Support Vector Machines and Their Use in deciding Bio-markers for Neurological disease study

Support vector machines are one of the most common pattern recognition machines used in Machine learning. It is considered as a successor to logistic regression due to the fact that it is based on maximum class seperatability.[1]

Mathematical Basis of Support Vector Machine:

a. An Intuition: Support vectors machine aims at maximizing the distance between the two class vectors and the discriminatory function. Hence the method is less probable to errors in testing phase than any other method like logistic regression which just increases the expectation of the probability density function[2] . Thus, Support vector machines are called margin maximizers.

b. Mathematical definition Problem: Given a vector and We need to find probability distribution drawn and identically distributed). Solution: Consider, a machine or simply a function, f(X, ), where is the training parameter. Expectation of the tests error: | Where R() cannot be calculated as both and out such that the limit of the bound approximates Consider, | | are not known, so a bound is to be found | , for given vector , is called a trusted source. , assuming that the data is IID (Independently

Now it can be proved that, ( ) We need to find h, such that the RHS is almost equal to LHS, then R() can be estimated, h is called VC dimension which is an integer, thus a perfect fit cannot be described, but a best fit is described by changing VC dimensions.

Linear SVM:
It is one of the most important models used in neuro applications as the sample size is smaller than the dimensionality of the system in many cases[3]. Mathematical Basis: If W is the hyper plane, since the hyperplane or discriminatory function is linear, we must have The optimum W is decided by optimizing "Margin". i.e., Thus the distance optimization gives rise to the distance. However, doing this optimization directly is difficult. Hence, convex optimization tools are used to get the solution, One of the approach, commonly followed is Lagrange Multipliers, Lagrange Multipliers[4]: Lagrange multipliers are used in optimization problems,
|| ||

, hence || || needs to be minimized to maximize

subject to: Consider a two dimension problem to be solved by Lagrange Multipliers,

is a curve in 3 dimension. However, using makes the curve a constrained curve restricted to 2 dimensions, differentiating the curve w.r to x, we get

Consider a two dimensional vector, T the tangent to the curve, Consider a two dimensional vector, Equation 1, can be written as only if , This means that equivalently written as, , Also we need to minimize and this is possible and are parallel to each other, which can be

consider,

,[

Solving the above three linear equations simultaneously, we the value of the Lagrange multiplier, hence by substituting the value of in the same set of equations we get the values of y and x. x corresponds to minima point and y is the minima. Now, we can use the concept of Lagrange multipliers shown above to solve the problem of ||w|| minimization. Here, we write the equation in terms of Lagrange multiplier i, where i=1,2,...l vector The solution of this equation is got by quadratic programming for those points for which i>0 are called support vectors, These points lie on the two hyperplanes H1 and H2, These points in hyperplanes are important because even though the points which are not in hyperplanes(points that are far away from discriminatory function) are removed, the discriminatory function does not change. However, If the points on Hyperplanes are removed the discriminatory function changes. Hence, in feature selection it is important, to make sure that feature matrix does not exclude the support vectors. , Where Lp is the Lagrangian and is the Lagrange multiplier

The two dotted lines are hyperplanes H1 and H2 on which the support vectors lie, The margin maximization yields support vectors and the classifier.[5] The above discussed is theoretical method, hence it is an analytical way of soling for the solution. However, once the sample size becomes large it is hard to solve the equation, as seen from the example a two sample problem requires simultaneous solution of 3 equations, However, there is no guarantee on the linearity of the equations, Hence, the algorithmic solution is required for solving the equation. Hence, an iterative method is required to solve for solution. Algorithms to solve the Lagrangian[3,16]: 1. Sequential Minimal Optimization: This algorithm is used in SVM solution and it uses the KarushKuhnTucker conditions , to solve the equations, steps: 1. guess the value of 1 and see whether it violates KKT conditions, if it does retain it else guess another 1 that violate the KKT conditions 2. Find 2 and using the pair (1,2) optimize 3. Go back to 1, if not converged, convergence is checked by KKT conditions KKT conditions[16] :

These four conditions together constitute KarushKuhnTucker conditions, used for optimization problems. This algorithm is also called Co-ordinate ascent, as only two of the variables are used in update rule

Non Linear SVM:

