Jim Vaught

Biospecimen Reporting for Improved Study Quality (BRISQ)

Human biospecimens are subject to a number of different collection, processing, and storage factors that can significantly alter their molecular composition and consistency. These biospecimen preanalytical factors, in turn, influence experimental outcomes and the ability to reproduce scientific results. Currently, the extent and type of information specific to the biospecimen preanalytical conditions reported in scientific publications and regulatory submissions varies widely. To improve the quality of research utilizing human tissues, it is critical that information regarding the handling of biospecimens be reported in a thorough, accurate, and standardized manner. The Biospecimen Reporting for Improved Study Quality (BRISQ) recommendations outlined herein are intended to apply to any study in which human biospecimens are used. The purpose of reporting these details is to supply others, from researchers to regulators, with more consistent and standardized information to better evaluate, interpret, compare, and reproduce the experimental results. The BRISQ guidelines are proposed as an important and timely resource tool to strengthen communication and publications around biospecimen-related research and help reassure patient contributors and the advocacy community that the contributions are valued and respected.

The Evolution of Biobanking Best Practices

Biobanks and biospecimens are critical components for many areas of clinical and basic research. The quality of biospecimens and associated data must be consistent and collected according to standardized methods in order to prevent spurious analytical results that can lead to artifacts being interpreted as valid findings. A number of international institutions have taken the initiative to develop and publish best practices, which include technical recommendations for handling biospecimens as well as recommendations for ethical and regulatory practices in biobanking. These sources of guidance have been useful in raising the overall consistency and quality of research involving biospecimens. However, the lack of international harmonization, uneven adoption, and insufficient oversight of best practices are preventing further improvements in biospecimen quality and coordination among collaborators and biobanking networks. In contrast to the more straightforward technical and management issues, ethical and regulatory practices often involve issues that are more controversial and difficult to standardize.

Biospecimen reporting for improved study quality (BRISQ)

Helen M. Moore, PhD; Andrea B. Kelly, PhD; Scott D. Jewell, PhD; Lisa M. McShane, PhD; Douglas P. Clark, MD; Renata Greenspan, MD; Daniel F. Hayes, MD; Pierre Hainaut, PhD, MS; Paula Kim; Elizabeth A. Mansfield, PhD; Olga Potapova, PhD; Peter Riegman, PhD; Yaffa Rubinstein, PhD; Edward Seijo, MS; Stella Somiari, PhD; Peter Watson, MB, BChir; Heinz-Ulrich Weier, PhD; Claire Zhu, PhD; and Jim Vaught, PhD

Long-term storage and recovery of buccal cell DNA from treated cards.

Economical methods for collecting and storing high-quality DNA are needed for large population-based molecular epidemiology studies. Buccal cell DNA collected via saliva and stored on treated filter paper cards could be an attractive method, but modest DNA yields and the potential for reduced recovery of DNA over time were unresolved impediments. Consequently, buccal cell DNA collection via oral mouthwash rinsing became the method of choice in epidemiologic studies. However, the amount of genomic DNA (gDNA) required for genotyping continues to decrease, and reliable whole genome amplification (WGA) methods further reduced the mass of gDNA needed for WGA to 10 ng, diminishing the obstacle of low DNA yields from cards. However, concerns about yield and DNA quality over time remained. We located and analyzed 42 buccal cell saliva samples collected and stored on treated cards for 7 years at room temperature, −20°C, and −80°C. We recovered DNA from the treated cards, estimated the concentration by a human-specific quantitative real-time PCR assay, and evaluated the quality by PCR amplification of 268-, 536-, and 989-bp fragments of the β-globin gene and by AmpFlSTR Identifiler assay analysis. Most DNA yields per 3-mm punch were <10 ng, and most PCR amplicons failed to amplify, where size of the amplicon was negatively associated with successful amplification. Using these methods, treated cards did not consistently provide sufficient quantities of buccal cell gDNA after 7 years of storage for genotyping or WGA.(Cancer Epidemiol Biomarkers Prev 2006;15(2):385–8)

Critical Issues in International Biobanking

Biobanking for clinical or research purposes includes the collection, processing, storage, and analysis of biological specimens. It is now well recognized that biobanking involves a complex array of technical and ethical/regulatory considerations. Biobanking policies and procedures are often documented by best practices that are usually voluntary but may be supplemented and reinforced by strict rules and regulations that govern informed consent, privacy, QC, and other critical issues. As biobanking has emerged as a global endeavor, with national networks and international collaboration becoming the norm, it has become even more critical that practices are coordinated and that quality standards are developed. Biobanking is also often a business endeavor, in that formal strategic and business plans need to be developed to ensure the long-term survival of the associated research programs. As new technologies are developed for using biospecimens to diagnose and treat disease, as well as to evaluate genetic risks, patients are becoming more aware of the importance and benefits of biobanking as part of the medical infrastructure. As a result, patients who donate biospecimens are becoming more interested in learning more about their own samples use and in seeing the actual results of the research. One of the aspects of these evolving attitudes toward biobanking was addressed in a previous QA Clin Chem 57:540–4). From the broad array of issues that could be addressed, this Q&A focuses on a few critical issues that many biobanks are facing today: quality management, biobank network design, long-term sustainability, conveying the importance of biobanking to the public, and the return of research results to biospecimen donors. Five experts who are engaged in national and international biobanking programs discuss these complex issues here. What are some of the important issues related to …

