BACKGROUND
taking laboratory discoveries and translating them into clinically useful diagnostic tests or targeted therapies requires the use of human samples for validation.
this process, referred to as translational research, requires carefully storing and maintaining detailed annotation of these samples.
tissue microarray  technology has created and efficient manner to accelerate discovery but has also created a new demand for databases to handle a large number of data points in a regulatory compliant manner.
the initial description of tissue microarray  technology by kononen et al.
<cit>  began a revolutionary change in the way that many tissue based research studies would be performed.
tma technology allows for the precise placement of typically up to 400– <dig> tissue samples into a single block in an array.
the approach some major advantages as compared to using standard slides.
tma technology decreases experimental variability, conserves tissue resources and provide a dramatic cost benefit once the initial tma block is constructed  <cit> .
tma technology also presents some challenges, which include issues related to sampling strategies  <cit> , evaluation of tma samples <cit> , ability to store and maintain the data derived from tma experiments  <cit> , and analysis of tma datasets  <cit> .
all of these issues are important to understanding the utility of tma technology and to help maximize its potential as a research tool.
in the collaborative setting of the specialized program of research excellence  for prostate cancer, a program for translational research, pathologists from the university of michigan, baylor school of medicine, and johns hopkins developed a working model to deal with these challenges.
we recognized some fundamental guiding principles:  tma technology provides a means to conserve finite tissue resources, while at the same time increasing the number of studies for qualified investigators;  tma technology is most valuable if data generated from each experiment is recorded and returned to a central database thus increasing the annotation and value of each sample; and  tma technology is ideally suited for collaborative biomarker research.
these important guidelines suggested to our working group that tma databasing tools would be a cornerstone to our translational research activities and would grow in importance over time and with the increasing number of experimental data.
in  <dig>  we described the blueprints for developing a means of storing, maintaining and evaluating tma data using internet tools and a relational database  <cit> .
from this original work has emerged an integrative framework for dealing with all aspects of tma research .
at the center of this process is an internet-based database system referred to as profiler.
this system has the capability of handling/managing a wide variety of sample types from different disease states  and because of its modular design can also store and maintain other types of molecular data including expression array data, karyotype data, and snp array data.
here within, we describe the process that has developed to deal with tma experiments and the profiler system used to manage the data associated with these experiments.
RESULTS
over the past  <dig> years, the profiler system has developed into a key ingredient into the process for tma based research.
the data included in this process not only includes the alpha-numeric annotations to each histospot but also the images that are associated with each study.
the profiler system has demonstrated a capacity to be extendable to other organ sites besides prostate and modular allowing for analysis of other types of molecular data.
to date multiple studies were built/conducted using this system  <cit> .
the following is a description of the process that has developed over years of tma research .
tma conceptual research design
tma design is crucial because it should address the needs of future experiments .
once the tma design is thought out, two different types of maps are created to assist in the tma fabrication, a picture map  and a punching map .
the picture map is a visual representation of the tma showing a lay out of all the tma cores.
different tissue types or diagnoses can be shown in colors.
the picture map provides orientation.
the punching map is needed for taking biopsy cores with the manual arrayer.
this map shows the x and y localization of each tma core and is used during the construction of the tma.
the physical configuration of the tma is entered into the profiler database.
all future studies  will maintain this structure and use the information from the punch file to help determine: 1) the type of tissue; 2) targeted diagnosis; 3) the x and y coordinates ; and 4) associated research identification code for potential links to clinical and pathology data from external or internal databases.
experiments
each antibody is evaluated using a small test tma.
a test tma consists of an assortment of different tissues to test the best experimental protocols including pre-treatments and dilutions.
the test tmas are then reviewed by a pathologist and the tma experiment will then be performed using these optimal conditions .
this process prevents wasting valuable large tmas.
scanning
as described in the methods section, the tma is scanned and the images are entered into the profiler database server for evaluation.
initially all slides were scanned with the bliss system.
however, more experiments are being performed using the other imaging systems .
study set up
at an administrative level, the research group determines who should be permitted access to evaluate the tma.
