Principles, organization, and operation of a DNA bank for clinical trials:: a Department of Veterans Affairs cooperative study

doi:10.1016/S0197-2456(02)00193-9

Controlled Clinical Trials

Volume 23, Issue 3, June 2002, Pages 222-239

https://doi.org/10.1016/S0197-2456(02)00193-9 Get rights and content

Abstract

The mapping and sequencing of the human genome promises rapid growth in understanding the genetically influenced mechanisms that underlie human disease. To realize this promise fully, it is necessary to relate genetic information to clinical phenotypes. Genetic tissue banking in clinical studies provides opportunities to analyze the genetic contribution to variation in response to treatments. The challenges to progress are likely to come from the complex organizational, social, political, and ethical issues that must be resolved in order to put clinical and DNA bank information together. Concerns about subjects' rights, informed consent, privacy, and ownership of genetic material require attention in the development of DNA banks. In this paper we describe one approach to the solution of these problems that was adopted by one clinical trials group, the Department of Veterans Affairs Cooperative Studies Program.

Introduction

The mapping and sequencing of the human genome is a watershed event in medical science. We are in a period of rapid growth of the body of knowledge of human genetics and the corresponding understanding of genetically determined mechanisms that underlie human disease 1, 2, 3. Some genetic assays are already available for clinicians to use in diagnosis, treatment, and prognosis. To realize fully the potential of the new tools being developed by genome science, it is necessary to relate genetic information to accurate and detailed clinical information, including onset, course, and outcome of disease (i.e., the clinical phenotype) 4, 5.

Randomized clinical trials and prospective observational studies that include storage of genetic tissue provide opportunities to gain insights into the genetic basis of variation in response to treatments [6]. Clinical trials provide the best evidence for treatment guidelines. However, future clinical practice may require that trial results be coupled with genetic information to determine treatment choices by genotype. The science of pharmacogenomics offers the prospect that information about the genetic determination of response to treatment can be used to individualize treatment selection and predict side effects [7]. Four essential elements or factors are needed for future progress: (1) high-resolution maps of the human genome with the ability to determine rapidly allelic variation in individuals, (2) high-quality, large-sample clinical datasets with well-characterized participants and longitudinal follow-up for effects of treatments, (3) stored DNA or other genetic tissue from the participants in the datasets and (4) advanced informatics for storage, retrieval, and correlation of complex clinical and genetic data.

The genotypes that play a role in most diseases are unknown, even in many diseases with a recognized genetic component. Stored DNA from persons with specific diseases can provide a rich resource for future genetic research in cardiovascular diseases, neurologic disorders, cancer, diabetes, respiratory disorders, and psychological disorders. Pharmaceutical companies and the biotechnology industry have a keen interest in finding high-quality clinical datasets that are linked to genetic material to advance the development of new therapies. Most importantly, patients will benefit from research based on stored DNA as new knowledge affects the diagnosis of disease, the development of new therapies, and how these therapies are targeted. For these reasons, storage of genetic tissue is beginning to be adopted as a regular part of clinical trials and observational studies.

If the use of genetic information were simply a matter of introducing a new diagnostic subtyping method, there would be little need for special consideration; genotyping would take its place beside blood chemistries, electrocardiography, and family history as a new tool for clinicians to use. However, the public perceives that genetic information is special. Many people believe that in some deep sense their genes carry their specific human identities, and the public is inclined to a greater belief in genetic determinism than even the most reductionist biological scientist [8]. Historical abuses of the science of inheritance, such as the eugenics movement in the early twentieth century, strengthen public concern.

Progress in clinical genomics in the next decade is likely to come from resolution of the complex organizational, social, political, and ethical issues that arise when linking clinical and DNA information to create a resource for future scientific use (a “DNA bank”). Stored DNA without linked information about diagnosis, treatment, and follow-up is much less valuable, while a clinical dataset without stored genetic material is incomplete. Yet concerns about subjects' rights (both as individuals and as groups), privacy, ownership of genetic material, and the stability of arrangements made to resolve these concerns require attention in the development of plans to store DNA 6, 9, 10. In this paper we describe one approach to the solution of these problems that was adopted by one clinical trials group, the Department of Veterans Affairs (VA) Cooperative Studies Program (CSP). Our decisions were determined in part by the special research context of our group. However, we hope this approach may be useful to others confronting similar problems.

