IOP PUBLISHING PHYSIOLOGICAL MEASUREMENT

Physiol. Meas. 28 (2007) L3–L7 doi:10.1088/0967-3334/28/12/L02

LETTER TO THE EDITOR

Reply to “Comment on ‘Analysis of

electroencephalograms in Alzheimer’s disease
patients with multiscale entropy’ ”
J Escudero1, D Abásolo1, R Hornero1, P Espino2 and M López1
1 Biomedical Engineering Group, ETSI Telecomunicación, University of Valladolid,

Camino del Cementerio s/n, 47011, Valladolid, Spain

2 Hospital Clı́nico San Carlos, c/Profesor Martı́n Lagos s/n, 28040, Madrid, Spain

E-mail: [email protected]

Received 6 September 2007, accepted for publication 12 November 2007

Published 3 December 2007
Online at stacks.iop.org/PM/28/L3

Abstract
We appreciate the interest of Dr Tang in our article. Certainly, our
previous results should be taken with caution due to the small database size.
Nevertheless, it must be noted that this limitation was clearly recognized
in our article. Furthermore, our hypothesis is completely justified from
the current state of the art in the analysis of electroencephalogram (EEG)
signals from Alzheimer’s disease (AD) patients. We evaluated whether the
multiscale entropy (MSE) analysis of the EEG background activity was useful
to distinguish AD patients and controls. We do believe that further discussions
about risk factors or related clinicophysiological protein aspects are clearly
beyond the scope of our article. For the sake of completeness, we now detail
some results that complement our previous analysis. They suggest that the
MSE analysis can provide relevant information about the dynamics of AD
patients’ EEG data. Thus, we must reaffirm our conclusions, although we
again acknowledge that further studies are needed.

Keywords: Alzheimer’s disease (AD), electroencephalogram (EEG), multiscale

entropy (MSE), receiver operating characteristic (ROC) curve

We appreciate the attention which Dr Tang has paid to our article (Escudero et al 2006).
Alzheimer’s disease (AD) is a heterogeneous neurodegenerative disorder mainly caused by
ageing (Cummings 2004). Additionally, there exist complex interactions of genetic and
environmental risk factors (Blennow et al 2006). Some of them are associated with vascular
disease, including hypercholesterolemia, hypertension, atherosclerosis, coronary heart disease,
smoking, obesity and diabetes. However, it is unclear whether these conditions are true causal
risk factors or whether they induce cerebrovascular pathology, exceeding the threshold for
AD (Blennow et al 2006). Although the analysis of these risk factors is relevant to the AD
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L4 Letter to the Editor

prognosis, we do feel that this discussion clearly exceeds the purpose of our original article.
Our objective must not be misunderstood. Rather than being focused on scrutinizing either the
risk factors and clinicophysiological aspects related to AD or the molecular changes underlying
the dementia, our technical article aimed to assess the application of multiscale entropy (MSE)
(Costa et al 2005) to electroencephalogram (EEG) recordings from AD patients. We wanted
to test whether the MSE might be a useful tool to increase our knowledge of this dementia and
to possibly help in its diagnosis (Escudero et al 2006).
Actually, the hypothesis tested in our article was that the MSE analysis of EEG background
activity might differentiate AD patients from control subjects (Escudero et al 2006). This
hypothesis is completely justified considering numerous studies that have revealed changes in
the nonlinear dynamics of EEG recordings from AD patients (for a review, see Jeong (2004)).
For instance, previous studies by our research group had found a decrease in irregularity
and complexity in AD patients’ EEG recordings when compared with those of age-matched
control subjects (Abásolo et al 2005, 2006a, 2006b). Hence, the MSE, which is a nonlinear
complexity measure recently developed by Costa et al (2002), seemed a useful technique to
characterize AD patients’ EEGs despite the fact that it had not been previously applied to this
kind of signals.
The methodology on which the MSE analysis is based is clearly presented in Costa
et al (2002, 2005), Ferrario et al (2006) and Escudero et al (2006), among others. Briefly, this
analysis is performed by computing the sample entropy on successive coarse-grained versions
of the original time series (Costa et al 2005, Escudero et al 2006). Different features can then
be extracted from the MSE profiles. In our study, the slope of the MSE profiles for large time
scales provided significant differences between controls and AD patients’ EEGs (Escudero
et al 2006). Furthermore, a recent study has found that this MSE feature also distinguishes
control subjects from AD patients when applied to magnetoencephalogram recordings (Gómez
et al 2007). Although these results are somewhat limited by the reduced number of subjects
analysed, they lead us to think that MSE analysis of EEG and MEG data might be helpful to
differentiate cognitively normal controls from mild demented patients, as Dr Tang suggests.
Nevertheless, further studies should be undertaken to verify this hypothesis.
As we have mentioned, we agree with Dr Tang that our study is limited by the small
sample size. This was clearly stated in the ‘Discussion and Conclusions’ section of our article
(Escudero et al 2006). Due to this limitation, we set a restrictive significance level (α = 0.01)
to minimize the type I error. We also stated that the study should be extended on a much
larger population before MSE-derived metrics could be accepted as clinical diagnostic tools
(Escudero et al 2006).
We applied a Student’s t-test to evaluate the statistical differences between the MSE
slopes of AD patients and control subjects at each electrode. Additionally, receiver operating
characteristic (ROC) curves were used to assess the ability of this analysis to discriminate
both subject groups (Bradley 1997, Fawcett 2006, Zweig and Campbell 1993). For each
electrode with significant differences, a threshold was estimated as the cut-off point at which
the highest accuracy was reached. This criterion implies a trade-off between the sensitivity
and specificity obtained for that threshold (Bradley 1997). It is always possible to achieve a
fixed value of sensitivity by decreasing specificity (and vice versa). Furthermore, both the true
negative and the true positive rates should be taken into account when assessing the ability
of a parameter to distinguish two subject groups (Zweig and Campbell 1993). Although it is
true that the selection of a specific threshold depends on the prevalence of AD patients and
on the false-positive and false-negative costs (Bradley 1997, Zweig and Campbell 1993), the
optimum accuracy criterion was used in our technical study to measure the ability of the MSE
analysis to tell both groups apart. This criterion enabled us to straightforwardly compare the
Letter to the Editor L5

