (HDL) cholesterol, diabetes mellitus, family his-
tory, etc. As traditional risk factors can explain only half of the
incidence of CVD, further efforts were taken to develop innova-
tive ways to improve the performance of risk prediction models.
The addition of new valuable genetic risk factors would be a
good choice to refine the current risk prediction algorithms.
In the results of a population-based case-control study
[11], the rate of myocardial infarction/primary cardiac arrest
(MI/PCA) among first-degree relatives of cardiac arrest patients
was almost 50% higher than that in first-degree relatives of con-
trol subjects [rate ratio (RR) 1.46, 95% confidence interval (CI)
1.23–1.72]. In a multivariate logistic model, family history of
MI/PCA was associated with PCA (RR 1.57, 95% CI 1.27–1.95)
even after adjustment for other common risk factors. Certainly,
796 IEEE TRANSACTIONS ON INFORMATION TECHNOLOGY IN BIOMEDICINE, VOL. 16, NO. 5, SEPTEMBER 2012
there were other studies that have examined and established
family history as a risk factor for incident CVD. Familial ge-
netic risk includes genetic variants and relates to environment
factors, such as behavior, lifestyle, etc. Moreover, the calcula-
tions for heritability were performed with variance-component
analysis in a family study [12]. The heritability of CVD has been
estimated and displayed a high heritability at 40–60%. With the
other studies [13], all the findings suggest the significant role
of genetic factors in CVD. Many groups have therefore been
studying the potential clinical use of genetic information. An
example is the Framingham Heart Study that has discovered
many genetic variants associated with CVD outcomes/traits of
cholesterol [14], body mass index [15], blood pressure [16], and
so on. Many other studies have also published genetic variants
that are associated with CVD outcomes/traits.
In this paper, genome-wide association studies (GWAS) for
CVD outcomes/traits will first be overviewed. The eligible
GWAS were mainly on those that have reached a P ≤ 10−7
from the National Human Genome Research Institute catalog
(last searched June 23, 2011) [17]. The genetic markers re-
viewed were those associated with CVD outcomes (coronary
heart disease, stroke, heart failure, etc.), established risk fac-
tors (systolic blood pressure, total cholesterol, HDL choles-
terol, LDL cholesterol, body mass index, hypertension, etc.),
and biomarker (C-reactive protein). Then, studies on the CVD
risk prediction using genetic information will be searched in
web of science and PubMed, and reviewed.
II. CONCEPT OF GENETIC RISK PREDICTION
As a major goal, GWAS are devoted to identifying inher-
ited genetic variants that are associated with complex disease.
The identification of such variants enables a clarification of the
disease mechanisms and improves the efficacy of disease diag-
nostics and therapeutics. Genetic information is introduced into
risk models to predict the risk of complex disease when it is in
its latent—or even earlier—period. The final objective is to use
this prediction so as to undertake active intervention on patients,
thereby preventing the occurrence of acute events. At present,
the most widely used procedures in genetic risk prediction fol-
lows these steps: 1) identifying the genes that will be used in
the prediction by studying the mechanism or reviewing pieces
of literature; 2) ascertaining the association between genes and
the risk of disease by GWAS; 3) developing clinical trials with
follow-up studies to make sure the predicted performance of the
genes; if the genes can predict the risk of the special disease,
then 4) using the outcomes of gene detection to predict whether
the samples suffer from the diseases; and 5) taking appropriate
therapy to prevent the diseases. In theory, if the performance of
the genetic risk prediction is identified, the person will suffer
from the disease when the gene is detected in the human blood.
Appropriate intervention should therefore be taken in order to
prevent the consequent outcomes in time.
For the complex CVD, genes have complicated associations
not only with the CVD outcomes but also with the established
risk factors, as shown in Fig. 2. Genes, which are associated
with the traditional risk factors of CVD, can associate with CVD
Fig. 2. Schematic diagram of the complicated association between genes and
complex CVDs. MI, CHD, HF, and stroke were the principal CVD outcomes.
LDL, SBP, BMI, and so on are the traditional risk factors of CVD outcomes. MI
indicates myocardial infarction; CHD, coronary heart disease; HF, heart failure;
LDL, low-density lipoprotein cholesterol; SBP, systolic blood pressure; BMI,
body mass index.
indirectly and make a contribution to predicting the incidence
of CVD events. Therefore, studies on the genetic risk prediction
would aim at the genes that are associated with both CVD
outcomes and CVD traits.
III. GWAS FOR CVD OUTCOMES/TRAITS
For complex diseases, associated genetic variants will refer
to hundreds or thousands of single-nucleotide polymorphisms
(SNPs), which are distributed in large regions with a particular
locus on different chromosomes. GWASs are adept in detect-
ing these genetic variants. In recent years, methods and related
instruments for SNPs genotyping have been rapidly developed.
Traditional methods include restriction fragment length poly-
morphism, single-strand conformation polymorphism, and so
on. They all need lengthy digestion and electrophoresis oper-
ation. Traditional methods are hard to apply on a large-scale
population and multiple SNPs, so they would slow down re-
search. More advanced technologies are therefore being de-
veloped. An excellent method for SNP genotyping should be
high-throughput, low-cost, robust, automated, easily developed,
accurate analysis of high volume data, simple operation, and so
on. It is definitely difficult to combine all of these attributes into
a single technology. There are some researchers that have de-
voted efforts to summarizing genotyping methods [18], [19]. To
date, the Illumina’s Infinium Beadchips, Affymetrix GeneChip
Human Mapping arrays, Perlegen Genotyping Platform, Invader
assays are the most widely used platforms suitable for GWAS,
which are listed in Table I. It is hoped that studies on CVD risk
prediction using genetic information will be continued using
current technology or more advanced technology that might be
developed in the future.
PU et al.: INVESTIGATION ON CARDIOVASCULAR RISK PREDICTION USING GENETIC INFORMATION
TABLE I
LIST OF SOME SNP GENOTYPING TECHNOLOGIES
Many GWAS have had initial success in discovering genes
that are associated with diseases, of which a significant frac-
tion is CVD outcomes/traits. In the Framingham Heart Study,
CVD is defined as a composite of coronary heart disease (CHD),
cerebrovascular events, peripheral artery disease, and heart fail-
ure (HF) [28]. The studies, which include cohort studies and
case-control studies, will all be introduced in detail on the genes
that are associated with CHD, MI, stroke, HF, and other CVD
outcomes/traits.
A. CHD and MI
There are regional studies indicating that more than 50% of
all cardiovascular outcomes are CHD in patients <75 years of
age [29], and a 49% lifetime risk for male and 32% for female
of developing CHD in the ones >40 years of age [30]. As one of
the serious results induced by CHD, MI has caused numerous
deaths in different countries. Therefore, predicting them in their
early periods and then taking interventions to reduce the acute
events or even avoid the events will make significant significance
to the society.
Genes, which are found to explain CHD and MI accurately,
can be useful for disease prediction, prevention, and therapy.
Gene detection for CHD and MI could help health professionals
identify disease risk and allow them to prepare for prevention.
Gene detection could also help doctors evaluate the risk, diag-
nose the etiology, and assist in preparing dose administration to
avoid acute events in their patients.
Recent GWAS have discovered that some genes have an as-
sociation with CHD and MI (as shown in Table II). In addition,
there are lots of variants in the GWAS for CHD; in order to avoid
tedious listing, OR > 1.2 and allele frequency (AF) in controls
>5% are chosen in some listed studies [31]–[34]. More detailed
information can be obtained from the references. All effects
were evaluated with the odds ratio (OR) and corresponding 95%
CIs, and it was shown that nine SNPs were associated with CHD
and 11 SNPs were associated with MI. From the outcomes of the
case-control studies, it could be obtained that four of the 20 SNPs
were all on the chromosome 9p21.3. These were rs1333049-C
(OR 1.36, 95% CI 1.27–1.46) [35] and rs1333049-C (OR 1.47,
95% CI 1.27–1.70) [36] with CHD, and rs4977574-G (OR 1.29,
95% CI 1.25–1.34) [34] and rs10757278-G (OR 1.28, 95% CI
1.22–1.35) with MI [37]. Therefore, there were more and more
797
studies focused on genes on chromosome 9p21.3 not just for
predicting CHD and MI, but also for other CVD outcomes.
B. Stroke
Stroke is a kind of severe disease which has been one of the
most frequent diseases that can cause sudden deaths. Even if
the unattended patients attacked stroke and survived, a great or
small part of the heart will still be always affected, and work of
heart involvement and the possibility of chronic HF will be pro-
duced. Moreover, arrhythmias will be caused. In China, there
were epidemiological studies that confirmed that stroke, which
has a fivefold higher incidence than that of MI, is the second
commonest cause of death [40]. Thus, stroke prediction using
genetic information has been developed and attracted increasing
attention. The identification of the underlying genes associated
with stroke may contribute to risk assessment and measurement
for CVD prevention and treatment. Table III lists the loci asso-
ciated with stroke.
There was an exciting GWAS cohort study that had a haz-
ard ratio of 1.29 [95% CI 1.19–1.41] [43]. Matarin et al. [44]
(not shown in Table III) found that rs7506045 (on chromosome
18p11.21, P = 7 × 10−7 ) was closely associated with stroke.
The effect size of OR reached 5.39 [95% CI 2.77–10.5], and its
risk AF in controls was 0.1. The excellent OR value should at-
tract more groups to study this SNP. In addition to technological
limitations, stroke has many different categories which make it
difficult to determine responsible genes ultimately.
C. HF
There are other severe cardiovascular outcomes, such as HF,
a kind of common disease, which can cause leg swelling, short-
ness of breath, and the other severe symptoms. There is a sta-
tistical data in developed countries which indicated that the rate
suffered from HF can reach around 2% of adults and even 6–
10% in the ones > 65 years of age [45], [46]. Certainly, HF can
be led by other diseases, such as rheumatic heart disease, anemic
heart disease, and toxic heart disease. In this paper, we did not
take into account these different causes. The events of HF attack
are all taken as CVD outcomes. It is not contrary to the definition
of CVD in the Framingham Heart Study [28]. If the genes asso-
ciated with these outcomes are discovered, the prediction model
would be greatly improved. As shown in Table IV, it was one co-
hort study developed by Smith et al. [47]. Rs10519210 on chro-
mosome 15q22.31 and rs11172782 on chromosome 12q14.1
were discovered to be associated with HF to some extent.
D. Risk Factors
Cardiovascular risk factors, which are traits or characteristics,
can help predict the risk of developing CVD in the monitored
objects. By now, some risk factors have been discovered to be
closely associated with CVD and so are excellent factors for
CVD risk prediction. The different degrees of the risk factors
make up the risk score. The greater risk score (i.e., severer risk
factors) predicts the higher risk of developing CVD. There-
fore, the work, which focused on discovering new risk factors
798 IEEE TRANSACTIONS ON INFORMATION TECHNOLOGY IN BIOMEDICINE, VOL. 16, NO. 5, SEPTEMBER 2012

TABLE II
LOCI ASSOCIATED WITH CHD AND MI FROM GWAS

TABLE III
LOCI ASSOCIATED WITH STROKE FROM GWAS

TABLE IV
LOCI ASSOCIATED WITH HEART FAILURE FROM GWAS

and studying the other factors that are associated with the tra-
ditional risk factors, developed in abundance rapidly. However,
the unknown biological mechanisms of complex CVD may play
an important role in CVD prediction by affecting the signifi-
cance of the CVD risk factors. Many studies have therefore been
developed.
There were many SNPs that have been discovered to be as-
sociated with other risk factors of CVD (eight SNPs have been
replicated for systolic blood pressure [43], [44]; five SNPs for
hypertension [48]–[50]; 14 SNPs for total cholesterol [51], [52];
56 SNPs for HDL cholesterol [50], [51], [53]–[59]; 59 SNPs for
LDL cholesterol [50]–[52], [53], [55], [56], [59], [60]–[64]; 60
SNPs for BMI [15], [65]–[72], one SNP for nicotine depen-
dence [73]; 90 SNPs for Type 2 Diabetes [74]–[96]; 37 SNPs
for C-reactive protein levels [97]–[102], etc.)
Although so many SNPs have been discovered to be associ-
ated with CVD outcomes/traits, the complete allelic architecture
of CVD still requires much study, especially long-term clinical
trials. However, these initial studies pave the way to genetic
CVD risk prediction. Many studies have had partial success
when attempting to use genetic variants as one of the informa-
tive tool for CVD prediction without knowing the mechanism.
IV. INITIAL STUDIES ON CVD RISK PREDICTION USING
GENETIC INFORMATION
As humans have genetic information linked to different dis-
eases, more studies should be developed to determine the value
in building individual CVD risk prediction models that incor-
porate genetic markers from individuals. A new genetic marker
PU et al.: INVESTIGATION ON CARDIOVASCULAR RISK PREDICTION USING GENETIC INFORMATION
should have important features when added into the prediction
model as a risk factor.
First, to make the clinical trial be more significant and the
experiment data more reliable, the sample population should be
in large size. Moreover, the cohort study should be followed up
for years in order to gain CVD events in sufficient quantity.
Second, the effect size of a new independent risk factor should
be evaluated through the traditional risk model (which is more
well founded, such as the atherosclerosis risk in communities
(ARIC) cardiovascular risk score, Framingham risk score) co-
operated with the established risk factors. Otherwise, the effect
size of the same risk factor can be different between when it is
taken as the only factor and as one of the risk factors that induced
one kind of disease, i.e., in univariate analysis and multivariate
analysis, so it will be hard to evaluate the effect size correctly
and objectively.
Third, it should have a positive effect on the metrics (risk dis-
crimination, calibration, risk reclassification, and clinical util-
ity). Discrimination is the cognitive and sensory ability to distin-
guish the ones who will suffer from disease from those who will
not. A practical way to ascertain discrimination is to observe the
area under the receiver operator curve (AUC). Perfect candidate
predictors will have AUC = 1.00, and those with no predictive
ability will have AUC = 0.5. Calibration of a risk model directly
determines the agreement between predicted and observed risk
across subgroups with different rank of the disease. Hosmer–
Lemeshow statistic is a metric for calibration commonly. Re-
classify estimates whether the addition of a novel marker im-
proves the risk classification of individuals or not. Proportion
reclassified and net reclassification improvement (NRI) are two
kinds of metrics for assessing the reclassification. Finally, the
other criterion is the clinical significance of the genetic informa-
tion. It should have consistent effects across diverse populations
when incorporating genetic information into the risk predic-
tion model, i.e., the heterogeneity of the study-specific effects
should be measured. A measure of it is I 2 metric (“inconsis-
tency”), whose values range from 0 to 100% and can be used
to assess the extent of heterogeneity beyond chance. Therefore,
large studies and meta-analyses are prerequisites across differ-
ent populations in the search for a new genetic marker for risk
prediction.
Several efforts devoted to reviewing CVD prediction using
genetic information have been published already (such as [103]
and [104]). Table V shows a simple list of several studies on
evaluating the genetic prediction power of single or multiple
SNPs from current publications. Although it is a pity that all the
studies did not assess the I 2 metric, all studies have chosen large
sample sizes to collect relatively credible experimental data. In
the previous studies, even for the SNP (rs10757274) that has
been repeatedly discovered to be strongly associated with CVD,
their clinical utility for CVD prediction is minimal [105]–[107].
