British Medical Bulletin, 2015, 114:29–38 doi: 10.1093/bmb/ldv012 Advance Access Publication Date: 24 April 2015
Developments in biospecimen research Jim Vaught* International Society for Biological and Environmental Repositories, Kensington, MD, USA
Accepted 12 March 2015
Abstract Introduction: Biobanking refers to the infrastructure, policies and practices involved in collecting, processing, storing and disseminating biological samples. Biospecimen methods research to support biobanking through evidence-based practices is now recognized as critical to the success of biobanking and translational research. Sources of data: Data concerning biospecimen research have appeared in the literature for many years, primarily in journals and textbooks focused on clinical chemistry, epidemiology and pathology. Recently, new efforts have been initiated to support the development of evidence-based biobanking practices. Areas of agreement: Generally, researchers who are engaged in studies involving biospecimen collection are aware of the effects of pre-analytical variables on their downstream analyses, and they normally take steps to control those variables to publish reproducible results. Knowledge of such biospecimen research data is often unknown in the clinical setting unless the researchers are engaged in a project requiring strict protocols. Areas of controversy: There is broad agreement of the need to develop evidence-based practices to achieve consistent quality for biospecimens and data. However, due to inconsistencies in the literature, there is some disagreement on whether biospecimens need to be collected according to a ‘platinum’ standard or local biobank standards for collecting samples as ‘fit-for-purpose’ will be sufficient. Growing points: New and expanded efforts, on an international basis where possible, need to be developed to better harmonize biospecimen management practices. Areas timely for developing research: Additional biospecimen methods research leading to the development of evidence-based practices is critical to translational research and personalized medicine. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: [email protected]
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*Correspondence address. International Society for Biological and Environmental Repositories, 3405 Wake Drive, Kensington, MD 20895, USA. E-mail: [email protected]
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Key words: biobank, biospecimen, evidence-based practices, translational research
Introduction
Data sources for biospecimen research As noted in several recent commentaries and reviews concerning the development of biospecimen research,3,9,10 this is a growing field which should ultimately lead to evidence-based best practices for biobanking.11,12 Evidence-based practices in biospecimen research have been promoted by programs such as the US National Cancer Institute’s Biospecimen Research Network4 (BRN), and SPIDIA, a consortium funded by the European Union and coordinated by QIAGEN in Germany.13 The aim of these programs is to identify the major questions of methodology and pre-analytical variables, and arrive at some consensus in terms of evidence-based practices which will mitigate the effects of such variables. Both the BRN and SPIDIA initiatives have resulted in significant findings that should advance the field of biospecimen research and promote best practices
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Biobanking (Biobanking is the most widely accepted term for the infrastructure, policies and procedures which comprise the collection, processing, storage and dissemination of biological specimens and other collections. Biobanking is equivalent to, in a general sense, and often used interchangeably with, Biorepositories, Biological Resource Centers, Biospecimen Resources) of human biospecimens (Biospecimens as used in this article comprises liquid samples such as blood, urine, saliva, as well as tissue and cellular samples) for clinical as well as basic and translational research purposes has been a part of the infrastructure of clinical and academic centers for many years.1 Many of the early efforts in biobanking focused on the collection of biospecimens from patients undergoing diagnostic or surgical procedures and were centered in pathology departments where collections of paraffin-embedded tissues have been maintained for decades.1,2 As biospecimen research has progressed over the past 20 years, the perception of the field has evolved from most investigators thinking that biospecimen collection, processing and storage involve simple empirical techniques, to recognition of the importance of the development of methods to optimize sample quality. This review is focused on more recent developments of biobanking in biomedical research, as the field has grown into a scientific endeavor with emerging technologies and complex regulatory issues.3 Examples are provided to demonstrate the evolution of the field toward consideration of the sources of inconsistent biospecimen quality and the adoption of evidence-based best practices. Many of the principles discussed are applicable to diverse collections of biological, environmental, museum and other sample types. To introduce the topic of biospecimen research, it is instructive to consider the ‘lifecycle of the biospecimen,’ in the clinical setting, as shown in Figure 1. When a tissue biospecimen is removed from a surgical patient, the top priority of course is for the sample to be processed by a pathologist for
diagnostic purposes. However, with the current trends in translational research programs, a portion of the tissue sample may be collected for research purposes, assuming proper consent has been obtained. Biospecimens collected for research purposes need to be processed in a standardized way that avoids the effects of pre-analytical variables which can affect the quality of the samples and downstream analyses.5,6 Examples of such variables ( pre-analytical variables may be pre- or postacquisition of the sample) are drugs that may have been taken by the patient before surgery or anesthesia administered during the procedure. In addition, a major focus of studies into pre-analytical variables is the effects of cold ischemia and warm ischemia, i.e. the time a biological sample spends in an ischemic state while in the patient’s body or after it has been removed for processing. These ischemic times can significantly affect downstream analyses,7,8 making it important that biospecimens are collected according to a standardized, evidence-based protocol to minimize such effects.
