Improving the in silico assessment of pathogenicity for compensated variants

Understanding the functional sequelae of amino-acid replacements is of fundamental importance in medical genetics. Perhaps, the most intuitive way to assess the potential pathogenicity of a given human missense variant is by measuring the degree of evolutionary conservation of the substituted amino-acid residue, a feature that generally serves as a good proxy metric for the functional/structural importance of that residue. However, the presence of putatively compensated variants as the wild-type alleles in orthologous proteins of other mammalian species not only challenges this classical view of amino-acid essentiality but also precludes the accurate evaluation of the functional impact of this type of missense variant using currently available bioinformatic prediction tools. Compensated variants constitute at least 4% of all known missense variants causing human-inherited disease and hence represent an important potential source of error in that they are likely to be disproportionately misclassified as benign variants. The consequent under-reporting of compensated variants is exacerbated in the context of next-generation sequencing where their inappropriate exclusion constitutes an unfortunate natural consequence of the filtering and prioritization of the very large number of variants generated. Here we demonstrate the reduced performance of currently available pathogenicity prediction tools when applied to compensated variants and propose an alternative machine-learning approach to assess likely pathogenicity for this particular type of variant

Objective evaluation of Parkinson's disease bradykinesia

Bradykinesia is the fundamental motor feature of Parkinson’s disease - obligatory for diagnosis and central to monitoring. It is a complex clinicalsign that describes movements with slow speed, small amplitude, irregular rhythm, brief pauses and progressive decrements. Clinical ascertainment of the presence and severity of bradykinesia relies on subjective interpretation of these components, with considerable variability amongst clinicians, and this may contribute to diagnostic error and inaccurate monitoring in Parkinson’s disease. The primary aim of this thesis was to assess whether a novel non-invasive device could objectively measure bradykinesia and predict diagnostic classification of movement data from Parkinson’s disease patients and healthy controls. The second aim was to evaluate how objective measures of bradykinesia correlate with clinical measures of bradykinesia severity. The third aim was to investigate the characteristic kinematic features of bradykinesia. Forty-nine patients with Parkinson’s disease and 41 healthy controls were recruited in Leeds. They performed a repetitive finger-tapping task for 30 seconds whilst wearing small electromagnetic tracking sensors on their finger and thumb. Movement data was analysed using two different methods - statistical measures of the separable components of bradykinesia and a computer science technique called evolutionary algorithms. Validation data collected independently from 13 patients and nine healthy controls in San Francisco was used to assess whether the results generalised. The evolutionary algorithm technique was slightly superior at classifying the movement data into the correct diagnostic groups, especially for the mildest clinical grades of bradykinesia, and they generalised to the independent group data. The objective measures of finger tapping correlated well with clinical grades of bradykinesia severity. Detailed analysis of the data suggests that a defining feature of Parkinson’s disease bradykinesia called the sequence effect may be a physiological rather than a pathological phenomenon. The results inform the development of a device that may support clinical diagnosis and monitoring of Parkinson’s disease and also be used to investigate bradykinesia

Radial Basis Function Neural Networks : A Review

Radial Basis Function neural networks (RBFNNs) represent an attractive alternative to other neural network models. One reason is that they form a unifying link between function approximation, regularization, noisy interpolation, classification and density estimation. It is also the case that training RBF neural networks is faster than training multi-layer perceptron networks. RBFNN learning is usually split into an unsupervised part, where center and widths of the Gaussian basis functions are set, and a linear supervised part for weight computation. This paper reviews various learning methods for determining centers, widths, and synaptic weights of RBFNN. In addition, we will point to some applications of RBFNN in various fields. In the end, we name software that can be used for implementing RBFNNs

A gaussian mixture-based approach to synthesizing nonlinear feature functions for automated object detection

