Population-based Biobanks Research Articles

Wanted: Human Biospecimens

Collecting and using tissue, blood, urine, and other human biospecimens for various types of research is not new. But for personalized medicine to realize its potential, researchers will need thousands more of these samples for genetic studies. And the particular nature of genetic research--the sensitivity of the information it reveals--has raised host of ethical questions, some which are new to human subjects research. What counts as informed consent when biospecimen may be stored for years and used for unforeseen research? How freely can the biospecimens and the genetic information they contain be shared with other researchers? If research uncovers genetic risk factor or some other important medical information about an individual, should that person be told? Biospecimens are collected and used in number of different ways. Sometimes researchers ask individuals to contribute biospecimens for specific type of genetic study. For example, the National Cancer Institute is recruiting thirty-five hundred patients with inherited urologic malignancies and their relatives to provide blood and tissue samples for study on the genetic contributions to these cancers. (1) Researchers also ask patients enrolled in clinical drug trials, especially cancer studies, to contribute biospecimens to learn more about the genetic contributions to their disease. A different approach is to ask individuals to donate their biospecimens to large biorepository, or biobank, to be used for unspecified future research. The UK Biobank, launched in 2006, was one of the first large-scale, population-based biobanks. It announced recently that it reached its goal of obtaining biospecimens from five hundred thousand Britons aged forty to sixtynine for a diverse range of research intended to improve the prevention, diagnosis and treatment of illness, and the promotion of health throughout society. (2) In addition, these individuals answered questions about their health, lifestyle, diet, memory, work, and family history. Their blood pressure, pulse rate, height, weight, body fat, vision, fitness, grip strength, bone density, and lung function were measured, as well. Similar biobanks have emerged in the United States, including the Personal Genome Project, the NuGene Project, Mayo Clinic Biobank, and Kaiser Permanente's Research Program on Genes, Environment and Health. Something Old, Something New With the growing practice of storing biospecimens, sharing them, and using the materials and their genetic data over time, researchers, ethics oversight bodies, regulatory officials, and the public have had to take new look at some of the core ethical issues involving research with humans. Those issues were rendered in vivid detail with the story of Henrietta Lacks, poor black woman whose normal and cervical cancer tissue were given to researchers without her consent. Her cells, known as the HeLa cell line, have been used by researchers for over fifty years for multitude of studies, including research related to the first polio vaccine, as well as cancer and AIDS-related studies. Familiar ethical issues related to research keep cropping up in the context of storing and sharing biospecimens and genetic data. These include concerns about ethics review and approval of proposed studies, informed consent of research participants and surrogates, and the privacy and confidentiality of research data and participants' other personal and health information. Yet biospecimens and genetic data are not the living, identifiable humans that federal research regulations were designed to protect. And the traditional concept of consent as an agreement to participate in research after being informed about the purpose of specific study--how long it will last, how many people will participate, and the potential risks and benefits of participation--isn't good fit for research with bodily materials and data stored for multiple future purposes, some unforeseeable. …

Biobank Recruitment: Motivations for Nonparticipation

Molecular data, essential for genomics research, can be captured more efficiently in large-scale, population-based biobanks of genetic material rather than by individual studies. Biobanks also offer improved quality and reliability of genetic samples and access through automated sample retrieval. However, it is challenging to adequately inform participants of the broad nature of the research and participation risks and benefits. In addition, recent studies suggest concerns about data sharing and return of research results, or future research topics (eg, stereotypical or potentially stigmatizing traits). We evaluated the interest in participating in a biobank and reasons for nonparticipation.