As CVD is a complex disease, many studies included multiple
SNPs in the prediction model and only obtained results that were
not clinically useful, and the most genetic variants have been just
successfully used for the reclassification of CVD risk. Recently,
a cheerful study has discovered that the genetic variants perform
a positive effect on CVD risk prediction significantly [108]. In
799
their study, the genetic variants chosen are all associated with
type-2 diabetes mellitus. Even in nondiabetic individuals, the
one with higher number of alleles associated with higher CVD
incidence (including overall mortality).
V. CHALLENGES IN ADDING GENETIC INTO CVD RISK
PREDICTION
With the aforementioned combination of outcomes, several
studies shown that it is likely to have the potential that adding
genetic variants into CVD risk prediction can do improve the
performance of the risk prediction model, and there was a study
to prove the clinical utility of the genetic variants in the CVD
risk prediction. We expected more and better performance of
the genetic risk prediction in the near future, especially on de-
veloping individual CVD risk prediction. It will still be hard to
carry out because it needs abundant studies with clinical trials
to prove it. With the requirement of long-time follow-up and
large-size samples in the trials, there are many challenges that
exist.
First, there are a large number of genes that have or will be
discovered to associate with complex disease (see Fig. 2). The
established risk factors have been explained half of the CVD risk
and included the most part of important risk factors for CVD,
adding that only one or a few genetic variants will be hard to
improve the performance of the traditional prediction model.
Owing to the complexity of CVD, it is only possible to explain
it with multiple genes. There is a simulation on how the number
of genes with constant OR influence discriminative accuracy
of genetic profiling for predicting complex diseases (Fig. 3).
By now, a majority of the GWAS have shown the value of
OR < 1.5. So, the potential genetic risk factor should be made
up of hundreds of genetic variants when AUC > 0.85. Many
of these genetic variants require much effort and time to seek
the gene group that explains CVD disease exactly. Therefore,
the cost was an obstacle for lots of groups, especially when
genotyping methods of SNPs needed to have high flux, high
accuracy, adapted sensitivity, and high specificity. Information
about family history, on the other hand, can be collected simply,
quickly, and cheaply. The genetic variants are easily replaced
by family history in many follow-up studies just because of the
high cost—especially, there are other obstacles.
Second, different races, lifestyles, and living environments
could induce these genetic variants to be differently explained.
Many genes were detected in the subject’s body, but they did
not explain the disease because of the special lifestyles and liv-
ing environment. Some GWAS enrolled extreme subjects with
and control subjects without a family history of CVD to iden-
tify some genetic associations more clearly. Other problems
occurred in some GWAS, for example, too more subjects died
or lost before the follow-up finished. All the phenomena would
influence the experimental results and induce attenuated effect
size in the further replication with larger sample sizes.
Third, it takes too much time to genotype SNP and collect
useful information for evaluating the merits of genetic CVD risk
prediction for clinical use. Although case-control studies would
only require a relatively short time to research the association
800 IEEE TRANSACTIONS ON INFORMATION TECHNOLOGY IN BIOMEDICINE, VOL. 16, NO. 5, SEPTEMBER 2012
TABLE V
GWAS RESEARCH ON THE CVD RISK PREDICTION USING GENETIC INFORMATION
Fig. 3. Discriminative accuracy of genetic profiling (Constant OR in each
simulation). OR indicates odds ratio; AUC, area under the receiver-operating
characteristic curve. In each simulation, all the genes were assumed to have
equal ORs with disease prevalence of 10% and AF of 10% for all risk alleles.
Reprinted with permission from Janssens et al. [118], Copyright 2006 Nature
Publishing Group.
between genetic variants and CVD, the association should be
further evaluated by follow-up studies. However, to the asymp-
tomatic people, waiting for a certain amount of outcomes/traits
to make the study significant will spend years or even longer.
Moreover, most GWAS used OR to evaluate the effect size
of some genetic risk factors, which can overestimate the true
risk ratio, because CVD is not a kind of rare disease [119].
When combined the results of several independent studies,
meta-analysis usually used fixed effect model. However, once
heterogeneity between studies is present, the significance of
the results might be doubted and should be estimated further;
lots of cases induce missing heritability, such as gene–gene in-
teractions, gene–environment interactions, imprecision of the
genotyping approaches, allelic architecture of complex traits,
variants of low minor AF (MAF) (0.5% < MAF < 5%), or of
rare variants (MAF < 0.5%) [120].
Owing to the high costs of the studies as well as other factors,
too few clinical trials were undertaken, meaning that insuffi-
cient experimental data were obtained for genetic CVD risk
prediction.
VI. CONCLUSION
The epidemic of CVD has caused huge losses and caught
the attention of society. It is imperative to predict the risk CVD
individually in its early phase and take appropriate intervention
to prevent the occurrence of acute events. Genes will be gen-
erally stable in human body for quite a long time after birth,
so gene detection will play an important role in predicting and
preventing all kinds of diseases (including CVD), as well as
in extending and improving human life. Based on advanced
PU et al.: INVESTIGATION ON CARDIOVASCULAR RISK PREDICTION USING GENETIC INFORMATION
technology, gene discoveries have been developed rapidly and
found lots of useful genetic variants associated with CVD out-
comes/traits. Furthermore, there is a study that has proved the
clinical utility of genetic risk prediction. However, more efforts
should still be made before integrating genetic information into
CVD risk prediction model clinically, because the genes that
can fully explain complex CVD have not yet been identified. In
the future studies, there are some strategies that might acceler-
ate the pieces of research, such as increasing the size of sample
and expanding the sample regions, improving the precision of
genotyping methods, choosing appropriate “effect model” in
the meta-analysis, sharing data with protections for consent,
and privacy between different studies for large size of meta-
analysis or further replication if data are available. It will be a
very long process. Nevertheless, we are still looking forward
to more discoveries in the area of genetic CVD risk prediction,
and we are excited about more clinical utility of using genetic
information in CVD prediction models.
ACKNOWLEDGMENT
The authors would like to thank the associate editor and all
reviewers for their careful reading of the paper and their valu-
able suggestions. The authors are grateful to Value Platforms
Ltd., PCCW Ltd., and NovoCare Technology Company, Ltd.,
Beijing, for their supports to the ITF projects. The authors are
also thankful to Dr. E. MacPherson for her assistance in revising
the paper.
REFERENCES
[1] R. Beaglehole and R. Bonita, “Global public health: A scorecard,”
Lancet, vol. 372, no. 9654, pp. 1988–1996, 2008.
[2] C. D. Mathers and D. Loncar, “Projections of global mortality and burden
of disease from 2002 to 2030,” PLoS Med., vol. 3, no. 11, pp. 2011–2030,
2006.
[3] WHO, World Health Statistics 2007—Part 1: Ten Statistical Highlights
in Global Public Health. Geneva, Switzerland: World Health Organi-
zation, 2007, pp. 10–20.
[4] M. Naghavi, P. Libby, E. Falk, S. W. Casscells, S. Litovsky, J. Rumberger,
J. J. Badimon, C. Stefanadis, P. Moreno, G. Pasterkamp, Z. Fayad, P. H.
Stone, S. Waxman, P. Raggi, M. Madjid, A. Zarrabi, A. Burke, C. Yuan,
P. J. Fitzgerald, D. S. Siscovick, C. L. De Korte, M. Aikawa, K. E.
J. Airaksinen, G. Assmann, C. R. Becker, J. H. Chesebro, A. Farb, Z.
S. Galis, C. Jackson, I. K. Jang, W. Koenig, R. A. Lodder, K. March, J.
Demirovic, M. Navab, S. G. Priori, M. D. Rekhter, R. Bahr, S. M. Grundy,
R. Mehran, A. Colombo, E. Boerwinkle, C. Ballantyne, W. Insull, R. S.
Schwartz, R. Vogel, P. W. Serruys, G. K. Hansson, D. P. Faxon, S. Kaul, H.
Drexler, P. Greenland, J. E. Muller, R. Virmani, P. M. Ridker, D. P. Zipes,
P. K. Shah, and J. T. Willerson, “From vulnerable plaque to vulnerable
patient—A call for new definitions and risk assessment strategies: Part
I,” Circ. Cardiovasc. Genet., vol. 108, no. 14, pp. 1664–1672, 2003.
[5] P. W. Wilson, R. B. D’agostino, D. Levy, A. M. Belanger, H. Silbershatz,
and W. B. Kannel, “Prediction of coronary heart disease using risk factor
categories,” Circ. Cardiovasc. Genet., vol. 97, no. 18, pp. 1837–1847,
1998.
[6] A. J. Jehle, “Third report of the national cholesterol education program
(NCEP) expert panel on detection, evaluation, and treatment of high
blood cholesterol in adults (Adult Treatment Panel III) final report,”
Circulation, vol. 106, no. 25, pp. 3143–3421, 2002.
[7] R. M. Conroy, K. Pyorala, A. P. Fitzgerald, S. Sans, A. Menotti, G. De
Backer, D. De Bacquer, P. Ducimetiere, P. Jousilahti, U. Keil, I. Njolstad,
R. G. Oganov, T. Thomsen, H. Tunstall-Pedoe, A. Tverdal, H. Wedel,
P. Whincup, L. Wilhelmsen, I. M. Graham, and SCORE Project Grp,
“Estimation of ten-year risk of fatal cardiovascular disease in Europe:
The SCORE project,” Eur. Heart J., vol. 24, no. 11, pp. 987–1003, 2003.
801
[8] G. Assmann, P. Cullen, and H. Schulte, “Simple scoring scheme for
calculating the risk of acute coronary events based on the 10-year follow-
up of the prospective cardiovascular Munster (PROCAM) study,” Circ.
Cardiovasc. Genet., vol. 105, no. 3, pp. 310–315, 2002.
[9] J. Hippisley-Cox, C. Coupland, Y. Vinogradova, J. Robson, M. May, and
P. Brindle, “Derivation and validation of QRISK, a new cardiovascular
disease risk score for the United Kingdom: Prospective open cohort
study,” Brit. Med. J., vol. 335, no. 7611, pp. 136–141, 2007.
[10] Y. Wu, X. Liu, X. Li, Y. Li, L. Zhao, Z. Chen, X. Rao, B. Zhou, R.
Detrano, K. Liu, USA-PRC Collaborative Study of Cardiovascular and
Cardiopulmonary Epidemiology Research Group, and China Multicenter
Collaborative Study of Cardiovascular Epidemiology Research Group,
“Estimation of 10-year risk of fatal and nonfatal ischemic cardiovascular
diseases in Chinese adults,” Circulation, vol. 114, no. 21, pp. 2217–2225,
2006.
[11] Y. Friedlander, D. S. Siscovick, S. Weinmann, M. A. Austin, B. M. Psaty,
R. N. Lemaitre, P. Arbogast, T. E. Raghunathan, and L. A. Cobb, “Family
history as a risk factor for primary cardiac arrest,” Circulation, vol. 97,
no. 2, pp. 155–160, 1998.
[12] M. Fischer, U. Broeckel, S. Holmer, A. Baessler, C. Hengstenberg,
B. Mayer, J. Erdmann, G. Klein, G. Riegger, H. J. Jacob, and H. Schun-
kert, “Distinct heritable patterns of angiographic coronary artery dis-
ease in families with myocardial infarction,” Circ. Cardiovasc. Genet.,
vol. 111, no. 7, pp. 855–862, 2005.
[13] J. J. Nora, R. H. Lortscher, R. D. Spangler, A. H. Nora, and W. J. Kim-
berling, “Genetic–epidemiologic study of early-onset ischemic heart dis-
ease,” Circ. Cardiovasc. Genet., vol. 61, no. 3, pp. 503–508, 1980.
[14] L. Ma, J. Yang, H. B. Runesha, T. Tanaka, L. Ferrucci, S. Bandinelli,
and Y. Da, “Genome-wide association analysis of total cholesterol and
high-density lipoprotein cholesterol levels using the Framingham heart
study data,” BMC Med. Genet., vol. 11, Art. no. 55, 2010.
[15] C. S. Fox, N. Heard-Costa, L. A. Cupples, J. Dupuis, R. S. Vasan, and
L. D. Atwood, “Genome-wide association to body mass index and waist
circumference: The Framingham Heart Study 100K project,” BMC Med.
Genet., vol. 8, no. Suppl 1, Art. no. S18, 2007.
[16] D. Levy, M. G. Larson, E. J. Benjamin, C. Newton-Cheh, T. J. Wang,
S. J. Hwang, R. S. Vasan, and G. F. Mitchell, “Framingham Heart Study
100K Project: Genome-wide associations for blood pressure and arterial
stiffness,” BMC Med. Genet., vol. 8, no. Suppl 1, Art. no. S3, 2007.
[17] L. A. Hindorff, J. MacArthur, A. Wise, H. A. Junkins, P.
N. Hall, A. K. Klemm, and T. A. Manolio, (2011). A catalog
of published genome-wide association studies [Online]. Available:
http://www.genome.gov/GWAStudies.
[18] P. Y. Kwok, “Methods for genotyping single nucleotide polymorphisms,”
Annu. Rev. Genom. Hum. Genet., vol. 2, pp. 235–258, 2001.
[19] J. Ragoussis, “Genotyping technologies for genetic research,” Annu.
Rev. Genom. Hum. Genet., vol. 10, pp. 117–133, 2009.
[20] K. L. Gunderson, F. J. Steemers, G. Lee, L. G. Mendoza, and M. S. Chee,
“A genome-wide scalable SNP genotyping assay using microarray tech-
nology,” Nature Genet., vol. 37, pp. 549–554, 2005.
[21] F. J. Steemers, W. Chang, G. Lee, D. L. Barker, R. Shen, and K. L.
Gunderson, “Whole-genome genotyping with the single-base extension
assay,” Nature Methods, vol. 3, no. 1, pp. 31–33, 2006.
[22] D. G. Wang, J. B. Fan, C. J. Siao, A. Berno, P. Young, R. Sapolsky, G.
Ghandour, N. Perkins, E. Winchester, J. Spencer, L. Kruglyak, L. Stein,
L. Hsie, T. Topaloglou, E. Hubbell, E. Robinson, M. Mittmann, M. S.
Morris, N. Shen, D. Kilburn, J. Rioux, C. Nusbaum, S. Rozen, T. J.
Hudson, R. Lipshutz, M. Chee, and E. S. Lander, “Large-scale identifi-
cation, mapping, and genotyping of single-nucleotide polymorphisms in
the human genome,” Science, vol. 280, no. 5366, pp. 1077–1082, 1998.
[23] H. Matsuzaki, S. Dong, H. Loi, X. Di, G. Liu, E. Hubbell, J. Law, T.
Berntsen, M. Chadha, H. Hui, G. Yang, G. C. Kennedy, T. A. Webster, S.
Cawley, P. S. Walsh, K. W. Jones, S. P. Fodor, and R. Mei, “Genotyping
over 100000 SNPs on a pair of oligonucleotide arrays,” Nature Methods,
vol. 1, no. 2, pp. 109–111, 2004.
[24] N. Patil, A. J. Berno, D. A. Hinds, W. A. Barrett, J. M. Doshi,
C. R. Hacker, C. R. Kautzer, D. H. Lee, C. Marjoribanks, D. P. Mc-
donough, B. T. Nguyen, M. C. Norris, J. B. Sheehan, N. Shen, D. Stern,
R. P. Stokowski, D. J. Thomas, M. O. Trulson, K. R. Vyas, K. A. Frazer,
S. P. Fodor, and D. R. Cox, “Blocks of limited haplotype diversity re-
vealed by high-resolution scanning of human chromosome 21,” Science,
vol. 294, no. 5547, pp. 1719–1723, 2001.
