Pre-exposure cognitive performance variability is associated with severity of respiratory infection.

Using data from a longitudinal viral challenge study, we find that the post-exposure viral shedding and symptom severity are associated with a novel measure of pre-exposure cognitive performance variability (CPV), defined before viral exposure occurs. Each individual's CPV score is computed from data collected from a repeated NeuroCognitive Performance Test (NCPT) over a 3 day pre-exposure period. Of the 18 NCPT measures reported by the tests, 6 contribute materially to the CPV score, prospectively differentiating the high from the low shedders. Among these 6 are the 4 clinical measures digSym-time, digSym-correct, trail-time, and reaction-time, commonly used for assessing cognitive executive functioning. CPV is found to be correlated with stress and also with several genes previously reported to be associated with cognitive development and dysfunction. A perturbation study over the number and timing of NCPT sessions indicates that as few as 5 sessions is sufficient to maintain high association between the CPV score and viral shedding, as long as the timing of these sessions is balanced over the three pre-exposure days. Our results suggest that variations in cognitive function are closely related to immunity and susceptibility to severe infection. Further studying these relationships may help us better understand the links between neurocognitive and neuroimmune systems which is timely in this COVID-19 pandemic era.

Struct2Graph: a graph attention network for structure based predictions of protein-protein interactions.

BACKGROUND: Development of new methods for analysis of protein-protein interactions (PPIs) at molecular and nanometer scales gives insights into intracellular signaling pathways and will improve understanding of protein functions, as well as other nanoscale structures of biological and abiological origins. Recent advances in computational tools, particularly the ones involving modern deep learning algorithms, have been shown to complement experimental approaches for describing and rationalizing PPIs. However, most of the existing works on PPI predictions use protein-sequence information, and thus have difficulties in accounting for the three-dimensional organization of the protein chains. RESULTS: In this study, we address this problem and describe a PPI analysis based on a graph attention network, named Struct2Graph, for identifying PPIs directly from the structural data of folded protein globules. Our method is capable of predicting the PPI with an accuracy of 98.89% on the balanced set consisting of an equal number of positive and negative pairs. On the unbalanced set with the ratio of 1:10 between positive and negative pairs, Struct2Graph achieves a fivefold cross validation average accuracy of 99.42%. Moreover, Struct2Graph can potentially identify residues that likely contribute to the formation of the protein-protein complex. The identification of important residues is tested for two different interaction types: (a) Proteins with multiple ligands competing for the same binding area, (b) Dynamic protein-protein adhesion interaction. Struct2Graph identifies interacting residues with 30% sensitivity, 89% specificity, and 87% accuracy. CONCLUSIONS: In this manuscript, we address the problem of prediction of PPIs using a first of its kind, 3D-structure-based graph attention network (code available at https://github.com/baranwa2/Struct2Graph ). Furthermore, the novel mutual attention mechanism provides insights into likely interaction sites through its unsupervised knowledge selection process. This study demonstrates that a relatively low-dimensional feature embedding learned from graph structures of individual proteins outperforms other modern machine learning classifiers based on global protein features. In addition, through the analysis of single amino acid variations, the attention mechanism shows preference for disease-causing residue variations over benign polymorphisms, demonstrating that it is not limited to interface residues.

A Pattern Dictionary Method for Anomaly Detection.

In this paper, we propose a compression-based anomaly detection method for time series and sequence data using a pattern dictionary. The proposed method is capable of learning complex patterns in a training data sequence, using these learned patterns to detect potentially anomalous patterns in a test data sequence. The proposed pattern dictionary method uses a measure of complexity of the test sequence as an anomaly score that can be used to perform stand-alone anomaly detection. We also show that when combined with a universal source coder, the proposed pattern dictionary yields a powerful atypicality detector that is equally applicable to anomaly detection. The pattern dictionary-based atypicality detector uses an anomaly score defined as the difference between the complexity of the test sequence data encoded by the trained pattern dictionary (typical) encoder and the universal (atypical) encoder, respectively. We consider two complexity measures: the number of parsed phrases in the sequence, and the length of the encoded sequence (codelength). Specializing to a particular type of universal encoder, the Tree-Structured Lempel-Ziv (LZ78), we obtain a novel non-asymptotic upper bound, in terms of the Lambert W function, on the number of distinct phrases resulting from the LZ78 parser. This non-asymptotic bound determines the range of anomaly score. As a concrete application, we illustrate the pattern dictionary framework for constructing a baseline of health against which anomalous deviations can be detected.

Recurrent neural networks enable design of multifunctional synthetic human gut microbiome dynamics.

