BIOPRESERVATION AND BIOBANKING Volume 10, Number 1, 2012 ª Mary Ann Liebert, Inc. DOI: 10.1089/bio.2011.0038
Electronic Biorepository Application System: Web-Based Software to Manage Receipt, Peer Review, and Approval of Researcher Applications to a Biobank Matloob Khushi,1 Jane E. Carpenter,1 Rosemary L. Balleine,1–3 and Christine L. Clarke1–3
The importance of suitably characterized and preserved biospecimens for research is acknowledged, yet providing information about the availability of biospecimens and associated data, responding to enquiries from researchers, processing applications for material, and seeking independent scientific review of proposed projects are complex and time-consuming processes. Most biorepositories operate as not-for-profit entities; therefore, cost containment is a major consideration. We identified that online systematizing and automation of all of the tasks associated with application management could reduce the administrative workload and therefore reduce costs and improve the efficiency of a biobank. Accordingly, we have developed a Web-based electronic Biorepository Application System (eBAS) that allows researchers to search for suitable material from the biobank database, submit an online expression of interest, and complete all the information required for a full application. Peer review is also managed through eBAS. Implementation of eBAS has streamlined application management and external peer review of researcher applications, and has facilitated automated record storage and management. This approach has potential to reduce the costs and complexities of administering researcher applications. We have also linked eBAS to an open-source clinical research and specimen management database, Caisis.
breast cancer research. Material is collected and stored at multiple sites and the project is coordinated by a central management team. The ABCTB began collecting material and data in 2006, and in March 2008 held enough material for it to be made available to researchers. Currently *4500 have participated as donors to the ABCTB with this number increasing by an average of 94 new donors each month. Individual specimen numbers approach 75,000 and are coupled with a detailed clinical data set. In such an expanding environment, manual processing of applications and responding to enquiries are time consuming, prompting the development of electronic solutions for application management. We identified that providing an online specimen search facility, and online application and reviewing processes would be beneficial for researchers, and would facilitate the administrative tasks associated with managing researcher applications.5 To ensure that access to ABCTB material is based on sound scientific review of applications received, external peer review of the scientific and logistical aspects of the project application is conducted; to minimize the workload on external reviewers, we developed online
Introduction
T
he value of bioresources to advancing research programs is acknowledged,1 and the advent of highthroughput technologies has resulted in increased demand for suitably annotated and preserved biospecimens and clinical data for research into specific diseases.2,3 Management and peer review of applications from researchers for biospecimens and data, and provision of such material, represent a major challenge for biobanks.4 While most biobanks have policies that cover access to their material for research, which include requirements for ethical clearance, justification for amount of material/data requested, expertise of the applicants in the proposed research, and feasibility of the study, many biobanks rely on paper-based application processes, and peer review is often conducted internally.3 There are currently no/few fully electronic processes for managing the receipt, external peer review, tracking, and management of applications from researchers. The Australian Breast Cancer Tissue Bank (ABCTB) is a repository of biospecimens and data, designed to support
1 Breast Cancer Tissue Bank, Westmead Millennium Institute, Sydney Medical School—Westmead, University of Sydney, Westmead, Australia. 2 Translational Oncology, Sydney West Cancer Network, Western Sydney and Nepean Blue Mountains Local Health Districts, NSW, Australia. 3 Westmead Institute for Cancer Research, Westmead Millennium Institute, Sydney Medical School—Westmead, University of Sydney, Westmead, Australia.
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38 solutions to manage all aspects of the peer review process. Accordingly, we have developed Web-based software, the electronic Biorepository Application System (eBAS), for management of all aspects of biospecimen searching, application submission, and peer review.
KHUSHI ET AL. sons: first, to prevent malicious Web site code being installed on the servers while visiting a Web site; second, if the servers are broken into, no data can be transferred easily to a remote location.
Backups Materials and Methods eBAS development The eBAS was developed using Microsoft’s ASP.NET, C#, SQL Server 2008 technologies (microsoft.com). The eBAS can also be installed on the free database version SQL Server 2008 Express. The eBAS front-end and back-end application management is completely browser based, and has been tested on all major browsers including Firefox 3 and higher, Internet Explorer 6.0 and higher, Safari 4.0 and higher.
Caisis integration We have developed a specimen search module for the ABCTB public Web site (abctb.org.au) that allows researchers to search for suitable specimens. The results from the search are populated from a stored procedure that is linked to a customized version of the Caisis (caisis.org) database6,7 that is used for storing the clinical and biospecimen information on ABCTB donors. The stored procedure has readonly restricted access to only those tables, and to fields in Caisis that have no patient identifiable information. This is vital, so that in the event of any SQL injection attack,8 the Caisis database and patient identified information are not compromised.
The SQL database backup is scheduled by a stored procedure that runs every night. The stored procedure starts a new backup file every month and writes a full backup on the first day of a month followed by a differential backup, every night, which is appended to the backup file for the rest of the month. This provision allows us to retrieve data more quickly in case of disaster. These database backup files are further backed up on tape drives. These tapes are stored away from the central servers so that in the event of fire or other disaster, the system could be rebuilt.12 For tape backup, recovery, and archiving, we use the EMC (EMC Corporation) commercial product NetWorker server (emc.com).
Availability Searching specimens and viewing digital slide images online at the ABCTB Web site is free. Specimen and data search module, in use by the ABCTB Web site, can be requested from the corresponding author. To obtain a license to the eBAS software, please contact Sydnovate (sydney .edu.au/sydnovate/), the commercialization office of the University of Sydney.