Sometimes it is not possible to classify data using planes alone, we need non linear classifier functions. These functions can be implemented using kernels. There are many non-linear Kernels used, like Gaussian kernel, quadratic kernels, sin and tan kernels are used[6]. However, Neurological diagnosis applications , mostly linear kernels are used. This is because, non-linear SVM are tougher to solve. Further in neurological applications sample size is small compared to the size of the feature space, in such situations linear SVM fit better.[7] The Kernels used are mainly in non linear SVM are: 1. Polynomial 2. Sigmoid 3.Guassian 1. Polynomial: Polynomial SVM are used in the case of smaller feature size, and recognition problems known to have polynomial dependency, like house price classification problem, marking scheme problem[8]. Polynomial kernel may be of any type, it depends on experimental parameter of the problem. For example, this is a two dimensional cubic kernel, used in handwriting recognition[8]

2. Sigmoid: Sigmoid is a kernel used for probabilistic applications, that would be in gene prediction problems[8]. The sigmoid kernel, a one dimensional one would be * +. Sigmoid function estimates the probability. Thus sigmoid shown in bracket, its range varies from [0,1]. 3. Gaussian: Gaussian Kernels are used in nature-related problems. This is because, most of the natural phenomenon have Gaussian decay function. A two dimensional Gaussian kernel is of the form [
[ ]

Multiclass Support Vector Machine:

Many a times, classification of data into different categories is required, For example we may need to categorize the data into A.D, M.C.I and Healthy. In such a case multi class SVM needs to be used to categorize the data. A Multiclass linear SVM is made of n hyperplanes if the number of classes are n-1. The Method of training is the same but the system is to be trained for multiple times taking two features at a time and getting the hyperplane. Thus , from hyperplanes hyperplanes are selected. The selection of hyperplanes is done by selecting the hyperplanes that give the maximum margin. This method, gives a local solution. However there is no guarantee of an optimum solution[9]. Thus a dynamic programming approach gives a better solution. If given n classes, Firstly, the class of 1 and (n-1) subsets are made, then 2 and (n-2), and so on in all permutations, results are dynamically stored in each step and finally global optimum is reached, since the method explores all possibilities through a tree[9]. Thus, a multiclass SVM can be made, using single class SVM. However, in the case of NonLinear SVM, multiclass SVM is trained using multi-class dynamic kernel approach[9]

Steps for SVM

a. Preprocessing Steps: The pre-processing steps include, mainly representation of features and scaling.

Discriminatory features are normally, marked by integers, for example: white matter if encoded as zero, then grey matter is encoded as one. In the case of scaling, the data is scaled to follow a normal distribution, i.e., , Where X is the value of the feature, and are mean and standard deviation of distribution respectively. By, normalization a standard reference is got[10]

b. Model Selection: By model selection, a kernel selection is implied. In bio medical applications, normally linear kernels are selected because the feature vector is much larger compared to sample size, typically feature vectors have about 3000 pixels in case of MRI images. However, a sample size of such a large size is not possible, thus linear SVM is a good model[14]. c. Validation: There could be two types of validation methods carried out, a simple validation or a cross validation. In the case of a simple validation method the data is divided into training (50%) and test data(50%) and then the model is trained and tested and accuracy is reported. In case of cross validation, a method called v-fold validation is carried out. Here, the database is partitioned into v subsets. With each (v-1) combinations of subsets the model is trained and the remaining subset is used to evaluate the performance, the combination of subsets that gives greatest accuracy is chosen and the accuracy is marked the accuracy of the model[11]. In the case of medical applications, accuracy alone is not a good criteria, here sensitivity and specificity is used. Sensitivity is the percentage of diseased individuals marked as diseased, and specificity is the number of healthy controls marked as healthy by the algorithm[14]

Implementation for Marker detection:

1.feature Extraction from either MRI or fMRI 2.Feature dimension reduction or feature selection if required, using correlation matrix or PCA 3.Training the support Vector using the samples till a global minima is reached 4.Testing of the support vector using any of the validation methods

