Data analysis techniques in phosphoproteomics.

The interpretation of phosphoproteomics data sets is crucial for generating hypotheses that guide therapeutic solutions, yet not many techniques have been applied to this type of analysis. This paper intends to give an overview about the two main standard techniques that can be applied to the analysis of these large scale data sets. These are data-driven or exploratory techniques based on a statistical model and topology-driven methods that analyze the signaling network from a dynamical standpoint. While employing different paradigms, these algorithms will detect unique "fingerprints" by revealing the intricate interactions at the proteome level and will support the experimental environment for novel therapeutics for many diseases.

Controllability and Robustness of Functional and Structural Connectomic Networks in Glioma Patients.

Previous studies suggest that the topological properties of structural and functional neural networks in glioma patients are altered beyond the tumor location. These alterations are due to the dynamic interactions with large-scale neural circuits. Understanding and describing these interactions may be an important step towards deciphering glioma disease evolution. In this study, we analyze structural and functional brain networks in terms of determining the correlation between network robustness and topological features regarding the default-mode network (DMN), comparing prognostically differing patient groups to healthy controls. We determine the driver nodes of these networks, which are receptive to outside signals, and the critical nodes as the most important elements for controllability since their removal will dramatically affect network controllability. Our results suggest that network controllability and robustness of the DMN is decreased in glioma patients. We found losses of driver and critical nodes in patients, especially in the prognostically less favorable IDH wildtype (IDHwt) patients, which might reflect lesion-induced network disintegration. On the other hand, topological shifts of driver and critical nodes, and even increases in the number of critical nodes, were observed mainly in IDH mutated (IDHmut) patients, which might relate to varying degrees of network plasticity accompanying the chronic disease course in some of the patients, depending on tumor growth dynamics. We hereby implement a novel approach for further exploring disease evolution in brain cancer under the aspects of neural network controllability and robustness in glioma patients.

Structural Target Controllability of Brain Networks in Dementia.

Controlling the dynamics of large-scale neural circuits might play an important role in aberrant cognitive functioning as found in Alzheimer's disease (AD). Analyzing the disease trajectory changes is of critical relevance when we want to get an understanding of the neurodegenerative disease evolution. Advanced control theory offers a multitude of techniques and concepts that can be easily translated into the dynamic processes governing disease evolution at the patient level, treatment response evaluation and revealing some central mechanisms in brain connectomic networks that drive alterations in these diseases. Two types of controllability - the modal and average controllability - have been applied in brain research to provide the mechanistic explanation of how the brain operates in different cognitive states. In this paper, we apply the concept of target controllability to structural (MRI) connectivity graphs for control (CN), mild cognitive impairment (MCI) and Alzheimer's disease (AD) subjects. In target controllability, only a subset of the network states are steered towards a desired objective. We show the graph-theoretic necessary and sufficient conditions for the structural target controllability of the above-mentioned brain networks and demonstrate that only local topological information is needed for its verification. Certain areas of the brain and corresponding to nodes in the brain network graphs can act as drivers and move the system (brain) into specific states of action. We select first the drivers that ensures the controllability of these networks and since they do not represent the smallest set, we employ the concept of structural target controllability to determine those nodes that can steer a collection of states being representative for the transitions between CN, MCI and AD networks. Our results applied on structural brain networks in dementia suggest that this novel technique can accurately describe the different node roles in controlling trajectories of brain networks and being relevant for disease evolution.

A theta-scheme approximation of basic reproduction number for an age-structured epidemic system in a finite horizon.

This paper focuses on numerical approximation of the basic reproduction number R0, which is the threshold defined by the spectral radius of the next-generation operator in epidemiology. Generally speaking, R0 cannot be explicitly calculated for most age-structured epidemic systems. In this paper, for a deterministic age-structured epidemic system and its stochastic version, we discretize a linear operator produced by the infective population with a theta scheme in a finite horizon, which transforms the abstract problem into the problem of solving the positive dominant eigenvalue of the next-generation matrix. This leads to a corresponding threshold R0,n . Using the spectral approximation theory, we obtain that R0,n → R0 as n → +∞. Some numerical simulations are provided to certify the theoretical results.

Impact of Machine Learning With Multiparametric Magnetic Resonance Imaging of the Breast for Early Prediction of Response to Neoadjuvant Chemotherapy and Survival Outcomes in Breast Cancer Patients.