Section snippets

The Cooperative Studies Program

The VA CSP is one of the oldest clinical trials organizations in the world. At any time, over 30 clinical trials and observational studies are ongoing in diseases that affect veterans. Many CSP studies enroll over 1000 patients, and follow-up may extend for several years, assessing outcomes such as mortality, major morbidity, and utilization of health resources. The multicenter clinical trials and prospective cohort studies in the CSP provide an opportunity for collecting and storing DNA for

DNA bank versus genetics substudy

Even in an individual clinical trial (single- or multisite), a DNA bank differs importantly from a genetics substudy. A substudy focuses on specific genetic hypotheses, which in turn define the extent of genotyping as well as the plans for analyses relating the genotypes to the clinical phenotypes and outcome of disease. In contrast, a DNA bank is oriented toward future hypotheses that may not be framed at the outset. It must justify itself on the basis of the latent scientific value of the

Guiding principles

The CSP DNA Bank operations are guided by six key principles:

Organization and operations

In this section, we describe the organization of the Bank and step through the standard operating procedures, beginning with informed consent and proceeding through handling, shipping, and storage of specimens, linking of clinical and genetic data, and review of proposals for use. The Bank has five components, providing it with adequate resources to store DNA, to conduct analyses that relate the genetic and clinical information, to manage and maximize the scientific use of the Bank, and to

Informatics and statistical analysis

The informatics system of the CSP DNA Bank is designed to protect the patient's privacy by securing the linked clinical and genetic databases against intrusion, unauthorized copying, loss, and other threats. At the same time, it is useful for potential clients of the Bank to be able to browse the protocol, forms, and procedure manuals of the parent studies to assess the suitability of the Bank data for testing their hypotheses. The Bank also will provide convenient access to aggregate summaries

Discussion

The undeniable scientific potential of gene science is accompanied by persistent public wariness about the ends and means of genetics research. For public trust to flourish, rules, institutions, and methods for the ethical and efficient conduct of genetics research must develop alongside the technical advances in genotyping. The CSP confronted the issues raised by DNA banking in clinical research as part of a more general VA research and development review of the implications of gene science

Acknowledgements

The opinions expressed herein are the opinions of the authors and do not represent official position of the Department of Veterans Affairs. This work was funded by the Department of Veterans Affairs Cooperative Studies Program as CSP#478.

