Wenlu Zhang

Deep convolutional neural networks for multi-modality isointense infant brain image segmentation.

The segmentation of infant brain tissue images into white matter (WM), gray matter (GM), and cerebrospinal fluid (CSF) plays an important role in studying early brain development in health and disease. In the isointense stage (approximately 6-8 months of age), WM and GM exhibit similar levels of intensity in both T1 and T2 MR images, making the tissue segmentation very challenging. Only a small number of existing methods have been designed for tissue segmentation in this isointense stage; however, they only used a single T1 or T2 images, or the combination of T1 and T2 images. In this paper, we propose to use deep convolutional neural networks (CNNs) for segmenting isointense stage brain tissues using multi-modality MR images. CNNs are a type of deep models in which trainable filters and local neighborhood pooling operations are applied alternatingly on the raw input images, resulting in a hierarchy of increasingly complex features. Specifically, we used multi-modality information from T1, T2, and fractional anisotropy (FA) images as inputs and then generated the segmentation maps as outputs. The multiple intermediate layers applied convolution, pooling, normalization, and other operations to capture the highly nonlinear mappings between inputs and outputs. We compared the performance of our approach with that of the commonly used segmentation methods on a set of manually segmented isointense stage brain images. Results showed that our proposed model significantly outperformed prior methods on infant brain tissue segmentation. In addition, our results indicated that integration of multi-modality images led to significant performance improvement.

Deep learning based imaging data completion for improved brain disease diagnosis.

Combining multi-modality brain data for disease diagnosis commonly leads to improved performance. A challenge in using multimodality data is that the data are commonly incomplete; namely, some modality might be missing for some subjects. In this work, we proposed a deep learning based framework for estimating multi-modality imaging data. Our method takes the form of convolutional neural networks, where the input and output are two volumetric modalities. The network contains a large number of trainable parameters that capture the relationship between input and output modalities. When trained on subjects with all modalities, the network can estimate the output modality given the input modality. We evaluated our method on the Alzheimers Disease Neuroimaging Initiative (ADNI) database, where the input and output modalities are MRI and PET images, respectively. Results showed that our method significantly outperformed prior methods.

Deep Model Based Transfer and Multi-Task Learning for Biological Image Analysis

A central theme in learning from image data is to develop appropriate image representations for the specific task at hand. Traditional methods used handcrafted local features combined with high-level image representations to generate image-level representations. Thus, a practical challenge is to determine what features are appropriate for specific tasks. For example, in the study of gene expression patterns in Drosophila melanogaster, texture features based on wavelets were particularly effective for determining the developmental stages from in situ hybridization (ISH) images. Such image representation is however not suitable for controlled vocabulary (CV) term annotation because each CV term is often associated with only a part of an image. Here, we developed problem-independent feature extraction methods to generate hierarchical representations for ISH images. Our approach is based on the deep convolutional neural networks (CNNs) that can act on image pixels directly. To make the extracted features generic, the models were trained using a natural image set with millions of labeled examples. These models were transferred to the ISH image domain and used directly as feature extractors to compute image representations. Furthermore, we employed multi-task learning method to fine-tune the pre-trained models with labeled ISH images, and also extracted features from the fine-tuned models. Experimental results showed that feature representations computed by deep models based on transfer and multi-task learning significantly outperformed other methods for annotating gene expression patterns at different stage ranges. We also demonstrated that the intermediate layers of deep models produced the best gene expression pattern representations.

A sparsity-inducing formulation for evolutionary co-clustering

Traditional co-clustering methods identify block structures from static data matrices. However, the data matrices in many applications are dynamic; that is, they evolve smoothly over time. Consequently, the hidden block structures embedded into the matrices are also expected to vary smoothly along the temporal dimension. It is therefore desirable to encourage smoothness between the block structures identified from temporally adjacent data matrices. In this paper, we propose an evolutionary co-clustering formulation for identifying co-cluster structures from time-varying data. The proposed formulation encourages smoothness between temporally adjacent blocks by employing the fused Lasso type of regularization. Our formulation is very flexible and allows for imposing smoothness constraints over only one dimension of the data matrices, thereby enabling its applicability to a large variety of settings. The optimization problem for the proposed formulation is non-convex, non-smooth, and non-separable. We develop an iterative procedure to compute the solution. Each step of the iterative procedure involves a convex, but non-smooth and non-separable problem. We propose to solve this problem in its dual form, which is convex and smooth. This leads to a simple gradient descent algorithm for computing the dual optimal solution. We evaluate the proposed formulation using the Allen Developing Mouse Brain Atlas data. Results show that our formulation consistently outperforms methods without the temporal smoothness constraints.

A Probabilistic Latent Semantic Analysis Model for Coclustering the Mouse Brain Atlas

The mammalian brain contains cells of a large variety of types. The phenotypic properties of cells of different types are largely the results of distinct gene expression patterns. Therefore, it is of critical importance to characterize the gene expression patterns in the mammalian brain. The Allen Developing Mouse Brain Atlas provides spatiotemporal in situ hybridization gene expression data across multiple stages of mouse brain development. It provides a framework to explore spatiotemporal regulation of gene expression during development. We employ a graph approximation formulation to cocluster the genes and the brain voxels simultaneously for each time point. We show that this formulation can be expressed as a probabilistic latent semantic analysis (PLSA) model, thereby allowing us to use the expectation-maximization algorithm for PLSA to estimate the coclustering parameters. To provide a quantitative comparison with prior methods, we evaluate the coclustering method on a set of standard synthetic data sets. Results indicate that our method consistently outperforms prior methods. We apply our method to cocluster the Allen Developing Mouse Brain Atlas data. Results indicate that our clustering of voxels is more consistent with classical neuroanatomy than those of prior methods. Our analysis also yields sets of genes that are co-expressed in a subset of the brain voxels.

