Biobank literature update week 43 (2015)
[1] The Genotype-Tissue Expression (GTEx) Project. Carithers LJ, Moore HM. Biopreserv Biobank 2015; 13:307-308.
[2] Times Are Changing: 35 Years of Human Biospecimen Procurements for the National Disease Research
Interchange. Bell TJ, Leinweber B. Biopreserv Biobank 2015; 13:309-310.
[3] A Novel Approach to High-Quality Postmortem Tissue Procurement: The GTEx Project. Carithers LJ, Ardlie K, Barcus
M et al. Biopreserv Biobank 2015; 13:311-319. The Genotype-Tissue Expression (GTEx) project, sponsored by the NIH
Common Fund, was established to study the correlation between human genetic variation and tissue-specific gene
expression in non-diseased individuals. A significant challenge was the collection of high-quality biospecimens for
extensive genomic analyses. Here we describe how a successful infrastructure for biospecimen procurement was
developed and implemented by multiple research partners to support the prospective collection, annotation, and
distribution of blood, tissues, and cell lines for the GTEx project. Other research projects can follow this model and form
beneficial partnerships with rapid autopsy and organ procurement organizations to collect high quality biospecimens
and associated clinical data for genomic studies. Biospecimens, clinical and genomic data, and Standard Operating
Procedures guiding biospecimen collection for the GTEx project are available to the research community.
[4] Surgical Specimens of Colorectal Cancer Fixed with PAXgene Tissue System Preserve High-Quality RNA. Hara K,
Watanabe A, Matsumoto S et al. Biopreserv Biobank 2015; 13:325-334. BACKGROUND: RNA analysis of surgical
specimens is one of the most useful methods for exploring biomarkers of advanced cancer. The most readily available
source for RNA is formalin-fixed, paraffin-embedded (FFPE) specimens, but RNA isolated from FFPE tissue is of limited
use. The PAXgene Tissue (PAX) system is a formalin-free system designed to improve the quality of molecular analysis
without diminishing the quality of histopathological analysis. In this human colorectal cancer tissue study, we aimed to
evaluate whether surgical specimens fixed with PAX can preserve high-quality RNA in comparison with FFPE and freshfrozen tissue specimens. METHODS: Ten consecutive advanced colorectal cancer patients undergoing colectomy were
examined. Each specimen was processed in three ways: as frozen tissue, as PAX-fixed tissue, and as formalin-fixed
tissue. RNA integrity numbers (RINs) were assessed using an Agilent Bioanalyzer. RNA transcript levels and stability were
investigated by quantitative real-time PCR. We also evaluated the immunohistochemical intensity of Ki-67, CEA, and
EGFR in the PAX samples. RESULTS: The average RINs of RNA extracted from frozen and PAX samples were significantly
higher than those from FFPE samples (p < 0.001). The cycle threshold (Ct) values were similar in PAX and frozen samples,
but significantly increased in FFPE samples (p < 0.001). Most of the DeltaCt values in the PAX samples did not differ
significantly from those in the matched frozen samples. On the other hand, most of the DeltaCt values in the FFPE
samples differed significantly from those in the matched frozen samples. The immunohistochemical intensity in the PAX
samples was well preserved. CONCLUSIONS: The quality of RNA extracted from PAX samples may be slightly inferior to
that from frozen samples, but is greatly superior to that from FFPE samples.
[5] The Impact of Different Preservation Conditions and Freezing-Thawing Cycles on Quality of RNA, DNA, and
Proteins in Cancer Tissue. Wang Y, Zheng H, Chen J et al. Biopreserv Biobank 2015; 13:335-347. BACKGROUND: Highquality cancer tissues are essential for future research, especially molecular research. For the sake of better quality of
tissues, some storage methods are chosen according to lab conditions. But the impact of different storing conditions on
the quality of RNA, DNA (especially the degree of DNA methylation), and protein of tissues that have undergone a
thawing process, is not clear. METHODS: We analyzed the influence of different storage conditions including in RNALater
solution, normal saline, Opti-mum Cutting Temperature compound (OCT), and snap frozen with no protective reagent
(as control) in paired tissue samples on the quality of RNA (RNA Integrity Number value and mRNA expression), DNA
quality (DNA amplification and DNA methylation degree of gene RASSF1a), and protein quality. Further, we analyzed the
RNA quality of tissues that underwent three freeze-thaw cycles. RESULTS: The RNALater-treated group retained good
RNA quality as expected on three repeated freeze-thaw cycles (RIN>8), but the snap-frozen tissues showed relatively
poor results after one freeze-thaw cycle (RIN<7) and three times repeated freeze-thaw cycles (RIN<6). RNA from salineand OCT-treated groups also yielded good results when we repeated freezing and thawing one time (RIN>7) and two
times (RIN>6). The impact of different storing conditions on DNA amplification is small. However, DNA methylation and
Biobank literature update week 43 (2015)
protein quality are different with different storing conditions. OCT seems to be more secure and stable compared with
other two experimental groups, and show a similar trend with control group. CONCLUSIONS: In consideration of budget
and efficiency, we suggest OCT as the best storing method that not only preserves RNA quality during the freezingthawing process well, but also ensures more secure and stable DNA and protein.