[25] D. A. Hinds, R. P. Stokowski, N. Patil, K. Konvicka, D. Kershenobich, D.
R. Cox, and D. G. Ballinger, “Matching strategies for genetic association
studies in structured populations,” Amer. J. Hum. Genet., vol. 74, no. 2,
pp. 317–325, 2004.
802 IEEE TRANSACTIONS ON INFORMATION TECHNOLOGY IN BIOMEDICINE, VOL. 16, NO. 5, SEPTEMBER 2012
[26] V. Lyamichev, A. L. Mast, J. G. Hall, J. R. Prudent, M. W. Kaiser,
T. Takova, R. W. Kwiatkowski, T. J. Sander, M. De Arruda, D. A. Arco,
B. P. Neri, and M. A. Brow, “Polymorphism identification and quantita-
tive detection of genomic DNA by invasive cleavage of oligonucleotide
probes,” Nature Biotechnol., vol. 17, no. 3, pp. 292–296, 1999.
[27] T. M. Hsu, S. M. Law, S. Duan, B. P. Neri, and P. Y. Kwok, “Geno-
typing single-nucleotide polymorphisms by the invader assay with dual-
color fluorescence polarization detection,” Clin. Chem., vol. 47, no. 8,
pp. 1373–1377, 2001.
[28] R. B. Sr D’agostino, R. S. Vasan, M. J. Pencina, P. A. Wolf, M. Cobain,
J. M. Massaro, and W. B. Kannel, “General cardiovascular risk profile
for use in primary care: The Framingham Heart Study,” Circulation, vol.
117, no. 6, pp. 743–753, 2008.
[29] V. Fuster, R. W. Alexander, and R. A. O’Rourke, Hurst’s the Heart, 10th
ed. New York: McGraw-Hill, 2001, part 6.
[30] D. M. Lloyd-Jones, M. G. Larson, A. Beiser, and D. Levy, “Lifetime
risk of developing coronary heart disease,” Lancet, vol. 353, no. 9147,
pp. 89–92, 1999.
[31] P. S. Wild, T. Zeller, A. Schillert, S. Szymczak, C. R. Sinning, A. Deis-
eroth, R. B. Schnabel, E. Lubos, T. Keller, M. S. Eleftheriadis, C. Bickel,
H. J. Rupprecht, S. Wilde, H. Rossmann, P. Diemert, L. A. Cupples, C.
Perret, J. Erdmann, K. Stark, M. E. Kleber, S. E. Epstein, B. F. Voight,
K. Kuulaasma, M. Li, A. S. Schafer, N. Klopp, P. S. Braund, H. B. Sager,
S. Demissie, C. Proust, I. R. Konig, H. E. Wichmann, W. Reinhard, M.
M. Hoffmann, J. Virtamo, M. S. Burnett, D. Siscovick, P. G. Wiklund, L.
Qu, N. E. El Mokthari, J. R. Thompson, A. Peters, A. V. Smith, E. Yon,
J. Baumert, C. Hengstenberg, W. Marz, P. Amouyel, J. Devaney, S. M.
Schwartz, O. Saarela, N. N. Mehta, D. Rubin, K. Silander, A. S. Hall, J.
Ferrieres, T. B. Harris, O. Melander, F. Kee, H. Hakonarson, J. Schrezen-
meir, V. Gudnason, R. Elosua, D. Arveiler, A. Evans, D. J. Rader, T. Illig,
S. Schreiber, J. C. Bis, D. Altshuler, M. Kavousi, J. C. Witteman, A. G.
Uitterlinden, A. Hofman, A. R. Folsom, M. Barbalic, E. Boerwinkle, S.
Kathiresan,M. P. Reilly, C. J. O’donnell, N. J. Samani, H. Schunkert, F.
Cambien, K. J. Lackner, L. Tiret, V. Salomaa, T. Munzel, A. Ziegler,
and S. Blankenberg, “A genome-wide association study identifies LIPA
as a susceptibility gene for coronary artery disease,” Circ. Cardiovasc.
Genet., vol. 4, no. 4, pp. 403–412, 2011.
[32] H. Schunkert, I. R. Konig, S. Kathiresan, M. P. Reilly, T. L. Assimes,
H. Holm, M. Preuss, A. F. Stewart, M. Barbalic, C. Gieger, D. Absher,
Z. Aherrahrou, H. Allayee, D. Altshuler, S. S. Anand, K. Andersen, J.
L. Anderson, D. Ardissino, S. G. Ball, A. J. Balmforth, T. A. Barnes,
D. M. Becker, L. C. Becker, K. Berger, J. C. Bis, S. M. Boekholdt, E.
Boerwinkle, P. S. Braund, M. J. Brown, M. S. Burnett, I. Buysschaert, J.
F. Carlquist, L. Chen, S. Cichon, V. Codd, R. W. Davies, G. Dedoussis, A.
Dehghan, S. Demissie, J. M. Devaney, P. Diemert, R. Do, A. Doering, S.
Eifert, N. E. Mokhtari, S. G. Ellis, R. Elosua, J. C. Engert, S. E. Epstein,
U. De Faire, M. Fischer, A. R. Folsom, J. Freyer, B. Gigante, D. Girelli,
S. Gretarsdottir, V. Gudnason, J. R. Gulcher, E. Halperin, N. Hammond,
S. L. Hazen, A. Hofman, B. D. Horne, T. Illig, C. Iribarren, G. T. Jones,
J. W. Jukema, M. A. Kaiser, L. M. Kaplan, J. J. Kastelein, K. T. Khaw,
J. W. Knowles, G. Kolovou, A. Kong, R. Laaksonen, D. Lambrechts, K.
Leander, G. Lettre, M. Li, W. Lieb, C. Loley, A. J. Lotery, P. M. Mannucci,
S. Maouche, N. Martinelli, P. P. Mckeown, C. Meisinger, T. Meitinger,
O. Melander, P. A. Merlini, V. Mooser, T. Morgan, T. W. Muhleisen, J. B.
Muhlestein, T. Munzel, K. Musunuru, J. Nahrstaedt, C. P. Nelson, M. M.
Nothen, O. Olivieri, R. S. Patel, C. C. Patterson, A. Peters, F. Peyvandi, L.
Qu, A. A. Quyyumi, D. J. Rader, L. S. Rallidis, C. Rice, F. R. Rosendaal,
D. Rubin, V. Salomaa, M. L. Sampietro, M. S. Sandhu, E. Schadt, A.
Schafer, A. Schillert, S. Schreiber, J. Schrezenmeir, S. M. Schwartz, D. S.
Siscovick, M. Sivananthan, S. Sivapalaratnam, A. Smith, T. B. Smith, J.
D. Snoep, N. Soranzo, J. A. Spertus, K. Stark, K. Stirrups, M. Stoll, W. H.
Tang, S. Tennstedt, G. Thorgeirsson, G. Thorleifsson, M. Tomaszewski,
A. G. Uitterlinden, A. M. Van Rij, B. F. Voight, N. J. Wareham, G. A.
Wells, H. E. Wichmann, P. S. Wild, C. Willenborg, J. C. Witteman, B.
J. Wright, S. Ye, T. Zeller, A. Ziegler, F. Cambien, A. H. Goodall, L. A.
Cupples, T. Quertermous, W. Marz, C. Hengstenberg, S. Blankenberg, W.
H. Ouwehand, A. S. Hall, P. Deloukas, J. R. Thompson, K. Stefansson, R.
Roberts, U. Thorsteinsdottir, C. J. O’donnell, R. Mcpherson, J. Erdmann,
and N. J. Samani, “Large-scale association analysis identifies 13 new
susceptibility loci for coronary artery disease,” Nature Genet., vol. 43,
no. 4, pp. 333–338, 2011.
[33] J. F. Peden, J. C. Hopewell, D. Saleheen, J. C. Chambers, J. Hager,
N. Soranzo, R. Collins, J. Danesh, P. Elliott, M. Farrall, K. Stirrups,
W. Zhang, A. Hamsten, S. Parish, M. Lathrop, H. Watkins, R. Clarke,
P. Deloukas, J. S. Kooner, A. Goel, H. Ongen, R. J. Strawbridge, S.
Heath, A. Mälarstig, A. Helgadottir, J. Öhrvik, M. Murtaza, S. Potter,
S. E. Hunt, M. Delepine, S. Jalilzadeh, T. Axelsson, A. C. Syvanen, R.
Gwilliam, S. Bumpstead, E. Gray, S. Edkins, L. Folkersen, T. Kyriakou,
A. Franco-Cereceda, A. Gabrielsen, U. Seedorf, MuTHER Consortium,
P. Eriksson, A. Offer, L. Bowman, P. Sleight, J. Armitage, R. Peto, G.
Abecasis, N. Ahmed, M. Caulfield, P. Donnelly, P. Froguel, A. S. Kooner,
M. I. McCarthy, N. J. Samani, J. Scott, J. Sehmi, A. Silveira, M. L.
Hellénius, F. M. van’t Hooft, G. Olsson, S. Rust, G. Assman, S. Barlera,
G. Tognoni, M. G. Franzosi, P. Linksted, F. R. Green, A. Rasheed, M.
Zaidi, N. Shah, M. Samuel, N. H. Mallick, M. Azhar, K. S. Zaman, A.
Samad, M. Ishaq, A. R. Gardezi, M. Fazal-ur-Rehman, P. M. Frossard,
T. Spector, L. Peltonen, M. S. Nieminen, J. Sinisalo, V. Salomaa, S.
Ripatti, D. Bennett, K. Leander, B. Gigante, U. de Faire, S. Pietri, F.
Gori, R. Marchioli, S. Sivapalaratnam, J. J. Kastelein, M. D. Trip, E. V.
Theodoraki, G. V. Dedoussis, J. C. Engert, S. Yusuf, and S. S. Anand, “A
genome-wide association study in Europeans and South Asians identifies
five new loci for coronary artery disease,” Nature Genet., vol. 43, no. 4,
pp. 339–344, 2011.
[34] R. H. Hansen, “Advanced power management of a telehandler using
electronic load sensing,” presented at the 10th Int. Workshop Res. Educ.
Mechatronics, Glasgow, U.K., 2009.
[35] N. J. Samani, J. Erdmann, A. S. Hall, C. Hengstenberg, M. Mangino,
B. Mayer, R. J. Dixon, T. Meitinger, P. Braund, H. E. Wichmann, J.
H. Barrett, I. R. Konig, S. E. Stevens, S. Szymczak, D. A. Tregouet,
M. M. Iles, F. Pahlke, H. Pollard, W. Lieb, F. Cambien, M. Fischer, W.
Ouwehand, S. Blankenberg, A. J. Balmforth, A. Baessler, S. G. Ball, T.
M. Strom, I. Braenne, C. Gieger, P. Deloukas, M. D. Tobin, A. Ziegler,
J. R. Thompson, H. Schunkert, WTCC Consortium, and C. Consor-
tium, “Genomewide association analysis of coronary artery disease,”
New Engl. J. Med., vol. 357, no. 5, pp. 443–453, 2007.
[36] S. Henikoff, “ENCODE and our very busy genome,” Nature Genet.,
vol. 39, no. 7, pp. 817–818, 2007.
[37] A. Helgadottir, G. Thorleifsson, A. Manolescu, S. Gretarsdottir,
T. Blondal, A. Jonasdottir, A. Sigurdsson, A. Baker, A. Palsson, G.
Masson, D. Gudbjartsson, K. Magnusson, K. Andersen, A. Levey, V.
Backman, S. Matthiasdottir, T. Jonsdottir, S. Palsson, H. Einarsdottir,
S. Gunnarsdottir, A. Gylfason, V. Vaccarino, W. Hooper, M. Reilly,
C. Granger, H. Austin, D. Rader, S. Shah, A. Quyyumi, J. Gulcher,
G. Thorgeirsson, U. Thorsteinsdottir, A. Kong, and K. Stefansson, “A
common variant on chromosome 9p21 affects the risk of myocardial
infarction,” Science, vol. 316, no. 5830, pp. 1491–1493, 2007.
[38] D.-A. Trégouët, I. R. König, J. Erdmann, A. Munteanu, P. S. Braund,
A. S. Hall, A. Grohennig, P. Linsel-Nitschke, C. Perret, M. Desuremain,
T. Meitinger, B. J. Wright, M. Preuss, A. J. Balmforth, S. G. Ball, C.
Meisinger, C. Germain, A. Evans, D. Arveiler, G. Luc, J.-B. Ruidavets,
C. Morrison, P. V. D. Harst, S. Schreiber, K. Neureuther, A. Schäfer,
P. Bugert, N. E. E. Mokhtari, J. Schrezenmeir, K. Stark, D. Rubin, H.-
E. Wichmann, C. Hengstenberg, W. Ouwehand, WTCC. Consortium,
C. Consortium, A. Ziegler, L. Tiret, J. R. Thompson, F. Cambien, H.
Schunkert, and N. J. Samani, “Genome-wide haplotype association study
identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for
coronary artery disease,” Nature Genet., vol. 41, no. 3, pp. 283–285,
2009.
[39] M. P. Reilly, M. Li, J. He, J. F. Ferguson, I. M. Stylianou, N. N. Mehta, M.
S. Burnett, J. M. Devaney, C. W. Knouff, J. R. Thompson, B. D. Horne, A.
F. Stewart, T. L. Assimes, P. S. Wild, H. Allayee, P. L. Nitschke, R. S. Pa-
tel, MI-GEN Consortium, WTCC Consortium, N. Martinelli, D. Girelli,
A. A. Quyyumi, J. L. Anderson, J. Erdmann, A. S. Hall, H. Schunkert, T.
Quertermous, S. Blankenberg, S. L. Hazen, R. Roberts, S. Kathiresan, N.
J. Samani, S. E. Epstein, and D. J. Rader, “Identification of ADAMTS7
as a novel locus for coronary atherosclerosis and association of ABO
with myocardial infarction in the presence of coronary atherosclerosis:
Two genome-wide association studies,” Lancet, vol. 377, no. 9763, pp.
383–392, 2011.
[40] R. Bonita, S. Mendis, T. Truelsen, J. Bogousslavsky, J. Toole, and
F. Yatsu, “The global stroke initiative,” Lancet Neurol., vol. 3, no. 7,
pp. 391–393, 2004.
[41] M. A. Ikram, S. Seshadri, J. C. Bis, M. Fornage, A. L. Destefano, Y. S.
Aulchenko, S. Debette, T. Lumley, A. R. Folsom, E. G. Van Den Herik, M.
J. Bos, A. Beiser, M. Cushman, L. J. Launer, E. Shahar, M. Struchalin, Y.
Du, N. L. Glazer, W. D. Rosamond, F. Rivadeneira, M. Kelly-Hayes, O. L.
Lopez, J. Coresh, A. Hofman, C. Decarli, S. R. Heckbert, P. J. Koudstaal,
Q. Yang, N. L. Smith, C. S. Kase, K. Rice, T. Haritunians, G. Roks, P. L.
De Kort, K. D. Taylor, L. M. De Lau, B. A. Oostra, A. G. Uitterlinden, J.
I. Rotter, E. Boerwinkle, B. M. Psaty, T. H. Mosley, C. M. Van Duijn, M.
PU et al.: INVESTIGATION ON CARDIOVASCULAR RISK PREDICTION USING GENETIC INFORMATION
M. Breteler, W. T. Longstreth, and P. A. Wolf, “Genomewide association
studies of stroke,” New Engl. J. Med., vol. 360, no. 17, pp. 1718–1728,
2009.
