Australasian Physical & Engineering Sciences in Medicine

An Adaptive Technique for Multiscale Entropy (MSEbin) Threshold (r) selection:

Application to Heart Rate Variability (HRV) and Systolic Blood Pressure Variability
(SBPV) under Postural Stress
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Manuscript Number: APES-D-15-00239

Full Title: An Adaptive Technique for Multiscale Entropy (MSEbin) Threshold (r) selection:
Application to Heart Rate Variability (HRV) and Systolic Blood Pressure Variability
(SBPV) under Postural Stress

Article Type: Technical Paper

Keywords: Heart rate variability, blood pressure variability, sample entropy, multiscale entropy,
cross multiscale entropy

Corresponding Author: Amritpal Singh

INDIA

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First Author: Amritpal Singh

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Order of Authors: Amritpal Singh

BS Saini

D Singh

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Abstract: Multiscale Entropy (MSE) is used to quantify the complexity of a time series as a
function of time scale . Sample Entropy (SampEn) tolerance threshold selection 'r' is
based on either: 1) arbitrary selection in the recommended range (0.1-0.25) times
standard deviation of time series 2) or finding maximum SampEn (SampEnmax) i.e.,
the point where self-matches start to prevail over other matches and choosing the
corresponding 'r'
(rmax) as threshold 3) or computing rchon by empirically finding the relation between
rmax, SD1/SD2 ratio and N using curve fitting, where, SD1 and SD2 are short-term
and long-term variability of a time series respectively. None of these methods is gold
standard for selection of 'r'. In our previous study [1], an adaptive procedure for
selection of 'r' is proposed for approximate entropy (ApEn). In this paper, this is
extended to multiple time scales using MSEbin and multiscale cross-MSEbin
(XMSEbin). We applied this to simulations i.e. 50 realizations (n=50) of random
number series, fractional Brownian motion (fBm) and MIX (P) [1] series of data length
of N=300 and short term recordings of HRV and SBPV performed under postural
stress from supine to standing. MSEbin and XMSEbin analysis was performed on
laboratory recorded data of 50 healthy young subjects experiencing postural stress
from supine to upright. The study showed that i) SampEnbin of HRV is more than
SBPV in supine position but is lower than SBPV in upright position ii) SampEnbin of
HRV decreases from supine i.e. 1.73240.112 (MeanSD) to upright 1.49160.108
due to vagal inhibition iii) SampEnbin of SBPV increases from supine i.e. 1.55350.098
to upright i.e. 1.62410.101 due sympathetic activation iv) individual and cross
complexities of RRi and SBP series depend on time scale under consideration v)
XMSEbin calculated using SampEnmax is correlated with cross-MSE calculated using
SampEn (0.1-0.26) in steps of 0.02 at each time scale in supine and upright position

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 and is concluded that SampEn0.26 has highest correlation at most scales vi) choice of
'r' is critical in interpreting interactions between RRi and SBP and in ascertaining true
complexity of the individual RRi and SBP series.

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1 An Adaptive Technique for Multiscale Entropy (MSEbin) Threshold

2 (r) selection: Application to Heart Rate Variability (HRV) and
3 Systolic Blood Pressure Variability (SBPV) under Postural Stress
4

6 Authors:

7 A. Singh,

8 Research Scholar,

9 Department of Electronics and Communication Engineering,

10 Dr. B. R. Ambedkar National Institute of Technology, PB, India

11 Associate Professor, Lovely Professional University, PB, India

12 apsingh.lpu@gmail.com

13

14 B.S. Saini,

15 Associate Professor,

16 Department of Electronics and Communication Engineering,

17 Dr. B. R. Ambedkar National Institute of Technology, PB, India

18

19 D. Singh,

20 Associate Professor,

21 Department of Instrumentation and Control,

22 Dr. B. R. Ambedkar National Institute of Technology, PB, India

23

24

25

26
27 An Adaptive Technique for Multiscale Entropy (MSEbin)
28 Threshold (r) selection: Application to Heart Rate
29 Variability (HRV) and Systolic Blood Pressure
30 Variability (SBPV) under Postural Stress
31 A Singh, BS Saini, and D Singh
32 Abstract- Multiscale Entropy (MSE) is used to quantify the complexity of a time series as a
33 function of time scale . Sample Entropy (SampEn) tolerance threshold selection r is based
34 on either: 1) arbitrary selection in the recommended range (0.1-0.25) times standard
35 deviation of time series 2) or finding maximum SampEn (SampEnmax) i.e., the point where
36 self-matches start to prevail over other matches and choosing the corresponding r
37 (rmax) as threshold 3) or computing rchon by empirically finding the relation between rmax,
38 SD1/SD2 ratio and N using curve fitting, where, SD1 and SD2 are short-term and long-term
39 variability of a time series respectively. None of these methods is gold standard for selection
40 of r. In our previous study [1], an adaptive procedure for selection of r is proposed for
41 approximate entropy (ApEn). In this paper, this is extended to multiple time scales using
42 MSEbin and multiscale cross-MSEbin (XMSEbin). We applied this to simulations i.e. 50
43 realizations (n=50) of random number series, fractional Brownian motion (fBm) and MIX
44 (P) [1] series of data length of N=300 and short term recordings of HRV and SBPV
45 performed under postural stress from supine to standing. MSEbin and XMSEbin analysis was
46 performed on laboratory recorded data of 50 healthy young subjects experiencing postural
47 stress from supine to upright. The study showed that i) SampEnbin of HRV is more than
48 SBPV in supine position but is lower than SBPV in upright position ii) SampEnbin of HRV
49 decreases from supine i.e. 1.73240.112 (MeanSD) to upright 1.49160.108 due to vagal
50 inhibition iii) SampEnbin of SBPV increases from supine i.e. 1.55350.098 to upright i.e.
51 1.62410.101 due sympathetic activation iv) individual and cross complexities of RRi and
52 SBP series depend on time scale under consideration v) XMSEbin calculated using
53 SampEnmax is correlated with cross-MSE calculated using SampEn (0.1-0.26) in steps of 0.02
54 at each time scale in supine and upright position and is concluded that SampEn0.26 has
55 highest correlation at most scales vi) choice of r is critical in interpreting interactions
56 between RRi and SBP and in ascertaining true complexity of the individual RRi and SBP
57 series.
58 Keywords: Heart rate variability, blood pressure variability, sample entropy, multiscale
59 entropy, cross multiscale entropy
60 I. INTRODUCTION