PURPOSE: The aim of this study was to assess the potential of machine learning with multiparametric magnetic resonance imaging (mpMRI) for the early prediction of pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) and of survival outcomes in breast cancer patients. MATERIALS AND METHODS: This institutional review board-approved prospective study included 38 women (median age, 46.5 years; range, 25-70 years) with breast cancer who were scheduled for NAC and underwent mpMRI of the breast at 3 T with dynamic contrast-enhanced (DCE), diffusion-weighted imaging (DWI), and T2-weighted imaging before and after 2 cycles of NAC. For each lesion, 23 features were extracted: qualitative T2-weighted and DCE-MRI features according to BI-RADS (Breast Imaging Reporting and Data System), quantitative pharmacokinetic DCE features (mean plasma flow, volume distribution, mean transit time), and DWI apparent diffusion coefficient (ADC) values. To apply machine learning to mpMRI, 8 classifiers including linear support vector machine, linear discriminant analysis, logistic regression, random forests, stochastic gradient descent, decision tree, adaptive boosting, and extreme gradient boosting (XGBoost) were used to rank the features. Histopathologic residual cancer burden (RCB) class (with RCB 0 being a pCR), recurrence-free survival (RFS), and disease-specific survival (DSS) were used as the standards of reference. Classification accuracy with area under the receiving operating characteristic curve (AUC) was assessed using all the extracted qualitative and quantitative features for pCR as defined by RCB class, RFS, and DSS using recursive feature elimination. To overcome overfitting, 4-fold cross-validation was used. RESULTS: Machine learning with mpMRI achieved stable performance as shown by mean classification accuracies for the prediction of RCB class (AUC, 0.86) and DSS (AUC, 0.92) based on XGBoost and the prediction of RFS (AUC, 0.83) with logistic regression. The XGBoost classifier achieved the most stable performance with high accuracies compared with other classifiers. The most relevant features for the prediction of RCB class were as follows: changes in lesion size, complete pattern of shrinkage, and mean transit time on DCE-MRI; minimum ADC on DWI; and peritumoral edema on T2-weighted imaging. The most relevant features for prediction of RFS were as follows: volume distribution, mean plasma flow, and mean transit time; DCE-MRI lesion size; minimum, maximum, and mean ADC with DWI. The most relevant features for prediction of DSS were as follows: lesion size, volume distribution, and mean plasma flow on DCE-MRI, and maximum ADC with DWI. CONCLUSIONS: Machine learning with mpMRI of the breast enables early prediction of pCR to NAC as well as survival outcomes in breast cancer patients with high accuracy and thus may provide valuable predictive information to guide treatment decisions.

Classification of small contrast enhancing breast lesions in dynamic magnetic resonance imaging using a combination of morphological criteria and dynamic analysis based on unsupervised vector-quantization.

PURPOSE: To evaluate the diagnostic value of breast magnetic resonance imaging (MRI) in small focal lesions using dynamic analysis based on unsupervised vector quantization in combination with a score for morphologic criteria. MATERIALS AND METHODS: We examined 85 mammographically indetermintate lesions (BIRADS 3-4; 47 malignant, mean lesion size 1.2 cm; 38 benign, mean lesion size 1.1 cm). MRI was performed with a dynamic T1-weighted gradient echo sequence (1 precontrast and 5 postcontrast series). Lesions with an initial contrast enhancement >/=50% were selected with semiautomatic segmentation. For conventional dynamic analysis, we calculated the mean initial signal increase and postinitial course of all voxels included in a lesion. Secondly, all voxels within the lesions were assigned to 4 clusters using minimal-free-energy vector quantization. Dynamic and morphologic criteria were summarized in a diagnostic score and evaluated by receiver operating characteristic analysis. RESULTS: In the present collection of small lesions, morphologic criteria [area under the curve (AUC) = 0.610] were inferior to dynamic criteria in the detection of breast cancer. Dynamic analysis with vector quantization (AUC = 0.760) presented slightly better results compared with standard dynamic analysis (AUC = 0.693). There was no benefit for combined morphologic and dynamic analysis. CONCLUSION: In small MR-mammographic lesions, dynamic analysis with vector quantization alone tends to result in a higher diagnostic accuracy compared with combined morphologic and dynamic analysis.

Model-Free Visualization of Suspicious Lesions in Breast MRI Based on Supervised and Unsupervised Learning.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has become an important tool in breast cancer diagnosis, but evaluation of multitemporal 3D image data holds new challenges for human observers. To aid the image analysis process, we apply supervised and unsupervised pattern recognition techniques for computing enhanced visualizations of suspicious lesions in breast MRI data. These techniques represent an important component of future sophisticated computer-aided diagnosis (CAD) systems and support the visual exploration of spatial and temporal features of DCE-MRI data stemming from patients with confirmed lesion diagnosis. By taking into account the heterogeneity of cancerous tissue, these techniques reveal signals with malignant, benign and normal kinetics. They also provide a regional subclassification of pathological breast tissue, which is the basis for pseudo-color presentations of the image data. Intelligent medical systems are expected to have substantial implications in healthcare politics by contributing to the diagnosis of indeterminate breast lesions by non-invasive imaging.