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for biospecimen use in clinical and basic research programs.14,15 However, such efforts will not necessarily lead to changes in the short term in clinical practice when studies involve biospecimens and biobanks. Additional efforts are needed to develop and disseminate evidence-based practices, and promote integration of the results of such studies into clinical practice. A major source of information and data about biospecimen research is the US National Cancer Institute’s (NCI) Biospecimen Research Database16 (BRD). Since 2008, the BRD staff has been collecting information from dozens of journals, and to date, over 2000 papers have been reviewed and curated. As stated on the BRD web site: The BRD is a free and publicly accessible literature database that contains peer-reviewed primary and review articles in the field of human Biospecimen Science. Each entry has been created by a team of curators to capture the following: (1) relevant parameters that include the biospecimen investigated (type and location, patient diagnosis), preservation method, analyte (s) of interest and technology platform(s) used for analysis; (2) the pre-analytical factors investigated, including those relating to pre-acquisition, acquisition, preservation, processing, storage,
and analysis; and (3) an original summary of relevant results.
However, a search of the BRD often gives conflicting results, in terms of evidence which would be useful in changing laboratory or clinical practice with regard to biospecimen collection and processing. For example, a search of the BRD for papers concerning circulating cell-free DNA (ccfDNA), which in recent years has shown promise as a diagnostic marker for several diseases,17,18 produces a list of ∼20 papers. Evidence from several of these studies shows that factors such as type of additive in the blood collection tube, as well as temperature and duration of storage, affects the amount of ccfDNA recovered. Given the number of studies and somewhat conflicting data, it would be difficult to arrive at a consensus for a standard operating procedure for collecting such samples that could be routinely applied in a clinical setting. There are many other such examples in the literature which make it difficult to develop conclusive, evidence-based recommendations. Figure 2 shows an example from the BRD of the review of a paper concerning circulating microRNAs.19 This paper is a good example of the type of research that is needed to develop evidence-based practices, many of which could, if confirmed and
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Fig. 1 The lifecycle of a surgical biospecimen and pre- and post-analytical variables that can affect the molecular integrity of the sample, from US NCI Biospecimen Research Network web page: http://biospecimens.cancer.gov/researchnetwork/lifecycle.asp.4
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adopted, have significant impacts on clinical practice involving biospecimen collection.
Example: UK biobank methods studies As noted on its web site:20 UK Biobank is a major national health resource, and a registered charity in its own right, with the aim of improving the prevention, diagnosis and treatment of a wide range of serious and lifethreatening illnesses – including cancer, heart diseases, stroke, diabetes, arthritis, osteoporosis, eye disorders, depression and forms of dementia. UK Biobank recruited 500000 people aged between 40–69 years in 2006–2010 from across the country to take part in this project. They have undergone measures, provided blood, urine and saliva samples for future analysis, detailed
information about themselves and agreed to have their health followed. Over many years this will build into a powerful resource to help scientists discover why some people develop particular diseases and others do not.
However, well before starting to collect biological samples from its large study population, UK Biobank’s lead scientific investigators conducted a series of methods development studies that resulted in a series of articles in the International Journal of Epidemiology in 2008.21–23 These studies represented a solid approach to biospecimen research. For example, one study focused on methods for collecting blood and urine, and determined the most appropriate additives and preservatives necessary for samples to be suitable for downstream us (e.g. standard hematology assays). Other papers in this series were concerned with optimal methodology for collecting saliva for biomarker
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Fig. 2 Example of manuscript review summary from the NCI Biospecimen Research Database.16,19
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analyses and the results of new technology development for automated separation of blood fractions. Ultimately, such studies result in time and cost savings, as collection and analysis efforts are standardized from the outset of the project.
Example: human epidermal growth factor receptor 2 assay discrepancies
In theory, the pre-analytical variables that may affect biospecimen quality and analysis in biomarker discovery and development are fairly straightforward. Some examples have already been noted: time to fixation or freezing after collection (cold ischemic time); timing and duration of tissue fixation; stabilization method (freezing, fixation); storage temperature; number of thawing and refreezing cycles; additives to blood collection tubes (e.g. EDTA, heparin, citrate). Of course not all of these variables will affect sample quality or analysis, as an assessment of such studies has shown.11 The factors that have traditionally been used to evaluate tissue quality for histopathological applications are not necessarily applicable to newer molecular analyses.10,30 Methods that may properly preserve tissues for clinical diagnostic purposes may compromise the biomolecules necessary for biomarker discovery and development. Hewitt et al. 10 propose (see Tables 1 and 2, reference 9) a series of ‘first-order’ and ‘second-order’ issues that need to be considered for biomarker discovery and development.10 Among these are the intended use of the biomarker assay; the type of biospecimen (tissue, fluid); its clinical utility; stability of the samples under the intended storage conditions; replicability of the assay in various laboratories; the minimum sample size necessary; pre-analytical variables, such as fixative used, blood tube additives and other handling procedures to consider and sources of assay interference. These are factors that are not often fully evaluated in the process of biomarker discovery and development, but should be. As noted by Spruessel et al.,7 ‘while scientists control variables in their experimental settings and try to minimize them as much as possible, they usually barely know about the background of clinical samples’.
