Accurately and preoperatively predicting survival for high-grade gliomas (HGGs) is important for optimizing treatment strategies. Increasing evidence suggests that brain structural and functional connectivity networks derived from advanced magnetic resonance imaging (MRI) are promising predictors for HGG survival. However, advanced MRIs (e.g., diffusion MRI and functional MRI) are generally clinically inaccessible for HGG patients before initiating therapy. To compensate for lack of advanced MRI modalities in brain network studies, in this paper we evaluate the feasibility and performance of predicting HGG survival using exclusively preoperative multi-modal basic structural MRI (sMRI, e.g., T1- and T2-weighted MRI) based brain regional radiomics similarity networks (R2SNs). To this end, we propose a new cooperative multiplex graph neural network (GNN) based multi-modal R2SN integration framework for preoperative HGG survival prediction. First, multi-modal R2SNs are represented by a multiplex network, where each modality-specific R2SN forms one multiplex layer and nodes (i.e., brain regions of interest (ROIs)) are coupled to their replicas across multiplex layers. This facilitates flexible inter-ROI communications both within and between R2SNs. Second, a cooperative GNN is applied to capture intra-modal node feature propagations within each multiplex layer, followed by attention mechanisms used to capture inter-modal node feature interactions across multiplex layers. Finally, a tailored tumor-aware graph pooling is developed to assemble features from the tumor-intersecting ROIs for survival prediction. Extensive experiments on a collected HGG database with three basic sMRI modalities demonstrate the superiority of our method over state-of-the-art baselines in survival stratification. The code is available at https://github.com/ZiLaoTou/TCM-GNN.

Multimodal neuroimaging data modeling has become a widely used approach but confronts considerable challenges due to their heterogeneity, which encompasses variability in data types, scales, and formats across modalities. This variability necessitates the deployment of advanced computational methods to integrate and interpret diverse datasets within a cohesive analytical framework. In our research, we combine functional magnetic resonance imaging (fMRI), diffusion tensor imaging (DTI), and structural MRI (sMRI) for joint analysis. This integration capitalizes on the unique strengths of each modality and their inherent interconnections, aiming for a comprehensive understanding of the brain's connectivity and anatomical characteristics. Utilizing the Glasser atlas for parcellation, we integrate imaging-derived features from multiple modalities-functional connectivity from fMRI, structural connectivity from DTI, and anatomical features from sMRI-within consistent regions. Our approach incorporates a masking strategy to differentially weight neural connections, thereby facilitating an amalgamation of multimodal imaging data. This technique enhances interpretability at the connectivity level, transcending traditional analyses centered on singular regional attributes. The model is applied to the Human Connectome Project's Development study to elucidate the associations between multimodal imaging and cognitive functions throughout youth. The analysis demonstrates improved prediction accuracy and uncovers crucial anatomical features and neural connections, deepening our understanding of brain structure and function. This study not only advances multimodal neuroimaging analytics by offering a novel method for integrative analysis of diverse imaging modalities but also improves the understanding of intricate relationships between brain's structural and functional networks and cognitive development.

Resting-state functional magnetic resonance imaging (rs-fMRI) is a noninvasive technique pivotal for understanding human neural mechanisms of intricate cognitive processes. Most rs-fMRI studies compute a single static functional connectivity matrix across brain regions of interest, or dynamic functional connectivity matrices with a sliding window approach. These approaches are at risk of oversimplifying brain dynamics and lack proper consideration of the goal at hand. While deep learning has gained substantial popularity for modeling complex relational data, its application to uncovering the spatiotemporal dynamics of the brain is still limited. In this study we propose a novel interpretable deep learning framework that learns goal-specific functional connectivity matrix directly from time series and employs a specialized graph neural network for the final classification. Our model, DSAM , leverages temporal causal convolutional networks to capture the temporal dynamics in both low- and high-level feature representations, a temporal attention unit to identify important time points, a self-attention unit to construct the goal-specific connectivity matrix, and a novel variant of graph neural network to capture the spatial dynamics for downstream classification. To validate our approach, we conducted experiments on the Human Connectome Project dataset with 1075 samples to build and interpret the model for the classification of sex group, and the Adolescent Brain Cognitive Development Dataset with 8520 samples for independent testing. Compared our proposed framework with other state-of-art models, results suggested this novel approach goes beyond the assumption of a fixed connectivity matrix, and provides evidence of goal-specific brain connectivity patterns, which opens up potential to gain deeper insights into how the human brain adapts its functional connectivity specific to the task at hand. Our implementation can be found on https://github.com/bishalth01/DSAM . • Multilevel Temporal Feature Extraction: • Utilizes a novel multilevel Temporal Convolutional Network (TCN) adaptation to directly extract temporal features from raw brain activity data. • Shared Temporal Attention for Key Time Points: • Implements shared temporal attention mechanisms to selectively focus on the most informative time points, enhancing model efficiency. • Node-Node Self-Attention for Dynamic Brain Connectivity: • Leverages self-attention mechanisms to dynamically construct a goal-specific brain connectivity matrix, capturing complex inter-node interactions. • ROI-Aware Graph Neural Networks (GNNs): • Introduces ROI-aware GNNs to model spatial brain dynamics, ensuring region-specific contextual learning and improving interpretability.

Time-series data such as fMRI and MEG carry a wealth of inherent spatio-temporal coupling relationship, and their modeling via deep learning is essential for uncovering biological mechanisms. However, current machine learning models for mining spatio-temporal information usually overlook this intrinsic coupling association, in addition to poor explainability. In this paper, we present an explainable learning framework for spatio-temporal coupling. Specifically, this framework constructs a deep learning network based on spatio-temporal correlation, which can well integrate the time-varying coupled relationships between node representation and inter-node connectivity. Furthermore, it explores spatio-temporal evolution at each time step, providing a better explainability of the analysis results. Finally, we apply the proposed framework to brain dynamic functional connectivity (dFC) analysis. Experimental results demonstrate that it can effectively capture the variations in dFC during brain development and the evolution of spatio-temporal information at the resting state. Two distinct developmental functional connectivity (FC) patterns are identified. Specifically, the connectivity among regions related to emotional regulation decreases, while the connectivity associated with cognitive activities increases. In addition, children and young adults display notable cyclic fluctuations in resting-state brain dFC.

Pediatric teeth exhibit significant changes in type and spatial distribution across different age groups. This variation makes pediatric teeth segmentation from cone-beam computed tomography (CBCT) more challenging than that in adult teeth. Existing methods mainly focus on adult teeth segmentation, which however cannot be adapted to spatial distribution of pediatric teeth with individual changes (SDPTIC) in different children, resulting in limited accuracy for segmenting pediatric teeth. Therefore, we introduce a novel topology structure-guided graph convolutional network (TSG-GCN) to generate dynamic graph representation of SDPTIC for improved pediatric teeth segmentation. Specifically, this network combines a 3D GCN-based decoder for teeth segmentation and a 2D decoder for dynamic adjacency matrix learning (DAML) to capture SDPTIC information for individual graph representation. 3D teeth labels are transformed into specially-designed 2D projection labels, which is accomplished by first decoupling 3D teeth labels into class-wise volumes for different teeth via one-hot encoding and then projecting them to generate instance-wise 2D projections. With such 2D labels, DAML can be trained to adaptively describe SDPTIC from CBCT with dynamic adjacency matrix, which is then incorporated into GCN for improving segmentation. To ensure inter-task consistency at the adjacency matrix level between the two decoders, a novel loss function is designed. It can address the issue with inconsistent prediction and unstable TSG-GCN convergence due to two heterogeneous decoders. The TSG-GCN approach is finally validated with both public and multi-center datasets. Experimental results demonstrate its effectiveness for pediatric teeth segmentation, with significant improvement over seven state-of-the-art methods.

Patients with glioblastoma (GBM) have a poor survival rate. In order to facilitate early interventions and personalized therapeutic treatment, there is a pressing need for employing routine non-invasive MRI for preoperative GBM survival prediction. In this paper, we investigate to what extent regional radiomics similarity networks (R2SNs) can be used to predict overall survival (OS) time in GBM. Different from the widely used MRI-derived radiomics features that focus on single or several brain regions independently, the R2SNs can take into account the potential associations among brain regions with radiomics similarity for improved survival prediction. Specifically, we first introduce a distance correlation based R2SN (DC-R2SN), where distance correlation (instead of Pearson’s correlation in the traditional R2SN) is adopted to measure the more complex interactions between a pair of brain regions defined by the corresponding radiomics features. A graph neural network (GNN) framework is then proposed for fusing DCR2SNs and clinical data to predict OS time of GBM patients. Experimental results on the publicly available UPenn-GBM database demonstrate the effectiveness of our proposed GNN based survival prediction framework with the DC-R2SNs.

Recently, functional connectivity network (FCN) analysis via graph convolutional networks (GCNs) has greatly boosted diagnostic performance of brain diseases on a population graph for subject classification. However, most existing methods only focus on FCNs based on a single brain atlas (ignoring complementary information among multiatlas-based FCNs), and the population graph structure is preconstructed and fixed during the GCN training (not truly reflecting the relation between subjects). In this paper, we propose an adaptive multiview community-preserved graph convolutional network (CP-GCN) method to accommodate multiatlas-based FCNs. Specifically, we first introduce a multiview FCN fusion module to obtain multiatlas FCN embeddings via concatenating both intra- and inter-atlas embeddings that are extracted separately from fully connected layers. We then develop a multihead similarity learning module to adaptively learn the population graph structure, best serving GCN for node classification. Finally, under the learned graph structure, a CP-GCN based node classification module is applied for subject classification through designing a community-preserved constraint on the GCN. Experimental results on the ABIDE validate the effectiveness of our method for autism identification, and our findings related to autism can be easily traced back with biological interpretability.