Multi-stage optimization of a deep model: A case study on ground motion modeling.

In this study, a multi-stage optimization procedure is proposed to develop deep neural network models which results in a powerful deep learning pipeline called intelligent deep learning (iDeepLe). The proposed pipeline is then evaluated by a challenging real-world problem, the modeling of the spectral acceleration experienced by a particle during earthquakes. This approach has three main stages to optimize the deep model topology, the hyper-parameters, and its performance, respectively. This pipeline optimizes the deep model via adaptive learning rate optimization algorithms for both accuracy and complexity in multiple stages, while simultaneously solving the unknown parameters of the regression model. Among the seven adaptive learning rate optimization algorithms, Nadam optimization algorithm has shown the best performance results in the current study. The proposed approach is shown to be a suitable tool to generate solid models for this complex real-world system. The results also show that the parallel pipeline of iDeepLe has the capacity to handle big data problems as well.

Automated Detection and Segmentation of Nonmass-Enhancing Breast Tumors with Dynamic Contrast-Enhanced Magnetic Resonance Imaging.

Nonmass-enhancing (NME) lesions constitute a diagnostic challenge in dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of the breast. Computer-aided diagnosis (CAD) systems provide physicians with advanced tools for analysis, assessment, and evaluation that have a significant impact on the diagnostic performance. Here, we propose a new approach to address the challenge of NME lesion detection and segmentation, taking advantage of independent component analysis (ICA) to extract data-driven dynamic lesion characterizations. A set of independent sources was obtained from the DCE-MRI dataset of breast cancer patients, and the dynamic behavior of the different tissues was described by multiple dynamic curves, together with a set of eigenimages describing the scores for each voxel. A new test image is projected onto the independent source space using the unmixing matrix, and each voxel is classified by a support vector machine (SVM) that has already been trained with manually delineated data. A solution to the high false-positive rate problem is proposed by controlling the SVM hyperplane location, outperforming previously published approaches.

Independent Component Analysis-Support Vector Machine-Based Computer-Aided Diagnosis System for Alzheimer's with Visual Support.

Computer-aided diagnosis (CAD) systems constitute a powerful tool for early diagnosis of Alzheimer's disease (AD), but limitations on interpretability and performance exist. In this work, a fully automatic CAD system based on supervised learning methods is proposed to be applied on segmented brain magnetic resonance imaging (MRI) from Alzheimer's disease neuroimaging initiative (ADNI) participants for automatic classification. The proposed CAD system possesses two relevant characteristics: optimal performance and visual support for decision making. The CAD is built in two stages: a first feature extraction based on independent component analysis (ICA) on class mean images and, secondly, a support vector machine (SVM) training and classification. The obtained features for classification offer a full graphical representation of the images, giving an understandable logic in the CAD output, that can increase confidence in the CAD support. The proposed method yields classification results up to 89% of accuracy (with 92% of sensitivity and 86% of specificity) for normal controls (NC) and AD patients, 79% of accuracy (with 82% of sensitivity and 76% of specificity) for NC and mild cognitive impairment (MCI), and 85% of accuracy (with 85% of sensitivity and 86% of specificity) for MCI and AD patients.

Fully automated biomedical image segmentation by self-organized model adaptation.

In this paper, we present a fully automated image segmentation method based on an algorithm that provides adaptive plasticity in function approximation problems: the deformable (feature) map (DM) algorithm. The DM approach reduces a class of similar function approximation problems to the explicit supervised one-shot training of a single data set. This is followed by a subsequent, appropriate similarity transformation, which is based on a self-organized deformation of the underlying multidimensional probability distributions. We apply this algorithm to the real-world problem of fully automated voxel-based multispectral image segmentation, employing magnetic resonance data sets of the human brain. In contrast to previous segmentation approaches, the knowledge obtained within the segmentation procedure of a single prototypical reference data set can be re-utilized for the segmentation of new, 'similar' data employing a strategy of incremental adaptive learning based on the DM algorithm. Thus, we obtain a fully automatic segmentation method that does neither require manual contour tracing of training regions, visual classification of voxel clusters, nor any other kind of human intervention. Our application demonstrates that flexible learning by a strategy of self-organized incremental model adaptation can contribute to increase the efficiency and practicability of biomedical image processing systems.

Integrative biological analysis for neuropsychopharmacology.