Validity of Maternal Genotypes in DNA from Archival Pregnancy Serum Samples

Much functional genomic research has focused on genotypic data from large cohorts or entire populations(1). The large population-based serum biobanks collected for maternal (pregnancy) screening and stored in many countries could be useful for genetic epidemiologic studies if DNA extracted from archival serum and plasma is of sufficient quantity and quality for successful genotyping analyses(2)(3)(4). Serum collected during pregnancy also contains cell-free DNA from the fetus(5), however, which might affect the outcome of genotyping analyses. We have evaluated the concordance of genotypes between DNA extracted from archival maternal sera with DNA from fresh whole blood from the same women. The median DNA yield was 15 mg/L (range 1–34 mg/L) using QiaAmp DNA minipreps (Qiagen) on 200 μL fresh whole blood from 137 women and 90 μg/L (range 0–4800 μg/L) using the MagNA Pure LC and Total Nucleic Acid Isolation Kit (MagNAPure; Roche Diagnostics) on 200 μL of 191 archival maternal sera from the same women. DNA yield decreased with increasing serum sample age ( P = 0.005, Jonckheere–Terpstra) (Fig. 1⇓ ), with no difference due to first- or second-trimester sampling ( P = 0.616, …

Community consultation and communication for a population‐based DNA biobank: The Marshfield clinic personalized medicine research project

The purpose of this article is to describe community consultation and communication efforts for the Personalized Medicine Research Project (PMRP), a population-based biobank. A series of focus group discussions was held in the year preceding initial recruitment efforts with potentially eligible community residents and slightly less than a year after initial recruitment with eligible residents who had declined participation in PMRP. A Community Advisory Group, with 19 members reflecting the demographics of the eligible community, was formed and meets twice yearly to provide advice and feedback to the PMRP Principal Investigator and the local IRB. Ongoing communication with study subjects, who consent on the condition that personal genetic results will not be disclosed, takes place through a newsletter that is distributed twice yearly, community talks and media coverage. Most focus group participants were concerned about the confidentiality of both their medical and genetic data. Focus group discussions with eligible residents who elected not to participate in PMRP revealed that many knew very little about the project, but thought that too much information had been provided, leading them to believe that it would take too long for them to understand and enroll in the study. In conclusion, an engaged community advisory group can provide a sounding board to study investigators for many study issues and can provide guidance for broader communication activities. Researchers need to balance the provision of information for potential subjects to make informed decisions about study participation, with respect for individuals' time to read and interpret study materials.

Characterization of Low‐Density Lipoprotein Cholesterol‐Lowering Efficacy for Atorvastatin in a Population‐Based DNA Biorepository

The Marshfield Clinic Personalized Medicine Research Project (PMRP) represents a large population-based biobank located in central Wisconsin. To position the PMRP database for large-scale pharmacogenetic association studies in the context of lipid-lowering therapy, we constructed an electronic phenotyping algorithm to quantify exposure and dose-response for atorvastatin, the most commonly prescribed lipid-lowering agent within this population. The resulting datasets were used to generate five distinct parameters for atorvastatin-induced changes in low-density lipoprotein (LDL) cholesterol level: (i) pretreatment, baseline LDL level [E(0)]; (ii) absolute reduction in LDL; (iii) relative reduction in LDL; (iv) potency [ED(50)]; and (v) maximal efficacy [E(max)]. These parameters will facilitate the efficient application of electronic phenotyping for drug outcomes in the context of large pharmacogenetic association studies.

The Marshfield Clinic Personalized Medicine Research Project: 2008 scientific update and lessons learned in the first 6years.

The Marshfield Clinic Personalized Medicine Research Project is the largest population-based biobank in the USA, with the ability to recontact subjects to obtain additional information to facilitate gene-environment studies. Nearly 20,000 adults have enrolled in the Personalized Medicine Research Project since 2001, after providing active written consent to access their Marshfield Clinic medical records to define phenotype and providing blood samples from which DNA, plasma and serum samples were stored. Numerous studies are underway in the area of pharmacogenetics and genetic epidemiology. In addition to the scientific discoveries being made, much has been learned regarding biobanking and the management of large amounts of data being generated. The purpose of this paper is to share the advice provided by the external Scientific Advisory Board and the scientific lessons learned along the way to build this research infrastructure and facilitate its use.

