Member, IEEE Nizar Bouhlel
email: nizar.bouhlel@free.fr

Member, IEEE Vahid Akbari

Member, IEEE Stéphane Méric

Change Detection in Multilook Polarimetric SAR Imagery With Determinant Ratio Test Statistic

Keywords: Change detection, complex Wishart distribution, determinant ratio test (DRT), Hotelling-Lawley trace (HLT), likelihood ratio test (LRT), multilook polarimetric synthetic aperture radar (SAR) data, Wilks

In this article, we propose a determinant ratio test (DRT) statistic to measure the similarity of two covariance matrices for unsupervised change detection in polarimetric radar images. The multilook complex covariance matrix is assumed to follow a scaled complex Wishart distribution. In doing so, we provide the distribution of the DRT statistic that is exactly Wilks's lambda of the second kind distribution, with density expressed in terms of Meijer G-functions. Due to this distribution, the constant false alarm rate (CFAR) algorithm is derived in order to achieve the required performance. More specifically, a threshold is provided by the CFAR to apply to the DRT statistic producing a binary change map. Finally, simulated and real multilook polarimetric SAR (PolSAR) data are employed to assess the performance of the method and is compared with the Hotelling-Lawley trace (HLT) statistic and the likelihood ratio test (LRT) statistic.

I. INTRODUCTION

T HE synthetic aperture radar (SAR) image change detec- tion has become very important in remote sensing for monitoring dynamic processes on the Earth, for instance, damage assessment in urban areas, deforestation and clearcut detection, flooding, and monitoring of glaciers. Change detection is a process that analyzes multitemporal remote sensing images acquired on the same geographical area for identifying changes that occurred at distinct observation dates. The result is a generation of a change detection map in which changed areas are explicitly identified.

Several unsupervised change detection methods have been proposed in the literature. Two families of methods handle the change detection process: the statistical information theory and the hypothesis test theory. The first family is based on information-theoretic measures in order to design a distance between images. In doing so, surrounding pixels are modeled by a given distribution and distance measures are applied to obtain a comparative statistic. With this family, the change detection is less sensitive to acquisition conditions since the used methodology considers information from the neighborhood. This information is relevant when dealing with data corrupted by speckle or/and the number of looks is low: to name a few of statistical information distances: mutual information [START_REF] Gueguen | Change detection based on information measure[END_REF], [START_REF] Erten | A new coherent similarity measure for temporal multichannel scene characterization[END_REF], variational and mixed information [START_REF] Gueguen | Change detection based on information measure[END_REF], [START_REF] Gueguen | Mixed information measure: Application to change detection in Earth observation[END_REF], and stochastic distances such as the Kullback-Leibler, Rényi, Bhattacharyya, and Hellinger distances [START_REF] Nascimento | Hypothesis testing in speckled data with stochastic distances[END_REF].

The second family aims to compute a covariance equality test and to test the hypotheses of change versus no-change where an asymptotic distribution is usually employed by the test statistic. The simplest one is to compute the ratio of SAR amplitudes or intensities observed at different times. This kind of ratios is a well-known test statistic in singlechannel SAR-based change detection [START_REF] Akbari | Polarimetric SAR change detection with the complex Hotelling-Lawley trace statistic[END_REF]. A large number of test statistics have been developed and described in the literature for automatic and unsupervised change detection, such as mean ratio/log-ratio measures [START_REF] Rignot | Change detection techniques for ERS-1 SAR data[END_REF], [START_REF] Bazi | An unsupervised approach based on the generalized Gaussian model to automatic change detection in multitemporal SAR images[END_REF], Gauss log ratios [START_REF] Hou | Unsupervised change detection in SAR image based on gauss-log ratio image fusion and compressed projection[END_REF], multitemporal coherence analysis [START_REF] Rignot | Change detection techniques for ERS-1 SAR data[END_REF], and maximumlikelihood ratios [START_REF] Lombardo | Maximum likelihood signal processing techniques to detect a step pattern of change in multitemporal SAR images[END_REF].

Polarimetric SAR (PolSAR) gives more scattering information than single-polarization channel SAR data, which can be used to detect the change and increase the quality of the change detection map. The first work on test statistics for change detection in multilook PolSAR data was proposed by Conradsen et al. [START_REF] Conradsen | A test statistic in the complex wishart distribution and its application to change detection in polarimetric SAR data[END_REF]. They proposed a likelihood ratio test (LRT) for the equality of two complex covariance matrices 1 and 2 and gave the approximated distribution of the LRT statistic. The LRT algorithm worked by comparing two hypotheses: the null hypothesis (H 0 ) corresponding to "no-change" and an alternative hypothesis (H 1 ) corresponding to "change."

The LRT approach was extended to the multitemporal case [START_REF] Conradsen | Change detection in polarimetric SAR data over several time points[END_REF], [START_REF] Conradsen | Determining the points of change in time series of polarimetric SAR data[END_REF] and multifrequency data [START_REF] Nielsen | Change detection in full and dual polarization, Single-and multifrequency SAR data[END_REF]. Kersten et al. [START_REF] Kersten | A comparison of change detection statistics in POLSAR images[END_REF] compared three test statistics: the LRT statistic also called the Bartlett test, the contrast ratio test, and the ellipticity test. The second one was based on the largest and the smallest eigenvalues of 1 -1 2 , and then, the change was represented by these eigenvalues. The third test statistic was based on the combination of the determinant and the trace of 1 -1 2 by using the eigenvalues.

Later, Akbari et al. [START_REF] Akbari | Polarimetric SAR change detection with the complex Hotelling-Lawley trace statistic[END_REF] proposed a simpler test statistic to detect changes in many scenarios. The test assumed the . scaled complex Wishart distribution for the covariance matrix data. It was based on the complex-kind Hotelling-Lawley trace (HLT) that was used to measure the similarity of two covariance matrices. They applied a decision threshold to the test statistic to detect changes. The threshold was determined using the constant false alarm rate (CFAR) algorithm [START_REF] Bunch | A constant-false-alarm-rate algorithm[END_REF]. Akbari et al. proposed the Fisher-Snedecor (FS) distribution as the approximation of the sampling distribution of the HLT test statistic. The parameters of the FS distribution depended only on the dimension of the polarimetric data and the equivalent number of looks (ENL) estimated for images. They used the method of the matrix log cumulants [START_REF] Anfinsen | Estimation of the equivalent number of looks in polarimetric synthetic aperture radar imagery[END_REF] to estimate the ENL.

In this article, the ratio of the determinant of two matrices is proposed as a new test statistic to measure the similarity of two covariance matrices that are assumed to follow scaled complex Wishart distributions. The new test is called the determinant ratio test (DRT) statistic and it is able to produce a scalar value, to which a threshold is applied. The distribution of the test statistic under the null hypothesis is exactly Wilks's lambda of the second kind distribution with density expressed in terms of Meijer G-functions [START_REF] Pham-Gia | Exact distribution of the generalized Wilks's statistic and applications[END_REF]. Wilks's lambda distribution corresponds to the product of d independent Beta distributed of the second kind random variables, where d is the number of polarimetric channels. The latter distribution depends on the dimension of the polarimetric data and the ENL.

For the production of a binary change detection map, a threshold is applied to the test statistic. Several thresholding methods have been suggested in the literature to determine the threshold in a completely unsupervised manner: to name a few of them, CFAR algorithm [START_REF] Bunch | A constant-false-alarm-rate algorithm[END_REF], Otsu's method [START_REF] Otsu | A threshold selection method from gray-level histograms[END_REF], and Kittler and Illingworth (K&I) algorithm [START_REF] Kittler | Minimum error thresholding[END_REF], [START_REF] Ghanbari | Unsupervised change detection in polarimetric SAR data with the hotelling-lawley trace statistic and minimumerror thresholding[END_REF]. In this article, we limit ourselves to the CFAR algorithm since we are more interested in the test statistic rather than the thresholding method. Consequently, the final binary change map is made at a predefined false alarm rate (FAR). To further illustrate the potential of our method in change detection for multilook PolSAR data, the well-known HLT and LRT test statistics for measuring the equality of two multilook covariance matrices are compared with our approach. Simulated and real multilook PolSAR data are used for this comparison.

This article is organized as follows. Section II introduces the statistical model for the covariance matrix data. Section III describes some properties related to the scaled complex Wishart distribution, the DRT for equality of two complex scaled Wishart distributions, and its sampling distribution. In Section IV, the proposed polarimetric change detection algorithm based on the DRT is presented, followed by the CFAR principle to determine the threshold. The HLT and LRT methods are briefly shown for a later comparison with our method. Section V demonstrates the performance of the method with a simulated and real PolSAR data set and discusses the results. Section VI is dedicated to a summary and a conclusion.

