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Biospecimens and Biorepositories: From Afterthought to Science

Biospecimens and Biorepositories: From Afterthought to Science
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   Editorial  Biospecimens and Biorepositories: From Afterthoughtto Science Jimmie B. Vaught 1 , Marianne K. Henderson 2 , and Carolyn C. Compton 1  Abstract Biospecimens are recognized as critical components of biomedical research, from basic studies to clinicaltrialsandepidemiologicinvestigations.Biorepositorieshaveexistedin variousformsfor morethan150years,from early small collections in pathology laboratories to modern automated facilities managing millions of samples.Ascollaborativesciencehasdeveloped,ithasbeenrecognizedthatbiospecimensmustbeofconsistentquality.Recentyearshaveseenaproliferationofbestpracticesandtherecognitionofthefieldof"biospecimenscience."Thefutureof this fieldwilldependon thedevelopmentof more evidence-basedpracticesin both theresearch and clinical settings. As the field matures, educating a new generation of biospecimen/biobankingscientists will be an important need.  Cancer Epidemiol Biomarkers Prev; 21(2); 253–5.  2012 AACR. Good Biospecimens Are Hard to Find This editorial could also have been entitled "Biobank-ing 1 :ATrickyEndeavor"butthatwasalreadyusedforthe biospecimen session at the  AACR  conference on TheScience of Cancer Health Disparities held in September2011 (1). Biospecimens (blood, urine, tissue—fresh-fro-zen, paraffin-embedded, saliva, various cells) have beenorganized into formal collections in the United States. formorethan150years,startingintheCivilWarerawiththepathologyspecimensthatresultedinthelargestcollectionin the United States at the Armed Forces Institute of Pathology(2).Manysmallercollectionsexistinpathologylaboratories and clinics. And larger population-basedcollectionsaremanagedatmultipleacademicandclinicalcenters and at the NIH (Bethesda, MD; ref. 2). Standards Were Late in Coming Given the millions of samples collected for clinical andresearch purposes, for most of the history of biobanking,there has been a serious lack of attention to control thequality and consistency of collection, processing, andstorage of biospecimens. A brief list of high-profile bios-pecimen-related problem areas include the following: (i)high rates of false positives and false negatives in HER2analyses traced to inconsistent biospecimen handlingamong laboratories (3); (ii) invalid results from earlyclinical proteomic and other biomarker studies related todifferences in biospecimen handling protocols (4); and(iii) more recently, inadequate quality of tissue samplesforTheCancerGenomeAtlaspilotstudy(5).Astheseandotherspecimen-relatedissueshaveemergedoverthepast10 years, efforts have been under way to develop bestpractices to guide biobank managers and investigatorswho rely on biospecimens for their research (6). In addi-tion to technical approaches to biospecimen collection,processing, and storage, best practices also include guid-ance on important overarching issues such as qualitymanagement, ethical and regulatory requirements, andinformation systems management (7). The emerging eth-ical,regulatory,andsocietalissuesfacingbiobanksarethemost difficult to coordinate and standardize, includingissues such as the return of research results, pediatricconsent, and the accessibility of specimens and data (8).Although "best practices" have been increasinglyadopted, it has to be noted that they are generally basedon empirical observations, that is, not evidence-based.Thereisstillalotthatisnotknownaboutoptimalbiospeci-menpractices.Forexample,formanybloodanalyses,dataconcerning the effects of multiple freeze-thaw cycles andother preanalytic variables are difficult to find. Recently,the National Cancer Institute (NCI) and other programshave developed biospecimen research initiatives to sys-tematically study such variables and produce evidence- based standards (9, 10). The Issues Are Global Many research initiatives are now international innature. This presents special problems for studies involv-ingbiospecimens.Althoughasnotedthereisaproliferation  Authors' Af  fi liations:  1 Of  fi ce of Biorepositories and BiospecimenResearch, and  2 Division of Cancer Epidemiology and Genetics, NationalCancer Institute, NIH, Bethesda, Maryland Corresponding Author:  Jimmie B. Vaught, Of  fi ce of Biorepositories andBiospecimen Research, National Cancer Institute, 11400 Rockville Pike,Rockwall I, Suite 700, Bethesda, MD 20892. Phone: 301-451-7314; Fax:301-480-4814; E-mail: doi:  10.1158/1055-9965.EPI-11-1179  2012 American Association for Cancer Research. 