Graph convolutional deep learning has emerged as a promising method to explore the functional organization of the human brain in neuroscience research. This paper presents a novel framework that utilizes the gated graph transformer (GGT) model to predict individuals' cognitive ability based on functional connectivity (FC) derived from fMRI. Our framework incorporates prior spatial knowledge and uses a random-walk diffusion strategy that captures the intricate structural and functional relationships between different brain regions. Specifically, our approach employs learnable structural and positional encodings (LSPE) in conjunction with a gating mechanism to efficiently disentangle the learning of positional encoding (PE) and graph embeddings. Additionally, we utilize the attention mechanism to derive multi-view node feature embeddings and dynamically distribute propagation weights between each node and its neighbors, which facilitates the identification of significant biomarkers from functional brain networks and thus enhances the interpretability of the findings. To evaluate our proposed model in cognitive ability prediction, we conduct experiments on two large-scale brain imaging datasets: the Philadelphia Neurodevelopmental Cohort (PNC) and the Human Connectome Project (HCP). The results show that our approach not only outperforms existing methods in prediction accuracy but also provides superior explainability, which can be used to identify important FCs underlying cognitive behaviors.

The imaging genetics approach generates large amount of high dimensional and multi-modal data, providing complementary information for comprehensive study of Schizophrenia, a complex mental disease. However, at the same time, the variety of these data in structures, resolutions, and formats makes their integrative study a forbidding task. In this paper, we propose a novel model called Joint Sparse Collaborative Regression (JSCoReg), which can extract class-specific features from different health conditions/disease classes. We first evaluate the performance of feature selection in terms of Receiver operating characteristic curve and the area under the ROC curve in the simulation experiment. We demonstrate that the JSCoReg model can achieve higher accuracy compared with similar models including Joint Sparse Canonical Correlation Analysis and Sparse Collaborative Regression. We then applied the JSCoReg model to the analysis of schizophrenia dataset collected from the Mind Clinical Imaging Consortium. The JSCoReg enables us to better identify biomarkers associated with schizophrenia, which are verified to be both biologically and statistically significant.

Magnetic resonance imagings (MRIs) are providing increased access to neuropsychiatric disorders that can be made available for advanced data analysis. However, the single type of data limits the ability of psychiatrists to distinguish the subclasses of this disease. In this paper, we propose an ensemble hybrid features selection method for the neuropsychiatric disorder classification. The method consists of a 3D DenseNet and a XGBoost, which are used to select the image features from structural MRI images and the phenotypic feature from phenotypic records, respectively. The hybrid feature is composed of image features and phenotypic features. The proposed method is validated in the Consortium for Neuropsychiatric Phenomics (CNP) dataset, where samples are classified into one of the four classes (healthy controls (HC), attention deficit hyperactivity disorder (ADHD), bipolar disorder (BD), and schizophrenia (SD)). Experimental results show that the hybrid feature can improve the performance of classification methods. The best accuracy of binary and multi-class classification can reach 91.22 and 78.62 percent, respectively. We analyze the importance of phenotypic features and image features in different classification tasks. The importance of the structure MRI images is highlighted by incorporating phenotypic features with image features to generate hybrid features. We also visualize the features of three neuropsychiatric disorders and analyze their locations in the brain region.

With the development of multi-model neuroimaging technology and gene detection technology, the efforts of integrating multi-model imaging genetics data to explore the virulence factors of schizophrenia (SZ) are still limited. To address this issue, we propose a novel algorithm called group sparse of joint non-negative matrix factorization on orthogonal subspace (GJNMFO). Our algorithm fuses single nucleotide polymorphism (SNP) data, function magnetic resonance imaging (fMRI) data and epigenetic factors (DNA methylation) by projecting three-model data into a common basis matrix and three different coefficient matrices to identify risk genes, epigenetic factors and abnormal brain regions associated with SZ. Specifically, we introduce orthogonal constraints on the basis matrix to discard unimportant features in the row of coefficient matrices. Since imaging genetics data have rich group information, we draw into group sparse on three coefficient matrices to make the extracted features more accurate. Both the simulated and real Mind Clinical Imaging Consortium (MCIC) datasets are performed to validate our approach. Simulation results show that our algorithm works better than other competing methods. Through the experiments of MCIC datasets, GJNMFO reveals a set of risk genes, epigenetic factors and abnormal brain functional regions, which have been verified to be both statistically and biologically significant.

Total anomalous pulmonary venous connection (TAPVC) is a rare but mortal congenital heart disease in children and can be repaired by surgical operations. However, some patients may suffer from pulmonary venous obstruction (PVO) after surgery with insufficient blood supply, necessitating special follow-up strategy and treatment. Therefore, it is a clinically important yet challenging problem to predict such patients before surgery. In this paper, we address this issue and propose a computational framework to determine the risk factors for postoperative PVO (PPVO) from computed tomography angiography (CTA) images and build the PPVO risk prediction model. From clinical experiences, such risk factors are likely from the left atrium (LA) and pulmonary vein (PV) of the patient. Thus, 3D models of LA and PV are first reconstructed from low-dose CTA images. Then, a feature pool is built by computing different morphological features from 3D models of LA and PV, and the coupling spatial features of LA and PV. Finally, four risk factors are identified from the feature pool using the machine learning techniques, followed by a risk prediction model. As a result, not only PPVO patients can be effectively predicted but also qualitative risk factors reported in the literature can now be quantified. Finally, the risk prediction model is evaluated on two independent clinical datasets from two hospitals. The model can achieve the AUC values of 0.88 and 0.87 respectively, demonstrating its effectiveness in risk prediction.

Tucker decomposition can provide an intuitive summary to understand brain function by decomposing multi-subject fMRI data into a core tensor and multiple factor matrices, and was mostly used to extract functional connectivity patterns across time/subjects using orthogonality constraints. However, these algorithms are unsuitable for extracting common spatial and temporal patterns across subjects due to distinct characteristics such as high-level noise. Motivated by a successful application of Tucker decomposition to image denoising and the intrinsic sparsity of spatial activations in fMRI, we propose a low-rank Tucker-2 model with spatial sparsity constraint to analyze multi-subject fMRI data. More precisely, we propose to impose a sparsity constraint on spatial maps by using an$ \ell _{p} $norm (${0}< {p}\le {1}$), in addition to adding low-rank constraints on factor matrices via the Frobenius norm. We solve the constrained Tucker-2 model using alternating direction method of multipliers, and propose to update both sparsity and low-rank constrained spatial maps using half quadratic splitting. Moreover, we extract new spatial and temporal features in addition to subject-specific intensities from the core tensor, and use these features to classify multiple subjects. The results from both simulated and experimental fMRI data verify the improvement of the proposed method, compared with four related algorithms including robust Kronecker component analysis, Tucker decomposition with orthogonality constraints, canonical polyadic decomposition, and block term decomposition in extracting common spatial and temporal components across subjects. The spatial and temporal features extracted from the core tensor show promise for characterizing subjects within the same group of patients or healthy controls as well.

Recent studies show that multi-modal data fusion techniques combine information from diverse sources for comprehensive diagnosis and prognosis of complex brain disorder, often resulting in improved accuracy compared to single-modality approaches. However, many existing data fusion methods extract features from homogeneous networs, ignoring heterogeneous structural information among multiple modalities. To this end, we propose a Hypergraph-based Multi-modal data Fusion algorithm, namely HMF. Specifically, we first generate a hypergraph similarity matrix to represent the high-order relationships among subjects, and then enforce the regularization term based upon both the inter- and intra-modality relationships of the subjects. Finally, we apply HMF to integrate imaging and genetics datasets. Validation of the proposed method is performed on both synthetic data and real samples from schizophrenia study. Results show that our algorithm outperforms several competing methods, and reveals significant interactions among risk genes, environmental factors and abnormal brain regions.

The reliability of functional network connectivity (FNC) measured using independent component analysis (ICA) has frequently been explored within the literature, with results displaying varying levels of reliability and demonstrating that minor changes in data preprocessing procedures can significantly alter FC results and reliability. However, one important avenue of research that has not been explored within the current literature is the effect of spatial normalization techniques on FNC reliability. Spatially constrained independent component analysis techniques such as multi-objective optimization with reference (MOO-ICAR) is one of many methods used to study brain functional connectivity (FC) using fMRI that is theoretically robust to variations which may arise in data as a result of normalization procedures. In this work, we deploy MOO-ICAR across 30 different spatial normalization pipelines varying across participant template, normalization modality (anatomical vs functional), and one vs. two-stage warps to MNI space. Most components display relatively high consistency intraclass-correlation coefficients (ICCs), with the vast majoritv (~80%) ereater than 0.5.