II. MULTILOOK POLSAR IMAGE MODEL

The polarimetric scattering vector is defined as

s = [s hh , s hv , s vh , s vv ] T ∈ C d (1)
with s xy representing the complex scattering coefficients, where x is the transmit and y is the receive polarization. Moreover, h denotes horizontal, v denotes vertical [START_REF] Lee | Polarimetric Radar Imaging: From Basics to Application[END_REF], [.] T means transposition, and d = dim(s) is the vector dimension. The vector s is a single-look polarimetric complex format representation of PolSAR data. It is assumed that s is a d-dimensional speckle vector, which follows a circular complex Gaussian distribution (s ∼ N C d (0, )), with a zero-mean vector and a covariance matrix . The multilooking of PolSAR data reduces the speckle effect characteristic of coherent imaging systems. The polarimetric multilooking operation is given by

X = 1 L L =1 s s H , L ≥ d ( 2
)
where L is the number of looks, (.) H denotes the Hermitian operator, and X ∈ + ⊂ C d×d is the multilook polarimetric covariance matrix considered as a random matrix defined on the cone, denoted + , of the positive definite complex Hermitian matrices. When L ≥ d, the unnormalized sample covariance matrix defined as Z = LX follows the nonsingular complex Wishart distribution [START_REF] Goodman | Statistical analysis based on a certain multivariate complex Gaussian distribution[END_REF] denoted as Z ∼ W C d (L, ) and X follows a scaled complex Wishart distribution, denoted X ∼ sW C d (L, ), with a probability density function (pdf) given by f

X (X) = f Z (LX)| J Z→X |, where |J Z→X | = L d 2 is the Jacobian determinant of the transformation Z = LX [23]. The pdf of X is f X (X) = L Ld |X| L-d d (L)| | L etr(-L -1 X) (3)
where etr(.) = exp(tr(.)) is the exponential trace operator, |.| is the determinant operator, and d (L) is the multivariate gamma function of the complex kind defined as

d (L) = π d(d-1)/2 d-1 i=0 (L -i ) (4)
where (L) is the standard Euler gamma function.

III. THEORY

This section describes some properties related to the scaled complex Wishart distribution and the DRT for equality of two complex scaled Wishart distributions.

Theorem 1 (Goodman [START_REF] Goodman | The distribution of the determinant of a complex Wishart distributed matrix[END_REF]): Let X be a complex Hermitian positive definite random d × d matrix that follows a scaled complex Wishart distribution, X ∼ sW C d (L, ). The random variable (2L) d |X|/| | is distributed as the product of d independent chi-square (χ 2 ) distributed random variables with 2L, 2(L -1), . . . , 2(Ld + 1) degrees of freedom, respectively, i.e.,

(2L) d |X| | | ∼ d-1 i=0 χ 2 (2(L -i )). ( 5
)
Proof: The characteristic functions of the random variable ln((2L

) d |X|/| |) and ln( d-1 i=0 χ 2 (2(L-i ))
) are computed and seen to be equal (for more details, see Appendix A).

. Corollary 2: Let X and Y be two complex Hermitian positive definite random d × d matrices that follow scaled complex Wishart distributions defined as:

X ∼ sW C d (L x , ) and Y ∼ sW C d (L y , ). (6)
The random variable defined by the determinant ratio of L x X and L y Y is distributed as the product of d independent Beta distributed of the second kind (also called Beta prime) random variables with parameters (L xi ) and (L yi )

|L x X| |L y Y| ∼ d-1 i=0 Beta II (L x -i, L y -i ) ( 7
)
where the pdf for Beta II (L xi, L yi ) is given by

f i (x) = (L x + L y -2i ) (L x -i ) (L y -i ) x L x -i-1 (1 + x) L x +L y -2i (8) = 1 (L x -i ) (L y -i ) G 1,1 1,1 -L y + i L x -i -1 x ( 9
)
where

G 1,1 1,1 • • • is the Meijer G-function defined in
Section II-A.

Proof: Corollary 2 is the consequence of ( 5) and the relationship between the ratio of two independent χ 2 random variables and the Fisher (F) distribution with two parameters given as follows.

1)

If X ∼ χ 2 (d 1 ) and Y ∼ χ 2 (d 2 ) are two independent random variables, then ((X/d 1 )/(Y/d 2 )) ∼ F(d 1 , d 2 ). 2) If X ∼ F(2α, 2β) has an F-distribution, then (α/β)X ∼
Beta II (α, β).

A. Meijer G-Function

The Meijer G-function is a generalization of the generalized hypergeometric function that is defined using the contour integral representation [START_REF] Luke | The Special Functions and Their Approximations/YudellL[END_REF]

G m,n p,q a 1 , . . . , a p b 1 , . . . , b q x = 1 2πi × L m j =1 (b j -s) n j =1 (1 -a j + s) q j =1+m (1 -b j + s) p j =1+n (a j -s) × x s ds ( 10
)
where {a j } p j =1 and {b j } q j =1 are, in general, complex-valued. Contour L is a suitable integration contour that separates the poles of function (b j -s) from the poles of (1-a j +s). The Meijer G-function has been implemented in some commercial software packages, such as MATLAB and MAPLE.

B. Wilks' Lambda Distribution of Determinant Ratio Statistic

Definition 3: For noninteger values of n and q and integer values of p with n ≥ q ≥ p, the pdf of Wilks's lambda distribution of the second kind, denoted as (n, p, q), is given as [START_REF] Pham-Gia | Exact distribution of the generalized Wilks's statistic and applications[END_REF]

f (x) = A × G p, p p, p -q, -(q -1), . . . , -(q -( p -1)) n -q -1, n -q -2, . . . , n -q -p x ( 11
)
where Theorem 4: The pdf g(z) of the product

A = p-1 j =0 (1/( (n -q -j ) (q -j ))).
Z = d-1 i=0 X i of d independent X i variables Beta distributed of the second kind, X i ∼ Beta I I (L x -i, L y -i ), is a Meijer G-function multiplied by a normalizing constant A, i.e., g(z) = A × G d,d d,d -L y , -(L y -1), . . . , -(L y -(d -1)) L x -1, L x -2, . . . , L x -d z ( 12
)
where

A = d-1 i=0 (1/( (L x -i ) (L y -i ))).

The cumulative distribution function is given by

G(z) = Az × G d,d+1 d+1,d+1 -L y , -(L y -1), . . . , -(L y -(d -1)), 0 L x -1, L x -2, . . . , L x -d, -1 z . ( 13
)
The kth moment E{Z k } is given by

E{Z k } = d-1 i=0 (L y -i -k) (L y -i ) (L x -i + k) (L x -i ) . ( 14
)
Proof: See Appendix B. With reference to Definition 3, the distribution of ((|L x X|)/(|L y Y|)) is given as follows:

|L x X| |L y Y| ∼ (L x + L y , d, L y ). ( 15
)
It is worthy to note that the determinant ratio depends on the parameters L x and L y . In the case L x = L y = L, Wilks's lambda distribution of the second kind is given by (2L, d, L). .

IV. POLARIMETRIC CHANGE DETECTOR

We consider X and Y two statistically independent Hermitian positive definite random d × d matrices that follow scaled complex Wishart distributions with different distribution parameters defined as:

X ∼ sW C d (L x , x ) and Y ∼ sW C d (L y , y ). ( 16
)
Multilook PolSAR images acquired over the same geographical area before event (at time t x ) and after event (at time t y ) are used to detect any change by comparing at each position (i, j ) the full polarimetric information before change and after change given, respectively, by X(i, j ) and Y(i, j ). Here, we suppose that at each (i, j ), we have two matrices X(i, j ) and Y(i, j ). As a consequence, we resort to compute the determinant ratio of L x X and L y Y described in Section IV-A.

A. Determinant Ratio Statistic

The determinant ratio statistic is defined by

τ DRT = |L x X| |L y Y| . ( 17
)
DRT is used to measure the similarity between the two polarimetric covariance matrices X and Y and perform change detection by choosing between hypotheses [5]

H 0 : x = y H 1 : x = y . ( 18
)
Null hypothesis (H 0 ) corresponds to no-change, and hypothesis (H 1 ) corresponds to change. To quantify the difference between H 0 and H 1 , a threshold selection procedure is applied to the test statistic τ DRT . It is worth mentioning that the hypothesis tests are developed with distinct ENLs, i.e., L x = L y . Nevertheless, in the first experiment with simulations, we assume that the ENL is the same for both images. The exact distribution of the DRT statistic under null hypothesis (H 0 ) is Wilks's lambda distribution of the second kind given by

τ DRT ∼ (L x + L y , d, L y ). ( 19
)
For particular case where L x = L y = L, the DRT statistic becomes τ DRT ∼ (2L, d, L).

B. CFAR Thresholding Method

In our study, change detection is realized by applying a decision threshold to the test statistics [START_REF] Akbari | Polarimetric SAR change detection with the complex Hotelling-Lawley trace statistic[END_REF]. We choose the CFAR algorithm [START_REF] Bunch | A constant-false-alarm-rate algorithm[END_REF] as a thresholding method in order to perform a fair comparison between our proposed approach and the HLT method since we are interested in the test statistic rather than the thresholding method. Let f τ DRT (τ ) be the distribution of the ratio τ DRT under the hypothesis H 0 . The significance level of the test α c , expressed in percent, is given as a function of the desired false alarm probability P fa and then given by α c = 100P fa . The threshold is determined from the distribution of the determinant ratio statistic.

We adopt the same approach presented in the paper of Akbari et al. [START_REF] Akbari | Polarimetric SAR change detection with the complex Hotelling-Lawley trace statistic[END_REF] where changes from X to Y and reversely from Y to X were considered in the CFAR change detector. This results in using the following two ratios:

τ DRT = |L x X| |L y Y| , and τ DRT = |L y Y| |L x X| . ( 20
)
The combined test is given by

max τ DRT , τ DRT H 1 ≷ H 0 T. ( 21
)
The combined threshold T is derived from

P fa = 2 +∞ T f τ DRT (τ |H 0 )dτ. ( 22
)
When P fa is specified, the threshold is obtained by solving [START_REF] Goodman | Statistical analysis based on a certain multivariate complex Gaussian distribution[END_REF], and then, the CFAR change detector is obtained.

The proposed unsupervised change detection based on DRT between two multilook PolSAR data acquired before and after change is summarized in the following steps. 1) Find a global estimation of Lx and L y .

