ABSTRACT
The active debate about the return of incidental or secondary findings in research has primarily focused on return to research participants, or in some cases, family members. Particular attention has been paid to return of genomic findings. Yet, research may generate other types of findings that warrant consideration for return, including findings related to the pathology of donated biospecimens. In the case of deceased biospecimen donors who are also organ and/or tissue transplant donors, pathology incidental findings may be relevant not to family members, but to potential organ or tissue transplant recipients. This paper will describe the ethical implications of pathology incidental findings in the Genotype-Tissue Expression (GTEx) project, the process for developing a consensus approach as to if/when such findings should be returned, possible implications for other research projects collecting postmortem tissues and how the scenario encountered in GTEx fits into the larger return of results/incidental findings debate.
Subject(s)
Disclosure/ethics , Genomics/ethics , Incidental Findings , Pathology/ethics , Transplant Recipients , Confidentiality/ethics , HumansABSTRACT
For more than 20 years, the Ethical, Legal, and Social Implications (ELSI) Program of the National Human Genome Research Institute has supported empirical and conceptual research to anticipate and address the ethical, legal, and social implications of genomics. As a component of the agency that funds much of the underlying science, the program has always been an experiment. The ever-expanding number of issues the program addresses and the relatively low level of commitment on the part of other funding agencies to support such research make setting priorities especially challenging. Program-supported studies have had a significant impact on the conduct of genomics research, the implementation of genomic medicine, and broader public policies. The program's influence is likely to grow as ELSI research, genomics research, and policy development activities become increasingly integrated. Achieving the benefits of increased integration while preserving the autonomy, objectivity, and intellectual independence of ELSI investigators presents ongoing challenges and new opportunities.
Subject(s)
Genome, Human/genetics , National Human Genome Research Institute (U.S.)/ethics , National Human Genome Research Institute (U.S.)/legislation & jurisprudence , Public Policy , Genetic Testing , Humans , National Human Genome Research Institute (U.S.)/trends , United StatesABSTRACT
Health equity is the state in which everyone has fair and just opportunities to attain their highest level of health. The field of human genomics has fallen short in increasing health equity, largely because the diversity of the human population has been inadequately reflected among participants of genomics research. This lack of diversity leads to disparities that can have scientific and clinical consequences. Achieving health equity related to genomics will require greater effort in addressing inequities within the field. As part of the commitment of the National Human Genome Research Institute (NHGRI) to advancing health equity, it convened experts in genomics and health equity research to make recommendations and performed a review of current literature to identify the landscape of gaps and opportunities at the interface between human genomics and health equity research. This Perspective describes these findings and examines health equity within the context of human genomics and genomic medicine.
Subject(s)
Genomics , Health Equity , Humans , Genomics/methods , United States , Genome, Human , National Human Genome Research Institute (U.S.)ABSTRACT
PURPOSE: On 11 and 12 June 2012, the National Cancer Institute hosted a think tank concerning the identifiability of biospecimens and "omic" data in order to explore challenges surrounding this complex and multifaceted topic. METHODS: The think tank brought together 46 leaders from several fields, including cancer genomics, bioinformatics, human subject protection, patient advocacy, and commercial genetics. RESULTS: The first day involved presentations regarding the state of the science of reidentification; current and proposed regulatory frameworks for assessing identifiability; developments in law, industry, and biotechnology; and the expectations of patients and research participants. The second day was spent by think tank participants in small breakout groups designed to address specific subtopics under the umbrella issue of identifiability, including considerations for the development of best practices for data sharing and consent, and targeted opportunities for further empirical research. CONCLUSION: We describe the outcomes of this 2-day meeting, including two complementary themes that emerged from moderated discussions following the presentations on day 1, and ideas presented for further empirical research to discern the preferences and concerns of research participants about data sharing and individual identifiability.