Effects of Electron-Beam Irradiation on Whole Genome Amplification

Electron-beam (E-beam) irradiation, currently being used to sterilize mail addressed to selected ZIP codes in the United States, has significant negative effects on the genomic integrity of DNA extracted from buccal-cell washes. We investigated the yield, composition, and genotyping performance of whole genome amplified DNA (wgaDNA) derived from 24 matched samples of E-beam–irradiated and nonirradiated genomic DNA (gDNA) as a model for the effects of degraded gDNA on the performance of whole genome amplification. gDNA was amplified using the Multiple Displacement Amplification method. Three methods of DNA quantification analysis were used to estimate the yield and composition of wgaDNA, and 65 short tandem repeat and single nucleotide polymorphism genotyping assays were used to evaluate the genotyping performance of irradiated and nonirradiated gDNA and wgaDNA. Compared with wgaDNA derived from nonirradiated gDNA, wgaDNA derived from irradiated gDNA exhibited a significantly reduced yield of wgaDNA and significantly reduced short tandem repeat and single nucleotide polymorphism genotyping completion and concordance rates (P < 0.0001). Increasing the amount of irradiated gDNA input into whole genome amplification improved genotyping performance of wgaDNA but not to the level of wgaDNA derived from nonirradiated gDNA. Multiple Displacement Amplification wgaDNA derived from E-beam–irradiated gDNA is not suitable for genotyping analysis.

Effects of electron-beam irradiation on buccal-cell DNA

Buccal cells were collected from 29 participants, by use of mouthwash rinses, and were split into equal aliquots, with one aliquot irradiated by electron-beam (E-beam) irradiation equivalent to the sterilizing dosage used by the U.S. Postal Service and the other left untreated. Aliquots were extracted and tested for DNA yields (e.g., TaqMan assay for quantifying human genomic DNA), genomic integrity, and amplification-based analysis of genetic variants (e.g., single-nucleotide polymorphisms [SNPs] and single tandem repeats [STRs]). Irradiated aliquots had lower median DNA yields (3.7 microg/aliquot) than untreated aliquots (7.6 microg/aliquot) (P<.0005) and were more likely to have smaller maximum DNA fragment size, on the basis of genomic integrity gels, than untreated aliquots (P<.0005). Irradiated aliquots showed poorer PCR amplification of a 989-bp beta-globin target (97% for weak amplification and 3% for no amplification) than untreated aliquots (7% for weak amplification and 0% for no amplification) (P<.0005), but 536-bp and 268-bp beta-globin targets were amplified from all aliquots. There was no detectable irradiation effect on SNP assays, but there was a significant trend for decreased detection of longer STRs (P=.01) in irradiated versus untreated aliquots. We conclude that E-beam irradiation reduced the yield and quality of buccal-cell specimens, and, although irradiated buccal-cell specimens may retain sufficient DNA integrity for some amplified analyses of many common genomic targets, assays that target longer DNA fragments (>989 bp) or require whole-genome amplification may be compromised.

Economics: the neglected "omics" of biobanking.