Results Preimplementation
Hosting and security The eBAS front-end application and back-end database are hosted on Windows Server 2003 and the servers are placed behind a demilitarized zone (DMZ). We have hosted the ABCTB Microsoft Internet Security and Acceleration (ISA) Server within the DMZ that is acting as a software firewall and reverse proxy (Appendix). In addition, the Microsoft ISA Server acts as a fully functional firewall, Virtual Private Network, Web-caching proxy, and application reverse-proxy solution.9 The eBAS MS SQL database and Web front-end is split across 2 servers using the hardware virtualization technology VMWare software (vmware.com). The VMWare acts as a hypervisor or virtual machine monitor that allows multiple operating systems to run concurrently on a host computer.10 By separating the SQL Server database from the Web frontend, we have ensured that in case of any security breach at the Web front-end, the database is protected. Moreover requests to and from eBAS are via the ISA reverse proxy11 and this monitors for any suspicious network requests/activities. In addition, security certificate (Secure Sockets Layers) encryption is performed at the ISA Server. We have employed the following protocols for maximum hosting security. (i) All traffic in DMZ is filtered and only traffic requesting the public Web site (www.abctb.org.au) on ports 80 or 443 is allowed. (ii) All types of port scanning spider traffic are rejected. (iii) Internal network access to the servers is restricted. (iv) Initiating an Internet session from the servers is blocked, which means that the World Wide Web cannot be browsed from the servers. This is for 2 rea-
The ABCTB began accepting enquiries and applications from researchers in 2008. In the preimplementation phase, the ABCTB administrative staff reviewed all the queries received since initiation of researcher requests, and noted that these queries were generally about the availability of specific types of samples based on disease diagnosis. Initially, such queries from researchers were responded to manually. However, it was noted that the time commitment on ABCTB administrative staff began to increase, and it was resolved to automate the process by first developing an online query tool through which researchers could identify whether the ABCTB held samples of potential interest to them, and second, by implementing an expression of interest (EOI) Web form through which researchers could seek further information prior to submission of a full application. We further reviewed the processes that are required for researchers to make an application to ABCTB and identified that there are 4 key components: (i) researchers apply to the bank, (ii) the applications are reviewed, (iii) decisions are made, and (iv) material/data are supplied. The eBAS application process comprises 4 key components, which are detailed in the following paragraphs. Figure 1 explains the workflow of the eBAS process. The EOI. Researchers who are interested in sourcing biospecimens and/or data from the ABCTB are required to submit an EOI by completing a Web form that requests title and abstract of the project, the specimens and/or data they wish to access, and their contact details. Applicants can also indicate whether their proposed work is a pilot project. The
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FIG. 1. Workflow of eBAS application system. Expression of interest (EOI) can be approved as a full project or as a pilot/small project. In cases where an application is refused, the applicant is informed and if they can address the issues raised to the satisfaction of the Australian Breast Cancer Tissue Bank Access Committee, then the decision maybe reversed.
EOI process is designed to enable the ABCTB to review its capacity to support the proposed project. When an EOI submission is received, a predefined automatic e-mail is sent to the researcher providing them with a unique project identifier code. This identifier, referred to as the Project Key, is then used throughout the remainder of the application process. Another e-mail is also automatically transmitted to the ABCTB operation team to advise them that a new EOI has been received. If the EOI is approved, the applicant receives a second automatic e-mail explaining that their EOI has been approved and that they are now required to log into the eBAS using the supplied username and password in order to submit a pilot or full application. The eBAS keeps a log of which ABCTB member has approved the EOI with e-mail and time stamps. Submission of a pilot or a full application. The eBAS full application process is composed of 5 different screens, including project outline, coinvestigator(s) information, samples requested, whether the project has already undergone peer review, ethics (Institutional Review Board) approval information, and evidence of financial viability. Electronic versions of documents such as ethics approval, and documents relating to funded grants are required to be uploaded directly to the system. The information requested for pilot applications includes project details, coinvestigator(s), samples requested, and ethics approval information. Once the researcher has submitted their application, the links on the application dashboard are grayed out and the applicant is not able to further modify the forms, but the status and progress of the application is still visible. An automated e-mail thanks the applicant, and another automated e-mail alerts the ABCTB that a pilot/full application has been submitted. Applicants can submit multiple EOIs and can be working on multiple applications at the same time using one user-
name/password. All applications can be completed in multiple sessions and the user can change their automatically assigned password at any time. Application review process. Through the eBAS administrative section, the ABCTB administrative team can select and view the completed application forms and their associated uploaded documents. Applications that have received peer review already, or pilot applications, are sent for evaluation and decision to the ABCTB Access Committee, which includes investigators associated with the ABCTB collection sites. All full applications that have not been previously peer reviewed are subjected to external peer review. The eBAS includes a register of potential reviewers with details of their particular areas of expertise. Depending on the nature of the project application, one or more reviewers are selected for each application (Fig. 1). The Reviewer Assignment form is completed in 3 steps as shown in Fig. 2, sections a–c. The screen (Fig. 2, section a) also shows whether this reviewer has submitted reviews recently, to avoid inadvertently requesting multiple reviews from the same individual, our practice being that no reviewer should be allocated > 2 reviews per year. Selecting ‘‘Save & Add to Review List’’ assigns the project to the reviewer and populates the Review List shown in Fig. 2, section c. An automated e-mail is sent to the selected reviewer with the project title and abstract, asking for their willingness to provide a review on the project. A link in the e-mail takes the reviewer directly to a Web page where they indicate their availability and willingness to review by choosing ‘‘YES’’ or ‘‘NO.’’ The reviewer’s willingness is indicated on project dashboard with different icons (Fig. 3). If a reviewer is not able to provide a review, then the project is removed from the reviewer’s list and assigned to another reviewer. If a reviewer agrees to review the project, they receive an automatic e-mail with their login details and a link
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FIG. 2. (a) Selected reviewer’s e-mail and past review submissions are shown. Selecting a project from available projects’ list and clicking on the Select button reveals the Project Review Section on the bottom of the page, shown as (b). The Project Review section is used to indicate whether the project requires full scientific review. Based on this selection, the form to be completed by the reviewer is autopopulated accordingly. (c) Saving the form in (b) adds the project to the reviewer’s review list.