Predicting the dynamics and functions of microbiomes constructed from the bottom-up is a key challenge in exploiting them to our benefit. Current models based on ecological theory fail to capture complex community behaviors due to higher order interactions, do not scale well with increasing complexity and in considering multiple functions. We develop and apply a long short-term memory (LSTM) framework to advance our understanding of community assembly and health-relevant metabolite production using a synthetic human gut community. A mainstay of recurrent neural networks, the LSTM learns a high dimensional data-driven non-linear dynamical system model. We show that the LSTM model can outperform the widely used generalized Lotka-Volterra model based on ecological theory. We build methods to decipher microbe-microbe and microbe-metabolite interactions from an otherwise black-box model. These methods highlight that Actinobacteria, Firmicutes and Proteobacteria are significant drivers of metabolite production whereas Bacteroides shape community dynamics. We use the LSTM model to navigate a large multidimensional functional landscape to design communities with unique health-relevant metabolite profiles and temporal behaviors. In sum, the accuracy of the LSTM model can be exploited for experimental planning and to guide the design of synthetic microbiomes with target dynamic functions.

Penalized ensemble Kalman filters for high dimensional non-linear systems.

The ensemble Kalman filter (EnKF) is a data assimilation technique that uses an ensemble of models, updated with data, to track the time evolution of a usually non-linear system. It does so by using an empirical approximation to the well-known Kalman filter. However, its performance can suffer when the ensemble size is smaller than the state space, as is often necessary for computationally burdensome models. This scenario means that the empirical estimate of the state covariance is not full rank and possibly quite noisy. To solve this problem in this high dimensional regime, we propose a computationally fast and easy to implement algorithm called the penalized ensemble Kalman filter (PEnKF). Under certain conditions, it can be theoretically proven that the PEnKF will be accurate (the estimation error will converge to zero) despite having fewer ensemble members than state dimensions. Further, as contrasted to localization methods, the proposed approach learns the covariance structure associated with the dynamical system. These theoretical results are supported with simulations of several non-linear and high dimensional systems.

Adaptive Multi-Channel Event Segmentation and Feature Extraction for Monitoring Health Outcomes.

OBJECTIVE: To develop a multi-channel device event segmentation and feature extraction algorithm that is robust to changes in data distribution. METHODS: We introduce an adaptive transfer learning algorithm to classify and segment events from non-stationary multi-channel temporal data. Using a multivariate hidden Markov model (HMM) and Fisher's linear discriminant analysis (FLDA) the algorithm adaptively adjusts to shifts in distribution over time. The proposed algorithm is unsupervised and learns to label events without requiring a priori information about true event states. The procedure is illustrated on experimental data collected from a cohort in a human viral challenge (HVC) study, where certain subjects have disrupted wake and sleep patterns after exposure to an H1N1 influenza pathogen. RESULTS: Simulations establish that the proposed adaptive algorithm significantly outperforms other event classification methods. When applied to early time points in the HVC data, the algorithm extracts sleep/wake features that are predictive of both infection and infection onset time. CONCLUSION: The proposed transfer learning event segmentation method is robust to temporal shifts in data distribution and can be used to produce highly discriminative event-labeled features for health monitoring. SIGNIFICANCE: Our integrated multisensor signal processing and transfer learning method is applicable to many ambulatory monitoring applications.

Expectation-propagation for weak radionuclide identification at radiation portal monitors.

We propose a sparsity-promoting Bayesian algorithm capable of identifying radionuclide signatures from weak sources in the presence of a high radiation background. The proposed method is relevant to radiation identification for security applications. In such scenarios, the background typically consists of terrestrial, cosmic, and cosmogenic radiation that may cause false positive responses. We evaluate the new Bayesian approach using gamma-ray data and are able to identify weapons-grade plutonium, masked by naturally-occurring radioactive material (NORM), in a measurement time of a few seconds. We demonstrate this identification capability using organic scintillators (stilbene crystals and EJ-309 liquid scintillators), which do not provide direct, high-resolution, source spectroscopic information. Compared to the EJ-309 detector, the stilbene-based detector exhibits a lower identification error, on average, owing to its better energy resolution. Organic scintillators are used within radiation portal monitors to detect gamma rays emitted from conveyances crossing ports of entry. The described method is therefore applicable to radiation portal monitors deployed in the field and could improve their threat discrimination capability by minimizing "nuisance" alarms produced either by NORM-bearing materials found in shipped cargoes, such as ceramics and fertilizers, or radionuclides in recently treated nuclear medicine patients.

A deep learning architecture for metabolic pathway prediction.