1 Generally biobank, biorepository, biospecimen resource, and biologicresource center all refer to the facilities and related processes that governthe collection, processing, and storage of biologic specimens. Cancer Epidemiology,Biomarkers& Prevention  253 on June 25, 2016. © 2012 American Association for Cancer Research. Downloaded from  ofbestpractices,thereislittleinternationalcoordinationof  biospecimen standards, both from the operational andethical/legal perspectives (6). As a result, investigatorssharing samples and otherwise collaborating across bor-ders must take care that quality standards are establishedprior to specimen collection. In addition, there are manypolitical and regulatory obstacles to send specimens out-sideofvariouscountries.However,anumberofproductive biospecimen networks have been developed, especiallyin Europe, Australia, and Asia that have been successfulin establishing standards and sustainable businessmodels (11). Evolution of Biospecimen Types Traditionally, the major divisionamong biorepositorytypes has been between tissue and blood samples col-lected in surgical and pathology suites for clinicalresearch applications and those collected for popula-tion-based studies, generally blood, urine, and salivasamples. As new technologies suchas tissue andexpres-sion microarrays (12) have evolved, so have the spec-imen types and the methods to collect them changed(13). More recently, methods have been developed toisolate and study circulating tumor cells with high-resolution imaging techniques (14). A major factoraffecting these trends is the availability of new analytictechnologies. As smaller and smaller samples are need-ed for analyses, collection methodologies continue toevolve as well. For example, where microgram quanti-ties of DNA were needed for early genomic analyses,nanogram quantities are now sufficient and DNA fromsaliva is increasingly used (15). And methods such aslaser capture microdissection provide additional toolsfor specialized analytic applications (16). Technologies and Economics Assampletypeshaveevolved,sohavethetechnologiesnecessary to process and store the increasing variety of  biospecimens. One key to this process is the increasingrecognition that biospecimen management is an expen-siveproposition.Alargeepidemiologicbiorepositorythatprocesses and houses millions of samples each year cancost millions of dollars to construct and operate. Therequirements for such a large facility include sophisticat-ed equipment monitoring and alarm systems; back-upgenerators for power failures; quality management pro-tocols; and well-developed procedures for processing,storing, and shipping samples (17). For studies whereextra aliquots of samples are maintained in freezerswhereas others are undergoing analyses, storage costsalone can be $10,000 or more on an annual basis.Economic factors, along with the need for other space-saving and efficiency measures, have led to the develop-ment of new technologies. Among these are automatedsamplealiquotingandnucleicacidextractioninstrumentsthat have greatly increased the productivity of biorepo-sitories (18, 19). Additional efforts have gone into devel-oping alternative storage models. Although the Centersfor Disease Control and Prevention has been collectingand analyzing newborn blood spot cards for many years,newerdry-statetechniques,forexample,fromBiomatrica(20) and GenVault (21) have led to additional advances,reducing costs while maintaining blood, nucleic acids,proteins, and saliva samples at ambient temperatures. The Molecular Epidemiology Perspective Biospecimensformolecularepidemiologystudieshavecontinued to focus on genetics and genomics (i.e.,genome-wide association studies, high-density sequenc-ing, and exome sequencing) in the last few years and thistrend will continue (22, 23). But the need to measuremetabolites, such as estrogens/androgens (24), small-moleculeproteinsandpathways,largeproteins,andevencomponents of the microbiome (25), has expanded. Theincreasingneedforbloodandbloodproducts,tissues,andother body fluids is driven by new analytic tests. There isstill a need to understand optimal ways to process andstorespecimensforthesetestsandfutureapplicationsandmethods to store specimens in more cost-effective, ener-gy-efficient ways. These needs include new automationwhere appropriate, initially in the processing, handling,andtestingareasasthousandsofsamplesoftenneedtobeanalyzed.In terms of molecular epidemiologic study initiatives,the genetic focus with an attempt to identify gene–envi-ronment interactions has necessitated larger and largersample sizes. With this in mind, investigators are poolingsamples from a variety of international study sites (26).Thisglobalizationofinvestigationsintroducesthehazardof variable collection, processing and storage conditionsamong sample sets, and the accompanying chance thatassayresultswilldifferduetothesevariedconditions.Asis the case for clinical studies, evidence-based protocolsthat are widely recognized and adopted are needed tominimize the problems associated with comparison of assay results across collections.Foradditionalinformation,seethe  Focus:BiomarkersandBiospecimens  section published in the April 2010 issue of  Cancer Epidemiology, Biomarkers, and Prevention  (19:901–1015). Degree Programs and Beyond As was the case in the development of molecularepidemiology2decadesago,wheretrainingofepidemiol-ogists in laboratory science had to be integrated anddeveloped over time, biospecimen science has evolvedinformallyand"onthejob"undertheleadershipofexpertsin pathology, epidemiology, clinical chemistry, biochem-istry, molecular biology, and related disciplines. Untilnow, there has been no formal training in the new fieldof biospecimen science. Recently, a new masters degreeprogram in biobank management was initiated in France  Vaught et al.Cancer Epidemiol Biomarkers Prev; 21(2) February 2012  Cancer Epidemiology, Biomarkers & Prevention 254 on June 25, 2016. © 2012 American Association for Cancer Research. Downloaded from   by the International Agency for Research on Cancer (27).Similarideasarebeingdiscussedinotherparts ofEuropeand the United States. Also, as biorepositories become"professionalized," several organizations are developingformal evaluation programs, such as the InternationalSociety for Biological and Environmental RepositoriesSelf-Assessment Tool and Biorepository Proficiency Test-ing Program (28) and the formal accreditation and certi-ficationofbiorepositoriesbytheU.S.CollegeofAmericanPathologists (29).As degree programs, evidence-based practices, profi-ciency testing, accreditation programs, and biospecimenresearch and publications grow and expand in scope, it isobvious that the field of biobanking has evolved from theearlier view that simply embedding or freezing biospeci-mens with no consideration of preanalytic variables wassufficient, into a true scientific discipline. But, it is still atricky endeavor. Disclosure of Potential Con fl icts of Interest No potential conflicts of interest were disclosed.Received December 15, 2011; accepted December 21, 2011; publishedonline February 7, 2012. References 1.  AmericanAssociationforCancerResearch.FourthConferenceonTheScience of Cancer Health Disparities [cited 2012 Jan 10]. Availablefrom: – workshops/ cancer-health-disparities.aspx. 2.  Eiseman E, Haga S. A handbook of human tissue sources: a nationalresource of human tissue samples. Santa Monica, CA: RAND Corpo-ration; 2000. 3.  Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, CoteRJ, et al. American Society of Clinical Oncology/College of AmericanPathologistsguidelinerecommendationsforhumanepidermalgrowthfactor receptor testing in breast cancer. Arch Pathol Lab Med2007;131:18 – 43. 4.  RansohoffDF, Gourlay ML. Sources ofbiasinspecimensfor researchabout molecular markers for cancer. J Clin Oncol 2010;28:698 – 704. 5.  Silberman S. The  fl esh  fi les. Wired 2010;157. 6.  Vaught J, Caboux E, Hainaut P. International efforts to develop bios-pecimen best practices. Cancer Epidemiol Biomarkers Prev 2010;19:912 – 5. 7.  NCI Best Practices for Biospecimen Resources [cited 2012 Jan 10]. Available from: 8.  Knoppers BM, Hudson TJ. The art and science of biobanking. HumGenet 2011;130:329 – 32. 9.  