using profiler study set up tools, the administrator is given a set of options for the reviewer to have available at time of review.
for example, in some studies, staining intensity and percentage intensity are the only parameters that need to be annotated.
in another study, nuclear grade may be required.
these types of decisions are based on the goals of the study.
once the study is set up, the reviewers are sent a unique user password for them to gain access to studies they are responsible for reviewing.
the advantage of this approach is flexibility.
as we have seen over the past  <dig> years, each research group needs to enter data fields that are not readily generalizable to all other groups nor are they relevant.
as a specific example, tumor grading systems are often organ specific .
therefore flexibility is critical to allow each group to be able to enter relevant data for their studies.
one major disadvantage is that we do not anticipate being able to develop a "standard" set of look up tables to cover every research groups needs and therefore a programmer will be needed to make modifications to the system until it meets an individual groups needs.
tma evaluation
each user gains access to a tma slide based on their experiments.
the reviewer can only see their own folders and not those from other research groups.
these safety features are part of the oracle security tools that are required for e-commerce.
as the user views each tma core image, information about the tma core is displayed in the region of the screen adjacent to the diagnostic parameters .
the tma core's x and y coordinates are displayed with its organ type and target diagnosis.
the diagnostic parameters are inputted along with stain intensity, staining location, and path diagnosis using pull down menus.
comments can be entered in a separate free text field.
once a tma slide evaluation is complete, the user can finalize the evaluation preventing any further changes in the diagnostic parameters.
the study design is flexible differing dramatically based on the research group.
clinical and pathology information can be either presented or not.
for example, the tma map is usually available .
however, one could imagine a study where the investigators may know the design of the tma and therefore would be biased if this information were available at time of review.
we have also found that the tissue diagnosis of each histospot is critical during the evaluation process.
when drilling deeper into a block, tma samples may demonstrate different tissue types  due to tumor heterogeneity.
data storage
after each tma core is reviewed and diagnostic parameters are inputted, the user will submit the information and the next tma core image will be displayed with all the diagnostic parameters reset for another submission .
the diagnostic data is uploaded onto the data server.
analysis
the methods used to analyze tmas are beyond the scope of this current study.
however, it is important to point out that, once a tma slide has been finalized, all of the raw data is maintained on the profiler system and available for analysis.
the data and images can be queried based on desired features such as all tumor samples staining positive for biomarkers x, y, and z. this feature recalls previous evaluations from the server based on specified parameters  and displays the data and the corresponding image showing multiple evaluations of one patient adjacent to one another.
query results and single experiment data can be exported as an excel spreadsheet or as a tab delimited text file for further statistical analysis.
the system is capable of displaying uploaded data from automated immunostaining results from the chromavision system, so as all the data stored in the database being related to a specific dataset of interest.
additional resources
the profiler system can be setup to assist in submitted publications as supplementary data showing all information about the study giving raw data as well as the images of the tma slides.
this was recently done with the publication of a biomarker study called jagged <dig> <cit> .
profiler usage
the profiler system is currently running at dana farber harvard comprehensive cancer and the university of michigan comprehensive cancer center containing  <dig>  k and  <dig>  k data points, respectively.
<dig> tma slides have been scanned and  <dig> k histospots evaluated by  <dig> pathologists.
of the tmas evaluated,  <dig> major user groups use the systems including  <dig> s.p.o.r.e.
groups with two groups having directly linked clinical data containing over  <dig> patients giving immediate access.
availability and requirements
one can register for a standard non-anonymous demonstration <cit> .
this demonstration provides the user with some but not all of the features of the database.
the system is accessible via the internet and currently works on pc computers using internet explorer.
discussion
in the current study, we describe the evolution of a process that has developed over the past  <dig> years to use tmas for biomarker studies.
at the center of this process is a relational database tool, profiler, which allows users to handle all steps of tma research .
the profiler system was originally developed for work in the field of prostate cancer biomarker research but has now been expanded to allow for the analysis of any tissue type.
this system has been extensively used by investigators from several academic institutions.