1. Feature Extraction: There are various methods to extract the features. The feature extraction is mainly consists of two types namely structural features and functional features. Structural features are the features got from MRI and functional features are got from fMRI. Structural features can be got in many ways. One of the crudest methods being taking voxels containing the volume of interest and encoding these intensity values of the voxels into a single column matrix[12]. The methods encoding pattern of grey and white matter also give good results. Here, in a given image if grey matter is encoded as zero, white matter could be encoded as one. This encoded image is again made a single column matrix used as a feature[13]. Through structural features a good accuracy of classification of about 76-88% is possible for classification of PDAT from HC[14]. Functional features can be got from encoding from fMRI data and the accuracy varies between 71-85%. fMRI is popularly used in functional feature encoding. However a combination of both structural and function features gives better accuracy, even a 100% accuracy is possible[15] Set of Features:
Biomarkers

Diffusion Tensor Imaging

Functional MRI

Structural MRI

Mean Diffusability

Functional Connectivity

Grey Matter , White matter , CSF percentages Shape and size of hippocampus

Spatial coherence

Functional Activation

spacial connectivity

Cortical Thickness

Biomarkers

CT scan

PET scan

Ventricular brain ratio

Functional connectivity

Voxel electron density Medial Temporal Lobe width percentage volume of CSF

Blood flow

Glucose uptake

Amyloid binding

Regional Activation

a. Structural Features from MRI[17]

Mainly, three methods are used: 1. Voxel Based 2.Vertex Based 3. ROI based 1. Voxel based methods( Grey matter, White matter, CSF): Direct method Voxels are processed by SPM5 module to segment to segment grey matter, white matter and CSF[18]. This method is gives a high accuracy, a accuracy of 95% was obtained by Klppel.et.al (2008). This method uses a software called SPM5, available at http://www.fil.ion.ucl.ac.uk/spm. The study has indicated that study of tissues along with CSF to find ratio of A40 and A42 yields better classification results. However, measurement of A is an invasive method, hence it is not preferred[38].

Image obtained from the MRI scanner Segment the image into white matter, grey matter and CSF regions. Registration of grey matter done by marking it as 1, and marking others as 0 This procedure followed on all the samples to obtain dataset which is trained using SVM Validation carried out to obtain the sensitivity and specificity values
The feature matrix is simply the segmented image arranged as columns.

[ where , represents the kth sample and its marked training matrix of the support vector machine.

] pixel, the matrix shown above is the

Stand score method: In the first method all the voxels were used, In this method only the voxels having CSF more than 50% are used to form feature matrix other voxels are discarded[19]. This method reduces the dimension of feature space, to optimize the classification. However, the results have not improved compared to the first method. This method uses, feature reduction to increase the classification efficiency. Atlas based methods (voxel atlas): Voxels are segmented into anatomical regions using labeled atlas into a total of 116 regions. Here a software called COMPARE is used and not SPM5[20]. Based on these each voxel would be having a map indexed from 0 to 115. This method too, has reported substantial improvement in the results.

2. Vertex based Methods (Using Cortical Thickness): Here the cortical thickness is the feature used in classification , it is a direct marker of Atrophy. Cortical thickness becomes input for the support vector machine. The various methods used are direct measurement of cortical thickness, or a thickness atlas is used, the atlas has 68 gyrals based ROI, in each ROI cortical thickness is computed. In another method, ROI is determined and the cortical thickness pattern in the ROI becomes a feature matrix[21]. A Better method than just finding cortical thickness would be to measure cortical thickness in different regions. The study has shown that Entrohinal Cortex, Lateral middle temporal gyrus, Inferior pariental cortex, Medial Orbito frontal Cortex show significant change in thickness for AD and non-AD patients, while Rostral Midfrontal Cortx and Retro spinal Cortex show not much significant diiference in thickness[37,39]. 3.Hippocampus Segmentation methods: Volume and the shape of the hippocampus is used as a feature to be fed into SVM to the train the support vector. Even though, this method is most commonly used clinical method, it yields lower accuracy in SVM modeling of about 68%[22]

b. Classification from Functional Data (fMRI):

1. Functional Connectivity: fMRI can be an important biomarker in AD[25]. It uses BOLD- Bold Oxygen Level Dependent contrast. The deoxygenated hemoglobin has greater magnetism than oxygenated blood. Hence, it distorts the magnetic field around it and induces a faster decay(T2). Hence, a higher neural activity means a higher decay signal. Hence, Gradient Echo EPI pulse sequence is applied as it is sensitive to T2 decay. It is observed that because in activation stage there is no change but in deactivation stage in AD patients there is reduced deactivation. However resting state fMRI is used to get the class discriminatory features for classification. fMRI is method used to get the class discriminatory features , fMRI is based on the BOLD signals from the brain. fMRI can be an active one, to decide activation during different activities like reading, listening etc, or a resting state fMRI done on the subject in resting state[23]. The fMRI data is a time series signal. The study on functional connectivity gives good class discrimination. Functional connectivity is defined as statistical dependency among spatially remote neuro physiological subjects. Functional connectivity can be found out by Single Value Decomposition (SVD)[24]. A computationally simpler method is to calculate the Pearson correlation matrix for a set of ROIs, and comparing them with time to construct a good classifier.