Recent advances in imaging genetics make it possible to combine different types of data including medical images like functional magnetic resonance imaging (fMRI) and genetic data like single nucleotide polymorphisms (SNPs) for comprehensive diagnosis of mental disorders. Understanding complex interactions among these heterogeneous data may give rise to a new perspective, while at the same time demand statistical models for their integration. Various graphical models have been proposed for the study of interaction or association networks with continuous, binary, and count data as well as the mixture of them. However, limited efforts have been made for the multinomial case, for instance, SNP data. Our goal is therefore to fill the void by developing a graphical model for the integration of fMRI image and SNP data, which can provide deeper understanding of the unknown neurogenetic mechanism. In this article, we propose a latent Gaussian copula model for mixed data containing multinomial components. We assume that the discrete variable is obtained by discretizing a latent (unobserved) continuous variable and then create a semi-rank based estimator of the graph structure. The simulation results demonstrate that the proposed latent correlation has more steady and accurate performance than several existing methods in detecting graph structure. When applying to a real schizophrenia data consisting of SNP array and fMRI image collected by the Mind Clinical Imaging Consortium (MCIC), the proposed method reveals a set of distinct SNP-brain associations, which are verified to be biologically significant. The proposed model is statistically promising in handling mixed types of data including multinomial components, which can find widespread applications. To promote reproducible research, the R code is available at https://github.com/Aiying0512/LGCM.

Functional magnetic resonance imaging (fMRI) is a powerful technique with the potential to estimate individual variations in behavioral and cognitive traits. Joint learning of multiple datasets can utilize their complementary information so as to improve learning performance, but it also gives rise to the challenge for data fusion to effectively integrate brain patterns elicited by multiple fMRI data. However, most of the current data fusion methods analyze each single dataset separately and further infer the relationship among them, which fail to utilize the multidimensional structure inherent across modalities and may ignore complex but important interactions. To address this issue, we propose a novel sparse tensor decomposition method to integrate multiple task-stimulus (paradigm) fMRI data. Seeing each paradigm fMRI as one modality, our proposed method considers the relationships across subjects and modalities simultaneously. In specific, a third-order tensor is first modeled by using the functional network connectivity (FNC) of subjects in multiple fMRI paradigms. A novel sparse tensor decomposition with the regularization terms is designed to factorize the tensor into a series of rank-one components, which can extract the shared components across modalities as the embedded features. The L2,1-norm regularizer (i.e., group sparsity) is enforced to select a few common features among multiple subjects. Validation of the proposed method is performed on realistic three paradigm fMRI datasets from the Philadelphia Neurodevelopmental Cohort (PNC) study, for the study of the relationship between the FNC and human cognitive abilities. Experimental results show our method outperforms several other competing methods in the prediction of individuals with different cognitive behaviors via the wide range achievement test (WRAT). Furthermore, our method discovers the FNC related to the cognitive behaviors, such as the connectivity associated with the default mode network (DMN) for three paradigms, and the connectivity between DMN and visual (VIS) domains within the emotion task.

With the development of neuroimaging techniques, a growing amount of multi-modal brain imaging data are collected, facilitating comprehensive study of the brain. In this paper, we jointly analyzed functional magnetic resonance imaging (fMRI) collected under different paradigms in order to understand cognitive behaviors of an individual. To this end, we proposed a novel multi-view learning algorithm called structure-enforced collaborative regression (SCoRe) to extract co-expressed discriminative brain regions under the guidance of anatomical structure of the brain. An advantage of SCoRe over its predecessor collaborative regression (CoRe) lies in its incorporation of group structures in the brain imaging data, which makes the model biologically more meaningful. Results from real data analysis has confirmed that by incorporating prior knowledge of brain structure, SCoRe can deliver better prediction performance and is less sensitive to hyper-parameters than CoRe. After validation with simulation experiments, we applied SCoRe to fMRI data collected from the Philadelphia Neurodevelopmental Cohort and adopted the scores from the wide range achievement test (WRAT) to evaluate an individual's cognitive skills. We located 14 relevant brain regions that can efficiently predict WRAT scores and these brain regions were further confirmed by other independent studies.

The combination of multimodal imaging and genomics provides a more comprehensive way for the study of mental illnesses and brain functions. Deep network-based data fusion models have been developed to capture their complex associations, resulting in improved diagnosis of diseases. However, deep learning models are often difficult to interpret, bringing about challenges for uncovering biological mechanisms using these models. In this work, we develop an interpretable multimodal fusion model to perform automated diagnosis and result interpretation simultaneously. We name it Grad-CAM guided convolutional collaborative learning (gCAM-CCL), which is achieved by combining intermediate feature maps with gradient-based weights. The gCAM-CCL model can generate interpretable activation maps to quantify pixel-level contributions of the input features. Moreover, the estimated activation maps are class-specific, which can therefore facilitate the identification of biomarkers underlying different groups. We validate the gCAM-CCL model on a brain imaging-genetic study, and demonstrate its applications to both the classification of cognitive function groups and the discovery of underlying biological mechanisms. Specifically, our analysis results suggest that during task-fMRI scans, several object recognition related regions of interests (ROIs) are activated followed by several downstream encoding ROIs. In addition, the high cognitive group may have stronger neurotransmission signaling while the low cognitive group may have problems in brain/neuron development due to genetic variations.

Schizophrenia (SZ) is a complex disease. Single nucleotide polymorphism (SNP), brain activity measured by functional magnetic resonance imaging (fMRI) and DNA methylation are all important biomarkers that can be used for the study of SZ. To our knowledge, there has been little effort to combine these three datasets together. In this study, we propose a group sparse joint nonnegative matrix factorization (GSJNMF) model to integrate SNP, fMRI, and DNA methylation for the identification of multi-dimensional modules associated with SZ, which can be used to study regulatory mechanisms underlying SZ at multiple levels. The proposed GSJNMF model projects multiple types of data onto a common feature space, in which heterogeneous variables with large coefficients on the same projected bases are used to identify multi-dimensional modules. We also incorporate group structure information available from each dataset. The genomic factors in such modules have significant correlations or functional associations with several brain activities. At the end, we have applied the method to the analysis of real data collected from the Mind Clinical Imaging Consortium (MCIC) for the study of SZ and identified significant biomarkers. These biomarkers were further used to discover genes and corresponding brain regions, which were confirmed to be significantly associated with SZ.

The study of healthy brain development helps to better understand both brain transformation and connectivity patterns, which happen during childhood to adulthood. This study presents a sparse machine learning solution across whole-brain functional connectivity measures of three datasets, derived from resting state functional magnetic resonance imaging (rs-fMRI) and two task fMRI data including a working memory n-back task (nb-fMRI) and an emotion identification task (em-fMRI). The fMRI data are collected from the Philadelphia Neurodevelopmental Cohort (PNC) for the prediction of brain age in adolescents. Due to extremely large variable-to-instance ratio of PNC data, a high-dimensional matrix with several irrelevant and highly correlated features is generated, and hence a sparse learning approach is necessary to extract effective features from fMRI data. We propose a sparse learner based on the residual errors along the estimation of an inverse problem for extreme learning machine (ELM). Our proposed method is able to overcome the overlearning problem by pruning several redundant features and their corresponding output weights. The proposed multimodal sparse ELM classifier based on residual errors is highly competitive in terms of classification accuracy compared to its counterparts such as conventional ELM, and sparse Bayesian learning ELM.

The context-based convolutional neural network (CNN) is one of the most well-known CNNs to improve the performance of semantic segmentation. It has achieved remarkable success in various medical image segmentation tasks. However, extracting rich and useful context information from complex and changeable medical images is a challenge for medical image segmentation. In this study, a novel Multi-Receptive-Field CNN (MRFNet) is proposed to tackle this challenge. MRFNet offers the optimal receptive field for each subnet in the encoder-decoder module (EDM) and generates multi-receptive-field context information at the feature map level. Moreover, MRFNet fuses these multi-feature maps by the concatenation operation. MRFNet is evaluated on 3 public medical image data sets, including SISS, 3DIRCADb, and SPES. Experimental results show that MRFNet achieves the outstanding performance on all 3 data sets, and outperforms other segmentation methods on 3DIRCADb test set without pre-training the model.

Current developments of neuroimaging and genetics promote an integrative and compressive study of schizophrenia. However, it is still difficult to explore how gene mutations are related to brain abnormalities due to the high dimension but low sample size of these data. Conventional approaches reduce the dimension of dataset separately and then calculate the correlation, but ignore the effects of the response variables and the structure of data. To improve the identification of risk genes and abnormal brain regions on schizophrenia, in this paper, we propose a novel method called Independence and Structural sparsity Canonical Correlation Analysis (ISCCA). ISCCA combines independent component analysis (ICA) and Canonical Correlation Analysis (CCA) to reduce the collinear effects, which also incorporate graph structure of the data into the model to improve the accuracy of feature selection. The results from simulation studies demonstrate its higher accuracy in discovering correlations compared with other competing methods. Moreover, applying ISCCA to a real imaging genetics dataset collected by Mind Clinical Imaging Consortium (MCIC), a set of distinct gene-ROI interactions are identified, which are verified to be both statistically and biologically significant.