2) Generate the DRT statistics image using max{τ DRT , τ DRT } computed from two multilook PolSAR data.

3) Compute the CFAR threshold for a specific P fa . 4) Apply the threshold and obtain the binary change detection map. It is important to mention that the quality of the change detection map depends on the estimation accuracy of L x and L y . For an efficient estimation of the ENL, many methods have been put forward in the literature for automatic estimate. To name a few of them, we mention the following. First, the method of Anfinsen et al. [START_REF] Anfinsen | Estimation of the equivalent number of looks in polarimetric synthetic aperture radar imagery[END_REF] was based on the maximum likelihood estimator for the ENL under the assumption that data follow the complex Wishart distribution. Second, the method proposed by Tao et al. [START_REF] Tao | Texture-invariant estimation of equivalent number of looks based on trace moments in polarimetric radar imagery[END_REF] was based on the development of trace moments (DTMs). This ENL estimator cancels the textural variation using trace moments. Finally, the method developed by Bouhlel [START_REF] Bouhlel | Parameter estimation of multilook polarimetric SAR data based on fractional determinant moments[END_REF] was based on the fractional moments of the determinant of the multilook polarimetric covariance (FMDC) matrix. The FMDC estimator of the ENL had the particularity of being independent of the distribution of the texture model. All these methods consisted in performing a local estimate of the ENL by using a sliding window covering the whole image. Then, the distribution of estimates was drawn and the mode value of the density corresponds to the desired global estimate of the ENL. It is worthy to note that the presence of texture and correlation between samples can affect the estimation of the ENL.

In Section IV-C, we briefly describe the HLT and the LRT statistics in order to compare them with our proposed statistic.

C. HLT Statistic

The complex-kind HLT statistic is defined as

τ HLT = tr(Y -1 X). ( 23
)
The exact distribution of the HLT statistic is difficult to derive and an approximation was put forward by Akbari et al. [START_REF] Akbari | Polarimetric SAR change detection with the complex Hotelling-Lawley trace statistic[END_REF].

. It is the FS 1 distribution with three parameters used as an approximation to τ HLT and is given as follows:

τ HLT ∼ FS(ξ, ζ, μ). ( 24
)
The expression of the FS distribution is given by

f τ HLT (τ ) = (ζ + ξ) (ξ ) (ζ ) ξ μ(ζ -1) ξτ μ(ζ -1) ξ -1 1 + ξτ μ(ζ -1)
ξ +ζ [START_REF] Luke | The Special Functions and Their Approximations/YudellL[END_REF] where μ = E{τ HLT } > 0 is a scale parameter and ξ, ζ > 0 are two shape parameters. The parameters of the FS distribution are computed in terms of distribution parameters of scaled Wishart matrices X and Y. The solutions for μ, ξ , and ζ are defined by the following equation system [START_REF] Akbari | Polarimetric SAR change detection with the complex Hotelling-Lawley trace statistic[END_REF]:

m (FS) ν (μ, ξ, ζ ) = m (HLT) ν (L x , L y , d), ν = 1, 2, 3 (26)
where m (FS) ν and m (HLT) ν are the νth order moments of the FS distribution and the HLT statistic, respectively. For more details about the expressions of the moments, reader can refer to [START_REF] Akbari | Polarimetric SAR change detection with the complex Hotelling-Lawley trace statistic[END_REF] and [START_REF] Akbari | Multitemporal analysis of multipolarization synthetic aperture radar images for robust surface change detection[END_REF]. Technically, to estimate the shape parameters ξ and ζ , a minimum distance optimization is used to solve the following:

( ξ, ζ ) = arg min (ξ,ζ ) 3 ν=2 m (FS) ν -m (HLT) ν 2 . ( 27
)
Finally, a good fitting of the FS distribution depends on the estimation accuracy of (μ, ξ, ζ ), which in turn depends on the estimates of L x and L y [START_REF] Akbari | Polarimetric SAR change detection with the complex Hotelling-Lawley trace statistic[END_REF]. It is worth noticing that the FS distribution of the HLT detector for a low number of looks does not provide a good approximation and fitting as it will be seen in the experiments. The combined test is derived as follows:

max τ HLT , τ HLT H 1 ≷ H 0 T. ( 28
)
The threshold is determined from the resolution of the following equation:

P fa = 2 +∞ T f τ HLT (τ |H 0 )dτ. ( 29
)

D. LRT Statistic

The Wishart LRT statistic was derived as [10]

Q = (L x + L y ) d(L x +L y ) L d L x x L d L y y |L x X| L x |L y Y| L y |L x X + L y Y| L x +L y . ( 30
)
The test statistic for change detection based on the LRT is given by

τ LRT = -2ρ ln Q ( 31
)
where The distribution of τ LRT under the null hypothesis (H 0 ) is approximated by using the associated asymptotic distribution of the test statistic [START_REF] Conradsen | A test statistic in the complex wishart distribution and its application to change detection in polarimetric SAR data[END_REF]

ρ = 1 - 2d 2 -1 6d 1 L x + 1 L y - 1 L x + L y . ( 32
)
τ LRT ∼ χ 2 (d 2 ) + w 2 [χ 2 (d 2 + 4) -χ 2 (d 2 )] ( 33
)
where χ 2 (d 2 ) denotes a central χ 2 distribution with d 2 degrees of freedom and

w 2 = - d 2 4 1 - 1 ρ 2 + d 2 (d 2 -1) 24
× 1 L 2 x + 1 L 2 y - 1 (L x + L y ) 2 1 ρ 2 . (34)
The test with a desired P fa is given by

τ LRT H 1 ≷ H 0 T ( 35
)
where the threshold T is determined through the equation

P fa = +∞ T f τ LRT (τ |H 0 )dτ. ( 36
)
It is worth mentioning that the LRT is a one-sided test; however, the DRT and HLT are two-sided test.

V. EXPERIMENTAL RESULTS

The performance of the proposed DRT statistic is evaluated on both simulated and real PolSAR images. The HLT and the LRT tests are implemented for comparison with our test.

A. Simulated Data

We simulate two quad-pol data containing two L-look Pol-SAR images of 250 × 250 pixels and having four polarimetric channels (d = 4). The generated data follow a scaled Wishart distribution with a covariance matrix of the speckle j defined in Table I where j = {1, . . . , 7}. Then, the polarimetric data contain seven different classes (areas). Area 7 corresponds to the polarimetric properties of a heterogeneous urban area. Area 3 is simulated with the polarimetric properties of a homogeneous water region. The rest of the areas correspond to the properties of agricultural crops and vegetation regions. Different values of the number of looks L are used in this study, L ∈ {5, 6, 7, 8}. Fig. 2 shows the Pauli decomposition of the two simulated five-look quad-pol PolSAR data corresponding to images before and after change and the binary . By computing the DRT, HLT, and LRT statistics, Fig. 3 shows the results of change detection relative to these methods and for different cases of L. As it can be seen, each row corresponds to a particular value of L starting from 5 for the first row to 8 for the last row. Fig. 3(ai), (ai'), and (ai") where i∈ {1, 2, 3, 4} show, respectively, the logarithm of DRT, the logarithm of HLT, and the LRT statistics for different values of L. In addition, Fig. 3(bi) shows the comparison between the normalized histograms of τ DRT and the estimated Wilks's lambda of the second kind pdfs computed over the nonchange area. It is clear that the estimated pdf curves fit well with the normalized histograms. The same comparison is made in Fig. 3(bi') between τ HLT and the estimated FS pdfs used as approximations. It is shown that for a low number of looks smaller than 7, the FS distribution of the HLT detector is not providing a good fitting. However, the DRT detector works better for the small number of looks.

.

TABLE II VALUES OF KS AND p-VALUES (%) OBTAINED BY USING WILK'S OF SECOND KIND DISTRIBUTION FOR SIMULATED DATA WITH DIFFERENT LEVELS OF MULTILOOKING

Another comparison is made in Fig. 3(bi") between τ LRT and the estimated pdf given by [START_REF] Springer | The distribution of products of independent random variables[END_REF]. Furthermore, Fig. 3(ci), (ci'), and (ci") shows the corresponding binary change maps obtained by the thresholding CFAR algorithm. Indeed, binary change detection map is obtained by the rejection of the hypothesis test at a 1% significance level for the DRT, HLT, and LRT detectors. It is noted that changes can be seen in these statistics for each case of L-values. Moreover, the proposed method detects more efficiently the changed area even for highly speckled cases with a low number of looks. It is also worth noticing that at the central part of the binary images (region 2), where heterogeneous change detection is present, the DRT is better than the others, but all three detectors seem not to work properly. This leads us to extend this work under non-Wishart case [START_REF] Liu | Change detection of multilook polarimetric SAR images using heterogeneous clutter models[END_REF], [START_REF] Bouhlel | Multilook polarimetric SAR change detection using stochastic distances between matrix-variate Gd0 distributions[END_REF] or relaxed Wishart distribution where the ENL is a local parameter [START_REF] Akbari | A change detector for polarimetric SAR data based on the relaxed Wishart distribution[END_REF].

The fit ability between the estimated Wilks's of the second kind pdfs and the normalized histograms of τ DRT is evaluated qualitatively by using the Kolmogorov-Smirnov (KS) hypothesis test. The smaller value of KS indicates better the hypothesized model fits with the empirical distribution. A small value of p-value of the test indicates strong incompatibilities of the data with the employed distribution hypothesis. Table II lists the values of KS and the p-values of the test (in percentage) obtained for the four cases of L under null hypothesis (H 0 ). It is evident from the p-value that the fitted Wilk's of the second kind distribution can perfectly model the no-change area.