to the Web-based review form. The ABCTB is also notified of the reviewer’s acceptance. If reviewers do not submit the review within 2 weeks, then they are reminded using the link shown in Fig. 2. The reviewer logs into the eBAS and submits the review online (Fig. 4). As with the applicants, reviewers can save their review and return to complete at a later date. When the review is submitted, automatic e-mails thank the reviewer, and advise the ABCTB that a review has been completed and submitted. ABCTB application approval. The decision to approve or decline an application is made by the ABCTB Access Committee and recorded using the Decision link on the Project Dashboard (Fig. 3). Material Transfer Agreements (MTAs) are completed with the applicants offline and the data and/ or materials are provided. Hard copies of the signed MTAs are retained, but not uploaded to eBAS in this first release of the software.
The eBAS administrative section The eBAS administrative dashboard provides a comprehensive summary of all projects under review such as project title, principal investigator, forms completed, various dates, and reviewing progress status as shown in Fig. 3. The status column shows various stages of application along with
milestone dates. Clicking on the Event Information icon opens a window-less popup that displays a list of all events. Hovering the mouse over the review date link displays additional information such as reviewer name and e-mail. This provides the ABCTB with an overview of the status of an application, and in case of any substantial delay the ABCTB can provide additional advice or guidance.
Project tracking in Caisis All outgoing specimens and patients are flagged by the eBAS Project Key in Caisis,6,7 and donors and specimens involved in any particular study can be identified using tools built into the customized version of the open-source clinical research database, Caisis,6 in which all ABCTB clinical and biospecimen information is stored.
Evaluation of eBAS The eBAS was evaluated initially by internal ABCTB users, to test for usability of the forms, and completeness of the information requested. After internal testing, eBAS was tested by a range of external interested parties, by provision of test instances of the software. These external individuals approached ABCTB requesting to test the system, after
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FIG. 3. Snapshot of the eBAS administrative section shows a comprehensive view of progress on all applications. Graphical icons allow rapid identification of the status of an application. Hovering the mouse over the review date link displays additional information such as reviewer name and e-mail.
having observed it being presented initially at the 2009 ISBER meeting,5 and subsequently at a number of national meetings. ABCTB collected feedback on all aspects of eBAS from these users, which was used to further improve eBAS functionality, usability, and the complexity of the system. ABCTB also received feedback from researchers on their use of the eBAS system. The feedback received from all these sources included specific mention of the user friendliness of the system, both for applicants and for reviewers.
Discussion Previous studies13 have shown that local or desktop-based database systems have been unable to accommodate all aspects of managing biospecimen and/or data requests from biobanks, and have been superseded by Web-based systems driven by central databases. Although a number of such Web-based systems have been developed by biorepositories,
these do not overlap fully with the features available in eBAS. For instance, the Cooperative Human Tissue Network has developed a Web-based system for tissue tracking; however, its scope does not include the submission of online applications and automated peer reviewing.13 The Tayside Tissue Bank14 has an online application system; however, it does not have an internal reviewing system and it does not have an online query tool such as the one described in this paper. Proprietary software also exists, such as LabMatrix (biofortis.com/labmatrix)15 that supports Web-based searching and management of specimens; however, such software lacks the functionality to manage applications from researchers, and peer reviewing. The NIH-based Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC) includes application management and peer reviewing (referred as ‘‘voting’’ in BioLINCC).16 However extending BioLINCC to other platforms and biobanks may be challenging, as applications are encouraged based on
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FIG. 4. Project Review form: the sections requesting reviewer evaluation of the scientific aims and feasibility of the study are only displayed for projects that require scientific review.