Biobanks: transnational, European and global networks

Biobanks contain biological samples and associated information that are essential raw materials for advancement of biotechnology, human health, and research and development in life sciences. Population-based and disease-oriented biobanks are major biobank formats to establish the disease relevance of human genes and provide opportunities to elucidate their interaction with environment and lifestyle. The developments in personalized medicine require molecular definition of new disease subentities and biomarkers for identification of relevant patient subgroups for drug development. These emerging demands can only be met if biobanks cooperate at the transnational or even global scale. Establishment of common standards and strategies to cope with the heterogeneous legal and ethical landscape in different countries are seen as major challenges for biobank networks. The Central Research Infrastructure for Molecular Pathology (CRIP), the concept for a pan-European Biobanking and Biomolecular Resources Research Infrastructure (BBMRI), and the Organization for Economic Co-operation and Development (OECD) global Biological Resources Centres network are examples for transnational, European and global biobank networks that are described in this article.

Assessing Quality and Functionality of DNA from Fresh and Archival Dried Blood Spots and Recommendations for Quality Control Guidelines

Dried blood spots (DBS) are a convenient and inexpensive method for biobanking. Although many countries have established population-based DBS biobanks from neonatal screening programs, the quality and usefulness of DNA from DBS have not been extensively assessed. We compared 4 common DNA extraction methods (Qiagen, EZNA, Chelex 100, and alkaline lysis) in a pilot study using fresh DBS with known lymphocyte count. We assessed suitability for multiple displacement amplification (MDA) and subsequent single-nucleotide polymorphism (SNP) analyses. We selected the EZNA method for DNA extraction from archival samples up to 27 years old, stored at room temperature or -20 degrees C, and SNP analyses were performed after MDA. Extraction using alkaline lysis failed in most tests, and Chelex 100 was unsuccessful in real-time PCR, whereas the EZNA and Qiagen methods were successful by all evaluated quality indices. DNA extraction by EZNA, MDA, and SNP analyses were successful for the archival samples stored at -20 degrees C. Routine protocols for evaluation of the quality and functional integrity of DNA based on DNA yield, DNA size, and quantification of amplifiable DNA allow use of sufficient template for MDA and successful SNP analyses from both primary DBS extract and MDA product. A single 3-mm disc can yield sufficient DNA for several thousand SNP analyses. DNA from DBS is thus suitable for genetic epidemiology studies.

Clinical phenome scanning.

Large population-based cohorts are ideal for the study of common, complex disorders because they allow characterization of gene-gene and gene-environment interactions. We propose a clinical phenome scanning approach to genotype-phenotype association studies, as this approach acknowledges the heterogeneous nature of common diseases and takes advantage of the unprecedented density of phenotypic data available in population-based DNA biobanks. By analogy to genome-wide scanning, the construction of a clinical phenome scan includes a complete scan of all clinically available information (housed in electronic medical records). This is done on a subject-by-subject basis and the resulting phenomes can subsequently be interrogated for association with a single allele for any given gene. By prioritizing phenotype (rather than genotype), this approach allows investigators to ask the question "Which disease is associated with a given gene?" rather than "Which gene is associated with a given disease?".

Healthy People 2010 disease prevalence in the Marshfield Clinic Personalized Medicine Research Project cohort: opportunities for public health genomic research.