The need for evidence-based practices Biospecimen research is not a controversial area of science. When made aware of issues such as those discussed in this review, investigators want to learn more about how to avoid such pitfalls in their own
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A good example of pre-analytical issues affecting clinical practice involves human epidermal growth factor receptor 2 (HER2) assays and breast cancer treatment with Herceptin®. During the period around 2005–07, the American Society of Clinical Oncology24 (ASCO) and the College of American Pathologists25 (CAP) undertook a detailed study of HER2 assay practices and results from various clinical laboratories.26,27 The findings showed that false positives and false negatives in HER2 assay results occurred at rates approaching 20%. Of course these discrepancies resulted in stress to the patient for false positives, as well as the economics of unnecessary treatment. False negatives would of course delay treatment and result in significant harm to patients needing treatment. In light of these findings, ASCO and CAP members collaborated on their publication, with recommendations for improving HER2 assay performance. In terms of biospecimen practices, it is noteworthy that one of the recommendations involved standardizing the time and duration of formalin fixation of breast samples used in the assays.26 These and other discrepancies in laboratory practices led to inter-laboratory variability with the assays. In 2013, ASCO and CAP published a review and update of the HER2 assay performance and the guidelines.27 The update provided evidence that HER2 assay performance had improved since publications of the initial guidelines in 2007. In addition, the update provided detailed recommendations to clinicians for informing patients about the importance of HER2 testing, and how their tissue samples will be used in assays and how results will be interpreted. The HER2 story is only one of several such examples identified by CAP and independently by various investigators. Additional information is available from other studies concerning the effect of pre-analytical variables on clinical laboratory practices.28,29
Pre-analytic factors in biomarker discovery and development
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surrounding such ‘ELSI’ (ethical, legal and social issues) practices can result in significant delays and modifications to biospecimen research plans and operations. However, ELSI practices were developed to protect patients who donate specimens from physical harm, as well as from concerns about privacy. Adherence to such practices is critical to the success and ethical conduct of all research studies involving human biospecimens.
Emerging biospecimen types and personalized medicine Much of the discussion in this review is relevant to a fairly limited number of specimen types: formalinfixed, paraffin-embedded tissues; frozen tissue; blood and blood fractions and saliva. To date, most studies and reviews concerning biospecimen research have also generally been limited to these types of biospecimens. However, one premise of biospecimen research is never to assume that practices (e.g. processing and storage conditions) developed for one type will be applicable to another biospecimen type. The approach to collecting dozens of sample types for the study of human papilloma virus (HPV) and cervical neoplasia in Costa Rica35 exemplifies the complexities involved in collecting multiple biospecimen types for a single project. The multiple types of blood samples and cervical cells collected each required careful consideration of the processing and storage parameters necessary for valid downstream analyses. In addition, as discussed in the paper, complex logistical arrangements and biobanking protocols were necessary to collect samples in Costa Rica and transport portions of them to the USA. The results of this project in Costa Rica, with significant biospecimen research and biobanking components, were instrumental in the development of the HPV vaccines. In recent years, due to significant advances in analytical techniques and the discovery of new biomarkers and other factors, new specimen types are now routinely collected for diagnostic and prognostic purposes for various diseases. Among these are circulating tumor cells36 (CTC) and ccfDNA.17,18 Studies are now showing that there are multiple
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work. Over the last 10 years, a lot of momentum has been gained through the efforts of the US NCI BRN, SPIDIA and other initiatives.4,13 However, there is considerable ambiguity in publications related to developing evidence-based practices, as noted for the NCI BRD. Such discrepancies in biospecimen research results make it difficult to arrive at final recommendations for incorporation into basic and clinical research best practices. A primary consideration where biospecimen research may affect clinical practice is the additional cost associated with the collection and processing of biospecimens from patients, while not necessarily improving patient care. Unless these costs can either be absorbed by the affected clinical departments, or a cost recovery mechanism is in place, there is general reluctance to adopt new biospecimen-related standards. However, some changes in pre-analytical standards do not come at further cost. The reluctance to adopt new standards may not relate to sustainability, but rather consistency over time in an existing biobank resource. It is difficult for a biobank to change practices mid-stream, as there is the risk of samples collected after such a change being incompatible with samples collected beforehand in a given research project. Too many changes over the course of time can result in a varied and fragmented biospecimen resource. The economics of biobanking and long-term sustainability are emerging areas of research in biobanking.31 In addition to biospecimen research that may lead to new evidence-based technical standards, it is worth noting that an entirely distinct area of biobanking involves ethical and regulatory issues that can affect all other aspects of this field.32,33 These topics are too complex to discuss in detail in this review. However, the reader is encouraged to see reviews32 concerning the following: informed consent, return of research results to patients, incidental findings, intellectual property and material transfer agreements, patient privacy, and ownership of biospecimens and data. The NCI Best Practices for Biospecimen Resources address these issues in some detail and provide additional references and web links.34 These issues arise repeatedly in biobanking publications and conferences. The complexities
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Discussion This review has concentrated on the development of biospecimen research with regard to the discovery and control of pre-analytical variables and other factors that can affect the quality of samples and the relevance and reliability of downstream analyses. Importantly, some of these factors can affect the reliability of clinical research results and patient safety. In addition, more so than in earlier times, research is now a global enterprise, making it even more important that international standards and practices are developed and adhered to. In light of these developments, some critical initiatives that should be expanded or developed by biobankers and clinical investigators are highlighted below: 1. Adopt biobanking best practices: There are many sets of biospecimen guidelines that are widely available from organizations such as the International Society for Biological and Environmental