61 Numerous regulatory mechanisms contribute to cardiovascular control and these interactions occur
62 at multiple time scales. In order to characterize these cardiovascular interactions, both variability
63 analyses i.e. information generation and asymmetry analysis i.e. information transfer need to be
64 typified at multiple temporal scales. The amount of information conveyed from one source to
65 another is correlated with the difference in variability between the dynamics of the two sources
66 [2]. Short term ANS control using sympathetic and vagal actions occur at a faster pace while other
67 mechanisms like vasomotor control, chemoreflex regulation and thermoregulation are sluggish
68 [3]. These reflex and non-reflex physiological mechanisms employed at diverse time scales are
69 accountable towards beat-to-beat oscillations of cardiovascular variables aiming at sustaining the
70 rhythmical variations within safe thresholds. Physiologically, RR interval i.e. the R-to-R distance
71 between two consecutive QRS complexes of electrocardiogram influences SBP not merely due to
72 baroreflex feedback (FB) loop but involves collective influence of Starlings law and diastolic
73 runoff in a feed-forward (FF) way [4]. The prevailing mechanism is determined by the
74 predominant causal direction. Cardiovascular interactions between RRi and SBP are regulated
75 through baroreflex. When baroreflex is impaired, RRi oscillates without any regulation which
76 results in decreased complexity of RRi series; however SBP is still under the control of arterial
77 baroreflex through adjustment in peripheral vascular resistance. Under normal circumstances RRi
78 and SBP are strongly linked and have mutual interactions that share similar dynamics. The
79 dynamics vary when ANS modulations change due to any disturbance in vagal or sympathetic
80 drive and since they operate at different speeds, multiple time scales comes into picture.
81 Irrefutably, the complexity of the beat-to-beat HRV is sensitive to different physiological
82 conditions including disease [5-8] and ANS modulation caused by pharmaceutical innervations
83 [9-11] or postural changes [12-14]. Multiscale nature of HRV has been studied in the past using
84 different techniques such as detrended fluctuation analysis, mutual information rate and multiscale
85 entropy (MSE) [15-17]. MSE employed in these studies was based on sample entropy (SampEn)
86 statistics as it is considered to a more consistent measure of analyzing the regularity of a time series
87 because unlike approximate entropy (ApEn), it is free from bias. Calculation of ApEn involves
88 self matches so that ln (0) is avoided. So the eventual ApEn value will be biased and will be lower
89 than the actual. On the other hand, sample entropy (SampEn) is free from this bias. ApEn and
90 SampEn depends upon two vital parameters i.e., embedding dimension (m) and tolerance threshold
91 (r). m defines pattern length to be compared and is recommended as m=2 [18, 19] or it is found by
92 finding the false nearest neighbor [20, 21]. r is suggested in the range (0.1 to 0.25) times the
93 standard deviation (SD) of the time series [18, 20, 21]. Many studies have advocated careful
94 selection of r for true interpretation of regularity of simulated as well as real signals [22-25].
95 Selection of r is of great importance to precisely estimate the regularity of a time series. Both
 96 ApEn and SampEn are sensitive to r and therefore a crisp value of r chosen by assuming a
97 Heaviside function may not accurately determine the regularity of time series [31]. In our recent
98 study [1], an adaptive technique for selection of r is presented. In this study, this approach is
99 applied to SampEn and extended to MSE and new measure MSEbin and cross-MSEbin (XMSEbin)
100 are computed. Another types of SampEn i.e., SampEnchon proposed by Chons method [26] and
101 the SampEnmax corresponding to maximum r value calculated from whole spectrum of r ranging
102 from 0 to 1 in steps of 0.01 [20] are used for comparison. This adaptive technique is based on
103 tuning the r selected as per recommended range to a new value rbin that is attuned to contain
104 collection of distance points near r by binning them into a matrix called the distance matrix (DM).
105 rbin embraces the distance points up to and including the modal bin till a reduction in the percentage
106 of distance points is encountered in the subsequent bins. SampEnbin is found using this adaptively
107 selected rbin without and provide an alternative to calculation of rmax to find SampEnmax. It is
108 hypothesized that SampEnbin performs equitably well as compared to SampEnmax, SampEn0.2 and
109 SampEnchon. Simulated data consists of 50 realizations of random number (RN) series, fractional
110 Brownian motion (fBM) and MIX (P) series [15] on which the results were obtained. Real RR
111 interval (RRi) and SBP series were also recorded and the results were obtained on these as well.
112 Sympathetic and parasympathetic drives of autonomic control alters HRV and SBPV under
113 postural stress from supine to upright that leads to variation in the complexities of both. It is also
114 hypothesized that individual and cross complexities of RRi and SBP series depend on the time
115 scale under consideration. It has been established that the complexity of HRV evaluated using RRi
116 series is more than complexity of BPV evaluated using SBP series. Also change in posture from
117 supine to upright (inhibition of vagal drive) decreases the complexity of HRV and increases the
118 complexity of BPV. In this paper we analyzed whether threshold r influences the correct
119 interpretation of complexity under postural stress. Since we varied the r in steps of 0.02, the
120 recommended range has been slightly altered to (0.1-0.26) times SD of the time series under
121 consideration. We verified that i) for MSEbin, how rmax varies as a function of for RRi series in
122 supine and upright conditions? ii) MSEbin, how rmax varies as a function of for SBP series in
123 supine and upright conditions? iii) how rmax varies as a function of for XMSEbin analysis of RRi
124 and SBP series in supine and upright conditions? iv) how XMSEbin calculated using SampEnmax is
125 correlated with XMSEbin calculated within the recommended range of (0.1-0.26) times SD i.e.
126 SampEn0.1, SampEn0.12, SampEn0.14, SampEn0.16, SampEn0.18, SampEn0.2, SampEn0.22, SampEn0.24
127 and SampEn0.26 at each time scale in supine and upright position v) to verify whether all r values
128 within recommended range provide similar physiological interpretation using complexity
129 information.