The purpose of this study was to estimate the prevalence of Healthy People2010 disease conditions in a large population-based cohort in central Wisconsin (WI, USA) and to consider how these conditions can be prioritized for research based on the use of healthcare services, the prevalence of various disease states and the resulting study power. Healthy People2010 diagnoses were estimated for participants in the Personalized Medicine Research Project (PMRP), a large population-based biobank for residents aged 18years and older living in central Wisconsin. By interrogating the electronic medical record, three parameters were calculated for each diagnosis: mean number of concomitant diagnoses, mean number of annual clinic visits before diagnosis and mean number of clinic visits after diagnosis. A total of 18,239adults enrolled in PMRP from September 2002 to May 2005 and were included in the study. They had a mean age of 49years (standard deviation:18.5), ranging from 18-98years; 57% were female. At least one Healthy People2010 disease was diagnosed in 86.4% of the participants; 13.6% had never been diagnosed with any of these conditions. The median number of diagnoses per subject was three (range:1-15). The median number of annual visits after diagnosis was lowest for chronic obstructive pulmonary disease (9.1) and highest for sleep apnea (17.9). Subjects with a diabetic retinopathy diagnosis had the highest number of concomitant diagnoses (mean:6.8). All of the diseases within the Healthy People2010 list are purported to have at least some genetic component, with the exception of injuries. The PMRP cohort is large enough that diseases of public health importance can be studied in the context of a variety of clinical and environmental covariates. This database is being developed as a national resource and is particularly useful where the estimated disease prevalence is 5% or greater. For less common diseases, additional cases can be recruited from throughout the Marshfield Clinic system of care, with population-based controls selected from the main PMRP study cohort.

Construction of Atorvastatin Dose–Response Relationships Using Data from a Large Population‐Based DNA Biobank

Construction of Atorvastatin Dose–Response Relationships Using Data from a Large Population‐Based DNA Biobank

Mapping Translational Research in Personalized Therapeutics: From Molecular Markers to Health Policy

Translational research is frequently used in the bioscience literature to refer to the translation of basic science into practical applications at the point of patient care. With the introduction of theragnostics, a new medical subspecialty that fuses therapeutics and diagnostic medicine with the goal of providing individualized pharmacotherapy, we suggest that the focus of translational research is shifting. We identify two bottlenecks or gaps in translational research for theragnostics: GAP1 translation from basic science to first-in-human proof-of-concept; and GAP2 translation from clinical proof-of-concept to development of evidence-based personalized treatment guidelines. GAP1 translational research in theragnostics is usually performed in traditional craft-based studies with small sample sizes and led by independent academic or industry researchers. In contrast, GAP2 translational investigations typically rely on large research consortiums and population-based biobanks that couple biomarker information with longitudinal 'real-life' observational data on a broad range of pharmacological phenotypes. Despite an abundance of research on the use of biobanks in disease gene discovery, there has been little conceptual work on whether and to what extent population biobanks can be utilized for translating genomics discoveries to practical treatment guidelines for theragnostic tests.

Biobanks and Legislation in Switzerland – a data protection perspective

AbstractThe combination of health and lifestyle data with bodily substances and genetic information has led over the last few years to the creation of so-called biobanks. These biobanks are used to research a large number of diseases of modern civilization and their genetic interactions. One of the best-known projects in this respect is without a doubt the Icelandic biobank, operated since 1998 by a private pharmaceutical company, deCode Genetics, and set up with government support. The database contains family histories and medical records, as well as biological samples taken from a large section of Iceland's homogeneous population. The hope is that this data will allow a correlation to be established between genetic predispositions and the onset of widespread diseases. Other examples of population-based biobanks include the Estonian Genome Project, launched in 2001 by the Estonian Government, as well as the UK Biobank in the UK and PopGen in the state of Schleswig-Holstein in Germany.

The power of ethics: a case study from Sweden on the social life of moral concerns in policy processes

In this paper I report on an ethnographic study of an ethics policy developed by a start-up genomics company at the time it gained all commercial rights to a population-based biobank in the town of Umeå in northern Sweden. Tracing the interdependencies between power and morality, my research compares moral reflections and stances among 1) policymakers, 2) health professionals and 3) donors, in relation to the issues identified in the policy. These people seem to agree that trust and fairness are important issues and that 'something' needs protection in the face of commercial genetic research. However, their perceptions of trust, fairness and what it is that needs protection differ significantly. I conclude by considering the implications of variances in moral perspectives for the social study of ethics.