[42] S. Gretarsdottir, G. Thorleifsson, A. Manolescu, U. Styrkarsdottir, A.
Helgadottir, A. Gschwendtner, K. Kostulas, G. Kuhlenbmangumer, S.
Bevan, T. Jonsdottir, H. Bjarnason, J. Saemundsdottir, S. Palsson, D.
Arnar, H. Holm, G. Thorgeirsson, E. Valdimarsson, S. Sveinbjmeirns-
dottir, C. Gieger, K. Berger, H. Wichmann, J. Hillert, H. Markus, J.
Gulcher, E. Ringelstein, A. Kong, M. Dichgans, D. Gudbjartsson, U.
Thorsteinsdottir, and K. Stefansson, “Risk variants for atrial fibrillation
on chromosome 4q25 associate with ischemic stroke,” Ann. Neurol.,
vol. 64, no. 4, pp. 402–409, 2008.
[43] J. Erdmann, C. Willenborg, J. Nahrstaedt, M. Preuss, I. R. Konig,
J. Baumert, P. Linsel-Nitschke, C. Gieger, S. Tennstedt, P. Belcredi,
Z. Aherrahrou, N. Klopp, C. Loley, K. Stark, C. Hengstenberg, P. Bruse,
J. Freyer, A. K. Wagner, A. Medack, W. Lieb, A. Grosshennig, H. B.
Sager, A. Reinhardt, A. Schafer, S. Schreiber, N. E. El Mokhtari, D.
Raaz-Schrauder, T. Illig, C. D. Garlichs, A. B. Ekici, A. Reis, J. Schrezen-
meir, D. Rubin, A. Ziegler, H. E. Wichmann, A. Doering, C. Meisinger,
T. Meitinger, A. Peters, and H. Schunkert, “Genome-wide association
study identifies a new locus for coronary artery disease on chromosome
10p11.23,” Eur. Heart J., vol. 32, no. 2, pp. 158–168, 2010.
[44] M. Matarin, W. M. Brown, S. Scholz, J. Simon-Sanchez, H. C. Fung,
D. Hernandez, J. R. Gibbs, F. W. De Vrieze, C. Crews, A. Britton, C.
D. Langefeld, T. G. Brott, R. D. Brown, Jr., B. B. Worrall, M. Frankel,
S. Silliman, L. D. Case, A. Singleton, J. A. Hardy, S. S. Rich, and J. F.
Meschia, “A genome-wide genotyping study in patients with ischaemic
stroke: Initial analysis and data release,” Lancet Neurol., vol. 6, no. 5,
pp. 414–420, 2007.
[45] J. J. Mcmurray and M. A. Pfeffer, “Heart failure,” Lancet, vol. 365,
no. 9474, pp. 1877–1889, 2005.
[46] K. Dickstein, A. Cohen-Solal, G. Filippatos, J. J. Mcmurray,
P. Ponikowski, P. A. Poole-Wilson, A. Stromberg, D. J. Van Veldhuisen,
D. Atar, A. W. Hoes, A. Keren, A. Mebazaa, M. Nieminen, S. G. Priori,
and K. Swedberg, “ESC guidelines for the diagnosis and treatment of
acute and chronic heart failure 2008: The Task Force for the diagnosis
and treatment of acute and chronic heart failure 2008 of the European
Society of Cardiology. Developed in collaboration with the Heart Failure
Association of the ESC (HFA) and endorsed by the European Society of
Intensive Care Medicine (ESICM),” Eur. J. Heart Fail., vol. 10, no. 10,
pp. 933–989, 2008.
[47] N. L. Smith, J. F. Felix, A. C. Morrison, S. Demissie, N. L. Glazer, L. R.
Loehr, L. A. Cupples, A. Dehghan, T. Lumley, W. D. Rosamond, W. Lieb,
F. Rivadeneira, J. C. Bis, A. R. Folsom, E. Benjamin, Y. S. Aulchenko,
T. Haritunians, D. Couper, J. Murabito, Y. A. Wang, B. H. Stricker, J.
S. Gottdiener, P. P. Chang, T. J. Wang, K. M. Rice, A. Hofman, S. R.
Heckbert, E. R. Fox, C. J. O’donnell, A. G. Uitterlinden, J. I. Rotter, J.
T. Willerson, D. Levy, C. M. Van Duijn, B. M. Psaty, J. C. Witteman,
E. Boerwinkle, and R. S. Vasan, “Association of genome-wide variation
with the risk of incident heart failure in adults of European and African
ancestry: A prospective meta-analysis from the cohorts for heart and
aging research in genomic epidemiology (CHARGE) consortium,” Circ.
Cardiovasc. Genet., vol. 3, no. 3, pp. 256–266, 2010.
[48] D. Levy, G. B. Ehret, K. Rice, G. C. Verwoert, L. J. Launer,
A. Dehghan, N. L. Glazer, A. C. Morrison, A. D. Johnson, T. Aspelund,
Y. Aulchenko, T. Lumley, A. Kottgen, R. S. Vasan, F. Rivadeneira, G.
Eiriksdottir, X. Guo, D. E. Arking, G. F. Mitchell, F. U. Mattace-Raso,
A. V. Smith, K. Taylor, R. B. Scharpf, S. J. Hwang, E. J. Sijbrands, J.
Bis, T. B. Harris, S. K. Ganesh, C. J. O’donnell, A. Hofman, J. I. Rotter,
J. Coresh, E. J. Benjamin, A. G. Uitterlinden, G. Heiss, C. S. Fox, J. C.
Witteman, E. Boerwinkle, T. J. Wang, V. Gudnason, M. G. Larson, A.
Chakravarti, B. M. Psaty, and C. M. Van Duijn, “Genome-wide associa-
tion study of blood pressure and hypertension,” Nature Genet., vol. 41,
no. 6, pp. 677–687, 2009.
[49] S. Padmanabhan, O. Melander, T. Johnson, A. M. Di Blasio, W. K. Lee,
D. Gentilini, C. E. Hastie, C. Menni, M. C. Monti, C. Delles, S. Laing,
B. Corso, G. Navis, A. J. Kwakernaak, P. Van Der Harst, M. Bochud, M.
Maillard, M. Burnier, T. Hedner, S. Kjeldsen, B. Wahlstrand, M. Sjogren,
C. Fava, M. Montagnana, E. Danese, O. Torffvit, B. Hedblad, H. Snieder,
J. M. Connell, M. Brown, N. J. Samani, M. Farrall, G. Cesana, G. Mancia,
S. Signorini, G. Grassi, S. Eyheramendy, H. E. Wichmann, M. Laan, D. P.
Strachan, P. Sever, D. C. Shields, A. Stanton, P. Vollenweider, A. Teumer,
H. Volzke, R. Rettig, C. Newton-Cheh, P. Arora, F. Zhang, N. Soranzo,
T. D. Spector, G. Lucas, S. Kathiresan, D. S. Siscovick, J. Luan, R. J.
Loos, N. J. Wareham, B. W. Penninx, I. M. Nolte, M. Mcbride, W. H.
803
Miller, S. A. Nicklin, A. H. Baker, D. Graham, R. A. Mcdonald, J. P.
Pell, N. Sattar, P. Welsh, P. Munroe, M. J. Caulfield, A. Zanchetti, and
A. F. Dominiczak, “Genome-wide association study of blood pressure
extremes identifies variant near UMOD associated with hypertension,”
PLoS Genet., vol. 6, no. 10, art no. e1001177, 2010.
[50] G. Lettre, C. D. Palmer, T. Young, K. G. Ejebe, H. Allayee, E. J. Ben-
jamin, F. Bennett, D. W. Bowden, A. Chakravarti, A. Dreisbach, D. N.
Farlow, A. R. Folsom, M. Fornage, T. Forrester, E. Fox, C. A. Haiman,
J. Hartiala, T. B. Harris, S. L. Hazen, S. R. Heckbert, B. E. Henderson,
J. N. Hirschhorn, B. J. Keating, S. B. Kritchevsky, E. Larkin, M. Li, M.
E. Rudock, C. A. Mckenzie, J. B. Meigs, Y. A. Meng, T. H. Mosley, A.
B. Newman, C. H. Newton-Cheh, D. N. Paltoo, G. J. Papanicolaou, N.
Patterson, W. S. Post, B. M. Psaty, A. N. Qasim, L. Qu, D. J. Rader,
S. Redline, M. P. Reilly, A. P. Reiner, S. S. Rich, J. I. Rotter, Y. Liu, P.
Shrader, D. S. Siscovick, W. H. Tang, H. A. Taylor, R. P. Tracy, R. S.
Vasan, K. M. Waters, R. Wilks, J. G. Wilson, R. R. Fabsitz, S. B. Gabriel,
S. Kathiresan, and E. Boerwinkle, “Genome-wide association study of
coronary heart disease and its risk factors in 8090 African Americans:
The NHLBI CARe Project,” PLoS Genet., vol. 7, no. 2, art no. e1001300,
2011.
[51] Y. S. Aulchenko, S. Ripatti, I. Lindqvist, D. Boomsma, I. M. Heid, P.
P. Pramstaller, B. W. Penninx, A. C. Janssens, J. F. Wilson, T. Spector,
N. G. Martin, N. L. Pedersen, K. O. Kyvik, J. Kaprio, A. Hofman, N.
B. Freimer, M. R. Jarvelin, U. Gyllensten, H. Campbell, I. Rudan, A.
Johansson, F. Marroni, C. Hayward, V. Vitart, I. Jonasson, C. Pattaro, A.
Wright, N. Hastie, I. Pichler, A. A. Hicks, M. Falchi, G. Willemsen, J. J.
Hottenga, E. J. De Geus, G. W. Montgomery, J. Whitfield, P. Magnusson,
J. Saharinen, M. Perola, K. Silander, A. Isaacs, E. J. Sijbrands, A. G.
Uitterlinden, J. C. Witteman, B. A. Oostra, P. Elliott, A. Ruokonen,
C. Sabatti, C. Gieger, T. Meitinger, F. Kronenberg, A. Doring, H. E.
Wichmann, J. H. Smit, M. I. Mccarthy, C. M. Van Duijn, L. Peltonen,
and ENGAGE Consortium, “Loci influencing lipid levels and coronary
heart disease risk in 16 European population cohorts,” Nature Genet.,
vol. 41, no. 1, pp. 47–55, 2009.
[52] H. Q. Shen, C. M. Damcott, E. Rampersaud, T. I. Pollin, R. B. Horenstein,
P. F. Mcardle, P. A. Peyser, L. F. Bielak, W. S. Post, Y. P. C. Chang,
K. A. Ryan, M. Miller, J. A. Rumberger, P. F. Sheedy, J. Shelton, J.
R. O’connell, A. R. Shuldiner, and B. D. Mitchell, “Familial defective
apolipoprotein B-100 and increased low-density lipoprotein cholesterol
and coronary artery calcification in the old order amish,” Arch. Intern.
Med., vol. 170, no. 20, pp. 1850–1855, 2010.
[53] D. M. Waterworth, S. L. Ricketts, K. Song, L. Chen, J. H. Zhao, S. Ripatti,
Y. S. Aulchenko, W. Zhang, X. Yuan, N. Lim, J. Luan, S. Ashford,
E. Wheeler, E. H. Young, D. Hadley, J. R. Thompson, P. S. Braund,
T. Johnson, M. Struchalin, I. Surakka, R. Luben, K. T. Khaw, S. A.
Rodwell, R. J. Loos, S. M. Boekholdt, M. Inouye, P. Deloukas, P. Elliott,
D. Schlessinger, S. Sanna, A. Scuteri, A. Jackson, K. L. Mohlke, J.
Tuomilehto, R. Roberts, A. Stewart, Y. A. Kesaniemi, R. W. Mahley, S.
M. Grundy, WTCC Consortium, W. Mcardle, L. Cardon, G. Waeber, P.
Vollenweider, J. C. Chambers, M. Boehnke, G. R. Abecasis, V. Salomaa,
M. R. Jarvelin, A. Ruokonen, I. Barroso, S. E. Epstein, H. H. Hakonarson,
D. J. Rader, M. P. Reilly, J. C. Witteman, A. S. Hall, N. J. Samani, D.
P. Strachan, P. Barter, C. M. Van Duijn, J. S. Kooner, L. Peltonen, N. J.
Wareham, R. Mcpherson, V. Mooser, and M. S. Sandhu, “Genetic variants
influencing circulating lipid levels and risk of coronary artery disease,”
Arterioscler. Thromb. Vasc. Biol., vol. 30, no. 11, pp. 2264–2276, 2010.
[54] P. M. Ridker, G. Pare, A. N. Parker, R. Y. Zee, J. P. Miletich, and
D. I. Chasman, “Polymorphism in the CETP gene region, HDL choles-
terol, and risk of future myocardial infarction: Genomewide analysis
among 18 245 initially healthy women from the Women’s Genome Health
Study,” Circ. Cardiovasc. Genet., vol. 2, no. 1, pp. 26–33, 2009.
[55] S. Kathiresan, C. J. Willer, G. M. Peloso, S. Demissie, K. Musunuru,
E. E. Schadt, L. Kaplan, D. Bennett, Y. Li, T. Tanaka, B. F. Voight,
L. L. Bonnycastle, A. U. Jackson, G. Crawford, A. Surti, C. Guiducci,
N. P. Burtt, S. Parish, R. Clarke, D. Zelenika, K. A. Kubalanza, M. A.
Morken, L. J. Scott, H. M. Stringham, P. Galan, A. J. Swift, J. Kuusisto,
R. N. Bergman, J. Sundvall, M. Laakso, L. Ferrucci, P. Scheet, S. Sanna,
M. Uda, Q. Yang, K. L. Lunetta, J. Dupuis, P. I. W. De Bakker, C. J.
O’donnell, J. C. Chambers, J. S. Kooner, S. Hercberg, P. Meneton, E.
G. Lakatta, A. Scuteri, D. Schlessinger, J. Tuomilehto, F. S. Collins,
L. Groop, D. Altshuler, R. Collins, G. M. Lathrop, O. Melander, V.
Salomaa, L. Peltonen, M. Orho-Melander, J. M. Ordovas, M. Boehnke,
G. R. Abecasis, K. L. Mohlke, and L. A. Cupples, “Common variants at
30 loci contribute to polygenic dyslipidemia,” Nature Genet., vol. 41,
no. 1, pp. 56–65, 2009.
804 IEEE TRANSACTIONS ON INFORMATION TECHNOLOGY IN BIOMEDICINE, VOL. 16, NO. 5, SEPTEMBER 2012
[56] C. Sabatti, S. K. Service, A. L. Hartikainen, A. Pouta, S. Ripatti,
J. Brodsky, C. G. Jones, N. A. Zaitlen, T. Varilo, M. Kaakinen, U. Sovio,
A. Ruokonen, J. Laitinen, E. Jakkula, L. Coin, C. Hoggart, A. Collins, H.
Turunen, S. Gabriel, P. Elliot, M. I. Mccarthy, M. J. Daly, M. R. Jarvelin,
N. B. Freimer, and L. Peltonen, “Genome-wide association analysis of
metabolic traits in a birth cohort from a founder population,” Nature
Genet., vol. 41, no. 1, pp. 35–46, 2009.
[57] I. M. Heid, E. Boes, M. Muller, B. Kollerits, C. Lamina, S. Coassin, C.