130 II. ADAPTIVE SampEn THRESHOLD (r) SELECTION

131 A. Computation of SampEn

132 For an N samples time series given by {u (i): 1 i N}, template vectors
133 1 , 2 , 3 , +1

are formulated as per equation (1).

134 = {(), ( + 1), , ( + 1)}, = 1,2, , + 1 (1)

135 The maximum norm distance between two such vectors is given by equation (2).

136 Di, j =() () , j i (2)

137 where . is the maximum norm distance between the two vectors x (i) and x (j). Fig. 1 depicts
138 the return map formulated for a mean subtracted RRi series. r is shown as a circle of radius r on
139 the return map depicting the tolerance within which template matching is to be performed for the
140 computation of SampEn. SampEn is computed as per equation (3).

() +1 ()
+1 ( ) (
=1 +1 =1 )
141 (, ) = (3)
+1

142 Where () and +1 () are the CPs that the distance between the two vectors lie within r for
143 window length m remains within r for window length m+1, respectively.
144

145 Figure 1: Return map of an RRi series. Circle of radius r shows the tolerance within which
146 template matching is performed [1].
147 B. Computation of SampEnbin

148 For the computation of SampEnbin at first r is selected as any value lying within the recommended
149 range. For inclusion of the distance points around r, the distance values Di,j in DM are aggregated
150 into k bins using equation (4) [1].

151 = (4)
=1

152 where h gives aggregation distance points in each l bin . This is shown by the histogram in Fig. 2.
 12
increase in %age of points indicate cluster of points near r
points included upto this bin by selecting r=0.2
10 r-bin will include points in this bin

8
%age of points

0
-0.05-0.03-0.01 0.01 0.03 0.05 0.07 0.09 0.11 0.13 0.15 0.17 0.19 0.21 0.23 0.25 0.27 0.29 0.31 0.33 0.35 0.37
Di,j
153

154 Figure 2: Histogram displaying rise in %age of distance points in the subsequent bin after the bin
155 of r = 0.2*SD. SampEnbin will take in these distance points that otherwise could have been left [1].

156 To find the distance points near r, the percentage of distance points housed by each bin are
157 calculated. To take-in the distance points in proximity of r, percentage of distance points at the bin
158 corresponding to r is compared with percentage of distance points in the subsequent bin thereby
159 incrementing r by of 0.01 till a reduction in the percentage is detected [1]. This corresponds to
160 the new threshold value rbin as per equation (5) [1].

161 For instance, if r = 0.2 is chosen, 10.6% of the distance points falling in the (n+1)th bin in
162 comparison to 9.8% of distance points in the nth bin will be left out. To include these distance
163 points r is incremented to a revised value as per equation (5) till a decrease in percentage is
164 observed [1].

165 = (5)

166 r is incremented in steps of 0.01 till rbin approaches.

167 In short, rbin is found by binning the values in DM and selecting r that embraces distance points
168 up to and including the modal bin till a reduction in the percentage of distance points is found in
169 the subsequent bins [1]. This rbin forms the outer circle as shown in Fig. 3. Figure 3 shows distance
170 points between the outer circle of radius rbin and the inner circle of radius r in the return map of
171 an RRi series.

172

173 Figure 3: Distance points embraced by the outer circle of radius rbin, which were initially left out
174 by inner circle of radius r shown on the return map of RRi series [1].

175

176

177 After computing rbin, the SampEn is defined as SampEnbin as per equation (6).

( ) +1 ( )

=1 (
+1
=1 ( + 1) )
178 (, ) = (6)
+1

179 C. Computation of SampEn0.2

180 SampEn0.2 is computed by choosing r = 0.2*SD from within the recommended range of r i.e., (0.1
181 -0.25)*SD of the time series.
182 D. Computation of SampEnmax

183 Selection of r as per recommended range may sometimes lead to inappropriate deductions about
184 complexity of a time series. It is depicted in [8] that from a set of white noise, cross chirp and
185 sinusoidal signals, cross chirp signal has smaller SampEn value than that of white noise which is
186 obviously an ambiguous result if r is selected as per recommended range. Consequently, the use
187 of SampEnmax is encouraged where r is varied from 0 to 1 in steps of 0.01 till maximum SampEn
188 reaches as shown in Fig. 4 and the corresponding r is called as rmax.
SampEn

189

190 Figure 4: Variation of SampEn with r varied from 0 to 1 in steps of 0.01 for an RRi series.

191 E. Calculation of SampEnchon

192 In order to avoid computation of SampEnmax that involves more calculations Chon et al. [20]
193 developed SampEnchon using some empirical relations between rmax, SD1/SD2 ratio and N where
194 SD1 and SD2 are short term and long term variability of the time series [20] by non-linear least
195 squares curve fitting. Threshold thus obtained is termed as rchon as shown in equations (7) and (8).

196 For m=2;

1 4
197 = (0.036 + 0.026 ) (7)
2 1000

198 For m=3;

 1 4
199 = (0.08 + 0.46 ) (8)
2 1000

200 F. Calculation of MSEbin

201 MSEbin is found using a coarse graining procedure adopted in [15]. After breaking the given RRi
202 and SBP series into multiple time scales, SampEbin calculated using equation (7) for each series
203 from time scale =1 to 10.

204 G. Calculation of XMSEbin

205 XMSEbin is calculated using SampEnbin coarse-grained RRi and SBP series at time scales = 1 to
206 10. RRi is chosen as target series as SBP is taken as the template series.

207 IV. SIMULATED and EXPERIMENTAL DATA

208 A. Simulated data

209 50 simulated signals each of random number (RN) series, fractional Brownian motion (fBM) and
210 MIX(P) series [28] are used to measure the complexity using SampEnbin and compared to
211 SampEn0.2, SampEnchon and SampEnmax.

212 B. Experimental data

213 Recording of 50 young healthy male subjects aged 232.2 (MeanSD) was carried out using
214 MP100 Biopac System in a quite darkened room. They were refrained from any medication,
215 alcohol, caffeine and tobacco for atleast 12 Hrs. Informed consent was taken from all the subjects.
216 The study was conducted as per ethical standards and was as recommended by the research
217 advisory committee of the National Institute of Technology, Punjab, India. All the subjects initially
218 rested for 10 minutes. ECG and continuous arterial BP signal were recorded for these subjects in
219 supine and upright (standing) positions. 20 minutes recordings were obtained for each position
220 with a 3 minutes break at a sampling frequency of 500 Hz.