previous study resources, and the application system is specific to the activities of BioLINCC. Moreover BioLINCC is developed in the Python language and uses the PostgreSQL database, and links to a proprietary specimen management system, BSI (Biological Specimen Inventory System, bsi-ii .com), limiting its broader applicability. The eBAS, and the software linked to it for specimen management, Caisis, are developed in Asp.Net, C# and SQL Server, facilitating the linking of these functions. Caisis, as an open-source research database that includes a specimen management module, can provide all the informatic functions required of a standard biobank,6 when coupled with eBAS. The implementation of eBAS has converted all aspects of the process of application receipt, evaluation and approval from a manual process, involving paper records, extensive administrative engagement, and time-consuming manual notification processes, to a largely automated process. The receipt and review of researcher applications, and the 2-way
communication between the ABCTB and researchers, is largely facilitated by the eBAS interface, as is the process of peer review of applications received by the ABCTB. Another benefit of eBAS is that the process of managing researcher applications has become significantly more traceable: the project dashboard provides a comprehensive status of the progress of each application, and milestone events against an application are logged, facilitating the tracking and management of applications. Another benefit is that administrative complexity is reduced, as all communications from eBAS to applicants, to the ABCTB, and to external peer reviewers are via automatic e-mail. Implementation of eBAS has also produced cost savings: (i) paper copies are no longer produced for reviewers or the ABCTB Access committee, resulting in cost savings both of consumables as well as ABCTB administration time; (ii) each ABCTB personnel member has a unique login, which has increased traceability of activity and personnel
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productivity; (iii) implementation of eBAS has streamlined the process of managing applications from researchers and fewer administrative staff need to be deployed to manage these processes. In addition to the administrative and cost benefits of implementing eBAS, the regular reporting functions of a biobank can be facilitated by a centralized system like eBAS: a biobank can run a range of reports such as how many EOIs have progressed to full applications, or the average time taken in reviewing and reaching a final decision. Such reports can assist in further reviews of quality systems and improvement of the processes. The features of eBAS are largely generic to biobanks that receive applications from researchers, where submission, tracking, and peer reviewing of applications are required. The eBAS is scalable, and can be adapted for use by other biobanks or similar organizations. Although the ABCTB employs external peer review, from a technical viewpoint a reviewer is just an eBAS user with limited access to the system, so biobanks that only conduct internal review could still use the reviewing functions of eBAS, in which case reviewers could be internal members of the organization. In conclusion, the eBAS is purpose-built software for managing receipt, peer reviews, and approval of applications to a biobank. The fully electronic process has reduced reliance on paper records, and facilitated coordination of activities by the ABCTB, demonstrating that the eBAS software can play an important role in the management and peer review of applications to a biobank.
4. Christopher Womack NMG. Providing human tissue for research: 1996–2006. Pathobiology 2007;74:212–217. 5. Carpenter J, Khushi M, Balleine R, et al. Development of a Webbased system for electronic submission and processing of applications to the breast cancer tissue bank. Biopreserv Biobank 2009;7:51–88. 6. Khushi M, Carpenter JE, Balleine RL, et al. Development of a data entry auditing protocol and quality assurance for a tissue bank database. Cell Tissue Bank 2011 DOI: 10.1007/s10561-0119240-X. [Epub ahead of print]. 7. Fearn P, Sculli F. The CAISIS research data system. In Ochs MF, Casagrande JT, Davuluri RV, eds. Biomedical Informatics for Cancer Research. NY: Springer;2010:215–25. 8. Kieyzun A, Guo PJ, Jayaraman K, et al. Automatic creation of SQL Injection and cross-site scripting attacks. Proceedings of the 31st International Conference on Software Engineering, Washington, DC. 1555036, IEEE Computer Society;2009:99–209. 9. Noel M. Microsoft ISA Server 2006 unleashed. Indianapolis: Sams, 2007. ISBN: 0672329190. 10. Soltesz S, Potzl H, Fiuczynski ME, et al. Container-based operating system virtualization: a scalable, high-performance alternative to hypervisors. Proceedings of the 2nd ACM SIGOPS/ EuroSys European Conference on Computer Systems 2007. Lisbon, Portugal, 1273025, ACM;2007:275–287. 11. Datta A, Dutta K, Thomas H, et al. Proxy-based acceleration of dynamically generated content on the World Wide Web: an approach and implementation. ACM Trans Database Syst 2004;29:403–443. 12. Choy M, Leong HV, Wong MH. Disaster recovery techniques for database systems. Commun ACM 2000;43(11es):6. 13. Edgerton M, Grizzle W, Washington MK. The deployment of a tissue request tracking system for the CHTN: a case study in managing change in informatics for biobanking operations. BMC Med Inform Decis Making 2010;10:32. 14. Tayside Tissue Bank. 2011. Available at www.tissuebank .dundee.ac.uk/?page = resinfo-tisreq 15. Suh KS, Remache Y, Patel J, et al. Informatics-guided procurement of patient samples for biomarker discovery projects in cancer research. Cell Tissue Bank 2009;10:43–48. 16. BioLINCC. Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC) website. 2011. Available at https://biolincc.nhlbi.nih.gov/home/
Acknowledgments The ABCTB is funded by the National Health and Medical Research Council of Australia (Enabling Grant 307750), the National Breast Cancer Foundation, and the Cancer Institute New South Wales (CINSW). Rosemary L. Balleine is a CINSW Fellow.
Author Disclosure Statement No competing financial interests exist.
References 1. Signoretti S, Bratslavsky G, Waldman FM, et al. Tissue-based research in kidney cancer: current challenges and future directions. Clin Cancer Res 2008;14:3699–3705. 2. Womack C, Gray NM. Banking human tissue for research: vision to reality. Cell Tissue Bank 2009;10:267–270. 3. Jim Vaught, Andrea Kelly, Hewitt R. A Review of International Biobanks and Networks: success factors and key benchmarks. Biopreserv Biobank 2009;7:143–150.
Address correspondence to: Mr. Matloob Khushi Breast Cancer Tissue Bank Westmead Millennium Institute Sydney Medical School—Westmead University of Sydney Westmead 2145 Australia E-mail: [email protected] Received 10 August, 2011/Accepted 19 October, 2011
(Appendix follows/)
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Appendix The Australian Breast Cancer Tissue Bank Web and database servers are hosted behind a demilitarized zone (DMZ), and a Microsoft ISA Server is deployed in addition to a number of hardware firewalls. ISA, Internet Security and Acceleration.