Although advances in psychotherapy have been made in recent years, drug discovery for brain diseases such as schizophrenia and mood disorders has stagnated. The need for new biomarkers and validated therapeutic targets in the field of neuropsychopharmacology is widely unmet. The brain is the most complex part of human anatomy from the standpoint of number and types of cells, their interconnections, and circuitry. To better meet patient needs, improved methods to approach brain studies by understanding functional networks that interact with the genome are being developed. The integrated biological approaches--proteomics, transcriptomics, metabolomics, and glycomics--have a strong record in several areas of biomedicine, including neurochemistry and neuro-oncology. Published applications of an integrated approach to projects of neurological, psychiatric, and pharmacological natures are still few but show promise to provide deep biological knowledge derived from cells, animal models, and clinical materials. Future studies that yield insights based on integrated analyses promise to deliver new therapeutic targets and biomarkers for personalized medicine.

The extended TILAR approach: a novel tool for dynamic modeling of the transcription factor network regulating the adaption to in vitro cultivation of murine hepatocytes.

BACKGROUND: Network inference is an important tool to reveal the underlying interactions of biological systems. In the liver, a complex system of transcription factors is active to distribute signals and induce the cellular response following extracellular stimuli. Plenty of information is available about single transcription factors important for the different functions of the liver, but little is known about their causal relations to each other. RESULTS: Given a DNA microarray time series dataset of collagen monolayers cultured murine hepatocytes, we identified 22 differentially expressed genes for which the corresponding protein is known to exhibit transcription factor activity. We developed the Extended TILAR (ExTILAR) network inference algorithm based on the modeling concept of the previously published TILAR algorithm. Using ExTILAR, we inferred a transcription factor network based on gene expression data which puts these important genes into a functional context. This way, we identified a previously unknown relationship between Tgif1 and Atf3 which we validated experimentally. Beside its known role in metabolic processes, this extends the knowledge about Tgif1 in hepatocytes towards a possible influence of processes such as proliferation and cell cycle. Moreover, two positive (i.e. double negative) regulatory loops were predicted that could give rise to bistable behavior. We further evaluated the performance of ExTILAR by systematic inference of an in silico network. CONCLUSIONS: We present the ExTILAR algorithm, which combines the advantages of the regression based inference algorithm TILAR, like large network sizes processable and low computational costs, with the advantages of dynamic network models based on ordinary differential equation (i.e. in silico knock-down simulations). Like TILAR, ExTILAR makes use of various prior-knowledge types such as transcription factor binding site information and gene interaction knowledge to infer biologically meaningful gene regulatory networks. Therefore, ExTILAR is especially useful when a large number of genes is modeled using a small number of experimental data points.

On the application of (topographic) independent and tree-dependent component analysis for the examination of DCE-MRI data.

In this contribution we investigate the applicability of different methods from the field of independent component analysis (ICA) for the examination of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data from breast cancer research. DCE-MRI has evolved in recent years as a powerful complement to X-ray based mammography for breast cancer diagnosis and monitoring. In DCE-MRI the time related development of the signal intensity after the administration of a contrast agent can provide valuable information about tissue states and characteristics. To this end, techniques related to ICA, offer promising options for data integration and feature extraction at voxel level. In order to evaluate the applicability of ICA, topographic ICA and tree-dependent component analysis (TCA), these methods are applied to twelve clinical cases from breast cancer research with a histopathologically confirmed diagnosis. For ICA these experiments are complemented by a reliability analysis of the estimated components. The outcome of all algorithms is quantitatively evaluated by means of receiver operating characteristics (ROC) statistics whereas the results for specific data sets are discussed exemplarily in terms of reification, score-plots and score images.

Global stability analysis and robust design of multi-time-scale biological networks under parametric uncertainties.

Biological networks are prone to internal parametric fluctuations and external noises. Robustness represents a crucial property of these networks, which militates the effects of internal fluctuations and external noises. In this paper biological networks are formulated as coupled nonlinear differential systems operating at different time-scales under vanishing perturbations. In contrast to previous work viewing biological parametric uncertain systems as perturbations to a known nominal linear system, the perturbed biological system is modeled as nonlinear perturbations to a known nonlinear idealized system and is represented by two time-scales (subsystems). In addition, conditions for the existence of a global uniform attractor of the perturbed biological system are presented. By using an appropriate Lyapunov function for the coupled system, a maximal upper bound for the fast time-scale associated with the fast state is derived. The proposed robust system design principles are potentially applicable to robust biosynthetic network design. Finally, two examples of two important biological networks, a neural network and a gene regulatory network, are presented to illustrate the applicability of the developed theoretical framework.