Brain Gene Co-Expression Network Analysis Identifies 22q13 Region Genes Associated with Autism, Intellectual Disability, Seizures, Language Impairment, and Hypotonia.

Phelan-McDermid syndrome (PMS) is a rare genetic neurodevelopmental disorder caused by 22q13 region deletions or SHANK3 gene variants. Deletions vary in size and can affect other genes in addition to SHANK3. PMS is characterized by autism spectrum disorder (ASD), intellectual disability (ID), developmental delays, seizures, speech delay, hypotonia, and minor dysmorphic features. It is challenging to determine individual gene contributions due to variability in deletion sizes and clinical features. We implemented a genomic data mining approach for identifying and prioritizing the candidate genes in the 22q13 region for five phenotypes: ASD, ID, seizures, language impairment, and hypotonia. Weighted gene co-expression networks were constructed using the BrainSpan transcriptome dataset of a human brain. Bioinformatic analyses of the co-expression modules allowed us to select specific candidate genes, including EP300, TCF20, RBX1, XPNPEP3, PMM1, SCO2, BRD1, and SHANK3, for the common neurological phenotypes of PMS. The findings help understand the disease mechanisms and may provide novel therapeutic targets for the precise treatment of PMS.

Interictal Epileptiform Discharge Detection in EEG in Different Practice Settings.

OBJECTIVE: The goal of the study was to measure the performance of academic and private practice (PP) neurologists in detecting interictal epileptiform discharges in routine scalp EEG recordings. METHODS: Thirty-five EEG scorers (EEGers) participated (19 academic and 16 PP) and marked the location of ETs in 200 30-second EEG segments using a web-based EEG annotation system. All participants provided board certification status, years of Epilepsy Fellowship Training (EFT), and years in practice. The Persyst P13 automated IED detection algorithm was also run on the EEG segments for comparison. RESULTS: Academic EEGers had an average of 1.66 years of EFT versus 0.50 years of EFT for PP EEGers (P < 0.0001) and had higher rates of board certification. Inter-rater agreement for the 35 EEGers was fair. There was higher performance for EEGers in academics, with at least 1.5 years of EFT, and with American Board of Clinical Neurophysiology and American Board of Psychiatry and Neurology-E specialty board certification. The Persyst P13 algorithm at its default setting (perception value = 0.4) did not perform as well at the EEGers, but at substantially higher perception value settings, the algorithm performed almost as well human experts. CONCLUSIONS: Inter-rater agreement among EEGers in both academic and PP settings varies considerably. Practice location, years of EFT, and board certification are associated with significantly higher performance for IED detection in routine scalp EEG. Continued medical education of PP neurologists and neurologists without EFT is needed to improve routine scalp EEG interpretation skills. The performance of automated detection algorithms is approaching that of human experts.

Interictal epileptiform discharge characteristics underlying expert interrater agreement.

OBJECTIVE: The presence of interictal epileptiform discharges (IED) in the electroencephalogram (EEG) is a key finding in the medical workup of a patient with suspected epilepsy. However, inter-rater agreement (IRA) regarding the presence of IED is imperfect, leading to incorrect and delayed diagnoses. An improved understanding of which IED attributes mediate expert IRA might help in developing automatic methods for IED detection able to emulate the abilities of experts. Therefore, using a set of IED scored by a large number of experts, we set out to determine which attributes of IED predict expert agreement regarding the presence of IED. METHODS: IED were annotated on a 5-point scale by 18 clinical neurophysiologists within 200 30-s EEG segments from recordings of 200 patients. 5538 signal analysis features were extracted from the waveforms, including wavelet coefficients, morphological features, signal energy, nonlinear energy operator response, electrode location, and spectrogram features. Feature selection was performed by applying elastic net regression and support vector regression (SVR) was applied to predict expert opinion, with and without the feature selection procedure and with and without several types of signal normalization. RESULTS: Multiple types of features were useful for predicting expert annotations, but particular types of wavelet features performed best. Local EEG normalization also enhanced best model performance. As the size of the group of EEGers used to train the models was increased, the performance of the models leveled off at a group size of around 11. CONCLUSIONS: The features that best predict inter-rater agreement among experts regarding the presence of IED are wavelet features, using locally standardized EEG. Our models for predicting expert opinion based on EEGer's scores perform best with a large group of EEGers (more than 10). SIGNIFICANCE: By examining a large group of EEG signal analysis features we found that wavelet features with certain wavelet basis functions performed best to identify IEDs. Local normalization also improves predictability, suggesting the importance of IED morphology over amplitude-based features. Although most IED detection studies in the past have used opinion from three or fewer experts, our study suggests a "wisdom of the crowd" effect, such that pooling over a larger number of expert opinions produces a better correlation between expert opinion and objectively quantifiable features of the EEG.

Characteristics of EEG Interpreters Associated With Higher Interrater Agreement.