the key feature to profiler's functionality is the ability to access tma images over the internet and enter data in a secure manner.
during the course of our first tma experiments, we observed that there was a high probability of annotating the wrong tma histospot when multiple pathology reviewers were involved due to density of these tmas, which typically have  <dig> tma cores.
we therefore developed a system to present tma images to the reviewer thus avoiding having to physically identify the tma histospot by examining the slide.
manually evaluating a tma slide under the microscope can be a common source of error, since it is reasonably easy to loose track of which samples have been evaluated.
profiler keeps track of which cores have been reviewed so the entire tmas can be analyzed over a single session or multiple sessions.
the integration of tma data with other data sets is critical for the development of biomarkers.
in version  <dig>  of profiler, other databases can be loaded securely onto the system.
over the past  <dig> years, several groups with rich clinical and pathology data have used the system to evaluate molecular biomarkers.
profiler's database keeps different datasets separate from each other, maintaining private space for research groups to develop projects.
this has become an important issue with some cooperative groups that need to maintain control over their clinical databases based on pre-existing sharing agreements.
worldwide, one of the guiding principles for any database that maintains clinical data is compliance with local regulatory agencies to protect patient confidentiality.
in the united states, hippa regulations guide how clinical databases can be integrated with the data stored in profiler.
we have developed two approaches.
the first approach is to maintain both datasets separately and then the integration of the profiler tma data is performed by the clinical group.
they are then typically able to provide a completely integrated dataset without any patient identifiers.
this dataset is now ready for analysis.
the second approach is to integrate the clinical data into the profiler system as a separate clinical module.
we have done this for several groups and have used oracle security and administrative tools to ensure that the clinical module is only available for viewing and modifying by the designated clinical groups researchers.
all queries require the group leader's approval and each time a query is performed on the clinical data, the time, date, and investigator are recorded and send via email to the group leaders.
this monitoring feature is critical to ensure that the clinical database is only used by qualified investigators.
the system administrator assigns users different levels of access at different sites using password protected user profiles.
the tracking of standard operating procedures  is critical for the interpretation of experimental results over time.
therefore the development of a "laboratory book" feature as a new module is critical to the adequate annotation of samples and experiments.
we are currently developing the ability to input experiment related data such that a laboratory technician could annotate the staining protocol of each experiment .
in addition, acquisition settings and image analysis procedures will also be stored in this module of profiler.
validation studies require specific protocols to reproduce all of the experimental conditions, this module should ensure that this data is available.
few papers have been published so far on tma data organization and management.
liu et al.
<cit>  presented a system for high-throughput analysis and storage of tma immuno-staining data, using a combination of commercially available software and novel software.
similarly, shaknovich et al.
<cit>  proposed a way to manipulate tma data and images, using commercially available software.
other academic groups are working on the development of systems integrating commercially available software for the acquisition of digital images and the automatic evaluation of markers with custom solutions for data organization and management.
the johns hopkins tissue microarray laboratory has also developed a set of software tools and underlying database structure to manage tma data <cit> .
it allows the storage of a wide variety of information related to tma samples, including patient clinical data, specimens, donor blocks, core, and recipient block information.
a dynamic database structure allows users to add custom fields for different organ systems.
the client application facilitates automated and manual entry of data related to patients, specimens, tissue blocks, and tissue sub-blocks .
the system allows users to design their own block arrays.
digital images generated by the bacus labs inc. slide scanner   <cit>  are imported into the database and available for on line visualization and evaluation.
although this system developed separately from the profiler system, the two groups worked closely initially as part of the s.p.o.r.e.
initiative to develop tmatechnology for translational research <cit> .
some other systems have been developed to automatically acquire and evaluate tma samples, such as the tmalab ™   <cit> , or the pathfinder™ morphoscan™  <cit> .
these solutions work well with high quality tma slides, usually by superimposing a grid on the panoramic overview of the slide, but they require considerable manual intervention if the tma samples are not well aligned.
these systems are similar to the bliss and chromavision systems in that none of these systems identify the histospots automatically.