221 C. R-Peak and systolic peak detection

222 R peaks form ECG and systolic peaks from arterial BP waveform were detected using empirical
223 mode decomposition (EMD) [29]. Figure 5 (a) and 5 (b) the detected R-peaks and systolic peaks
224 of ECG and arterial blood pressure (ABP) series. First degree interpolation was used to removethe
225 ectopic beats. Tachogram i.e., time series of RRi and systogram i.e., time series of systolic peaks
226 was formed. Both the time series were mean subtracted. 500 samples each of RRi and systolic SBP
227 values were used for analysis.
Detected R-peak in record f2y01
600

400

200
Amplitude

-200

-400

-600
4.3 4.32 4.34 4.36 4.38 4.4
Samples 5
228 x 10

229 Figure 5(a): R-peaks detected from ECF recording of a typical subject using EMD [29]

230

231 Figure 5(b): Systolic peaks detected from typical subjects ABP recording using EMD [29]

232

233 V. RESULTS

234 A. Comparison of all the measures of SampEn i.e., SampEn0.2, SampEnmax, SampEnchon and
235 SampEnbin
236
237 SampEnmax is known to be the most appropriate method to analyze the complexity of wide variety
238 of signals including physiological signals [20, 21]. However, it is an arduous and time consuming
239 method. SampEnchon is an alternative to estimate the complexity of a time series. Table 1 shows
240 the comparison of SampEn0.2, SampEnmax, SampEnchon and SampEnbin,obtained for simulated
241 signals.
242 Table 1. Mean and SD of all the measures of SampEn and r for 3 types of simulated signals
243
RN Series fBM (H=0.2) MIX(0.1)
Measures Mean SD Mean SD Mean SD
SampEn values
SampEn0.2 1.458 0.0212 0.931 0.083 1.0362 0.312
SampEnmax 2.152 0.0251 1.738 0.072 1.3428 0.272

SampEnchon 1.962 0.0426 1.627 0.131 1.3948 0.152

SampEnbin 2.038 0.0278 1.710 0.045 1.3141 0.062
r values
rmax 0.278 0.0224 0.038 0.025 0.211 0.035
rchon 0.251 0.0313 0.045 0.034 0.209 0.048
rbin 0.137 0.0142 0.036 0.021 0.216 0.032
244
245 Table 2 presents mean and SD of SampEn and r values using all measures for RR interval and SBP
246 series in supine and upright position of 50 healthy subjects.
247
248
249 Table 2: Comparison of SampEn mesures (MeanSD) obtained from tachogram and systogram in
250 supine and upright position.
RRi in Supine RRi in SBP series in SBP series in
position Upright Supine position Upright position
position
 Measures Mean SD Mean SD p- Mean SD Mean SD p-
values values
SampEn values
SampEn0.2 1.5814 0.132 1.4315 0.127 0.152 1.3242 0.159 1.4538 0.216 0.263
SampEnmax 1.7285 0.147 1.4901 0.119 0.048 1.5623 0.125 1.6215 0.141 0.036
SampEnchon 1.7021 0.151 1.4726 0.137 0.041 1.5472 0.148 1.5525 0.152 0.048
SampEnbin 1.7324 0.112 1.4916 0.108 0.026 1.5535 0.098 1.6246 0.101 0.027
r values
rmax 0.202 0.052 0.199 0.036 0.032 0.102 0.025 0.1042 0.031 0.035
rchon 0.198 0.072 0.186 0.069 0.075 0.107 0.049 0.1172 0.037 0.028
rbin 0.216 0.028 0.198 0.038 0.009 0.104 0.025 0.1017 0.012 0.015
251

252 B. MSEbin analysis of RRi series

253 MSEbin of RRi series is a decreasing function of with a plateau observed from scale 5 to 7 and 8
254 to 9 for subjects in supine. In the upright position, the trend is similar but plateau is observed for
255 scales > 6. On scale 1, median of MSEbin in supine is greater than the median in upright position.
256 This confirms that change in posture from supine to upright (inhibition of vagal drive) decreases
257 the complexity of HRV. There are significant differences found in MSEbin values over supine and
258 upright position in scale 1,2,3,5,7,8,9 with a crossover occurring at scale 4 and 8. MSEbin -

259 supine<MSEbin-upright at scale 4, 5, 8 and 10 as depicted in Fig. 6. Table 3 shows number of subjects
260 where RRi MSEbin-upright<MSEbin-supine obtained using various measures of MSE. MSEbin performs
261 better than MSEmax as it finds 49 subjects out of 50 having MSEupright < MSEsupine as compared to
262 40 out of 50 subjects on scale 1. Also, MSEbin performs better than all measures in the
263 recommended range i.e. (0.1-0.26) and MSEmax when considered over all time scales taken
264 together with a total of 332 correct determinations out of 500.

265
 1.8

1.6

1.4
MSEbin
ApEnmax

1.2

0.8

0.6

0.4

266 1 2 3 4 5 6 7 8 9 10
10
1

scale function
267 Scale function

268 Fig. 6: Box plots of SampEnbin of RRi series as a function of scale factor - supine SampEnbin (filled
269 vertical bars with dots as medians) vs. upright SampEnbin (unfilled boxes with horizontal lines as
270 medians)

271 Table 3: Number of subjects where RRi MSEupright<MSEsupine obtained using various measures of
272 MSE
Measures =1 =2 =3 =4 =5 =6 =7 =8 =9 =10
MSEbin 49 40 25 28 20 30 25 25 50 40
MSEmax 40 28 35 25 20 28 35 28 40 28
MSE0.1 28 23 28 30 33 23 20 30 28 23
MSE0.12 30 25 18 35 25 23 28 30 30 25
MSE0.14 25 28 28 30 30 30 23 30 25 28
MSE0.16 35 20 13 30 28 23 20 25 35 20
MSE0.18 48 25 25 25 28 23 23 33 48 25
MSE0.2 43 39 27 23 22 31 24 27 46 34
MSE0.22 45 28 28 23 18 23 23 23 45 28
MSE0.24 48 35 30 25 20 25 28 13 48 35
MSE0.26 45 35 33 18 20 35 28 20 45 35
273

