Gene expression patterns analysis with microarray provides quantitative information that shows how a gene is expressed under a particular condition. Whole mount in situ hybridization, on the other hand, can be used to capture the spatio-temporal characteristics of the gene expression pattern. Therefore, visual integration of gene expression data from both techniques with a digital atlas data of a model-organism can help identifying not only spatial and temporal but also quantitative aspects of gene expression in different stages of development. In this paper, we present an approach using web services to provide an integrative online visualization of gene expression patterns in within a digital atlas of zebrafish in different stages of development. We developed SOAP web services that provide programmatic access to the 3D data and spatial-temporal whole mount gene expression data to our readily developed information systems; the 3D digital atlas of zebrafish development and the Gene Expression Management System (GEMS). We also created web applications that exploit the newly developed web services to retrieve data from our repositories. The web applications also uses the web services to retrieve relevant quantitative microarray analysis gene expression data from community resources; i.e. the ArrayExpress Atlas. All the gene expression patterns data and the 3D atlas data are subsequently integrated using ontology based mapping. In order to deliver the integrated visualization to end users, we developed a Java based 3D-viewer client that can be integrated in a web interface allowing users to visualize the information over Internet.

1. ACEEE Int. J. on Information Technology, Vol. 01, No. 03, Dec 2011
3D Visual Integration of Spatio-Temporal Gene
Expression Patterns on Digital Atlas of Zebrafish
Embryo using Web Service
D. Potikanond, F. J. Verbeek
Section Imaging and Bioinformatics, Leiden Institute of Advanced Computer Science
Leiden University, Leiden, The Netherlands
Email: {dpotikan, fverbeek}@liacs.nl
Abstract—Gene expression patterns analysis with microarray interact to control biological processes. Identifying both
provides quantitative information that shows how a gene is temporal and spatial aspects of gene expression in
expressed under a particular condition. Whole mount in situ developmental is a crucial step for additional functional
hybridization, on the other hand, can be used to capture the
analysis of genes. The microarray technique [4] is one of the
spatio-temporal characteristics of the gene expression pattern.
Therefore, visual integration of gene expression data from
major experimental breakthroughs enabling high throughput
both techniques with a digital atlas data of a model-organism measurement and analysis of the expression patterns of (tens
can help identifying not only spatial and temporal but also of) thousands of genes simultaneously [5]. However, in multi-
quantitative aspects of gene expression in different stages of cellular organism such as zebrafish, gene expression
development. In this paper, we present an approach using web influences the development of a cell or group of cells.
services to provide an integrative online visualization of gene Therefore whole-specimen microarray analysis cannot fully
expression patterns in within a digital atlas of zebrafish in document the spatio-temporal relations. Whole mount in situ
different stages of development. We developed SOAP web hybridization, on the other hand, can be used to obtain such
services that provide programmatic access to the 3D data and
information. To this end, we built the Gene Expression
spatial-temporal whole mount gene expression data to our
readily developed information systems; the 3D digital atlas of
Management System (GEMS) [6] as an information system
zebrafish development and the Gene Expression Management for 3D spatio-temporal gene expression patterns which are
System (GEMS). We also created web applications that exploit generated through Fluorescent In Situ Hybridization
the newly developed web services to retrieve data from our (zebraFISH) [7] protocol.