the misalignment of tma histospots is inevitable due to the way the samples are processed.
after a thin 4– <dig> micron thick section is cut, the histotechnologist floats the sample in a water bath.
even when done by the best-trained technologists, there is slight movement of the samples.
therefore using a grid will never be a practical solution to automate the identification of the samples.
the aqua system uses an object recognition approach to exactly identify the spatial coordinate of each spot, but lacks in ordering and assigning them to proper patient and/or clinical information based on construction information <cit> .
the bioinfomatics group of itc in trento, italy, has developed an integrated framework for the management of tma experiment data  <cit> .
this system called tmaboost is a patient centered web based system.
it integrates a custom made tma digital environment for the automatic localization, identification, acquisition and evaluation of tma single spot.
one unique feature of this system is the ability to recognize the histospots taking the tma map into account  <cit> .
a probability is determined as to the likelihood that a specific histospot is being correctly identified based on the physical map of the tma.
this feature is particularly useful, as during the course of preparing a slide for immunohistochemisty, some histospots may be lost.
ambiguously located histospots would then be excluded or can be manually resolved.
this feature using the existing data reduces the chance that tma histospots are pared with the incorrect x-y coordinate.
another important feature of tma based studies is the growing need to share data and information among different institutions .
in such a setting, the implementation of standard data exchange protocols becomes critical as up to now there have not been standard approaches to collecting data at different institutions and sometimes even within the same institution and as centralized solutions are not feasible.
as a result of several tma workshops in the area of tma bioinformatics, tma exchange specifications have been released that allow tma data to be organized in a self-describing xml document annotated with well-defined common data elements.
tma data exchange specifications have recently been described by berman et al.
<cit> .
adopting these standards should allow for a seamless integration of public tma databases.
the public sharing of tma data following publication of data, similar to standards developed for expression array data exchange should facilitate biomedical research.
as part of a national biospecimens pilot project <cit> , the  <dig> prostate cancer s.p.o.r.e.
groups will adopt these standard and work with the cancer biomedical informatics grid  program  <cit>  to ensure that these standards remain compliant.
future versions of this system will adopt an ontology system developed in collaboration with the cabig program.
currently our vocabulary and definitions have been more locally defined and will need to be adjusted as these standards become better defined.
profiler can be set up at academic institutions that would like to use this system.
although the system is currently written for oracle, the profiler application can be deployed to open source software.
apache web server  <cit>  and tomcat engine  <cit>  are currently open source software.
all front end codes for profiler application can modify to support to open source.
there are several open source databases such as mysql  <cit>  or postgresql  <cit>  that can be integrated with profiler application with small modification of jdbc drivers and java codes.
we are currently looking for an open source image application to support tma images.
the profiler system is available to all academic intuitions using a standard academic licensing agreement.
this procedure is intended to make the system widely available and is required by our institutions based on their established intellectual properties policies.
any interested investigators should contact the corresponding author to begin the licensing procedure.
groups using a different database system  may need to modify the database scripts and perform additional testing.
but in general both the code and the relational database schema are highly portable.
CONCLUSIONS
in summary, we have described a process to deal with tma experiments using a system called profiler.
the tma module of profiler allows for a secure and reliable way to evaluate and store tma images over the internet.
the database allows for integration of other types of dataset including clinical and pathology data.
the system has been extensively used for the evaluation of biomarkers and has proven to be reliable and stable at two comprehensive cancer centers.
this system is freely available to academic intuitions through a standard licensing agreement.