PURPOSE: The goal of the project is to determine characteristics of academic neurophysiologist EEG interpreters (EEGers), which predict good interrater agreement (IRA) and to determine the number of EEGers needed to develop an ideal standardized testing and training data set for epileptiform transient (ET) detection algorithms. METHODS: A three-phase scoring method was used. In phase 1, 19 EEGers marked the location of ETs in two hundred 30-second segments of EEG from 200 different patients. In phase 2, EEG events marked by at least 2 EEGers were annotated by 18 EEGers on a 5-point scale to indicate whether they were ETs. In phase 3, a third opinion was obtained from EEGers on any inconsistencies between phase 1 and phase 2 scoring. RESULTS: The IRA for the 18 EEGers was only fair. A select group of the EEGers had good IRA and the other EEGers had low IRA. Board certification by the American Board of Clinical Neurophysiology was associated with better IRA performance but other board certifications, years of fellowship training, and years of practice were not. As the number of EEGers used for scoring is increased, the amount of change in the consensus opinion decreases steadily and is quite low as the group size approaches 10. CONCLUSIONS: The IRA among EEGers varies considerably. The EEGers must be tested before use as scorers for ET annotation research projects. The American Board of Clinical Neurophysiology certification is associated with improved performance. The optimal size for a group of experts scoring ETs in EEG is probably in the 6 to 10 range.

Comparison of a Novel Dry Electrode Headset to Standard Routine EEG in Veterans.

OBJECTIVE: This purpose of this study was to evaluate the usefulness of a prototype battery-powered dry electrode system (DES) EEG recording headset in Veteran patients by comparing it with standard EEG. METHODS: Twenty-one Veterans had both a standard electrode system recording and DES recording in nine different patient states at the same encounter. Setup time, patient comfort, and subject preference were measured. Three experts performed technical quality rating of each EEG recording in a blinded fashion using the web-based EEGnet system. Power spectra were compared between DES and standard electrode system recordings. RESULTS: The average time for DES setup was 5.7 minutes versus 21.1 minutes for standard electrode system. Subjects reported that the DES was more comfortable during setup. Most subjects (15 of 21) preferred the DES. On a five-point scale (1-best quality to 5-worst quality), the technical quality of the standard electrode system recordings was significantly better than for the DES recordings, at 1.25 versus 2.41 (P < 0.0001). But experts found that 87% of the DES EEG segments were of sufficient technical quality to be interpretable. CONCLUSIONS: This DES offers quick and easy setup and is well tolerated by subjects. Although the technical quality of DES recordings was less than standard EEG, most of the DES recordings were rated as interpretable by experts. SIGNIFICANCE: This DES, if improved, could be useful for a telemedicine approach to outpatient routine EEG recording within the Veterans Administration or other health system.

Generalized periodic discharges and 'triphasic waves': A blinded evaluation of inter-rater agreement and clinical significance.

OBJECTIVES: Generalized periodic discharges (GPDs) are associated with nonconvulsive seizures. Triphasic waves (TWs), a subtype of GPDs, have been described in relation to metabolic encephalopathy and not felt to be associated with seizures. We sought to establish the consistency of use of this descriptive term and its association with seizures. METHODS: 11 experts in continuous EEG monitoring scored 20 cEEG samples containing GPDs using Standardized Critical Care EEG Terminology. In the absence of patient information, the inter-rater agreement (IRA) for EEG descriptors including TWs was assessed along with raters' clinical EEG interpretation and compared with actual patient information. RESULTS: The IRA for 'generalized' and 'periodic' was near-perfect (kappa=0.81), but fair for 'triphasic' (kappa=0.33). Patients with TWs were as likely to develop seizures as those without (25% vs 26%, N.S.) and surprisingly, patients with TWs were less likely to have toxic-metabolic encephalopathy than those without TWs (55% vs 79%, p<0.01). CONCLUSIONS: While IRA for the terms "generalized" and "periodic" is high, it is only fair for TWs. EEG interpreted as TWs presents similar risk for seizures as GPDs without triphasic appearance. GPDs are commonly associated with metabolic encephalopathy, but 'triphasic' appearance is not predictive. SIGNIFICANCE: Conventional association of 'triphasic waves' with specific clinical conditions may lead to inaccurate EEG interpretation.

A study of morphology-based wavelet features and multiple-wavelet strategy for EEG signal classification: results and selected statistical analysis.

Automatic detection and classification of Epileptiform transients is an open and important clinical issue. In this paper, we test 5 feature sets derived from a group of morphology-based wavelet features and compare the results with that of a Guler-suggested feature set. We also implement a multiple-mother-wavelet strategy and compare performance with the usual single-mother-wavelet strategy. The results indicate that both the derived features and the multiple-mother-wavelet strategy improved classifier performance, using a variety of performance measures. We assess the statistical significance of the performance improvement of the new feature sets/strategy. In most cases, the performance improvement is either significant or highly significant.

A linear programming approach to reconstructing subcellular structures from confocal images for automated generation of representative 3D cellular models.