Repositories (ISBER), NCI, the International Agency for Research on Cancer (IARC), the Organisation for Economic Cooperation and Development (OECD) and other national and international organizations.40 However, there is little international coordination and harmonization of practices.41 Importantly, local and national regulations sometimes make it difficult to coordinate the legal collection and transport of biospecimens across inter-national borders.42 Additional efforts are needed, perhaps through international organizations such as ISBER and the European, Middle Eastern and African Society for Biopreservation and Biobanking (ESBB),43 to promote international coordination of biobanking practices. In the USA, the College of American Pathologists has taken a significant step toward promoting best practices among biobanks through the development of its Biorepository Accreditation Program,44 which is based on NCI, ISBER and other well-developed guidelines. The Canadian Tumour Repository Network (CTRNet) has published a full set of SOPs that are readily useable by biobanks globally.45 2. Develop and adopt evidence-based practices: Through the large institutional efforts described in this review (e.g. NCI BRN, BRD, SPIDIA, CAP) as well as those of individual investigators, some critical areas of biospecimen research have been identified. In some instances, such as for HER2 analyses, the investigations have resulted in adoption of new practices in clinical settings. More organized efforts to develop and adopt evidence-based standards are needed. Major strides are being made through the efforts of the European Biobanking and BioMolecular Research Resources Infrastructure (BBMRI),46 and national biobanking networks, but more widespread global adoption of such approaches is needed. To move from ‘opinion-based’ to evidence-based practices, such international coordination will require new approaches to cooperative development and adoption of such practices. It is important that new evidence-based practices are developed and adopted in an organized manner involving well-recognized experts. Expert working groups could be appointed from
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clinical associations that can be derived from studying these biomarkers.36 However, with each new biospecimen type, there is the necessity to develop evidence-based practices for its collection, processing and storage. In 2013, Basik et al. 37 published a review in which they discussed ‘next-generation biobanking,’ and proposed that clinical biobanking has evolved into a new era where liquid biopsies will be the norm and a broader array of clinical practitioners and informaticians will be involved in collecting samples and generating ‘-omics’ data for targeted or personalized therapies. This and other publications have confirmed that biospecimens are important for drug and diagnostics co-development, and that biomarker assays which are integral to diagnosis and treatment must include proper, consistent handling of biospecimens to accurately tailor treatment.38 In 2011, the US NCI Biorepositories and Biospecimen Research Branch (BBRB) hosted a workshop to discuss this issue. The Workshop on Biospecimen Reference Sets and Drug-Diagnostic Co-development report is available on the BBRB web site.39
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sample collection and processing time points for example). Several journals have adopted BRISQ into their instructions for authors and reviewers.48 Similarly, the Standard Preanalytical Code (SPREC)49 is a set of codes that are used to simplify reporting of biospecimen collection and processing conditions, and have been widely adopted. 5. Encourage changes in clinical practice involving biospecimen collection: Many clinical practices involving biospecimen collection are based on decades-long approaches to diagnostic procedures, making this a more difficult proposition. As noted, biobanking actually originated primarily in pathology departments where formalinfixed, paraffin-embedded samples have been the standard for diagnosis and research for many years. Only more recently have clinical departments recognized the value of developing translational research programs and taking more care to adopt standard practices. The obstacles to creating and/or following evidence-based practices may be difficult to overcome, since there may be significant economic issues that prevent changes in practice.
Conclusions This review outlines some of the more recent advances in biobanking, to trace its transformation from an infrastructure-based support activity into a true scientific endeavor, biospecimen research. This evolution into a more organized set of standards and practices supported by methodological studies was necessitated by several factors, including high-profile problems encountered during the course of some expensive projects, and the increasingly global nature of research. These factors combined to encourage investigators to examine their biospecimen-based practices and come together in the form of societies and publications to move the field forward. Hopefully over the next few years, such international collaborations can lead to a more harmonized field and further development and adoption of evidence-based clinical biospecimen practices. The global nature of biobanking seems to be leading us in that direction.50
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members of existing organizations such as BBMRI, CAP, ISBER and ESBB. Importantly, the CAP Biorepository Accreditation Program is well recognized internationally as a new set of standards that many biobanks are preparing to adopt. Since the CAP accreditation standards are based on NCI, ISBER and other existing biobank best practices, they could become an important conduit for advancing evidence-based practices. 3. Publish standard procedures and biospecimen research study results: One issue that has challenged progress in such research over the years has been the lack of peer-reviewed publications supporting issues relating to optimization of biospecimen quality. In addition, as noted, such papers are published in a variety of journals from multiple disciplines. The US NCI has undertaken a major effort to compile, analyze and publish summaries of biospecimen research efforts. However, more such initiatives will be necessary to encourage investigators to consider biospecimen research a priority and to publish and present their results at national and international conferences. 4. Adopt standards for reporting biospecimen collection and processing conditions: The Reporting Recommendations for Tumor Marker Prognostic Studies47 (REMARK) includes recommendations with several direct and indirect references to reporting on biospecimen collection and analysis parameters. More recently, guidelines were recommended for biospecimen collection, stabilization, processing and storage conditions that should be reported by authors in their manuscripts [Biospecimen Reporting for Improved Study Quality (BRISQ)]. These factors are considered important for reviewers and journal editors to evaluate before accepting and publishing papers.48 These BRISQ recommendations are organized into three tiers of sample data elements. Tier 1 is recommended as the minimal set of sample collection and processing conditions that should be reported. Tiers 2 and 3 comprise information on conditions which may be important pre-analytic factors, but are less likely to be routinely monitored and reported (specific
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Conflict of Interest statement The authors has no potential conflicts of interest.