 taking laboratory discoveries and translating them into clinically useful diagnostic tests or targeted therapies requires the use of human samples for validation. this process, referred to as translational research, requires carefully storing and maintaining detailed annotation of these samples. tissue microarray technology has created and efficient manner to accelerate discovery but has also created a new demand for databases to handle a large number of data points in a regulatory compliant manner. the initial description of tissue microarray technology by kononen et al. began a revolutionary change in the way that many tissue based research studies would be performed. tma technology allows for the precise placement of typically up to 400– tissue samples into a single block in an array. the approach some major advantages as compared to using standard slides. tma technology decreases experimental variability, conserves tissue resources and provide a dramatic cost benefit once the initial tma block is constructed. tma technology also presents some challenges, which include issues related to sampling strategies, evaluation of tma samples, ability to store and maintain the data derived from tma experiments, and analysis of tma datasets. all of these issues are important to understanding the utility of tma technology and to help maximize its potential as a research tool. in the collaborative setting of the specialized program of research excellence for prostate cancer, a program for translational research, pathologists from the university of michigan, baylor school of medicine, and johns hopkins developed a working model to deal with these challenges. we recognized some fundamental guiding principles: tma technology provides a means to conserve finite tissue resources, while at the same time increasing the number of studies for qualified investigators; tma technology is most valuable if data generated from each experiment is recorded and returned to a central database thus increasing the annotation and value of each sample; and tma technology is ideally suited for collaborative biomarker research. these important guidelines suggested to our working group that tma databasing tools would be a cornerstone to our translational research activities and would grow in importance over time and with the increasing number of experimental data. in we described the blueprints for developing a means of storing, maintaining and evaluating tma data using internet tools and a relational database. from this original work has emerged an integrative framework for dealing with all aspects of tma research. at the center of this process is an internet-based database system referred to as profiler. this system has the capability of handling/managing a wide variety of sample types from different disease states and because of its modular design can also store and maintain other types of molecular data including expression array data, karyotype data, and snp array data. here within, we describe the process that has developed to deal with tma experiments and the profiler system used to manage the data associated with these experiments.  over the past years, the profiler system has developed into a key ingredient into the process for tma based research. the data included in this process not only includes the alpha-numeric annotations to each histospot but also the images that are associated with each study. the profiler system has demonstrated a capacity to be extendable to other organ sites besides prostate and modular allowing for analysis of other types of molecular data. to date multiple studies were built/conducted using this system. the following is a description of the process that has developed over years of tma research. tma conceptual research design tma design is crucial because it should address the needs of future experiments. once the tma design is thought out, two different types of maps are created to assist in the tma fabrication, a picture map and a punching map. the picture map is a visual representation of the tma showing a lay out of all the tma cores. different tissue types or diagnoses can be shown in colors. the picture map provides orientation. the punching map is needed for taking biopsy cores with the manual arrayer. this map shows the x and y localization of each tma core and is used during the construction of the tma. the physical configuration of the tma is entered into the profiler database. all future studies will maintain this structure and use the information from the punch file to help determine: 1) the type of tissue; 2) targeted diagnosis; 3) the x and y coordinates; and 4) associated research identification code for potential links to clinical and pathology data from external or internal databases. experiments each antibody is evaluated using a small test tma. a test tma consists of an assortment of different tissues to test the best experimental protocols including pre-treatments and dilutions. the test tmas are then reviewed by a pathologist and the tma experiment will then be performed using these optimal conditions. this process prevents wasting valuable large tmas. scanning as described in the methods section, the tma is scanned and the images are entered into the profiler database server for evaluation. initially all slides were scanned with the bliss system. however, more experiments are being performed using the other imaging systems. study set up at an administrative level, the research group determines who should be permitted access to evaluate the tma. using profiler study set up tools, the administrator is given a set of options for the reviewer to have available at time of review. for example, in some studies, staining intensity and percentage intensity are the only parameters that need to be annotated. in another study, nuclear grade may be required. these types of decisions are based on the goals of the study. once the study is set up, the reviewers are sent a unique user password for them to gain access to studies they are responsible for reviewing. the advantage of this approach is flexibility. as we have seen over the past years, each