274 C. MSEbin analysis of SBP series

275 MSEbin of SBP series is a decreasing function of with a plateau observed from scale 8 to 9 for
276 subjects in supine. In the upright position, the trend is similar but an increase observed from scale
277 7 to 8 and a plateau observed for scales 9 to 10. On scale 1, median of MSEbin in supine is less than
278 the median in upright position as depicted in Fig. 7. This confirms that change in posture from
279 supine to upright (sympathetic predominance) increases the complexity of BPV. There are
280 significant differences found in MSEbin values over supine and upright position all scales except
281 scale 7 no crossover at any scale. Table 4 shows number of subjects where RRi MSEbin-
282 upright<MSEbin-supine obtained using various measures of MSE. MSEbin performs better than MSEmax
283 as it finds 42 subjects out of 50 having MSEupright > MSEsupine as compared to 39 out of 50 subjects
284 indicated by MSEmax on scale 1. Also, MSEbin performs better than all measures in the
285 recommended range i.e. (0.1-0.26) when considered over all time scales taken together with total
286 385 correct determinations out of 500 followed by MSEmax and MSE0.22 with 374 and 371
287 determinations respectively.

1.9

1.8

1.7

1.6

1.5
ApEnmax
MSEbin

1.4

1.3

1.2

1.1

0.9
288 1 2 3 4 5 6 7 8 9 10
10
1

289 Scale function

290 Fig. 7: Box plots of SampEnbin of SBP series as a function of scale factor supine SampEnbin (filled
291 vertical bars with dots as medians) vs. upright SampEnbin (unfilled boxes with horizontal lines as
292 medians)

293

294
295 Table 4: Number of subjects where SBP MSEupright>MSEsupine obtained using various measures of
296 MSE
Number of subjects where SBP MSEupright>MSEsupine
Measures =1 =2 =3 =4 =5 =6 =7 =8 =9 =10
MSEbin 42 44 36 37 38 33 34 38 39 44
MSEmax 39 41 37 39 39 30 30 39 39 41
MSE0.1 41 26 26 26 26 26 22 28 41 26
MSE0.12 35 33 24 26 22 26 26 28 35 33
MSE0.14 39 30 28 28 30 35 26 33 39 30
MASE0.16 41 43 30 33 30 35 33 37 41 43
MSE0.18 37 39 43 39 30 28 41 33 37 39
MSE0.2 37 39 41 39 30 30 37 35 37 39
MSE0.22 37 39 39 41 39 33 37 30 37 39
MSE0.24 37 39 39 41 35 35 33 30 37 39
MSE0.26 37 41 37 39 37 33 28 37 37 41
297

298 D. Cross-MSE (XMSE) analysis

299 XMSEbin of RRi and SBP series is a decreasing function of with a plateau observed from scale 6
300 to 7 and an increase observed from 9 to 10 for subjects in supine. In the upright position, the trend
301 is similar till scale 5 with a plateau observed for scales 5 to 8 and an increase observed from scale
302 9 to 10. On scale 1, median of XMSEbin in supine is greater than the median in upright position.
303 This reverses in the subsequent scales. There are significant differences found in XMSEbin values
304 over supine and upright position over all scales except scale 9. Table 5 shows number of subjects
305 where SBP XMSEbin-upright>XMSEbin-supine obtained using various measures of MSE. For all scales
306 except scale 9, XMSEbin-supine<XMSEbin-upright. MSE0.1 performs better than MSEbin as it finds 26
307 subjects out of 50 having XMSEbin-upright < XMSEbin-supine as compared to 23 out of 50 subjects on
308 scale 1. However, XMSEbin performs better than all measures in the recommended range i.e. (0.1-
309 0.26) when considered over all time scales taken together with total 366 correct determinations out
310 of 500.
 2

1.8

1.6

1.4
Cross-ApEnmax
bin

1.2
XMSE

0.8

0.6

0.4

311 1 2 3 4 5 6 7 8 9 10

10
1

312 Scale function

313 Fig. 4: Box plots of XMSEbin of RRi and SBP series as a function of scale factor - supine cross-
314 SampEnmax (filled vertical bars with dots as medians) vs. upright cross-SampEnbin (unfilled boxes with
315 horizontal lines as medians)

316 Table 5: Number of subjects where XMSEupright>XMSEsupine obtained using various measures of
317 XMSE
Number of subjects where RRi-SBP XMSEupright>XMSEsupine
Measures =1 =2 =3 =4 =5 =6 =7 =8 =9 =10
XMSEbin 23 39 40 40 38 42 37 45 24 38
XMSEmax 22 33 35 41 33 37 37 37 22 33
XMSE0.1 26 35 37 41 37 39 37 35 26 35
XMSE0.12 22 35 37 39 37 39 41 37 22 35
XMSE0.14 20 33 39 39 37 41 41 39 20 33
XMSE0.16 22 35 39 39 37 41 41 39 22 35
XMSE0.18 22 37 39 39 39 41 39 43 22 37
XMSE0.2 17 30 39 39 35 39 43 46 17 30
XMSE0.22 15 30 35 39 37 39 39 39 15 30
XMSE0.24 15 33 35 41 37 39 41 39 15 33
XMSE0.26 17 35 33 43 39 41 39 39 17 35
318

319
320 E. rmax for MSE analysis of RRi and SBP

321 It is worth noting that for RRi series there is a range of rmax over which SampEnmax is constant for
322 most of the subjects on scale 1 for both supine as well as upright position. Therefore, the mean rmax
323 is found using both minimum and maximum value of this range. Mean rmax is 0.134 in supine and
324 0.117 in upright position if minimum of range is chosen. Mean rmax is 0.178 in supine and 0.166
325 in standing if maximum of range is chosen as shown in table 6. So choosing maximum of the range
326 is suggested as it provides results closer to the recommended value of 0.2 SD. rmax shows an
327 increasing trend with the scale function and hence the recommended range is not suitable for
328 analyzing HRV at higher scales. Moreover, rmax in supine is greater than rmax in upright with a
329 crossover at =5 after which it shows fluctuating trend. This may be due to more number of similar
330 patterns occurring in upright position thereby increasing the regularity of the RRi series and
331 achieving SampEnmax faster than in supine position. The similar analysis was carried out for SBP
332 series. The suggested value of r = 0.2 times SD is not true for SBP series as we have obtained rmax
333 = 0.117 in supine and rmax = 0.119 in upright position on scale 1 as shown in table 7. These also
334 show an increasing trend as a function of time scale and falls outside recommended range for
335 > 4. Since BPV is more in upright position due to sympathetic predominance, SampEnmax reaches
336 slightly later than in supine position due lesser number of similar patterns occurring in the upright
337 position.

