Journal of Cardiology (2012) 59, 190194

Available online at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/jjcc

Original article

Coronary heart disease diagnosis by articial neural

networks including genetic polymorphisms and
clinical parameters
Oleg Yu. Atkov (MD, PhD) a, Svetlana G. Gorokhova (MD, PhD) b,,
Alexandr G. Sboev (PhD) c, Eduard V. Generozov (PhD) d,
Elena V. Muraseyeva (MD, PhD) e, Svetlana Y. Moroshkina d,
Nadezhda N. Cherniy c
a

N.I. Pirogov Russian State Medical University, Moscow, Russia

I.M. Sechenov First Moscow State Medical University, Moscow, Russia
c
MEPhI National Research Nuclear University, Moscow, Russia
d
Research Institute of Physical-Chemical Medicine, Moscow, Russia
e
Central Clinical Hospital No. 2 of Russian Railways JSC, Moscow, Russia
b

Received 18 November 2011; accepted 21 November 2011

Available online 2 January 2012

KEYWORDS
Coronary heart
disease;
Risk factors;
Articial neural
networks

Summary The aim of this study was to develop an articial neural networks-based (ANNs)
diagnostic model for coronary heart disease (CHD) using a complex of traditional and genetic
factors of this disease. The original database for ANNs included clinical, laboratory, functional,
coronary angiographic, and genetic [single nucleotide polymorphisms (SNPs)] characteristics of
487 patients (327 with CHD caused by coronary atherosclerosis, 160 without CHD). By changing
the types of ANN and the number of input factors applied, we created models that demonstrated
6494% accuracy. The best accuracy was obtained with a neural networks topology of multilayer
perceptron with two hidden layers for models included by both genetic and non-genetic CHD
risk factors.
2011 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Introduction

Corresponding author at: 43 ul. Losinoostrovskaya, Moscow,

107150, Russia I.M. Sechenov First Moscow State Medical University, Cardiology Branch of the Department of Family Medicine.
Tel.: +7 903 597 91 95; fax: +7 499 160 12 05.
E-mail address: cafedra2004@mail.ru (S.G. Gorokhova).

The mortality rate caused by coronary heart disease (CHD)

has been changing since the 1990s and, in some industrialized countries, shows a decline. However, morbidity from
myocardial infarction and angina/CHD remains high in some
subgroups, the highest being male workers and the elderly
[16]. It poses a serious problem, and the development of

0914-5087/$ see front matter 2011 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.jjcc.2011.11.005

coronary heart disease diagnostics

methods for CHD prediction is of immediate scientic and
practical interest.
Several algorithms of risk stratication and diagnostic
models for CHD have already been created. They are based
on different sets of risk factors, established in epidemiologic
studies and randomized controlled trials, such as arterial
hypertension, hypercholesterolemia, diabetes mellitus, and
smoking [1,712]. Some authors suggest using a coronary
calcium score [13,14] and retinal vascular signs [15] etc. as
additional factors. Recent developments focus on genetic
markers for prediction of CHD and recommend including
single nucleotide polymorphisms (SNPs) for risk assessment
[1619].
It seems that objective difculties in CHD detection are
caused by the multiplicity of risk factors to be taken into
consideration. This makes it necessary to survey the structure of the variable risk factors and to create an efcient
classication system. Therefore, the development of algorithms for correct classication of CHD risk factors is an
important problem. Nowadays, computer methods of intelligent data processing are available and applied for this
purpose, and, on this basis, expert medical systems have
been created.
One of these promising methods is articial neural networks (ANNs), a highly effective tool used in classication
tasks, as well as to solve many important problems, such as
signal enhancement, identication, and prediction of signals
and factors. The important feature of ANNs is their adaptivity. This enables them to be applied in cases when it is
impossible to create a strict mathematical model but where
there is a sufciently representative set of samples. The
other important characteristic of neural networks is their
capacity to generalize input information and to give correct
answers for unfamiliar data, which makes them effective in solving complicated classication problems [20,21].
Today, ANNs are applied in clinical and genetic research.
Attempts have been made to create diagnostic models for
various diseases with the use of ANNs of different topologies [2225]. It is assumed that using complexes of signs of
CHD will allow ANNs to not only diagnose, but also to predict
clinically signicant events, myocardial infarction being the
rst.
The aim of this study was to develop an ANNs-based diagnostic model for CHD using the complex of traditional and
genetic factors of this disease.

Materials and methods

The study included 487 patients (males 425, females
62, mean age: 51.25 9.74 years) hospitalized in Central
Clinical Hospital No. 2 of Russian Railways JSC for a coronary angiography to diagnose CHD. All patients underwent
uniform standard clinical examinations (laboratory tests,
electrocardiogram, Holter monitoring, stress tests, echocardiography etc.), coronary angiography (Advantx, General
Electric, Waukesha, WI, USA), and genetic analysis. The
diagnosis of CHD was made following both the clinical and
coronarography results. The information obtained from testing and genotyping allowed us to create a database of
patients that was subsequently used to diagnose CHD using
ANNs.

