Biomedical research labs have used various tools to generate data of unprecedented depth, timeliness and diversity for scientists and clinicians to attack the problems of preventing and curing human cancer. The diversity of data utilizes heterogeneous storage formats (plain text, Excel spreadsheet, Access database, various SQL databases, etc), different database schemas, metadata, and various interfaces for accessing the data. This diversity impedes the integration and interoperation of disparate data systems created in each research lab for the purposes of performing data analyses of multiple types [1Komatsoulis G, Warzel D, Hartel F, et al. caCORE version 3: Implementation of a model driven, service-oriented architecture for semantic interoperability J Biomed Inform 2008; 41: 106-23.]. The solution to this problem is to build data systems utilizing an architecture that facilitates such interoperability.

In 2003, the National Cancer Institute (NCI) launched the cancer Biomedical Informatics Grid (caBIG^TM), an international collaboration to facilitate and enable research teams to share data, applications, and infrastructure that facilitate collaborations that accelerate the conversion of data from information to knowledge [2Eschenbach AC, Buetow K. Cancer Informatics Vision: caBIGTM Cancer Inform 2006; 2: 22-4.]. To accomplish this goal, the caBIG^TM community is developing standards, policies, guidelines, common applications, open-source tools, and middleware infrastructure to enable more effective sharing of data and research tools among scientists and organizations in a multi-institutional environment [3Saltz J, Oster S, Hastings S, et al. caGrid: design and implementation of the core architecture of the cancer biomedical informatics grid Bioinformatics 2006; 22(15): 1910-6.]. In the latest version (v3.0) of the caBIG^TM Compatibility Guidelines [4caBIGTM Compatibility Guidelines Available from: https://gforge. nci.nih.gov/frs/download.php/3948/caBIG_Compatibility_Guidelines_v3.0_Final.pdf ], four maturity levels of interoperability between systems are described: legacy, bronze, silver, and gold.

Under the leadership of the NCI, its Center for Bioinformatics (NCICB) and caBIG^TM participants, many infrastructures, tools, and services (such as: caGrid 1.2 [5caGrid 1.2 Available from: http://cagrid.org/wiki/CaGrid:Softw are:Release:1.2 ], cancer Common Ontological Representation Environment Software Development Kit (caCORE SDK) [6Cancer Common Ontologic Representation Environment Software Development Kit 4.0 (caCORE SDK 4.0) Available from: http://ncicb.nci.nih.gov/download/downloadcacoresdk.jsp ], Semantic Integration Workbench (SIW), and UML Model Loader 4.0 [7Semantic Integration Workbench (SIW) and UML Loader 4.0 Available from: https://gforge.nci.nih.gov/docman/index.php?. group_id=16&selected_doc_group_id=4199&language_id=1 ]) have been implemented to help design, develop, and deploy data and analytical services with full syntactic and semantic interoperability.

caGrid is an underlying Grid middleware infrastructure for caBIG^TM to support fully syntactic and semantic interoperability among resources through a federation of such resources [8Saltz J, Kurc T, Hastings S, et al. e-Science, caGrid, and translational biomedical research IEEE Comput Soc 2008; 41(11): 58-66.]. caGrid is a model-driven and service-oriented architecture that synthesizes and extends a number of technologies such as Globus Toolkit, Mobius Global Model Exchange (Mobius GME), cancer Data Standards Repository (caDSR) [9Cancer Data Standards Repository (caDSR) Available from: http://ncicb.nci.nih.gov/NCICB/infrastructure/cacore_overview/cadsr ], Enterprise Vocabulary Services (EVS) [10Enterprise Vocabulary Services (EVS) Available from: http://ncicb.nci.nih.gov/NCICB/infrastructure/cacore_overview/vocabulary ], ActiveBPEL, Grouper, etc. to provide a standardized framework for the advertising, discovery, and invocation of data and analytical resources [3Saltz J, Oster S, Hastings S, et al. caGrid: design and implementation of the core architecture of the cancer biomedical informatics grid Bioinformatics 2006; 22(15): 1910-6.]. The latest release version is caGrid 1.2 [5caGrid 1.2 Available from: http://cagrid.org/wiki/CaGrid:Softw are:Release:1.2 ]. caGrid 1.2 provides the common grid infrastructure upon which the caBIG^TM silver level compliant grid services and tools are built.

caCORE is an interoperability infrastructure based on Model Driven Architecture (MDA), n-tier architecture, and a common application programming interface (API) for data access [1Komatsoulis G, Warzel D, Hartel F, et al. caCORE version 3: Implementation of a model driven, service-oriented architecture for semantic interoperability J Biomed Inform 2008; 41: 106-23.]. Biomedical data systems built using the caCORE fulfill both aspects of interoperability: exchanging data (syntactic interoperability) and processing the exchanged data (semantic interoperability) [11Tobias J, Chilukuri R, Komatsoulis G, et al. The CAP cancer protocols – a case study of caCORE based data standards implementation to integrate with the Cancer Biomedical Informatics Grid BMC Med Inform Decision Making 2006; 6: 25.]. The caCORE infrastructure consists of an integrated set of three components: a controlled terminology service (the EVS), a standards-based metadata repository (the caDSR), and an information system with an API based on domain MDA [1Komatsoulis G, Warzel D, Hartel F, et al. caCORE version 3: Implementation of a model driven, service-oriented architecture for semantic interoperability J Biomed Inform 2008; 41: 106-23.].