KHUSHI ET AL.
Electronic Biorepository Application System: Web-Based Software to Manage Receipt, Peer Review, and Approval of Researcher Applications to a Biobank Matloob Khushi,1 Jane E. Carpenter,1 Rosemary L. Balleine,1–3 and Christine L. Clarke1–3
The importance of suitably characterized and preserved biospecimens for research is acknowledged, yet providing information about the availability of biospecimens and associated data, responding to enquiries from researchers, processing applications for material, and seeking independent scientific review of proposed projects are complex and time-consuming processes. Most biorepositories operate as not-for-profit entities; therefore, cost containment is a major consideration. We identified that online systematizing and automation of all of the tasks associated with application management could reduce the administrative workload and therefore reduce costs and improve the efficiency of a biobank. Accordingly, we have developed a Web-based electronic Biorepository Application System (eBAS) that allows researchers to search for suitable material from the biobank database, submit an online expression of interest, and complete all the information required for a full application. Peer review is also managed through eBAS. Implementation of eBAS has streamlined application management and external peer review of researcher applications, and has facilitated automated record storage and management. This approach has potential to reduce the costs and complexities of administering researcher applications. We have also linked eBAS to an open-source clinical research and specimen management database, Caisis.
breast cancer research. Material is collected and stored at multiple sites and the project is coordinated by a central management team. The ABCTB began collecting material and data in 2006, and in March 2008 held enough material for it to be made available to researchers. Currently *4500 have participated as donors to the ABCTB with this number increasing by an average of 94 new donors each month. Individual specimen numbers approach 75,000 and are coupled with a detailed clinical data set. In such an expanding environment, manual processing of applications and responding to enquiries are time consuming, prompting the development of electronic solutions for application management. We identified that providing an online specimen search facility, and online application and reviewing processes would be beneficial for researchers, and would facilitate the administrative tasks associated with managing researcher applications.5 To ensure that access to ABCTB material is based on sound scientific review of applications received, external peer review of the scientific and logistical aspects of the project application is conducted; to minimize the workload on external reviewers, we developed online
Introduction
T
he value of bioresources to advancing research programs is acknowledged,1 and the advent of highthroughput technologies has resulted in increased demand for suitably annotated and preserved biospecimens and clinical data for research into specific diseases.2,3 Management and peer review of applications from researchers for biospecimens and data, and provision of such material, represent a major challenge for biobanks.4 While most biobanks have policies that cover access to their material for research, which include requirements for ethical clearance, justification for amount of material/data requested, expertise of the applicants in the proposed research, and feasibility of the study, many biobanks rely on paper-based application processes, and peer review is often conducted internally.3 There are currently no/few fully electronic processes for managing the receipt, external peer review, tracking, and management of applications from researchers. The Australian Breast Cancer Tissue Bank (ABCTB) is a repository of biospecimens and data, designed to support
1 Breast Cancer Tissue Bank, Westmead Millennium Institute, Sydney Medical School—Westmead, University of Sydney, Westmead, Australia. 2 Translational Oncology, Sydney West Cancer Network, Western Sydney and Nepean Blue Mountains Local Health Districts, NSW, Australia. 3 Westmead Institute for Cancer Research, Westmead Millennium Institute, Sydney Medical School—Westmead, University of Sydney, Westmead, Australia.
37
38 solutions to manage all aspects of the peer review process. Accordingly, we have developed Web-based software, the electronic Biorepository Application System (eBAS), for management of all aspects of biospecimen searching, application submission, and peer review.
KHUSHI ET AL. sons: first, to prevent malicious Web site code being installed on the servers while visiting a Web site; second, if the servers are broken into, no data can be transferred easily to a remote location.
Backups Materials and Methods eBAS development The eBAS was developed using Microsoft’s ASP.NET, C#, SQL Server 2008 technologies (microsoft.com). The eBAS can also be installed on the free database version SQL Server 2008 Express. The eBAS front-end and back-end application management is completely browser based, and has been tested on all major browsers including Firefox 3 and higher, Internet Explorer 6.0 and higher, Safari 4.0 and higher.
Caisis integration We have developed a specimen search module for the ABCTB public Web site (abctb.org.au) that allows researchers to search for suitable specimens. The results from the search are populated from a stored procedure that is linked to a customized version of the Caisis (caisis.org) database6,7 that is used for storing the clinical and biospecimen information on ABCTB donors. The stored procedure has readonly restricted access to only those tables, and to fields in Caisis that have no patient identifiable information. This is vital, so that in the event of any SQL injection attack,8 the Caisis database and patient identified information are not compromised.
The SQL database backup is scheduled by a stored procedure that runs every night. The stored procedure starts a new backup file every month and writes a full backup on the first day of a month followed by a differential backup, every night, which is appended to the backup file for the rest of the month. This provision allows us to retrieve data more quickly in case of disaster. These database backup files are further backed up on tape drives. These tapes are stored away from the central servers so that in the event of fire or other disaster, the system could be rebuilt.12 For tape backup, recovery, and archiving, we use the EMC (EMC Corporation) commercial product NetWorker server (emc.com).
Availability Searching specimens and viewing digital slide images online at the ABCTB Web site is free. Specimen and data search module, in use by the ABCTB Web site, can be requested from the corresponding author. To obtain a license to the eBAS software, please contact Sydnovate (sydney .edu.au/sydnovate/), the commercialization office of the University of Sydney.
