Deep Convolutional Neural Networks for Annotating Gene Expression Patterns in the Mouse Brain

Background: Profiling gene expression in brain structures at various spatial and temporal scales is essential to understanding how genes regulate the development of brain structures. The Allen Developing Mouse Brain Atlas provides high-resolution 3-D in situ hybridization (ISH) gene expression patterns in multiple developing stages of the mouse brain. Currently, the ISH images are annotated with anatomical terms manually. In this paper, we propose a computational approach to annotate gene expression pattern images in the mouse brain at various structural levels over the course of development. Results: We applied deep convolutional neural network that was trained on a large set of natural images to extract features from the ISH images of developing mouse brain. As a baseline representation, we applied invariant image feature descriptors to capture local statistics from ISH images and used the bag-of-words approach to build image-level representations. Both types of features from multiple ISH image sections of the entire brain were then combined to build 3-D, brain-wide gene expression representations. We employed regularized learning methods for discriminating gene expression patterns in different brain structures. Results show that our approach of using convolutional model as feature extractors achieved superior performance in annotating gene expression patterns at multiple levels of brain structures throughout four developing ages. Overall, we achieved average AUC of 0.894 ± 0.014, as compared with 0.820 ± 0.046 yielded by the bag-of-words approach. Conclusions: Deep convolutional neural network model trained on natural image sets and applied to gene expression pattern annotation tasks yielded superior performance, demonstrating its transfer learning property is applicable to such biological image sets

Deep convolutional neural networks for annotating gene expression patterns in the mouse brain

Abstract Background Profiling gene expression in brain structures at various spatial and temporal scales is essential to understanding how genes regulate the development of brain structures. The Allen Developing Mouse Brain Atlas provides high-resolution 3-D in situ hybridization (ISH) gene expression patterns in multiple developing stages of the mouse brain. Currently, the ISH images are annotated with anatomical terms manually. In this paper, we propose a computational approach to annotate gene expression pattern images in the mouse brain at various structural levels over the course of development. Results We applied deep convolutional neural network that was trained on a large set of natural images to extract features from the ISH images of developing mouse brain. As a baseline representation, we applied invariant image feature descriptors to capture local statistics from ISH images and used the bag-of-words approach to build image-level representations. Both types of features from multiple ISH image sections of the entire brain were then combined to build 3-D, brain-wide gene expression representations. We employed regularized learning methods for discriminating gene expression patterns in different brain structures. Results show that our approach of using convolutional model as feature extractors achieved superior performance in annotating gene expression patterns at multiple levels of brain structures throughout four developing ages. Overall, we achieved average AUC of 0.894 ± 0.014, as compared with 0.820 ± 0.046 yielded by the bag-of-words approach. Conclusions Deep convolutional neural network model trained on natural image sets and applied to gene expression pattern annotation tasks yielded superior performance, demonstrating its transfer learning property is applicable to such biological image sets.http://deepblue.lib.umich.edu/bitstream/2027.42/111637/1/12859_2015_Article_553.pd

A mesh generation and machine learning framework for Drosophilagene expression pattern image analysis

abstract: Background Multicellular 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. Results We 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/. Conclusions Our mesh generation and machine learning methods and tools improve upon the flexibility, ease-of-use and accuracy of existing methods.The electronic version of this article is the complete one and can be found online at: http://bmcbioinformatics.biomedcentral.com/articles/10.1186/1471-2105-14-37

Learning Sparse Representations for Fruit-Fly Gene Expression Pattern Image Annotation and Retrieval

