Computational Intelligence Methods for the

Identification of Early Cardiac Autonomic

Neuropathy
David Cornforth Mika Tarvainen Herbert F. Jelinek
School of Design, Communication and IT Department of Physics and Mathematics Centre for Research in Complex Systems
University of Newcastle University of Eastern Finland Charles Sturt University
Callaghan, Australia Kuopio, Finland Albury, Australia
Email: David.Cornforth@newcastle.edu.au Email: Mika.Tarvainen@uaf.fi Email: Herbert.Jelinek@csu.edu.au

Abstract—Cardiac Autonomic Neuropathy (CAN) is a disease

that involves nerve damage leading to abnormal control of heart
rate. CAN affects the correct operation of the heart and in turn
leads to associated co-morbidities. An open question is to what
extent this condition is detectable by the measurement of Heart
Rate Variability (HRV). However, if possible we wish to detect
CAN in its early stage, to improve treatment and outcomes.
HRV provides information only on the interval between heart
beats, but is relatively non-invasive and easy to obtain. HRV
has been conventionally analysed with time- and frequency-
domain methods, however more recent analysis methods have
shown an increased sensitivity for identifying risk of future
morbidity and mortality in diverse patient groups. A promising
non-linear method is the Renyi entropy, which is calculated by Fig. 1. Normal ECG recording showing RR interval.
considering the probability of sequences of values occurring in
the HRV data. An exponent α of the probability can be varied
to provide a spectrum of measures. In previous work we have the health outlook and quality of life for those people living
shown a difference in the Renyi spectrum between participants with CAN. This work provides that possibility.
identified with CAN and controls. In this work we applied
the multi-scale Renyi entropy, as well as a variety of other A standard ECG signal is shown in Fig. 1. This type of
measures, for identification of early CAN in diabetes patients, signal has been extensively studied and the diagnostic value
using computational intelligence methods. The work was based of the different features is well established. ECG features are
on measurements from 67 people with early CAN and 71 controls. referred to using letters. The large spike is referred to as the
Results suggest that Renyi entropy forms a useful contribution to QRS complex, with R being the peak of the wave or fiducial
the detection of CAN even in the early stages of the disease, and
that it can be distinguished from controls with a correct rate of point, while the smaller peak to the left is the P wave and to
68%. This is a significant achievement given the simple nature the right of the QRS is the T wave. The signal is degraded
of the information collected, and raises prospects of a simple by the presence of noise, so that the most reliable feature that
screening test and improved outcomes of patients. can be obtained from low quality recordings (and therefore
the most easily obtained measurement) is the interval between
I. I NTRODUCTION successive R peaks, known as the RR interval, NN interval
What are the prospects for detecting Cardiac Autonomic or heart rate. This can be expressed as beats per minute and
Neuropathy (CAN) at an early stage from the analysis of Heart varies considerably between individuals, but a typical rate is
Rate Variability (HRV) alone? This paper describes recent 60-80 beats per minute. The natural rhythm of the human heart
work using advanced Signal Processing and Computational is subject to variation that is believed to indicate the health
Intelligence methods to explore the frontiers of diagnostic of the cardiovascular system. RR intervals are obtained from
ability of the simple and relatively non-invasive measurement the recorded ECG and subjected to further analysis through a
of HRV. Detection of CAN is difficult as current tests are variety of algorithms in order to yield variables with good
invasive and labour intensive, and many people at risk of this discriminant power. However, the RR interval can also be
disease are not routinely screened. Detection of CAN at an obtained from a simple and cheap chest strap device, which
early stage would greatly assist in management of this disease. makes it particularly suitable as a non-invasive test which may
The possibility of automatic detection of early CAN from a encourage more people to be screened.
simple measure such as HRV would be a huge leap forward in For the purposes of further analysis, the RR interval can
terms of detection and most importantly, in terms of improving also be expressed as the time between beats (measured in