Gieger, A. Doring, N. Klopp, R. Frikke-Schmidt, A. Tybjaerg-Hansen,
A. Brandstaetter, A. Luchner, T. Meitinger, H. E. Wichmann, and F. Kro-
nenberg, “Genome-wide association analysis of high-density lipoprotein
cholesterol in the population-based KORA study sheds new light on in-
tergenic regions,” Circ. Cardiovasc. Genet., vol. 1, no. 1, pp. 10–20,
2008.
[58] J. A. Kanaley, S. Shadid, M. T. Sheehan, Z. Guo, and M. D. Jensen, “Re-
lationship between plasma free fatty acid, intramyocellular triglycerides
and long-chain acylcarnitines in resting humans,” J. Physiol., vol. 587,
no. 24, pp. 5939–5950, 2009.
[59] C. J. Willer, S. Sanna, A. U. Jackson, A. Scuteri, L. L. Bonnycastle,
R. Clarke, S. C. Heath, N. J. Timpson, S. S. Najjar, H. M. Stringham, J.
Strait, W. L. Duren, A. Maschio, F. Busonero, A. Mulas, G. Albai, A. J.
Swift, M. A. Morken, N. Narisu, D. Bennett, S. Parish, H. Q. Shen, P.
Galan, P. Meneton, S. Hercberg, D. Zelenika, W. M. Chen, Y. Li, L. J.
Scott, P. A. Scheet, J. Sundvall, R. M. Watanabe, R. Nagaraja, S. Ebrahim,
D. A. Lawlor, Y. Ben-Shlomo, G. Davey-Smith, A. R. Shuldiner, R.
Collins, R. N. Bergman, M. Uda, J. Tuomilehto, A. Cao, F. S. Collins, E.
Lakatta, G. M. Lathrop, M. Boehnke, D. Schlessinger, K. L. Mohlke, and
G. R. Abecasis, “Newly identified loci that influence lipid concentrations
and risk of coronary artery disease,” Nature Genet., vol. 40, no. 2,
pp. 161–169, 2008.
[60] Y. Hiura, C. S. Shen, Y. Kokubo, T. Okamura, T. Morisaki, H.
Tomoike, T. Yoshida, H. Sakamoto, Y. Goto, H. Nonogi, and
N. Iwai, “Identification of genetic markers associated with high-
density lipoprotein-cholesterol by genome-wide screening in a Japanese
population—the Suita study,” Circ. J., vol. 73, no. 6, pp. 1119–1126,
2009.
[61] R. Burkhardt, E. E. Kenny, J. K. Lowe, A. Birkeland, R. Josowitz,
M. Noel, J. Salit, J. B. Maller, I. Pe’er, M. J. Daly, D. Altshuler, M.
Stoffel, J. M. Friedman, and J. L. Breslow, “Common SNPs in HMGCR
in micronesians and whites associated with LDL-cholesterol levels af-
fect alternative splicing of Exon13,” Arterioscler. Thromb. Vasc. Biol.,
vol. 28, no. 11, pp. 2078–2084, 2008.
[62] M. S. Sandhu, D. M. Waterworth, S. L. Debenham, E. Wheeler,
K. Papadakis, J. H. Zhao, K. J. Song, X. Yuan, T. Johnson, S. Ash-
ford, M. Inouye, R. Luben, M. Sims, D. Hadley, W. Mcardle, P. Barter,
Y. A. Kesaniemi, R. W. Mahley, R. Mcpherson, S. M. Grundy, S. A. Bing-
ham, K. T. Khaw, R. J. F. Loos, G. Waeber, I. Barroso, D. P. Strachan, P.
Deloukas, P. Vollenweider, N. J. Wareham, V. Mooser, and W. T. C. C.
Consor, “LDL-cholesterol concentrations: A genome-wide association
study,” Lancet, vol. 371, no. 9611, pp. 483–491, 2008.
[63] S. Kathiresan, O. Melander, C. Guiducci, A. Surti, N. P. Burtt,
M. J. Rieder, G. M. Cooper, C. Roos, B. F. Voight, A. S. Havulinna,
B. Wahlstrand, T. Hedner, D. Corella, E. S. Tai, J. M. Ordovas, G.
Berglund, E. Vartiainen, P. Jousilahti, B. Hedblad, M. R. Taskinen, C.
Newton-Cheh, V. Salomaa, L. Peltonen, L. Groop, D. M. Altshuler, and
M. Orho-Melander, “Six new loci associated with blood low-density
lipoprotein cholesterol, high-density lipoprotein cholesterol or triglyc-
erides in humans,” Nature Genet., vol. 40, no. 2, pp. 189–197, 2008.
[64] C. Wallace, S. J. Newhouse, P. Braund, F. Zhang, M. Tobin, M. Falchi,
K. Ahmadi, R. J. Dobson, A. C. Marcano, C. Hajat, P. Burton, P. De-
loukas, M. Brown, J. M. Connell, A. Dominiczak, G. M. Lathrop, J.
Webster, M. Farrall, T. Spector, N. J. Samani, M. J. Caulfield, and P. B.
Munroe, “Genome-wide association study identifies genes for biomark-
ers of cardiovascular disease: Serum urate and dyslipidemia,” Amer. J.
Hum. Genet., vol. 82, no. 1, pp. 139–149, 2008.
[65] D. C. Croteau-Chonka, A. F. Marvelle, E. M. Lange, N. R. Lee,
L. S. Adair, L. A. Lange, N. R. Lee, L. S. Adair, L. A. Lange, and
K. L. Mohlke, “Genome-wide association study of anthropometric traits
and evidence of interactions with age and study year in Filipino women,”
Obesity (Silver Spring), vol. 19, no. 5, pp. 1019–1027, 2010.
[66] E. K. Speliotes, C. J. Willer, S. I. Berndt, K. L. Monda, G. Thorleifsson,
A. U. Jackson, H. L. Allen, C. M. Lindgren, J. Luan, R. Magi, J. C.
Randall, S. Vedantam, T. W. Winkler, L. Qi, T. Workalemahu, I. M.
Heid, V. Steinthorsdottir, H. M. Stringham, M. N. Weedon, E. Wheeler,
A. R. Wood, T. Ferreira, R. J. Weyant, A. V. Segre, K. Estrada, L. Liang, J.
Nemesh, J. H. Park, S. Gustafsson, T. O. Kilpelainen, J. Yang, N. Bouatia-
Naji, T. Esko, M. F. Feitosa, Z. Kutalik, M. Mangino, S. Raychaudhuri,
A. Scherag, A. V. Smith, R. Welch, J. H. Zhao, K. K. Aben, D. M.
Absher, N. Amin, A. L. Dixon, E. Fisher, N. L. Glazer, M. E. Goddard,
N. L. Heard-Costa, V. Hoesel, J. J. Hottenga, A. Johansson, T. Johnson,
S. Ketkar, C. Lamina, S. Li, M. F. Moffatt, R. H. Myers, N. Narisu, J. R.
Perry, M. J. Peters, M. Preuss, S. Ripatti, F. Rivadeneira, C. Sandholt, L.
J. Scott, N. J. Timpson, J. P. Tyrer, S. Van Wingerden, R. M. Watanabe, C.
C. White, F. Wiklund, C. Barlassina, D. I. Chasman, M. N. Cooper, J. O.
Jansson, R. W. Lawrence, N. Pellikka, I. Prokopenko, J. Shi, E. Thiering,
H. Alavere, M. T. Alibrandi, P. Almgren, A. M. Arnold, T. Aspelund, L.
D. Atwood, B. Balkau, A. J. Balmforth, A. J. Bennett, Y. Ben-Shlomo,
R. N. Bergman, S. Bergmann, H. Biebermann, A. I. Blakemore, T. Boes,
L. L. Bonnycastle, S. R. Bornstein, M. J. Brown, T. A. Buchanan, F.
Busonero, H. Campbell, F. P. Cappuccio, C. Cavalcanti-Proenca, Y. D.
Chen, C. M. Chen, P. S. Chines, R. Clarke, L. Coin, J. Connell, I. N. Day,
M. Heijer, J. Duan, S. Ebrahim, P. Elliott, R. Elosua, G. Eiriksdottir, M. R.
Erdos, J. G. Eriksson, M. F. Facheris, S. B. Felix, P. Fischer-Posovszky,
A. R. Folsom, N. Friedrich, N. B. Freimer, M. Fu, S. Gaget, P. V. Gejman,
E. J. Geus, C. Gieger, A. P. Gjesing, A. Goel, P. Goyette, H. Grallert, J.
Grassler, D. M. Greenawalt, C. J. Groves, V. Gudnason, C. Guiducci, A.
L. Hartikainen, N. Hassanali, A. S. Hall, A. S. Havulinna, C. Hayward,
A. C. Heath, C. Hengstenberg, A. A. Hicks, A. Hinney, A. Hofman, G.
Homuth, J. Hui, W. Igl, C. Iribarren, B. Isomaa, K. B. Jacobs, I. Jarick,
E. Jewell, U. John, T. Jorgensen, P. Jousilahti, A. Jula, M. Kaakinen, E.
Kajantie, L. M. Kaplan, S. Kathiresan, J. Kettunen, L. Kinnunen, J. W.
Knowles, I. Kolcic, I. R. Konig, S. Koskinen, P. Kovacs, J. Kuusisto, P.
Kraft, K. Kvaloy, J. Laitinen, O. Lantieri, C. Lanzani, L. J. Launer, C.
Lecoeur, T. Lehtimaki, G. Lettre, J. Liu, M. L. Lokki, M. Lorentzon, R.
N. Luben, B. Ludwig, MAGIC, P. Manunta, D. Marek, M. Marre, N.
G. Martin, W. L. Mcardle, A. Mccarthy, B. Mcknight, T. Meitinger, O.
Melander, D. Meyre, K. Midthjell, G. W. Montgomery, M. A. Morken,
A. P. Morris, R. Mulic, J. S. Ngwa, M. Nelis, M. J. Neville, D. R. Nyholt,
C. J. O’donnell, S. O’rahilly, K. K. Ong, B. Oostra, G. Pare, A. N. Parker,
M. Perola, I. Pichler, K. H. Pietilainen, C. G. Platou, O. Polasek, A.
Pouta, S. Rafelt, O. Raitakari, N. W. Rayner, M. Ridderstrale, W. Rief,
A. Ruokonen, N. R. Robertson, P. Rzehak, V. Salomaa, A. R. Sanders, M.
S. Sandhu, S. Sanna, J. Saramies, M. J. Savolainen, S. Scherag, S. Schipf,
S. Schreiber, H. Schunkert, K. Silander, J. Sinisalo, D. S. Siscovick, J.
H. Smit, N. Soranzo, U. Sovio, J. Stephens, I. Surakka, A. J. Swift,
M. L. Tammesoo, J. C. Tardif, M. Teder-Laving, T. M. Teslovich, J. R.
Thompson, B. Thomson, A. Tonjes, T. Tuomi, J. B. Van Meurs, G. J.
Van Ommen, V. Vatin, J. Viikari, S. Visvikis-Siest, V. Vitart, C. I. Vogel,
B. F. Voight, L. L. Waite, H. Wallaschofski, G. B. Walters, E. Widen, S.
Wiegand, S. H. Wild, G. Willemsen, D. R. Witte, J. C. Witteman, J. Xu,
Q. Zhang, L. Zgaga, A. Ziegler, P. Zitting, J. P. Beilby, I. S. Farooqi, J.
Hebebrand, H. V. Huikuri, A. L. James, M. Kahonen, D. F. Levinson, F.
Macciardi, M. S. Nieminen, C. Ohlsson, L. J. Palmer, P. M. Ridker, M.
Stumvoll, J. S. Beckmann, H. Boeing, E. Boerwinkle, D. I. Boomsma, M.
J. Caulfield, S. J. Chanock, F. S. Collins, L. A. Cupples, G. D. Smith, J.
Erdmann, P. Froguel, H. Gronberg, U. Gyllensten, P. Hall, T. Hansen, T.
B. Harris, A. T. Hattersley, R. B. Hayes, J. Heinrich, F. B. Hu, K. Hveem,
T. Illig, M. R. Jarvelin, J. Kaprio, F. Karpe, K. T. Khaw, L. A. Kiemeney,
H. Krude, M. Laakso, D. A. Lawlor, A. Metspalu, P. B. Munroe, W.
H. Ouwehand, O. Pedersen, B. W. Penninx, A. Peters, P. P. Pramstaller,
T. Quertermous, T. Reinehr, A. Rissanen, I. Rudan, N. J. Samani, P.
E. Schwarz, A. R. Shuldiner, T. D. Spector, J. Tuomilehto, M. Uda, A.
Uitterlinden, T. T. Valle, M. Wabitsch, G. Waeber, N. J. Wareham, H.
Watkins, J. F. Wilson, A. F. Wright, M. C. Zillikens, N. Chatterjee, S.
A. Mccarroll, S. Purcell, E. E. Schadt, P. M. Visscher, T. L. Assimes, I.
B. Borecki, P. Deloukas, C. S. Fox, L. C. Groop, T. Haritunians, D. J.
Hunter, R. C. Kaplan, K. L. Mohlke, J. R. O’connell, L. Peltonen, D.
Schlessinger, D. P. Strachan, C. M. Van Duijn, H. E. Wichmann, T. M.
Frayling, U. Thorsteinsdottir, G. R. Abecasis, I. Barroso, M. Boehnke, K.
Stefansson, K. E. North, M. I. Mccarthy, J. N. Hirschhorn, E. Ingelsson
and R. J. Loos, “Association analyses of 249796 individuals reveal 18
new loci associated with body mass index,” Nature Genet., vol. 42, no.
11, pp. 937–948, 2010.
[67] J. Z. Liu, S. E. Medland, M. J. Wright, A. K. Henders, A. C. Heath,
P. A. Madden, A. Duncan, G. W. Montgomery, N. G. Martin, and A. F.
Mcrae, “Genome-wide association study of height and body mass index
in Australian twin families,” Twin Res. Hum. Genet., vol. 13, no. 2,
pp. 179–193, 2010.
[68] A. Johansson, F. Marroni, C. Hayward, C. S. Franklin, A. V. Kirichenko,
I. Jonasson, A. A. Hicks, V. Vitart, A. Isaacs, T. Axenovich, S. Campbell,
PU et al.: INVESTIGATION ON CARDIOVASCULAR RISK PREDICTION USING GENETIC INFORMATION
J. Floyd, N. Hastie, S. Knott, G. Lauc, I. Pichler, K. Rotim, S. H. Wild, I.
V. Zorkoltseva, J. F. Wilson, I. Rudan, H. Campbell, C. Pattaro, P. Pram-
staller, B. A. Oostra, A. F. Wright, C. M. Van Duijn, Y. S. Aulchenko,
U. Gyllensten, and EUROSPAN Consortium, “Linkage and genome- [72]
wide association analysis of obesity-related phenotypes: Association of
weight with the MGAT1 gene,” Obesity (Silver Spring), vol. 18, no. 4,
pp. 803–808, 2010.
[69] G. Thorleifsson, G. B. Walters, D. F. Gudbjartsson, V. Steinthorsdottir,
P. Sulem, A. Helgadottir, U. Styrkarsdottir, S. Gretarsdottir, S. Thor-
lacius, I. Jonsdottir, T. Jonsdottir, E. J. Olafsdottir, G. H. Olafsdottir,
T. Jonsson, F. Jonsson, K. Borch-Johnsen, T. Hansen, G. Andersen,
T. Jorgensen, T. Lauritzen, K. K. Aben, A. L. Verbeek, N. Roeleveld,
E. Kampman, L. R. Yanek, L. C. Becker, L. Tryggvadottir, T. Rafnar,
D. M. Becker, J. Gulcher, L. A. Kiemeney, O. Pedersen, A. Kong, U.
Thorsteinsdottir, and K. Stefansson, “Genome-wide association yields [73]
new sequence variants at seven loci that associate with measures of obe-
sity,” Nature Genet., vol. 41, no. 1, pp. 18–24, 2009.