repositories. The web applications also uses the web services There are a number of information systems providing
to retrieve relevant quantitative microarray analysis gene information on zebrafish anatomy and/or gene expression
expression data from community resources; i.e. the data such as the Zebrafish Information Network (ZFIN) [8],
ArrayExpress Atlas. All the gene expression patterns data and ArrayExpress [9], Entrez Gene [10] and Ensembl [11]. However,
the 3D atlas data are subsequently integrated using ontology
the anatomical data and gene expression data are typically
based mapping. In order to deliver the integrated visualization
to end users, we developed a Java based 3D-viewer client that
not integrated nor represented in such a way that they can
can be integrated in a web interface allowing users to visualize be visualized jointly in a 3D context. To help understanding
the information over Internet. the spatio-temporal context of genes expression and the
involvement in changing anatomical structures, it is important
Index Terms—Visualization, Web services, Zebrafish Atlas, 3D to have a visualization system that integrates data from these
reconstruction, Gene expression patterns different domains. For example, in the mouse (Mus musculus),
there are the e-Mouse Atlas Project (EMAP) [12], the e-Mouse
I. INTRODUCTION Atlas of Gene Expression (EMAGE) [13] and the Digital
3D imaging and graphical models have been used Atlasing and Standardization in the Mouse Brain [14]. The
effectively as a common technical framework for representing Berkeley Drosophila Transcription Network Project (BDTNP)
spatial information in biomedical research. Among the well- provides resources and visualization tools for viewing 3D
known techniques for capturing 3D data are the serial gene expression patterns in early Drosophila embryo at cellular
sectioning methods [1, 2]. These methods are used to produce resolution [15, 16]. However, there is no such thing available
3D contour information from multiple regions of interest for zebrafish.
(ROIs) in 3D data and thereby allowing reconstructing 3D In this paper, we describe an approach to provide web
surface models. Earlier, we created the 3D digital atlas of services that helps visualizing gene expression information
zebrafish development [3] which provides an online 3D within 3D graphical models of zebrafish atlas. This way,
visualization of the anatomy in the zebrafish embryo. It serves detailed information about gene expression in zebrafish
as a framework of reference for researchers. Therefore in the becomes available embedded into their 3D spatial context.
context of the atlas, ROIs are anatomical domains in zebrafish To provide programming interfaces to access our 3D
embryo. One of the crucial challenges in developmental reconstruction data and gene expression patterns data, we
biology and molecular genetics is to determine how genes have created the 3D reconstruction (TDR) and the GEMS
web services. Even though GEMS provides semantic
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information on spatio-temporal gene expression, it is yet to histological section images of a zebrafish embryo using our
provide quantitative gene expression data. Hence we need dedicated acquisition station [2].
to retrieve this related information from a microarray gene The image datasets for spatial gene expression patterns,
expression resource, the ArrayExpress Atlas [17, 18]. The on the other hand, are produced using the zebraFISH protocol.
ArrayExpress Atlas of Gene Expression contains a subset of The patterns are acquired with the confocal laser scanner
curated and re-annotated archive data from the ArrayExpress microscope as multi-channel 3D images containing the outline
Repository which is one of the recommended international of the embryo and the spatial patterns of gene expression in
repositories to archive publication related functional separated channels. The next step is to create 3D
genomics data [19]. It can be queried for individual gene reconstruction models from both atlas and gene expression
expression under different biological conditions across image datasets using our reconstruction software, TDR-
experiments. 3Dbased [2] (Fig. 1). The reconstruction software is basically
In order to integrate these data correctly we need to a tool for 3D annotation and surface reconstruction. We used
provide a basis for cross-domain communication. In this work, a graphical annotation to specify domains of interest which,
we used controlled vocabularies from standard ontologies in this context, are the boundaries of anatomical domains
to annotate the anatomical domains and genes domains on and/or patterns of gene expression. Textual annotation is
both atlas and gene expression patterns data. This allows accomplished by attaching a term to each graphical
our data to be linked together and also enables interoperability annotation. Anatomical domains are annotated with
and communication with external community resources as anatomical terms from the Developmental Anatomy Ontology
well. (DAOZ) [21] and gene expression patterns data are annotated
To this end, we have developed the Bio-Visualization web with proper gene terms from GEMS. In fact, all controlled
service as an intermediate component that is responsible for vocabularies in both DAOZ and GEMS are extracted from
retrieving related information from the underlying web the standard ontologies, i.e.,
services, including the ArrayExpress Atlas web service. The
Bio-Visualization filters and integrates all related gene
expression data from external information source(s) onto the
existing reconstruction model in order to generate a new
visualization model. The web service is designed to be
extensible to support more external information source in the
future. In support of this work, we developed web applications
based on the web services that provide the underlying data
required. The web applications provide an overview and allow
users to query on our 3D digital atlas along with related gene
expression data. In order to deliver the data to end users, we
integrate our Java based 3D-viewer (TDRViewer) with the
web applications allowing users to visualize the integrated
visualization over Internet.