This paper presents a novel computer vision algorithm to analyze 3D stacks of confocal images of fluorescently stained single cells. The goal of the algorithm is to create representative in silico model structures that can be imported into finite element analysis software for mechanical characterization. Segmentation of cell and nucleus boundaries is accomplished via standard thresholding methods. Using novel linear programming methods, a representative actin stress fiber network is generated by computing a linear superposition of fibers having minimum discrepancy compared with an experimental 3D confocal image. Qualitative validation is performed through analysis of seven 3D confocal image stacks of adherent vascular smooth muscle cells (VSMCs) grown in 2D culture. The presented method is able to automatically generate 3D geometries of the cell's boundary, nucleus, and representative F-actin network based on standard cell microscopy data. These geometries can be used for direct importation and implementation in structural finite element models for analysis of the mechanics of a single cell to potentially speed discoveries in the fields of regenerative medicine, mechanobiology, and drug discovery.

A computational approach to understand phenotypic structure and constitutive mechanics relationships of single cells.

The goal of this study is to construct a representative 3D finite element model (FEM) of individual cells based on their sub-cellular structures that predicts cell mechanical behavior. The FEM simulations replicate atomic force microscopy (AFM) nanoindentation experiments on live vascular smooth muscle cells. Individual cells are characterized mechanically with AFM and then imaged in 3D using a spinning disc confocal microscope. Using these images, geometries for the FEM are automatically generated via image segmentation and linear programming algorithms. The geometries consist of independent structures representing the nucleus, actin stress fiber network, and cytoplasm. These are imported into commercial software for mesh refinement and analysis. The FEM presented here is capable of predicting AFM results well for 500 nm indentations. The FEM results are relatively insensitive to both the exact number and diameter of fibers used. Despite the localized nature of AFM nanoindentation, the model predicts that stresses are distributed in an anisotropic manner throughout the cell body via the actin stress fibers. This pattern of stress distribution is likely a result of the geometric arrangement of the actin network.

Standardized database development for EEG epileptiform transient detection: EEGnet scoring system and machine learning analysis.

The routine scalp electroencephalogram (rsEEG) is the most common clinical neurophysiology procedure. The most important role of rsEEG is to detect evidence of epilepsy, in the form of epileptiform transients (ETs), also known as spike or sharp wave discharges. Due to the wide variety of morphologies of ETs and their similarity to artifacts and waves that are part of the normal background activity, the task of ET detection is difficult and mistakes are frequently made. The development of reliable computerized detection of ETs in the EEG could assist physicians in interpreting rsEEGs. We report progress in developing a standardized database for testing and training ET detection algorithms. We describe a new version of our EEGnet software system for collecting expert opinion on EEG datasets, a completely web-browser based system. We report results of EEG scoring from a group of 11 board-certified academic clinical neurophysiologists who annotated 30-s excepts from rsEEG recordings from 100 different patients. The scorers had moderate inter-scorer reliability and low to moderate intra-scorer reliability. In order to measure the optimal size of this standardized rsEEG database, we used machine learning models to classify paroxysmal EEG activity in our database into ET and non-ET classes. Based on our results, it appears that our database will need to be larger than its current size. Also, our non-parametric classifier, an artificial neural network, performed better than our parametric Bayesian classifier. Of our feature sets, the wavelet feature set proved most useful for classification.

Morphology-based wavelet features and multiple mother wavelet strategy for spike classification in EEG signals.

New wavelet-derived features and strategies that can improve autonomous EEG classifier performance are presented. Various feature sets based on the morphological structure of wavelet subband coefficients are derived and evaluated. The performance of these new feature sets is superior to Guler's classic features in both sensitivity and specificity. In addition, the use of (scalp electrode) spatial information is also shown to improve EEG classification. Finally, a new strategy based upon concurrent use of several mother wavelets is shown to result in increased sensitivity and specificity. Various attempts at reducing feature vector dimension are shown. A non-parametric method, k-NNR, is implemented for classification and 10-fold cross-validation is used for assessment.

Web-based collection of expert opinion on routine scalp EEG: software development and interrater reliability.

Computerized detection of epileptiform transients (ETs), characterized by interictal spikes and sharp waves in the EEG, has been a research goal for the last 40 years. A reliable method for detecting ETs would assist physicians in interpretation and improve efficiency in reviewing long-term EEG recordings. Computer algorithms developed thus far for detecting ETs are not as reliable as human experts, primarily due to the large number of false-positive detections. Comparing the performance of different algorithms is difficult because each study uses individual EEG test datasets. In this article, we present EEGnet, a distributed web-based platform for the acquisition and analysis of large-scale training datasets for comparison of different EEG ET detection algorithms. This software allows EEG scorers to log in through the web, mark EEG segments of interest, and categorize segments of interest using a conventional clinical EEG user interface. This software platform was used by seven board-certified academic epileptologists to score 40 short 30-second EEG segments from 40 patients, half containing ETs and half containing artifacts and normal variants. The software performance was adequate. Interrater reliability for marking the location of paroxysmal activity was low. Interrater reliability of marking artifacts and ETs was high and moderate, respectively.