The visualization of Orphadata neurology phenotypes.

Disease phenotypes are characterized by signs (what a physician observes during the examination of a patient) and symptoms (the complaints of a patient to a physician). Large repositories of disease phenotypes are accessible through the Online Mendelian Inheritance of Man, Human Phenotype Ontology, and Orphadata initiatives. Many of the diseases in these datasets are neurologic. For each repository, the phenotype of neurologic disease is represented as a list of concepts of variable length where the concepts are selected from a restricted ontology. Visualizations of these concept lists are not provided. We address this limitation by using subsumption to reduce the number of descriptive features from 2,946 classes into thirty superclasses. Phenotype feature lists of variable lengths were converted into fixed-length vectors. Phenotype vectors were aggregated into matrices and visualized as heat maps that allowed side-by-side disease comparisons. Individual diseases (representing a row in the matrix) were visualized as word clouds. We illustrate the utility of this approach by visualizing the neuro-phenotypes of 32 dystonic diseases from Orphadata. Subsumption can collapse phenotype features into superclasses, phenotype lists can be vectorized, and phenotypes vectors can be visualized as heat maps and word clouds.

Local Stability and Convergence Analysis of Neural Network Controllers With Error Integral Inputs.

This article investigates the local stability and local convergence of a class of neural network (NN) controllers with error integrals as inputs for reference tracking. It is formally proved that if the input of the NN controller consists exclusively of error terms, the control system shows a non-zero steady-state error for any constant reference except for one specific point, for both single-layer and multi-layer NN controllers. It is further proved that adding error integrals to the input of the (single- and multi-layers) NN controller is one sufficient way to remove the steady-state error for any constant reference. Due to the nonlinearity of the NN controllers, the NN control systems are linearized at the equilibrium points. We provide proof that if all the eigenvalues of the linearized NN control system have negative real parts, local asymptotic stability and local exponential convergence are guaranteed. Two case studies were explored to verify the theoretical results: a single-layer NN controller in a 1-D system and a four-layer NN controller in a 2-D system applied to renewable energy integration. Simulations demonstrate that when NN controllers and the corresponding generalized proportional-integral (PI) controllers have the same eigenvalues, all control systems exhibit almost the same responses in a small neighborhood of their respective equilibrium points.

iCVI-ARTMAP: Using Incremental Cluster Validity Indices and Adaptive Resonance Theory Reset Mechanism to Accelerate Validation and Achieve Multiprototype Unsupervised Representations.

This article presents an adaptive resonance theory predictive mapping (ARTMAP) model, which uses incremental cluster validity indices (iCVIs) to perform unsupervised learning, namely, iCVI-ARTMAP. Incorporating iCVIs to the decision-making and many-to-one mapping capabilities of this adaptive resonance theory (ART)-based model can improve the choices of clusters to which samples are incrementally assigned. These improvements are accomplished by intelligently performing the operations of swapping sample assignments between clusters, splitting and merging clusters, and caching the values of variables when iCVI values need to be recomputed. Using recursive formulations enables iCVI-ARTMAP to considerably reduce the computational burden associated with cluster validity index (CVI)-based offline clustering. In this work, six iCVI-ARTMAP variants were realized via the integration of one information-theoretic and five sum-of-squares-based iCVIs into fuzzy ARTMAP. With proper choice of iCVI, iCVI-ARTMAP either outperformed or performed comparably to three ART-based and four non-ART-based clustering algorithms in experiments using benchmark datasets of different natures. Naturally, the performance of iCVI-ARTMAP is subject to the selected iCVI and its suitability to the data at hand; fortunately, it is a general model in which other iCVIs can be easily embedded.

Incremental Cluster Validity Index-Guided Online Learning for Performance and Robustness to Presentation Order.