research group needs to enter data fields that are not readily generalizable to all other groups nor are they relevant. as a specific example, tumor grading systems are often organ specific. therefore flexibility is critical to allow each group to be able to enter relevant data for their studies. one major disadvantage is that we do not anticipate being able to develop a "standard" set of look up tables to cover every research groups needs and therefore a programmer will be needed to make modifications to the system until it meets an individual groups needs. tma evaluation each user gains access to a tma slide based on their experiments. the reviewer can only see their own folders and not those from other research groups. these safety features are part of the oracle security tools that are required for e-commerce. as the user views each tma core image, information about the tma core is displayed in the region of the screen adjacent to the diagnostic parameters. the tma core's x and y coordinates are displayed with its organ type and target diagnosis. the diagnostic parameters are inputted along with stain intensity, staining location, and path diagnosis using pull down menus. comments can be entered in a separate free text field. once a tma slide evaluation is complete, the user can finalize the evaluation preventing any further changes in the diagnostic parameters. the study design is flexible differing dramatically based on the research group. clinical and pathology information can be either presented or not. for example, the tma map is usually available. however, one could imagine a study where the investigators may know the design of the tma and therefore would be biased if this information were available at time of review. we have also found that the tissue diagnosis of each histospot is critical during the evaluation process. when drilling deeper into a block, tma samples may demonstrate different tissue types due to tumor heterogeneity. data storage after each tma core is reviewed and diagnostic parameters are inputted, the user will submit the information and the next tma core image will be displayed with all the diagnostic parameters reset for another submission. the diagnostic data is uploaded onto the data server. analysis the methods used to analyze tmas are beyond the scope of this current study. however, it is important to point out that, once a tma slide has been finalized, all of the raw data is maintained on the profiler system and available for analysis. the data and images can be queried based on desired features such as all tumor samples staining positive for biomarkers x, y, and z. this feature recalls previous evaluations from the server based on specified parameters and displays the data and the corresponding image showing multiple evaluations of one patient adjacent to one another. query results and single experiment data can be exported as an excel spreadsheet or as a tab delimited text file for further statistical analysis. the system is capable of displaying uploaded data from automated immunostaining results from the chromavision system, so as all the data stored in the database being related to a specific dataset of interest. additional resources the profiler system can be setup to assist in submitted publications as supplementary data showing all information about the study giving raw data as well as the images of the tma slides. this was recently done with the publication of a biomarker study called jagged. profiler usage the profiler system is currently running at dana farber harvard comprehensive cancer and the university of michigan comprehensive cancer center containing k and k data points, respectively. tma slides have been scanned and k histospots evaluated by pathologists. of the tmas evaluated, major user groups use the systems including s.p.o.r.e. groups with two groups having directly linked clinical data containing over patients giving immediate access. availability and requirements one can register for a standard non-anonymous demonstration. this demonstration provides the user with some but not all of the features of the database. the system is accessible via the internet and currently works on pc computers using internet explorer. discussion in the current study, we describe the evolution of a process that has developed over the past years to use tmas for biomarker studies. at the center of this process is a relational database tool, profiler, which allows users to handle all steps of tma research. the profiler system was originally developed for work in the field of prostate cancer biomarker research but has now been expanded to allow for the analysis of any tissue type. this system has been extensively used by investigators from several academic institutions. the key feature to profiler's functionality is the ability to access tma images over the internet and enter data in a secure manner. during the course of our first tma experiments, we observed that there was a high probability of annotating the wrong tma histospot when multiple pathology reviewers were involved due to density of these tmas, which typically have tma cores. we therefore developed a system to present tma images to the reviewer thus avoiding having to physically identify the tma histospot by examining the slide. manually evaluating a tma slide under the microscope can be a common source of error, since it is reasonably easy to loose track of which samples have been evaluated. profiler keeps track of which cores have been reviewed so the entire tmas can be analyzed over a single session or multiple sessions. the integration of tma data with other data sets is critical for the development of biomarkers. in version of profiler, other databases can be loaded securely onto the system. over the past years, several groups with rich clinical and pathology data have used the system to evaluate molecular biomarkers. profiler's database keeps different datasets separate from each other, maintaining private space for research groups to develop projects. this has become an important issue with some cooperative groups that need to maintain control over their