References
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Developments in biospecimen research Jim Vaught* International Society for Biological and Environmental Repositories, Kensington, MD, USA
Accepted 12 March 2015
Abstract Introduction: Biobanking refers to the infrastructure, policies and practices involved in collecting, processing, storing and disseminating biological samples. Biospecimen methods research to support biobanking through evidence-based practices is now recognized as critical to the success of biobanking and translational research. Sources of data: Data concerning biospecimen research have appeared in the literature for many years, primarily in journals and textbooks focused on clinical chemistry, epidemiology and pathology. Recently, new efforts have been initiated to support the development of evidence-based biobanking practices. Areas of agreement: Generally, researchers who are engaged in studies involving biospecimen collection are aware of the effects of pre-analytical variables on their downstream analyses, and they normally take steps to control those variables to publish reproducible results. Knowledge of such biospecimen research data is often unknown in the clinical setting unless the researchers are engaged in a project requiring strict protocols. Areas of controversy: There is broad agreement of the need to develop evidence-based practices to achieve consistent quality for biospecimens and data. However, due to inconsistencies in the literature, there is some disagreement on whether biospecimens need to be collected according to a ‘platinum’ standard or local biobank standards for collecting samples as ‘fit-for-purpose’ will be sufficient. Growing points: New and expanded efforts, on an international basis where possible, need to be developed to better harmonize biospecimen management practices. Areas timely for developing research: Additional biospecimen methods research leading to the development of evidence-based practices is critical to translational research and personalized medicine. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: [email protected]
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*Correspondence address. International Society for Biological and Environmental Repositories, 3405 Wake Drive, Kensington, MD 20895, USA. E-mail: [email protected]
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Key words: biobank, biospecimen, evidence-based practices, translational research
Introduction
Data sources for biospecimen research As noted in several recent commentaries and reviews concerning the development of biospecimen research,3,9,10 this is a growing field which should ultimately lead to evidence-based best practices for biobanking.11,12 Evidence-based practices in biospecimen research have been promoted by programs such as the US National Cancer Institute’s Biospecimen Research Network4 (BRN), and SPIDIA, a consortium funded by the European Union and coordinated by QIAGEN in Germany.13 The aim of these programs is to identify the major questions of methodology and pre-analytical variables, and arrive at some consensus in terms of evidence-based practices which will mitigate the effects of such variables. Both the BRN and SPIDIA initiatives have resulted in significant findings that should advance the field of biospecimen research and promote best practices
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Biobanking (Biobanking is the most widely accepted term for the infrastructure, policies and procedures which comprise the collection, processing, storage and dissemination of biological specimens and other collections. Biobanking is equivalent to, in a general sense, and often used interchangeably with, Biorepositories, Biological Resource Centers, Biospecimen Resources) of human biospecimens (Biospecimens as used in this article comprises liquid samples such as blood, urine, saliva, as well as tissue and cellular samples) for clinical as well as basic and translational research purposes has been a part of the infrastructure of clinical and academic centers for many years.1 Many of the early efforts in biobanking focused on the collection of biospecimens from patients undergoing diagnostic or surgical procedures and were centered in pathology departments where collections of paraffin-embedded tissues have been maintained for decades.1,2 As biospecimen research has progressed over the past 20 years, the perception of the field has evolved from most investigators thinking that biospecimen collection, processing and storage involve simple empirical techniques, to recognition of the importance of the development of methods to optimize sample quality. This review is focused on more recent developments of biobanking in biomedical research, as the field has grown into a scientific endeavor with emerging technologies and complex regulatory issues.3 Examples are provided to demonstrate the evolution of the field toward consideration of the sources of inconsistent biospecimen quality and the adoption of evidence-based best practices. Many of the principles discussed are applicable to diverse collections of biological, environmental, museum and other sample types. To introduce the topic of biospecimen research, it is instructive to consider the ‘lifecycle of the biospecimen,’ in the clinical setting, as shown in Figure 1. When a tissue biospecimen is removed from a surgical patient, the top priority of course is for the sample to be processed by a pathologist for
diagnostic purposes. However, with the current trends in translational research programs, a portion of the tissue sample may be collected for research purposes, assuming proper consent has been obtained. Biospecimens collected for research purposes need to be processed in a standardized way that avoids the effects of pre-analytical variables which can affect the quality of the samples and downstream analyses.5,6 Examples of such variables ( pre-analytical variables may be pre- or postacquisition of the sample) are drugs that may have been taken by the patient before surgery or anesthesia administered during the procedure. In addition, a major focus of studies into pre-analytical variables is the effects of cold ischemia and warm ischemia, i.e. the time a biological sample spends in an ischemic state while in the patient’s body or after it has been removed for processing. These ischemic times can significantly affect downstream analyses,7,8 making it important that biospecimens are collected according to a standardized, evidence-based protocol to minimize such effects.