[70] C. J. Willer, E. K. Speliotes, R. J. Loos, S. Li, C. M. Lindgren, I. M.
Heid, S. I. Berndt, A. L. Elliott, A. U. Jackson, C. Lamina, G. Lettre, N.
Lim, H. N. Lyon, S. A. Mccarroll, K. Papadakis, L. Qi, J. C. Randall,
R. M. Roccasecca, S. Sanna, P. Scheet, M. N. Weedon, E. Wheeler,
J. H. Zhao, L. C. Jacobs, I. Prokopenko, N. Soranzo, T. Tanaka, N.
J. Timpson, P. Almgren, A. Bennett, R. N. Bergman, S. A. Bingham,
L. L. Bonnycastle, M. Brown, N. P. Burtt, P. Chines, L. Coin, F. S.
Collins, J. M. Connell, C. Cooper, G. D. Smith, E. M. Dennison, P.
Deodhar, P. Elliott, M. R. Erdos, K. Estrada, D. M. Evans, L. Gianniny,
C. Gieger, C. J. Gillson, C. Guiducci, R. Hackett, D. Hadley, A. S.
Hall, A. S. Havulinna, J. Hebebrand, A. Hofman, B. Isomaa, K. B.
Jacobs, T. Johnson, P. Jousilahti, Z. Jovanovic, K. T. Khaw, P. Kraft, M. [74]
Kuokkanen, J. Kuusisto, J. Laitinen, E. G. Lakatta, J. Luan, R. N. Luben,
M. Mangino, W. L. Mcardle, T. Meitinger, A. Mulas, P. B. Munroe, N.
Narisu, A. R. Ness, K. Northstone, S. O’rahilly, C. Purmann, M. G. Rees,
M. Ridderstrale, S. M. Ring, F. Rivadeneira, A. Ruokonen, M. S. Sandhu,
J. Saramies, L. J. Scott, A. Scuteri, K. Silander, M. A. Sims, K. Song,
J. Stephens, S. Stevens, H. M. Stringham, Y. C. Tung, T. T. Valle, C. M. [75]
Van Duijn, K. S. Vimaleswaran, P. Vollenweider, G. Waeber, C. Wallace,
R. M. Watanabe, D. M. Waterworth, N. Watkins, WTCC Consortium, J.
C. Witteman, E. Zeggini, G. Zhai, M. C. Zillikens, D. Altshuler, M. J.
Caulfield, S. J. Chanock, I. S. Farooqi, L. Ferrucci, J. M. Guralnik, A. T.
Hattersley, F. B. Hu, M. R. Jarvelin, M. Laakso, V. Mooser, K. K. Ong,
W. H. Ouwehand, V. Salomaa, N. J. Samani, T. D. Spector, T. Tuomi,
J. Tuomilehto, M. Uda, A. G. Uitterlinden, N. J. Wareham, P. Deloukas,
T. M. Frayling, L. C. Groop, R. B. Hayes, D. J. Hunter, K. L. Mohlke,
L. Peltonen, D. Schlessinger, D. P. Strachan, H. E. Wichmann, M. I.
Mccarthy, M. Boehnke, I. Barroso, G. R. Abecasis, J. N. Hirschhorn,
and GIANT Consortium, “Six new loci associated with body mass index [76]
highlight a neuronal influence on body weight regulation,” Nature Genet.,
vol. 41, no. 1, pp. 25–34, 2009.
[71] R. J. Loos, C. M. Lindgren, S. Li, E. Wheeler, J. H. Zhao, I. Prokopenko,
M. Inouye, R. M. Freathy, A. P. Attwood, J. S. Beckmann, S. I. Berndt,
PLCO cancer screening trial, K. B. Jacobs, S. J. Chanock, R. B. Hayes,
S. Bergmann, A. J. Bennett, S. A. Bingham, M. Bochud, M. Brown, S.
Cauchi, J. M. Connell, C. Cooper, G. D. Smith, I. Day, C. Dina, S. De,
E. T. Dermitzakis, A. S. Doney, K. S. Elliott, P. Elliott, D. M. Evans,
I. Sadaf Farooqi, P. Froguel, J. Ghori, C. J. Groves, R. Gwilliam, D.
Hadley, A. S. Hall, A. T. Hattersley, J. Hebebrand, I. M. Heid, KORA, C.
Lamina, C. Gieger, T. Illig, T. Meitinger, H. E. Wichmann, B. Herrera,
A. Hinney, S. E. Hunt, M. R. Jarvelin, T. Johnson, J. D. Jolley, F. Karpe,
A. Keniry, K. T. Khaw, R. N. Luben, M. Mangino, J. Marchini, W. L.
Mcardle, R. Mcginnis, D. Meyre, P. B. Munroe, A. D. Morris, A. R.
Ness, M. J. Neville, A. C. Nica, K. K. Ong, S. O’rahilly, K. R. Owen,
C. N. Palmer, K. Papadakis, S. Potter, A. Pouta, L. Qi, Nurses’ Health
Study, J. C. Randall, N. W. Rayner, S. M. Ring, M. S. Sandhu, A.
Scherag, M. A. Sims, K. Song, N. Soranzo, E. K. Speliotes, Diabetes
Genetics Initiative, H. E. Syddall, S. A. Teichmann, N. J. Timpson, J.
H. Tobias, M. Uda, C. I. Vogel, C. Wallace, D. M. Waterworth, M. N.
Weedon, WTCC Consortium, C. J. Willer, FUSION, Wraight, X. Yuan,
E. Zeggini, J. N. Hirschhorn, D. P. Strachan, W. H. Ouwehand, M. J.
Caulfield, N. J. Samani, T. M. Frayling, P. Vollenweider, G. Waeber,
V. Mooser, P. Deloukas, M. I. Mccarthy, N. J. Wareham, I. Barroso,
K. B. Jacobs, S. J. Chanock, R. B. Hayes, C. Lamina, C. Gieger, T.
Illig, T. Meitinger, H. E. Wichmann, P. Kraft, S. E. Hankinson, D. J.
Hunter, F. B. Hu, H. N. Lyon, B. F. Voight, M. Ridderstrale, L. Groop, P.
Scheet, S. Sanna, G. R. Abecasis, G. Albai, R. Nagaraja, D. Schlessinger,
A. U. Jackson, J. Tuomilehto, F. S. Collins, M. Boehnke, and K. L.
805
Mohlke, “Common variants near MC4R are associated with fat mass,
weight and risk of obesity,” Nature Genet., vol. 40, no. 6, pp. 768–775,
2008.
T. M. Frayling, N. J. Timpson, M. N. Weedon, E. Zeggini, R. M. Freathy,
C. M. Lindgren, J. R. Perry, K. S. Elliott, H. Lango, N. W. Rayner, B.
Shields, L. W. Harries, J. C. Barrett, S. Ellard, C. J. Groves, B. Knight,
A. M. Patch, A. R. Ness, S. Ebrahim, D. A. Lawlor, S. M. Ring, Y. Ben-
Shlomo, M. R. Jarvelin, U. Sovio, A. J. Bennett, D. Melzer, L. Errucci,
R. Loos, I. Barroso, N. J. Wareham, F. Karpe, K. R. Owen, L. R. Cardon,
M. Walker, G. A. Hitman, C. N. Palmer, A. S. Doney, A. D. Morris, G.
D. Smith, WTCC Consortium, A. T. Hattersley, and M. I. Mccarthy, “A
common variant in the FTO gene is associated with body mass index and
predisposes to childhood and adult obesity,” Science, vol. 316, no. 5826,
pp. 889–894, 2007.
T. E. Thorgeirsson, F. Geller, P. Sulem, T. Rafnar, A. Wiste, K. P.
Magnusson, A. Manolescu, G. Thorleifsson, H. Stefansson, A. Inga-
son, S. N. Stacey, J. T. Bergthorsson, S. Thorlacius, J. Gudmundsson, T.
Jonsson, M. Jakobsdottir, J. Saemundsdottir, O. Olafsdottir, L. J. Gud-
mundsson, G. Bjornsdottir, K. Kristjansson, H. Skuladottir, H. J. Isaks-
son, T. Gudbjartsson, G. T. Jones, T. Mueller, A. Gottsater, A. Flex, K.
K. Aben, F. De Vegt, P. F. Mulders, D. Isla, M. J. Vidal, L. Asin, B. Saez,
L. Murillo, T. Blondal, H. Kolbeinsson, J. G. Stefansson, I. Hansdottir,
V. Runarsdottir, R. Pola, B. Lindblad, A. M. Van Rij, B. Dieplinger, M.
Haltmayer, J. I. Mayordomo, L. A. Kiemeney, S. E. Matthiasson, H. Os-
karsson, T. Tyrfingsson, D. F. Gudbjartsson, J. R. Gulcher, S. Jonsson,
U. Thorsteinsdottir, A. Kong, and K. Stefansson, “A variant associated
with nicotine dependence, lung cancer and peripheral arterial disease,”
Nature, vol. 452, no. 7187, pp. 638–642, 2008.
X. O. Shu, J. Long, Q. Cai, L. Qi, Y. B. Xiang, Y. S. Cho, E. S. Tai, X.
Li, X. Lin, W. H. Chow, M. J. Go, M. Seielstad, W. Bao, H. Li, M. C.
Cornelis, K. Yu, W. Wen, J. Shi, B. G. Han, X. L. Sim, L. Liu, Q. Qi, H.
L. Kim, D. P. Ng, J. Y. Lee, Y. J. Kim, C. Li, Y. T. Gao, W. Zheng, and F.
B. Hu, “Identification of new genetic risk variants for type 2 diabetes,”
PLoS Genet., vol. 6, no. 9, art no. e1001127, 2010.
T. Yamauchi, K. Hara, S. Maeda, K. Yasuda, A. Takahashi, M. Horikoshi,
M. Nakamura, H. Fujita, N. Grarup, S. Cauchi, D. P. Ng, R. C. Ma,
T. Tsunoda, M. Kubo, H. Watada, H. Maegawa, M. Okada-Iwabu, M.
Iwabu, N. Shojima, H. D. Shin, G. Andersen, D. R. Witte, T. Jørgensen,
T. Lauritzen, A. Sandbaek, T. Hansen, T. Ohshige, S. Omori, I. Saito,
K. Kaku, H. Hirose, W. So, D. Beury, J. C. Chan, K. S. Park, E. S. Tai,
C. Ito, Y. Tanaka, A. Kashiwagi, R. Kawamori, M. Kasuga, P. Froguel,
O. Pedersen, N. Kamatani, Y. Nakamura, and T. Kadowaki, “A genome-
wide association study in the Japanese population identifies susceptibility
loci for type 2 diabetes at UBE2E2 and C2CD4A-C2CD4B,” Nature
Genet., vol. 42, no. 10, pp. 864–868, 2010.
B. F. Voight, L. J. Scott, V. Steinthorsdottir, A. P. Morris, C. Dina, R.
P. Welch, E. Zeggini, C. Huth, Y. S. Aulchenko, G. Thorleifsson, L.
J. Mcculloch, T. Ferreira, H. Grallert, N. Amin, G. Wu, C. J. Willer,
S. Raychaudhuri, S. A. Mccarroll, C. Langenberg, O. M. Hofmann, J.
Dupuis, L. Qi, A. V. Segre, M. Van Hoek, P. Navarro, K. Ardlie, B.
Balkau, R. Benediktsson, A. J. Bennett, R. Blagieva, E. Boerwinkle, L.
L. Bonnycastle, K. Bengtsson Bostrom, B. Bravenboer, S. Bumpstead,
N. P. Burtt, G. Charpentier, P. S. Chines, M. Cornelis, D. J. Couper, G.
Crawford, A. S. Doney, K. S. Elliott, A. L. Elliott, M. R. Erdos, C. S. Fox,
C. S. Franklin, M. Ganser, C. Gieger, N. Grarup, T. Green, S. Griffin, C. J.
Groves, C. Guiducci, S. Hadjadj, N. Hassanali, C. Herder, B. Isomaa, A.
U. Jackson, P. R. Johnson, T. Jorgensen, W. H. Kao, N. Klopp, A. Kong,
P. Kraft, J. Kuusisto, T. Lauritzen, M. Li, A. Lieverse, C. M. Lindgren,
V. Lyssenko, M. Marre, T. Meitinger, K. Midthjell, M. A. Morken, N.
Narisu, P. Nilsson, K. R. Owen, F. Payne, J. R. Perry, A. K. Petersen,
C. Platou, C. Proenca, I. Prokopenko, W. Rathmann, N. W. Rayner, N.
R. Robertson, G. Rocheleau, M. Roden, M. J. Sampson, R. Saxena, B.
M. Shields, P. Shrader, G. Sigurdsson, T. Sparso, K. Strassburger, H. M.
Stringham, Q. Sun, A. J. Swift, B. Thorand, J. Tichet, T. Tuomi, R. M.
Van Dam, T. W. Van Haeften, T. Van Herpt, J. V. Van Vliet-Ostaptchouk,
G. B. Walters, M. N. Weedon, C. Wijmenga, J. Witteman, R. N. Bergman,
S. Cauchi, F. S. Collins, A. L. Gloyn, U. Gyllensten, T. Hansen, W. A.
Hide, G. A. Hitman, A. Hofman, D. J. Hunter, K. Hveem, M. Laakso,
K. L. Mohlke, A. D. Morris, C. N. Palmer, P. P. Pramstaller, I. Rudan, E.
Sijbrands, L. D. Stein, J. Tuomilehto, A. Uitterlinden, M. Walker, N. J.
Wareham, R. M. Watanabe, G. R. Abecasis, B. O. Boehm, H. Campbell,
M. J. Daly, A. T. Hattersley, F. B. Hu, J. B. Meigs, J. S. Pankow, O.
Pedersen, H. E. Wichmann, I. Barroso, J. C. Florez, T. M. Frayling, L.
Groop, R. Sladek, U. Thorsteinsdottir, J. F. Wilson, T. Illig, P. Froguel, C.
M. Van Duijn, K. Stefansson, D. Altshuler, M. Boehnke, M. I. Mccarthy,
806 IEEE TRANSACTIONS ON INFORMATION TECHNOLOGY IN BIOMEDICINE, VOL. 16, NO. 5, SEPTEMBER 2012
MAGIC investigators, and GIANT Consortium, “Twelve type 2 diabetes
susceptibility loci identified through large-scale association analysis,”
Nature Genet., vol. 42, no. 7, pp. 579–589, 2010.
[77] L. Qi, M. C. Cornelis, P. Kraft, K. J. Stanya, W. H. Linda Kao, J. S.
Pankow, J. Dupuis, J. C. Florez, C. S. Fox, G. Paré, Q. Sun, C. J. Girman,
C. C. Laurie, D. B. Mirel, T. A. Manolio, D. I. Chasman, E. Boerwinkle,
P. M. Ridker, D. J. Hunter, J. B. Meigs, C. H. Lee, F. B. Hu, R. M. Van
Dam, MAGIC, and DIAGRAM Consortium, “Genetic variants at 2q24
are associated with susceptibility to type 2 diabetes,” Hum. Mol. Genet.,
vol. 19, no. 13, pp. 2706–2715, 2010.