[6] Big Data: the challenge for small research groups in the era of cancer genomics. Noor AM, Holmberg L, Gillett C,
Grigoriadis A. British journal of cancer 2015. In the past decade, cancer research has seen an increasing trend towards
high-throughput techniques and translational approaches. The increasing availability of assays that utilise smaller
quantities of source material and produce higher volumes of data output have resulted in the necessity for data storage
solutions beyond those previously used. Multifactorial data, both large in sample size and heterogeneous in context,
needs to be integrated in a standardised, cost-effective and secure manner. This requires technical solutions and
administrative support not normally financially accounted for in small- to moderate-sized research groups. In this
review, we highlight the Big Data challenges faced by translational research groups in the precision medicine era; an era
in which the genomes of over 75 000 patients will be sequenced by the National Health Service over the next 3 years to
advance healthcare. In particular, we have looked at three main themes of data management in relation to cancer
research, namely (1) cancer ontology management, (2) IT infrastructures that have been developed to support data
management and (3) the unique ethical challenges introduced by utilising Big Data in research.British Journal of Cancer
advance online publication 22 October 2015; doi:10.1038/bjc.2015.341 www.bjcancer.com.
[7] INTRODUCTION: Return of Research Results: What About the Family? Wolf SM. The Journal of law, medicine &
ethics : a journal of the American Society of Law, Medicine & Ethics 2015; 43:437-439.
[8] Returning a Research Participant's Genomic Results to Relatives: Analysis and Recommendations. Wolf SM,
Branum R, Koenig BA et al. The Journal of law, medicine & ethics : a journal of the American Society of Law, Medicine &
Ethics 2015; 43:440-463. Genomic research results and incidental findings with health implications for a research
participant are of potential interest not only to the participant, but also to the participant's family. Yet investigators lack
guidance on return of results to relatives, including after the participant's death. In this paper, a national working group
offers consensus analysis and recommendations, including an ethical framework to guide investigators in managing this
challenging issue, before and after the participant's death.
[9] Preferences Regarding Return of Genomic Results to Relatives of Research Participants, Including after Participant
Death: Empirical Results from a Cancer Biobank. Breitkopf CR, Petersen GM, Wolf SM et al. The Journal of law, medicine
& ethics : a journal of the American Society of Law, Medicine & Ethics 2015; 43:464-475. Data are lacking with regard to
participants' perspectives on return of genetic research results to relatives, including after the participant's death. This
paper reports descriptive results from 3,630 survey respondents: 464 participants in a pancreatic cancer biobank, 1,439
family registry participants, and 1,727 healthy individuals. Our findings indicate that most participants would feel
obligated to share their results with blood relatives while alive and would want results to be shared with relatives after
their death.
[10] Patients' Choices for Return of Exome Sequencing Results to Relatives in the Event of Their Death. Amendola LM,
Horike-Pyne M, Trinidad SB et al. The Journal of law, medicine & ethics : a journal of the American Society of Law,
Medicine & Ethics 2015; 43:476-485. The informed consent process for genetic testing does not commonly address
preferences regarding disclosure of results in the event of the patient's death. Adults being tested for familial colorectal
cancer were asked whether they want their exome sequencing results disclosed to another person in the event of their
death prior to receiving the results. Of 78 participants, 92% designated an individual and 8% declined to. Further
research will help refine practices for informed consent.
Biobank literature update week 43 (2015)
[11] Mapping the Ethics of Translational Genomics: Situating Return of Results and Navigating the Research-Clinical
Divide. Wolf SM, Burke W, Koenig BA. The Journal of law, medicine & ethics : a journal of the American Society of Law,
Medicine & Ethics 2015; 43:486-501. Both bioethics and law have governed human genomics by distinguishing research
from clinical practice. Yet the rise of translational genomics now makes this traditional dichotomy inadequate. This
paper pioneers a new approach to the ethics of translational genomics. It maps the full range of ethical approaches
needed, proposes a "layered" approach to determining the ethics framework for projects combining research and
clinical care, and clarifies the key role that return of results can play in advancing translation.
[12] Canadian Research Ethics Board Leadership Attitudes to the Return of Genetic Research Results to Individuals
and Their Families. Fernandez CV, O'Rourke PP, Beskow LM. The Journal of law, medicine & ethics : a journal of the
American Society of Law, Medicine & Ethics 2015; 43:514-522. Genomic research may uncover results that have direct
actionable benefit to the individual. An emerging debate is the degree to which researchers may have responsibility to
offer results to the biological relatives of the research participant. In a companion study to one carried out in the United
States, we describe the attitudes of Canadian Research Ethics Board (REB) chairs to this issue and their opinions as to the
role of the REB in developing related policy.