II. CONSTRUCTING INFORMATON MODEL
In this section the acquisition of the raw data for creating
both reconstruction models and patterns of gene expression
will be discussed. The 3D reconstruction models and 3D gene
expression patterns data in GEMS are created from 3D-image
dataset, however, from different modalities. The input data in
both cases need to be annotated using terms from standard
ontologies. The only difference is that the annotation for
reconstruction models is done before submitting the models
to the TDR repository whereas annotation for the gene
expression data in GEMS has to be done as part of the
submission process.
A. The 3D Reconstruction Models
Figure 1. The TDR-3Dbase reconstruction software. This figure
In the past few years, we have produced a number of 3D- shows how to create a 3D reconstruction model of 24 hpf zebrafish
models of for the zebrafish atlas as well as spatial patterns of embryo. The 3D reconstruction dataset consists of a model
gene expression, in a range of developmental stages; 24, 36, description (TDRML) file, section images, contour information
and 3D surface information.
48, 72 hours post-fertilisation (hpf ) [20]. The first step is to
acquire raw data. The 3D image datasets for atlas were ZFIN Anatomical Ontology and the Gene Ontology (GO) [22]
acquired in both a normal and high resolution from respectively. A reconstruction model also contains metadata
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that need to be annotated correctly with terms from our as YOLK, DIENCEPHALON and ECTODERM, while we
ontologies, e.g., the stage of development. Annotation for annotate 3D gene expression domains with standard gene
reconstruction models has to be done in the reconstruction symbols derived from GO, such as fgf8a and hoxa9a. We
software and therefore completes before submitting the annotate all of the 3D models together with the stage of
model to the atlas repository. Each 3D reconstruction model developmental. Annotating the datasets with terms derived
is considered as a single instance of data and is described by from standard ontologies provides us the capability to
a model description, 3D Reconstruction Markup Language integrate our data with a broad range of external
(TDRML), which provides scalability and extensibility, both bioinformatics resources, i.e., ZFIN, Ensembl, ArrayExpress
of which are very important for a project that is subject to Atlas. Therefore, mapping the gene expression data from
updates in order to improve quality of the data. Moreover, GEMS and ArrayExpress Atlas onto the 3D reconstruction
TDRML facilitates easy exchange between different models is relatively straightforward. This mapping helps
platforms. Each model description contains information about answering the question in which anatomical structures in
metadata, section images and annotated domains. Each zebrafish a gene of interest is expressed at a particular
domain is attached with its contour information and 3D developmental stage of the embryo. For example, “Which
surface data. All of the information described in the model anatomical structures of zebrafish that the gene fgf8a is
description file will be extracted and subsequently aggregated expressed at the developmental stage of High-pec?”
into a relational database management system, i.e., MySQL. The result from mapping is the list of structures where
This process is realized by submitting the reconstruction the gene of interest is expressed, along with other related
instance to the TDR data repository through a web quantitative experimental data such as P-value and the
application. significant of gene expression. This result will be used later
on by the web services to generate proper 3D visualization.
B. The Gene Expression Patterns Data
Other than providing controlled vocabulary for textual III. VISUALIZATION OF GENE EXPRESSION IN
annotation, GEMS aims to be an integrative information 3D GRAPHICAL MODEL
system and repository for 3D spatio-temporal patterns of
gene expression. It provides links to related gene expression A. Mapping Gene Expression Data to Geometry
data on other external gene expression resources [6]. GEMS In this context, the gene expression data can be classified
is capable of organizing and comparing multiple spatial into geometric and non-geometric data. Geometric gene
patterns of gene expression at tissue level. GEMS uses the expression data refers to the 3D graphical representation of
same 3D gene expression patterns image datasets as those the locations where a gene is expressed, which, in our case,
for creating reconstruction model for input data. For each 3D are the surface data of 3D gene expression patterns derived
image dataset, we used the DAOZ to provide common terms from 3D image datasets. This type of gene expression data
to describe anatomical features and the developmental stages, can be mapped directly into the 3D visualization scene
e.g., list of anatomical structures and developmental stage together with other 3D anatomical structures data from the
where a particular gene is expressed. We used terms from GO zebrafish atlas. Non-geometric gene expression data, i.e., the
to describe the expressed gene in the image datasets. In semantic and quantitative analysis microarray gene
addition, the input image datasets are annotated with imaging expression data, is represented by 3D annotations which can
conditions and preparation protocol as well. All data be visualized by using 2D/3D texts and symbols and are
annotations have to be done during data submission process. integrated into the 3D scene. Typically, there is a lot of
Due to the lacking of array-based functional genomics data quantitative and semantic gene expression information
in our local resources, we retrieve this information from an compare to the limited area in the visualization scene, therefore
external microarray analysis gene expression resource, the pop-up table and dialog box containing links to further
ArrayExpress Atlas [18]. ArrayExpress Atlas is a curated set information on external information resources will be used.