Results Preimplementation
Hosting and security The eBAS front-end application and back-end database are hosted on Windows Server 2003 and the servers are placed behind a demilitarized zone (DMZ). We have hosted the ABCTB Microsoft Internet Security and Acceleration (ISA) Server within the DMZ that is acting as a software firewall and reverse proxy (Appendix). In addition, the Microsoft ISA Server acts as a fully functional firewall, Virtual Private Network, Web-caching proxy, and application reverse-proxy solution.9 The eBAS MS SQL database and Web front-end is split across 2 servers using the hardware virtualization technology VMWare software (vmware.com). The VMWare acts as a hypervisor or virtual machine monitor that allows multiple operating systems to run concurrently on a host computer.10 By separating the SQL Server database from the Web frontend, we have ensured that in case of any security breach at the Web front-end, the database is protected. Moreover requests to and from eBAS are via the ISA reverse proxy11 and this monitors for any suspicious network requests/activities. In addition, security certificate (Secure Sockets Layers) encryption is performed at the ISA Server. We have employed the following protocols for maximum hosting security. (i) All traffic in DMZ is filtered and only traffic requesting the public Web site (www.abctb.org.au) on ports 80 or 443 is allowed. (ii) All types of port scanning spider traffic are rejected. (iii) Internal network access to the servers is restricted. (iv) Initiating an Internet session from the servers is blocked, which means that the World Wide Web cannot be browsed from the servers. This is for 2 rea-
The ABCTB began accepting enquiries and applications from researchers in 2008. In the preimplementation phase, the ABCTB administrative staff reviewed all the queries received since initiation of researcher requests, and noted that these queries were generally about the availability of specific types of samples based on disease diagnosis. Initially, such queries from researchers were responded to manually. However, it was noted that the time commitment on ABCTB administrative staff began to increase, and it was resolved to automate the process by first developing an online query tool through which researchers could identify whether the ABCTB held samples of potential interest to them, and second, by implementing an expression of interest (EOI) Web form through which researchers could seek further information prior to submission of a full application. We further reviewed the processes that are required for researchers to make an application to ABCTB and identified that there are 4 key components: (i) researchers apply to the bank, (ii) the applications are reviewed, (iii) decisions are made, and (iv) material/data are supplied. The eBAS application process comprises 4 key components, which are detailed in the following paragraphs. Figure 1 explains the workflow of the eBAS process. The EOI. Researchers who are interested in sourcing biospecimens and/or data from the ABCTB are required to submit an EOI by completing a Web form that requests title and abstract of the project, the specimens and/or data they wish to access, and their contact details. Applicants can also indicate whether their proposed work is a pilot project. The
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FIG. 1. Workflow of eBAS application system. Expression of interest (EOI) can be approved as a full project or as a pilot/small project. In cases where an application is refused, the applicant is informed and if they can address the issues raised to the satisfaction of the Australian Breast Cancer Tissue Bank Access Committee, then the decision maybe reversed.
EOI process is designed to enable the ABCTB to review its capacity to support the proposed project. When an EOI submission is received, a predefined automatic e-mail is sent to the researcher providing them with a unique project identifier code. This identifier, referred to as the Project Key, is then used throughout the remainder of the application process. Another e-mail is also automatically transmitted to the ABCTB operation team to advise them that a new EOI has been received. If the EOI is approved, the applicant receives a second automatic e-mail explaining that their EOI has been approved and that they are now required to log into the eBAS using the supplied username and password in order to submit a pilot or full application. The eBAS keeps a log of which ABCTB member has approved the EOI with e-mail and time stamps. Submission of a pilot or a full application. The eBAS full application process is composed of 5 different screens, including project outline, coinvestigator(s) information, samples requested, whether the project has already undergone peer review, ethics (Institutional Review Board) approval information, and evidence of financial viability. Electronic versions of documents such as ethics approval, and documents relating to funded grants are required to be uploaded directly to the system. The information requested for pilot applications includes project details, coinvestigator(s), samples requested, and ethics approval information. Once the researcher has submitted their application, the links on the application dashboard are grayed out and the applicant is not able to further modify the forms, but the status and progress of the application is still visible. An automated e-mail thanks the applicant, and another automated e-mail alerts the ABCTB that a pilot/full application has been submitted. Applicants can submit multiple EOIs and can be working on multiple applications at the same time using one user-
name/password. All applications can be completed in multiple sessions and the user can change their automatically assigned password at any time. Application review process. Through the eBAS administrative section, the ABCTB administrative team can select and view the completed application forms and their associated uploaded documents. Applications that have received peer review already, or pilot applications, are sent for evaluation and decision to the ABCTB Access Committee, which includes investigators associated with the ABCTB collection sites. All full applications that have not been previously peer reviewed are subjected to external peer review. The eBAS includes a register of potential reviewers with details of their particular areas of expertise. Depending on the nature of the project application, one or more reviewers are selected for each application (Fig. 1). The Reviewer Assignment form is completed in 3 steps as shown in Fig. 2, sections a–c. The screen (Fig. 2, section a) also shows whether this reviewer has submitted reviews recently, to avoid inadvertently requesting multiple reviews from the same individual, our practice being that no reviewer should be allocated > 2 reviews per year. Selecting ‘‘Save & Add to Review List’’ assigns the project to the reviewer and populates the Review List shown in Fig. 2, section c. An automated e-mail is sent to the selected reviewer with the project title and abstract, asking for their willingness to provide a review on the project. A link in the e-mail takes the reviewer directly to a Web page where they indicate their availability and willingness to review by choosing ‘‘YES’’ or ‘‘NO.’’ The reviewer’s willingness is indicated on project dashboard with different icons (Fig. 3). If a reviewer is not able to provide a review, then the project is removed from the reviewer’s list and assigned to another reviewer. If a reviewer agrees to review the project, they receive an automatic e-mail with their login details and a link
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FIG. 2. (a) Selected reviewer’s e-mail and past review submissions are shown. Selecting a project from available projects’ list and clicking on the Select button reveals the Project Review Section on the bottom of the page, shown as (b). The Project Review section is used to indicate whether the project requires full scientific review. Based on this selection, the form to be completed by the reviewer is autopopulated accordingly. (c) Saving the form in (b) adds the project to the reviewer’s review list.