In this issue of Biopreservation and Biobanking, Gonzalez-Sanchez, et al. describe their work in cost modeling for the Spanish National Biobank Network. The article outlines the network’s strategy to assess and analyze the costs necessary to collect, process, store, and disseminate biospecimens. In recent years, as biobanking has progressed to encompass all other ‘‘–omics’’ analyses, including genomics, proteomics, metabolomics, transcriptomics and the like, this sort of economic analysis has been lacking. Although several major economic models have been developed to sustain biobanks, funding is often supported by centralized budgets within institutions. This arrangement can lead to poor longterm management as the various stakeholders are unaware of the true cost of operating the facility. Often, those costs are not itemized in a way that individual users can understand. And not being accountable for the costs of their individual collections can lead to wasteful practices, including costly long-term storage of unused specimens (a problem in itself!). The Spanish National Biobank Network investigators outline one important aspect of biobanking economics—a detailed analysis of the costs of a complex operation. This analysis is a critical first step in developing a business plan for a biobank or a biobanking network. Depending on the policies and procedures within a particular institution, such a business plan may also involve establishing a cost recovery plan and other strategies to assure the biobank’s long-term sustainability. In 2011, our group at the National Cancer Institute published two ‘‘biobankonomics’’ papers which included recommendations for developing a sustainable business model for a biobank. In addition to the cost analysis, the following items were recommended for consideration: Managing variations in the availability of funding; assessing the ‘‘market need’’ for specimens and data collected by the biobank; the long-term ‘‘total cost of ownership’’; cost recovery and analysis of return on investment; effect of inventory turnover rates; and the development of public-private partnerships to achieve long-term sustainability. In the second of the two papers, we analyzed the potential economic benefits of developing standardized, centralized biobanks. These include quantifiable actions that have economic impact such as implementing strict standards to avoid repeat collection and analyses due to poor specimen quality. Other long-term economic impacts are less quantifiable without further study, but may include: Benefits due to strict adherence to best practices; lower costs for clinical trials and patient care due to production of better quality specimens and data; and efficiencies of scale if biospecimen resources choose to form a network or a centralized biobank that adheres to a set of standard practices. However, most of the above discussion about the development of biobanking business practices and quantifying economic impact is limited to theory. Except for strictly commercial operations, such business policies and practices are not in widespread use in most biobanks. Usually the development of a few simple practices such as cost analysis and partial cost recovery is the result of an economic crisis caused by loss of a funding source, or a strain on the biobank’s resources due to lack of turnover of specimens, and investigators’ lack of accountability in managing their collections. In order to further explore some of these issues, later this year the NCI will start two new biobanking economics projects: One will assess biobank costs and funding mechanisms in order to gain a better understanding of the types of models that result in better long-term sustainability; a second project will develop a cost-and-revenue-stream model and web-based tool that can be used by biobanks for business planning. We hope that these studies will encourage biobank managers to take a more proactive and standardized approach to business planning. Thanks to Gonzalez-Sanchez and coauthors for their contribution to the scarce literature on the economics of biobanking. Informative discussions of these issues have also occurred over the past few years on the ISBER listserv, in the latest editions of the ISBER and NCI Best Practices, as well as in a few contributions to Biopreservation and Biobanking. I would like to see more manuscripts submitted concerning the economics of biobanking, and I encourage those with interest in this topic to send me a note (jvaught@liebertpub.com). We can work together on a special section in the journal to further advance a topic that is critical for the future success of biobanks during these economically challenging times.

What Are the Main Roadblocks to Transnational Biobank Collaboration, and How Can We Overcome Them?

The question is concise but the answer depends both on the interpretation of the sometimes awkward word ‘‘transnational’’ and on the perspective on two assumptions that underlie the question. I will cover these in turn and then address the question. What does transnational mean? It means across regions that host groups of people with a unifying government, frequently but not always associated with a specific geographical area. The word therefore applies to biobank collaboration between countries but equally can apply to collaboration across diverse nations (e.g., indigenous peoples), provinces/states/territories, and ‘‘distinct societies’’ that all exist for example within a country such as Canada. Distinct governance for each group is reflected in laws, ethics perspectives, and attitudes that relate to the activities of biobanking. Experience in building collaboration between regional biobanks that exist within or interface with all of these frames my answer. Are there reasons for biobanks to want to collaborate across regional and/or national borders? Relative to the biobank, there are ‘‘internal’’ reasons to collaborate regionally, nationally, and internationally to share ideas and information on biobank models, processes and operations to build better biobanks. There are also ‘‘external’’ reasons to collaborate to expand the capability of the biobank to support research users to address the same questions on comparable biospecimens, broader questions on a larger scale or narrower questions with a rare focus. These two categories of reasons frame my answer. Are there roadblocks to overcome at all? Collaborations for internal reasons once faced roadblocks mostly because of the relative isolation of biobanks in the absence of recognition of the discipline, but also because of funding models that created competition. But the growth of national (e.g. CTRNet), and international (p3G) networks, forums (e.g. Marble Arch Working Group), societies and meetings (e.g. ISBER), and a biobanking journal (Biopreservation and Biobanking) has essentially dismantled the first barrier. And the competitive funding models that had some merits a decade ago to stimulate new ideas for biobanks are also a diminishing roadblock, as competitive grant funding for biobanks is so rare in practice. But roadblocks to internal and external collaboration still persist. So, to address the question. The main roadblock to transnational collaboration to address internal values has changed and is diminished. It is no longer the ability or will to communicate, it is the relatively poor recognition of the value of biobanking which still significantly restricts the effort that is or can be dedicated to biobank leadership, activities, and productive collaboration within our health and research organizations to build these values. The solutions lie in recent efforts to develop tools to classify biobank activities, track intermediate products, and measure overall impact of biobanks. Collaborations between biobanks to address external values face several different and more significant roadblocks. These relate to privacy laws, ethics policies, funding models, and also to practical issues of local medical terminology and definitions and sometimes ownership perceptions fostered by organizations. But among these the most significant are privacy laws. Privacy laws are very important to most of us, but have largely been designed with a focus on issues that are unrelated to medical research, by minds that favor the pendulum swing away from the rights of societies, and have been enacted without sufficient consideration and debate on the collateral damage to other societal objectives such as better health. This roadblock might once have been mitigated by field testing to enable modifications to harmonize these across regions and strategies to be developed to minimize negative impact, but the latter opportunity is long gone and the barrier remains significant and threatens to grow because of the way our political systems function. However the solutions lie in raising these complex issues for balanced and public opinion rather than lobby driven and representative debate, through tools such as deliberative democracy and by establishment of better governance, transparent engagement of donors and education of oversight bodies.