191

Risk factors
CHD risk factors included in the analysis were: age,
gender, total cholesterol, high-density lipoprotein (HDL)
cholesterol, low-density lipoprotein (LDL) cholesterol, verylow-density lipoprotein (VLDL) cholesterol, triglycerides,
cholesterol ratio, fasting plasma glucose, arterial hypertension, diabetes mellitus, current tobacco smoking status,
obesity (Quetelet index, body mass index BMI > 30), and a
family history of CHD. Additional factors taken into account
were profession (locomotive driving), risk of fatal cardiovascular disease according to the European SCORE project
scale (SCORE index) [1], left ventricular ejection fraction,
and coronary angiography data.

Genotyping
Genotyping was performed by an allele-specic primer
extension of multiplex amplied products and detection
with a matrix-assisted laser desorption/ionization time-ofight mass spectroscopy on an AutoPhlex II MALDI-TOF MS
(Bruker Daltonics, Billerica, MA, USA). The analyzed panel
includes 14 SNPs localized in genes involved in CHD pathogenesis: lipoprotein lipase [LIPC 250G/A (rs2070895) and
LIPC 514C/T (rs1800588)], nitric oxide synthase [NOS E298D
(rs1799983)], methylenetetrahydrofolate reductase [MTHFR
A223V (rs1801133)], angiotensin-converting enzyme [ACE
Alu Ins/Del I>D (rs4646994)], angiotensinogen [AGT M235T
(rs699)], and AGT T174M (rs4762) variants, angiotensin
II type 1 receptor [AGTR A1166C (rs5186)], plasminogen
activator inhibitor-1 [PAI-1 5G/4G (rs1799889)], and Creactive protein [CRP-1 (rs1800947)], CRP-2 (rs1417938),
CRP-3 (rs1205), CRP-4 (rs3093068), and CRP-5 (rs1130864)].

Articial neural network

The neural network model was created using a multilayer
perceptron, the multi-level neural feedforward network
taught by the statistical backpropagation of error. The sets
of variable parameters were selected in order to adjust
ANN models by pairwise correlation between the database
parameters and CHD diagnosis.
Accuracy of models was improved by a genetic algorithm with different optimization parameters [26] including
number of neurons in the hidden layer, number of inputs
to the neural network, and slope coefcient of activation
functions. NeuroSolutions 5.0 development environment
(NeuroDimension Inc., Gainesville, FL, USA) was used to
check the possibilities of optimization.
The ANN was created by inputting the specied variable
factors. The task to solve was of two-class classication:
1 CHD, 0 healthy. A total of 287 examples were
used for teaching, 100 for cross-validation, and 100 for testing.

Results
Based on the results of the clinical instrumental research,
CHD caused by coronary atherosclerosis was diagnosed in

192
Table 1

O.Yu. Atkov et al.

Accuracy of ANN models for CHD diagnosis.a

Model

Factors

Accuracy (%)

Age, profession, diabetes, arterial hypertension, smoking, obesity, family anamnesis of

CHD, glucose, cholesterol
Age, profession, diabetes, arterial hypertension, smoking, obesity, family anamnesis of
CHD, glucose, cholesterol
Age, profession, diabetes, arterial hypertension, smoking, obesity, family anamnesis of
CHD, glucose, total cholesterol, HDL, LDL, VLDL, triglycerides, cholesterol ratio
Age, profession, diabetes, arterial hypertension, smoking, obesity, heredity, glucose,
total cholesterol, HDL, LDL, VLDL, triglycerides, cholesterol ratio, coronary angiography
data
NOS, ACE, AGT-235, AGT-174, AGTR, CRP-1, CRP-2, CRP-3 SNPs
NOS, ACE, AGT-235, AGT-174, AGTR, CRP-1, CRP-2, CRP-3 SNPs, SCORE index
NOS, ACE, AGT-235, AGT-174, AGTR, CRP-1, CRP-2, CRP-3 SNPs, coronary angiography
data
NOS, ACE, AGT-235, AGT-174, AGTR, CRP-1, CRP-2, CRP-3 SNPs, SCORE index, coronary
angiography data
NOS, ACE, AGT-235, AGT-174, AGTR, CRP-1, CRP-2, CRP-3 SNPs, HDL, LDL, glucose
NOS, ACE, AGT-235, AGT-174, AGTR, CRP-1, CRP-2, CRP-3 SNPs, age, smoking, obesity,
family anamnesis of CHD, HDL, LDL

64

II
III
IV

V
VI
VII
VIII
IX
X

77
83
91

90
83
89
93
90
88

CHD, coronary heart disease; HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol; VLDL, very-low-density
lipoprotein cholesterol; SNP, single nucleotide polymorphisms.
a In all cases, the multilayer perceptron neuronal network topology with two buried 4-neuron layers was used.

