Abstract

Summary: Standardized phenotyping protocols are essential for the characterization of phenotypes so that results are comparable between different laboratories and phenotypic data can be related to ontological descriptions in an automated manner. We describe a web-based resource for the visualization, searching and downloading of standard operating procedures and other documents, the European Mouse Phenotyping Resource for Standardized Screens—EMPReSS.

Availability: Direct access: http://www.empress.har.mrc.ac.uk

Contact:e.green@har.mrc.ac.uk

INTRODUCTION

With the completion of the human, mouse and rat genome sequences, genetics is set to enter a new era of discovery. It will now be possible to interpret the relationship between gene and phenotype, and gene and disease in the context of a comprehensive knowledge of the gene content of mammalian genomes.

To fully realize the potential of model organisms to bridge the gap between phenotype and genotype, it is essential to provide structured descriptions of phenotypes that can be interpreted in a consistent fashion. We have recently suggested ways of using combinations of ontologies to describe mouse phenotypes (Gkoutos et al., 2004a,bhttp://genomebiology.com/2004/6/1/R8) and provided tools that allow the storage, active updating and visualization of multiple ontologies (Gkoutos et al., 2005http://bioinformatics.oupjournals.org/cgi/reprint/bti147v1). Vital to this approach is the establishment of standardized methods (standard operating procedures, SOPs) for the measurement of phenotypic attributes.

EUMORPHIA (http://www.eumorphia.org) is a consortium of 18 research institutes across 8 European countries which is developing and standardizing SOPs for mouse phenotyping for all body systems, in collaboration with other world centres and in consultation with clinicians and human geneticists. The European Mouse Phenotyping Resource for Standardized Screens (EMPReSS) constitutes the first phase of this initiative and consists of a set of first line SOPs: SOPs that are simple to apply, require little specialist equipment and can be used for preliminary screening of mutant phenotypes. Here we present a web-based resource which allows searching, retrieval and visualization of EMPReSS-related documents (SOPs, appendices and annexes) held in a custom database.

SOP DEVELOPMENT AND VALIDATION

The SOPs within EMPReSS have been developed to form a coherent sequence of tests that can be performed to fully characterize a mutant mouse. They have been developed by dedicated working groups drawn from EUMORPHIA consortium members and made up of leading European experts in mouse phenotyping (http://www.eumorphia.org/). Each SOP is subjected to validation by comparison of results on selected inbred mouse strains and/or selected mutants at more than two EUMORPHIA laboratories. SOPs are grouped according to the system to be characterized (clinical chemistry and haematology, sensory systems, etc.).

IMPLEMENTATION

The system is composed of two tiers: the database backend (SOPdb) and a user interface.

An open source XML database [eXist (http://exist.sourceforge.net/)] was used to implement SOPdb. The user interface is made up of a JavaScript menu and two types of JAVA servlets:

  • Query servlets—these connect to the database, execute queries and retrieve results via the XML:DB application programming interface (API) of the database.

  • Browsing servlets—these connect to the database and retrieve requested documents via the representational state transfer (REST)-style HTTP interface of the database.

XML documents are transformed to HTML presentations using XSLT, a language for XML transformation for browser visualization (http://www.w3.org/TR/xslt). A print formatter [FOP (http://xml.apache.org/fop/)] is invoked with XSLT to produce PDF-formatted documents.

USER INTERFACE

The user interface displays four frames.

The main frame is situated in the middle of the browser. This frame is the main visualization area for documents as well as the results generated by queries.

The search frame, situated above the main frame, facilitates searching of the documents. Searches can be refined by accessing different metadata fields. The results summary page, generated in the main frame, consists of the document name, number of hits and a link to view these hits. The number of hits displayed refers, depending on the type of search, either to the number of sections within the document or to the number of points within a named section. The query servlets group the returned documents according to the phenotypic area and colour code them depending on their type by accessing the appropriate metadata categories.

The navigation frame is situated to the left of the main frame. It contains a JavaScript-encoded hierarchical tree, with the documents categorized into phenotypic areas. These tree representations are automatically generated from assay vocabularies by custom parsers. Browsing a phenotypic area results in its description being presented as well as its expansion to reveal its substructure. The description gives general and background information about the selected phenotypic area and denotes the usage of SOPs in phenotyping batteries in a table, e.g. age of mouse to be tested and the order in which the SOPs should be carried out. These phenotyping battery tables, as well as any associated information, are automatically generated from the metadata carried in the XML documents.

The links frame situated below the main frame, dynamically changes its content, depending on the main frame content, to provide printing and/or navigation links.

The interface has been tested and provides full functionality using Netscape 7.1, Firefox 1.0 and Internet Explorer 6.0 running on Microsoft Windows XP and Netscape 7.1 and Firefox 1.0 running on Apple Macintosh OS X. During testing it was noted that some popular browsers (Safari 1.2 and Internet Explorer 5.2) running on Apple Macintosh OS X do not provide full functionality as they do not implement the W3C recommendations for XML and XSLT processing.

FUTURE WORK

The protocols in EMPReSS represent the first stage of the development of a comprehensive set of phenotyping protocols by the EUMORPHIA consortium. Subsequent updates of the system will present more specialized (secondary and tertiary) screens. We are currently in the process of developing links between EMPReSS, phenotype ontologies (Gkoutos et al., 2004b), assay controlled vocabularies (Gkoutos et al., 2004b) and databases that contain phenotypic data (Strivens et al., 2000; Blake et al., 2000). This will facilitate the automatic generation of phenotype descriptions and advanced mining, indexing and retrieval mechanisms. We are also considering ways of linking this dataset to that held by the mouse Phenome Project (Bogue, 2003). These efforts, coupled with tools like CRAVE (Gkoutos et al., 2005), will facilitate the realization of a semantic web implementation (Gkoutos et al., 2001) that is phenotype-aware.

The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.

This project is funded by the European Commission under contract number QLG2-CT-2002-00930. We thank Simon Greenaway, Hilary Gates, Steve Brown and the EUMORPHIA Consortium for helpful discussions.

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