Feature design is an important part to identify objects of interest into a known number of categories or classes in object detection. Based on the depth-first search for higher order feature functions, the technique of automated feature synthesis is generally considered to be a process of creating more effective features from raw feature data during the run of the algorithms. This dynamic synthesis of nonlinear feature functions is a challenging problem in object detection. This thesis presents a combinatorial approach of genetic programming and the expectation maximization algorithm (GP-EM) to synthesize nonlinear feature functions automatically in order to solve the given tasks of object detection. The EM algorithm investigates the use of Gaussian mixture which is able to model the behaviour of the training samples during an optimal GP search strategy. Based on the Gaussian probability assumption, the GP-EM method is capable of performing simultaneously dynamic feature synthesis and model-based generalization. The EM part of the approach leads to the application of the maximum likelihood (ML) operation that provides protection against inter-cluster data separation and thus exhibits improved convergence. Additionally, with the GP-EM method, an innovative technique, called the histogram region of interest by thresholds (HROIBT), is introduced for diagnosing protein conformation defects (PCD) from microscopic imagery. The experimental results show that the proposed approach improves the detection accuracy and efficiency of pattern object discovery, as compared to single GP-based feature synthesis methods and also a number of other object detection systems. The GP-EM method projects the hyperspace of the raw data onto lower-dimensional spaces efficiently, resulting in faster computational classification processes

Detection of gait initiation Failure in Parkinson's disease based on wavelet transform and Support Vector Machine

© 2017 IEEE. Gait initiation Failure (GIF) is the situation in which patients with Parkinson's disease (PD) feel as if their feet get 'stuck' to the floor when initiating their first steps. GIF is a subtype of Freezing of Gait (FOG) and often leads to falls and related injuries. Understanding of neurobiological mechanisms underlying GIF has been limited by difficulties in eliciting and objectively characterizing such gait phenomena in the clinical setting. Studies investigating the effects of GIF on brain activity using EEG offer the potential to study such behavior. In this preliminary study, we present a novel methodology where wavelet transform was used for feature extraction and Support Vector Machine for classifying GIF events in five patients with PD and FOG. To deal with the large amount of EEG data, a Principal Component Analysis (PCA) was applied to reduce the data dimension from 15 EEG channels into 6 principal components (PCs), retaining 93% of the information. Independent Component Analysis using Entropy Bound Minimization (ICA-EBM) was applied to 6 PCs for source separation with the aim of improving detection ability of GIF events as compared to the normal initiation of gait (Good Starts). The results of this analysis demonstrated the correct identification of GIF episodes with an 83.1% sensitivity, 89.5% specificity and 86.3% accuracy. These results suggest that our proposed methodology is a promising non-invasive approach to improve GIF detection in PD and FOG

A Review of the Assessment Methods of Voice Disorders in the Context of Parkinson's Disease

In recent years, a significant progress in the field of research dedicated to the treatment of disabilities has been witnessed. This is particularly true for neurological diseases, which generally influence the system that controls the execution of learned motor patterns. In addition to its importance for communication with the outside world and interaction with others, the voice is a reflection of our personality, moods and emotions. It is a way to provide information on health status, shape, intentions, age and even the social environment. It is also a working tool for many, but an important element of life for all. Patients with Parkinson’s disease (PD) are numerous and they suffer from hypokinetic dysarthria, which is manifested in all aspects of speech production: respiration, phonation, articulation, nasalization and prosody. This paper provides a review of the methods of the assessment of speech disorders in the context of PD and also discusses the limitations

Improving automatic detection of obstructive sleep apnea through nonlinear analysis of sustained speech

We present a novel approach for the detection of severe obstructive sleep apnea (OSA) based on patients' voices introducing nonlinear measures to describe sustained speech dynamics. Nonlinear features were combined with state-of-the-art speech recognition systems using statistical modeling techniques (Gaussian mixture models, GMMs) over cepstral parameterization (MFCC) for both continuous and sustained speech. Tests were performed on a database including speech records from both severe OSA and control speakers. A 10 % relative reduction in classification error was obtained for sustained speech when combining MFCC-GMM and nonlinear features, and 33 % when fusing nonlinear features with both sustained and continuous MFCC-GMM. Accuracy reached 88.5 % allowing the system to be used in OSA early detection. Tests showed that nonlinear features and MFCCs are lightly correlated on sustained speech, but uncorrelated on continuous speech. Results also suggest the existence of nonlinear effects in OSA patients' voices, which should be found in continuous speech