[78] F. J. Tsai, C. F. Yang, C. C. Chen, L. M. Chuang, C. H. Lu, C. T. Chang,
T. Y. Wang, R. H. Chen, C. F. Shiu, Y. M. Liu, C. C. Chang, P. Chen,
C. H. Chen, C. S. Fann, Y. T. Chen, and J. Y. Wu, “A genome-wide
association study identifies susceptibility variants for type 2 diabetes in
Han Chinese,” PLoS Genet., vol. 6, no. 2, art no. e1000847, 2010.
[79] F. Takeuchi, M. Serizawa, K. Yamamoto, T. Fujisawa, E. Nakashima,
K. Ohnaka, H. Ikegami, T. Sugiyama, T. Katsuya, M. Miyagishi, N.
Nakashima, H. Nawata, J. Nakamura, S. Kono, R. Takayanagi, and N.
Kato, “Confirmation of multiple risk Loci and genetic impacts by a
genome-wide association study of type 2 diabetes in the Japanese popu-
lation,” Diabetes, vol. 58, no. 7, pp. 1690–1699, 2009.
[80] N. J. Timpson, C. M. Lindgren, M. N. Weedon, J. Randall, W. H.
Ouwehand, D. P. Strachan, N. W. Rayner, M. Walker, G. A. Hitman,
A. S. Doney, C. N. Palmer, A. D. Morris, A. T. Hattersley, E. Zeggini,
T. M. Frayling, and M. I. Mccarthy, “Adiposity-related heterogeneity
in patterns of type 2 diabetes susceptibility observed in genome-wide
association data,” Diabetes, vol. 58, no. 2, pp. 505–510, 2009.
[81] H. Unoki, A. Takahashi, T. Kawaguchi, K. Hara, M. Horikoshi,
G. Andersen, D. P. Ng, J. Holmkvist, K. Borch-Johnsen, T. Jorgensen, A.
Sandbaek, T. Lauritzen, T. Hansen, S. Nurbaya, T. Tsunoda, M. Kubo,
T. Babazono, H. Hirose, M. Hayashi, Y. Iwamoto, A. Kashiwagi, K.
Kaku, R. Kawamori, E. S. Tai, O. Pedersen, N. Kamatani, T. Kad-
owaki, R. Kikkawa, Y. Nakamura, and S. Maeda, “SNPs in KCNQ1
are associated with susceptibility to type 2 diabetes in East Asian and
European populations,” Nature Genet., vol. 40, no. 9, pp. 1098–1102,
2008.
[82] K. Yasuda, K. Miyake, Y. Horikawa, K. Hara, H. Osawa, H. Furuta, Y.
Hirota, H. Mori, A. Jonsson, Y. Sato, K. Yamagata, Y. Hinokio, H. Y.
Wang, T. Tanahashi, N. Nakamura, Y. Oka, N. Iwasaki, Y. Iwamoto, Y.
Yamada, Y. Seino, H. Maegawa, A. Kashiwagi, J. Takeda, E. Maeda, H.
D. Shin, Y. M. Cho, K. S. Park, H. K. Lee, M. C. Ng, R. C. Ma, W. Y. So,
J. C. Chan, V. Lyssenko, T. Tuomi, P. Nilsson, L. Groop, N. Kamatani,
A. Sekine, Y. Nakamura, K. Yamamoto, T. Yoshida, K. Tokunaga, M.
Itakura, H. Makino, K. Nanjo, T. Kadowaki, and M. Kasuga, “Variants in
KCNQ1 are associated with susceptibility to type 2 diabetes mellitus,”
Nature Genet., vol. 40, no. 9, pp. 1092–1097, 2008.
[83] E. Zeggini, L. J. Scott, R. Saxena, B. F. Voight, J. L. Marchini, T. Hu, P.
I. De Bakker, G. R. Abecasis, P. Almgren, G. Andersen, K. Ardlie, K.
B. Bostrom, R. N. Bergman, L. L. Bonnycastle, K. Borch-Johnsen, N. P.
Burtt, H. Chen, P. S. Chines, M. J. Daly, P. Deodhar, C. J. Ding, A. S.
Doney, W. L. Duren, K. S. Elliott, M. R. Erdos, T. M. Frayling, R. M.
Freathy, L. Gianniny, H. Grallert, N. Grarup, C. J. Groves, C. Guiducci, T.
Hansen, C. Herder, G. A. Hitman, T. E. Hughes, B. Isomaa, A. U. Jackson,
T. Jorgensen, A. Kong, K. Kubalanza, F. G. Kuruvilla, J. Kuusisto, C.
Langenberg, H. Lango, T. Lauritzen, Y. Li, C. M. Lindgren, V. Lyssenko,
A. F. Marvelle, C. Meisinger, K. Midthjell, K. L. Mohlke, M. A. Morken,
A. D. Morris, N. Narisu, P. Nilsson, K. R. Owen, C. N. Palmer, F. Payne,
J. R. Perry, E. Pettersen, C. Platou, I. Prokopenko, L. Qi, L. Qin, N.
W. Rayner, M. Rees, J. J. Roix, A. Sandbaek, B. Shields, M. Sjogren,
V. Steinthorsdottir, H. M. Stringham, A. J. Swift, G. Thorleifsson, U.
Thorsteinsdottir, N. J. Timpson, T. Tuomi, J. Tuomilehto, M. Walker, R.
M. Watanabe, M. N. Weedon, C. J. Willer, WTCC consortium, T. Illig, K.
Hveem, F. B. Hu, M. Laakso, K. Stefansson, O. Pedersen, N. J. Wareham,
I. Barroso, A. T. Hattersley, F. S. Collins, L. Groop, M. I. Mccarthy, M.
Boehnke, and D. Altshuler, “Meta-analysis of genome-wide association
data and large-scale replication identifies additional susceptibility loci
for type 2 diabetes,” Nature Genet., vol. 40, no. 5, pp. 638–645, 2008.
[84] R. L. Hanson, C. Bogardus, D. Duggan, S. Kobes, M. Knowlton,
A. M. Infante, L. Marovich, D. Benitez, L. J. Baier, and W. C. Knowler,
“A search for variants associated with young-onset type 2 diabetes in
American Indians in a 100 K genotyping array,” Diabetes, vol. 56,
no. 12, pp. 3045–3052, 2007.
[85] M. G. Hayes, A. Pluzhnikov, K. Miyake, Y. Sun, M. C. Ng, C. A. Roe,
J. E. Below, R. I. Nicolae, A. Konkashbaev, G. I. Bell, N. J. Cox, and C.
L. Hanis, “Identification of type 2 diabetes genes in Mexican Americans
through genome-wide association studies,” Diabetes, vol. 56, no. 12,
pp. 3033–3044, 2007.
[86] E. Rampersaud, C. M. Damcott, M. Fu, H. Shen, P. Mcardle, X. Shi,
J. Shelton, J. Yin, Y. P. Chang, S. H. Ott, L. Zhang, Y. Zhao, B. D.
Mitchell, J. O’connell, and A. R. Shuldiner, “Identification of novel
candidate genes for type 2 diabetes from a genome-wide association
scan in the Old Order Amish: Evidence for replication from diabetes-
related quantitative traits and from independent populations,” Diabetes,
vol. 56, no. 12, pp. 3053–3062, 2007.
[87] J. T. Salonen, P. Uimari, J. M. Aalto, M. Pirskanen, J. Kaikkonen,
B. Todorova, J. Hypponen, V. P. Korhonen, J. Asikainen, C. Devine,
T. P. Tuomainen, J. Luedemann, M. Nauck, W. Kerner, R. H. Stephens,
J. P. New, W. E. Ollier, J. M. Gibson, A. Payton, M. A. Horan, N. Pendle-
ton, W. Mahoney, D. Meyre, J. Delplanque, P. Froguel, O. Luzzatto, B.
Yakir, and A. Darvasi, “Type 2 diabetes whole-genome association study
in four populations: The DiaGen consortium,” Amer. J. Hum. Genet.,
vol. 81, no. 2, pp. 338–345, 2007.
[88] A. L. Dixon, L. Liang, M. F. Moffatt, W. Chen, S. Heath, K. C. Wong,
J. Taylor, E. Burnett, I. Gut, M. Farrall, G. M. Lathrop, G. R. Abecasis,
and W. O. Cookson, “A genome-wide association study of global gene
expression,” Nature Genet., vol. 39, no. 10, pp. 1202–1207, 2007.
[89] Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund
University, and Novartis Institutes of BioMedical Research, R. Saxena,
B. F. Voight, V. Lyssenko, N. P. Burtt, P. I. De Bakker, H. Chen, J.
J. Roix, S. Kathiresan, J. N. Hirschhorn, M. J. Daly, T. E. Hughes, L.
Groop, D. Altshuler, P. Almgren, J. C. Florez, J. Meyer, K. Ardlie, K.
Bengtsson Bostrom, B. Isomaa, G. Lettre, U. Lindblad, H. N. Lyon, O.
Melander, C. Newton-Cheh, P. Nilsson, M. Orho-Melander, L. Rastam,
E. K. Speliotes, M. R. Taskinen, T. Tuomi, C. Guiducci, A. Berglund, J.
Carlson, L. Gianniny, R. Hackett, L. Hall, J. Holmkvist, E. Laurila, M.
Sjogren, M. Sterner, A. Surti, M. Svensson, M. Svensson, R. Tewhey, B.
Blumenstiel, M. Parkin, M. Defelice, R. Barry, W. Brodeur, J. Camarata,
N. Chia, M. Fava, J. Gibbons, B. Handsaker, C. Healy, K. Nguyen, C.
Gates, C. Sougnez, D. Gage, M. Nizzari, S. B. Gabriel, G. W. Chirn, Q.
Ma, H. Parikh, D. Richardson, D. Ricke, and S. Purcell, “Genome-wide
association analysis identifies loci for type 2 diabetes and triglyceride
levels,” Science, vol. 316, no. 5829, pp. 1331–1336, 2007.
[90] L. J. Scott, K. L. Mohlke, L. L. Bonnycastle, C. J. Willer, Y. Li,
W. L. Duren, M. R. Erdos, H. M. Stringham, P. S. Chines, A. U. Jack-
son, L. Prokunina-Olsson, C. J. Ding, A. J. Swift, N. Narisu, T. Hu, R.
Pruim, R. Xiao, X. Y. Li, K. N. Conneely, N. L. Riebow, A. G. Sprau,
M. Tong, P. P. White, K. N. Hetrick, M. W. Barnhart, C. W. Bark, J.
L. Goldstein, L. Watkins, F. Xiang, J. Saramies, T. A. Buchanan, R. M.
Watanabe, T. T. Valle, L. Kinnunen, G. R. Abecasis, E. W. Pugh, K. F.
Doheny, R. N. Bergman, J. Tuomilehto, F. S. Collins, and M. Boehnke,
“A genome-wide association study of type 2 diabetes in Finns detects
multiple susceptibility variants,” Science, vol. 316, no. 5829, pp. 1341–
1345, 2007.
[91] V. Steinthorsdottir, G. Thorleifsson, I. Reynisdottir, R. Benediktsson,
T. Jonsdottir, G. B. Walters, U. Styrkarsdottir, S. Gretarsdottir, V. Emils-
son, S. Ghosh, A. Baker, S. Snorradottir, H. Bjarnason, M. C. Ng, T.
Hansen, Y. Bagger, R. L. Wilensky, M. P. Reilly, A. Adeyemo, Y. Chen,
J. Zhou, V. Gudnason, G. Chen, H. Huang, K. Lashley, A. Doumatey, W.
Y. So, R. C. Ma, G. Andersen, K. Borch-Johnsen, T. Jorgensen, J. V. Van
Vliet-Ostaptchouk, M. H. Hofker, C. Wijmenga, C. Christiansen, D. J.
Rader, C. Rotimi, M. Gurney, J. C. Chan, O. Pedersen, G. Sigurdsson, J.
R. Gulcher, U. Thorsteinsdottir, A. Kong, and K. Stefansson, “A variant
in CDKAL1 influences insulin response and risk of type 2 diabetes,”
Nature Genet., vol. 39, no. 6, pp. 770–775, 2007.
[92] E. Zeggini, M. N. Weedon, C. M. Lindgren, T. M. Frayling, K. S. Elliott,
H. Lango, N. J. Timpson, J. R. Perry, N. W. Rayner, R. M. Freathy, J. C.
Barrett, B. Shields, A. P. Morris, S. Ellard, C. J. Groves, L. W. Harries,
J. L. Marchini, K. R. Owen, B. Knight, L. R. Cardon, M. Walker, G. A.
Hitman, A. D. Morris, A. S. Doney, M. I. Mccarthy, and A. T. Hattersley,
“Replication of genome-wide association signals in UK samples reveals
risk loci for type 2 diabetes,” Science, vol. 316, no. 5829, pp. 1336–1341,
2007.
[93] R. Sladek, G. Rocheleau, J. Rung, C. Dina, L. Shen, D. Serre, P. Boutin,
D. Vincent, A. Belisle, S. Hadjadj, B. Balkau, B. Heude, G. Charpentier,
T. J. Hudson, A. Montpetit, A. V. Pshezhetsky, M. Prentki, B. I. Posner,
D. J. Balding, D. Meyre, C. Polychronakos, and P. Froguel, “A genome-
wide association study identifies novel risk loci for type 2 diabetes,”
Nature, vol. 445, no. 7130, pp. 881–885, 2007.
[94] J. Rung, S. Cauchi, A. Albrechtsen, L. Shen, G. Rocheleau, C. Cavalcanti-
Proenca, F. Bacot, B. Balkau, A. Belisle, K. Borch-Johnsen,
PU et al.: INVESTIGATION ON CARDIOVASCULAR RISK PREDICTION USING GENETIC INFORMATION
G. Charpentier, C. Dina, E. Durand, P. Elliott, S. Hadjadj, M. R. Jarvelin,
J. Laitinen, T. Lauritzen, M. Marre, A. Mazur, D. Meyre, A. Montpetit, C.
Pisinger, B. Posner, P. Poulsen, A. Pouta, M. Prentki, R. Ribel-Madsen,
A. Ruokonen, A. Sandbaek, D. Serre, J. Tichet, M. Vaxillaire, J. F.
Wojtaszewski, A. Vaag, T. Hansen, C. Polychronakos, O. Pedersen, P.
Froguel, and R. Sladek, “Genetic variant near IRS1 is associated with
type 2 diabetes, insulin resistance and hyperinsulinemia,” Nature Genet.,
vol. 41, no. 10, pp. 1110–1115, 2009.
[95] X. Sim, R. T. Ong, C. Suo, W. T. Tay, J. Liu, D. P. Ng, M. Boehnke, K. S.
Chia, T. Y. Wong, M. Seielstad, Y. Y. Teo, and E. S. Tai, “Transferability
of type 2 diabetes implicated loci in multi-ethnic cohorts from Southeast
Asia,” PLoS Genet., vol. 7, no. 4, art no. e1001363, 2011.
[96] E. J. Parra, J. E. Below, S. Krithika, A. Valladares, J. L. Barta, N. J.
Cox, C. L. Hanis, N. Wacher, J. Garcia-Mena, P. Hu, M. D. Shriver,
DIAGRAM Consortium, J. Kumate, P. M. Mckeigue, J. Escobedo, and
M. Cruz, “Genome-wide association study of type 2 diabetes in a sample
from mexico city and a meta-analysis of a mexican-american sample
from starr county, Texas,” Diabetologia, vol. 54, no. 8, pp. 2038–2046,
2011.