In streaming data applications, the incoming samples are processed and discarded, and therefore, intelligent decision-making is crucial for the performance of lifelong learning systems. In addition, the order in which the samples arrive may heavily affect the performance of incremental learners. The recently introduced incremental cluster validity indices (iCVIs) provide valuable aid in addressing such class of problems. Their primary use case has been cluster quality monitoring; nonetheless, they have been recently integrated in a streaming clustering method. In this context, the work presented, here, introduces the first adaptive resonance theory (ART)-based model that uses iCVIs for unsupervised and semi-supervised online learning. Moreover, it shows how to use iCVIs to regulate ART vigilance via an iCVI-based match tracking mechanism. The model achieves improved accuracy and robustness to ordering effects by integrating an online iCVI module as module B of a topological ART predictive mapping (TopoARTMAP)-thereby being named iCVI-TopoARTMAP-and using iCVI-driven postprocessing heuristics at the end of each learning step. The online iCVI module provides assignments of input samples to clusters at each iteration in accordance to any of the several iCVIs. The iCVI-TopoARTMAP maintains useful properties shared by the ART predictive mapping (ARTMAP) models, such as stability, immunity to catastrophic forgetting, and the many-to-one mapping capability via the map field module. The performance and robustness to the presentation order of iCVI-TopoARTMAP were evaluated via experiments with synthetic and real-world datasets.

Tau kinetics in Alzheimer's disease.

The cytoskeletal protein tau is implicated in the pathogenesis of Alzheimer's disease which is characterized by intra-neuronal neurofibrillary tangles containing abnormally phosphorylated insoluble tau. Levels of soluble tau are elevated in the brain, the CSF, and the plasma of patients with Alzheimer's disease. To better understand the causes of these elevated levels of tau, we propose a three-compartment kinetic model (brain, CSF, and plasma). The model assumes that the synthesis of tau follows zero-order kinetics (uncorrelated with compartmental tau levels) and that the release, absorption, and clearance of tau is governed by first-order kinetics (linearly related to compartmental tau levels). Tau that is synthesized in the brain compartment can be released into the interstitial fluid, catabolized, or retained in neurofibrillary tangles. Tau released into the interstitial fluid can mix with the CSF and eventually drain to the plasma compartment. However, losses of tau in the drainage pathways may be significant. The kinetic model estimates half-life of tau in each compartment (552 h in the brain, 9.9 h in the CSF, and 10 h in the plasma). The kinetic model predicts that an increase in the neuronal tau synthesis rate or a decrease in tau catabolism rate best accounts for observed increases in tau levels in the brain, CSF, and plasma found in Alzheimer's disease. Furthermore, the model predicts that increases in brain half-life of tau in Alzheimer's disease should be attributed to decreased tau catabolism and not to increased tau synthesis. Most clearance of tau in the neuron occurs through catabolism rather than release to the CSF compartment. Additional experimental data would make ascertainment of the model parameters more precise.

Hamiltonian-Driven Adaptive Dynamic Programming With Efficient Experience Replay.

This article presents a novel efficient experience-replay-based adaptive dynamic programming (ADP) for the optimal control problem of a class of nonlinear dynamical systems within the Hamiltonian-driven framework. The quasi-Hamiltonian is presented for the policy evaluation problem with an admissible policy. With the quasi-Hamiltonian, a novel composite critic learning mechanism is developed to combine the instantaneous data with the historical data. In addition, the pseudo-Hamiltonian is defined to deal with the performance optimization problem. Based on the pseudo-Hamiltonian, the conventional Hamilton-Jacobi-Bellman (HJB) equation can be represented in a filtered form, which can be implemented online. Theoretical analysis is investigated in terms of the convergence of the adaptive critic design and the stability of the closed-loop systems, where parameter convergence can be achieved under a weakened excitation condition. Simulation studies are investigated to verify the efficacy of the presented design scheme.

Reinforcement Learning-Based Cooperative Optimal Output Regulation via Distributed Adaptive Internal Model.