Automated identification of cell-type-specific genes in the mouse brain by image computing of expression patterns.

BackgroundDifferential gene expression patterns in cells of the mammalian brain result in the morphological, connectional, and functional diversity of cells. A wide variety of studies have shown that certain genes are expressed only in specific cell-types. Analysis of cell-type-specific gene expression patterns can provide insights into the relationship between genes, connectivity, brain regions, and cell-types. However, automated methods for identifying cell-type-specific genes are lacking to date.ResultsHere, we describe a set of computational methods for identifying cell-type-specific genes in the mouse brain by automated image computing of in situ hybridization (ISH) expression patterns. We applied invariant image feature descriptors to capture local gene expression information from cellular-resolution ISH images. We then built image-level representations by applying vector quantization on the image descriptors. We employed regularized learning methods for classifying genes specifically expressed in different brain cell-types. These methods can also rank image features based on their discriminative power. We used a data set of 2,872 genes from the Allen Brain Atlas in the experiments. Results showed that our methods are predictive of cell-type-specificity of genes. Our classifiers achieved AUC values of approximately 87% when the enrichment level is set to 20. In addition, we showed that the highly-ranked image features captured the relationship between cell-types.ConclusionsOverall, our results showed that automated image computing methods could potentially be used to identify cell-type-specific genes in the mouse brain.

A Mesh Generation and Machine Learning Framework for Drosophila Gene Expression Pattern Image Analysis

BackgroundMulticellular organisms consist of cells of many different types that are established during development. Each type of cell is characterized by the unique combination of expressed gene products as a result of spatiotemporal gene regulation. Currently, a fundamental challenge in regulatory biology is to elucidate the gene expression controls that generate the complex body plans during development. Recent advances in high-throughput biotechnologies have generated spatiotemporal expression patterns for thousands of genes in the model organism fruit fly Drosophila melanogaster. Existing qualitative methods enhanced by a quantitative analysis based on computational tools we present in this paper would provide promising ways for addressing key scientific questions.ResultsWe develop a set of computational methods and open source tools for identifying co-expressed embryonic domains and the associated genes simultaneously. To map the expression patterns of many genes into the same coordinate space and account for the embryonic shape variations, we develop a mesh generation method to deform a meshed generic ellipse to each individual embryo. We then develop a co-clustering formulation to cluster the genes and the mesh elements, thereby identifying co-expressed embryonic domains and the associated genes simultaneously. Experimental results indicate that the gene and mesh co-clusters can be correlated to key developmental events during the stages of embryogenesis we study. The open source software tool has been made available at http://compbio.cs.odu.edu/fly/.ConclusionsOur mesh generation and machine learning methods and tools improve upon the flexibility, ease-of-use and accuracy of existing methods.

Sparsity Learning Formulations for Mining Time-Varying Data

Traditional clustering and feature selection methods consider the data matrix as static. However, the data matrices evolve smoothly over time in many applications. A simple approach to learn from these time-evolving data matrices is to analyze them separately. Such strategy ignores the time-dependent nature of the underlying data. In this paper, we propose two formulations for evolutionary co-clustering and feature selection based on the fused Lasso regularization. The evolutionary co-clustering formulation is able to identify smoothly varying hidden block structures embedded into the matrices along the temporal dimension. Our formulation is very flexible and allows for imposing smoothness constraints over only one dimension of the data matrices. The evolutionary feature selection formulation can uncover shared features in clustering from time-evolving data matrices. We show that the optimization problems involved are non-convex, non-smooth and non-separable. To compute the solutions efficiently, we develop a two-step procedure that optimizes the objective function iteratively. We evaluate the proposed formulations using the Allen Developing Mouse Brain Atlas data. Results show that our formulations consistently outperform prior methods.

Evolutionary soft co-clustering: formulations, algorithms, and applications

We consider the co-clustering of time-varying data using evolutionary co-clustering methods. Existing approaches are based on the spectral learning framework, thus lacking a probabilistic interpretation. We overcome this limitation by developing a probabilistic model in this paper. The proposed model assumes that the observed data are generated via a two-step process that depends on the historic co-clusters. This allows us to capture the temporal smoothness in a probabilistically principled manner. To perform maximum likelihood parameter estimation, we present an EM-based algorithm. We also establish the convergence of the proposed EM algorithm. An appealing feature of the proposed model is that it leads to soft co-clustering assignments naturally. We evaluate the proposed method on both synthetic and real-world data sets. Experimental results show that our method consistently outperforms prior approaches based on spectral method. To fully exploit the real-world impact of our methods, we further perform a systematic application study on the analysis of Drosophila gene expression pattern images. We encode the spatial gene expression information at a particular developmental time point into a data matrix using a mesh-generation pipeline. We then co-cluster the embryonic domains and the genes simultaneously for multiple time points using our evolutionary co-clustering method. Results show that the co-clusters of gene and embryonic domains reflect the underlying biology.