RESUMO
With the introduction of Next Generation Sequencing (NGS) techniques increasing numbers of disease-associated variants are being identified. This ongoing progress might lead to diagnoses in formerly undiagnosed patients and novel insights in already solved cases. Therefore, many studies suggest introducing systematic reanalysis of NGS data in routine diagnostics. Introduction will, however, also have ethical, economic, legal and (psycho)social (ELSI) implications that Genetic Health Professionals (GHPs) from laboratories should consider before possible implementation of systematic reanalysis. To get a first impression we performed a scoping literature review. Our findings show that for the vast majority of included articles ELSI aspects were not mentioned as such. However, often these issues were raised implicitly. In total, we identified nine ELSI aspects, such as (perceived) professional responsibilities, implications for consent and cost-effectiveness. The identified ELSI aspects brought forward necessary trade-offs for GHPs to consciously take into account when considering responsible implementation of systematic reanalysis of NGS data in routine diagnostics, balancing the various strains on their laboratories and personnel while creating optimal results for new and former patients. Some important aspects are not well explored yet. For example, our study shows GHPs see the values of systematic reanalysis but also experience barriers, often mentioned as being practical or financial only, but in fact also being ethical or psychosocial. Engagement of these GHPs in further research on ELSI aspects is important for sustainable implementation.
Assuntos
Testes Genéticos , Humanos , Testes Genéticos/ética , Testes Genéticos/economia , Testes Genéticos/legislação & jurisprudência , Testes Genéticos/normas , Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala/ética , Genômica/ética , Genômica/legislação & jurisprudência , Genômica/métodos , Laboratórios ClínicosRESUMO
Implementing genome and exome sequencing in clinical practice presents challenges, including obtaining meaningful informed consent. Consent may be challenging due to test limitations such as uncertainties associated with test results and interpretation, complexity created by the potential for additional findings and high patient expectations. We drew on the experiences of research teams within the Clinical Sequencing Exploratory Research (CSER1) Consortium on informed consent for clinical genome and exome sequencing (CGES) to negotiate consensus considerations. We present six considerations for clinicians and 12 key points to communicate as they support patients in deciding whether to undergo CGES. These considerations and key points provide a helpful starting point for informed consent to CGES, grounded in the Clinical Sequencing Exploratory Research (CSER1) experience.
Assuntos
Sequenciamento do Exoma/ética , Consentimento Livre e Esclarecido/legislação & jurisprudência , Tomada de Decisões , Ética Médica , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala/ética , Humanos , Guias de Prática Clínica como AssuntoRESUMO
Access to active search for actionable secondary findings (SF) in diagnostic practice is a major psychological and ethical issue for genomic medicine. In this study, we analyzed the preferences of patients and their families regarding SF and identified the reporting procedures necessary for informed consent. We interviewed parents of patients with undiagnosed rare diseases potentially eligible for exome sequencing and patients affected by the diseases listed in the ACMG recommendations. Four focus groups (FG) were formed: parents of patients with undiagnosed rare diseases (FG1, nâ¯=â¯5); patients with hereditary cancers (FG2, nâ¯=â¯10); patients with hereditary cardiac conditions (FG3, nâ¯=â¯3); and patients with metabolic diseases (FG4, nâ¯=â¯3). Psychologists presented three broad topics for discussion: 1. Favorable or not to SF access, 2. Reporting procedures, 3. Equity of access. Discussions were recorded and analyzed using simplified Grounded Theory. Overall, 8 participants declared being favorable to SF because of the medical benefit (mainly FG1); 11 were unfavorable because of the psychological consequences (mainly FG2, FG3, FG4); 2 were ambivalent. The possibility of looking for SF in minors was debated. The 4 key information-based issues for participants ranked as follows: explanation of SF issues, autonomy of choice, importance of a reflection period, and quality of interactions between patients and professionals. Examining equity of access to SF led to philosophical discussions on quality of life. In conclusion, individual experience and life context (circumstances) were decisive in participants' expectations and fears regarding access to SF. Additional longitudinal studies based on actual SF disclosure announcements are needed to establish future guidelines.