327 (67.2%) patients. A total of 160 (32.8%) patients had an

intact coronary artery wall and no evidence of CHD.
Correlation analysis between the specied variable factors and CHD allowed us to choose 32 factors associated with
the disease. These factors were analyzed by ANNs.
Approaches using different ANN types and a variable
number of input factors (from 5 to 10) led to the models with 6494% diagnostic accuracy. The best result (94%)
was achieved in a multilayer perceptron (MLP) model with
two buried layers and 10 factors (profession, LDL, HDL,
triglycerides, cholesterol rate, SCORE index, left ventricular
ejection fraction, family CHD history, coronary arteriography data, PAI gene). On the other hand, the same ANN
type with 5 factors (coronary arteriography data, cholesterol rate, SCORE index, left ventricular ejection fraction,
PAI gene) had a lower diagnostic accuracy (78%). However, the same 10 factors analyzed by other ANN types
yielded a 79% result. This suggests that the diagnostic accuracy depends on the ANN type and the number of variable
factors.
The next step included an analysis of 10 models of CHD
prediction formed by different combinations of examination
blocks (demographic characteristics, CHD history, laboratory
tests, echocardiography and coronary angiography data,
genes) by the MLP with two buried 4-neuron layers. The number of variable input factors ranged from 8 (models I and V)
to 15 (model IV). The results are shown in Table 1. The minimal accuracy of 64% was obtained in model I, which included
8 non-genetic factors. Models IV, V, VIII, and IX, which had
signicantly different sets of variables, showed 90% diagnostic accuracy. Model IV included only non-genetic factors;
model V included only eight SNPs (NOS, ACE, AGT-235, AGT174, AGTR, CRP-1, CRP-2 and CRP-3); model VIII included the

same SNPs in combination with coronary angiography data

and SCORE index; model IX included the same SNPs and HDL,
LDL, and glucose. Thereby the optimal accuracy was more
often achieved when a diagnostic model included genetic
factors.

Discussion
One of the modern approaches to the solution of classication problems is intelligent data processing based on
resolving optimization tasks using ANNs. Our results suggest
that ANNs may also be used to create a highly accurate and
effective model for CHD prediction.
In this research we have examined the inuence of different parameters, teaching methods, and neural network
topologies on the accuracy of CHD diagnosis. We revealed
that the optimal topology to resolve this classication task
is a MLP with two buried layers. The optimal input parameters are 810 of the most signicant factors: the use of all
factors seems to excessively complicate the model, while,
at the same time, smaller numbers do not provide essential
information for resolving this problem. It is of interest to
note that, in some models, the accuracy of CHD diagnosis
was lower than 90% in spite of including coronary arteriography data, which are considered the gold standard for
CHD diagnosis in clinical practice.
Publications on the possibilities of cardiologic application of articial intelligence, ANN, rst of all, are usually
limited to different combinations of traditional laboratory
and instrumental methods [2225]. Therefore, the novelty
of our study is the inclusion of genes as risk factors in order to
estimate capabilities of CHD prediction. In this connection,

coronary heart disease diagnostics

it is important to note that the accuracy of the diagnosis
based on genetic factors only was found to be almost equal
to that in the model combining 15 non-genetic factors (90%
and 91%, respectively). The most informative (93%) was the
model that included 8 SNPs, SCORE index, and coronary arteriography data. Taking into account the fact that genetic
information is a permanent parameter, it can be assumed
that analysis of NOS, ACE, AGT-3, AGT-4, AGTR, CRP-1, CRP2, and CRP-3 SNPs enables prediction of CHD with a high
accuracy.
The diagnostic accuracy can be improved not only by
increasing the number of genetic markers, but also by their
precise selection. Good candidates for consideration may
be genes involved in vascular cell growth, apoptosis, and
inammation, or others associated with CHD, e.g. ABCA1
(ATP-binding cassette-transporter A1), CYP1A2 (cytochrome
P450), ADRB group (-adrenoreceptors), HSF1 (heat shock
factors) [27], CLOCK, and BMAL1 [28]. The last ones are
of interest because they are associated with the regulation
of circadian rhythms, including those in the cardiovascular
system [29].
The obtained experience in the development of neural
network models for CHD prediction constitutes a basis for
the design of applied software products for the diagnosis of
cardiovascular diseases, including screening tests.

Conclusion
The purpose of this study was to create CHD diagnostic models with appropriate analytical characteristics using
MLP ANNs. The best accuracy was obtained in models that
included both genetic and non-genetic factors associated
with the disease. The models of >90% accuracy may serve as
the basis for the development of software tools for diagnosis
and prediction of CHD.

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