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for biospecimen use in clinical and basic research programs.14,15 However, such efforts will not necessarily lead to changes in the short term in clinical practice when studies involve biospecimens and biobanks. Additional efforts are needed to develop and disseminate evidence-based practices, and promote integration of the results of such studies into clinical practice. A major source of information and data about biospecimen research is the US National Cancer Institute’s (NCI) Biospecimen Research Database16 (BRD). Since 2008, the BRD staff has been collecting information from dozens of journals, and to date, over 2000 papers have been reviewed and curated. As stated on the BRD web site: The BRD is a free and publicly accessible literature database that contains peer-reviewed primary and review articles in the field of human Biospecimen Science. Each entry has been created by a team of curators to capture the following: (1) relevant parameters that include the biospecimen investigated (type and location, patient diagnosis), preservation method, analyte (s) of interest and technology platform(s) used for analysis; (2) the pre-analytical factors investigated, including those relating to pre-acquisition, acquisition, preservation, processing, storage,
and analysis; and (3) an original summary of relevant results.
However, a search of the BRD often gives conflicting results, in terms of evidence which would be useful in changing laboratory or clinical practice with regard to biospecimen collection and processing. For example, a search of the BRD for papers concerning circulating cell-free DNA (ccfDNA), which in recent years has shown promise as a diagnostic marker for several diseases,17,18 produces a list of ∼20 papers. Evidence from several of these studies shows that factors such as type of additive in the blood collection tube, as well as temperature and duration of storage, affects the amount of ccfDNA recovered. Given the number of studies and somewhat conflicting data, it would be difficult to arrive at a consensus for a standard operating procedure for collecting such samples that could be routinely applied in a clinical setting. There are many other such examples in the literature which make it difficult to develop conclusive, evidence-based recommendations. Figure 2 shows an example from the BRD of the review of a paper concerning circulating microRNAs.19 This paper is a good example of the type of research that is needed to develop evidence-based practices, many of which could, if confirmed and
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Fig. 1 The lifecycle of a surgical biospecimen and pre- and post-analytical variables that can affect the molecular integrity of the sample, from US NCI Biospecimen Research Network web page: http://biospecimens.cancer.gov/researchnetwork/lifecycle.asp.4
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adopted, have significant impacts on clinical practice involving biospecimen collection.
Example: UK biobank methods studies As noted on its web site:20 UK Biobank is a major national health resource, and a registered charity in its own right, with the aim of improving the prevention, diagnosis and treatment of a wide range of serious and lifethreatening illnesses – including cancer, heart diseases, stroke, diabetes, arthritis, osteoporosis, eye disorders, depression and forms of dementia. UK Biobank recruited 500000 people aged between 40–69 years in 2006–2010 from across the country to take part in this project. They have undergone measures, provided blood, urine and saliva samples for future analysis, detailed
information about themselves and agreed to have their health followed. Over many years this will build into a powerful resource to help scientists discover why some people develop particular diseases and others do not.
However, well before starting to collect biological samples from its large study population, UK Biobank’s lead scientific investigators conducted a series of methods development studies that resulted in a series of articles in the International Journal of Epidemiology in 2008.21–23 These studies represented a solid approach to biospecimen research. For example, one study focused on methods for collecting blood and urine, and determined the most appropriate additives and preservatives necessary for samples to be suitable for downstream us (e.g. standard hematology assays). Other papers in this series were concerned with optimal methodology for collecting saliva for biomarker
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Fig. 2 Example of manuscript review summary from the NCI Biospecimen Research Database.16,19
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analyses and the results of new technology development for automated separation of blood fractions. Ultimately, such studies result in time and cost savings, as collection and analysis efforts are standardized from the outset of the project.
Example: human epidermal growth factor receptor 2 assay discrepancies
In theory, the pre-analytical variables that may affect biospecimen quality and analysis in biomarker discovery and development are fairly straightforward. Some examples have already been noted: time to fixation or freezing after collection (cold ischemic time); timing and duration of tissue fixation; stabilization method (freezing, fixation); storage temperature; number of thawing and refreezing cycles; additives to blood collection tubes (e.g. EDTA, heparin, citrate). Of course not all of these variables will affect sample quality or analysis, as an assessment of such studies has shown.11 The factors that have traditionally been used to evaluate tissue quality for histopathological applications are not necessarily applicable to newer molecular analyses.10,30 Methods that may properly preserve tissues for clinical diagnostic purposes may compromise the biomolecules necessary for biomarker discovery and development. Hewitt et al. 10 propose (see Tables 1 and 2, reference 9) a series of ‘first-order’ and ‘second-order’ issues that need to be considered for biomarker discovery and development.10 Among these are the intended use of the biomarker assay; the type of biospecimen (tissue, fluid); its clinical utility; stability of the samples under the intended storage conditions; replicability of the assay in various laboratories; the minimum sample size necessary; pre-analytical variables, such as fixative used, blood tube additives and other handling procedures to consider and sources of assay interference. These are factors that are not often fully evaluated in the process of biomarker discovery and development, but should be. As noted by Spruessel et al.,7 ‘while scientists control variables in their experimental settings and try to minimize them as much as possible, they usually barely know about the background of clinical samples’.