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Other strengths of the VA include an altruistic Veteran population, over 100 research-ready medical centers, a state-of-the-art biorepository, a bioinformatics infrastructure to enable secure access to genetic and medical data, and an intramural clinical research network is embedded in the health care environment, serving to support the overall health care mission of VHA. As of the early 2000s, genomic research activities in the VA had already included the creation of a DNA Bank, managed by the VA Cooperative Studies Program (CSP), to support genetic studies among participants enrolled in multisite clinical trials [16]. Subsequent discussions focused on the creation of a primary resource for genomic analyses.
To describe the design and ongoing conduct of the Million Veteran Program (MVP), as an observational cohort study and mega-biobank in the Department of Veterans Affairs (VA) health care system.
Data are being collected from participants using questionnaires, the VA electronic health record, and a blood sample for genomic and other testing. Several ongoing projects are linked to MVP, both as peer-reviewed research studies and as activities to help develop an infrastructure for future, broad-based research uses.
Formal planning for MVP commenced in 2009; the protocol was approved in 2010, and enrollment began in 2011. As of August 3, 2015, and with a steady state of ≈50 recruiting sites nationwide, N = 397,104 veterans have been enrolled. Among N = 199,348 with currently available genotyping data, most participants (as expected) are male (92.0%) between the ages of 50 and 69 years (55.0%). On the basis of self-reported race, white (77.2%) and African American (13.5%) populations are well represented.
By helping to promote the future integration of genetic testing in health care delivery, including clinical decision making, the MVP is designed to contribute to the development of precision medicine.
The genetics of schizophrenia
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These are phenotypic variables that should be heritable, co-segregate with a psychiatric illness, yet be present even when the disease is not (i.e. state independent), and be found in non-affected family members at a higher rate than in the population (Gottesman and Gould, 2003). They also should be more easily quantifiable, part of the causal process by which disease arises (Lavori et al., 2002), or at least be involved in a biologically plausible mechanism of pathogenesis (Tsuang et al., 1993; Castellanos and Tannock, 2002). In other words, endophenotypes should provide a genetically tractable target, one that lies in the gap between gene and clinical diagnosis, so that, by dissecting their genetic basis, we would understand something about the biology of a psychiatric disorder.
Research on the genetic factors conferring risk for schizophrenia has not provided definitive answers. In the present review, we will discuss potential clinical and genetic limitations intrinsic to the strategies using a diagnostic phenotype. Among clinical factors, uncertainty of the phenotype is certainly a major limitation. Genetic problems include locus heterogeneity and the complex genetic architecture of the phenotype. Given these limiting factors, we will also discuss another hypothesis-driven strategy to uncover genetic risk: the use of quantitative measures (intermediate phenotypes) within more specific neurobiological mechanisms. As a clear example of all these issues and because of the longstanding involvement in the pathophysiology of this disorder, we will review the association of the gene for dopamine D2 receptors (DRD2) with diagnosis of schizophrenia and with specific working memory behavioral and brain activity phenotypes. We conclude by suggesting that hypothesis-free and hypothesis-driven are not mutually exclusive strategies and may provide information at different levels that are both useful and equally valid about genetic risk for a complex diagnostic entity like schizophrenia and for a complex phenotype like psychosis.
Characteristics associated with participation in DNA banking: The National Registry of Veterans with ALS
2007, Contemporary Clinical Trials
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The DNA bank is a collaboration among the ALS Registry (Epidemiologic Research and Information Center, Durham VAMC), the VA DNA Coordinating Center (DNACC-Palo Alto VAMC), and the Genetic Tissues Core Laboratory (GTCL) at the Massachusetts Epidemiological Research and Information Center (Boston VAMC). The DNACC has established procedures for all VA protocols that involve DNA banking [2]. These procedures ensure the protection of individual rights while facilitating the pursuit of responsible medical research and treatment goals.
Characteristics that may influence participation in DNA banks are not well defined. The purpose of this study was to examine characteristics associated with participation in a DNA bank among veterans diagnosed with Amyotrophic Lateral Sclerosis (ALS).
Veterans who screened eligible for the National Registry of Veterans with ALS were initially contacted about the DNA Bank via telephone and then mailed a consent form. Registry participants were then categorized as consented for the DNA bank, actively refused, or passively refused (consent form not returned after > 3 months and multiple reminders). The associations of consent status with age, gender, race, military branch, years of military service, VA health system use, and ALS Functional Rating Scale (ALSFRS) scores were examined.
Registry participants (N = 1020) were 98% male, 9.5% non-white, and the mean age was 64.1 years. 61.1% of participants were current VA health system users, and the branches of service were: Army (46.1%), Navy (22.1%), Air Force (23.2%), and Marines (8.3%). A total of 14.7% of Registry participants refused DNA banking (9.4% active refusal, 5.3% passive refusal). Results from multivariable models indicated participants who were non-White, VA users, or had lower ALSFRS scores (reflecting poorer function) had higher odds of refusal. Race and VA use were associated with active refusal, while age and ALSFRS score were associated with passive refusal.