MooreHM,ComptonCC,AlperJ,VaughtJB.Internationalapproachesto advancing biospecimen science. Cancer Epidemiol BiomarkersPrev 2011;20:729 – 32. 10.  HatzisC, Sun H,Yao H,Hubbard RE, Meric-BernstamF,Babiera,etal.Perioperative ischemiaand tissuepreservationeffects onRNA integrityand microarrays of breast cancer. J Natl Cancer Inst 2011;103:1 – 13. 11.  Vaught J, Kelly A, Hewitt R. A review of international biobanks andnetworks: success factors and key benchmarks. Biopreserv Biobank-ing 2010;7:143 – 50. 12.  Sherman ME, Howatt W, Blows FM, Pharoah P, Hewitt SM, Garcia-Closas M. Molecular pathology in epidemiologic studies: a primer.Cancer Epidemiol Biomarkers Prev 2010;19:966 – 72. 13.  Ergin B, Meding S, Langer R, Kap M, Viertler C, Schott C, et al.Proteomic analysis of PAXgene- fi xed tissues. J Proteome Res2010;9:5188 – 96. 14.  Marrinucci D, Bethel K, Lazar D, Fisher J, Huynh E, Clark P, et al.Cytomorphologyofcirculatingtumorcells:asmallcaseseries.JOncol2010;2010:861341. 15.  Bahlo M, Stankovich J, Danoy P, Hickey PF, Taylor BV, Browning SR.Saliva-derived DNA performs well in large-scale, high-density single-nucleotide polymorphism microarray studies. Cancer Epidemiol Bio-markers Prev 2010;19:794 – 6. 16.  XuC,HouckJR,FanW,WangP,ChenY,UptonM,etal.Simultaneousisolation of DNA and RNA from the same cell population obtained bylasercapturemicrodissectionforgenomeandtranscriptomepro fi ling.J Mol Diagn 2008;10:129 – 34. 17.  Baird PM, Frome RJ. Large-scale repository design. Cell PreservTechnol 2005;3:265 – 66. 18.  Elliott P, Peakman TC. The UK biobank sample handling and storageprotocol for the collection, processing and archiving of human bloodand urine. Int J Epidemiol 2008;37:234 – 44. 19.  European,MiddleEasternandAfricanSocietyforBiopreservationandBiobanking [cited2012 Jan10]. Availablefrom: market_fold/automation.html. 20.  LeeSB,CrouseCA,KlineMC.OptimizingstorageandhandlingofDNA extracts. Forensic Sci Rev 2010;22:131 – 43. 21.  Davis JC, Shon J, Wong DT, Jaffe S, McEvoy J. A DNA-basedbiological sample tracking method. Cell Preserv Technol 2005;3:54 – 60. 22.  Hunter DJ, Chanock SJ. Genome-wide association studies and "theart of the soluble". J Natl Cancer Inst 2010;102:836 – 7. 23.  National Heart, Lung and Blood Institute. The Exome Project [cited2012 Jan 10]. Available from: exome.htm. 24.  Stanczyk FZ, Jurow J, Hsing AW. Limitations of direct immunoassaysfor measuring circulating estradiol levels in postmenopausal womenandmeninepidemiologicstudies.Cancer Epidemiol Biomarkers Prev2010;19:903 – 6. 25.  NIHHumanMicrobiomeProject.Clinicalsampling[cited2012Jan10]. Available from: 26.  National Cancer Institute. Cohort Consortium [cited 2012 Jan 10]. Available from: 27.  Gormally E, Hardy I, di Donato JH, Caboux E, Hofman P, Hainaut P.Development of a curriculum at the master level for managers of biobanksandbiological resourcecenters: apilot program. BiopreservBiobanking 2011;9:308. 28.  International Society for Biological and Environmental Repositories[cited 2012 Jan 10]. Available from: 29.  College of American Pathologists Accreditation for Biorepositories[cited 2012 Jan 10]. Available from: laboratory_accreditation/lap_info/bio_brochure_042011.pdf. Biospecimens and Biorepositories: From Afterthought to Cancer Epidemiol Biomarkers Prev; 21(2) February 2012  255 on June 25, 2016. © 2012 American Association for Cancer Research. Downloaded from  2012;21:253-255. Cancer Epidemiol Biomarkers Prev Jimmie B. Vaught, Marianne K. Henderson and Carolyn C. Compton   Biospecimens and Biorepositories: From Afterthought to Science   Updated version the most recent version of this article at:   Cited articles article cites 19 articles, 9 of which you can access for free at:   Citing articles article has been cited by 6 HighWire-hosted articles. Access the articles at:   E-mail alerts  related to this article or journal.Sign up to receive free email-alerts   SubscriptionsReprints and .pubs@aacr.orgatTo order reprints of this article or to subscribe to the journal, contact the AACR Publications Department   Permissions  .permissions@aacr.orgTo request permission to re-use all or part of this article, contact the AACR Publications Department at on June 25, 2016. © 2012 American Association for Cancer Research. Downloaded from
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