of gene expression datasets that are publicly available
B. Emphasized Visualization
through a web services. The query results from the web
services are the corresponding experiments and p-values for One approach for visualization gene expression data is to
the differentially expressed genes. WikiPathways Atlas hide and emphasize the geometric data of 3D gene expression
Mapper [23] is an example of online biological pathway and 3D anatomical structures. Important objects, or even just
resource that provides visualization of an integrative pathway a certain object of interest, are highlighted whereas less
interactions data and gene expression data from ArrayExpress important objects are hidden, removed or reduced in
Atlas. perceptibility. Apart from the removal case, this technique
can be accomplished using only color, transparency and
C. Ontology Based Data Mapping outlines for the visualization.
For the visualization of the gene expression data within
3D reconstruction model, both data models have to be IV. VISUALIZATION SERVICE ARCHITECTURE
integrated. In the 3D reconstruction models, we annotate 3D
In this section we will discuss the service architecture of
anatomical domains with anatomical terms from DAOZ, such
our visualization service (Fig. 2). Various information sources
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are accessed to retrieve the required data. The reconstruction [17]. The result is in Microarray Gene Expression Markup
data repository of 3D atlas data and the 3D patterns of gene Language (MAGE-ML) [25] (Fig. 4). The XML-based format
expression are stored in a MySQL database server and the has been developed by The Functional Genomics Data (FGED)
server file system. In addition, in to facilitate access to our society [26] and Object Management Group (OMG) [27].
repositories, TDR and GEMS web services have been
implemented. These web services can be used to develop
client applications providing users a functionality to retrieve
and modify the reconstruction and gene expression patterns
data in the repositories. The Bio-Visualization web service is
an intermediate component that provides standard interfaces
for retrieving data from local and external web services. In
this work, we developed web applications that allow users to
browse and query 3D models in the zebrafish atlas and related
patterns of gene expression. The web application uses the
Bio-Visualization web service to get related microarray data
from external information sources, i.e. the ArrayExpress Atlas,
and deliver an online visualization of gene expression data
within 3D reconstruction models to end users using Java
applets.
A. Web Services
The TDR web service is implemented to enable query
access to the 3D reconstruction data in the zebrafish atlas
repository. In similar fashion, the GEMS web service is
implemented to provide access to data in GEMS. Both web
services can be accessed through the Simple Object Access
protocol (SOAP), and the data structure and available
functions are described in Web Service Description Language
(WSDL). Both SOAP and WSDL are commonly supported
standards [24].
With TDR web service, a complete or partial Figure 2. System architecture of visualization service.
reconstruction model description can be downloaded in After receiving XML results from all of the underlying
TDRML format (Fig. 3). It provides also interfaces to retrieve web services, the Bio-Visualization web service filters out
binary data of a particular reconstruction model, for instance, the unnecessary information received from the ArrayExpress
section images, contour and surface reconstruction Atlas such as the data that is related to the anatomical parts
information. Together, a client obtains all necessary data to which do not exist in the 3D reconstruction model of interest.
create a 3D visualization of a reconstruction model. GEMS The filtered microarray data will be mapped onto the 3D
web service provides a query interface for the client to retrieve reconstruction data received from TDR web service and the
gene expression data based on annotated information, for extended version of TDRML will be generated. This version
instance, gene of interest, stage of development and location of TDRML contains not only the original 3D reconstruction
where the gene is expressed. All the text-based results are data but also contains the quantitative microarray data related
returned in XML format. Both web services also allow the each anatomical structure existing in the 3D model of interest.
client software to publish information to their underlying data In the end, the output TDRML will be delivered to the
repository as well. visualization client, the TDRViewer, over Internet along with
The Bio-Visualization web service is implemented as the the related binary data, i.e., section images, 3D contour and
intermediate component for a client. The web service uses surface information.