338 Table 6: Mean value of rmax over scale factors in supine and standing position for minimum and
339 maximum of the range of rmax for RRi series

Mean rmax Mean rmax Mean rmax Mean rmax

Scale (supine) (upright) (supine) (upright)
If Min. is chosen If Max. is chosen
=1 0.134 0.117 0.178 0.166
=2 0.207 0.181 0.226 0.198
=3 0.256 0.229 0.263 0.237
=4 0.279 0.272 0.282 0.277
=5 0.306 0.306 0.308 0.310
=6 0.337 0.323 0.339 0.327
=7 0.343 0.371 0.344 0.374
 =8 0.384 0.372 0.385 0.375
=9 0.383 0.410 0.383 0.411
=10 0.404 0.398 0.404 0.400
340
341 Table 7: Mean value of rmax over scale factors in supine and standing position for SBP series
342
Scale =1 =2 =3 =4 =5 =6 =7 =8 =9 =10
rmax (Supine) 0.117 0.17 0.207 0.244 0.286 0.31 0.337 0.362 0.386 0.407
rmax (Upright) 0.119 0.184 0.228 0.26 0.289 0.313 0.339 0.365 0.381 0.418
343

344 F. rmax for XMSE analysis of RRi and SBP

345 Table 8 carry mean rmax values for all the subjects from time scales =1 to =10 in supine and
346 upright positions. In the cases, rmax shows an increasing trend from lower to higher scales.
347 Moreover, mean of rmax at supine is larger than that at upright position indicating that XMSEmax
348 reaches quickly in upright position as compared to supine position. This further indicates lesser
349 complexity or more regularity as RRi and SBP are tightly coupled due more active baroreflex in
350 the upright position.

351 Table 8: Mean value of rmax (XMSE) over scale factors in supine and standing position
352
Scale =1 =2 =3 =4 =5 =6 =7 =8 =9 =10
rmax (Supine) 0.163 0.229 0.286 0.33 0.385 0.403 0.453 0.469 0.408 0.521
rmax (Upright) 0.149 0.217 0.264 0.294 0.33 0.348 0.377 0.392 0.415 0.421
353

354 G. Correlation of XMSEbin with XMSE (0.1-0.26) an XMSEbin on all scales

355 Pearson correlation analysis was performed to ascertain the correlation of XMSEmax with XMSE
356 (0.1-0.26) with significant levels of 0.05 and 0.00005. Results are depicted in table 19 and 20 for
357 supine and upright positions respectively. It is found that in supine position on scale 1, XMSE0.16
358 has the highest correlation of 0.935 (p = 6.27x10-11) with XMSEmax. Highest correlation shift
359 towards higher r values as a function of time scale with 0.22 at = 2, 0.24 at = 3 and 0.26 at >
360 3 with no significant correlation achieved within the recommended range at = 10. It is found that
361 in upright position on scale 1, XMSE0.16 has the highest correlation of 0.927 (not significant) with
362 XMSEmax. The highest significant value of 0.689 (p = 2.74x10-4) occurred for XMSE0.26. Highest
363 correlation shift towards higher r values as a function of time scale with 0.24 at = 2, 0.26 for >
364 2 with no significant correlation achieved within the recommended range at = 7 and = 10.
365 Results are depicted in table 9 and 10.

366 H. Selection of r is critical in characterizing cardiovascular interactions

367 Fig. 5 shows cross-SampEnbin at scale 1 for a healthy subject. It is worth noting that selection of r
368 is critical in interpreting the nature of cardiovascular interactions. Cross-SampEnbin in supine is
369 greater than Cross-SampEnbin in upright position. But this reverses if r is selected as greater than
370 0.18. This analysis was carried out for all the young healthy subjects it was found that out of 50
371 subjects 39 subjects showed correct interpretation of cross complexity between RRi and SBP in
372 the supine and standing positions. Therefore, choice of r becomes utmost important in analyzing
373 the autonomic response to postural stress.

374

375 Fig. 5: Cross-SampEn at scale 1 for a healthy subject. It is worth noting that selection of r is critical in
376 interpreting the nature of cardiovascular interactions. Cross-SampEnbin in supine is greater than Cross-
377 SampEnbin in upright position. But this reverses if r is selected as greater than 0.18.
378

379 Table 9: Correlation coefficient (CC) of XMSEbin with XMSE at thresholds in the recommended range
380 (0.1-0.26) and XMSEmax on all scales for subjects in supine position