to the Web-based review form. The ABCTB is also notified of the reviewer’s acceptance. If reviewers do not submit the review within 2 weeks, then they are reminded using the link shown in Fig. 2. The reviewer logs into the eBAS and submits the review online (Fig. 4). As with the applicants, reviewers can save their review and return to complete at a later date. When the review is submitted, automatic e-mails thank the reviewer, and advise the ABCTB that a review has been completed and submitted. ABCTB application approval. The decision to approve or decline an application is made by the ABCTB Access Committee and recorded using the Decision link on the Project Dashboard (Fig. 3). Material Transfer Agreements (MTAs) are completed with the applicants offline and the data and/ or materials are provided. Hard copies of the signed MTAs are retained, but not uploaded to eBAS in this first release of the software.
The eBAS administrative section The eBAS administrative dashboard provides a comprehensive summary of all projects under review such as project title, principal investigator, forms completed, various dates, and reviewing progress status as shown in Fig. 3. The status column shows various stages of application along with
milestone dates. Clicking on the Event Information icon opens a window-less popup that displays a list of all events. Hovering the mouse over the review date link displays additional information such as reviewer name and e-mail. This provides the ABCTB with an overview of the status of an application, and in case of any substantial delay the ABCTB can provide additional advice or guidance.
Project tracking in Caisis All outgoing specimens and patients are flagged by the eBAS Project Key in Caisis,6,7 and donors and specimens involved in any particular study can be identified using tools built into the customized version of the open-source clinical research database, Caisis,6 in which all ABCTB clinical and biospecimen information is stored.
Evaluation of eBAS The eBAS was evaluated initially by internal ABCTB users, to test for usability of the forms, and completeness of the information requested. After internal testing, eBAS was tested by a range of external interested parties, by provision of test instances of the software. These external individuals approached ABCTB requesting to test the system, after
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FIG. 3. Snapshot of the eBAS administrative section shows a comprehensive view of progress on all applications. Graphical icons allow rapid identification of the status of an application. Hovering the mouse over the review date link displays additional information such as reviewer name and e-mail.
having observed it being presented initially at the 2009 ISBER meeting,5 and subsequently at a number of national meetings. ABCTB collected feedback on all aspects of eBAS from these users, which was used to further improve eBAS functionality, usability, and the complexity of the system. ABCTB also received feedback from researchers on their use of the eBAS system. The feedback received from all these sources included specific mention of the user friendliness of the system, both for applicants and for reviewers.
Discussion Previous studies13 have shown that local or desktop-based database systems have been unable to accommodate all aspects of managing biospecimen and/or data requests from biobanks, and have been superseded by Web-based systems driven by central databases. Although a number of such Web-based systems have been developed by biorepositories,
these do not overlap fully with the features available in eBAS. For instance, the Cooperative Human Tissue Network has developed a Web-based system for tissue tracking; however, its scope does not include the submission of online applications and automated peer reviewing.13 The Tayside Tissue Bank14 has an online application system; however, it does not have an internal reviewing system and it does not have an online query tool such as the one described in this paper. Proprietary software also exists, such as LabMatrix (biofortis.com/labmatrix)15 that supports Web-based searching and management of specimens; however, such software lacks the functionality to manage applications from researchers, and peer reviewing. The NIH-based Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC) includes application management and peer reviewing (referred as ‘‘voting’’ in BioLINCC).16 However extending BioLINCC to other platforms and biobanks may be challenging, as applications are encouraged based on
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FIG. 4. Project Review form: the sections requesting reviewer evaluation of the scientific aims and feasibility of the study are only displayed for projects that require scientific review.