The term “head and neck cancer” refers to a group of biologically similar cancers originating from the upper aerodigestive tract, including the lip, oral cavity (mouth), nasal cavity, paranasal sinuses, pharynx, and larynx. Head and neck cancer is highly curable if detected early. The effective treatment for head and neck cancer is usually some kind of surgery, but chemotherapy and radiation therapy may also play important roles [12Head and Neck Cancer Available from: http://en.wikipedia.org/ wiki/Head_and_neck_cancer ].

We designed and implemented the head and neck cancer tissue database (HNCTD) system following the cancer Biomedical Informatics Grid (caBIG^TM) paradigm. The system fully supports syntactic and semantic interoperability. It is caBIG^TM silver level compatible according to caBIG^TM compatibility guidelines [4caBIGTM Compatibility Guidelines Available from: https://gforge. nci.nih.gov/frs/download.php/3948/caBIG_Compatibility_Guidelines_v3.0_Final.pdf ]. The HNCTD is an Internal Review Board (IRB)-approved Health Insurance Portability and Accountability Act (HIPAA) compliant data system. Currently, the HNCTD contains information on 209 cases of head and neck squamous cell carcinomas (HNSCC) from 1996-2003. All tissues in the database are formalin fixed, paraffin embedded tissues housed at either Emory University Hospital or Emory Midtown Hospital. Information from consented patients is extracted from the Surgical Pathology files in the Department of Pathology and Laboratory Medicine [13Wang H, Kuehn A, Bouzyk E, et al. Web-based head and neck cancer tissue database American Association for Cancer Research (AACR) 2009 annual meeting poster, April 18-22, 2009, Denver, CO ].

The information in the HNCTD includes date of birth, date of diagnosis, tumor site, tumor stage and grade, smoking history, radiation treatment, chemotherapy treatment, date of recurrence, and date of last follow up or date of death. In addition, if the patient developed a second primary tumor the related information was also documented. The database is divided into two groups: no metastases (NoMET) and metastases (MET).

We designed and implemented the head and neck cancer tissue database system based on the caBIG^TM paradigm. We utilize the open source software such as ArgoUML (the UML modeling tool) [14ArgoUML Available from: http://argouml.tigris.org ], caCORE SDK 4.0, caGrid 1.2, and Introduce (the caGrid service creation toolkit) [15Introduce Available from: http://cagrid.org/wiki/Introduce ], etc. The process flow for the system design is shown in Fig. (1).

Fig. (1) Process flow for the system design.

The algorithmic steps for the process flow are described as:

End.

According to step 1, we first need to create the object and data models for the underlying database system. Here, we use ArgoUML 0.26, a freeware application, to create the models. The output of this procedure is a UML (XML format) file. As we mentioned before, the head and neck cancer tissue database is divided into two groups: metastasis and non-metastasis. Therefore, we model domain objects in two classes. Screenshots of the object and data models in ArgoUML 0.26 are shown in Figs. (2, 3).

Fig. (2) Object models of the HNCTD.

Fig. (3) Data models of the HNCTD.

One design requirement of the HNCTD is that principle investigators (PIs) and researchers who use the system can add new columns (biomarks) to the existing MET and NoMET tables, which means the database schema changes over time. In next subsection, we describe the principle of a semi-automatic time variant schema-enabled UML file generator. Basically, it is a reengineering process to get new domain object and data models using existing database schema.

Semi-Automatic Time Variant Schema-Enabled UML File Generator

We are able to automate the generation of the UML file each time the HNCTD schema is modified. A script is run on the web server at intervals specified by the administrator. The script queries the database and returns every column. The query is then compared to a previous query to check for any changes in the database’s state. If a change has been detected, the script modifies the UML file appropriately and notifies the administrator of the change via e-mail. The administrator can run the SIW to check the new UML file and submit it to the NCICB for annotation and loading into the caDSR. The UML file in use by the caCORE SDK is replaced by the modified UML file so that access to up-to-date data is always available. The process flow of the semi-automatic time variant schema-enabled UML file generator is shown in Fig. (4). The script is available for downloading at: http://sisyphus.emory.edu/UML_generator.zip.

Fig. (4) Flowchart of UML file generator.

System Architecture

Because the database contains identifiable patient information, such as patient’s name, medical record number, date of birth, etc., we prioritize the security of the whole data system to make it a HIPAA compliant. We integrate the Common Security Module (CSM) [16Common Security Module Available from: http://ncicb.nci.nih. gov/NCICB/infrastructure/cacore_overview/csm ], Grid Authentication, and Authorization with Reliably Distributed Services (GAARDS) [17Langella S, Hastings S, Oster S, et al. Sharing data and analytical resources securely in a biomedical research grid environment J Am Med Inform Assoc 2008; 15(3): 363-73.] into the system architecture. The high level architecture of the caGrid-enabled caBIG^TM silver level compatible HNCTD system is shown in Fig. (5).