With the rapid development of high-throughput technologies, a growing amount of multi-omics data are collected, giving rise to a great demand for combining such data for biomedical discovery. Due to the cost and time to label the data manually, the number of labelled samples is limited. This motivated the need for semi-supervised learning algorithms. In this work, we applied a graph-based semi-supervised learning (GSSL) to classify a severe chronic mental disorder, schizophrenia (SZ). An advantage of GSSL is that it can simultaneously analyse more than two types of data, while many existing models focus on pairwise data analysis. In particular, we applied GSSL to the analysis of single nucleotide polymorphism (SNP), functional magnetic resonance imaging (fMRI) and DNA methylation data, which accounts for genetics, brain imaging (endophenotypes), and environmental factors (epigenomics) respectively. While parameter selection has been an open challenge for most models, another key contribution of this work is that we explored the parameter space to interpret their meaning and established practical guidelines. Based on the practical significance of each hyper-parameter, a relatively small range of candidate values can be determined in a data-driven way to both optimize and speed up the parameter tuning process. We validated the model through both synthetic data and a real SZ dataset of 184 subjects from the Mental Illness and Neuroscience Discovery (MIND) Clinical Imaging Consortium. In comparison to several existing approaches, our algorithm achieved better performance in terms of classification accuracy. We also confirmed the significance of several brain regions associated with SZ.

Human brain development is a complex and dynamic process caused by several factors such as genetics, sex hormones, and environmental changes. A number of recent studies on brain development have examined functional connectivity (FC) defined by the temporal correlation between time series of different brain regions. We propose to add the directional flow of information during brain maturation. To do so, we extract effective connectivity (EC) through Granger causality (GC) for two different groups of subjects, i.e., children and young adults. The motivation is that the inclusion of causal interaction may further discriminate brain connections between two age groups and help to discover new connections between brain regions. The contributions of this study are threefold. First, there has been a lack of attention to EC-based feature extraction in the context of brain development. To this end, we propose a new kernel-based GC (KGC) method to learn nonlinearity of complex brain network, where a reduced Sine hyperbolic polynomial (RSP) neural network was used as our proposed learner. Second, we used causality values as the weight for the directional connectivity between brain regions. Our findings indicated that the strength of connections was significantly higher in young adults relative to children. In addition, our new EC-based feature outperformed FC-based analysis from Philadelphia neurocohort (PNC) study with better discrimination of different age groups. Moreover, the fusion of these two sets of features (FC + EC) improved brain age prediction accuracy by more than 4%, indicating that they should be used together for brain development studies.

Canonical polyadic decomposition (CPD) of multi-subject complex-valued fMRI data can be used to provide spatially and temporally shared components among groups with both magnitude and phase information. However, the CPD model is not well formulated due to the large subject variability in the spatial and temporal modalities, as well as the high noise level in complexvalued fMRI data. Considering that the shift-invariant CPD can model temporal variability across subjects, we propose to further impose a phase sparsity constraint on the shared spatial maps to denoise the complex-valued components and to model the inter-subject spatial variability as well. More precisely, subject-specific time delays are first estimated for the complex-valued shared time courses in the framework of real-valued shift-invariant CPD. Source phase sparsity is then imposed on the complex-valued shared spatial maps. A smoothed ℓ0norm is specifically used to reduce voxels with large phase values after phase de-ambiguity based on the small phase characteristic of BOLD-related voxels. The results from both the simulated and experimental fMRI data demonstrate improvements of the proposed method over three complex-valued algorithms, namely, tensor-based spatial ICA, shift-invariant CPD and CPD without spatiotemporal constraints. When comparing with a real-valued algorithm combining shiftinvariant CPD and ICA, the proposed method detects 178.7% more contiguous task-related activations.

Recently, a hypergraph constructed from functional magnetic resonance imaging (fMRI) was utilized to explore brain functional connectivity networks (FCNs) for the classification of neurodegenerative diseases. Each edge of a hypergraph (called hyperedge) can connect any number of brain regions-of-interest (ROIs) instead of only two ROIs, and thus characterizes high-order relations among multiple ROIs that cannot be uncovered by a simple graph in the traditional graph based FCN construction methods. Unlike the existing hypergraph based methods where all hyperedges are assumed to have equal weights and only certain topological features are extracted from the hypergraphs, we propose a hypergraph learning based method for FCN construction in this paper. Specifically, we first generate hyperedges from fMRI time series based on sparse representation, then employ hypergraph learning to adaptively learn hyperedge weights, and finally define a hypergraph similarity matrix to represent the FCN. In our proposed method, weighting hyperedges results in better discriminative FCNs across subjects, and the defined hypergraph similarity matrix can better reveal the overall structure of brain network than using those hypergraph topological features. Moreover, we propose a multi-hypergraph learning based method by integrating multi-paradigm fMRI data, where the hyperedge weights associated with each fMRI paradigm are jointly learned and then a unified hypergraph similarity matrix is computed to represent the FCN. We validate the effectiveness of the proposed method on the Philadelphia Neurodevelopmental Cohort dataset for the classification of individuals' learning ability from three paradigms of fMRI data. Experimental results demonstrate that our proposed approach outperforms the traditional graph based methods (i.e., Pearson's correlation and partial correlation with the graphical Lasso) and the existing unweighted hypergraph based methods, which sheds light on how to optimize estimation of FCNs for cognitive and behavioral study.

Adolescence is a transitional period between the childhood and adulthood with physical changes, as well as increasing emotional development. Studies have shown that the emotional sensitivity is related to a second period of rapid brain growth. However, there is little focus on the trend of brain development during this period. In this paper, we aim to track functional brain connectivity development from late childhood to young adulthood. Mathematically, this problem can be modeled via the estimation of multiple Gaussian graphical models (GGMs). However, most existing methods either require the graph sequence to be fairly long or are only applicable to small graphs. In this paper, we adapted a Bayesian approach incorporating joint estimation of multiple GGMs to overcome the short sequence difficulty, which is also computationally efficient. The data used are the functional magnetic resonance imaging (fMRI) images obtained from the publicly available Philadelphia Neurodevelopmental Cohort (PNC). They include 855 individuals aged 8-22 years who were divided into five different adolescent stages. We summarized the networks with global measurements and applied a hypothesis test across age groups to detect the developmental patterns. Three patterns were detected and defined as consistent development, late puberty, and temporal change. We also discovered several anatomical areas, such as the middle frontal gyrus, putamen gyrus, right lingual gyrus, and right cerebellum crus 2 that are highly involved in the brain functional development. The functional networks, including the salience, subcortical, and auditory networks are significantly developing during the adolescent period.

Estimating dynamic functional network connectivity (dFNC) of the brain from functional magnetic resonance imaging (fMRI) data can reveal both spatial and temporal organization and can be applied to track the developmental trajectory of brain maturity as well as to study mental illness. Resting state fMRI (rs-fMRI) is regarded as a promising task since it reflects the spontaneous brain activity without an external stimulus. The sliding window method has been successfully used to extract dFNC but typically assumes a fixed window size. The hidden Markov model (HMM) based method is an alternative approach for estimating time-varying connectivity. In this paper, we propose a sparse HMM based on Gaussian HMM and Gaussian graphical model (GGM). In this model, the time-varying neural processes are represented as discrete brain states which are described with functional connectivity networks. By enforcing the sparsity on the precision matrix, we can get interpretable connectivity between different functional regions. The optimization of our model can be realized with the expectation maximization (EM) and graphical least absolute shrinkage and selection operator (glasso) algorithms. The proposed model is validated on both simulated blood oxygenation-level dependent (BOLD) time series and rs-fMRI data. Results indicate that the proposed model can capture both stationary and abrupt brain activity fluctuations. We also compare dFNC patterns between children and young adults from the Philadelphia Neurodevelopmental Cohort (PNC) study. Both spatial and temporal behavior of the dFNC are analyzed and compared. The results provide insight into the developmental trajectory across childhood and motivate further research on brain connectivity.

We propose a joint least squares and least absolute deviations (JOLESALAD) model, show that the proposed model can cover least absolute shrinkage and selection operator (LASSO) and two of its variants, namely the generalized LASSO (gLASSO) and the constrained LASSO (cLASSO), and prove that under a full rank condition, the JOLESALAD can be transformed into cLASSO. Based on this equivalency, rich tools currently available for LASSO models can be applied to solve gLASSO and cLASSO. As an example of illustration, we demonstrate an application of the proposed model to the restoration of a noisy ramp signal that needs proper use of penalty term.

Schizophrenia (SZ) is a chronic and severe mental disorder that affects how a person thinks, feels, and behaves. It has been proposed that this disorder is related to disrupted brain connectivity, which has been verified by many studies. With the development of functional magnetic resonance imaging (fMRI), further exploration of brain connectivity was made possible. Region-based networks are commonly used for mapping brain connectivity. However, they fail to illustrate the connectivity within regions of interest (ROIs) and lose precise location information. Voxel-based networks provide higher precision, but are difficult to construct and interpret due to the high dimensionality of the data. In this paper, we adopt a novel high-dimensional Gaussian graphical model - ψ-learning method, which can help ease computational burden and provide more accurate inference for the underlying networks. This method has been proven to be an equivalent measure of the partial correlation coefficient and, thus, is flexible for network comparison through statistical tests. The fMRI data we used were collected by the mind clinical imaging consortium using an auditory task in which there are 92 SZ patients and 116 healthy controls. We compared the networks at three different scales by using global measurements, community structure, and edge-wise comparisons within the networks. Our results reveal, at the highest voxel resolution, sets of distinct aberrant patterns for the SZ patients, and more precise local structures are provided within ROIs for further investigation.