978-1-4673-6322-8/13/$31.00 2013
c IEEE 929
 while the power is expressed as ms2 or when normalised is
expressed in normalised units (n.u.). The ratio of low to high
frequency components is also calculated as well as the total
power (ms2 ) [4].
Detrended Fluctuation Analysis (DFA) was introduced for
characterising the RR interval by [6]. To obtain DFA alpha1
(the short time correlation exponent) and alpha2 (the long time
Fig. 2. Normal R-R interval graph.
correlation exponent), the RR time series is first integrated
and the integrated series y(k) divided into segments of equal
milliseconds), and this can be plotted against time to produce length n. The trend in RR intervals in each of the segments
the graph shown in Fig. 2. This illustrates the natural variation is determined by fitting a least squares lines to the data. The
of RR interval that is indicative of a healthy cardiac system, y(k) is detrended by subtracting the local trend, yn (k), in each
as the heart rate is continuously varied to adapt to current segment. The average fluctuation of segment size n is indicated
needs of oxygenation and perfusion. It is the absence of such as F (n) in the equation:
a variation that can indicate cardiac disease. 
 N
HRV has been conventionally analysed with time- and 1 
F (n) = 
2
frequency-domain methods. Time domain methods are gener- (y(k) − yn (k)) (1)
N
ally variations upon moments of RR intervals; frequency based k=1

methods include Fourier analysis; and non-linear methods where N is the total length of the heart rate signal and
include fractal analysis and entropy measures. More recent k is the heart rate signal number. F (n) is repeated over
non-linear analysis has shown an increased sensitivity for segment sizes from 4 beats to 64 beats to provide a relationship
identifying risk of future morbidity and mortality in diverse between F (n) and segment size n. F (n) typically increases
patient groups. For example, an estimate of HRV using the with segment size. The slope of the line relating logF (n) to
standard deviation of RR intervals found that this is higher in log(n) provides the scaling exponent (α), with α1 based on
well-functioning hearts but can be decreased in coronary artery smaller segments (4-11 beats) and α2 on larger segments (12
disease, congestive heart failure and diabetic neuropathy [2]. to 64 beats). A value α = 0.5 indicates no correlations exist in
Although HRV is useful in disease detection, when only the the time series (corresponding to white noise). A value α = 1
standard deviation of RR intervals is used, it is no better than indicates the presence of fractal correlation properties (fractal
the average heart rate and in fact contains less information dimension property) and self-similarity. In biological signals
for risk prediction after acute myocardial infarction [3]. This α1 is typically between 0.8 to 1.2 for healthy subjects [7].
indicates that more advanced measures of HRV should be Sample Entropy is the negative natural logarithm of an
explored. Some of the measures derived from the RR interval estimate of the conditional probability that sub-series (epochs)
and used in this work are now discussed. of length m that match pointwise within a tolerance r also
The mean of RR interval is calculated before detrend- match at the next point [8]. D2 is the correlation dimension
ing (see below) and is expressed in milliseconds (ms). The based on fractal analysis.
Standard Deviation of the RR interval (SDNN) is likewise Other measures are derived from properties of the recur-
calculated before detrending and is also expressed in ms. rence plot, which is constructed by comparing all samples with
The square root of the mean squared difference of successive all others to create a square matrix. At each location of the
intervals is abbreviated to RMSSD (ms). The number of pairs matrix a point is placed if the two samples are sufficiently
of successive intervals that differ by more than 50ms divided close, otherwise the location is left blank. The recurrence rate
by the total number of intervals is known as pNN50. The HRV (REC) is the percentage of points drawn on the plot. The
triangular index is based on estimating the density distribution determinism (DET) is the percentage of points that form lines
of RR intervals. The area under the curve (integral) provides parallel to the main diagonal. The mean line length (Lmean)
the number of all intervals and is divided by the maximum is the mean of lines parallel to the main diagonal [9].
value of the distribution [4]. The triangular interpolation of the More recent analysis methods, including entropy measures,
interval histogram (TINN) is the estimated width of the density have shown an increased sensitivity for identifying risk of fu-
distribution. The Poincaré plot is a visual representation of the ture morbidity and mortality in cardiac patients. Renyi entropy
time series and is constructed by plotting each consecutive has shown significant differentiation of cardiovascular disease,
RR interval as a point where y = RRt and x = RRt−1 . An along with several other measures. In previous work, we have
ellipse is fitted to the resulting cloud of points and the major shown that Renyi Entropy can distinguish CAN from controls
and minor axes of the ellipse are estimated as SD1 and SD2, [1]. In this work we show that it is useful in distinguishing
both expressed as ms [5]. CAN even in the early stages of the disease.
Frequency domain methods divide the spectral distribution
into regions labelled as low or high frequency. Low frequency II. T HE M ULTI -S CALE R ENYI E NTROPY
is regarded as in the range 0.04-0.15 Hz while high frequency The multi-scale Renyi entropy was introduced and applied
is in the range 0.15-0.4 Hz. The peak value is expressed as Hz to physiologic time series by [10]. Renyi entropy Hα is a