Statin‐use phenotyping in the advanced elderly ‐ validation in a large, population‐based DNA Biobank

Hydroxy-methyl-glutaryl (HMG) coenzyme A reductase inhibitors (statins) are considered both safe and efficacious. To quantify statin use in the advanced elderly, a cohort of subjects over 80 years of age was identified within the Marshfield Clinic Personalized Medicine Research Project (PMRP). The PMRP represents one of the largest population-based DNA Biobanks in the world (Science 298 1158–1161, 2002). Ninety-five subjects were identified (mean age 88.3 + 3.2 years), and retrospective drug-use histories were constructed through manual data abstraction. Twenty-one percent of subjects were using a statin at most recent examination (95% C.I. 13.4 – 30.6). To assess the utility of electronic phenotyping, we constructed independent statin use histories in the same subjects through the application of natural language processing software (Language and Computing, Inc.). The electronic phenotype for current medication use was 100% sensitive and 96% specific. The initial positive predictive value (PPV) was 87%. After programmatic selection of only those electronic free text data containing a dose, PPV improved to 95%. Electronic statin use histories were then constructed for a 10-year period, and collated with electronically abstracted lipid panels, for each respective subject. This phenotyping strategy should facilitate characterization of electronic dose response curves in large population-based cohorts, and position investigators to conduct pharmacogenetic association studies on an unprecedented scale. (This work was funded by a grant from the Marshfield Clinic Research Foundation.)

Epidemiology of Kaposi's Sarcoma herpesvirus (HHV8) in Västerbotten county, Sweden

A population-based serosurvey of Human Herpesvirus type 8 (HHV8) in Västerbotten County, an area of Northern Sweden with high incidence of Kaposi's Sarcoma, was conducted. Serum samples from an age- and sex-stratified random sample of 520 subjects (260 men and 260 women) participating in a population-based biobanking project were tested for antibodies against HHV8, using a sensitive indirect immunofluorescence assay to latent and lytic HHV8 antigens. Buffy coat DNA was also analyzed for viral DNA using real time PCR assay. HHV8 DNA was not detectable in any one of the buffy coat samples. Eighty-four subjects (16.2%) were HHV8 seropositive, 14.4% for the lytic HHV8 antigen, and 1.7% for the latent HHV8 antigen. HHV8 seroprevalences were not associated significantly with sex or age. HHV8 seropositivity was more common among smokers (OR: 1.95, 95% CI: 1.02-3.75), but was less common among consumers of wine and spirits (OR: 0.44, 95% CI: 0.25-0.77 and OR: 0.50, 95% CI: 0.26-0.95, respectively). In summary, HHV8 has an intermediate high and stable seroprevalence rate in Northern Sweden, but environmental determinants that can explain the viral distribution were not found.

Studying Ethics as Policy

This article reports on a study of an ethics policy developed by a startup genomics company at the time it gained all commercial rights to a populationbased biobank in northern Sweden. Work in the anthropology of policy has been used as inspiration to study throughto identify how the policy took shape, to follow it through to the networks in which it took on social life, and finally to probe its social implications, in particular among the people for whom and on whom it was supposed to work. It is argued that as ethics takes the form of policy work, it tends to be so preoccupied with presenting solutions that it overlooks critical understanding and assessment of problems. It is suggested that anthropology might play a complementary role to the policy work of ethics by reintroducing otherwise marginalized moral voices and positions.

Marshfield Clinic Personalized Medicine Research Project (PMRP): design, methods and recruitment for a large population-based biobank.