A quantitative evaluation of the change detection performance is also provided at four different significance levels or specified FARs. Table III shows the measured FAR [false positive rate (FPR)] and the detection rate [true positive rate (TPR)] for DRT, HLT, and LRT statistics for various levels of multilooking and for different specified FARs. As shown in Table III, the DRT statistic realizes higher detection rates and lower overall error rates than the HLT and LRT statistics at specified FARs, especially when the speckle is strong and the number of looks L is low. As L increases to reach 8 and at specified FARs, the detection rates for these statistical tests increase and the overall error rates decrease. Likewise, when L passes to 8, the detection rate of both the DRT and HLT becomes close. It is also worth noticing that the measured FAR is close to the specified FAR regardless of the detector used.

Another quantitative evaluation of the performance of the method is provided by the receiver operating characteristic (ROC) curves that are plotted for these statistics using the ground truth. The ROC curve is the evolution of the TPR as a function of the FPR [START_REF] Cui | A benchmark evaluation of similarity measures for multitemporal SAR image change detection[END_REF]. Fig. 4 shows the ROC . In contrast, the black designates urban areas that do not satisfy the Wishart assumption. The ENL for both images before and after changes is estimated to be 7.2 and 6.9, respectively. Fig. 6(a), (a'), and (a"), respectively, shows the logarithm of the DRT, the logarithm of the HLT, and the LRT statistic. The plots of the normalized histograms and the estimated distributions for DRT, HLT, and LRT detectors are given, respectively, in Fig. 6(b), (b'), and(b"). Fig. 6(c), (c'), and(c") shows their corresponding binary change map obtained by the thresholding CFAR algorithm. The binary change detection map is obtained by the rejection of the hypothesis test at a 1% significance level for the DRT, HLT, and LRT detectors.

Regarding the quantitative assessment, the ROC curves for the DRT, HLT, and LRT statistics used in the experiments are given in Fig. 7. In this example, the obtained results show that the ROC curves of the HLT and LRT are above the ROC curve of the DRT. The measured AUC for these methods based on the DTR, HLT, and LRT statistics is 99.68%, 99.45%, and 99.13%, respectively. Different significance levels of the test are chosen where α c ∈ {0.5%, 1%, 5%, 10%} for evaluation. The detection rate, the measured FAR, and the overall error rate for the three methods are shown in Table V. At each specified FAR level, the best values are highlighted in red. We can clearly see that the DRT always gives the best detection rate for any specified FAR level. Also, for the overall error rate, the DRT gives good results in comparison with the other statistics for the case of a low value of significance levels . . We can see here a good fitting of the FS distribution with the normalized histograms. The same comparison is realized in Fig. 9(b"1) and (b"2) with the LRT statistic and the approximated pdf given by [START_REF] Springer | The distribution of products of independent random variables[END_REF] and computed over the nonchange area. As we can see, the estimated pdf curves based on χ 2 distributions do not fit well the normalized histograms. As consequence, the CFAR algorithm fails to provide the best threshold for the LRT statistic. Fig. 9(ci), (ci'), and (ci") shows the binary change . For a final comparison between these change detectors, we draw Table VI. It reports detection rate, the measured FAR, and the overall error rate computed for the three detectors for scenes 1 and 2, at four different significance levels of the test α c . The DRT statistic obtains the highest detection rate in this example, followed by the HLT statistic. The LRT statistic gives the worst performance. The DRT also achieves a lower overall error rate compared to the HLT and LRT statistics except for scene 1 when α c ≥ 5%. Regarding the measured FAR, the DRT gives values close to the specified FAR in most cases (cases of scene 2), but in other cases, the values are far apart (cases of scene 1). The performance of the DRT statistic is evaluated as well through the ROC curve and compared with that of the HLT and LRT statistic. Fig. 10 shows the corresponding ROC curves of the three detectors, indicating a better performance for the DRT statistic for low FPR values followed by the HLT and then by the LRT. The AUC is also provided for this example. For scene 1, it is 81.60% for the DRT, 80.42% for the HLT, and 78.96% for the LRT. For scene 2, it is 78.31% for the DRT, 77.77% for the HLT, and 74.41% for the LRT. Indeed, the AUC given by the DRT statistic is larger than the others.

VI. CONCLUSION

The DRT statistic has been proposed for change detection in multilook PolSAR images. Under the null hypothesis corresponding to no change, the statistic follows exactly Wilks's lambda distribution of the second kind depending on the ENL and the covariance matrix dimension. The fit ability is evaluated quantitatively using the KS goodness-of-fit test. With this statistic test distribution, the decision threshold can be efficiently determined at a specified probability of false alarm by using the CFAR-threshold method. The performance of the method has been evaluated on simulated and real multilook PolSAR data where ground-truth data were available and has been compared to the performance of the known HLT and LRT detectors. The results in terms of measured FAR, detection rate, ROC curve, and AUC have shown that the proposed DRT statistic outperforms the HLT and LRT performances especially for low ENL values and can perform a binary change detection map very close to the ground-truth data. The method can be extended to a heterogeneous model by considering the texture in the change detection process. The presence of texture can be useful to improve the detection, but additional texture parameters need to be estimated.

APPENDIX A

The characteristic function of the random variable V = ln((2L) d (|X|/| |)) is given as follows:

ψ V (t) = E{e it V } = E e it ln (2L) d |X| | | (37) = E (2L) d |X| | | it (38) = E 2 d |LX| | | it . ( 39
)
Let us consider the Hermitian matrix Z = LX, which follows the nonsingular complex Wishart distribution. The pdf of Z is as follows:

f Z (Z) = |Z| L-d d (L)| | L etr(--1 Z). (40)
Then, the integral over all the positive definite complex Hermitian matrices verifies

+ |Z| L-d etr(--1 Z)dZ = d (L)| | L . ( 41
)
We can write that

+ |Z| L+it-d etr(--1 Z)dZ = d (L + it)| | L+it . ( 42
)
As a consequence, (39) can be written as

ψ V (t) = + 2 d |Z| | | it f Z (Z)dZ (43) = 2 itd d (L)| | L+it + |Z| L+it-d etr(--1 Z)dZ (44) = 2 itd d (L)| | L+it d (L + it)| | L+it (45) = 2 itd d (L + it) d (L) (46) = 2 itd (L + it) (L + it -1) . . . (L + it -d + 1) (L) (L -1) . . . (L -d + 1) . ( 47
)
.

The pdf of the chi-squared distribution with 2L degrees of freedom χ 2 (2L) is given by

f χ 2 (2L) (x) = 1 2 L (L)
x L-1 e -x 2 .

(48)

Using the previous pdf, we can write +∞ 0

x L-1 e -x 2 dx = 2 L (L).

(49)

The characteristic function of an ln χ 2 (2L) random variable is given by ψ ln χ 2 (2L) (t) = E{e it ln X } = E{X it } (50)

= +∞ 0 x it f χ 2 (2L) (x)dx (51) = 1 2 L (L) +∞ 0
x L+it-1 e -x 2 dx (52)

= 2 it (L + it) (L) . ( 53
)
The characteristic function of the sum of independent ln χ 2 (2L), ln The Mellin integral transform of the density function g(z) of the product d-1 i=0 X i of d independent random variables X i with density functions f i (x i ) is given by [START_REF] Springer | The distribution of products of independent random variables[END_REF]

M{g(z)}(s) = d-1 i=0 M{ f i (x i )}(s). ( 58
)
Under suitable restrictions [START_REF] Titchmarsh | Introduction to the Theory of Fourier Integrals[END_REF], [START_REF] Springer | The distribution of products of beta, gamma and Gaussian random variables[END_REF] satisfied by all density functions, the density function g(z) is given by the following inverse formula:

g(z) = 1 2πi L z -s d-1 i=0 M{ f i (x i )}(s)ds. ( 59
)
Since the Mellin integral transform of 1/(1 + x) L x -i+L y -i is given by

M 1 (1 + x) L x -i+L y -i (s) = (L x -i + L y -i -s) (s) (L x -i + L y -i ) ( 60
)
and for any function f (x)

M{x L x -i-1 f (x)}(s) = M{ f (x)}(s + L x -i -1) (61)
it follows that the density function of the Beta distribution of the second kind has the following Mellin transform:

M{ f i (x i )}(s) = (1 + L y -i -s) (L y -i ) (L x -i -1 + s) (L x -i ) . (62)
Then, the Mellin integral transform of the pdf g(z) of the product of d independent random Beta type II variables is

M{g(z)}(s) = d-1 i=0 (1 + L y -i -s) (L y -i ) (L x -i -1 + s) (L x -i ) .
(63)

Accordingly, the g(z) pdf is written otherwise as a function of the inverse Mellin transform and is given as follows: Again, using the definition of the Meijer G-function [START_REF] Conradsen | A test statistic in the complex wishart distribution and its application to change detection in polarimetric SAR data[END_REF], this results in

g(z) = 1 2πi L z -s d-1 i=0 (1 + L y -i -s) (L y -i ) (L x -i -1 + s) (L x -i ) ds (64) = A 2πi L z s d-1 i=0 (1 + L y -i + s) (L x -i -1 -s)ds
G(t) = At 2πi L t s d-1 i=0 (1 + L y -i + s) (L x -i -1 -s) × (1 + s) (2 + s) ds (68) = At × G d,d+1
E{Z k } = Z (s)| s=k+1 = d-1 i=0 (L y -i -k) (L y -i ) (L x -i + k) (L x -i ) . ( 71
)
.

Fig. 1 .