As we mentioned before, we apply the caCORE SDK 4.0 with CSM enabled to our approved annotated model to generate a ‘caCORE-like’ data system. The generated data system only supports querying (to be discussed in Results section), but not data input (to be discussed in Results section). Therefore the data system is read-only.

In Fig. (5), there are three workflows (red line, green line, and orange line) to support the web-based user interface and one workflow (blue line) to support the caGrid data service API.

Fig. (5) High level architecture of the HNCTD system.

Fig. (6) A scatter plot of patient’s Intergrin Beta 1 value by his/her age in years.

Fig. (7) A boxplot for comparison of Intergrin Beta 1 between non metastasis and metastasis patients.

1. Workflow 1 (red line): The PIs and researchers of the head and neck cancer Specialized Programs of Research Excellence (SPORE) [18Head and Neck Cancer Specialized Programs of Research Excellence (HNC SPORE) Available from: http://spores.nci.nih. gov/current/hn/hn.html ] are internal users of the database system. They can interact with the web browsers to retrieve the archived head and neck cancer tissue data and input new tissue information. Results section will describe the design of this data input interface.
2. Workflow 2 (green line): The CSM administrator utilizes the User Provisioning Tool (UPT) [19User Provisioning Tool (UPT) Available from: https://wiki.nci.nih. gov/display/caCORE/FAQs+-+CSM+-+UPT#FAQs-CSM-UPT-CommonSecurityModuleUserProvisioningTool(UPT) ], a web-based management tool for authentication and authorization of users of the underlying database system, to set up credentials and different levels of access privileges for data, methods, and objects for external users. The CSM uses the credential provider’s database to authenticate and the common authorization schema and database to authorize.
3. Workflow 3 (orange line): The head HNCTD system’s external users use web browsers to query the tissue data. Firstly, the system will interact with the integrated CSM for authentication. If a user’s credentials are valid, the user can query the database according on assigned access privileges.
4. Workflow 4 (blue line): The HNCTD system also provides the caGrid data service API for third party applications to access the database with GAARDS-enabled security control. This data service interface supports fully syntactical and semantic integration among disparate systems.

To further improve treatment for cancer patients, it is necessary to conduct translational studies which link clinical outcomes with tissue based molecular data and unravel the mechanism of cancer in the molecular point of view. Some of the challenges in contemporary cancer translational research include, but not limited to, data sharing, data complexity, and organizational complexity. A sharing database built with the caBIG^TM paradigm is the answer for these challenges. Our database is established with the core of caBIG^TM paradigm, such as the XML, model driven architecture, object-relational mapping, semantic web, and grid computing technologies. Therefore, our database is easy to upgrade in the future and a similar database as ours can be easily established in other institutes according to their needs. In the market, caTissue is a good alternative caBIG^TM’s biorepository tool for biospecimen inventory management, tracking, and annotation. This tool enables users to contribute and retrieve data for the purpose of tissue storage, quality assurance, and distribution of biospecimens [22caTissue Suite Available from: https://cabig.nci.nih.gov/tools/catis suesuite ]. caTissue suite is open source, but its full service support requires high license fee.

Our HNCTD system mainly stores head & neck cancer clinical information. The system is designed and developed according to caBIG^TM paradigm. It facilitates the data sharing based on the open standards and has a user-friendly graphical user interface (GUI) to help access the patient data in the database. Because the HNCTD stores patient’s identity and private information, we put a lot of efforts for the security of the system in order to satisfy the HIPAA requirements. The HNCTD system also has some limitations. For example, it does not support the storage and retrieval of biospecimen such as image; it cannot integrate with the OnCore clinical system running in Winship Cancer Institute of Emory University; and it has not been integrated with caTissue Suite running in Emory University. But we are endeavoring to overcome these limitations by redesigning the system with caCORE SDK 4.1 after a future release of caGrid is available.

The HNCTD system is developed based on the caBIG^TM paradigm. It demonstrates the effectiveness of rapid application development for building ‘caCORE-like’ data system using model driven architecture (MDA) and n-tier distributed computing architecture methodology. The system is built with a set of open source applications that are easily accessible to any application development team. We deploy our caCORE SDK-generated data system on the caGrid infrastructure using the Introduce toolkit to make the whole system caBIG^TM silver level compatible. The HNCTD system realizes the syntactical and semantic interoperability among multisite which host the head & neck tissue data. In addition, the system has a lot of special features, such as: reporting, user management, logging, and adding/deleting new biomarkers.

Currently, the HNCTD is just open to the SPORE PIs, researchers, and biostatisticians. For the external users, he/she should register first and wait for the system administrator’s approval. In the future, we are going to advance the HNCTD by developing analytical services for the data mining of stored head and neck cancer tissue information. Also, we will develop a sophisticated time variant schema-enabled UML file generator for more general user case. We will also redesign the system to adopt caCORE SDK 4.1 (for the support of an API which enables data input) once we obtain a future release of caGrid.