The objective of this paper is to summarize the planning for Phase I of the Marshfield Clinic Personalized Medicine Research Project (PMRP) and to describe the recruitment efforts in the first 2 years. The purpose of Phase I of the PMRP was to develop a large population-based biobank with DNA, plasma and serum samples to facilitate genomics research. Planning and consultation was facilitated with three external boards: the Ethics and Security Advisory Board; the Scientific Advisory Board; and the Community Advisory Group. Commencing in September 2002, residents aged 18 and above who resided in 1 of 19 zip codes surrounding Marshfield, WI, USA, were invited to participate. After providing written informed consent, participants completed brief questionnaires that included questions about demographics, some environmental exposures, family history of disease, and adverse drug reactions, as well as family members living in the study area. Participants provided 50ml of blood from which DNA was extracted and plasma and serum samples were stored. The informed consent document allowed access to electronic medical records and included language about non-disclosure of personal research results. A tick-off box was also included so that participants could either allow or decline subsequent recontact for future research studies. A total of 17,463 subjects were enrolled during the first 23months of recruitment (44.3% of the residents who the Research Project Assistants were able to contact). The participants ranged in age from 18 to 98.5years (mean = 48.9, median = 48); 57.2% (n = 9986) were female. Self-reported race in the study cohort was similar to the year 2000 census for Wood County, WI, USA, with the majority (98%) reporting themselves to be White Caucasian. The majority of subjects (n= 13,391, 76.7%) indicated that they had German ancestry. Only 142participants (< 1%) opted out on the consent form for contact for future studies. The majority of the cohort reported that their current area of residence was a suburb, city or village (n = 10630, 60.87%); the remainder reported residence in a rural home or hobby farm (n=5365, 30.72%), or a working farm or ranch (n = 1451, 8.31%). More than half the cohort (n = 9409, 53.88%) had lived on a working farm at some point in their life. The PMRP database will allow research in three areas: genetic epidemiology, pharmacogenetics, and population genetics. The size and the stability of the population as well as the relative ethnic homogeneity will help facilitate longitudinal studies with valid research results that are not biased by population stratification.

Conflicting Notions of Personhood in Genetic Research

Background: 1985 saw the beginnings of a population-based biobank in Vasterbotten County, Sweden. In 1999, a start-up genomics company, UmanGenomics, obtained ‘all commercial rights’ to the biobank. The company introduced an ethics policy, which was well received in prestigious journals, focusing on public oversight and informed consent. Aims: To explore how social anthropology can aid understanding of the challenges posed by the new role of the biobank in Vasterbotten, and thus complement more established traditions in the field of medical ethics. An anthropological study of the ethics policy was executed. Theoretical perspective: Inspired by the anthropology of policy and social science perspectives on ethics and morality, the policy was studied at three analytical levels: policymakers (who formulate the policy), policy workers (who implement the policy, primarily nurses who obtain informed consent) and target group (for whom and on whom the policy is supposed to work: the potential donors to the biobank). Methods: Policymakers, nurses, and potential donors were interviewed, donations observed, and official documents analysed to mirror the moral problematizations made at the three levels in each other and to study the practical implications of the policy. To extend the reliability of the findings two surveys were executed: one among the general population, one among donors. Results: The qualitative studies show that policymakers distinguish between blood and data differently to potential donors. Informed consent seems more important to policymakers than potential donors, who are more concerned about political implications at a societal level. Among the respondents from the survey in the general public, a majority (66.8%) accepted surrogate decisions by Research Ethics Committees; a minority (4 %) stated informed consent as a principal concern; and genetic research based on biobank material was generally accepted (71%). Among the respondents to the survey in donors, 65% knew they had consented to donate a blood sample, and 32% knew they could withdraw their consent; 6% were dissatisfied with the information they had received; and 85% accepted surrogate decisions by Research Ethics Committees. Discussion: The ethics policy constitutes a particular naming and framing of moral problems in biobank-based research which overemphasises the need for informed consent, and underemphasises other concerns of potential donors. This embodies a political transformation where access to stored blood and medical information is negotiated in ethical terms, while it also has unacknowledged political implications. In particular, the relations between authorities and citizens in the Swedish welfare state are apparently transforming: from mutual obligation to individual contracts. Conclusion: Anthropology contributes to medical ethics with increased awareness of the practical implications of particular research ethical initiatives. This awareness promotes appreciation of the political implications of ethics policies and raises new issues for further consideration.