Subject(s)
Confidentiality , Genetic Privacy , Genomics , Information Dissemination , Humans , National Cancer Institute (U.S.) , Patient Advocacy , United StatesABSTRACT
Diagnostic discrepancies occur when the diagnosis made on a biospecimen during the course of review at a biobank differs from the original clinical diagnosis. These diagnostic discrepancies detected during biobanking present unique challenges that are distinct from other types of research results or incidental findings. The proposed process for reporting diagnostic discrepancies or pathological incidental findings identified through a quality assurance evaluation at the biobank includes verification of the biospecimen identity, verification of the diagnosis within the biobank, and re-review of the case by the pathologist at the biospecimen collection site. If the pathologist at the biobank and the original pathologist do not reach agreement, an impartial and knowledgeable third party is consulted. The decision as to whether and how to notify research participants of any confirmed changes in diagnosis would be determined by institutional procedures. Implementation of this proposed process will require clear delineation of the roles and responsibilities of all involved parties in order to promote excellence in patient care and ensure that researchers have access to biospecimens of requisite quality.Genet Med 2012:14(4):417-423.
Subject(s)
Biomedical Research/statistics & numerical data , Incidental Findings , Medical Informatics/statistics & numerical data , Research Subjects , Biomedical Research/ethics , Diagnostic Errors/ethics , Diagnostic Errors/statistics & numerical data , False Positive Reactions , Humans , Informed Consent/ethics , Medical Informatics/ethics , Pathology, Clinical/ethics , Pathology, Clinical/standards , Pathology, Clinical/statistics & numerical data , Tissue Banks/statistics & numerical data , Truth Disclosure/ethicsABSTRACT
Skeletal muscles can be injured by their own contractions, especially when the muscle is stretched during a lengthening contraction. Exposing a muscle to a conditioning protocol of stretches without activation (passive stretches) before lengthening contractions reduces contraction-induced injury. Although passive stretching does not damage muscle fibers, neutrophils are elevated in the muscle after passive stretches. Our purpose was to investigate the relationship between neutrophil accumulation following passive stretches and the protection from subsequent contraction-induced injury provided by the passive stretches. Our hypothesis was that passive stretch conditioning would not provide protection from subsequent lengthening contraction-induced injury under circumstances when the increase in muscle neutrophils in response to the conditioning was prevented. Extensor digitorum longus muscles of mice were conditioned with passive stretches 14 days before exposure to a protocol of damaging lengthening contractions. Mice were either untreated or treated with an antibody (RB6-8C5) that reduced the level of circulating neutrophils by over 95% before administration of passive stretches. Neutrophil levels recovered in treated mice by the time lengthening contractions were performed. Lengthening contractions were also administered to muscles with no prior exposure to passive stretches. Maximum isometric force, number of damaged fibers, and muscle neutrophil concentration were measured 3 days after lengthening contractions. Compared with nonconditioned control muscles, the severity of contraction-induced injury was not reduced by prior passive stretch conditioning when mice were treated with RB6-8C5 before conditioning. We conclude that neutrophils contribute to adaptations that protect muscles from injury.
Subject(s)
Adaptation, Physiological/physiology , Muscle Stretching Exercises , Muscle, Skeletal/injuries , Neutrophils/physiology , Animals , Cell Count , Data Interpretation, Statistical , Immunohistochemistry , Male , Mice , Mice, Inbred C57BL , Muscle Contraction/physiology , Muscle Fibers, Skeletal/pathology , Muscle, Skeletal/cytology , Muscle, Skeletal/pathology , Neutrophils/immunologyABSTRACT
Contraction-induced injury occurs when muscles are stretched while activated (lengthening contractions). The injury is initiated by mechanical damage followed by an inflammatory response. Old animals are particularly susceptible to contraction-induced injury, yet exposure to stretches without activation (passive stretches) before lengthening contractions lessens the injury. We hypothesized that, for muscles of both young and old mice, prior exposure to passive stretches reduces the initial mechanical damage induced by lengthening contractions. Compared with unconditioned muscles in both age groups, administration of passive stretches 1 hour before lengthening contractions decreased the force deficit at 3 days by one half, but did not affect the force deficit at 10 minutes. Force deficits immediately after two lengthening contractions were also not different for passive stretch-conditioned and unconditioned muscles. The similarity in force deficits immediately following lengthening contractions for conditioned and unconditioned muscle indicates that passive stretch conditioning does not decrease initial mechanical damage in young or old mice.