 1 Fig. 1. PDF of Wilks's lambda distribution of second kind, (2L , d, L) with several values of L and different cases. (a) d = 2. (b) d = 4.

Fig. 1 (

 1 a) and (b) shows the pdf of (2L, d, L), with multiple values of L, and different cases: d = 2 and d = 4, respectively.

Fig. 2 .

 2 Fig. 2. Pauli decomposition of simulated five-look quad-pol PolSAR data. (a) Before change. (b) After change. (c) Binary truth change map.

Fig. 3 .

 3 Fig. 3. Comparison between DRT, HLT, and LRT statistics for simulated data with different levels of multilooking. The number of looks is L ∈ {5, 6, 7, 8}, where the first raw L = 5 and the last raw L = 8. (ai) Logarithm of max{τ DRT , τ DRT }. (bi) Plots of τ DRT normalized histograms and estimated Wilk's lambda of second kind pdfs under (H 0 ) hypothesis. (ai') Logarithm of max{τ HLT , τ HLT }. (bi') Plots of τ HLT normalized histograms and estimated FS pdfs under (H 0 ) hypothesis. (ai") τ LRT . (bi") Plots of τ LRT normalized histograms and estimated distribution given by (33) under (H 0 ) hypothesis. Change detection map obtained by rejection of hypothesis test at 1% significance level for (ci) DRT, (ci') HLT, and (ci") LRT detector.

Fig. 4 .Fig. 5 .

 45 Fig. 4. ROC curves comparison of three statistical detectors DRT, HLT, and LRT for different levels of multilooking L ∈ {5, 6, 7, 8}. The probability of detection (TPR) is plotted as a function of the probability of a false alarm (FPR) for simulation data. The DRT statistic performs better than HLT and LRT statistics. (a) L = 5. (b) L = 6. (c) L = 7. (c) L = 8.

Fig. 6 .

 6 Fig. 6. Comparison between DRT, HLT, and LRT statistics for real experimental data set over Suzhou city. (a) Logarithm of max{τ DRT , τ DRT }. (a') Logarithm of max{τ HLT , τ HLT }. (a") τ LRT . Plots of normalized histograms and estimated distribution for (b) DRT, (b') HLT, and (b") LRT detectors. Change detection map at 1% significance level obtained from (c) DRT, (c') HLT, and (c") LRT statistic.

Fig. 7 .

 7 Fig. 7. ROC curves comparison between DRT, HLT, and LRT statistics for real PolSAR data set 1. The DRT detector performs better than the HLT and LRT detectors.

2 )

 2 Data set 2: Two coregistered pair of L-band polarimetric images (d = 3) corresponding to scenes 1 and 2 were acquired by the Jet Propulsion Laboratory/National Aeronautics and Space Administration UAVSAR (1.26 GHz) over the city of .

Fig. 8 .

 8 Fig. 8. UAVSAR images (in Pauli decomposition) over the city of Los Angeles, California. (a) and (a') April 23, 2009. (b) and (b') May 11, 2015. (c) and (c') ground truths, where white is change and black is no-change. Top: Scene 1. Bottom: Scene 2.

Fig. 9 .

 9 Fig. 9. Comparison between DRT, HLT, and LRT statistics for real experimental data set over Los Angeles. (ai) Logarithm of max{τ DRT , τ DRT } for scene i, i∈ {1, 2}. (ai') Logarithm of max{τ HLT , τ HLT }. (ai") τ LRT . Plots of normalized histograms and estimated distribution for (bi) DRT, (bi') HLT, and (bi") LRT detector. Change detection map at 1% significance level obtained from: (ci) DRT, (ci') HLT, and (ci") LRT statistic.

.

Fig. 10 .

 10 Fig. 10. ROC curves comparison between DRT, HLT, and LRT statistics for real PolSAR data set 2. Top: Scene1. Bottom: Scene2. The DRT detector performs better than the HLT and LRT detectors, especially for a low FPR.

  χ2 (2(L -1)),…, ln χ 2 (2(Ld + 1)) random variables isψ ln χ 2 (2L)+ln χ 2 (2(L-1))+•••+ln χ 2 (2(L-d+1)) (t) = ψ ln χ 2 (2L) (t) × ψ ln χ 2 (2(L-1)) (t) × • • • × ψ ln χ 2 (2(L-d+1)) (t) (55) = 2 itd (L + it) (L + it -1) . . . (L + itd + 1) (L) (L -1) . . . (Ld + 1) . (56)We can conclude thatψ V (t) = ψ ln χ 2 (2L)+ln χ 2 (2(L-1))+•••+ln χ 2 (2(L-d+1)) (t). (57)APPENDIX B

  is the Meijer G-function multiplied by constant A with bj = L xi -1 and a j = -(L yi ) g(z) = A × G d,d d,d -L y , -(L y -1), . . . , -(L y -(d -1)) L x -1, L x -2, . . . , L xd z (66)whereA = d-1 i=0 (1/( (L xi ) (L yi ))). The cumulative distribution function G(t) = t 0 g(z)dz is obtained by integrating (65) with respect to the inside contour integral by using t 0 z s dz = (1 + s) -1 t 1+s = t (1 + s) (2 + s) t s . (67)

-

  L y ,-(L y -1), . . . , -(L y -(d -1)), 0 L x -1, L x -2, . . . , L x -d,-1 t . (69)The Meijer G-function is viewed as an inverse Mellin transformG m,n p,q a 1 , . . . , a p b 1 , . . . , b q z = 1 2πi L z -s Z (s)ds (70)where Z (s) = M{g(z)}(s) is the Mellin transform of the g(z) pdf. The kth moment E{Z k } is given by

TABLE III CHANGE

 III DETECTION PERFORMANCE FOR SIMULATED DATA. THE BEST VALUES ARE MARKED BY RED curves for DRT, HLT, and LRT statistics and for different values of L. It is shown that the DRT statistics give the best performance for this example followed by the HLT statistics in all cases and then by the LRT statistics. The area under ROC curve (AUC) is also considered in this study. The larger the AUC, the better the performance. Accordingly, the AUC values are shown in TableIVfor these statistics and multiple

values of L, and we can easily conclude that the proposed DRT statistic outperforms both the HLT and the LRT statistics for low values of L. When the ENL increases, the AUC of the HLT reaches the AUC of the DRT statistic. Consequently, the two statistics give us similar results. The performance of the proposed change detection algorithm is further evaluated with different real multilook PolSAR data sets in Section V-B.

TABLE VI CHANGE

 VI DETECTION PERFORMANCE FOR REAL POLSAR DATA SET 2: SCENES 1 AND 2map obtained by the thresholding CFAR algorithm applied to the DRT, HLT, and LRT statistics, where the significance level of the test α c is chosen equal to 1%. It is worth to notice that with the DRT statistics, more regions are detected than those using the HLT statistics.

This notation is used for FS distribution with three parameters. However, with two parameters, we use the notation (F).

BOUHLEL et al.: CHANGE DETECTION IN MULTILOOK POLSAR IMAGERY WITH DRT STATISTIC

This article has been accepted for inclusion in a future issue of this journal. Content is final as presented, with the exception of pagination.

.


K G Monisha

Paramasivam Prabu

M Chokkalingam

Ram Murugesan

Dragan Milenkovic

Shiek S S J Ahmed
email: shiekssjahmed@gmail.com

Paramasivam Prabu

Clinical utility of brain-derived neurotrophic factor as a biomarker with left ventricular echocardiographic indices for potential diagnosis of coronary artery disease

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

molecular techniques such as genomics, transcriptomics, proteomics, and metabolomics plays a crucial role to understand the molecular mechanism of CAD, which pave the way to discover molecular diagnostic markers [START_REF] Pasipoularides | Genomic translational research: Paving the way to individualized cardiac functional analyses and personalized cardiology[END_REF] .

In recent times several markers such as high sensitive c-reactive protein (hs-CRP), interleukins, monocyte chemoattractant protein-1 (MCP-1), TNF-α, serum amyloid A (SAA), vascular adhesion molecule 1 (VCAM-1), selectins, vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPS) and soluble CD40 ligand is identified [START_REF] Zakynthinos | Inflammatory biomarkers in coronary artery disease[END_REF] . Of which, few are clinically useful to detect CAD, whereas other markers are neglected due to lack of direct involvement pathophysiological events of CAD [START_REF] Chacko | The role of biomarkers in the diagnosis and risk stratification of acute coronary syndrome[END_REF] . For example, hs-CRP is one of the known inflammatory markers proven associated with two-dimensional echocardiography of CAD individuals [START_REF] Osman | Critical appraisal of C-reactive protein throughout the spectrum of cardiovascular disease[END_REF] . Therefore, any new marker needs to be cross-linked with the gold standard imaging techniques making it useful for clinical application.