Assuntos
Ética Médica , Genômica/ética , Sequenciamento de Nucleotídeos em Larga Escala/ética , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/psicologia , Testes Genéticos , Genoma Humano , Humanos , Achados Incidentais , Pessoa de Meia-Idade , Sequenciamento do ExomaRESUMO
DNA is now commonly collected in clinical research either for immediate genomic analyses or stored for future studies. Many genomic studies were previously designed without awareness of the ethical issues that might arise regarding the disclosure of genomic test results. At the start of the Chronic Kidney Disease in Children (CKiD) Cohort Study in 2004, we did not foresee the advent of genomic technology or the associated ethical issues pertaining to genetic research in children. Recent genomic studies and ancillary proposals using genomic technology stimulated the CKiD investigators to reassess the current ethical and policy environment pertaining to genomic testing and results disclosure. We consider the issues pertaining to next generation sequencing and individual results disclosure that may guide current and future research practices.
Assuntos
Testes Genéticos/ética , Sequenciamento de Nucleotídeos em Larga Escala/ética , Pesquisa Qualitativa , Insuficiência Renal Crônica/genética , Adolescente , Criança , Pré-Escolar , Feminino , Previsões , Testes Genéticos/tendências , Genômica/ética , Política de Saúde , Sequenciamento de Nucleotídeos em Larga Escala/tendências , Humanos , Consentimento Livre e Esclarecido , Masculino , Pediatria/métodos , Formulação de Políticas , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , Projetos de Pesquisa , Revelação da Verdade , Estados UnidosAssuntos
Controle de Doenças Transmissíveis/organização & administração , Genômica/ética , Saúde Global/ética , Sequenciamento de Nucleotídeos em Larga Escala/ética , Saúde Pública/ética , Patógenos Transmitidos pelo Sangue/isolamento & purificação , Defesa Civil/métodos , Doenças Transmissíveis/diagnóstico , Doenças Transmissíveis/economia , Doenças Transmissíveis/terapia , Genômica/economia , Saúde Global/economia , Sequenciamento de Nucleotídeos em Larga Escala/economia , Humanos , Disseminação de Informação/ética , Pobreza/economia , Saúde Pública/economia , Vigilância em Saúde PúblicaRESUMO
High-throughput technologies for biological data acquisition are advancing at an increasing pace. Most prominently, the decreasing cost of DNA sequencing has led to an exponential growth of sequence information, including individual human genomes. This session of the 2019 Pacific Symposium on Biocomputing presents the distinctive privacy and ethical challenges related to the generation, storage, processing, study, and sharing of individuals' biological data generated by multitude of technologies including but not limited to genomics, proteomics, metagenomics, bioimaging, biosensors, and personal health trackers. The mission is to bring together computational biologists, experimental biologists, computer scientists, ethicists, and policy and lawmakers to share ideas, discuss the challenges related to biological data and privacy.
Assuntos
Big Data , Biologia Computacional/ética , Confidencialidade/ética , Privacidade Genética/ética , Registros Eletrônicos de Saúde/ética , Estudo de Associação Genômica Ampla/ética , Genômica/ética , Sequenciamento de Nucleotídeos em Larga Escala/ética , Humanos , Análise de Sequência de DNA/éticaAssuntos
Sequenciamento de Nucleotídeos em Larga Escala , Oncologia/tendências , Neoplasias/genética , Brasil , Genoma Humano/genética , Sequenciamento de Nucleotídeos em Larga Escala/economia , Sequenciamento de Nucleotídeos em Larga Escala/ética , Humanos , Oncologia/economia , Oncologia/legislação & jurisprudência , Neoplasias/diagnóstico , Neoplasias/terapia , Medicina de Precisão , Participação dos InteressadosRESUMO
Inherited platelet disorders can affect "only platelets", occur as a "syndromic phenotype" or be associated with "increased risk of hematological malignancies". Genetic testing is attractive for diagnosis of inherited platelet disorders. However, many physicians who refer patient blood for genetic testing are unaware of the association of certain inherited platelet disorders with other risks. Inherited platelet disorders associated with minor-moderate bleeding rarely cause patient distress. In contrast, identification of a mutation associated with an increased risk of leukemia may cause a major psychological disease burden, without offsetting the beneficial impact on management. Guidelines recommend postponing genetic testing "until the patient reaches adulthood or at least until the child is mature enough to participate in decision making". In our opinion, outside research, (genetic) testing in children with inherited platelet disorders should only be performed if it influences management. In adults, genes causing inherited platelet disorders associated with an increased risk of hematological malignancies should only be tested after obtaining explicit informed consent.