clinical databases based on pre-existing sharing agreements. worldwide, one of the guiding principles for any database that maintains clinical data is compliance with local regulatory agencies to protect patient confidentiality. in the united states, hippa regulations guide how clinical databases can be integrated with the data stored in profiler. we have developed two approaches. the first approach is to maintain both datasets separately and then the integration of the profiler tma data is performed by the clinical group. they are then typically able to provide a completely integrated dataset without any patient identifiers. this dataset is now ready for analysis. the second approach is to integrate the clinical data into the profiler system as a separate clinical module. we have done this for several groups and have used oracle security and administrative tools to ensure that the clinical module is only available for viewing and modifying by the designated clinical groups researchers. all queries require the group leader's approval and each time a query is performed on the clinical data, the time, date, and investigator are recorded and send via email to the group leaders. this monitoring feature is critical to ensure that the clinical database is only used by qualified investigators. the system administrator assigns users different levels of access at different sites using password protected user profiles. the tracking of standard operating procedures is critical for the interpretation of experimental results over time. therefore the development of a "laboratory book" feature as a new module is critical to the adequate annotation of samples and experiments. we are currently developing the ability to input experiment related data such that a laboratory technician could annotate the staining protocol of each experiment. in addition, acquisition settings and image analysis procedures will also be stored in this module of profiler. validation studies require specific protocols to reproduce all of the experimental conditions, this module should ensure that this data is available. few papers have been published so far on tma data organization and management. liu et al. presented a system for high-throughput analysis and storage of tma immuno-staining data, using a combination of commercially available software and novel software. similarly, shaknovich et al. proposed a way to manipulate tma data and images, using commercially available software. other academic groups are working on the development of systems integrating commercially available software for the acquisition of digital images and the automatic evaluation of markers with custom solutions for data organization and management. the johns hopkins tissue microarray laboratory has also developed a set of software tools and underlying database structure to manage tma data. it allows the storage of a wide variety of information related to tma samples, including patient clinical data, specimens, donor blocks, core, and recipient block information. a dynamic database structure allows users to add custom fields for different organ systems. the client application facilitates automated and manual entry of data related to patients, specimens, tissue blocks, and tissue sub-blocks. the system allows users to design their own block arrays. digital images generated by the bacus labs inc. slide scanner are imported into the database and available for on line visualization and evaluation. although this system developed separately from the profiler system, the two groups worked closely initially as part of the s.p.o.r.e. initiative to develop tmatechnology for translational research. some other systems have been developed to automatically acquire and evaluate tma samples, such as the tmalab ™, or the pathfinder™ morphoscan™. these solutions work well with high quality tma slides, usually by superimposing a grid on the panoramic overview of the slide, but they require considerable manual intervention if the tma samples are not well aligned. these systems are similar to the bliss and chromavision systems in that none of these systems identify the histospots automatically. the misalignment of tma histospots is inevitable due to the way the samples are processed. after a thin 4– micron thick section is cut, the histotechnologist floats the sample in a water bath. even when done by the best-trained technologists, there is slight movement of the samples. therefore using a grid will never be a practical solution to automate the identification of the samples. the aqua system uses an object recognition approach to exactly identify the spatial coordinate of each spot, but lacks in ordering and assigning them to proper patient and/or clinical information based on construction information. the bioinfomatics group of itc in trento, italy, has developed an integrated framework for the management of tma experiment data. this system called tmaboost is a patient centered web based system. it integrates a custom made tma digital environment for the automatic localization, identification, acquisition and evaluation of tma single spot. one unique feature of this system is the ability to recognize the histospots taking the tma map into account. a probability is determined as to the likelihood that a specific histospot is being correctly identified based on the physical map of the tma. this feature is particularly useful, as during the course of preparing a slide for immunohistochemisty, some histospots may be lost. ambiguously located histospots would then be excluded or can be manually resolved. this feature using the existing data reduces the chance that tma histospots are pared with the incorrect x-y coordinate. another important feature of tma based studies is the growing need to share data and information among different institutions. in such a setting, the implementation of standard data exchange protocols becomes critical as up to now there have not been standard approaches to collecting data at different institutions and sometimes even within the same institution and as centralized solutions are not feasible. as a result of several tma