In this article, a data-driven distributed control method is proposed to solve the cooperative optimal output regulation problem of leader-follower multiagent systems. Different from traditional studies on cooperative output regulation, a distributed adaptive internal model is originally developed, which includes a distributed internal model and a distributed observer to estimate the leader's dynamics. Without relying on the dynamics of multiagent systems, we have proposed two reinforcement learning algorithms, policy iteration and value iteration, to learn the optimal controller through online input and state data, and estimated values of the leader's state. By combining these methods, we have established a basis for connecting data-distributed control methods with adaptive dynamic programming approaches in general since these are the theoretical foundation from which they are built.

Heterogeneity in Blood Biomarker Trajectories After Mild TBI Revealed by Unsupervised Learning.

Concussions, also known as mild traumatic brain injury (mTBI), are a growing health challenge. Approximately four million concussions are diagnosed annually in the United States. Concussion is a heterogeneous disorder in causation, symptoms, and outcome making precision medicine approaches to this disorder important. Persistent disabling symptoms sometimes delay recovery in a difficult to predict subset of mTBI patients. Despite abundant data, clinicians need better tools to assess and predict recovery. Data-driven decision support holds promise for accurate clinical prediction tools for mTBI due to its ability to identify hidden correlations in complex datasets. We apply a Locality-Sensitive Hashing model enhanced by varied statistical methods to cluster blood biomarker level trajectories acquired over multiple time points. Additional features derived from demographics, injury context, neurocognitive assessment, and postural stability assessment are extracted using an autoencoder to augment the model. The data, obtained from FITBIR, consisted of 301 concussed subjects (athletes and cadets). Clustering identified 11 different biomarker trajectories. Two of the trajectories (rising GFAP and rising NF-L) were associated with a greater risk of loss of consciousness or post-traumatic amnesia at onset. The ability to cluster blood biomarker trajectories enhances the possibilities for precision medicine approaches to mTBI.

Hamiltonian-Driven Adaptive Dynamic Programming With Approximation Errors.

In this article, we consider an iterative adaptive dynamic programming (ADP) algorithm within the Hamiltonian-driven framework to solve the Hamilton-Jacobi-Bellman (HJB) equation for the infinite-horizon optimal control problem in continuous time for nonlinear systems. First, a novel function, "min-Hamiltonian," is defined to capture the fundamental properties of the classical Hamiltonian. It is shown that both the HJB equation and the policy iteration (PI) algorithm can be formulated in terms of the min-Hamiltonian within the Hamiltonian-driven framework. Moreover, we develop an iterative ADP algorithm that takes into consideration the approximation errors during the policy evaluation step. We then derive a sufficient condition on the iterative value gradient to guarantee closed-loop stability of the equilibrium point as well as convergence to the optimal value. A model-free extension based on an off-policy reinforcement learning (RL) technique is also provided. Finally, numerical results illustrate the efficacy of the proposed framework.

Subtypes of relapsing-remitting multiple sclerosis identified by network analysis.

We used network analysis to identify subtypes of relapsing-remitting multiple sclerosis subjects based on their cumulative signs and symptoms. The electronic medical records of 113 subjects with relapsing-remitting multiple sclerosis were reviewed, signs and symptoms were mapped to classes in a neuro-ontology, and classes were collapsed into sixteen superclasses by subsumption. After normalization and vectorization of the data, bipartite (subject-feature) and unipartite (subject-subject) network graphs were created using NetworkX and visualized in Gephi. Degree and weighted degree were calculated for each node. Graphs were partitioned into communities using the modularity score. Feature maps visualized differences in features by community. Network analysis of the unipartite graph yielded a higher modularity score (0.49) than the bipartite graph (0.25). The bipartite network was partitioned into five communities which were named fatigue, behavioral, hypertonia/weakness, abnormal gait/sphincter, and sensory, based on feature characteristics. The unipartite network was partitioned into five communities which were named fatigue, pain, cognitive, sensory, and gait/weakness/hypertonia based on features. Although we did not identify pure subtypes (e.g., pure motor, pure sensory, etc.) in this cohort of multiple sclerosis subjects, we demonstrated that network analysis could partition these subjects into different subtype communities. Larger datasets and additional partitioning algorithms are needed to confirm these findings and elucidate their significance. This study contributes to the literature investigating subtypes of multiple sclerosis by combining feature reduction by subsumption with network analysis.