Motivation: Extreme phenotype sampling (EPS) is a broadly-used design to identify candidate genetic factors contributing to the variation of quantitative traits. By enriching the signals in extreme phenotypic samples, EPS can boost the association power compared to random sampling. Most existing statistical methods for EPS examine the genetic factors individually, despite many quantitative traits have multiple genetic factors underlying their variation. It is desirable to model the joint effects of genetic factors, which may increase the power and identify novel quantitative trait loci under EPS. The joint analysis of genetic data in high-dimensional situations requires specialized techniques, e.g. the least absolute shrinkage and selection operator (LASSO). Although there are extensive research and application related to LASSO, the statistical inference and testing for the sparse model under EPS remain unknown. Results: We propose a novel sparse model (EPS-LASSO) with hypothesis test for high-dimensional regression under EPS based on a decorrelated score function. The comprehensive simulation shows EPS-LASSO outperforms existing methods with stable type I error and FDR control. EPS-LASSO can provide a consistent power for both low- and high-dimensional situations compared with the other methods dealing with high-dimensional situations. The power of EPS-LASSO is close to other low-dimensional methods when the causal effect sizes are small and is superior when the effects are large. Applying EPS-LASSO to a transcriptome-wide gene expression study for obesity reveals 10 significant body mass index associated genes. Our results indicate that EPS-LASSO is an effective method for EPS data analysis, which can account for correlated predictors. Availability and implementation: The source code is available at https://github.com/xu1912/EPSLASSO. Supplementary information: Supplementary data are available at Bioinformatics online.

It's increasingly important but difficult to determine potential biomarkers of schizophrenia (SCZ) disease, owing to the complex pathophysiology of this disease. In this study, a network-fusion based framework was proposed to identify genetic biomarkers of the SCZ disease. A three-step feature selection was applied to single nucleotide polymorphisms (SNPs), DNA methylation, and functional magnetic resonance imaging (fMRI) data to select important features, which were then used to construct two gene networks in different states for the SNPs and DNA methylation data, respectively. Two health networks (one is for SNP data and the other is for DNA methylation data) were combined into one health network from which health minimum spanning trees (MSTs) were extracted. Two disease networks also followed the same procedures. Those genes with significant changes were determined as SCZ biomarkers by comparing MSTs in two different states and they were finally validated from five aspects. The effectiveness of the proposed discovery framework was also demonstrated by comparing with other network-based discovery methods. In summary, our approach provides a general framework for discovering gene biomarkers of the complex diseases by integrating imaging genomic data, which can be applied to the diagnosis of the complex diseases in the future.

The method of Sorted L-One Penalized Estimation, or SLOPE, is a sparse regression method recently introduced by Bogdan et. al. [1] . It can be used to identify significant predictor variables in a linear model that may have more unknown parameters than observations. When the correlations between predictor variables are small, the SLOPE method is shown to successfully control the false discovery rate (the expected proportion of the irrelevant among all selected predictors) at a user specified level. However, the requirement for nearly uncorrelated predictors is too restrictive for genomic data, as demonstrated in our recent study [2] by an application of SLOPE to realistic simulated DNA sequence data. A possible solution is to divide the predictor variables into nearly uncorrelated groups, and to modify the procedure to select entire groups with an overall significant group effect, rather than individual predictors. Following this motivation, we extend SLOPE in the spirit of Group LASSO to Group SLOPE, a method that can handle group structures between the predictor variables, which are ubiquitous in real genomic data. Our theoretical results show that Group SLOPE controls the group-wise false discovery rate (gFDR), when groups are orthogonal to each other. For use in non-orthogonal settings, we propose two types of Monte Carlo based heuristics, which lead to gFDR control with Group SLOPE in simulations based on real SNP data. As an illustration of the merits of this method, an application of Group SLOPE to a dataset from the Framingham Heart Study results in the identification of some known DNA sequence regions associated with bone health, as well as some new candidate regions. The novel methods are implemented in the R package grpSLOPEMC , which is publicly available at https://github.com/agisga/grpSLOPEMC.

DNA methylation plays an important role in the development of various cancers mainly through the regulation on gene expression. Hence, the study on the relation between DNA methylation and gene expression is of particular interest to understand cancers. Recently, an increasing number of datasets are available from multiple cancers, which makes it possible to study both the similarity and difference of genomic alterations across multiple tumor types. However, most of the existing pan-cancer analysis methods perform simple aggregations, which may overlook the heterogeneity of the interactions. In this paper, we propose a novel method to jointly detect complex associations between DNA methylation and gene expression levels from multiple cancers. The main idea is to apply joint sparse canonical correlation analysis to detect a small set of methylated sites, which are associated with another set of genes either shared across cancers or specific to a particular group (group-specific) of cancers. These methylated sites and genes form a complex module with strong multivariate correlations. We further introduced a joint sparse precision matrix estimation method to identify driver methylation-gene pairs in the module. These pairs are characterized by significant partial correlations, which may imply high functional impacts and contribute to complementary information to the main step. We apply our method to The Cancer Genome Atlas(TCGA) datasets with 1166 samples from four cancers. The results reveal significant shared and groupspecific interactions between DNA methylation and gene expression levels. To promote reproducible research, the Matlab code is available at https://sites.google.com/site/jianfang86/jointTCGA.

Recent advances in imaging genetics produce large amounts of data including functional MRI images, single nucleotide polymorphisms (SNPs), and cognitive assessments. Understanding the complex interactions among these heterogeneous and complementary data has the potential to help with diagnosis and prevention of mental disorders. However, limited efforts have been made due to the high dimensionality, group structure, and mixed type of these data. In this paper we present a novel method to detect conditional associations between imaging genetics data. We use projected distance correlation to build a conditional dependency graph among high-dimensional mixed data, then use multiple testing to detect significant group level associations (e.g., ROI-gene). In addition, we introduce a scalable algorithm based on orthogonal greedy algorithm, yielding the greedy projected distance correlation (G-PDC). This can reduce the computational cost, which is critical for analyzing large-volume of imaging genomics data. The results from our simulations demonstrate a higher degree of accuracy with GPDC than distance correlation, Pearson's correlation and partial correlation, especially when the correlation is nonlinear. Finally, we apply our method to the Philadelphia Neurodevelopmental data cohort with 866 samples including fMRI images and SNP profiles. The results uncover several statistically significant and biologically interesting interactions, which are further validated with many existing studies. The Matlab code is available at https://sites.google.com/site/jianfang86/gPDC.

Functional connectivity (FC) estimated from functional magnetic resonance imaging (fMRI) time series, especially during resting state periods, provides a powerful tool to assess human brain functional architecture in health, disease, and developmental states. Recently, the focus of connectivity analysis has shifted toward the subnetworks of the brain, which reveals co-activating patterns over time. Most prior works produced a dense set of high-dimensional vectors, which are hard to interpret. In addition, their estimations to a large extent were based on an implicit assumption of spatial and temporal stationarity throughout the fMRI scanning session. In this paper, we propose an approach called dynamic sparse connectivity patterns (dSCPs), which takes advantage of both matrix factorization and time-varying fMRI time series to improve the estimation power of FC. The feasibility of analyzing dynamic FC with our model is first validated through simulated experiments. Then, we use our framework to measure the difference between young adults and children with real fMRI data set from the Philadelphia Neurodevelopmental Cohort (PNC). The results from the PNC data set showed significant FC differences between young adults and children in four different states. For instance, young adults had reduced connectivity between the default mode network and other subnetworks, as well as hyperconnectivity within the visual system in states 1 and 3, and hypoconnectivity in state 2. Meanwhile, they exhibited temporal correlation patterns that changed over time within functional subnetworks. In addition, the dSCPs model indicated that older people tend to spend more time within a relatively connected FC pattern. Overall, the proposed method provides a valid means to assess dynamic FC, which could facilitate the study of brain networks.

Reducing the number of false discoveries is presently one of the most pressing issues in the life sciences. It is of especially great importance for many applications in neuroimaging and genomics, where data sets are typically high-dimensional, which means that the number of explanatory variables exceeds the sample size. The false discovery rate (FDR) is a criterion that can be employed to address that issue. Thus it has gained great popularity as a tool for testing multiple hypotheses. Canonical correlation analysis (CCA) is a statistical technique that is used to make sense of the cross-correlation of two sets of measurements collected on the same set of samples (e.g., brain imaging and genomic data for the same mental illness patients), and sparse CCA extends the classical method to high-dimensional settings. Here, we propose a way of applying the FDR concept to sparse CCA, and a method to control the FDR. The proposed FDR correction directly influences the sparsity of the solution, adapting it to the unknown true sparsity level. Theoretical derivation as well as simulation studies show that our procedure indeed keeps the FDR of the canonical vectors below a user-specified target level. We apply the proposed method to an imaging genomics data set from the Philadelphia Neurodevelopmental Cohort. Our results link the brain connectivity profiles derived from brain activity during an emotion identification task, as measured by functional magnetic resonance imaging, to the corresponding subjects' genomic data.