Brain-derived neurotrophic factor (BDNF) is a neurotrophic protein expressed in the central and peripheral circulation [START_REF] Bathina | Brain-derived neurotrophic factor and its clinical implications[END_REF] . Although BDNF is a neurotrophic protein, it plays a vital role in the cardiac system [START_REF] Numakawa | Actions of brain-derived neurotrophin factor in the neurogenesis and neuronal function, and its involvement in the pathophysiology of brain diseases[END_REF] . Importantly, BDNF involved in the development of heart [START_REF] Clegg | Regulation of nerve growth factor mRNA levels in developing rat heart ventricle is not altered by sympathectomy[END_REF] , endothelial cells [START_REF] Nakahashi | Vascular endothelial cells synthesize and secrete brain-derived neurotrophic factor[END_REF] , vascular smooth muscle cells [START_REF] Donovan | Neurotrophin and neurotrophin receptors in vascular smooth muscle cells: regulation of expression in response to injury[END_REF] , macrophages [START_REF] Barouch | Macrophages express neurotrophins and neurotrophin receptors: regulation of nitric oxide production by NT-3[END_REF] , lymphocytes [START_REF] Kerschensteiner | Activated human T cells, B cells, and monocytes produce brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: a neuroprotective role of inflammation?[END_REF] and atherosclerotic vessels [START_REF] Donovan | Neurotrophin and neurotrophin receptors in vascular smooth muscle cells: regulation of expression in response to injury[END_REF] . Recent research emphasizes that BDNF induces oxidative stress by activating oxidase enzyme in the coronary artery vasculature [START_REF] Ejiri | Possible role of brain-derived neurotrophic factor in the pathogenesis of coronary artery disease[END_REF] . Low serum BDNF was observed in patients with CAD that causing future coronary events [START_REF] Kaess | Circulating brain-derived neurotrophic factor concentrations and the risk of cardiovascular disease in the community[END_REF] . In general, the ventricular function has been assessed by the twodimensional echocardiographic imaging recommended by the American Society of Echocardiography (ASE) [START_REF] Votavova | Echocardiography in coronary artery disease[END_REF] . Relating serum BDNF levels with echocardiographic indices may provide the involvement of BDNF in cardiac systems, which may be useful in developing a potential alternative method for CAD diagnosis. Recently Bahls et al., 2019 showed the association between low BDNF and echocardiographic indices in participants with traditional risk factors of future CAD [START_REF] Bahls | Brain-derived neurotrophic factor is related with adverse cardiac remodeling and high NTproBNP[END_REF] . However, the role of BDNF with cardiac left ventricular function and its ability to classify CAD from healthy controls is less well known.

This study aimed to investigate the relationship between serum BDNF levels with biochemical and echocardiographic indices in 221 participants for its utility as a CAD marker. We identified a significant molecular linkage between the BDNF with biochemical changes and echocardiographic indices associated with cardiovascular function. Further, we construct an automated CAD detection model using a support vector machine with BDNF showing improved accuracy making a rapid decision in CAD.

Results

patients characteristics and comparative analysis. The clinical and anthropometric characteristics of the participants involved in this study was illustrated in Table 1. All descriptive data expressed as mean ± standard deviation for control and CAD. All participants in control group are free from risk factors, Whereas the CAD group contains 10.2% of hypertensive, 15.3% of diabetes mellitus and 5.5% of smokers. However, most CAD participants in CAD are free from the risk factors. Further, the statistical t-test analysis showed a significant change in BMI, platelet, eosinophils, lymphocyte, monocytes, neutrophils, HbA1c (glycosylated hemoglobin), serum creatinine, low density lipid (LDL), high density lipid (HDL), triglyceride (TGL), and total cholesterol in CAD compared to control (Table 1). Mainly, serum BDNF was significantly (p ≤ 0.001) decreased in CAD (30.70 ± 5.4 ng/ml) compared to the control (46.580 ± 7.9 ng/ml). Although basophils, systolic, and diastolic pressure showed variations in CAD, but not statistically significant.

BDnf and cAD associated clinical and echocardiography parameters.

To determine the association between serum BDNF levels and clinical parameters, the CAD patients were quartile grouped as low and high (described in the method section). The BDNF concentration with ≤ 29.91 ng/ml considered as a low BDNF group, and those with levels > 29.92 ng/ml are considered a high BDNF group. The Supplementary Table A1 shows the characteristics of collected blood parameters and echocardiographic indices in low and high BDNF group. Elevated platelets, basophils, eosinophils, lymphocytes, monocytes, neutrophils, LDL, TGL, total cholesterol, HbA1c, and serum creatinine were observed in low BDNF group of CAD patients. In contrast, significant decreased BMI and HDL noticed in low BDNF groups compared to the high BDNF group. Similarly, the echocardiographic indices in low BDNF shows evaluated Biplane LVEF, PV AR (m/s), GLS LVEF, and decreased LVMI, MV E/A ratio, IVRT (ms), and PV S/D ratio compared to the high BDNF group. The statistical analysis of blood parameters and echocardiographic indices confirms the significance between the low and high BDNF groups, except LAD, MV S E/e' ratio, and L E/e' ratio (Supplementary Table A2).

Multivariate regression analysis.

We performed a multivariate regression analysis to determine the blood parameters influencing low BDNF concentration in CAD (Table 3). The neutrophils (β = -0.494, p ≤ 0.001) and total cholesterol (β = -0.407, p ≤ 0.001) were noticed to contribute low BDNF concentration in CAD with a model fit measure of r = 0.725 and r-square = 0.526. Similarly, the echocardiographic indices (Table 4), LVMI (β = 0.3380, p ≤ 0.001), MV E/A (β = -0.3751, p ≤ 0.001), PV AR (β = -0.3444, p ≤ 0.001) and Biplane LVEF (β = 0.3467, p = 0.010) were significantly linked with low BDNF concentration in CAD with a model fit measure r = 0.826 and r-square = 0.683. Overall, the analysis suggests low BDNF concentration is the measure of both blood (neutrophils and total cholesterol) and echocardiographic indices (LVMI, MV E/A, PV AR, and Biplane LVEF) in CAD.

Support vector machine classification of CAD from control. Support vector machine (SVM) based

classification model was developed to determine the influence of BDNF as a biomarker in predicting CAD. Prior to disease classification, we use SVM Attribute Evaluator with the ranker method to select most contributing predictor variables for CAD from clinical and echocardiographic indices. The BMI, HbA1c, HDL, LDL, and Total cholesterol were identified as the five most important blood predictor variables of CAD. Whereas in echocardiographic indices, Biplane LVEF, LAD, L E/e, IVRT, and GLS LVEF were determined as important indices for CAD prediction (Table 5). To check influence of BDNF in predicting CAD, four independent SVM models were developed, the model-A was trained with BMI, HbA1c, HDL, LDL, and Total cholesterol (Table 5). The model-B contains Biplane LVEF, LAD, L E/e, IVRT, and GLS LVEF echocardiographic indices (Table 5). The model-C was trained with model-A attributes along with BDNF concentration. Similarly, model-D was trained with model-B attributes along with BDNF concentration.

Discussion

BDNF has been extensively studied to promote neurogenesis [START_REF] Numakawa | Actions of brain-derived neurotrophic factor and glucocorticoid stress in neurogenesis[END_REF] and also plays a dominant role in the cardiovascular system [START_REF] Kermani | BDNF actions in the cardiovascular system: roles in development, adulthood and response to injury[END_REF] . BDNF expressed in endothelial cells, vascular smooth muscle cells, macrophages, lymphocytes, and atherosclerotic vessels [START_REF] Ejiri | Possible role of brain-derived neurotrophic factor in the pathogenesis of coronary artery disease[END_REF] . Framingham Heart Study 2015 suggests that high BDNF concentration was associated with a decreased risk of CVD and mortality [START_REF] Kaess | Circulating brain-derived neurotrophic factor concentrations and the risk of cardiovascular disease in the community[END_REF] . A recent study suggests the involvement of BDNF in oxidative stress in coronary artery vasculature and atherosclerotic plaque formation [START_REF] Bonomini | Atherosclerosis and oxidative stress[END_REF] . Despite various studies, the association of BDNF in CAD with non-invasive cardiovascular imaging techniques like two-dimension echocardiography imaging has not been reported. Therefore, we investigated the involvement of BDNF in CAD compared to healthy control. Elucidating the association of BDNF with CAD associated parameters may enable utilization of BDNF as a possible diagnostic biomarker for CAD. Particularly, establishing the relationship between alerted serum BDNF level and echocardiographic indices will help develop a potential alternative method for CAD diagnosis. This is the first study conducted in South Indian ethnicity to assess the association of serum BDNF levels with clinical parameters and echocardiography indices in CAD. We segmented our study design into threefold. First, we confirmed the significant changes in blood parameters, imaging indices, and BDNF levels in CAD compared to controls. Second, we use multivariate regression analysis to determine the blood parameters and imaging indices influencing low BDNF concentration in CAD. Finally, we generate SVM models to determine the influence BDNF in improving the classification of CAD from control by including and excluding the BDNF attribute while training and testing the models.

Our present study showed decreased serum BDNF in CAD which is in agreement with Eyileten et al., 2016, confirming the decreased serum BDNF that correlates with VCAM1 and soluble P-selectin in CAD [START_REF] Eyileten | Serum brain-derived neurotrophic factor is related to platelet reactivity but not to genetic polymorphisms within BDNF encoding gene in patients with type 2 diabetes[END_REF] . Similarly, Aleksandra Sustar et al., 2019 reports lower BDNF in the CAD associated with an increased risk of cardiovascular events and mortality [START_REF] Sustar | Association between reduced brain-derived neurotrophic factor concentration and coronary heart disease[END_REF] . Additionally, BDNF showed a significant association with traditional risk factors, including diabetes, hypertension, smoking, physical activity, and obesity [START_REF] Kurajoh | Plasma brain-derived neurotrophic factor concentration is a predictor of chronic kidney disease in patients with cardiovascular risk factors-Hyogo Sleep Cardio-Autonomic Atherosclerosis study[END_REF] . Similar results observed in our study relating low BDNF with a lipid profile and body mass index in CAD (Supplementary Table A1). Also, our results follows the similar outcome of Jiang H et al., 2011showing association with increased LDL, TGL, and decreased HDL levels with lower BDNF concentration in angina pectoris [START_REF] Jiang | Association of plasma brain-derived neurotrophic factor and cardiovascular risk factors and prognosis in angina pectoris[END_REF] . Interestingly, Ejiri et al., 2005 report altered BDNF in the coronary circulation between coronary sinus and aorta in patients with angina. Similarly, altered BDNF expression in human atheromatous intima, adventitia, macrophages, and smooth muscle cells in atherosclerotic coronary arteries [START_REF] Ejiri | Possible role of brain-derived neurotrophic factor in the pathogenesis of coronary artery disease[END_REF] . These results suspect us to investigate the association of serum BDNF with echocardiography indices in CAD.

