The Stanford Tissue Microarray Database

Robert J. Marinelli 1 2 Kelli Montgomery 0 Chih Long Liu 4 Nigam H. Shah 4 Wijan Prapong 4 Michael Nitzberg 2 Zachariah K. Zachariah 2 Gavin J. Sherlock 3 Yasodha Natkunam 0 Robert B. West 0 Matt van de Rijn 0 Patrick O. Brown 1 2 Catherine A. Ball 2 0 Department of Pathology, Stanford University School of Medicine 1 Howard Hughes Medical Institute 2 Department of Biochemistry, Stanford University School of Medicine 3 Department of Genetics, Stanford University School of Medicine , Stanford, CA, USA 4 Department of Medicine, Stanford University The Stanford Tissue Microarray Database (TMAD; http://tma.stanford.edu) is a public resource for disseminating annotated tissue images and associated expression data. Stanford University pathologists, researchers and their collaborators worldwide use TMAD for designing, viewing, scoring and analyzing their tissue microarrays. The use of tissue microarrays allows hundreds of human tissue cores to be simultaneously probed by antibodies to detect protein abundance (Immunohistochemistry; IHC), or by labeled nucleic acids (in situ hybridization; ISH) to detect transcript abundance. TMAD archives multi-wavelength fluorescence and brightfield images of tissue microarrays for scoring and analysis. As of July 2007, TMAD contained 205 161 images archiving 349 distinct probes on 1488 tissue microarray slides. Of these, 31 306 images for 68 probes on 125 slides have been released to the public. To date, 12 publications have been based on these raw public data. TMAD incorporates the NCI Thesaurus ontology for searching tissues in the cancer domain. Image processing researchers can extract images and scores for training and testing classification algorithms. The production server uses the Apache HTTP Server, Oracle Database and Perl application code. Source code is available to interested researchers under a no-cost license. - The Tissue Microarray Database (TMAD; http://tma. stanford.edu) at Stanford University is a web-based system that provides researchers with tissue microarray design tools, image scoring and annotation tools, data sharing mechanisms, an image archive, an analysis toolset and publication mechanism. Tissue microarray experiments provide in situ detection of protein, DNA and RNA targets on hundreds of tissue specimens per slide through chromogenic and fluorescence stains. Images at subcellular resolution of each specimen are taken for subsequent scoring and analysis. Each image is rich in multivariate information including cell composition and morphology as well as stain localization. In 1987, Wan et al. (1) described a method to immunohistochemically stain many different tissues simultaneously on a single slide, the stated advantages being great economies in time, reagents, tissue specimens and antibodies. Tissue microarrays in their current form were developed by Kallioniemi and Sauter (2) for highthroughput molecular profiling of tissue specimens. Twenty years later these advantages have proven to be true, and today the Stanford Tissue Microarray Database contains over 200 000 stained and scored tissue microarray images along with associated tissue metadata describing the tissues, associated clinical diagnosis and follow-up where available. TMAD includes tools for tissue microarray design, image and scoring import, and analysis tools via an intuitive web interface. Several database object models (3,4) and systems (510) have been described for managing tissue microarray data. Goals range from metadata modeling to comprehensive management of tissue microarrays for large research groups. While there are similarities, TMAD differs by providing public access to raw tissue microarray experiment data. As part of ongoing collaborations with nonUS research groups we have constructed a straightforward method to import images and metadata from collaborating institutions, eliminating sample and slide transportation between institutes and resulting complications and delays. The Human Protein Atlas project (11,12) has published a comprehensive public access antibody-based protein atlas based on the systematic creation of protein-specific antibodies applied to tissue microarrays and used to create expression and localization profiles in 48 normal human tissues, 20 varied cancers as well as 47 cell lines. Their version 2.0 Atlas available at http://www.proteinatlas.org/ includes over 1 200 000 images corresponding to over 1500 antibodies. We believe that TMAD provides a complementary service with selected probe data across a wider variety of disease tissues along with an integrated tissue microarray toolset. The Nordic Immunohistochemical Quality Control organization (13) publishes very detailed IHC results including thousands of images for clinically important epitopes. Their data comes from over 100 laboratories that participate in quality control studies by performing independent stains on serial sections of multiple tissue blocks that are then verified independently. Their in-depth information on antigens and protocols is available at http://www.nordiqc.org/. While TMAD includes standard clinical antibody probes, it adds many novel emerging antibody probes useful for the molecular sub-classification of cancers. We designed TMAD to allow for the release of raw supporting data (including images) at the time of publication for all experiments held in TMAD. Researchers using TMAD observe a policy of making data publicly available through TMAD at the point of publication (or earlier) (1420). We have implemented automated mechanisms that allow tagging the complete set of experiments associated with each new publication, resulting in nearly one click publication of the raw data (stained images and scores assigned by pathologists) through TMAD. As of July 2007, TMAD contained 205 161 images archiving 349 distinct probes on 1488 stained tissue microarray slides. Of these, 31 306 images for 68 probes on 125 slides have been released to the public. By focusing on the release of data for public use, we anticipate improved collaboration among data model and database developers. Our real world data can be used to validate both object models and eXtensible Markup Language (XML) (21) based tissue microarray data exchange specifications (22,23). Images from multiple automated microscopes using varied imaging modalities and stains should provide rich training and test datasets. As our user community is located around the world, all user interaction is via the Internet through standardscompliant web browser pages. All functions are available to authenticated Stanford researchers and their collaborators with authorization to access given experiments governed by experiment to group mappings maintained in the database. Data access is restricted by group until publication, at which time it is made visible to the public. Public data may be searched, the analysis pipeline may be run and both input and output datasets may be freely downloaded (...truncated)