previous study resources, and the application system is specific to the activities of BioLINCC. Moreover BioLINCC is developed in the Python language and uses the PostgreSQL database, and links to a proprietary specimen management system, BSI (Biological Specimen Inventory System, bsi-ii .com), limiting its broader applicability. The eBAS, and the software linked to it for specimen management, Caisis, are developed in Asp.Net, C# and SQL Server, facilitating the linking of these functions. Caisis, as an open-source research database that includes a specimen management module, can provide all the informatic functions required of a standard biobank,6 when coupled with eBAS. The implementation of eBAS has converted all aspects of the process of application receipt, evaluation and approval from a manual process, involving paper records, extensive administrative engagement, and time-consuming manual notification processes, to a largely automated process. The receipt and review of researcher applications, and the 2-way
communication between the ABCTB and researchers, is largely facilitated by the eBAS interface, as is the process of peer review of applications received by the ABCTB. Another benefit of eBAS is that the process of managing researcher applications has become significantly more traceable: the project dashboard provides a comprehensive status of the progress of each application, and milestone events against an application are logged, facilitating the tracking and management of applications. Another benefit is that administrative complexity is reduced, as all communications from eBAS to applicants, to the ABCTB, and to external peer reviewers are via automatic e-mail. Implementation of eBAS has also produced cost savings: (i) paper copies are no longer produced for reviewers or the ABCTB Access committee, resulting in cost savings both of consumables as well as ABCTB administration time; (ii) each ABCTB personnel member has a unique login, which has increased traceability of activity and personnel
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productivity; (iii) implementation of eBAS has streamlined the process of managing applications from researchers and fewer administrative staff need to be deployed to manage these processes. In addition to the administrative and cost benefits of implementing eBAS, the regular reporting functions of a biobank can be facilitated by a centralized system like eBAS: a biobank can run a range of reports such as how many EOIs have progressed to full applications, or the average time taken in reviewing and reaching a final decision. Such reports can assist in further reviews of quality systems and improvement of the processes. The features of eBAS are largely generic to biobanks that receive applications from researchers, where submission, tracking, and peer reviewing of applications are required. The eBAS is scalable, and can be adapted for use by other biobanks or similar organizations. Although the ABCTB employs external peer review, from a technical viewpoint a reviewer is just an eBAS user with limited access to the system, so biobanks that only conduct internal review could still use the reviewing functions of eBAS, in which case reviewers could be internal members of the organization. In conclusion, the eBAS is purpose-built software for managing receipt, peer reviews, and approval of applications to a biobank. The fully electronic process has reduced reliance on paper records, and facilitated coordination of activities by the ABCTB, demonstrating that the eBAS software can play an important role in the management and peer review of applications to a biobank.
4. Christopher Womack NMG. Providing human tissue for research: 1996–2006. Pathobiology 2007;74:212–217. 5. Carpenter J, Khushi M, Balleine R, et al. Development of a Webbased system for electronic submission and processing of applications to the breast cancer tissue bank. Biopreserv Biobank 2009;7:51–88. 6. Khushi M, Carpenter JE, Balleine RL, et al. Development of a data entry auditing protocol and quality assurance for a tissue bank database. Cell Tissue Bank 2011 DOI: 10.1007/s10561-0119240-X. [Epub ahead of print]. 7. Fearn P, Sculli F. The CAISIS research data system. In Ochs MF, Casagrande JT, Davuluri RV, eds. Biomedical Informatics for Cancer Research. NY: Springer;2010:215–25. 8. Kieyzun A, Guo PJ, Jayaraman K, et al. Automatic creation of SQL Injection and cross-site scripting attacks. Proceedings of the 31st International Conference on Software Engineering, Washington, DC. 1555036, IEEE Computer Society;2009:99–209. 9. Noel M. Microsoft ISA Server 2006 unleashed. Indianapolis: Sams, 2007. ISBN: 0672329190. 10. Soltesz S, Potzl H, Fiuczynski ME, et al. Container-based operating system virtualization: a scalable, high-performance alternative to hypervisors. Proceedings of the 2nd ACM SIGOPS/ EuroSys European Conference on Computer Systems 2007. Lisbon, Portugal, 1273025, ACM;2007:275–287. 11. Datta A, Dutta K, Thomas H, et al. Proxy-based acceleration of dynamically generated content on the World Wide Web: an approach and implementation. ACM Trans Database Syst 2004;29:403–443. 12. Choy M, Leong HV, Wong MH. Disaster recovery techniques for database systems. Commun ACM 2000;43(11es):6. 13. Edgerton M, Grizzle W, Washington MK. The deployment of a tissue request tracking system for the CHTN: a case study in managing change in informatics for biobanking operations. BMC Med Inform Decis Making 2010;10:32. 14. Tayside Tissue Bank. 2011. Available at www.tissuebank .dundee.ac.uk/?page = resinfo-tisreq 15. Suh KS, Remache Y, Patel J, et al. Informatics-guided procurement of patient samples for biomarker discovery projects in cancer research. Cell Tissue Bank 2009;10:43–48. 16. BioLINCC. Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC) website. 2011. Available at https://biolincc.nhlbi.nih.gov/home/
Acknowledgments The ABCTB is funded by the National Health and Medical Research Council of Australia (Enabling Grant 307750), the National Breast Cancer Foundation, and the Cancer Institute New South Wales (CINSW). Rosemary L. Balleine is a CINSW Fellow.
Author Disclosure Statement No competing financial interests exist.
References 1. Signoretti S, Bratslavsky G, Waldman FM, et al. Tissue-based research in kidney cancer: current challenges and future directions. Clin Cancer Res 2008;14:3699–3705. 2. Womack C, Gray NM. Banking human tissue for research: vision to reality. Cell Tissue Bank 2009;10:267–270. 3. Jim Vaught, Andrea Kelly, Hewitt R. A Review of International Biobanks and Networks: success factors and key benchmarks. Biopreserv Biobank 2009;7:143–150.
Address correspondence to: Mr. Matloob Khushi Breast Cancer Tissue Bank Westmead Millennium Institute Sydney Medical School—Westmead University of Sydney Westmead 2145 Australia E-mail: [email protected] Received 10 August, 2011/Accepted 19 October, 2011
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Appendix The Australian Breast Cancer Tissue Bank Web and database servers are hosted behind a demilitarized zone (DMZ), and a Microsoft ISA Server is deployed in addition to a number of hardware firewalls. ISA, Internet Security and Acceleration.
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