Although the overall refusal rate for DNA banking was relatively low, we still found important differences in consent by race, VA use, and functional status in this cohort of veterans with ALS. Because differential participation in DNA banking may influence generalizability, further efforts are needed to understand and intervene to reduce these differences.
Pharmacogenetics: the bioethical problem of DNA investment banking
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Concern about the ethics of clinical drug trials research on patients and healthy volunteers has been the subject of significant ethical analysis and policy development—protocols are reviewed by Research Ethics Committees and subjects are protected by informed consent procedures. More recently attention has begun to be focused on DNA banking for clinical and pharmacogenetics research. It is, however, surprising how little attention has been paid to the commercial nature of such research, or the unique issues that present when subjects are asked to consent to the storage of biological samples. Our contention is that in the context of pharmacogenetic add-on studies to clinical drug trials, the doctrine of informed consent fails to cover the broader range of social and ethical issues. Applying a sociological perspective, we foreground issues of patient/subject participation or ‘work’, the ambiguity of research subject altruism, and the divided loyalties facing many physicians conducting clinical research. By demonstrating the complexity of patient and physician involvement in clinical drug trials, we argue for more comprehensive ethical review and oversight that moves beyond reliance on informed consent to incorporate understandings of the social, political and cultural elements that underpin the diversity of ethical issues arising in the research context.
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Research aimed at elucidating the underlying neurobiology and genetics of bipolar disorder, and factors associated with treatment response, have been limited by a heterogeneous clinical phenotype and lack of knowledge about its underlying diathesis. We used a survey of clinical, epidemiological, neurobiological, and genetic studies to select and evaluate candidate endophenotypes for bipolar disorder. Numerous findings regarding brain function, brain structure, and response to pharmacological challenge in bipolar patients and their relatives deserve further investigation. Candidate brain function endophenotypes include attention deficits, deficits in verbal learning and memory, cognitive deficits after tryptophan depletion, circadian rhythm instability, and dysmodulation of motivation and reward. We selected reduced anterior cingulate volume and early-onset white matter abnormalities as candidate brain structure endophenotypes. Symptom provocation endophenotypes might be based on bipolar patients’ sensitivity to sleep deprivation, psychostimulants, and cholinergic drugs. Phenotypic heterogeneity is a major impediment to the elucidation of the neurobiology and genetics of bipolar disorder. We present a strategy constructed to improve the phenotypic definition of bipolar disorder by elucidating candidate endophenotypes. Studies to evaluate candidate endophenotypes with respect to specificity, heritability, temporal stability, and prevalence in unaffected relatives are encouraged.
Implementation of an iron reduction protocol in patients with peripheral vascular disease: VA Cooperative Study No. 410: The Iron (Fe) and Atherosclerosis Study (FeAST)
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Citation Excerpt :
Subprotocols to this study were approved by all regulatory bodies, and each required a separate consent. An example is the establishment of the National VA DNA Bank (Tissue Legacy Program) that has received samples from patients entered into this study.32 This study involved no experimental drugs or devices.
Iron accumulates imperceptibly over time in adults because intake exceeds loss and because no physiologic mechanism exists for excreting levels that may be toxic. Levels of stored iron represented by the serum ferritin concentration have been implicated in the pathogenesis of vascular (and other) diseases, but the role of such stored iron remains controversial. Our hypothesis was that reduction in body iron stores to levels typical of children and premenopausal women (corresponding to ferritin levels of approximately 25 ng/mL) would alter morbidity and mortality rates in patients with advanced peripheral vascular disease.
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^☆: Heidi Krause-Steinrauf was formerly with Palo Alto VA Health Care System; Edward W. Holmes was formerly with Duke University School of Medicine.

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Original articlePrinciples, organization, and operation of a DNA bank for clinical trials:: a Department of Veterans Affairs cooperative study☆

Abstract

Introduction

Section snippets

The Cooperative Studies Program

DNA bank versus genetics substudy

Guiding principles

Organization and operations

Informatics and statistical analysis

Discussion

Acknowledgements

Ann Epidemiol

Impact of the human genome project on epidemiologic research

Epidemiol Rev

Genetic epidemiology and the future of disease prevention and public health

Epidemiol Rev

The genetics of dilated cardiomyopathy — emerging clues to the puzzle

N Engl J Med

DNA banking in epidemiologic studies

Epidemiol Rev

Genetic epidemiology of psychiatric disorders

Epidemiol Rev

Pharmacogenomicstranslating functional genomics into rational therapeutics

Science

Genomics research and human subjects

Science

Breaking the stalematea prospective regulatory framework for unforeseen research uses of human tissue samples and health information

Wake Forest L Rev

Confidentiality in medicinea decrepit concept

N Engl J Med

Obligations and responsibilities of epidemiologists to research subjects

J Clin Epidemiol

Original article
Principles, organization, and operation of a DNA bank for clinical trials:: a Department of Veterans Affairs cooperative study☆