Multivariate regression analysis of blood parameters showed a significant contribution of neutrophils and total cholesterol with low BDNF (≤ 29.91 ng/ml) in angiogram proven CAD patients. Aleksandra Sustar et al., 2019 confirm the significant association of low BDNF with total cholesterol in coronary heart disease. Similar result was noticed in the Chinese population that relates low BDNF level with cardiovascular disease risk factors [START_REF] Sustar | Association between reduced brain-derived neurotrophic factor concentration and coronary heart disease[END_REF] . In addition to total cholesterol concentration, the increased neutrophils was noticed associated with low BDNF in CAD individuals. Neutrophils play a vital role in CAD, which promotes atherothrombotic mechanisms leading to cause myocardial infarction. Halade et al., 2013 confirm the interdependency of BDNF with neutrophils in recruiting macrophages into the infarcted region of BDNF haploinsufficient mice [START_REF] Halade | Reduced BDNF attenuates inflammation and angiogenesis to improve survival and cardiac function following myocardial infarction in mice[END_REF] . Besides, neutrophils involved in the release of reactive oxygen species, which activates the endothelium to deposit additional neutrophils for plaque formation. Simultaneously, our multivariate regression analysis of low BDNF group showed a significant association with echocariographic indices, including LVMI, MV E/A, and PV AR in angiogram proven CAD patients. Recently, Martin Bahls et al., 2019 demonstrated the role of BDNF on left ventricular cardiac remodeling in individuals with the risk of cardiovascular disease [START_REF] Bahls | Brain-derived neurotrophic factor is related with adverse cardiac remodeling and high NTproBNP[END_REF] . However, Martin Bahls et al., 2019 did not justify the role of BDNF on left ventricular dysfunction in the CAD population by comparing it with healthy control. Whereas, our results showed significant evidence of low BDNF in CAD that correlates with the echocardiograohic indices compared to healthy control. Overall, our analysis suggests low BDNF concentration is the representative of both blood parameters (neutrophils and total cholesterol) and echocardiographic indices (LVMI, MV E/A, PV AR and Biplane LVEF) in CAD.

We construct SVM models which showed significant improvement in detecting CAD with BDNF as one of the attributes (Table 5). Recently, Akella et al., 2020 use a variety of machine learning algorithms and achieved maximum accuracy of 93% in detecting CAD [START_REF] Akella | Machine learning algorithms for predicting coronary artery disease: efforts toward an open source solution[END_REF] . Interestingly our study showed benefit of adding the BDNF as one of the attribute to SVM models that represents blood parameters (neutrophils and total cholesterol) and echocardiography indices (LVMI, MV E/A, PV AR, and Biplane LVEF) in CAD (Tables 3,4). Although our findings provides significant improvement in CAD diagnostic research, there are few limitations that to be considered before its clinical utility. First, this study includes only the South Indian population. Second, we did not follow-up on the CAD patients. Third, the changes in BDNF levels was not studied on the improvement after the treatment of CAD. Alternatively, strength of the this study need to be acknowledged that (1) selection of participants both control and CAD has been proven with coronary angiogram. (2) this study integrates the blood parameters and echocardiography indices to develop a diagnostic method that has been strengthened with a machine learning algorithm showing better accuracy in detecting CAD.

In conclusion, our study has presented a novel approach for determining the association of decreased serum BDNF with blood parameters and echocardiography indices of CAD. The machine learning (SVM) algorithm was developed to determine accuracy of BDNF with blood parameters and echocardiography indices for disease classification in CAD and healthy controls. Although all our SVM models showed better accuracy in disease classification, the model-C and model-D will be significantly improve detecting CAD using serum BDNF concentration. Therefore, our results, along with machine-based disease classification, has demonstrated the emerging evidence of BDNF in the prediction of CAD with the best accuracy value that may pave the way towards bench side clinical application.

Methods patient selection.

The protocol of this study was approved by the institutional human ethical committee of the Chettinad Academy of Research and Education (IHEC/10-17/Proposal No:372). All experiments were performed in accordance with relevant guidelines and regulations. The individuals presenting angina pectoris were recruited from the Chettinad Super Specialty Hospital between October 2018 to June 2019. Written informed consent, demographic information, and health status was recorded for each participant by questionnaire. Based on the collected data, the 221 participants were selected following the exclusion and inclusion criteria. Exclusion criteria: the participants with the previous history of arterial revascularization such as stenting and bypass grafting, myocardial infarction (MI), heart failure (following the New York Heart Association Classification), valvular heart disease, pericardial diseases, idiopathic cardiomyopathy, acute or chronic infectious diseases, severe systemic disorders (malignancy, Immune diseases) and mental disorders. Inclusion criteria: (1) the participants belonging to south Indian origin between age 25 and 70 years, (2) the participants of both genders with angina, and (3) the physiological status was proven by coronary angiogram for the participant with CAD and without CAD (healthy controls, ≤ 30% lesion).

two-dimensional echocardiography and coronary angiogram examination.

Transthoracic twodimensional echocardiography was performed for all participants by qualified echocardiography technologist (KGM: one of the author) using the Esaote [MyLab 25Gold] following the American Society of Echocardiography guidelines. The echocardiography indices such as left ventricular (LV) mass index, biplane left ventricular ejection fraction (LVEF), early transmitral flow velocity (E), late transmitral flow velocity (A), mitral inflow E/A ratio, isovolumetric relaxation time, mitral lateral/septal peak myocardial early diastolic velocity (Le' and Se'), pulmonary vein AR duration (PV AR), pulmonary vein systole/diastole (PV S/D) ratio, and global longitudinal strain (GLS) were calculated to assess the cardiovascular function. Simultaneously, the coronary angiogram was performed by a qualified cardiologist (CM: one of the author) using contrast agents (omnipaque and visipaque) to determine coronary artery lesions using the GE INOVA 2100-IQ PLUS with ADW DICOM. Based on angiogram report, the study participants were classified as 1) CAD patients (lesion > 30% in the primary coronary artery or its major branches) and 2) healthy controls (lesion ≤ 30%). Of those 221 participants, 116 were CAD presenting single vessel (n = 41), double vessel (n = 39), and triple vessel disease (n = 36), while the other 105 participants with proven angiogram negative were designated as healthy control.

Quantification of serum BDNF. Overnight fasting blood (4 ml) was collected from the participants in BD vacutainer Plus Plastic Serum Tubes. The samples were immediately centrifuged at 3000 RPM for 15 min to separate serum from other cellular material and stored at -80 °C for future analysis. Serum BDNF levels (ng/ ml) were measured using the ELISA kit (R&D SYSTEMS, USA) following the manufacturer's instructions. The BDNF concentrations were measured based on the optical density (OD) curve using known standards concentration provided within the kit. In addition, the cellular and biochemical parameters such as complete blood count, lipid profile, HbA1c, and serum creatinine were determined by standard laboratory techniques as a part of routine blood tests.

Statistical analysis. Student t-test was performed to confirm the statistical significance of variables in CAD compared to healthy controls. Serum BDNF concentration in CAD was stratified into quartiles as low and high levels to determine its relationship with clinical and echocardiography indices. In brief, we divide CAD patients into quartiles by merging first and second quartile to have cut-off ≤ 29.91 ng/ml, represented as low BDNF group (n = 58). The third and fourth quartiles are merged obtaining a cut-off above 29.92 ng/ml, designated as high BDNF group (n = 58). Further, the multivariate regression analysis was performed to confirm the major contributing clinical and echocardiography indices associated with low serum BDNF levels in the CAD. All statistical analysis was performed using SPSS software (version 21), and the significance was considered based on p value < 0.05.

Classification based on the machine learning algorithm. Support Vector Machine (SVM) is one of the efficient and widely used supervised machine learning algorithms for disease classification [START_REF] Hongzong | Support vector machines classification for discriminating coronary heart disease patients from non-coronary heart disease[END_REF] . Prior to classification, the SVM Attribute Evaluator with ranker method [START_REF] Maolin | Classification models of HCV NS3 protease inhibitors based on support vector machine (SVM)[END_REF] was used to select most (top five) contributing blood parameter and echocardiographic indices to achieve maximum accuracy in CAD prediction. Further, we use SVM in Weka software [START_REF] Sanyal | Metallomic Biomarkers in Cerebrospinal fluid and Serum in patients with Parkinson's disease in Indian population[END_REF] to generate four SVM models (model-A, B, C, and D) with selected attributes from the data set (116 CAD and 105 control) for training and testing of each model. The predictor variables for model-A contains BMI, HbA1c, HDL, LDL, and Total cholesterol (Table 5). Whereas the model-B contains LVEF, LAD, L E/e, IVRT, and GLS LVEF, a top five echocardiographic indices for CAD prediction (Table 5). The attributes for model-C contains BDNF concentration as an additional attribute along with the other five predictor variables of model-A (Table 5). Similarly, the model-D contains BDNF concentration as additional attribute of model-B for CAD (Table 5). prediction. Each data set was represented with a class attribute of "CAD" or "control" for 221 instances designated based on the coronary angiogram. A tenfold cross-validation method was adopted to measure an unbiased prediction of the models. The performance of each model was assessed based on the accuracy, true positive (TP) rate, false positive (FP) rate, precision, recall, F-measure, and receiver operating characteristic (ROC). Comparing the models based on accuracy would enable us to explore the importance of BDNF in the classification of CAD from controls.