MOTIVATION: Understanding the mechanisms and structural mappings between molecules and pathway classes are critical for design of reaction predictors for synthesizing new molecules. This article studies the problem of prediction of classes of metabolic pathways (series of chemical reactions occurring within a cell) in which a given biochemical compound participates. We apply a hybrid machine learning approach consisting of graph convolutional networks used to extract molecular shape features as input to a random forest classifier. In contrast to previously applied machine learning methods for this problem, our framework automatically extracts relevant shape features directly from input SMILES representations, which are atom-bond specifications of chemical structures composing the molecules. RESULTS: Our method is capable of correctly predicting the respective metabolic pathway class of 95.16% of tested compounds, whereas competing methods only achieve an accuracy of 84.92% or less. Furthermore, our framework extends to the task of classification of compounds having mixed membership in multiple pathway classes. Our prediction accuracy for this multi-label task is 97.61%. We analyze the relative importance of various global physicochemical features to the pathway class prediction problem and show that simple linear/logistic regression models can predict the values of these global features from the shape features extracted using our framework. AVAILABILITY AND IMPLEMENTATION: https://github.com/baranwa2/MetabolicPathwayPrediction. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Geometric Estimation of Multivariate Dependency.

This paper proposes a geometric estimator of dependency between a pair of multivariate random variables. The proposed estimator of dependency is based on a randomly permuted geometric graph (the minimal spanning tree) over the two multivariate samples. This estimator converges to a quantity that we call the geometric mutual information (GMI), which is equivalent to the Henze-Penrose divergence. between the joint distribution of the multivariate samples and the product of the marginals. The GMI has many of the same properties as standard MI but can be estimated from empirical data without density estimation; making it scalable to large datasets. The proposed empirical estimator of GMI is simple to implement, involving the construction of an minimal spanning tree (MST) spanning over both the original data and a randomly permuted version of this data. We establish asymptotic convergence of the estimator and convergence rates of the bias and variance for smooth multivariate density functions belonging to a Hölder class. We demonstrate the advantages of our proposed geometric dependency estimator in a series of experiments.

Quantum-inspired computational imaging.

Computational imaging combines measurement and computational methods with the aim of forming images even when the measurement conditions are weak, few in number, or highly indirect. The recent surge in quantum-inspired imaging sensors, together with a new wave of algorithms allowing on-chip, scalable and robust data processing, has induced an increase of activity with notable results in the domain of low-light flux imaging and sensing. We provide an overview of the major challenges encountered in low-illumination (e.g., ultrafast) imaging and how these problems have recently been addressed for imaging applications in extreme conditions. These methods provide examples of the future imaging solutions to be developed, for which the best results are expected to arise from an efficient codesign of the sensors and data analysis tools.

Joint camera blur and pose estimation from aliased data.

A joint-estimation algorithm is presented that enables simultaneous camera blur and pose estimation from a known calibration target in the presence of aliasing. Specifically, a parametric maximum-likelihood (ML) point-spread function estimate is derived for characterizing a camera's optical imperfections through the use of a calibration target in an otherwise loosely controlled environment. The imaging perspective, ambient-light levels, target reflectance, detector gain and offset, quantum efficiency, and read-noise levels are all treated as nuisance parameters. The Cramér-Rao bound is derived, and simulations demonstrate that the proposed estimator achieves near optimal mean squared error performance. The proposed method is applied to experimental data to validate the fidelity of the forward models as well as to establish the utility of the resulting ML estimates for both system identification and subsequent image restoration.

Ensemble Estimation of Information Divergence †.

Recent work has focused on the problem of nonparametric estimation of information divergence functionals between two continuous random variables. Many existing approaches require either restrictive assumptions about the density support set or difficult calculations at the support set boundary which must be known a priori. The mean squared error (MSE) convergence rate of a leave-one-out kernel density plug-in divergence functional estimator for general bounded density support sets is derived where knowledge of the support boundary, and therefore, the boundary correction is not required. The theory of optimally weighted ensemble estimation is generalized to derive a divergence estimator that achieves the parametric rate when the densities are sufficiently smooth. Guidelines for the tuning parameter selection and the asymptotic distribution of this estimator are provided. Based on the theory, an empirical estimator of Rényi-α divergence is proposed that greatly outperforms the standard kernel density plug-in estimator in terms of mean squared error, especially in high dimensions. The estimator is shown to be robust to the choice of tuning parameters. We show extensive simulation results that verify the theoretical results of our paper. Finally, we apply the proposed estimator to estimate the bounds on the Bayes error rate of a cell classification problem.

Multi-Functional Sensing for Swarm Robots Using Time Sequence Classification: HoverBot, an Example.