The need for evidence-based practices Biospecimen research is not a controversial area of science. When made aware of issues such as those discussed in this review, investigators want to learn more about how to avoid such pitfalls in their own
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A good example of pre-analytical issues affecting clinical practice involves human epidermal growth factor receptor 2 (HER2) assays and breast cancer treatment with Herceptin®. During the period around 2005–07, the American Society of Clinical Oncology24 (ASCO) and the College of American Pathologists25 (CAP) undertook a detailed study of HER2 assay practices and results from various clinical laboratories.26,27 The findings showed that false positives and false negatives in HER2 assay results occurred at rates approaching 20%. Of course these discrepancies resulted in stress to the patient for false positives, as well as the economics of unnecessary treatment. False negatives would of course delay treatment and result in significant harm to patients needing treatment. In light of these findings, ASCO and CAP members collaborated on their publication, with recommendations for improving HER2 assay performance. In terms of biospecimen practices, it is noteworthy that one of the recommendations involved standardizing the time and duration of formalin fixation of breast samples used in the assays.26 These and other discrepancies in laboratory practices led to inter-laboratory variability with the assays. In 2013, ASCO and CAP published a review and update of the HER2 assay performance and the guidelines.27 The update provided evidence that HER2 assay performance had improved since publications of the initial guidelines in 2007. In addition, the update provided detailed recommendations to clinicians for informing patients about the importance of HER2 testing, and how their tissue samples will be used in assays and how results will be interpreted. The HER2 story is only one of several such examples identified by CAP and independently by various investigators. Additional information is available from other studies concerning the effect of pre-analytical variables on clinical laboratory practices.28,29
Pre-analytic factors in biomarker discovery and development
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surrounding such ‘ELSI’ (ethical, legal and social issues) practices can result in significant delays and modifications to biospecimen research plans and operations. However, ELSI practices were developed to protect patients who donate specimens from physical harm, as well as from concerns about privacy. Adherence to such practices is critical to the success and ethical conduct of all research studies involving human biospecimens.
Emerging biospecimen types and personalized medicine Much of the discussion in this review is relevant to a fairly limited number of specimen types: formalinfixed, paraffin-embedded tissues; frozen tissue; blood and blood fractions and saliva. To date, most studies and reviews concerning biospecimen research have also generally been limited to these types of biospecimens. However, one premise of biospecimen research is never to assume that practices (e.g. processing and storage conditions) developed for one type will be applicable to another biospecimen type. The approach to collecting dozens of sample types for the study of human papilloma virus (HPV) and cervical neoplasia in Costa Rica35 exemplifies the complexities involved in collecting multiple biospecimen types for a single project. The multiple types of blood samples and cervical cells collected each required careful consideration of the processing and storage parameters necessary for valid downstream analyses. In addition, as discussed in the paper, complex logistical arrangements and biobanking protocols were necessary to collect samples in Costa Rica and transport portions of them to the USA. The results of this project in Costa Rica, with significant biospecimen research and biobanking components, were instrumental in the development of the HPV vaccines. In recent years, due to significant advances in analytical techniques and the discovery of new biomarkers and other factors, new specimen types are now routinely collected for diagnostic and prognostic purposes for various diseases. Among these are circulating tumor cells36 (CTC) and ccfDNA.17,18 Studies are now showing that there are multiple
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work. Over the last 10 years, a lot of momentum has been gained through the efforts of the US NCI BRN, SPIDIA and other initiatives.4,13 However, there is considerable ambiguity in publications related to developing evidence-based practices, as noted for the NCI BRD. Such discrepancies in biospecimen research results make it difficult to arrive at final recommendations for incorporation into basic and clinical research best practices. A primary consideration where biospecimen research may affect clinical practice is the additional cost associated with the collection and processing of biospecimens from patients, while not necessarily improving patient care. Unless these costs can either be absorbed by the affected clinical departments, or a cost recovery mechanism is in place, there is general reluctance to adopt new biospecimen-related standards. However, some changes in pre-analytical standards do not come at further cost. The reluctance to adopt new standards may not relate to sustainability, but rather consistency over time in an existing biobank resource. It is difficult for a biobank to change practices mid-stream, as there is the risk of samples collected after such a change being incompatible with samples collected beforehand in a given research project. Too many changes over the course of time can result in a varied and fragmented biospecimen resource. The economics of biobanking and long-term sustainability are emerging areas of research in biobanking.31 In addition to biospecimen research that may lead to new evidence-based technical standards, it is worth noting that an entirely distinct area of biobanking involves ethical and regulatory issues that can affect all other aspects of this field.32,33 These topics are too complex to discuss in detail in this review. However, the reader is encouraged to see reviews32 concerning the following: informed consent, return of research results to patients, incidental findings, intellectual property and material transfer agreements, patient privacy, and ownership of biospecimens and data. The NCI Best Practices for Biospecimen Resources address these issues in some detail and provide additional references and web links.34 These issues arise repeatedly in biobanking publications and conferences. The complexities
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Discussion This review has concentrated on the development of biospecimen research with regard to the discovery and control of pre-analytical variables and other factors that can affect the quality of samples and the relevance and reliability of downstream analyses. Importantly, some of these factors can affect the reliability of clinical research results and patient safety. In addition, more so than in earlier times, research is now a global enterprise, making it even more important that international standards and practices are developed and adhered to. In light of these developments, some critical initiatives that should be expanded or developed by biobankers and clinical investigators are highlighted below: 1. Adopt biobanking best practices: There are many sets of biospecimen guidelines that are widely available from organizations such as the International Society for Biological and Environmental