Table 1 .

 1 Characteristics of the study population in anthropometric and blood parameters. *Significance at p < 0.05.

	Clinical parameters	Without CAD With CAD	p value
	Age (years)	54.49 ± 11.40	57.25 ± 10.44	0.062
	BMI (kg/m 2 )	22.64 ± 2.27	26.23 ± 3.05	< 0.001*
	Systolic BP (mmHg)	121.37 ± 13.60	123.70 ± 17.40	0.271
	Diastolic BP (mmHg)	81.61 ± 12.52	82.99 ± 13.18	0.426
	Platelet (LAC/C.mm)	2.18 ± 0.77	2.91 ± 1.05	< 0.001*
	Basophil (%)	0.82 ± 0.43	0.88 ± 0.66	0.4
	Eosinophil (%)	5.06 ± 2.20	6.53 ± 3.13	< 0.001*
	Lymphocyte (%)	29.38 ± 7.73	36.27 ± 14.59 < 0.001*
	Monocyte (%)	5.66 ± 2.02	7.85 ± 2.59	< 0.001*
	Neutrophil (%)	52.24 ± 12.67	57.89 ± 17.71 < 0.001*
	HbA1c (%)	4.73 ± 0.38	6.42 ± 1.16	< 0.001*
	HDL cholesterol (mg/dL)	47.12 ± 9.00	35.81 ± 8.24	< 0.001*
	LDL cholesterol (mg/dL)	84.27 ± 15.07	132.85 ± 36.95 < 0.001*
	TGL cholesterol (mg/dL)	96.29 ± 18.43	142.16 ± 59.04 < 0.001*
	T.Cholesterol (mg/dL)	131.25 ± 24.77	194.69 ± 66.03 < 0.001*
	Serum creatinine (mg/dL)	0.84 ± 0.23	1.06 ± 0.40	< 0.001*
	BDNF (ng/mL)	46.58 ± 7.95	30.69 ± 5.45	< 0.001*

Table 2 .

 2 Echocardiographic indices of the participants with CAD and without CAD. Biplane LVEF (biplane left ventricular ejection fraction); LAD (left atrial diameter), LVMI (left ventricular mass index), MV E/A (Mitral inflow E/A ratio), Le' /Se'(mitral lateral/septal peak myocardial early diastolic velocity), IVRT (isovolumetric relaxation time), PV AR (pulmonary vein AR duration), PV S/D (pulmonary vein systole / diastole ratio) and GLS EF (global longitudinal strain). *Significance at p < 0.05.

	Echo indices	Without CAD	With CAD	p value
	Biplane LVEF (%)	61.08 ± 3.01	44.75 ± 7.01	< 0.001*
	LAD (cm)	3.25 ± 0.30	3.45 ± 0.51	< 0.001*
	LVMI (g/m2)	82.31 ± 24.67	100.69 ± 24.35	< 0.001*
	MV E/A	1.06 ± 0.30	0.64 ± 0.45	< 0.001*
	S E/e'	8.42 ± 1.01	7.20 ± 1.28	< 0.001*
	L E/e'	10.46 ± 1.04	7.62 ± 1.14	< 0.001*
	IVRT (ms)	80.81 ± 16.34	114.57 ± 23.61	< 0.001*
	PV AR (m/s)	32.19 ± 5.80	27.78 ± 5.24	< 0.001*
	PV S/D	0.69 ± 0.23	1.29 ± 0.57	< 0.001*
	GLS EF (%)	-16.18 ± 0.47	-13.94 ± 1.27	< 0.001*

The accuracy, True Positive (TP) rate, False Positive (FP) rate, precision, recall, F-measure, and Receiver operating characteristic (ROC) of each model shown in Table

5

. All SVM models showed accuracy over 90%. For instance, model-A showed 90.95% accuracy, whereas adding the serum BDNF concentration in model-C showed 98.19% improved accuracy in detection CAD. As expected, the model-B with echocardiographic indices revealed high (98.64%) accuracy as the echocardiographic imaging is the important tool that routinely used in detecting CAD. However, the model-D with serum BDNF concentration as an additional attribute to the other echocardiographic parameters of model-B resulted 100% accuracy in detecting CAD.

Table 3 .

 3 Multivariate regression analysis showing low BDNF contributing blood parameters in CAD. Data are represented with β and p values with 95% confidence interval. *Significance at p < 0.05.

		Univariate analysis			Multivariate analysis
	Predictor	Coefficient correlation p value	95% confidence interval β	95% confidence interval p value
	Age (years)	0.06	0.63	-0.075 to 0.04
	BMI (kg/m2)	0.11	0.38	-0.12 to 0.30
	Systolic BP (mmHg)	0.05	0.70	-0.04 to 0.03
	Diastolic BP (mmHg)	0.03	0.79	-0.04 to 0.05
	Platelet (LAC/C.mm)	0.11	0.40	-0.38 to 0.92
	Basophil (%)	0.04	0.76	-0.754 to 1.03
	Eosinophil (%)	0.04	0.73	-0.28 to 0.20
	Lymphocyte (%)	0.02	0.87	-0.03 to 0.04
	Monocyte (%)	0.12	0.35	-0.13 to 0.37
	Neutrophil (%)	0.61	< 0.001* -0.11 to 0.05	-0.494 -0.09 to 0.04	< 0.001*
	HDL cholesterol (mg/dL) 0.01	0.93	-0.08 to 0.09
	LDL cholesterol (mg/dL) 0.12	0.34	-0.01 to 0.02
	TGL cholesterol (mg/dL) 0.01	0.91	-0.0098 to 0.01
	T.Cholesterol (mg/dL)	0.54	< 0.001* -0.02 to 0.01	-0.407 -0.020 to 0.007	< 0.001*
	HbA1c (%)	0.013	0.92	-0.52 to 0.58
	Serum Creatinine (mg/ dL)	0.12	0.3	-1.03 to 2.72

Table 4 .

 4 Multivariate regression analysis showing low BDNF contributing Echocardiographic indices in CAD. Data are represented with β and p values with 95% confidence interval. *Indicate significance at p < 0.05.

		Univariate analysis			Multivariate analysis
	Predictor	Coefficient correlation p value	95% confidence interval β	95% confidence interval p value
	Biplane LVEF (%)	0.45	< 0.001* 0.09 to 0.30		0.35 0.03 to 0.26	0.01*
	LAD (cm)	0.38	0.003* 0.752 to 3.5		0.13 -0.19 to 1.69	0.117
	LVMI (g/m2)	0.52	< 0.001* 0.034 to 0.09		0.33 0.01 to 0.05	< 0.001*
	MV E/A	0.32	0.012* 0.80 to 6.36	-0.37 -2.63 to-0.97	< 0.001*
	S E/e'	0.04	0.743 -0.86 to 1.21
	L E/e'	0.01	0.897 -1.40 to 1.59
	IVRT (ms)	0.18	0.163 -0.01 to 0.06
	PV AR (m/s)	0.61	< 0 .001* 0.18 to 0.38		0.34 0.06 to 0.24	< 0.001*
	PV S/D	0.12	0.338 -0.95 to 2.73
	GLS EF (%)	0.45	< 0.001* -1.62 to 0.497		0.05 -0.47 to 0.71	0.686

Table 5 .

 5 Model describing the parameters associated with the accuracy in classifying CAD from healthy control. TP true positive, FP false positive, ROC receiver operating characteristic.

	Model	Predictor variables	TP rate FP rate Precision Recall F-measure ROC area Accuracy (%)
	Model-A	BMI, HbA1c, HDL, LDL, and Total cholesterol	0.911	0.086	0.913	0.910	0.91	0.912	90.95
	Model-B	Biplane LVEF, LAD, L E/e, IVRT, and GLS LVEF	0.986	0.012	0.987	0.986	0.986	0.986	98.64
	Model-C	BDNF, BMI, HbA1c, HDL, LDL, and Total cholesterol	0.986	0.015	0.987	0.986	0.986	0.986	98.19
	Model-D	BDNF, Biplane LVEF, LAD, L E/e, IVRT, and GLS LVEF	1	0	1	1	1	1	100

Scientific RepoRtS| (2020) 10:16359 | https://doi.org/10.1038/s41598-020-73296-6

Scientific RepoRtS | (2020) 10:16359 | https://doi.org/10.1038/s41598-020-73296-6

Acknowledgements

Authors were thankful to the research participants for the selfless contribution of samples for this study. The author (MKG) especially thank the Chettinad Academy of Research and Education (CARE) for providing the research fellowship.

Author contributions

M.K.G. executed the protocol, performed echocardiography, interpretation of results, and wrote the draft manuscript; P.P. provide knowledge support to perform experiment, corrected the draft manuscript. C.M. was involved in the diagnosis and recruitment of participants. R.M. contributed designing and executing protocol; S.S.J. design the concept, interpret the data, finalized, and approved the manuscript. D.M. provides suggestions and corrected the draft manuscript.

competing interests

The authors declare no competing interests.

Additional information

Supplementary information is available for this paper at https ://doi.org/10.1038/s4159 8-020-73296 -6.

Correspondence and requests for materials should be addressed to S.S.S.J.A.

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