[13] Returning a Research Participant's Genomic Results to Relatives: Perspectives from Managers of Two Distinct
Research Biobanks. Petersen GM, Ness BV. The Journal of law, medicine & ethics : a journal of the American Society of
Law, Medicine & Ethics 2015; 43:523-528. Research biobanks are heterogeneous and exist to manage diverse biosample
types with the goal of facilitating and serving biomedical discovery. The perspectives of biobank managers are reviewed,
and the perspectives of two biobank directors, one with experience in institutional biobanks and the other with national
cooperative group banks, are presented. Most research biobanks are not designed, nor do they have the resources, to
return research results and incidental findings to participants or their families.
[14] Disclosing Secondary Findings from Pediatric Sequencing to Families: Considering the "Benefit to Families".
Wilfond BS, Fernandez CV, Green RC. The Journal of law, medicine & ethics : a journal of the American Society of Law,
Medicine & Ethics 2015; 43:552-558. Secondary findings for adult-onset diseases in pediatric clinical sequencing can
benefit parents or other family members. In the absence of data showing harm, it is ethically reasonable for parents to
request such information, because in other types of medical decision-making, they are often given discretion unless
their decisions clearly harm the child. Some parents might not want this information because it could distract them from
focusing on the child's underlying condition that prompted sequencing. Collecting family impact data may improve
future policy determinations.
[15] Return of Results from Research Using Newborn Screening Dried Blood Samples. Lewis MH, Goldenberg AJ. The
Journal of law, medicine & ethics : a journal of the American Society of Law, Medicine & Ethics 2015; 43:559-568. There
may be compelling reasons to return to parents a limited subset of results from research conducted using residual
newborn screening dried blood samples (DBS). This article explores the circumstances under which research results
might be returned, as well as the mechanisms by which state newborn screening programs might facilitate the return of
research results. The scope of any responsibility to return results of research conducted using DBS should be assessed in
light of the potential impact on the primary mission of state newborn screening programs.
[16] Certificates of Confidentiality: Protecting Human Subject Research Data in Law and Practice. Wolf LE, Patel MJ,
Williams Tarver BA et al. The Journal of law, medicine & ethics : a journal of the American Society of Law, Medicine &
Ethics 2015; 43:594-609. The federal Certificate of Confidentiality plays an important role in research on sensitive topics
by authorizing researchers to refuse to disclose identifiable research data in response to subpoenas in any legal setting.
However, there is little known about how effective Certificates are in practice. This article draws on our legal and
empirical research on this topic to fill this information gap. It includes a description of the purpose of Certificates, their
legislative and regulatory history, and a summary of the few reported and unreported cases that have dealt with
Certificates. In addition, we outline other statutory confidentiality protections, compare them to the Certificate's
Biobank literature update week 43 (2015)
protections, and analyze some of the vulnerabilities of a Certificate's protections. This analysis allows us to make specific
recommendations for strengthening the protections afforded to research data.
[17] To research (or not) that is the question: ethical issues in research when medical care is disrupted by political
action: a case study from Eldoret, Kenya. House DR, Marete I, Meslin EM. J Med Ethics 2015. While considerable
attention has been focused on understanding the myriad of ethical analysis in international research in low and middle
income countries, new issues always arise that have not been anticipated in guidelines or studied extensively. The
disruption of medical care arising as a direct result of political actions, including strikes, postelection violence and
related activities, is one such issue that leaves physician-researchers struggling to manage often conflicting professional
responsibilities. This paper discusses the ethical conflicts that arise for physician-researchers, particularly when
disruption threatens the completion of a study or completion is possible but at the expense of not addressing unmet
medical needs of patients. We review three pragmatic strategies and the ethical issues arising from each: not starting
research, stopping research that has already started, and continuing research already initiated. We argue that during
episodes of medical care disruption, research that has been started can be continued only if the ethical standards
imposed at the beginning of the study can continue to be met; however, studies that have been approved but not yet
started should not begin until the disruption has ended and ethical standards can again be assured.
[18] When Participants in Genomic Research Grow Up: Contact and Consent at the Age of Majority. Brothers KB, Holm
IA, Childerhose JE et al. The Journal of pediatrics 2015.
[19] The transcriptional landscape of age in human peripheral blood. Peters MJ, Joehanes R, Pilling LC et al. Nature
communications 2015; 6:8570. Disease incidences increase with age, but the molecular characteristics of ageing that
lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene
expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that
are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpGmethylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation
sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We
further used the gene expression profiles to calculate the 'transcriptomic age' of an individual, and show that differences
between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood
pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological
relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic
age in external cohorts.