381

=1 =2 =3 =4 =5 =6 =7 =8 =9 =10
XMSEmax 0.94325 0.93515 0.88352 0.79582 0.73272 0.68427 0.59353 0.66362 0.65266 0.5621
p-value 5.23E-10 4.41E-12 2.53E-02 0.00524 0.00126 0.00538 8.92E-05 7.67E-05 0.24204 0.02467
XMSE0.1 CC 0.3002 0.3544 0.5201 0.5212 0.3794 0.3819 0.1762 0.4061 -0.7190 0.2256
p-value 0.27694 0.19488 0.04687 0.04631 0.16309 0.16011 0.52986 0.13304 0.00252 0.41867
XMSE0.12 CC 0.72728 0.50541 0.51686 0.46783 0.51839 0.46951 0.50472 0.46319 -0.54219 0.23124
p-value 8.43E-05 0.01389 0.01156 0.02437 0.01127 0.0238 0.01404 0.02602 0.00753 0.28841
XMSE0.14 CC 0.9041 0.7036 0.63642 0.56116 0.54502 0.46882 0.54398 0.51344 -0.42593 0.28028
p-value 3.32E-09 1.80E-04 0.0011 0.00534 0.00716 0.02404 0.00729 0.01222 0.04272 0.19519
XMSE0.16 CC 0.93515 0.84342 0.73905 0.66076 0.59289 0.5107 0.56762 0.61557 -0.23282 0.21617
p-value 6.27E-11 4.32E-07 5.62E-05 5.99E-04 0.00287 0.01277 0.00473 0.00177 0.28504 0.32184
XMSE0.18 CC 0.87782 0.93874 0.81188 0.71241 0.64011 0.56766 0.57647 0.64449 -0.11131 0.25611
p-value 3.75E-08 3.51E-11 2.56E-06 1.37E-04 0.001 0.00472 0.00399 9.02E-04 0.61311 0.23818
XMSE0.2 CC 0.81233 0.97798 0.88493 0.77488 0.70608 0.62851 0.6451 0.65851 0.17079 0.24466
p-value 2.50E-06 8.88E-16 2.06E-08 1.42E-05 1.67E-04 0.00132 8.88E-04 6.35E-04 0.43588 0.26054
XMSE0.22 CC 0.75095 0.98117 0.94107 0.83837 0.72759 0.67446 0.66154 0.71026 0.36894 0.26464
p-value 3.65E-05 2.22E-16 2.36E-11 5.89E-07 8.34E-05 4.16E-04 5.87E-04 1.46E-04 0.0832 0.22235
XMSE0.24 CC 0.69294 0.95012 0.97406 0.88137 0.77413 0.70712 0.69933 0.72527 0.58635 0.40425
p-value 2.47E-04 4.27E-12 4.88E-15 2.79E-08 1.46E-05 1.61E-04 2.05E-04 9.01E-05 0.00328 0.05572
XMSE0.26 CC 0.66091 0.91706 0.99092 0.90309 0.81489 0.75345 0.73524 0.76637 0.69945 0.39084
p-value 5.96E-04 7.67E-10 0 3.69E-09 2.19E-06 3.32E-05 6.42E-05 2.01E-05 2.04E-04 0.06518
382

383

384

385

386

387
388 Table 10: Correlation coefficient (CC) of XMSEbin with XMSE at thresholds in the recommended range (0.1-0.26)
389 on all scales for subjects in upright position

390

=1 =2 =3 =4 =5 =6 =7 =8 =9 =10
XMSEmax 0.69352 0.94214 0.95632 0.78632 0.81984 0.47602 0.57124 0.74534 0.58543 0.42246
p-value 0.03713 7.97E-06 5.36E-07 3.83E-05 2.52E-03 0.02453 0.01432 8.12E-07 0.00421 0.4527
XMSE0.1 CC -0.28943 0.29994 0.3218 0.12326 0.07065 -0.11107 0.08773 -0.21778 -0.12029 -0.05709
p-value 0.1804 0.16438 0.13429 0.57527 0.74871 0.61389 0.69061 0.31816 0.58457 0.79582
XMSE0.12 CC -0.15017 0.43466 0.44821 0.26807 0.18779 -0.00224 0.18295 -0.04532 0.04205 -0.10862
p-value 0.49403 0.03821 0.03196 0.21619 0.39087 0.99192 0.40341 0.83733 0.84891 0.62176
XMSE0.14 CC -0.0201 0.53393 0.57021 0.39798 0.28769 0.14813 0.27027 0.03022 0.21659 -0.17545
p-value 0.92748 0.00869 0.0045 0.06 0.18315 0.49997 0.21231 0.89113 0.32088 0.42328
XMSE0.16 CC 0.15235 0.69254 0.65694 0.52945 0.44162 0.24191 0.38424 0.09134 0.33048 -0.05279
p-value 0.48769 2.50E-04 6.61E-04 0.00938 0.03489 0.2661 0.07026 0.67851 0.12351 0.81092
XMSE0.18 CC 0.34491 0.79836 0.78007 0.64236 0.56443 0.3829 0.49002 0.18413 0.48129 0.01827
p-value 0.10701 4.98E-06 1.14E-05 9.50E-04 0.00502 0.07133 0.01762 0.40031 0.02006 0.93406
XMSE0.2 CC 0.47602 0.89337 0.8622 0.75299 0.70587 0.44312 0.5594 0.21097 0.57553 0.10953
p-value 0.02167 9.63E-09 1.23E-07 3.38E-05 1.68E-04 0.0342 0.00552 0.3339 0.00406 0.61883
XMSE0.22 CC 0.60715 0.9572 0.92311 0.83771 0.81984 0.57124 0.6529 0.3196 0.65282 0.1994
p-value 0.00212 8.81E-13 3.55E-10 6.13E-07 1.69E-06 0.00441 7.32E-04 0.13713 7.33E-04 0.36169
XMSE0.24 CC 0.66202 0.96723 0.95829 0.92776 0.89218 0.73461 0.76287 0.46008 0.74534 0.25636
p-value 5.80E-04 5.57E-14 6.75E-13 1.89E-10 1.08E-08 6.56E-05 2.31E-05 0.02718 4.48E-05 0.23769
XMSE0.26 CC 0.68939 0.94302 0.9754 0.95531 0.951 0.82894 0.83904 0.5693 0.82862 0.33288
p-value 2.74E-04 1.67E-11 2.89E-15 1.38E-12 3.55E-12 1.02E-06 5.66E-07 0.00458 1.04E-06 0.12064
391

