All institutions participating in the CPCTR have Institutional Review Board (IRB) approval for human subjects research. Each CPCTR institution develops its own local protocols to protect the confidentiality and privacy of human subjects and obtains local IRB approval for all CPCTR activities. The IRB assurance numbers for each cooperating institution are: New York University – M1177; Medical College of Wisconsin – M1061; University of Pittsburgh Medical Center – M1256; and George Washington University Medical Center – M1125. Tissue data records from the cooperating institutions are submitted to a central data manager (Information Management Services, Inc., contracted by the NCI) as de-identified records. All institutions assign an arbitrary number to each record before submitting the de-identified record to the central database. This ensures that the central database has no links connecting records to patients. In addition, HIPAA's proscribed set of 18 data elements are omitted from core sample records (so-called safe harbor approach to HIPAA-compliance) 18.

The CPCTR maintains a publicly available Manual of Operations that describes its tissue collection procedures and policies 19.

Pathological characterization of specimens involves review of all cases by a CPCTR pathologist using diagnostic criteria explained in the publicly available CPCTR histologic atlas and manual 20.

Protocols for the construction the TMA block and TMA slide are publicly available documents available at the CPCTR web site and linked from the TMA Database 1617.

The Specification is an open access document that can be used without restriction 9.

The Specification requires four general sections for each TMA file:

1) Header, containing the specification Dublin Core identifiers, 2) Block, describing the paraffin-embedded array of tissues, 3) Slide, describing the glass slides produced from the Block, and 4) Core, containing all data related to the individual tissue samples contained in the array. The simplest possible structure for a conforming TMA file consists of nothing more than empty tags designating the four required sections [see Figure 2] 9.

Common Data Elements (CDEs) are metadata tags that describe the data elements included in an XML database. To be of value, CDEs must be well-defined, uniquely identified and available for human review or computer access. Eighty CDEs, conforming to the ISO-11179 21 specification for data elements constitute the XML tags provided in the Specification 9. CDE descriptors are publicly available 14. However, the only CDEs that must appear in any conforming TMA file are the section CDEs (header, block, slide and core), the root CDE (histo) and the tma CDE itself (tma). A set of six simple semantic rules describe the syntax for the data exchange specification 9.

The Specification was designed for maximal flexibility. Flexibility in the first version of an XML specification permits the addition of greater structure in later versions built on tested implementations. A similar approach has been used for ANSI/HL7 Common Data Architecture (CDE) wherein the earliest version (Level One) is intentionally sparse 22. At this time, there is no DTD (Data Type Definition) or Schema included in the Specification. For those wishing to use a DTD, a Specification-compliant DTD has been prepared by David G. Nohle, Ohio State University Department of Pathology and the Mid-Region AIDS & Cancer Specimen Resource (ACSR) 23.

Constructing a TMA Database consists of the following:

1. Filling the four sections (header, block, slide and core)

2. Assembling the four sections into a TMA file with a proper file declaration, root element and TMA CDE.

3. Validating that the TMA file conforms to the specification

The header, block and slide sections of the TMA will vary only slightly from project to project within a laboratory. The CPCTR header, block and slide sections were prepared "by hand" using the section-specific CDEs provided in the specification.

The header section contains descriptive information about the file and its contents. With the exception of one CDE (filename), the header CDEs are the same CDEs used in the Dublin Core set of XML identifiers used by librarians. Detailed information describing the Dublin Core elements is available 13. A link to the Dublin Core elements is also included in CPCTR TMA database. The first few lines of the TMA database are shown [see Figure 3]. The block and slide headers of the TMA database are short and are also completed manually.

The cores are distributed for each block in an array, with cores assigned to specific locations [see Figure 4], and all the cores in an array are assigned to a slide, which is a numbered section derived from a block [see Figure 5]. The core section contains annotated data for each core in the TMA. The central database for all CPCTR tissues is maintained as an Excel database by an NCI-contracted information management service (IMS, Rockville, MD). IMS extracts an Excel sub-file consisting of records pertaining to the tissues selected for the TMA block. CPCTR-specific data elements included in the IMS records are publicly available 15.

A Perl script was written that converts Excel files to XML, enclosing the data associated with the spreadsheet cells to XML CDEs corresponding to the column headings. This creates the "core" section of the TMA database. A sample of an XML-tagged extracted data record is shown [see Figure 6]. The Perl script is available as an open access file with this article [see Additional file 1].

The CPCTR prostate cancer TMA consists of 299 core samples distributed in four blocks, each block having 300 arrayed cores. Each block contains about 150 core samples in two different locations in each block. The core duplicates are staggered in the array, to maximize the chance that a given core will be represented if an area of the slide section is lost in processing. The distribution of one set of core samples in multiple array locations in four blocks yields a complex TMA that cannot be adequately represented by separate descriptions of each block. The Specification permits multi-block TMA files. Within the block CDE are the nested sets of four blocks that compose the complex TMA. Each core CDE is nested within a specific block CDE, and one core may have two associated array locations [see Figure 6].

The four sections are concatenated as a single XML database file. The CPCTR database file is provided with this manuscript [see Additional file 2].

Once a TMA database is prepared, it needs to be validated to ensure conformance with the Specification. At this time, all TMA files should be validated using a software implementation written in Perl and distributed as an open access supplemental file with the Specification and with this publication [see Additional file 3]. The validating script requires a Perl installation but should operate equally well on any operating system. The validation software has a simple command-line interface. When the file successfully validates, the Perl script outputs the encountered CDEs from the Specification, a statement that the file is valid, and a one-way hash value specific for the validated file [see Figure 7].

The Perl scripts and files for the production of TMA databases that meet the Specification are available with this publication. The example prostate cancer TMA database is available as a supplementary file with this article [see Additional file 1]. The actual tissue microarray slides are available after an application process Although the CPCTR is a non-profit, government-sponsored resource, a surcharge is attached for glass slides, to help defray a portion of the costs of TMA production. The application process and charges are described at the CPCTR web site 8. Questions regarding any aspect of the CPCTR can be directed to the CPCTR email query service [ask-cpctr-l@list.nih.gov].