Get the fMRI data from the machine Identify about 100 ROIs from the brain anatomy, and calculate the correlation matrix for the ROIs Identify the ROI pair with correlations greater than T1, and lesser than T2. Using these setof values obtained in the set the DCI (<T1) and ICI(>T2) is computed. Train the SVM using DCI and ICI values
After 100 ROIs are identified a Pearson correlation matrix is formed to which is a 100x100 matrix. The data is quantized as a histogram, and the indexes Decreased Connectivity Index(DCI) and Increased Connectivity Index(ICI) are computed.

DCI and ICI values are calculated for every sample and hence, the feature space becomes two dimensional, Hence, a 2D SVM classifier can be used , some methods even use Fisher Discriminant Analysis(FDA), to classify.

Diffusion Tensor Imaging Features:

Attenuation of the MR signal can be modeled as a function of Diffusion of water molecules. Diffusion is a tensor, and it is represented by matrix D [ ], where the matrix D is symmetric

The attenuation is measured by the equation

 Thus, attenuation A can be physically measured, hence D matrix can be measured.

Mean diffusability is computed for every voxel, hence the mean diffusabilty becomes a feature to be classified[27]

CT Scan features:
CT scan uses X-ray and gives a volumetric data, with the help of rendering and reconstruction techniques, CT scan images are obtained. It uses ionizing radiations hence it is not a safe method as MRI 1. Ventricular Brain ratio: Ventricular brain ratio is the ratio of the ventricle to the brain volume(intra cranial volume). It was found that the percentage decrease of Ventricular brain ratio was 2% in healthy controls and it was 9% in Alzheimer's disease patients. Hence, Ventricular brain ratio is an important bio marker in AD. Since CT scan gives a contrast for soft tissues and fluid, from this contrast difference Ventricular volume is measured[28]. 2. Percentage Volume of CSF: percentage of CSF can be found out from a CT scan as CT scan gives a difference between soft tissues and fluids by giving various contrasts to the images.

Age is directly related to percentage of Cerebral Spinal Fluid, thus, care has to be taken while interpreting the results, always healthy population and AD cohorts taken for study must be of the same age[29] . The studies have shown a significant difference in CSF percentage in AD patients in comparison with healthy patients. The percentage CSF in healthy adults was 12.59% while in AD patients it was 18.2%[30]. 3.Medial Temporal Lobe Width: From CT scan or MRI, Medial Temporal Lobe Features can be obtained: Four features can be measured from Medial Temporal Lobe: 1. A- Largest Vertical Height of Hippocampus formation

2. B- Largest horizontal width between hippocampus and brain stem 3. C- Largest vertical width of choroid fissure 4. D- Width of Temporal Horn. Atrophy can be measured by measuring these four quantities. Atrophy can be 1,2,3 or 4. Based on the increase of C,B and decrease of D,A[31]. To support this hypothesis study was conducted and from CT scan Medial Temporal width of AD patients and healthy controls was found out. It was found that the width was is smaller in AD patients by 16%[32].

PET SCAN Markers:

PET is Positron Emission Tomography. It is based on radioactive principles. Here, a radioactive substrate with a short decay time is injected into the blood. For example in most of the cases, Fluro-deoxy glucose (FDG) is injected into the blood, FDG being tracer decays and the electron emitted is measured and hence image data is formed. 1. Amyloid binding: Here Pittsburg Compound B is used for imaging. PiB is radioactive and also it binds with amyloid plaque. Neuroimaging studies have found that Amyloid deposits increases as AD progresses hence, an estimate of Amyloid content in brain is a bio marker for AD. PET scans done show a strong contrast for Amyloid plaques[33]. 2. Glucose Uptake: AD is characterized by decreased metabolism in the cerebrum. Hence, by measuring glucose uptake in the cerebrum, a direct measure of metabolism can be obtained. Hence, a decreased glucose uptake is a bio marker for AD. The PET scans for measuring glucose uptake are done by normal FDG PET scans, since FDG is analogous to glucose, Glucose uptake can be measured by contrast of the images[34] 3. Blood Flow: By taking the images in time blood flow is quantized. In AD, there is lower blood flow due to lower metabolism in cerebrum. However, This can be measured using Glucose uptake also, but by quantizing blood flow, a time dependent information is obtained and not just spacial information. Hence, blood flow gives additional information compared to Glucose uptake [35].