392 VI. DISCUSSIONS

393
394 There are quite a few findings from this work. Firstly, we found that autonomic balance altered by
395 postural stress from supine to upright by suppressing vagal tone, is visible in alteration of
396 SampEnbin that indicate variations in the complexity of RRi and SBP series. Moreover, cross-
397 SampEnbin between RRi and SBP is also sensitive to this shift in autonomic balance. It is also
398 noticed HRV series has greater complexity than SBPV series in supine as well as upright positions.
399 Physiologically this is due to the fact that HRV is affected by concurrent antagonistic effects of
400 vagal and sympathetic tone of ANS whereas BPV is influenced predominantly by sympathetic
401 tone. Also, complexity of HRV in supine is greater than that as in upright position as specified by
402 corresponding SampEn measures. Physiologically, this directs to the predominance of sympathetic
403 tone over vagal tone due reduced venous return with postural change from supine to upright. In
404 other words, it can be stated that parasympathetic inhibition in the upright position contributes to
405 the reduction in HRV complexity by restraining the ability of fast circuits. SampEnmax and
406 SampEnbin represent higher sensitivity to postural stress indicated by larger decrease in SampEn
407 from supine to upright. Secondly, these complexity measures have a time scale dependency which
408 means we observe different SampEnbin and MSEbin vary as functions of time scale (). Thirdly, we
409 found that choice of threshold r is critical in interpreting cardiovascular interactions between
410 RRi, SBP and ascertaining true complexity of the individual RRi and SBP series. Therefore, the
411 selection of r significantly influences the complexity of HRV from supine to upright. Again,
412 SampEnbin is close to SampEnmax as compared to SampEn0.2 and SampEnchon
413
414 VII. CONCLUSION
415 In this paper an adaptive tolerance threshold selection r proposed in our recent study [1] is
416 extended to SampEn. Further using this new SampEnbin, MSEbin, and XMSEbin is found and applied
417 to RRi series and SBPV series of subjects undergoing postural stress. It is concluded that i) MSEbin
418 values change with scale for both RRi and SBP series ii) MSEbin values are sensitive to alteration
419 in ANS drives caused by change in posture from supine to upright for both RRi and SBP series iii)
420 correct assessment of complexity of RRi and SBP depends upon choice of threshold r iv) both
421 rmax and MSEbin values vary from supine to upright and are different for RRi and SBP series v)
422 MSE values in supine and standing depict the physiological phenomenon behind HRV and BPV
423 affected by ANS control though vagal and sympathetic drives aptly vi) XMSEbin and
424 corresponding r vary as a function of and change in posture vii) XMSEbin shows correlations with
425 XMSE computed over the recommended range and XMSEmax at all the time scales and hence
426 provides an alternative to the cumbersome computation involved in obtaining XMSEmax for the
427 whole spectrum of r from 0 to 1.
428
429 6. References
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510
A Singh was born in Gurdaspur, Punjab, India, in 1981. He received his B.E. degree in Electrical & Electronics
Engineering from Visvesvaraya Technological University, Belgaum, Karnataka, India in 2002, M.Tech. degree in
Instrumentation & Coontrol Engineering from Punjab Technical University, Punjab, India in 2004 and currently
pursuing Ph.D. degree from National Institute of Technology, Jalandhar, Punjab, India. His research interests
include Biomedical Signal Processing, Nonlinear dynamics and control systems.

B S Saini was born in Jalandhar, India, in 1970. He received his B.Tech degree in Electronics & Communication
Engineering from Gulbarga University, India in 1994, M.Tech. degree in Electronics & Communication
Engineering from Kurukshetra University, India in 1996 and Ph.D. degree in the area of Signal Processing of heart
rate variability from NIT Jalandhar, India, in 2009.
He is serving as Associate Professor in Electronics & Communication Engineering Department, NIT Jalandhar,
India from last 15 years. His research interests include Biomedical Signal Processing, Image Processing,
Microprocessors & Microcontrollers, and Soft Computing.
He is a member of IEEE, IEEE EMBS, and Fellow IETE. He has guided more that 20 MTech students and guiding
06 PhD research scholars. He has published more than 20 research papers in International Journals of repute.
 D Singh was born in Adyana (Panipat). received his B.E. (Hons.) degree in Electrical Engineering from Punjab
Engineering College, Chandigarh in 1991, and M.E. degree in Control & Guidance from the University of Roorkee
in 1993, and the Ph.D. degree in Engineering from the Indian Institute of Technology Roorkee, in 2004. The Ph.D.
degree thesis was developed at the Instrumentation & Signal Processing Laboratory of the Electrical Engineering
Department under the direction of Prof Vinod Kumar, IIT Roorkee; Prof S. C. Saxena, Ex Director, IIT Roorkee
and Prof K. K. Deepak, All India Institute of Medical Sciences, New Delhi on Analyis and Interpretation of Heart
Rate and Blood Pressure Variability. After a brief stint at Goodyear India Limited, Faridabad, in September 1994
he joined the Department of Instrumentation and Control Engineering at of the Dr. B. R. Ambedkar National
Institute of Technology, Jalandhar, and presently serving as Associate Professor of Instrumentation & Control
Engineering there, where he is teaching UG/PG courses related to biomedical engineering, signal processing, and
instrumentation & control engg. His professional research interests are in signal processing, in particular applied
to biomedical applications. He has guided five PhDs and is guiding 4 doctoral and several Masters theses and has
over 80 research publications in internationally reputed Journals and Conference proceedings. He holds membership
of professional bodies as Member - IEEE; Life Member - ISTE; Life Member - Instrument Society of India; Life
Member - Biomedical Engineering Society of India; Fellow The Institution of Engineers; and Fellow - The
Institution of Electronics and Telecommunication Engineers. He has visited Glasgow University (MEDSIP-2006
and ICE-2013); New Jersey Institute of Technology, New Jersey (IEEE EMBS 2006); City University, London and
Brunel University London. He is local coordinator of international project Establishment of ECG Database of
Healthy Indian Population in collaboration with Professor P.W. Macfarlane, University of Glasgow; Professor
Vinod Kumar, IIT Roorkee; Professor S T Hamde, SGGS Institute of Engineering & Technology, Nanded. He is
also the Member Peer Group, VSAT-Enabled Mobile e-Learning Terminals, a project under National Mission on
Education through Information and Communication Technology of Ministry of Human Resource Development,
Government of India and Member AHEC, IITR Roorkee Team for Performance Testing and Evaluation of Small
Hydro Stations in India. He has conducted four AICTE/MHRD short term courses for the training of faculty of
technical institute. He has been the Organizing Secretary of 1 st and 2nd International Conferences on Biomedical
Engineering and Assistive Technologies (BEATS 2010 and BEATS 2012) at NIT Jalandhar.

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