Subject(s)
Aging , Isometric Contraction , Muscle, Skeletal/injuries , Muscular Diseases/prevention & control , Physical Conditioning, Animal/methods , Animals , Disease Models, Animal , Mice , Mice, Inbred C57BL , Muscle, Skeletal/physiopathology , Muscular Diseases/etiology , Muscular Diseases/physiopathology , Reflex, Stretch , Stress, MechanicalABSTRACT
UNLABELLED: Contraction-induced injury occurs when a muscle is stretched while activated (lengthening contraction). Exposure to a bout of lengthening contractions results in protection from subsequent lengthening contraction-induced injury as well as an elevation in phosphorylated Akt and p70S6K. Whether Akt or p70S6K is involved in the protection from contraction-induced injury is unclear. To test for a specific role of Akt and/or p70S6K to induce protective adaptations, we used a conditioning protocol of passive stretches that reduces contraction-induced injury with minimal involvement of other cellular responses that have been associated with the Akt signaling pathway, such as increased metabolism, cell growth, and cell death. PURPOSE: To determine whether activation of Akt or p70S6K is necessary to induce protective adaptations. METHODS: Extensor digitorum longus muscles of anesthetized mice were administered 75 lengthening contractions in situ with or without previous exposure to 75 passive stretches 1 h, 24 h, 3 d, or 14 d prior to lengthening contractions. RESULTS: Compared with unconditioned muscles, the deficit in isometric force and number of injured fibers 3 d following lengthening contractions were smaller by half for passive-stretch-conditioned muscles from all time points. Phosphorylation of Akt and p70S6K were analyzed by Western blot 0 or 3 h following either lengthening contractions or passive stretches. Whereas lengthening contractions increased phosphorylation of Akt at 0 h and p70S6K at 3 h, passive stretches did not at any time increase phosphorylation of Akt or p70S6K despite reducing contraction-induced injury. CONCLUSION: Activation of neither Akt nor p70S6K is necessary to induce adaptations that reduce the severity of contraction-induced injury.
Subject(s)
Adaptation, Physiological/physiology , Muscle Contraction/physiology , Muscle, Skeletal/physiology , Proto-Oncogene Proteins c-akt/physiology , Animals , Blotting, Western , Electric Stimulation , Isometric Contraction/physiology , Luminescence , Male , Mice , Mice, Inbred C57BL , Mice, Inbred Strains , Muscle Fibers, Skeletal/cytology , Muscle Fibers, Skeletal/physiology , Muscle, Skeletal/pathology , Phosphorylation , Proto-Oncogene Proteins c-akt/analysis , Regeneration/physiology , Ribosomal Protein S6 Kinases, 70-kDa/analysis , Ribosomal Protein S6 Kinases, 70-kDa/physiology , Signal Transduction/physiology , Specific Pathogen-Free Organisms , Time FactorsABSTRACT
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.