Biobanking on Multiple Continents: Will International Coordination Follow?

Two recent articles 1,2 by Scott et al. and Basik et al. provided excellent overviews of the current state of biobanking and future directions. As noted by Scott et al. referencing an Indiana University article, ‘‘biobanks exist on every continent, even Antarctica.’’ A map in this article shows that many current biobanks are centered in institutions in North America and Europe. However this landscape is quickly changing. Several meetings in the fall of 2013 highlighted the expanding global nature of biobanking, including the Annual Biobank China conference (http://www.scrcnet.org/ biobank2013/eindex.asp) and ESBB meeting in Verona Italy (http://www.esbb.org/verona/), as well as the French BIOBANQUES annual network meeting in Paris. During the ESBB meeting, planning for new biobanking networks in Israel and Africa were presented. H3Africa (http://h3africa.org/), as noted in our Biobanking in Emerging Countries Section in the December 2013 issue will have major infrastructure and ethical-regulatory challenges to overcome as it develops in the coming year. In Europe BBMRI-ERIC (Biobanking and Biomolecular Resources Research Infrastructure European Research Infrastructure Consortium, http://bbmri-eric.eu/) held its inaugural conference in Austria in September 2013. As noted on its web site BBMRI-ERIC ‘‘will increase efficacy and excellence of European biomedical research by: facilitating access to quality-defined human health/disease-relevant biological resources; including associated data in an efficient and ethically and legally compliant manner; reducing the fragmentation of the biomedical research landscape through harmonization of procedures, implementation of common standards and fostering high-level collaboration; capacity building in countries with less developed biobanking communities, thereby contributing to Europe’s cohesion policy.’’ As noted in multiple presentations at Annual Biobank China and ESBB, there are a number of recurring themes among existing and emerging biobanks and biobanking networks. In China, there are multiple efforts underway to develop new biobanks and networks. The international nature of the participants at the September meeting in Shanghai reflected the ever-expanding global nature of biobanking, as plans develop to realize the tremendous opportunities available for the growth of biospecimen resources in China. In the presentations at ESBB by Akin Abayomi concerning H3Africa, and Yehudit Cohen concerning the new national biobanking network in Israel, securing initial funding and planning for sustainability of these programs were noted as major focuses and challenges. And as always, any new biobanking effort requires close attention to infrastructure (e.g. IT systems, security, equipment validation and maintenance, quality management) and the ethical-regulatory frameworks. In their article ‘‘Biopsies: Next-Generation Biospecimens for Tailoring Therapy,’’ Basik et al. provide an excellent overview of the current state of biobanking practice, and propose a new paradigm for the future of tumor biobanking. Although this review focuses mostly on biospecimens from small biopsies and in the context of cancer research, there are several general themes that are applicable to current and new biobanking initiatives: the necessity for multidisciplinary teams including data managers and statisticians as well as pathologists, clinical coordinators and researchers; close attention to processes that recognize the effects of preanalytical variables on biospecimen quality; a comprehensive quality management system involving evidence-based standard procedures; collection and sharing of clinical data; comprehensive ethical and regulatory policies and; a plan for long-term sustainability. We think that we can agree that a vast amount of biobanking and biospecimen research knowledge is generated and shared at ISBER, Asian Network of Research Resource Centers (ANRRC), ESBB, Annual Biobank China and other international meetings, and within important efforts such as BIOBANQUES, BBMRI-ERIC and H3Africa. With the excellent analyses provided by the two articles described above, we think that the stage is set for additional dialogs that can move us to the next level of coordination (not necessarily harmonization) of biobanking practices and procedures. And we have not mentioned the emergence of biological resource educational programs, particularly in Europe, that will contribute to the ‘‘professionalization’’ and global coordination of biobanking initiatives. However, as we listened to various presentations during those meetings in the fall, we were impressed by the fact that as new biobanking networks are being developed, there is a tendency to ‘‘start from scratch’’ regarding some components such as policies and procedures for informed consent, information/inventory systems, business, and basic