Table 1. AUC results for the slope of the MSE profiles for large time scales on the channels at
which differences between groups were significant. In addition to the AUC value, the corresponding
p-value that the AUC is larger than 0.5 and the 95% CI for the AUC are shown.

Electrode AUC p-value 95% Confidence interval

F3 0.8430 0.006 0.6642 1.0000a
F7 0.8347 0.008 0.6535 1.0000a
Fp1 0.9339 0.001 0.8308 1.0000a
Fp2 0.8512 0.005 0.6821 1.0000a
T5 0.9174 0.001 0.7939 1.0000a
T6 0.9008 0.001 0.7756 1.0000a
P3 0.9174 0.001 0.7998 1.0000a
P4 0.8512 0.005 0.6878 1.0000a
O1 0.9174 0.001 0.7998 1.0000a
O2 0.8760 0.003 0.7315 1.0000a
a The upper bounds of the 95% CI for the AUC that were larger than 1 were rounded down to
1.0000.

classification achieved with MSE to that obtained in previous studies with other nonlinear
analysis methods (Abásolo et al 2006a, 2006b).
In addition to the particular values of the sensitivity/specificity pair, we also plotted
the ROC curves and provided the areas under the ROC curve (AUC) in order to offer a
comprehensive picture about the differences between both subject groups (Bradley 1997,
Zweig and Campbell 1993). ROC graphs do not depend on class distributions (Fawcett 2006).
The AUC can be interpreted as the probability that a randomly selected individual from the
control subjects’ group has a value smaller than that of a randomly chosen AD patient. This
concept is closely related to the Wilcoxon test of ranks, thus providing information about
the separation between the values for demented patients and controls (Bradley 1997, Fawcett
2006, Zweig and Campbell 1993). Additionally, a confidence interval (CI) can be computed.
We agree with Dr Tang that a reduced sample size may increase the standard error of the AUC.
Nevertheless, it has also been shown that this standard error decreases as the AUC increases
(Bradley 1997). Most of the AUC values reported in our article were larger than 0.85 (Escudero
et al 2006). Furthermore, it can also be assessed whether the AUC is significantly different
from 0.5. The rejection of this null hypothesis provides evidence that the test does have the
ability to distinguish the groups (Zweig and Campbell 1993). Finally, if the lower bound of
the 95% confidence interval for the AUC is higher than 0.5, the information offered by the
parameter can be considered useful for classification (Palacios et al 2007). For the sake of
completeness, we now include the p-value that the AUC is larger than 0.5 and the 95% CI
for the ROC curves shown in our article. These results are depicted in table 1. It can be
observed that, despite the small sample size, all AUC values are significantly different from
0.5 (p-value < 0.01), and that the 95% CIs are better than those roughly guessed by Dr Tang
in his comment. In five cases (Fp1, T5, T6, P3 and O1), the lower bound of the 95% CI was
higher than 0.75.
As Dr Tang has commented, it is difficult to compare multiple analysis techniques. In
our article, the MSE analysis was compared with approximate entropy, sample entropy and
Lempel–Ziv complexity. It should be noted that all these nonlinear analysis methods were
applied to the same database (Abásolo et al 2006a, 2006b, Escudero et al 2006). This allowed
us to straightforwardly compare the statistical differences and the classification results provided
by all these methods even though the sample size is small. This comparison suggests that the
MSE analysis may characterize the EEG of AD patients better than other nonlinear analysis
techniques. This might be because the MSE considers several time scales simultaneously.
L6 Letter to the Editor