4. Functional Connectivity: Functional connectivity is analysis is done from resting state PET scan, functional connectivity is similar to functional connectivity analysis in a fMRI scan. An Independent Components analysis is applied to get independent components and principal component analysis is applied on the data to reduce the number of components, An SVM classification is finally applied to get the differentiating features[36]. 5. Regional Activation: The information processing like encoding of object information and their recognition happens differently in AD and non-AD patients. In these tasks, shapes are shown one by one and the subject has to identify it as old or new object. The experiment was done using injected into the blood. The PET images are taken over the time and relative Cerebral Blood Flow (rCBF) is obtained using SPM software. rCBF activation information is analyzed statistically using correlation measures[40].

MRS scan Markers:

MRS is Magnetic Resonance Spectroscopy, the technique is very useful in in-vivo quantization of Neurochemicals. However, the MRS data must be preprocessed before interpreting to avoid wrong values in quantization. Therefore, good fitting methods have been evolved to fit the MRS data for its correct quantization. 1. GSH concentration in right frontal cortex: GSH is Glutathione is indicative of oxidative stress and thus it is an important marker to demonstrate the progression of the disease[41] . GSH cannot be indicated directly by PRESS or STEAM pulse sequence. The method indicated is

MRI image from test subjects

H inverted using selective 180 pulse

H not inverted as selective 180 pulse is not applied

From ,the two spectrograms obtained difference is calculated, the so obtained difference spectrogram indicates the level of GSH. GSH is the direct indicator of oxidative stress. Oxidative stress is main indicator of Alzheimer's disease[41]. SVM hypothesis

Solving this equation by using convex optimization in MATLAB toolbox, we could find the W matrix which indicates the three n-dimensional planes used to bifurcate the data into four groups. This algorithm in MATLAB uses Cross-validation and Expectation Maximization. The support vector machine is trained on a large data to give class discriminatory features. The vector X could be entire spectrograph of n samples or could be only the concentration of GSH could be used.

To validate the data, multiple features can be helpful, 2. pH in the left Hippocampus pH levels in left hippocampus is a good indication of A.D, hence it can be a great bio marker[14]

pH is measured by the equation:

is chemical shift difference between PCR and resonant peak of Pi. It was observed that pH in left hippocampus changes towards Alkali region in AD patients[42]. Thus pH is a biomarker that can be used in pattern recognition algorithm. Since the system would have three markers a neural network could be trained to recognize the patterns of Alzheimer's disease subject to the tree bio markers. 3.Cho/Cr ratio: In AD patients Cho/Cr ratio obtained from MRS is lower than the control subjects, Cho is Choline containing Compounds, The measure is not done as Absolute quantity of Cho as there is great variations among individuals in Cho concentration. However, the ratio is bio marker to be used the study[43] 4. NAA concentration The NAA concentration is a marker for AD, however, the absolute quantization gives no results. Hence quantization by ratio is chosen, NAA is N-Acetyl aspartic acid. The ratio commonly used are NAA/Cr, However NAA/Cr has lesser sensitivity compared to NAA/myo-Inositol. Thus this method is more popular and gives a better accuracy over NAA/Cr[44]. 5. Whole spectrum classification by SVM: To do a whole brain MRS spectra study with the help of SVM, voxel of interest is chosen to get the spectra, once the spectra is obtained; the same procedure is repeated over all samples. The spectra amplitude values can be represented by a column matrix and hence the column matrix becomes the training data for SVM and optimal classifier may be found out. However, the data can be classified into metabolites concentration by ICA and thus reduces the feature space and SVM algorithm is run on the reduced feature space and a optimal classifier can be got to distinguish between AD and non-AD patients[45]

Image segmentation algorithms:

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