930 2013 IEEE 8th Conference on Industrial Electronics and Applications (ICIEA)
generalisation of the Shannon entropy: subsets. A number of tests are performed where each subset
 n  in turn becomes the holdout set. In this way the classifier is
1  tested against all available data.
α
Hα (X) = log2 pi (2)
1−α i=1
A number of automated classifier algorithms are available
using the excellent Weka toolbox [14]. For this work we have
where pi is the probability that X = x and α is the order selected one algorithm from each major group available in
of the entropy measure. Varying α produces the multiscale Weka, to provide an overview of what performance can be
entropy. The probability can be estimated by comparing the expected. These are briefly discussed below.
sample i with all other samples by estimating the probability The Nave Bayes algorithm [15] estimates prior probabilities
density function of all other samples xj then estimating pi as by calculating simple frequencies of the occurrence of each
the probability given by this density function: feature value given each class, then returns a probability of
n
  each class, given an unclassified set of features.
 −dist2ij
pi = exp (3) Sequential Minimal Optimisation (SMO) is a classifier
j=0
2σ 2 based on the Support Vector Machine (SVM). The SVM builds
a set of exemplars that define the boundaries of the different
where σ is a parameter controlling the width of the density
classes. SMO builds on this using polynomial kernels [16].
function and dist() is a distance measure:
The Nearest Neighbours algorithm [17] simply stores sam-
π
 ples. When an example is presented to the classifier, it looks
2
distij = (xi+k − xj+k ) (4) for the nearest match from the examples in the training set,
k=0 and labels the unknown example with the same class.
Here, π is the pattern length over which comparison occurs. The Decision Table algorithm divides the dataset into cells,
In this work the multi-scale Renyi Entropy was calculated from where each cell contains identical records. A record with
−5 < α < +5, where α = 0 is the Shannon entropy and α = 2 unknown class is assigned the majority, or most frequent, class
is the squared entropy. represented in the cell [18].
The Decision Tree Induction algorithm [19] uses the C4.5
III. C OMPUTATIONAL I NTELLIGENCE M ETHODS algorithm to form a tree by splitting each variable and mea-
This work relies on a number of data analytic methods, Ma- suring the information gain provided. The split with the most
chine Learning and Genetic Algorithms. Principal Component information gain is chosen, and then the process is repeated
Analysis (PCA) is a transformation from a multidimensional until the information gain provided is below a threshold.
space to a smaller dimensional space consisting of uncorrelated In order to apply these techniques to real problems, it
variables. It is commonly used for dimensionality reduction in is necessary to obtain a number of measures, or features,
data analysis and is often one of the first methods used in which can form the input vector u. These are the measures
exploratory data analysis. discussed above. It is to be expected that of the many measures
Automatic discrimination of different categories or classes available, some are better than other at discriminating between
(such as early CAN or normal) is a well-studied class of the classes. Methods for choosing the best feature set for
computational intelligence. Here the key is to determine some detecting cardiac dysfunction have been demonstrated by Teich
relationship between a set of input vectors that represent and co-workers [20]. However, in this study we are concerned
stimuli, and a corresponding set of values on a nominal scale with detecting early CAN.
that represent category or class. The relationship is obtained It is well known that using too many features can actually
by applying an algorithm to training samples that are 2-tuples degrade accuracy of the prediction, so optimising the accuracy
< u, z >, consisting of an input vector u and a class label of such methods involves a choice not only of classifier
z. The learned relationship can then be applied to instances algorithm, but also of the appropriate features. Kohavi suggests
of u not included in the training set, in order to discover the that the optimum feature subset will depend on the classifier
corresponding class label z [11]. A number of computational model chosen [21]. Therefore the subset may be considered
intelligence techniques including neural networks [12] have a parameter of the model. In addition, Kohavi suggests a
been shown to be very effective for solving such problems. Wrapper approach where the actual classifier algorithm is used
In evaluating the performance of any classifier, the accuracy to evaluate the features selected, and perform a search for the
is the most common measure used. In order to avoid bias in set of features that maximises classifier accuracy. The Weka
reporting this figure, it is necessary to report the accuracy on package also provides a Wrapper algorithm that can be used
data not seen by the classifier during training. This requires in conjunction with a number of search algorithms.
splitting the available data into two sets, the training set and The Genetic Algorithm (GA) is a search method suitable
the holdout set. The classifier is trained on the first dataset then for Wrapper evaluation for the feature subset, and in operation
evaluated by its performance on the holdout set. The holdout mimics some features of biological evolution. A GA randomly
set must be chosen carefully to prevent a source of bias. generates a population of candidate solutions then modifies
The most popular way of testing involves the cross validation those solutions in order to bring them closer to some desired
method [13] where the dataset is divided into a number of target [22], [23]. Modification usually involves combining two

2013 IEEE 8th Conference on Industrial Electronics and Applications (ICIEA) 931
 TABLE I
VARIABLES CALCULATED BY ANALYSIS OF THE RR INTERVAL FROM 140
PATIENTS .