abstract: Background Fruit fly embryogenesis is one of the best understood animal development systems, and the spatiotemporal gene expression dynamics in this process are captured by digital images. Analysis of these high-throughput images will provide novel insights into the functions, interactions, and networks of animal genes governing development. To facilitate comparative analysis, web-based interfaces have been developed to conduct image retrieval based on body part keywords and images. Currently, the keyword annotation of spatiotemporal gene expression patterns is conducted manually. However, this manual practice does not scale with the continuously expanding collection of images. In addition, existing image retrieval systems based on the expression patterns may be made more accurate using keywords. Results In this article, we adapt advanced data mining and computer vision techniques to address the key challenges in annotating and retrieving fruit fly gene expression pattern images. To boost the performance of image annotation and retrieval, we propose representations integrating spatial information and sparse features, overcoming the limitations of prior schemes. Conclusions We perform systematic experimental studies to evaluate the proposed schemes in comparison with current methods. Experimental results indicate that the integration of spatial information and sparse features lead to consistent performance improvement in image annotation, while for the task of retrieval, sparse features alone yields better results.The electronic version of this article is the complete one and can be found online at: http://bmcbioinformatics.biomedcentral.com/articles/10.1186/1471-2105-13-10

Automated annotation of gene expression image sequences via non-parametric factor analysis and conditional random fields

Motivation: Computational approaches for the annotation of phenotypes from image data have shown promising results across many applications, and provide rich and valuable information for studying gene function and interactions. While data are often available both at high spatial resolution and across multiple time points, phenotypes are frequently annotated independently, for individual time points only. In particular, for the analysis of developmental gene expression patterns, it is biologically sensible when images across multiple time points are jointly accounted for, such that spatial and temporal dependencies are captured simultaneously. Methods: We describe a discriminative undirected graphical model to label gene-expression time-series image data, with an efficient training and decoding method based on the junction tree algorithm. The approach is based on an effective feature selection technique, consisting of a non-parametric sparse Bayesian factor analysis model. The result is a flexible framework, which can handle large-scale data with noisy incomplete samples, i.e. it can tolerate data missing from individual time points. Results: Using the annotation of gene expression patterns across stages of Drosophila embryonic development as an example, we demonstrate that our method achieves superior accuracy, gained by jointly annotating phenotype sequences, when compared with previous models that annotate each stage in isolation. The experimental results on missing data indicate that our joint learning method successfully annotates genes for which no expression data are available for one or more stages

Learning Sparse Representations for Fruit Fly Gene Expression Pattern Image Annotation and Retreival

Background: Fruit fly embryogenesis is one of the best understood animal development systems, and the spatiotemporal gene expression dynamics in this process are captured by digital images. Analysis of these high-throughput images will provide novel insights into the functions, interactions, and networks of animal genes governing development. To facilitate comparative analysis, web-based interfaces have been developed to conduct image retrieval based on body part keywords and images. Currently, the keyword annotation of spatiotemporal gene expression patterns is conducted manually. However, this manual practice does not scale with the continuously expanding collection of images. In addition, existing image retrieval systems based on the expression patterns may be made more accurate using keywords. Results: In this article, we adapt advanced data mining and computer vision techniques to address the key challenges in annotating and retrieving fruit fly gene expression pattern images. To boost the performance of image annotation and retrieval, we propose representations integrating spatial information and sparse features, overcoming the limitations of prior schemes. Conclusions: We perform systematic experimental studies to evaluate the proposed schemes in comparison with current methods. Experimental results indicate that the integration of spatial information and sparse features lead to consistent performance improvement in image annotation, while for the task of retrieval, sparse features alone yields better results

A bag-of-words approach for Drosophila gene expression pattern annotation

abstract: Background Drosophila gene expression pattern images document the spatiotemporal dynamics of gene expression during embryogenesis. A comparative analysis of these images could provide a fundamentally important way for studying the regulatory networks governing development. To facilitate pattern comparison and searching, groups of images in the Berkeley Drosophila Genome Project (BDGP) high-throughput study were annotated with a variable number of anatomical terms manually using a controlled vocabulary. Considering that the number of available images is rapidly increasing, it is imperative to design computational methods to automate this task. Results We present a computational method to annotate gene expression pattern images automatically. The proposed method uses the bag-of-words scheme to utilize the existing information on pattern annotation and annotates images using a model that exploits correlations among terms. The proposed method can annotate images individually or in groups (e.g., according to the developmental stage). In addition, the proposed method can integrate information from different two-dimensional views of embryos. Results on embryonic patterns from BDGP data demonstrate that our method significantly outperforms other methods. Conclusion The proposed bag-of-words scheme is effective in representing a set of annotations assigned to a group of images, and the model employed to annotate images successfully captures the correlations among different controlled vocabulary terms. The integration of existing annotation information from multiple embryonic views improves annotation performance.The electronic version of this article is the complete one and can be found online at: http://bmcbioinformatics.biomedcentral.com/articles/10.1186/1471-2105-10-11