Repositories (ISBER), NCI, the International Agency for Research on Cancer (IARC), the Organisation for Economic Cooperation and Development (OECD) and other national and international organizations.40 However, there is little international coordination and harmonization of practices.41 Importantly, local and national regulations sometimes make it difficult to coordinate the legal collection and transport of biospecimens across inter-national borders.42 Additional efforts are needed, perhaps through international organizations such as ISBER and the European, Middle Eastern and African Society for Biopreservation and Biobanking (ESBB),43 to promote international coordination of biobanking practices. In the USA, the College of American Pathologists has taken a significant step toward promoting best practices among biobanks through the development of its Biorepository Accreditation Program,44 which is based on NCI, ISBER and other well-developed guidelines. The Canadian Tumour Repository Network (CTRNet) has published a full set of SOPs that are readily useable by biobanks globally.45 2. Develop and adopt evidence-based practices: Through the large institutional efforts described in this review (e.g. NCI BRN, BRD, SPIDIA, CAP) as well as those of individual investigators, some critical areas of biospecimen research have been identified. In some instances, such as for HER2 analyses, the investigations have resulted in adoption of new practices in clinical settings. More organized efforts to develop and adopt evidence-based standards are needed. Major strides are being made through the efforts of the European Biobanking and BioMolecular Research Resources Infrastructure (BBMRI),46 and national biobanking networks, but more widespread global adoption of such approaches is needed. To move from ‘opinion-based’ to evidence-based practices, such international coordination will require new approaches to cooperative development and adoption of such practices. It is important that new evidence-based practices are developed and adopted in an organized manner involving well-recognized experts. Expert working groups could be appointed from
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clinical associations that can be derived from studying these biomarkers.36 However, with each new biospecimen type, there is the necessity to develop evidence-based practices for its collection, processing and storage. In 2013, Basik et al. 37 published a review in which they discussed ‘next-generation biobanking,’ and proposed that clinical biobanking has evolved into a new era where liquid biopsies will be the norm and a broader array of clinical practitioners and informaticians will be involved in collecting samples and generating ‘-omics’ data for targeted or personalized therapies. This and other publications have confirmed that biospecimens are important for drug and diagnostics co-development, and that biomarker assays which are integral to diagnosis and treatment must include proper, consistent handling of biospecimens to accurately tailor treatment.38 In 2011, the US NCI Biorepositories and Biospecimen Research Branch (BBRB) hosted a workshop to discuss this issue. The Workshop on Biospecimen Reference Sets and Drug-Diagnostic Co-development report is available on the BBRB web site.39
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sample collection and processing time points for example). Several journals have adopted BRISQ into their instructions for authors and reviewers.48 Similarly, the Standard Preanalytical Code (SPREC)49 is a set of codes that are used to simplify reporting of biospecimen collection and processing conditions, and have been widely adopted. 5. Encourage changes in clinical practice involving biospecimen collection: Many clinical practices involving biospecimen collection are based on decades-long approaches to diagnostic procedures, making this a more difficult proposition. As noted, biobanking actually originated primarily in pathology departments where formalinfixed, paraffin-embedded samples have been the standard for diagnosis and research for many years. Only more recently have clinical departments recognized the value of developing translational research programs and taking more care to adopt standard practices. The obstacles to creating and/or following evidence-based practices may be difficult to overcome, since there may be significant economic issues that prevent changes in practice.
Conclusions This review outlines some of the more recent advances in biobanking, to trace its transformation from an infrastructure-based support activity into a true scientific endeavor, biospecimen research. This evolution into a more organized set of standards and practices supported by methodological studies was necessitated by several factors, including high-profile problems encountered during the course of some expensive projects, and the increasingly global nature of research. These factors combined to encourage investigators to examine their biospecimen-based practices and come together in the form of societies and publications to move the field forward. Hopefully over the next few years, such international collaborations can lead to a more harmonized field and further development and adoption of evidence-based clinical biospecimen practices. The global nature of biobanking seems to be leading us in that direction.50
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members of existing organizations such as BBMRI, CAP, ISBER and ESBB. Importantly, the CAP Biorepository Accreditation Program is well recognized internationally as a new set of standards that many biobanks are preparing to adopt. Since the CAP accreditation standards are based on NCI, ISBER and other existing biobank best practices, they could become an important conduit for advancing evidence-based practices. 3. Publish standard procedures and biospecimen research study results: One issue that has challenged progress in such research over the years has been the lack of peer-reviewed publications supporting issues relating to optimization of biospecimen quality. In addition, as noted, such papers are published in a variety of journals from multiple disciplines. The US NCI has undertaken a major effort to compile, analyze and publish summaries of biospecimen research efforts. However, more such initiatives will be necessary to encourage investigators to consider biospecimen research a priority and to publish and present their results at national and international conferences. 4. Adopt standards for reporting biospecimen collection and processing conditions: The Reporting Recommendations for Tumor Marker Prognostic Studies47 (REMARK) includes recommendations with several direct and indirect references to reporting on biospecimen collection and analysis parameters. More recently, guidelines were recommended for biospecimen collection, stabilization, processing and storage conditions that should be reported by authors in their manuscripts [Biospecimen Reporting for Improved Study Quality (BRISQ)]. These factors are considered important for reviewers and journal editors to evaluate before accepting and publishing papers.48 These BRISQ recommendations are organized into three tiers of sample data elements. Tier 1 is recommended as the minimal set of sample collection and processing conditions that should be reported. Tiers 2 and 3 comprise information on conditions which may be important pre-analytic factors, but are less likely to be routinely monitored and reported (specific
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Conflict of Interest statement The authors has no potential conflicts of interest.
References
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