[97] Y. Okada, A. Takahashi, H. Ohmiya, N. Kumasaka, Y. Kamatani,
N. Hosono, T. Tsunoda, K. Matsuda, T. Tanaka, M. Kubo, Y. Naka-
mura, K. Yamamoto, and N. Kamatani, “Genome-wide association
study for C-reactive protein levels identified pleiotropic associations
in the IL6 locus,” Hum. Mol. Genet., vol. 20, no. 6, pp. 1224–1231,
2010.
[98] P. Elliott, J. C. Chambers, W. Zhang, R. Clarke, J. C. Hopewell, J.
F. Peden, J. Erdmann, P. Braund, J. C. Engert, D. Bennett, L. Coin, D.
Ashby, I. Tzoulaki, I. J. Brown, S. Mt-Isa, M. I. Mccarthy, L. Peltonen, N.
B. Freimer, M. Farrall, A. Ruokonen, A. Hamsten, N. Lim, P. Froguel, D.
M. Waterworth, P. Vollenweider, G. Waeber, M. R. Jarvelin, V. Mooser,
J. Scott, A. S. Hall, H. Schunkert, S. S. Anand, R. Collins, N. J. Samani,
H. Watkins, and J. S. Kooner, “Genetic loci associated with C-reactive
protein levels and risk of coronary heart disease,” J. Amer. Med. Assoc.,
vol. 302, no. 1, pp. 37–48, 2009.
[99] A. P. Reiner, M. J. Barber, Y. Guan, P. M. Ridker, L. A. Lange, D. I.
Chasman, J. D. Walston, G. M. Cooper, N. S. Jenny, M. J. Rieder, J. P.
Durda, J. D. Smith, J. Novembre, R. P. Tracy, J. I. Rotter, M. Stephens,
D. A. Nickerson, and R. M. Krauss, “Polymorphisms of the HNF1A
gene encoding hepatocyte nuclear factor-1 alpha are associated with C-
reactive protein,” Amer. J. Hum. Genet., vol. 82, no. 5, pp. 1193–1201,
2008.
[100] P. M. Ridker, G. Pare, A. Parker, R. Y. Zee, J. S. Danik, J. E. Buring, D.
Kwiatkowski, N. R. Cook, J. P. Miletich, and D. I. Chasman, “Loci related
to metabolic-syndrome pathways including LEPR, HNF1A, IL6R, and
GCKR associate with plasma C-reactive protein: The Women’s Genome
Health Study,” Amer. J. Hum. Genet., vol. 82, no. 5, pp. 1185–1192,
2008.
[101] A. Dehghan, J. Dupuis, M. Barbalic, J. C. Bis, G. Eiriksdottir, C. Lu, N.
Pellikka, H. Wallaschofski, J. Kettunen, P. Henneman, J. Baumert, D. P.
Strachan, C. Fuchsberger, V. Vitart, J. F. Wilson, G. Pare, S. Naitza, M.
E. Rudock, I. Surakka, E. J. De Geus, B. Z. Alizadeh, J. Guralnik, A.
Shuldiner, T. Tanaka, R. Y. Zee, R. B. Schnabel, V. Nambi, M. Kavousi,
S. Ripatti, M. Nauck, N. L. Smith, A. V. Smith, J. Sundvall, P. Scheet,
Y. Liu, A. Ruokonen, L. M. Rose, M. G. Larson, R. C. Hoogeveen, N.
B. Freimer, A. Teumer, R. P. Tracy, L. J. Launer, J. E. Buring, J. F.
Yamamoto, A. R. Folsom, E. J. Sijbrands, J. Pankow, P. Elliott, J. F.
Keaney, W. Sun, A. P. Sarin, J. D. Fontes, S. Badola, B. C. Astor, A.
Hofman, A. Pouta, K. Werdan, K. H. Greiser, O. Kuss, H. E. Meyer Zu
Schwabedissen, J. Thiery, Y. Jamshidi, I. M. Nolte, N. Soranzo, T. D.
Spector, H. Volzke, A. N. Parker, T. Aspelund, D. Bates, L. Young, K.
Tsui, D. S. Siscovick, X. Guo, J. I. Rotter, M. Uda, D. Schlessinger, I.
Rudan, A. A. Hicks, B. W. Penninx, B. Thorand, C. Gieger, J. Coresh, G.
Willemsen, T. B. Harris, A. G. Uitterlinden, M. R. Jarvelin, K. Rice, D.
Radke, V. Salomaa, K. Willems Van Dijk, E. Boerwinkle, R. S. Vasan,
L. Ferrucci, Q. D. Gibson, S. Bandinelli, H. Snieder, D. I. Boomsma,
X. Xiao, H. Campbell, C. Hayward, P. P. Pramstaller, C. M. Van Duijn,
L. Peltonen, B. M. Psaty, V. Gudnason, P. M. Ridker, G. Homuth, W.
Koenig, C. M. Ballantyne, J. C. Witteman, E. J. Benjamin, M. Perola,
and D. I. Chasman, “Meta-analysis of genome-wide association studies
in >80 000 subjects identifies multiple loci for C-reactive protein levels,”
Circulation, vol. 123, no. 7, pp. 731–738, 2011.
[102] Y. Wu, T. W. Mcdade, C. W. Kuzawa, J. Borja, Y. Li, L. S. Adair, K.
L. Mohlke, and L. A. Lange, “Genome-wide association with C-reactive
protein levels in CLHNS: evidence for the CRP and HNF1A loci and their
interaction with exposure to a pathogenic environment,” Inflammation,
vol. 35, no. 2, pp. 574–583, 2012.
807
[103] G. Thanassoulis and R. S. Vasan, “Genetic cardiovascular risk
prediction—Will we get there?” Circulation, vol. 122, no. 22, pp. 2323–
2334, 2010.
[104] J. P. A. Ioannidis, “Prediction of cardiovascular disease outcomes
and established cardiovascular risk factors by genome-wide associa-
tion markers,” Circ. Cardiovasc. Genet., vol. 2, no. 1, pp. 7–15,
2009.
[105] N. P. Paynter, D. I. Chasman, J. E. Buring, D. Shiffman, N. R. Cook, and
P. M. Ridker, “Cardiovascular disease risk prediction with and without
knowledge of genetic variation at chromosome 9p21.3,” Ann. Intern.
Med., vol. 150, no. 2, pp. 65–72, 2009.
[106] A. Brautbar, C. M. Ballantyne, K. Lawson, V. Nambi, L. Chambless, A.
R. Folsom, J. T. Willerson, and E. Boerwinkle, “Impact of adding a single
allele in the 9p21 locus to traditional risk factors on reclassification of
coronary heart disease risk and implications for lipid-modifying therapy
in the atherosclerosis risk in communities study,” Circ. Cardiovasc.
Genet., vol. 2, no. 3, pp. 279–285, 2009.
[107] P. J. Talmud, J. A. Cooper, J. Palmen, R. Lovering, F. Drenos, A. D.
Hingorani, and S. E. Humphries, “Chromosome 9p21.3 coronary heart
disease locus genotype and prospective risk of CHD in healthy middle-
aged men,” Clin. Chem., vol. 54, no. 3, pp. 467–474, 2008.
[108] A. G. Sousa, N. H. Lopes, W. A. Hueb, J. E. Krieger, and A. C. Pereira,
“Genetic variants of diabetes risk and incident cardiovascular events in
chronic coronary artery disease,” PLoS One, vol. 6, no. 1, art no. e16341,
2011.
[109] Y. Yamada, H. Izawa, S. Ichihara, F. Takatsu, H. Ishihara, H. Hirayama,
T. Sone, M. Tanaka, and M. Yokota, “Prediction of the risk of myocardial
infarction from polymorphisms in candidate genes,” New Engl. J. Med.,
vol. 347, no. 24, pp. 1916–1923, 2002.
[110] R. Y. Zee, N. R. Cook, S. Cheng, H. A. Erlich, K. Lindpaintner, and
P. M. Ridker, “Multi-locus candidate gene polymorphisms and risk of
myocardial infarction: A population-based, prospective genetic analy-
sis,” J. Thromb. Haemost., vol. 4, no. 2, pp. 341–348, 2006.
[111] A. C. Morrison, L. A. Bare, L. E. Chambless, S. G. Ellis, M. Malloy,
J. P. Kane, J. S. Pankow, J. J. Devlin, J. T. Willerson, and E. Boerwinkle,
“Prediction of coronary heart disease risk using a genetic risk score:
The atherosclerosis risk in communities study,” Amer. J. Epidemiol.,
vol. 166, no. 1, pp. 28–35, 2007.
[112] S. E. Humphries, J. A. Cooper, P. J. Talmud, and G. J. Miller, “Candidate
gene genotypes, along with conventional risk factor assessment, improve
estimation of coronary heart disease risk in healthy UK men,” Clin.
Chem., vol. 53, no. 1, pp. 8–16, 2007.
[113] S. Kathiresan, O. Melander, D. Anevski, C. Guiducci, N. P. Burtt,
C. Roos, J. N. Hirschhorn, G. Berglund, B. Hedblad, L. Groop, D. M.
Altshuler, C. Newton-Cheh, and M. Orho-Melander, “Polymorphisms
associated with cholesterol and risk of cardiovascular events,” New
Engl. J. Med., vol. 358, no. 12, pp. 1240–1249, 2008.
[114] F. Licastro, M. Chiappelli, E. Porcellini, G. Campo, M. Buscema,
E. Grossi, F. Garoia, and R. Ferrari, “Gene-gene and gene-clinical fac-
tors interaction in acute myocardial infarction: A new detailed risk chart,”
Curr. Pharm. Des., vol. 16, no. 7, pp. 783–788, 2010.
[115] N. P. Paynter, D. I. Chasman, G. Pare, J. E. Buring, N. R. Cook,
J. P. Miletich, and P. M. Ridker, “Association between a literature-based
genetic risk score and cardiovascular events in women,” J. Amer. Med.
Assoc., vol. 303, no. 7, pp. 631–637, 2010.
[116] M. Junyent, K. L. Tucker, J. Shen, Y. C. Lee, C. E. Smith, J. Mattei,
C. Q. Lai, L. D. Parnell, and J. M. Ordovas, “A composite scoring of
genotypes discriminates coronary heart disease risk beyond conventional
risk factors in the Boston Puerto Rican Health Study,” Nutr. Metab.
Cardiovasc. Dis., vol. 20, no. 3, pp. 157–164, 2010.
[117] L. Qi, J. Ma, Q. Qi, J. Hartiala, H. Allayee, and H. Campos, “Genetic
risk score and risk of myocardial infarction in Hispanics,” Circulation,
vol. 123, no. 4, pp. 374–380, 2011.
[118] A. C. J. W. Janssens, Y. S. Aulchenko, S. Elefante, G. J. Borsboom,
E. W. Steyerberg, and C. M. Van Duijn, “Predictive testing for complex
diseases using multiple genes: Fact or fiction?” Genet. Med., vol. 8,
no. 7, pp. 395–400, 2006.
[119] M. Nurminen, “To use or not to use the odds ratio in epidemiologic
analyses?” Eur. J. Epidemiol., vol. 11, no. 4, pp. 365–371, 1995.
[120] T. A. Manolio, F. S. Collins, N. J. Cox, D. B. Goldstein, L. A. Hindorff,
D. J. Hunter, M. I. Mccarthy, E. M. Ramos, L. R. Cardon, A. Chakravarti,
J. H. Cho, A. E. Guttmacher, A. Kong, L. Kruglyak, E. Mardis, C. N.
Rotimi, M. Slatkin, D. Valle, A. S. Whittemore, M. Boehnke, A. G. Clark,
E. E. Eichler, G. Gibson, J. L. Haines, T. F. Mackay, S. A. Mccarroll, and
P. M. Visscher, “Finding the missing heritability of complex diseases,”
Nature, vol. 461, no. 7265, pp. 747–753, 2009.
808 IEEE TRANSACTIONS ON INFORMATION TECHNOLOGY IN BIOMEDICINE, VOL. 16, NO. 5, SEPTEMBER 2012
Li-Na Pu received the M.S. degree from Peking
Union Medical College, Tsinghua University,
Beijing, China, in 2009.
She is currently an Assistant Professor at the Shen-
zhen Institutes of Advanced Technology, Chinese
Academy of Sciences, Beijing. Her current research
interests include biosignal processing, biomodeling,
and health informatics.
Ze Zhao received the B.S. and M.S. degrees
from Northeastern University, Shenyang, China, in
2007 and 2009, respectively, both in biomedical
engineering.
From January 2009 to February 2012, she was a
Research assistant at the Chinese University of Hong
Kong, Shatin, Hong Kong, and Shenzhen Institutes
of Advanced Technology, Chinese Academy of Sci-
ences, Beijing. During the study and work, her re-
search interests include biomedical image and signal
processing with wearable biomedical devices.
Yuan-Ting Zhang (M’90–SM’93–F’06) received
the Ph.D. degree from the University of New
Brunswick, Fredericton, NB, Canada, in 1990.
He is the Director of Joint Research Center for
Biomedical Engineering and a Professor in the De-
partment of Electronic Engineering, Chinese Univer-
sity of Hong Kong, Shatin, Hong Kong. He is also
the Director of the Key Lab for Health Informatics of
the Chinese Academy of Sciences, Shenzhen, China.
He has authored/coauthored more than 400 scien-
tific publications and 11 book chapters, and filed 31
patents. He has provided extensively professional services of significant value to
the local industries and global academic communities. His research spans sev-
eral fields, including wearable medical devices, body sensor networks, bio-THz
technologies, biomodeling and biosignal processing, neural engineering, health
informatics, and p-Health technologies, and is closely tied up to his teaching
and publishing activities.
Dr. Zhang was the Associate Editor of the IEEE TRANSACTIONS ON BIOMED-
ICAL ENGINEERING, founding Associate Editor of the IEEE TRANSACTIONS ON
MOBILE COMPUTING, and the Guest Editor for the IEEE TRANSACTIONS ON
INFORMATION TECHNOLOGY IN BIOMEDICINE and IEEE Communication Maga-
zine. He was previously the Vice President of the IEEE Engineering in Medicine
and Biology Society (EMBS) during 2000–2001. He served as the Technical
Program Chair and the General Conference Chair of the 20th and 27th IEEE-
EMBS Annual International Conferences in 1998 and 2005, respectively. He
currently serves on the International Academy of Medical and Biological En-
gineering Fellow Nomination Committee, the IEEE Medal on Innovations in
Healthcare Technology Award Committee, the IEEE-EMBS Standard Com-
mittee, HK-ITC Projects Assessment Panel, and the IEEE Fellow Elevation
Committee. He also serves as the Editorial Board Member for the Book Series
of Biomedical Engineering published by IEEE Press and Wiley, Chair of work-
ing group for developing IEEE standard on wearable cuffless blood pressure
measuring devices, and the Editor-in-Chief of the IEEE TRANSACTIONS ON IN-
FORMATION TECHNOLOGY IN BIOMEDICINE. He holds the fellowships from the
International Academy of Medical and Biological Engineering, the IEEE, and
the American Institute of Medical and Biological Engineering in recognition of
his outstanding contributions to the development of wearable medical devices
and mobile health technologies. His research work has won him a number of
awards including Best Journal Paper Awards and APICTA e-Health Award.