workshops in the area of tma bioinformatics, tma exchange specifications have been released that allow tma data to be organized in a self-describing xml document annotated with well-defined common data elements. tma data exchange specifications have recently been described by berman et al.. adopting these standards should allow for a seamless integration of public tma databases. the public sharing of tma data following publication of data, similar to standards developed for expression array data exchange should facilitate biomedical research. as part of a national biospecimens pilot project, the prostate cancer s.p.o.r.e. groups will adopt these standard and work with the cancer biomedical informatics grid program to ensure that these standards remain compliant. future versions of this system will adopt an ontology system developed in collaboration with the cabig program. currently our vocabulary and definitions have been more locally defined and will need to be adjusted as these standards become better defined. profiler can be set up at academic institutions that would like to use this system. although the system is currently written for oracle, the profiler application can be deployed to open source software. apache web server and tomcat engine are currently open source software. all front end codes for profiler application can modify to support to open source. there are several open source databases such as mysql or postgresql that can be integrated with profiler application with small modification of jdbc drivers and java codes. we are currently looking for an open source image application to support tma images. the profiler system is available to all academic intuitions using a standard academic licensing agreement. this procedure is intended to make the system widely available and is required by our institutions based on their established intellectual properties policies. any interested investigators should contact the corresponding author to begin the licensing procedure. groups using a different database system may need to modify the database scripts and perform additional testing. but in general both the code and the relational database schema are highly portable.  in summary, we have described a process to deal with tma experiments using a system called profiler. the tma module of profiler allows for a secure and reliable way to evaluate and store tma images over the internet. the database allows for integration of other types of dataset including clinical and pathology data. the system has been extensively used for the evaluation of biomarkers and has proven to be reliable and stable at two comprehensive cancer centers. this system is freely available to academic intuitions through a standard licensing agreement. 
due to the relational database structure, analysis can be easily performed on single or multiple tma experimental results. the tma module of profiler can maintain images acquired from multiple systems. this system is extendable to other types of molecular data as separate modules and is freely available to academic institutions for licensing. the profiler system allows investigator to reliably track, store, and evaluate tma experiments. over the past years, investigators at academic institutions have scanned tma experiments and collected digital images of these tissue samples. translational research requires taking basic science observations and developing them into clinically useful tests and therapeutics. we have developed a robust process to develop molecular biomarkers using tma technology and an internet-based database system to track all steps of this process. two groups directly link clinical data from over patients for immediate access and the remaining groups choose to maintain clinical and pathology data on separate systems. tma technology allows investigators to study hundreds of patient samples on a single glass slide resulting in the conservation of tissue and the reduction in inter-experimental variability. we have developed a process to develop molecular biomarkers for diagnosis and prognosis by integrating tissue microarray technology and an internet-database tool, profiler. here within we describe the process that has evolved through an empirical basis over the past years at two academic institutions.
 translational research requires taking basic science observations and developing them into clinically useful tests and therapeutics. we have developed a process to develop molecular biomarkers for diagnosis and prognosis by integrating tissue microarray technology and an internet-database tool, profiler. tma technology allows investigators to study hundreds of patient samples on a single glass slide resulting in the conservation of tissue and the reduction in inter-experimental variability. the profiler system allows investigator to reliably track, store, and evaluate tma experiments. here within we describe the process that has evolved through an empirical basis over the past years at two academic institutions.  the generic design of this system makes it compatible with multiple organ system. studies and folders are restricted to authorized users as required. over the past years, investigators at academic institutions have scanned tma experiments and collected digital images of these tissue samples. pathologists from major user groups have accessed the system. two groups directly link clinical data from over patients for immediate access and the remaining groups choose to maintain clinical and pathology data on separate systems. profiler currently has k data points such as staining intensity, tumor grade, and nuclear size. due to the relational database structure, analysis can be easily performed on single or multiple tma experimental results. the tma module of profiler can maintain images acquired from multiple systems.  we have developed a robust process to develop molecular biomarkers using tma technology and an internet-based database system to track all steps of this process. this system is extendable to other types of molecular data as separate modules and is freely available to academic institutions for licensing. 