In this paper, we consider the problem of estimating multiple sparse, co-activated brain regions from functional magnetic resonance imaging (fMRI) observations belonging to different classes. More precisely, we propose a method to analyze similarities and differences in functional connectivity between children and young adults. Often, analysis is conducted on each class separately, and differences across classes are identified with an additional postprocessing step using adequate statistical tools. Here, we propose to rely on a generalized fused Lasso penalty, which allows us to make use of the entire data set in order to estimate connectivity patterns that are either shared across classes, or specific to a given group. By using the entire population during the estimation, we hope to increase the power of our analysis. The proposed model falls in the category of population-wise matrix decomposition, and a simple and efficient alternating direction method of multipliers algorithm is introduced to solve the associated optimization problem. After validating our approach on simulated data, experiments are performed on resting-state fMRI imaging from the Philadelphia neurodevelopmental cohort data set, comprised of normally developing children from ages 8 to 21. Developmental differences were observed in various brain regions, as a total of three class-specific resting-state components were identified. Statistical analysis of the estimated subject-specific features, as well as classification results (based on age groups, up to 81% accuracy, samples) related to these components demonstrate that the proposed method is able to properly extract meaningful shared and class-specific sub-networks.

Among the challenges arising in brain imaging genetic studies, estimating the potential links between neurological and genetic variability within a population is key. In this paper, we propose a multivariate, multimodal formulation for variable selection that leverages co-expression patterns across various data modalities. Our approach is based on an intuitive combination of two widely used statistical models: sparse regression and canonical correlation analysis (CCA). While the former seeks multivariate linear relationships between a given phenotype and associated observations, the latter searches to extract co-expression patterns between sets of variables belonging to different modalities. In the following, we propose to rely on a "CCA-type" formulation in order to regularize the classical multimodal sparse regression problem (essentially incorporating both CCA and regression models within a unified formulation). The underlying motivation is to extract discriminative variables that are also co-expressed across modalities. We first show that the simplest formulation of such model can be expressed as a special case of collaborative learning methods. After discussing its limitation, we propose an extended, more flexible formulation, and introduce a simple and efficient alternating minimization algorithm to solve the associated optimization problem. We explore the parameter space and provide some guidelines regarding parameter selection. Both the original and extended versions are then compared on a simple toy data set and a more advanced simulated imaging genomics data set in order to illustrate the benefits of the latter. Finally, we validate the proposed formulation using single nucleotide polymorphisms data and functional magnetic resonance imaging data from a population of adolescents ( subjects, age 16.9 ± 1.9 years from the Philadelphia Neurodevelopmental Cohort) for the study of learning ability. Furthermore, we carry out a significance analysis of the resulting features that allow us to carefully extract brain regions and genes linked to learning and cognitive ability.

Schizophrenia (SZ) is a complex disease caused by a lot genetic variants, epigenetic and brain region abnormalities. In this study, we adopted a joint nonnegative matrix factorization method to integrate three datasets including single nucleotide polymorphism (SNP), brain activity measured by functional magnetic resonance imaging (fMRI) and DNA Methylation to identify multi-dimensional modules associated with SZ. They are then used to study the coordination between regulatory mechanisms at multiple levels. This method projects multiple types of data onto a common feature space, in which heterogeneous variables with large coefficients on the same projected bases form a multi-dimensional module. The genomic factors in such modules have significant correlations and likely functional associations with brain activities. We applied this method to the real data analysis and identified multi-dimensional modules including SNP, fMRI and DNA methylation sites. These selected biomarkers were finally used to identify genes and voxels, which were confirmed to be significantly associated with SZ.

Functional magnetic resonance imaging (fMRI) is a powerful tool to analyze brain development and neuronal activity. Identifying discriminative brain regions between various groups within a population has generated great interest in recent years. In this work, we consider the problem of estimating multiple sparse, co-activated brain regions from fMRI observations belonging to different classes. More precisely, we propose a method to analyze functional connectivity differences between children and young adults. Often, analysis is conducted on each class separately. Here, we propose to rely on a generalized fused Lasso penalty to extract both class-specific and shared co-expressed regions. In order to validate our method, experiments are performed on an fMRI dataset comprised of normally developing children from 8 to 21. The results demonstrate that the proposed method is able to properly extract meaningful sub-networks, which results in improved classification accuracy between the two classes.

BACKGROUND: With the advancement of high-throughput technologies and enrichment of popular public databases, more and more research focuses of bioinformatics research have been on computational integration of network and gene expression profiles for extracting context-dependent active subnetworks. Many methods for subnetwork searching have been developed. Scoring and searching algorithms present a range of computational considerations and implementations. The primary goal of present study is to comprehensively evaluate the performance of different subnetwork detection methods. Eleven popular methods were selected for comprehensive comparison. RESULTS: First, taking into account the dependence of genes given a protein-protein interaction (PPI) network, we simulated microarray gene expression data under case and control conditions. Then each method was applied to the simulated data for subnetwork identification. Second, a large microarray data set of prostate cancer was used to assess the practical performance of each method. Using both simulation studies and a real data application, we evaluated the performance of different methods in terms of recall and precision. CONCLUSIONS: jActiveModules, PinnacleZ and WMAXC performed well in identifying subnetwork with relative high precision and recall. BioNet performed very well only in precision. As none of methods outperformed other methods overall, users should choose an appropriate method based on the purposes of their studies.

In this study, in order to take advantage of complementary information from different types of data for better disease status diagnosis, we combined gene expression with DNA methylation data and generated a fused network, based on which the stages of Kidney Renal Cell Carcinoma (KIRC) can be better identified. It is well recognized that a network is important for investigating the connectivity of disease groups. We exploited the potential of the network's features to identify the KIRC stage. We first constructed a patient network from each type of data. We then built a fused network based on network fusion method. Based on the link weights of patients, we used a generalized linear model to predict the group of KIRC subjects. Finally, the group prediction method was applied to test the power of network-based features. The performance (e.g., the accuracy of identifying cancer stages) when using the fused network from two types of data is shown to be superior to that when using two patient networks from only one data type. The work provides a good example for using network based features from multiple data types for a more comprehensive diagnosis.

The 2D transfer function based on scalar value and gradient magnitude (SG-TF) is popularly used in volume rendering. However, it is plagued by the boundary-overlapping problem: different structures with similar attributes have the same region in SG-TF space, and their boundaries are usually connected. The SG-TF thus often fails in separating these structures (or their boundaries) and has limited ability to classify different objects in real-world 3D images. To overcome such a difficulty, we propose a novel method for boundary separation by integrating spatial connectivity computation of the boundaries and set operations on boundary voxels into the SG-TF. Specifically, spatial positions of boundaries and their regions in the SG-TF space are computed, from which boundaries can be well separated and volume rendered in different colors. In the method, the boundaries are divided into three classes and different boundary-separation techniques are applied to them, respectively. The complex task of separating various boundaries in 3D images is then simplified by breaking it into several small separation problems. The method shows good object classification ability in real-world 3D images while avoiding the complexity of high-dimensional transfer functions. Its effectiveness and validation is demonstrated by many experimental results to visualize boundaries of different structures in complex real-world 3D images.

In order to increase the accuracy for the diagnosis of schizophrenia (SCZ) disease, it is essential to integratively employ complementary information from multiple types of data. It is well known that a network is a graph based method for analyzing relationships between patients, with its nodes and edges representing patients and their relationships respectively. In this study, we developed a network-based prediction approach by taking advantage of fused network from multiple data types rather than individual networks. Specifically, we constructed a fused network using three types of data including genetic, epigenetic and neuroimaging data from the study of schizophrenia. The majority neighborhood of a node in the network was exploited for discriminating SCZ from healthy controls. In comparison with other 9 graph-based label prediction methods, our prediction method shows the best performance according to several metrics. The prediction power of our proposed method was also tested with different parameters and optimal parameters were determined. We show that the label prediction method based on network fusion from multiple data types shows promises for more accurate diagnosis of schizophrenia, which can also be extended to other disease models.

Schizophrenia (SCZ) disease ranks among the top 10 causes of disability in developed countries worldwide. Its onset is the combination result of genetic, biological and environmental factors. It is increasingly important but difficult to determine which genes are potential biomarkers for SCZ, owing to the complex nature of the pathophysiology of this disease. In our study, we integrated genomic, epigenomic and neuroimaging data to identify genetic biomarkers for schizophrenia. Important cross-correlated features were selected using multiple sparse canonical correlation analysis (smCCA) among single nucleotide polymorphism (SNP), DNA methylation and functional magnetic resonance imaging (fMRI) data. The features were then used to construct two state (health and case) gene-gene interaction networks for SNP or DNA methylation data. A network-based framework was proposed by comparing two different minimum spanning trees (MSTs), which were extracted from two fused state gene networks, respectively. We selected top 20 genes with significant changes of network features for schizophrenia. These genes were finally validated by disease association enrichment analysis, Gene Ontology (GO) enrichment analysis, pathway enrichment analysis and related literature reports. We also demonstrated the effectiveness of our framework through the comparison with other network-based discovery methods. Therefore, our proposed network-based approach can effectively discover biomarkers and resulting genes, promising better diagnosis and treatment of schizophrenia disease.