TDR and GEMS web services to get access to data in local The Bio-Visualization web service is designed to be
repositories. In addition, Bio-Visualization web service also extensible in order to support more external information
uses the ArrayExpress Atlas web service to retrieve related resources in the future. From the client point-of-view, the
experimental array-based gene expression data from the Bio-Visualization web service provides a consistent
ArrayExpress Repository. The web service allows the user to programming interface for client to retrieve data from
query for condition-specific based on set of genes by name, heterogeneous sources.
organism, and developmental stage. What is returned from
ArrayExpress Atlas web service is an XML containing the B. Web Applications
list of corresponding experimental data related to the gene of
The web applications provide query web interface
interest, each with P-values and an up/down characterizing
allowing users to search for the reconstruction model of
the significance and direction of differentially expressed genes
interest based on anatomical structures, developmental
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the visualization to users.
Figure 3. An example of TDRML resulted from TDR web service:
a complete model description for 3D reconstruction model of
spatial gene expression patterns: 14-3-3 in 48 hpf zebrafish
embryo. The geometrical gene expression data is outlined with red
box.
Figure 5. The first page of the web application shows the list of
available reconstruction models of atlas and 3D gene expression.
Figure 6. The model information page shows links to the related
3D gene expression model and the related whole mount in situ
Figure 4. An example of XML result from ArrayExpress Atlas web
hybridization data in GEMS. More information about each
service. The first part of the result contains gene information such
anatomical structure can also be found by following the link to
as GO and Ensembl identifiers, organism and gene name. The
external resource, ZFIN
second part contains a list of microarray gene expression data from
different experiments. C. The TDRViewer
stages (Fig. 5). For each reconstruction model, the web appli- In order to provide 3D interactive visualization over the
cations also provide the links, based on the developmental Internet, we have been developing and improving a highly
stage, to the related 3D gene expression patterns models and portable 3D reconstruction model viewer, TDRViewer (Fig.
the related whole mount in situ hybridization experimental 7). This viewer is an improved version of the atlas viewer we
data from GEMS (Fig. 6). The data access layer of the web developed earlier for the digital atlas of zebrafish development.
applications was implemented to adopt the newly introduced TDRViewer is implemented using Java technology and can
Bio-Visualization web service. The query performed by user be used as a stand-alone application or can be integrated
is subsequently executed using the underlying web services. with a web interface as a Java applet allowing online interactive
The web applications allow users to publish new 3D data of visualization.
atlas and gene expression to the corresponding repository as The TDRViewer allows users to visualize our datasets in
well. As the web applications receive all required 3D visual- both 2D and 3D views. The 2D view shows a particular section
ization data from the Bio-Visualization web service, they pass image together with its 2D graphical annotations of the
the data to the client, a Java-based 3D viewer applet to deliver domains of interest; anatomical structures for atlas dataset
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6. ACEEE Int. J. on Information Technology, Vol. 01, No. 03, Dec 2011
and the areas where a gene is expressed for spatial gene The viewer uses the available geometric data to construct 3D
expression data. The user has options to change the zooming scene and overlaying the gene expression data onto the 3D
level and the section image. The 3D view provides 3D graphical model of the reconstruction data. As previously
visualization in one of the three view modes: contour view, mentioned, the geometric gene expression data can be
solid view, and surface view. In the 3D view, user has options visualized directly into the 3D scene while the non-geometric
to visualize section plane and section images in 3D scene as data can be visualized as 3D annotations using texts and
well. In this paper, we integrate the TDRViewer with our web symbols. More information on each microarray experiment
application. After receiving the (extended version of) TDRML and results can be found by following the available link which
from the server, the TDRViewer parses all the data and requests redirects user to the ArrayExpress Repository web site.
for additional binary data described in TDRML; section
images, 3D contour and surface information. Aside from the V. CONCLUSIONS
TDRML file, all binary data are compressed on the server
We have developed a visualization system that provides
before sending and decompressed after receiving at the
online visualization of gene expression information within
viewer.