Scaling up robot swarms to collectives of hundreds or even thousands without sacrificing sensing, processing, and locomotion capabilities is a challenging problem. Low-cost robots are potentially scalable, but the majority of existing systems have limited capabilities, and these limitations substantially constrain the type of experiments that could be performed by robotics researchers. Instead of adding functionality by adding more components and therefore increasing the cost, we demonstrate how low-cost hardware can be used beyond its standard functionality. We systematically review 15 swarm robotic systems and analyse their sensing capabilities by applying a general sensor model from the sensing and measurement community. This work is based on the HoverBot system. A HoverBot is a levitating circuit board that manoeuvres by pulling itself towards magnetic anchors that are embedded into the robot arena. We show that HoverBot's magnetic field readouts from its Hall-effect sensor can be associated to successful movement, robot rotation and collision measurands. We build a time series classifier based on these magnetic field readouts. We modify and apply signal processing techniques to enable the online classification of the time-variant magnetic field measurements on HoverBot's low-cost microcontroller. We enabled HoverBot with successful movement, rotation, and collision sensing capabilities by utilising its single Hall-effect sensor. We discuss how our classification method could be applied to other sensors to increase a robot's functionality while retaining its cost.

Nasopharyngeal Protein Biomarkers of Acute Respiratory Virus Infection.

Infection of respiratory mucosa with viral pathogens triggers complex immunologic events in the affected host. We sought to characterize this response through proteomic analysis of nasopharyngeal lavage in human subjects experimentally challenged with influenza A/H3N2 or human rhinovirus, and to develop targeted assays measuring peptides involved in this host response allowing classification of acute respiratory virus infection. Unbiased proteomic discovery analysis identified 3285 peptides corresponding to 438 unique proteins, and revealed that infection with H3N2 induces significant alterations in protein expression. These include proteins involved in acute inflammatory response, innate immune response, and the complement cascade. These data provide insights into the nature of the biological response to viral infection of the upper respiratory tract, and the proteins that are dysregulated by viral infection form the basis of signature that accurately classifies the infected state. Verification of this signature using targeted mass spectrometry in independent cohorts of subjects challenged with influenza or rhinovirus demonstrates that it performs with high accuracy (0.8623 AUROC, 75% TPR, 97.46% TNR). With further development as a clinical diagnostic, this signature may have utility in rapid screening for emerging infections, avoidance of inappropriate antibacterial therapy, and more rapid implementation of appropriate therapeutic and public health strategies.

THE INTRINSIC VALUE OF HFO FEATURES AS A BIOMARKER OF EPILEPTIC ACTIVITY.

High frequency oscillations (HFOs) are a promising biomarker of epileptic brain tissue and activity. HFOs additionally serve as a prototypical example of challenges in the analysis of discrete events in high-temporal resolution, intracranial EEG data. Two primary challenges are 1) dimensionality reduction, and 2) assessing feasibility of classification. Dimensionality reduction assumes that the data lie on a manifold with dimension less than that of the features space. However, previous HFO analysis have assumed a linear manifold, global across time, space (i.e. recording electrode/channel), and individual patients. Instead, we assess both a) whether linear methods are appropriate and b) the consistency of the manifold across time, space, and patients. We also estimate bounds on the Bayes classification error to quantify the distinction between two classes of HFOs (those occurring during seizures and those occurring due to other processes). This analysis provides the foundation for future clinical use of HFO features and guides the analysis for other discrete events, such as individual action potentials or multi-unit activity.

Spectral identification of topological domains.

MOTIVATION: Topological domains have been proposed as the backbone of interphase chromosome structure. They are regions of high local contact frequency separated by sharp boundaries. Genes within a domain often have correlated transcription. In this paper, we present a computational efficient spectral algorithm to identify topological domains from chromosome conformation data (Hi-C data). We consider the genome as a weighted graph with vertices defined by loci on a chromosome and the edge weights given by interaction frequency between two loci. Laplacian-based graph segmentation is then applied iteratively to obtain the domains at the given compactness level. Comparison with algorithms in the literature shows the advantage of the proposed strategy. RESULTS: An efficient algorithm is presented to identify topological domains from the Hi-C matrix. AVAILABILITY AND IMPLEMENTATION: The Matlab source code and illustrative examples are available at http://bionetworks.ccmb.med.umich.edu/ CONTACT: : indikar@med.umich.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Foundational Principles for Large-Scale Inference: Illustrations Through Correlation Mining.