Mean RR (ms) LF peak (Hz) LF/HF ratio alpha2

SDNN (ms) HF peak (Hz) Total power (ms2 ) REC (%)
RMSSD (ms) LF power (ms2 ) SD1 (ms) DET (%)
pNN50 (%) HF power (ms2 ) SD2 (ms) Lmean
HRV triang. index LF power (n.u.) Sample Entropy D2
TINN (ms) HF power (n.u.) alpha1

or more solutions together to form a hybrid (in mimicry of

sexual reproduction) and random mutations. The desired target Fig. 3. Graph of the Renyi Entropy spectrum for Normal patients.
is known as the fitness function and in this work we use the
performance of the classifier, or the percentage of correctly
classified cases achieved on unseen data.

IV. M ETHODOLOGY

This work attempted the identification of early CAN in

patients reviewed at the Charles Sturt Diabetes Complications
Screening Group (DiScRi), Australia [24]. This study used the
Ewing battery of tests to identify the presence of early CAN
[25], [26]. Sixty seven participants with early CAN and seventy
one without CAN attending the screening clinic had their lead
II ECG recorded for 20 minutes and beat-to-beat fluctuations
analysed using the methods described above. From the 20-
Fig. 4. Graph of the Renyi Entropy spectrum for patients with early CAN.
minute recording, a 15 minutes segment was taken from the
middle of the original recording to remove start-up artefacts. TABLE II
Only the RR interval was retained, and no other information VARIABLES GIVEN RELATIVELY LARGE WEIGHTINGS IN THE PCA.
from the ECG was utilised in this study. The baseline was
Weighting Variable Weighting Variable
removed by subtracting the mean value of the RR interval from
the RR data. The resulting time series was used to derive the 0.811 HFpeak 0.469 LFpeak
parameters shown in Table I for each patient. -0.672 LFpeak -0.406 H(0)
In addition to these, the Renyi entropy was calculated for -0.517 SampEn -0.405 alpha2
exponents −5 < α < +5, giving a total of 23 + 11 = 34 -0.494 D2 0.403 MeanRR
variables. Before proceeding, we graphed the distribution of
Renyi entropy for all patients in the study. The Renyi entropy
V. R ESULTS
for normal or control patients is shown in Fig. 3, while those
for patients with early CAN are shown in Fig. 4. Both groups PCA resulted in 10 new variables made up of components of
have representatives with Renyi entropy close to 1 for all the original 34 variables. Out of the original variables, the ones
value of α. However, Normal patients have a higher range with the highest weighting are listed in Table II, along with
of values both for negative as well as for positive values of α. their weightings. This table indicates the relative importance
These graphs suggest that the Renyi entropy might be usefully of these variables and will be compared with the results from
employed to discriminate between these groups for diagnostic the second method. Notice that a variety of measures were
purposes. selected from time- and frequency domain, as well as from the
To address this, we performed a quantitative assessment non-linear and entropy measures. Some variables were selected
of the usefulness of all the variables, both from the methods more than once in the transformed variables. In particular,
shown in Table I and for the Renyi entropy. Two methods were LFpeak was well represented in two different transformed
used to assess the ability of variables to discriminate. In the variables.
first method, PCA was performed using all variables, resulting Results from the classifiers using transformed variables
in a set of transformed variables that were used as inputs to the from PCA are shown in Table III. The SMO classifier achieved
classifier for discriminating. In the second method, a Wrapper the highest accuracy of 64.5%. Normal patients were mostly
algorithm was used with a search using Genetic Algorithm, classified as Normal (52), and Early CAN patients were mostly
in conjunction with each classifier, to search for the set of classified as Early (37). The Receiver Operating Curve is
variables that maximised the classifier success rate. shown in Fig. 5. The area under the curve is 0.713. This is a

932 2013 IEEE 8th Conference on Industrial Electronics and Applications (ICIEA)
 TABLE III TABLE IV
VARIABLES CALCULATED BY ANALYSIS OF THE RR INTERVAL FROM 140 VARIABLES PROVIDED FROM A GA SEARCH . S TARRED VARIABLES WERE
PATIENTS . ALSO CONSIDERED SIGNIFICANT IN THE PCA, AS LISTED IN TABLE II.