3D reconstruction model for the early developmental stages
of zebrafish; i.e., 24, 36, 48 and 72 hpf. To support this, we
have implemented TDR and GEMS web services that provide
interfaces for a client to access our 3D reconstruction and 3D
gene expression patterns data in the repositories. We also
implemented an intermediate web service, the Bio-
Visualization, as a client for retrieving data from local and
external web services, i.e., TDR, GEMS and ArrayExpress
Atlas. The Bio-Visualization is responsible for filtering
unrelated experimental data received from the ArrayExpress
Atlas and mapping the result onto the 3D reconstruction
model. Mapping all aspects of related gene expression
patterns data is accomplished by using an ontology based
mapping; using annotated ontology terms to query related
gene expression data from local and external resources. The
Bio-Visualization web service generates an extended model
description, TDRML, which contains not only the original
Figure 7. TDRViewer in the digital atlas of zebrafish: a surface view
reconstruction data but also the related gene expression data.
of 3D digital atlas of a 48 hpf zebrafish embryo. The web service is designed to be extensible to support more
information resources in the future. It also provides a standard
data interface to retrieve data from underlying web services.
In order to deliver the visualization to end users, a web
application is developed. The web application provides a
query web interface allowing users to search for the
reconstruction model of interest based on anatomical
structures and developmental stages. The web application
also incorporates the TDRViewer applet allowing users to
visualize the graphically combined data interactively over
the Internet. The geometric representation of the gene
expression data such as the area where the gene is expressed
can be directly integrated into a 3D scene with 3D anatomical
domains but other gene expression data that do not have a
geometric representation (i.e. microarray data) can be
visualized as 3D annotations. To limit the amount of
annotated information in the 3D scene, a pop-up menu or
Figure 8. A surface visualization with a 3D section image of gene
dialog box containing links to further information on external
expression patterns: 14-3-3 gamma2 in a 48 hpf embryo; the gene information resources will be used. In this way, users are able
expression is annotated in white together with some reference to derive relations between the spatial information of 3D
anatomical structures. Related microarray gene expression data on reconstruction models and patterns of gene expression in a
the gene 14-3-3 from ArrayExpress Atlas are annotated in the
lower left corner of the 3D scene. This information indicates the
3D context.
anatomical structures that this gene is expressed and how much it is
expressed. The annotation also provides links to all related
experimental data in the ArrayExpress Atlas.
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7. ACEEE Int. J. on Information Technology, Vol. 01, No. 03, Dec 2011
ACKNOWLEDGMENTS [10] D. Maglott, J. Ostell, K. D. Pruitt, and T. Tatusova, “Entrez
Gene: gene-centered information at NCBI,” Nucleic acids research,
The authors wish to express their gratitude to Gerda vol. 39(suppl 1), pp. D52, 2011.
Lamers, Esther Dondorp, Rebecca Schoon, Laura Bertens, [11] P. Flicek, et al., “Ensembl 2011,” Nucleic acids research, vol.
Monique Welten, Willemijn Spoor and Aimy Sels for 39(suppl 1), pp. D800, 2011.
providing the experimental data and creating 3D [12] “The Edinburgh Mouse Atlas Project.” Available from: http:/
reconstruction models from atlas and 3D gene expression /genex.hgu.mrc.ac.uk.
patterns datasets. This work is partially supported by [13] “The Edinburgh Mouse Gene Expression Atlas.” Available
Netherlands’ council for Scientific Research (NWO) and a from: http://genex.hgu.mrc.ac.uk.
[14] M. Hawrylycz, et al., “Digital Atlasing and Standardization
personal grant from the Ministry of Science and Technology,
in the Mouse Brain,” PLoS Comput Biol, vol. 7(2), pp. e1001065,
Thai Government. 2011.
[15] G. H. Weber, et al., “Visual exploration of three-dimensional
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