Some authors have suggested that the simultaneous inspection of multiple time scales could
offer relevant information that is unavailable when analysing biomedical signals with other
techniques based on the inspection of only one temporal scale, such as approximate entropy
(Costa et al 2005, Hoyer et al 2005, Palacios et al 2007).
Additionally, Dr Tang also mentions the problem that may arise when many statistical
significance tests are simultaneously performed. In these cases, it may be necessary to correct
the computed p-values by a multiple comparison correction strategy, such as the Bonferroni
correction. This correction prevents the appearance of spurious significant differences between
groups (Jobson 1991). It may be necessary when high-density recording equipment is used,
such as by Gómez et al (2007) where comparisons between AD patients and age-matched
controls were simultaneously performed at 148 MEG channels. However, the number of
channels analysed in our study was limited to 16 (Escudero et al 2006). Consequently, we did
not apply any correction procedure to the Student’s t-test p-values. Additionally, the channels
at which significant differences were found were further analysed using ROC curves. It should
also be noted that the application of the well-known, restrictive Bonferroni correction would
have modified the p-values obtained in Abásolo et al (2006a, 2006b) in the same way as those
of Escudero et al (2006), and the results would still be straightforwardly comparable since
the same database was analysed. Furthermore, there may be large differences between groups
even though the Bonferroni-corrected p-values are not significant (Jobson 1991).
To sum up, we thank Dr Tang for his interest. We agree with Dr Tang that our results
should be taken with caution due to the small database size. This limitation was clearly
recognized in our article (Escudero et al 2006). Nevertheless, our original hypothesis is fully
justified taking into account the current state of the art in the analysis of AD patients’ EEG
recordings (Jeong 2004). We do believe that the goal of our study and its methodology must
not be misunderstood, since we do not aim to discuss the risk factors related to AD but to assess
the utility of MSE as a technique to analyse EEG recordings. For the sake of completeness,
in this document, we have included p-values for the null hypothesis that the AUC are larger
than 0.5 and the 95% CI for these parameters. These results, together with those included in
Escudero et al (2006), suggest that the MSE analysis can provide relevant information about
the dynamics of AD patients’ EEG recordings. Thus, we reaffirm our conclusion that AD
may be characterized not only by changes in the brain activity on the shortest time scale, but
also by an abnormal behaviour on deeper time scales (Escudero et al 2006). Nevertheless, we
want to recall that the MSE analysis of EEGs cannot yet be applied in AD diagnosis and that
further studies with larger databases are needed.

References

Abásolo D, Hornero R, Espino P, Álvarez D and Poza J 2006a Entropy analysis of the EEG background activity in
Alzheimer’s disease patients Physiol. Meas. 27 241–53
Abásolo D, Hornero R, Espino P, Poza J, Sánchez C I and de la Rosa R 2005 Analysis of regularity in the EEG
background activity of Alzheimer’s disease patients with approximate entropy Clin. Neurophysiol. 116 1826–34
Abásolo D, Hornero R, Gómez C, Garcı́a M and López M 2006b Analysis of EEG background activity in Alzheimer’s
disease patients with Lempel-Ziv complexity and central tendency measure Med. Eng. Phys. 28 315–22
Blennow K, de Leon M J and Zetterberg H 2006 Alzheimer’s disease Lancet 368 387–403
Bradley A P 1997 The use of the area under the ROC curve in the evaluation of machine learning algorithms Pattern
Recognit. 30 1145–59
Costa M, Goldberger A L and Peng C K 2002 Multiscale entropy analysis of complex physiologic time series Phys.
Rev. Lett. 89 068102
Costa M, Goldberger A L and Peng C K 2005 Multiscale entropy analysis of biological signals Phys. Rev. E 71 021906
Cummings J L 2004 Alzheimer’s disease New Engl. J. Med. 351 56–67
Letter to the Editor L7

Escudero J, Abásolo D, Hornero R, Espino P and López M 2006 Analysis of electroencephalograms in Alzheimer’s
disease patients with multiscale entropy Physiol. Meas. 27 1091–106
Fawcett T 2006 An introduction to ROC analysis Pattern Recognit. Lett. 27 861–74
Ferrario M, Signorini M G, Magines G and Cerutti S 2006 Comparison of entropy-based regularity estimators:
application to the fetal heart rate signal for the identification of fetal distress IEEE Trans. Biomed.
Eng. 53 119–25
Gómez C, Hornero R, Abásolo D, Fernández A and Escudero J 2007 Analysis of MEG recordings from Alzheimer’s
disease patients with sample and multiscale entropies Proc. 29th Ann. Int. Conf. of the IEEE Engineering in
Medicine and Biology Society (Lyon, France) pp 6183–6 (doi: 10.1109/IEMBS.2007.4353767)
Hoyer D, Pompe B, Chon K H, Hardraht H, Wicher C and Zwiener U 2005 Mutual information function assess
autonomic information flow of heart rate dynamics at different time scales IEEE Trans. Biomed. Eng. 52 584–92
Jeong J 2004 EEG dynamics in patients with Alzheimer’s disease Clin. Neurophysiol. 115 1490–505
Jobson J D 1991 Applied Multivariate Data Analysis (Regression and Experimental Design vol 1) (New York:
Springer) pp 409–16
Palacios M, Friedrich H, Götze C, Vallverdú M, Bayes de Luna A, Caminal P and Hoyer D 2007 Changes of autonomic
information flow due to idiopathic dilated cardiomyopathy Physiol. Meas. 28 677–88
Zweig M H and Campbell G 1993 Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in
clinical medicine Clin. Chem. 39 561–77