When can reliable inference be drawn in fue "Big Data" context? This paper presents a framework for answering this fundamental question in the context of correlation mining, wifu implications for general large scale inference. In large scale data applications like genomics, connectomics, and eco-informatics fue dataset is often variable-rich but sample-starved: a regime where the number n of acquired samples (statistical replicates) is far fewer than fue number p of observed variables (genes, neurons, voxels, or chemical constituents). Much of recent work has focused on understanding the computational complexity of proposed methods for "Big Data". Sample complexity however has received relatively less attention, especially in the setting when the sample size n is fixed, and the dimension p grows without bound. To address fuis gap, we develop a unified statistical framework that explicitly quantifies the sample complexity of various inferential tasks. Sampling regimes can be divided into several categories: 1) the classical asymptotic regime where fue variable dimension is fixed and fue sample size goes to infinity; 2) the mixed asymptotic regime where both variable dimension and sample size go to infinity at comparable rates; 3) the purely high dimensional asymptotic regime where the variable dimension goes to infinity and the sample size is fixed. Each regime has its niche but only the latter regime applies to exa cale data dimension. We illustrate this high dimensional framework for the problem of correlation mining, where it is the matrix of pairwise and partial correlations among the variables fua t are of interest. Correlation mining arises in numerous applications and subsumes the regression context as a special case. we demonstrate various regimes of correlation mining based on the unifying perspective of high dimensional learning rates and sample complexity for different structured covariance models and different inference tasks.

A Genomic Signature of Influenza Infection Shows Potential for Presymptomatic Detection, Guiding Early Therapy, and Monitoring Clinical Responses.

Early, presymptomatic intervention with oseltamivir (corresponding to the onset of a published host-based genomic signature of influenza infection) resulted in decreased overall influenza symptoms (aggregate symptom scores of 23.5 vs 46.3), more rapid resolution of clinical disease (20 hours earlier), reduced viral shedding (total median tissue culture infectious dose [TCID50] 7.4 vs 9.7), and significantly reduced expression of several inflammatory cytokines (interferon-γ, tumor necrosis factor-α, interleukin-6, and others). The host genomic response to influenza infection is robust and may provide the means for early detection, more timely therapeutic interventions, a meaningful reduction in clinical disease, and an effective molecular means to track response to therapy.

Empirically Estimable Classification Bounds Based on a Nonparametric Divergence Measure.

Information divergence functions play a critical role in statistics and information theory. In this paper we show that a non-parametric f-divergence measure can be used to provide improved bounds on the minimum binary classification probability of error for the case when the training and test data are drawn from the same distribution and for the case where there exists some mismatch between training and test distributions. We confirm the theoretical results by designing feature selection algorithms using the criteria from these bounds and by evaluating the algorithms on a series of pathological speech classification tasks.

An individualized predictor of health and disease using paired reference and target samples.

BACKGROUND: Consider the problem of designing a panel of complex biomarkers to predict a patient's health or disease state when one can pair his or her current test sample, called a target sample, with the patient's previously acquired healthy sample, called a reference sample. As contrasted to a population averaged reference this reference sample is individualized. Automated predictor algorithms that compare and contrast the paired samples to each other could result in a new generation of test panels that compare to a person's healthy reference to enhance predictive accuracy. This paper develops such an individualized predictor and illustrates the added value of including the healthy reference for design of predictive gene expression panels. RESULTS: The objective is to predict each subject's state of infection, e.g., neither exposed nor infected, exposed but not infected, pre-acute phase of infection, acute phase of infection, post-acute phase of infection. Using gene microarray data collected in a large scale serially sampled respiratory virus challenge study we quantify the diagnostic advantage of pairing a person's baseline reference with his or her target sample. The full study consists of 2886 microarray chips assaying 12,023 genes of 151 human volunteer subjects under 4 different inoculation regimes (HRV, RSV, H1N1, H3N2). We train (with cross-validation) reference-aided sparse multi-class classifier algorithms on this data to show that inclusion of a subject's reference sample can improve prediction accuracy by as much as 14 %, for the H3N2 cohort, and by at least 6 %, for the H1N1 cohort. Remarkably, these gains in accuracy are achieved by using smaller panels of genes, e.g., 39 % fewer for H3N2 and 31 % fewer for H1N1. The biomarkers selected by the predictors fall into two categories: 1) contrasting genes that tend to differentially express between target and reference samples over the population; 2) reinforcement genes that remain constant over the two samples, which function as housekeeping normalization genes. Many of these genes are common to all 4 viruses and their roles in the predictor elucidate the function that they play in differentiating the different states of host immune response. CONCLUSIONS: If one uses a suitable mathematical prediction algorithm, inclusion of a healthy reference in biomarker diagnostic testing can potentially improve accuracy of disease prediction with fewer biomarkers.