Kernel and Multiple Kernel Canonical Correlation Analysis (CCA) are employed to classify schizophrenic and healthy patients based on their SNPs, DNA Methylation and fMRI data. Kernel and Multiple Kernel CCA are popular methods for finding nonlinear correlations between high-dimensional datasets. Data was gathered from 183 patients, 79 with schizophrenia and 104 healthy controls. Kernel and Multiple Kernel CCA represent new avenues for studying schizophrenia, because, to our knowledge, these methods have not been used on these data before. Classification is performed via k nearest neighbors on the kernel matrix outputs of the Kernel and Multiple Kernel CCA algorithm. Accuracies of the Kernel and Multiple Kernel CCA classification are compared to that of the regularized linear CCA algorithm classification, and are found to be significantly more accurate. Both algorithms demonstrate maximal accuracies when the combination of DNA methylation and fMRI data are used, and experience lower accuracies when the SNP data are incorporated.

MOTIVATION: In searching for genetic variants for complex diseases with deep sequencing data, genomic marker sets of high-dimensional genotypic data and sparse functional variants are quite common. Existing sequence association tests are incapable of identifying such marker sets or individual causal loci, although they appeared powerful to identify small marker sets with dense functional variants. In sequence association studies of admixed individuals, cryptic relatedness and population structure are known to confound the association analyses. METHOD: We here propose a unified marker wise test (uFineMap) to accurately localize causal loci and a unified high-dimensional set based test (uHDSet) to identify high-dimensional sparse associations in deep sequencing genomic data of multi-ethnic individuals with random relatedness. These two novel tests are based on scaled sparse linear mixed regressions with Lp (0 < p < 1) norm regularization. They jointly adjust for cryptic relatedness, population structure and other confounders to prevent false discoveries and improve statistical power for identifying promising individual markers and marker sets that harbor functional genetic variants of a complex trait. RESULTS: With large scale simulation data and real data analyses, the proposed tests appropriately controlled Type I error rates and appeared to be more powerful than several prominent methods. We illustrated their practical utilities by the applications to DNA sequence data of Framingham Heart Study for osteoporosis. The proposed tests identified 11 novel significant genes that were missed by the prominent famSKAT and GEMMA. In particular, four out of six most significant pathways identified by the uHDSet but missed by famSKAT have been reported to be related to BMD or osteoporosis in the literature. AVAILABILITY AND IMPLEMENTATION: The computational toolkit is available for academic use: https://sites.google.com/site/shaolongscode/home/uhdset CONTACT: [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: Imaging genetics combines brain imaging and genetic information to identify the relationships between genetic variants and brain activities. When the data samples belong to different classes (e.g. disease status), the relationships may exhibit class-specific patterns that can be used to facilitate the understanding of a disease. Conventional approaches often perform separate analysis on each class and report the differences, but ignore important shared patterns. RESULTS: In this paper, we develop a multivariate method to analyze the differential dependency across multiple classes. We propose a joint sparse canonical correlation analysis method, which uses a generalized fused lasso penalty to jointly estimate multiple pairs of canonical vectors with both shared and class-specific patterns. Using a data fusion approach, the method is able to detect differentially correlated modules effectively and efficiently. The results from simulation studies demonstrate its higher accuracy in discovering both common and differential canonical correlations compared to conventional sparse CCA. Using a schizophrenia dataset with 92 cases and 116 controls including a single nucleotide polymorphism (SNP) array and functional magnetic resonance imaging data, the proposed method reveals a set of distinct SNP-voxel interaction modules for the schizophrenia patients, which are verified to be both statistically and biologically significant. AVAILABILITY AND IMPLEMENTATION: The Matlab code is available at https://sites.google.com/site/jianfang86/JSCCA CONTACT: [email protected] information: Supplementary data are available at Bioinformatics online.

BACKGROUND: Integrative analysis of multi-omics data is becoming increasingly important to unravel functional mechanisms of complex diseases. However, the currently available multi-omics datasets inevitably suffer from missing values due to technical limitations and various constrains in experiments. These missing values severely hinder integrative analysis of multi-omics data. Current imputation methods mainly focus on using single omics data while ignoring biological interconnections and information imbedded in multi-omics data sets. RESULTS: In this study, a novel multi-omics imputation method was proposed to integrate multiple correlated omics datasets for improving the imputation accuracy. Our method was designed to: 1) combine the estimates of missing value from individual omics data itself as well as from other omics, and 2) simultaneously impute multiple missing omics datasets by an iterative algorithm. We compared our method with five imputation methods using single omics data at different noise levels, sample sizes and data missing rates. The results demonstrated the advantage and efficiency of our method, consistently in terms of the imputation error and the recovery of mRNA-miRNA network structure. CONCLUSIONS: We concluded that our proposed imputation method can utilize more biological information to minimize the imputation error and thus can improve the performance of downstream analysis such as genetic regulatory network construction.

Multicolor Fluorescence In-Situ Hybridization (M-FISH) is an imaging technique for rapid detection of chromosomal abnormalities, where the segmentation of chromosomes has been a challenge. Multi-channel information of M-FISH images can be used in a segmentation algorithm to exploit the correlated information across channels for better image segmentation. In addition, the neighboring pixels share similar characteristics, so this spatial information can be further utilized to improve the robustness of the algorithm to the noise. Motivated by this fact, in this paper we proposed an improved Fuzzy C-means (FCM) clustering algorithm to overcome the problems of conventional FCM such as the sensitivity to noise by incorporating both spatial and spectral information. The experimental results on both simulated and real M-FISH images have shown that our proposed method can result in higher segmentation accuracy and lower false ratio than both conventional FCM and the improved adaptive FCM (IAFCM) we recently proposed.

Schizophrenia is one of the most prevalent mental diseases, and is considered to be caused by the interplay of a number of genetic factors. In this paper, by constructing a multilayer restricted Boltzmann machines (RBMs) deep network, we use the genomic data (i.e., SNP data) for unsupervised feature learning and disease diagnosis of schizophrenia. In order to obtain some more accurate diagnosis results by RBMs, firstly, we transform the SNP data into binary sequences, and then by training the multi-layer RBMs deep network on unlabeled data, the multi-level abstract features of the genomic data are obtained and stored in the network. Finally, by adding a linear classifier to the top of the multi-layer RBMs deep network, the classification results on the testing data are gained. The results show that the average performance of this method is better than that of other methods, e.g., SVM (including linear SVM as well as SVM with multilayer perceptron kernel), sparse representations based classifier and k-nearest neighbors method. It is indicated that the multi-layer RBMs deep network can extract deep hierarchical representations of the genomic data, and then promises a more comprehensive approach for the mental disease diagnosis.

MOTIVATION: Fast and accurate genotype imputation is necessary for facilitating gene-mapping studies, especially with the ever increasing numbers of both common and rare variants generated by high-throughput-sequencing experiments. However, most of the existing imputation approaches suffer from either inaccurate results or heavy computational demand. RESULTS: In this article, aiming to perform fast and accurate genotype-imputation analysis, we propose a novel, fast and yet accurate method to impute diploid genotypes. Specifically, we extend a hidden Markov model that is widely used to describe haplotype structures. But we model hidden states onto single reference haplotypes rather than onto pairs of haplotypes. Consequently the computational complexity is linear to size of reference haplotypes. We further develop an algorithm 'merge-and-recover (MAR)' to speed up the calculation. Working on compact representation of segmental reference haplotypes, the MAR algorithm always calculates an exact form of transition probabilities regardless of partition of segments. Both simulation studies and real-data analyses demonstrated that our proposed method was comparable to most of the existing popular methods in terms of imputation accuracy, but was much more efficient in terms of computation. The MAR algorithm can further speed up the calculation by several folds without loss of accuracy. The proposed method will be useful in large-scale imputation studies with a large number of reference subjects. AVAILABILITY: The implemented multi-threading software FISH is freely available for academic use at https://sites.google.com/site/lzhanghomepage/FISH.

Bioinformatics (2014) 30 (13), 1876–1883 The author would like to note an affiliation correction. The first affiliation address was mistakenly stated as ‘School of Public Health, Xi'an Jiaotong University, Shaanxi, China’, while the correct one should be ‘Center for Genetic Epidemiology and Genomics, School of Public Health, Soochow University, Jiangsu, P. R. China’.

In this paper we propose a novel and easy to use 3D reconstruction method. With the method, users only need to specify a small boundary surface patch in a 2D section image, and then an entire continuous implicit boundary surface (CIBS) can be automatically reconstructed from a 3D image. In the method, a hierarchical tracing strategy is used to grow the known boundary surface patch gradually in the 3D image. An adaptive detection technique is applied to detect boundary surface patches from different local regions. The technique is based on both context dependence and adaptive contrast detection as in the human vision system. A recognition technique is used to distinguish true boundary surface patches from the false ones in different cubes. By integrating these different approaches, a high-resolution CIBS model can be automatically reconstructed by adaptively expanding the small boundary surface patch in the 3D image. The effectiveness of our method is demonstrated by its applications to a variety of real 3D images, where the CIBS with complex shapes/branches and with varying gray values/gradient magnitudes can be well reconstructed. Our method is easy to use, which provides a valuable tool for 3D image visualization and analysis as needed in many applications.

Exome sequencing provides us an effective way to discover genetic factors that might be associated with phenotypes for complex diseases. Compared with the whole-genome sequencing, exome sequencing can satisfy the high sequencing coverage requirement while under the limited budge constraint. However, due to the nature that exons are distributed sparsely along the genome, and the technical variability between samples, the analysis of exome sequencing data is complicated and direct utilization of current whole-genome sequencing targeted methods yields wrong results. In this paper, we propose a novel model to represent the exome sequencing data. Under this model, we show that the technical variability as well as random sequencing error follow the generalized Gaussian distribution. Based on this observation, we propose a method to detect the copy number variation. Studies on real data from 1000 Genomes Projects validate the proposed algorithm.