Classifier Correct TN FP FN TP Sens. Spec. Naive SMO Nearest Decision Decision

Bayes Neighbour Table Tree
Naive Bayes 63.0% 38 33 18 49 0.731 0.535
SMO 64.5% 37 34 15 52 0.776 0.521 *MeanRR *MeanRR RMSSD *MeanRR pNN50
*HFpeak SDNN pNN50 *LFpeak LFpow.(ms)
Nearest Neighbour 57.2% 42 29 30 37 0.552 0.592 LFpow(nu) *HFpeak TINN *HFpeak LFpow.(nu)
Decision Table 56.5% 16 55 5 62 0.925 0.225 SD2 HFpow(nu) *LFpeak LFpow.(ms) *SampEn
Decision Tree 58.0% 31 40 18 49 0.731 0.437 alpha1 Tot.pow. LFpow(nu) HFpow.(nu) alpha1
*alpha2 SD2 LHratio LHratio *alpha2
Lmean alpha1 Tot.pow. H(-3) Lmean
H(-2) H(-3) SD1, SD2 H(-2) H(-3)
H(-1) H(-2) alpha1 H(4) H(-1)
*H(0) H(-1) *alpha2 *H(0)
*H(0) H(-1) H(4)
H(1) *H(0) H(5)
H(4)

TABLE V
C ORRECT CLASSIFICATION RESULTING FROM VARIABLES SELECTED BY
GA

Evaluation using classifier:

Variables Naive SMO Nearest Decision Decision
selected Bayes Neigh- Table Tree
using: bour
Naive 61.6% 63.8% 53.0% 60.9% 60.9%
Bayes
SMO 65.2% 66.7% 58.7% 63.0% 55.8%
Nearest 67.4% 65.9% 68.1% 63.8% 62.3%
Neighbour
Fig. 5. Receiver Operating Curve for Early diagnosis found from applying Decision 65.2% 63.0% 58.7% 67.4% 64.4%
SMO classifier to PCO transformed dataset. Table
Decision 63.0% 63.8% 61.6% 64.4% 67.4%
Tree
good result, indicating the usefulness of this method.
The Wrapper method using a Genetic Algorithm returned TABLE VI
the set of variables shown in Table IV. Each classifier selects a C ONFUSION M ATRIX RESULTING FROM CLASSIFICATION BY SMO ON A
different set of features. Of the time-based measures, MeanRR REDUCED VARIABLE SET OBTAINED FROM PCA.

was selected in 3 out of 5 of the Wrapper based searches. The

Classified as:
other time based measures were selected less often. Of the
Normal Early Real class:
frequency-based measures, the most frequently selected were
46 25 Normal
the HF peak (3 out of 5) and the LF power (n.u.) (3 out of
19 48 Early
5). The measures derived from DFA were selected relatively
frequently: alpha1 (4 out of 5) and alpha2 (3 out of 5). Notice
the relative importance accorded to the measures from the than the results obtained when features were transformed using
Renyi spectrum, indicating that the latter were preferred in PCA.
this analysis. Both H(-1) and H(0) were selected 4 out of The confusion matrix for the Nearest Neighbour result is
5 times. Several measures were not selected at all in any of shown in Table VI. This resulted in a false positive rate of
these tests, including the Triangular index, REC, and DET. D2 25/(25 + 48) = 0.34, and a false negative rate of 19/(19 +
was selected from PCA but not from wrapper analysis. This 48) = 0.28. The Receiver Operating Curve is shown in Fig.
suggests a relatively poor performance for these variables in 5. The area under the curve is 0.734. This is very similar to
distinguishing early CAN from controls but this should not be the previous result.
taken as a comment on their general usefulness in other types
of diagnostic test. VI. C ONCLUSION
The results of the classification using variables selected by This work shows that the automatic classification of early
GA are shown in Table V. The highest correct score was for the CAN from normal patients is feasible using a range of vari-
Nearest Neighbour classifier using features selected using the ables based only on measurement of the RR interval or heart
same algorithm was 69.6%. However, most of the classifiers rate. Two methods to find the best set of features to use for
did better when the features were selected using this algorithm. classification resulted in similar answers. PCA provided 10
Many of these figures for accuracy are similar or slightly better new features on which the best performance was found for

2013 IEEE 8th Conference on Industrial Electronics and Applications (ICIEA) 933
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934 2013 IEEE 8th Conference on Industrial Electronics and Applications (ICIEA)