Subsumption reduces dataset dimensionality without decreasing performance of a machine learning classifier.

When features in a high dimension dataset are organized hierarchically, there is an inherent opportunity to reduce dimensionality. Since more specific concepts are subsumed by more general concepts, subsumption can be applied successively to reduce dimensionality. We tested whether sub-sumption could reduce the dimensionality of a disease dataset without impairing classification accuracy. We started with a dataset that had 168 neurological patients, 14 diagnoses, and 293 unique features. We applied subsumption repeatedly to create eight successively smaller datasets, ranging from 293 dimensions in the largest dataset to 11 dimensions in the smallest dataset. We tested a MLP classifier on all eight datasets. Precision, recall, accuracy, and validation declined only at the lowest dimensionality. Our preliminary results suggest that when features in a high dimension dataset are derived from a hierarchical ontology, subsumption is a viable strategy to reduce dimensionality.Clinical relevance- Datasets derived from electronic health records are often of high dimensionality. If features in the dataset are based on concepts from a hierarchical ontology, subsumption can reduce dimensionality.

Schizophrenia Classification Using Resting State EEG Functional Connectivity: Source Level Outperforms Sensor Level.

Disrupted functional and structural connectivity measures have been used to distinguish schizophrenia patients from healthy controls. Classification methods based on functional connectivity derived from EEG signals are limited by the volume conduction problem. Recorded time series at scalp electrodes capture a mixture of common sources signals, resulting in spurious connections. We have transformed sensor level resting state EEG times series to source level EEG signals utilizing a source reconstruction method. Functional connectivity networks were calculated by computing phase lag values between brain regions at both the sensor and source level. Brain complex network analysis was used to extract features and the best features were selected by a feature selection method. A logistic regression classifier was used to distinguish schizophrenia patients from healthy controls at five different frequency bands. The best classifier performance was based on connectivity measures derived from the source space and the theta band.The transformation of scalp EEG signals to source signals combined with functional connectivity analysis may provide superior features for machine learning applications.

Blood biomarkers for mild traumatic brain injury: a selective review of unresolved issues.

BACKGROUND: The use of blood biomarkers after mild traumatic brain injury (mTBI) has been widely studied. We have identified eight unresolved issues related to the use of five commonly investigated blood biomarkers: neurofilament light chain, ubiquitin carboxy-terminal hydrolase-L1, tau, S100B, and glial acidic fibrillary protein. We conducted a focused literature review of unresolved issues in three areas: mode of entry into and exit from the blood, kinetics of blood biomarkers in the blood, and predictive capacity of the blood biomarkers after mTBI. FINDINGS: Although a disruption of the blood brain barrier has been demonstrated in mild and severe traumatic brain injury, biomarkers can enter the blood through pathways that do not require a breach in this barrier. A definitive accounting for the pathways that biomarkers follow from the brain to the blood after mTBI has not been performed. Although preliminary investigations of blood biomarkers kinetics after TBI are available, our current knowledge is incomplete and definitive studies are needed. Optimal sampling times for biomarkers after mTBI have not been established. Kinetic models of blood biomarkers can be informative, but more precise estimates of kinetic parameters are needed. Confounding factors for blood biomarker levels have been identified, but corrections for these factors are not routinely made. Little evidence has emerged to date to suggest that blood biomarker levels correlate with clinical measures of mTBI severity. The significance of elevated biomarker levels thirty or more days following mTBI is uncertain. Blood biomarkers have shown a modest but not definitive ability to distinguish concussed from non-concussed subjects, to detect sub-concussive hits to the head, and to predict recovery from mTBI. Blood biomarkers have performed best at distinguishing CT scan positive from CT scan negative subjects after mTBI.