We developed a new sparse multivariate regression method, collaborative sparse reduced rank regression(C-sRRR) for detecting genetic networks associated with brain functional networks in schizophrenia (SZ). Our study: 1) introduced both genetic and brain network structure to group single nucleotide polymorphism (SNP) and voxels simultaneously for utilizing the interacting effects implied in both features; 2) used collaborative sparse group lasso to perform genetic variants selection and nuclear norm penalty to address the interrelationship among voxels; 3) developed an efficient algorithm for solving the non-smooth optimization. In real data analysis, we constructed 8605 genetic sub-networks (modules) from 722177 SNPs with a median module size of 9. A functional brain network was extracted which also showed significant discriminative characteristics between SZ and healthy controls. A sub sampling strategy was applied to identify 57 highly ranked genes from 14 high-ranking modules. 14 of them are SZ susceptibility genes and 6 genes were consistent with the findings in previous study.

BACKGROUND: Copy number variation (CNV) is an important structural variation (SV) in human genome. Various studies have shown that CNVs are associated with complex diseases. Traditional CNV detection methods such as fluorescence in situ hybridization (FISH) and array comparative genomic hybridization (aCGH) suffer from low resolution. The next generation sequencing (NGS) technique promises a higher resolution detection of CNVs and several methods were recently proposed for realizing such a promise. However, the performances of these methods are not robust under some conditions, e.g., some of them may fail to detect CNVs of short sizes. There has been a strong demand for reliable detection of CNVs from high resolution NGS data. RESULTS: A novel and robust method to detect CNV from short sequencing reads is proposed in this study. The detection of CNV is modeled as a change-point detection from the read depth (RD) signal derived from the NGS, which is fitted with a total variation (TV) penalized least squares model. The performance (e.g., sensitivity and specificity) of the proposed approach are evaluated by comparison with several recently published methods on both simulated and real data from the 1000 Genomes Project. CONCLUSION: The experimental results showed that both the true positive rate and false positive rate of the proposed detection method do not change significantly for CNVs with different copy numbers and lengthes, when compared with several existing methods. Therefore, our proposed approach results in a more reliable detection of CNVs than the existing methods.

BACKGROUND: The emergence of high-throughput genomic datasets from different sources and platforms (e.g., gene expression, single nucleotide polymorphisms (SNP), and copy number variation (CNV)) has greatly enhanced our understandings of the interplay of these genomic factors as well as their influences on the complex diseases. It is challenging to explore the relationship between these different types of genomic data sets. In this paper, we focus on a multivariate statistical method, canonical correlation analysis (CCA) method for this problem. Conventional CCA method does not work effectively if the number of data samples is significantly less than that of biomarkers, which is a typical case for genomic data (e.g., SNPs). Sparse CCA (sCCA) methods were introduced to overcome such difficulty, mostly using penalizations with l-1 norm (CCA-l1) or the combination of l-1and l-2 norm (CCA-elastic net). However, they overlook the structural or group effect within genomic data in the analysis, which often exist and are important (e.g., SNPs spanning a gene interact and work together as a group). RESULTS: We propose a new group sparse CCA method (CCA-sparse group) along with an effective numerical algorithm to study the mutual relationship between two different types of genomic data (i.e., SNP and gene expression). We then extend the model to a more general formulation that can include the existing sCCA models. We apply the model to feature/variable selection from two data sets and compare our group sparse CCA method with existing sCCA methods on both simulation and two real datasets (human gliomas data and NCI60 data). We use a graphical representation of the samples with a pair of canonical variates to demonstrate the discriminating characteristic of the selected features. Pathway analysis is further performed for biological interpretation of those features. CONCLUSIONS: The CCA-sparse group method incorporates group effects of features into the correlation analysis while performs individual feature selection simultaneously. It outperforms the two sCCA methods (CCA-l1 and CCA-group) by identifying the correlated features with more true positives while controlling total discordance at a lower level on the simulated data, even if the group effect does not exist or there are irrelevant features grouped with true correlated features. Compared with our proposed CCA-group sparse models, CCA-l1 tends to select less true correlated features while CCA-group inclines to select more redundant features.

It is important to identify significant biomarkers such as SNPs for medical diagnosis and treatment. However, the size of a biological sample is usually far less than the number of measurements, which makes the problem more challenging. To overcome this difficulty, we propose a sparse representation based variable selection (SRVS) approach. A simulated data set was first tested to demonstrate the advantages and properties of the proposed method. Then, we applied the algorithm to a joint analysis of 759075 SNPs and 153594 functional magnetic resonance imaging (fMRJ) voxels in 208 subjects (92 cases/116 controls) to identify significant biomarkers for schizophrenia (SZ). When compared with previous studies, our proposed method located 20 genes out of the top 45 SZ genes that are publicly reported We also detected some interesting functional brain regions from the fMRI study. In addition, a leave one out (LOO) cross-validation was performed and the results were compared with that of a previously reported method, which showed that our method gave significantly higher classification accuracy. In addition, the identification accuracy with integrative analysis is much better than that of using single type of data, suggesting that integrative analysis may lead to better diagnostic accuracy by combining complementary SNP and fMRI data.

We developed a structure based sparse representation model for classifying chromosomes in M-FISH images. The sparse representation based classification model used in our previous work only considered one pixel without incorporating any structural information. The new proposed model extends the previous one to multiple pixels case, where each target pixel together with its neighboring pixels will be used simultaneously for classification. We also extend Orthogonal Matching Pursuit (OMP) algorithm to the multiple pixels case, named simultaneous OMP algorithm (SOMP), to solve the structure based sparse representation model. The classification results show that our new model outperforms the previous sparse representation model with the p-value less than le-6. We also discussed the effects of several parameters (neighborhood size, sparsity level, and training sample size) on the accuracy of the classification. Our proposed method can be affected by the sparsity level and the neighborhood size but is insensitive to the training sample size. Therefore, the comparison indicates that the structure based sparse representation model can significantly improve the accuracy of the chromosome classification, leading to improved diagnosis of genetic diseases and cancers.

We revisit the positive cone condition given by Efronfor the over-determined least absolute shrinkage and selection operator (LASSO). It is a sufficient condition ensuring that the number of nonzero entries in the solution vector keeps increasing when the penalty parameter decreases, based on which the least angle regression (LARS)and homotopyalgorithms yield the same iterates. We show that the positive cone condition is equivalent to the diagonal dominance of the Gram matrix inverse, leading to a simpler way to check the positive cone condition in practice. Moreover, we elaborate on a connection between the positive cone condition and the mutual coherence condition given by Donoho and Tsaig, ensuring the exact recovery of any$k$-sparse representation using both LARS and homotopy.

An adaptive fuzzy c-means algorithm was developed and applied to the segmentation and classification of multicolor fluorescence in situ hybridization (M-FISH) images, which can be used to detect chromosomal abnormalities for cancer and genetic disease diagnosis. The algorithm improves the classical fuzzy c-means algorithm (FCM) by the use of a gain field, which models and corrects intensity inhomogeneities caused by a microscope imaging system, flairs of targets (chromosomes), and uneven hybridization of DNA. Other than directly simulating the inhomogeneousely distributed intensities over the image, the gain field regulates centers of each intensity cluster. The algorithm has been tested on an M-FISH database that we have established, which demonstrates improved performance in both segmentation and classification. When compared with other FCM clustering-based algorithms and a recently reported region-based segmentation and classification algorithm, our method gave the lowest segmentation and classification error, which will contribute to improved diagnosis of genetic diseases and cancers.

We designed a sparse representation clustering (SRC) model to select the significant single nucleotide polymorphisms (SNPs) and proposed a novel SRC with a sliding window model for functional magnetic resonance imaging (fMRI) voxels selection. Then we combined two types of data to classify schizophrenia patients from healthy controls by linear support vector machine (SVM) to achieve a better diagnosis of schizophrenia. The effectiveness of the selected variables (SNPs or voxels) was validated by the leave one out (LOO) cross-validation method. The experimental results show that our proposed SRC method can effectively select the most discriminative variables in both SNPs and fMRI data. In particular, the combination of complementary fMRI and SNP data can significantly improve the classification of schizophrenia patients, which provides new insights in the study of schizophrenia.

DNA microarray gene expression and microarray-based comparative genomic hybridization (aCGH) have been widely used for biomedical discovery. Because of the large number of genes and the complex nature of biological networks, various analysis methods have been proposed. One such method is "gene shaving," a procedure which identifies subsets of the genes with coherent expression patterns and large variation across samples. Since combining genomic information from multiple sources can improve classification and prediction of diseases, in this paper we proposed a new method, "ICA gene shaving" (ICA, independent component analysis), for jointly analyzing gene expression and copy number data. First we used ICA to analyze joint measurements, gene expression and copy number, of a biological system and project the data onto statistically independent biological processes. Next, we used these results to identify patterns of variation in the data and then applied an iterative shaving method. We investigated the properties of our proposed method by analyzing both simulated and real data. We demonstrated that the robustness of our method to noise using simulated data. Using breast cancer data, we showed that our method is superior to the Generalized Singular Value Decomposition (GSVD) gene shaving method for identifying genes associated with breast cancer.