A Computational Framework for Learning from Complex Data: Formulations, Algorithms, and Applications

Many real-world processes are dynamically changing over time. As a consequence, the observed complex data generated by these processes also evolve smoothly. For example, in computational biology, the expression data matrices are evolving, since gene expression controls are deployed sequentially during development in many biological processes. Investigations into the spatial and temporal gene expression dynamics are essential for understanding the regulatory biology governing development. In this dissertation, I mainly focus on two types of complex data: genome-wide spatial gene expression patterns in the model organism fruit fly and Allen Brain Atlas mouse brain data. I provide a framework to explore spatiotemporal regulation of gene expression during development. I develop evolutionary co-clustering formulation to identify co-expressed domains and the associated genes simultaneously over different temporal stages using a mesh-generation pipeline. I also propose to employ the deep convolutional neural networks as a multi-layer feature extractor to generate generic representations for gene expression pattern in situ hybridization (ISH) images. Furthermore, I employ the multi-task learning method to fine-tune the pre-trained models with labeled ISH images. My proposed computational methods are evaluated using synthetic data sets and real biological data sets including the gene expression data from the fruit fly BDGP data sets and Allen Developing Mouse Brain Atlas in comparison with baseline existing methods. Experimental results indicate that the proposed representations, formulations, and methods are efficient and effective in annotating and analyzing the large-scale biological data sets

Development of web-based image annotation tool and application of machine learning methods

Thesis (M. Eng.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2011.Cataloged from PDF version of thesis.Includes bibliographical references (p. 91-92).Large-scale in situ hybridization screens are providing an abundance of spatio-temporal patterns of gene expression data that is valuable for understanding the mechanisms of gene regulation. Drosophila gene expression pattern images have been generated by the Berkeley Drosophila Genome Project (BDGP) for over 7,000 genes in over 90,000 digital images. These images are currently hand curated by field experts with developmental and anatomical terms based on the stained regions. These annotations enable the integration of spatial expression patterns with other genomic data sets that link regulators with their downstream targets. However, the manual curation has become a bottleneck in the process of analyzing the rapidly generated data therefore it is necessary to explore computational methods for the curation of gene expression pattern images. This thesis addresses improving the manual annotation process with a web-based image annotation tool and also enabling automation of the process using machine learning methods. First, a tool called LabelLife was developed to provide a systematic and flexible way of annotating images, groups of images, and shapes within images using terms from a controlled vocabulary. Second, machine learning methods for automatically predicting vocabulary terms for a given image based on image feature data were explored and implemented. The results of the applied machine learning methods are promising in terms of predictive ability, which has the potential to simplify and expedite the curation process hence increasing the rate that biologically significant data can be evaluated and new insights can be gained.by Anna Maria E. Ayuso.M.Eng

Automated annotation of Drosophila gene expression patterns using a controlled vocabulary

Motivation: Regulation of gene expression in space and time directs its localization to a specific subset of cells during development. Systematic determination of the spatiotemporal dynamics of gene expression plays an important role in understanding the regulatory networks driving development. An atlas for the gene expression patterns of fruit fly Drosophila melanogaster has been created by whole-mount in situ hybridization, and it documents the dynamic changes of gene expression pattern during Drosophila embryogenesis. The spatial and temporal patterns of gene expression are integrated by anatomical terms from a controlled vocabulary linking together intermediate tissues developed from one another. Currently, the terms are assigned to patterns manually. However, the number of patterns generated by high-throughput in situ hybridization is rapidly increasing. It is, therefore, tempting to approach this problem by employing computational methods