A Kinetic Model for Blood Biomarker Levels After Mild Traumatic Brain Injury.

Traumatic brain injury (TBI) imposes a significant economic and social burden. The diagnosis and prognosis of mild TBI, also called concussion, is challenging. Concussions are common among contact sport athletes. After a blow to the head, it is often difficult to determine who has had a concussion, who should be withheld from play, if a concussed athlete is ready to return to the field, and which concussed athlete will develop a post-concussion syndrome. Biomarkers can be detected in the cerebrospinal fluid and blood after traumatic brain injury and their levels may have prognostic value. Despite significant investigation, questions remain as to the trajectories of blood biomarker levels over time after mild TBI. Modeling the kinetic behavior of these biomarkers could be informative. We propose a one-compartment kinetic model for S100B, UCH-L1, NF-L, GFAP, and tau biomarker levels after mild TBI based on accepted pharmacokinetic models for oral drug absorption. We approximated model parameters using previously published studies. Since parameter estimates were approximate, we did uncertainty and sensitivity analyses. Using estimated kinetic parameters for each biomarker, we applied the model to an available post-concussion biomarker dataset of UCH-L1, GFAP, tau, and NF-L biomarkers levels. We have demonstrated the feasibility of modeling blood biomarker levels after mild TBI with a one compartment kinetic model. More work is needed to better establish model parameters and to understand the implications of the model for diagnostic use of these blood biomarkers for mild TBI.

Comparative study using inverse ontology cogency and alternatives for concept recognition in the annotated National Library of Medicine database.

This paper introduces inverse ontology cogency, a concept recognition process and distance function that is biologically-inspired and competitive with alternative methods. The paper introduces inverse ontology cogency as a new alternative method. It is a novel distance measure used in selecting the optimum mapping between ontology-specified concepts and phrases in free-form text. We also apply a multi-layer perceptron and text processing method for named entity recognition as an alternative to recurrent neural network methods. Automated named entity recognition, or concept recognition, is a common task in natural language processing. Similarities between confabulation theory and existing language models are discussed. This paper provides comparisons to MetaMap from the National Library of Medicine (NLM), a popular tool used in medicine to map free-form text to concepts in a medical ontology. The NLM provides a manually annotated database from the medical literature with concepts labeled, a unique, valuable source of ground truth, permitting comparison with MetaMap performance. Comparisons for different feature set combinations are made to demonstrate the effectiveness of inverse ontology cogency for entity recognition. Results indicate that using both inverse ontology cogency and corpora cogency improved concept recognition precision 20% over the best published MetaMap results. This demonstrates a new, effective approach for identifying medical concepts in text. This is the first time cogency has been explicitly invoked for reasoning with ontologies, and the first time it has been used on medical literature where high-quality ground truth is available for quality assessment.

Exploratory Analysis of Concussion Recovery Trajectories using Multi-modal Assessments and Serum Biomarkers.

Clinicians need better tools to assess severity, prognosis, and recovery from mild Traumatic Brain Injury (mTBI), which can cause long term impairment. To enable better mTBI outcome prediction, an initial step is to analyze the trajectory of recovery metrics over time. This study provides an assessment of recovery trajectories of mTBI while incorporating heterogeneity of individual responses. We analyze the trajectories over multiple discrete time points from baseline to 6 months post injury using a combination of neurocognitive and postural stability assessments and serum biomarkers. The data, obtained from FITBIR, consists of concussed subjects and a matched control group, to allow for comparison in prognostic assessment. Outcomes derived from this exploratory analysis will aid future studies in developing a mTBI recovery timeline model.Clinical relevance- This study further informs clinicians as to the recovery trajectory of clinical measures and biomarkers after mTBI to support return to play decisions. GFAP biomarker and measures related to balance, memory, orientation, and concentration were significantly different than controls early after mTBI.

Evaluation of standard and semantically-augmented distance metrics for neurology patients.