Subject(s)
Biomedical Research , Tissue Banks , Tissue and Organ Procurement , Biomedical Research/methods , Biomedical Research/organization & administration , Biomedical Research/standards , Humans , Tissue and Organ Procurement/methods , Tissue and Organ Procurement/organization & administration , Tissue and Organ Procurement/standardsABSTRACT
Normal human tissues, bodily fluids, and other biospecimens of known quality are essential for research to understand the development of cancer and other diseases and to develop new diagnostics and therapies. However, obtaining normal biospecimens appropriate for contemporary large-scale molecular and genomic research is one of the most challenging biospecimen acquisition problems for scientists and biospecimen resources that support research. Recognizing this challenge, the U.S. National Cancer Institute recently convened a series of workshops and meetings focused on the acquisition of normal tissues for research and produced an extensive document, Recommendations for Postmortem Recovery of Normal Human Biospecimens for Research. This article summarizes these recommendations, addressing key ethical, operational, and scientific elements for collecting normal reference biospecimens from postmortem donors in the U.S. Awareness of these recommendations can foster more effective collaborations and mitigate potential logistical challenges, while promoting postmortem biospecimen donation options for families and increasing the availability of high quality normal biospecimens for research. The recommendations have been put into practice in the collection of normal human biospecimens for the NIH Genotype-Tissue Expression Program (GTEx), a pilot study of human gene expression and regulation in multiple tissues which will provide valuable insights into the mechanisms of gene regulation and, in the future, its disease-related perturbations (http://commonfund.nih.gov/GTEx/).
Subject(s)
Biomedical Research , Guidelines as Topic , Postmortem Changes , Tissue Banks , Autopsy , Family , Humans , Quality Control , Residence Characteristics , Social Control, Formal , Tissue Banks/ethics , Tissue Banks/legislation & jurisprudence , Tissue DonorsABSTRACT
Biobanks and biospecimens are critical components for many areas of clinical and basic research. The quality of biospecimens and associated data must be consistent and collected according to standardized methods in order to prevent spurious analytical results that can lead to artifacts being interpreted as valid findings. A number of international institutions have taken the initiative to develop and publish best practices, which include technical recommendations for handling biospecimens as well as recommendations for ethical and regulatory practices in biobanking. These sources of guidance have been useful in raising the overall consistency and quality of research involving biospecimens. However, the lack of international harmonization, uneven adoption, and insufficient oversight of best practices are preventing further improvements in biospecimen quality and coordination among collaborators and biobanking networks. In contrast to the more straightforward technical and management issues, ethical and regulatory practices often involve issues that are more controversial and difficult to standardize.
Subject(s)
Biological Specimen Banks/organization & administration , Specimen Handling/standards , Biological Specimen Banks/ethics , Humans , Informed Consent/ethics , International Cooperation , Practice Guidelines as Topic , Quality Control , Specimen Handling/methodsSubject(s)
Biomedical Research/ethics , Genomics/ethics , Organ Transplantation , Tissue Donors , Tissue and Organ Procurement/ethics , Biomedical Research/legislation & jurisprudence , Genomics/legislation & jurisprudence , Humans , National Institutes of Health (U.S.) , Tissue and Organ Procurement/legislation & jurisprudence , United StatesABSTRACT
A movement to create a global patient registry for as many as 7,000 rare diseases was launched at a workshop, "Advancing Rare Disease Research: The Intersection of Patient Registries, Biospecimen Repositories, and Clinical Data." http://rarediseases.info.nih.gov/PATIENT_REGISTRIES_WORKSHOP/. The workshop was sponsored by the Office of Rare Diseases Research (ORDR). The focus was the building of an infrastructure for an internet-based global registry linking to biorepositories. Such a registry would serve the patients, investigators, and drug companies. To aid researchers the participants suggested the creation of a centralized database of biorepositories for rare biospecimens (RD-HUB)http://biospecimens.ordr.info.nih.gov/ that could be linked to the registry. Over two days of presentations and breakout sessions, several hundred attendees discussed government rules and regulations concerning privacy and patients' rights and the nature and scope of data to be entered into a central registry as well as concerns about how to validate patient and clinician-entered data to ensure data accuracy. Mechanisms for aggregating data from existing registries were also discussed. The attendees identified registry best practices, model coding systems, international systems for recruiting patients into clinical trials and novel ways of using the internet directly to invite participation in research. They also speculated about who would bear ultimate responsibility for the informatics in the registry and who would have access to the information. Hurdles associated with biospecimen collection and how to overcome them were detailed. The development of the recommendations was, in itself, an indication of the commitment of the rare disease community as never before.