BACKGROUND: Patient distances can be calculated based on signs and symptoms derived from an ontological hierarchy. There is controversy as to whether patient distance metrics that consider the semantic similarity between concepts can outperform standard patient distance metrics that are agnostic to concept similarity. The choice of distance metric can dominate the performance of classification or clustering algorithms. Our objective was to determine if semantically augmented distance metrics would outperform standard metrics on machine learning tasks. METHODS: We converted the neurological findings from 382 published neurology cases into sets of concepts with corresponding machine-readable codes. We calculated patient distances by four different metrics (cosine distance, a semantically augmented cosine distance, Jaccard distance, and a semantically augmented bipartite distance). Semantic augmentation for two of the metrics depended on concept similarities from a hierarchical neuro-ontology. For machine learning algorithms, we used the patient diagnosis as the ground truth label and patient findings as machine learning features. We assessed classification accuracy for four classifiers and cluster quality for two clustering algorithms for each of the distance metrics. RESULTS: Inter-patient distances were smaller when the distance metric was semantically augmented. Classification accuracy and cluster quality were not significantly different by distance metric. CONCLUSION: Although semantic augmentation reduced inter-patient distances, we did not find improved classification accuracy or improved cluster quality with semantically augmented patient distance metrics when applied to a dataset of neurology patients. Further work is needed to assess the utility of semantically augmented patient distances.

Neurotheology in interfaith dialogue.

In recent years, a growing interfaith movement has sought to bring together worldviews from various religious and spiritual backgrounds to investigate life's biggest questions. However, it is remarkable that such dialogue is possible given the vast differences that exist between individuals. A relatively new but burgeoning field, known as neurotheology, has sought to address the neurological processes and mechanisms of religious thought and experience. Overall, neurotheology provides insight into the common thread of religious belief across cultures and the ability of humans to participate in interfaith dialogue. In this manner, the shared overlap with the human mind and religious belief enables the ability to dialogue and face the vast unknowns of our modern world.

Safe Intermittent Reinforcement Learning With Static and Dynamic Event Generators.

In this article, we present an intermittent framework for safe reinforcement learning (RL) algorithms. First, we develop a barrier function-based system transformation to impose state constraints while converting the original problem to an unconstrained optimization problem. Second, based on optimal derived policies, two types of intermittent feedback RL algorithms are presented, namely, a static and a dynamic one. We finally leverage an actor/critic structure to solve the problem online while guaranteeing optimality, stability, and safety. Simulation results show the efficacy of the proposed approach.

An Improved N-Step Value Gradient Learning Adaptive Dynamic Programming Algorithm for Online Learning.

In problems with complex dynamics and challenging state spaces, the dual heuristic programming (DHP) algorithm has been shown theoretically and experimentally to perform well. This was recently extended by an approach called value gradient learning (VGL). VGL was inspired by a version of temporal difference (TD) learning that uses eligibility traces. The eligibility traces create an exponential decay of older observations with a decay parameter ( λ ). This approach is known as TD( λ ), and its DHP extension is known as VGL( λ ), where VGL(0) is identical to DHP. VGL has presented convergence and other desirable properties, but it is primarily useful for batch learning. Online learning requires an eligibility-trace-work-space matrix, which is not required for the batch learning version of VGL. Since online learning is desirable for many applications, it is important to remove this computational and memory impediment. This paper introduces a dual-critic version of VGL, called N -step VGL (NSVGL), that does not need the eligibility-trace-work-space matrix, thereby allowing online learning. Furthermore, this combination of critic networks allows an NSVGL algorithm to learn faster. The first critic is similar to DHP, which is adapted based on TD(0) learning, while the second critic is adapted based on a gradient of n -step TD( λ ) learning. Both networks are combined to train an actor network. The combination of feedback signals from both critic networks provides an optimal decision faster than traditional adaptive dynamic programming (ADP) via mixing current information and event history. Convergence proofs are provided. Gradients of one- and n -step value functions are monotonically nondecreasing and converge to the optimum. Two simulation case studies are presented for NSVGL to show their superior performance.