Assuntos
Transtornos Plaquetários/diagnóstico , Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Transtornos Plaquetários/genética , Transtornos Plaquetários/terapia , Aconselhamento Genético , Marcadores Genéticos , Predisposição Genética para Doença , Testes Genéticos/ética , Neoplasias Hematológicas/genética , Sequenciamento de Nucleotídeos em Larga Escala/ética , Humanos , Consentimento Livre e Esclarecido , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Medição de Risco , Fatores de RiscoRESUMO
PURPOSE: Clinical sequencing emerging in health care may result in secondary findings (SFs). METHODS: Seventy-four of 6240 (1.2%) participants who underwent genome or exome sequencing through the Clinical Sequencing Exploratory Research (CSER) Consortium received one or more SFs from the original American College of Medical Genetics and Genomics (ACMG) recommended 56 gene-condition pair list; we assessed clinical and psychosocial actions. RESULTS: The overall adjusted prevalence of SFs in the ACMG 56 genes across the CSER consortium was 1.7%. Initially 32% of the family histories were positive, and post disclosure, this increased to 48%. The average cost of follow-up medical actions per finding up to a 1-year period was $128 (observed, range: $0-$678) and $421 (recommended, range: $141-$1114). Case reports revealed variability in the frequency of and follow-up on medical recommendations patients received associated with each SF gene-condition pair. Participants did not report adverse psychosocial impact associated with receiving SFs; this was corroborated by 18 participant (or parent) interviews. All interviewed participants shared findings with relatives and reported that relatives did not pursue additional testing or care. CONCLUSION: Our results suggest that disclosure of SFs shows little to no adverse impact on participants and adds only modestly to near-term health-care costs; additional studies are needed to confirm these findings.
Assuntos
Testes Genéticos/economia , Achados Incidentais , Sequenciamento Completo do Genoma/ética , Adulto , Tomada de Decisões/ética , Revelação , Exoma , Feminino , Testes Genéticos/ética , Testes Genéticos/normas , Genômica/métodos , Custos de Cuidados de Saúde , Conhecimentos, Atitudes e Prática em Saúde , Pessoal de Saúde , Sequenciamento de Nucleotídeos em Larga Escala/ética , Humanos , Intenção , Masculino , Pacientes , Prevalência , Sequenciamento Completo do Genoma/economiaRESUMO
PURPOSE: Genomic sequencing can reveal variants with limited to no medical actionability. Previous research has assessed individuals' intentions to learn this information, but few report the decisions they made and why. METHODS: The North Carolina Clinical Genomic Evaluation by Next Generation Exome Sequencing (NCGENES) project evaluated adult patients randomized to learn up to six types of non-medically actionable secondary findings (NMASF). We previously found that most participants intended to request NMASF and intentions were strongly predicted by anticipated regret. Here we examine discrepancies between intentions and decisions to request NMASF, hypothesizing that anticipated regret would predict requests but that this association would be mediated by participants' intentions. RESULTS: Of the 76% who expressed intentions to learn results, only 42% made one or more requests. Overall, only 32% of the 155 eligible participants requested NMASF. Analyses support a plausible causal link between anticipated regret, intentions, and requests. CONCLUSIONS: The discordance between participants' expressed intentions and their actions provides insight into factors that influence patients' preferences for genomic information that has little to no actionability. These findings have implications for the timing and methods of eliciting preferences for NMASF and suggest that decisions to learn this information have cognitive and emotional components.
Assuntos
Achados Incidentais , Preferência do Paciente/psicologia , Sequenciamento Completo do Genoma/ética , Adulto , Idoso , Tomada de Decisões/ética , Emoções , Exoma , Feminino , Testes Genéticos/ética , Genômica/métodos , Conhecimentos, Atitudes e Prática em Saúde , Pessoal de Saúde , Sequenciamento de Nucleotídeos em Larga Escala/ética , Humanos , Intenção , Masculino , Pessoa de Meia-Idade , Pacientes , Sequenciamento Completo do Genoma/métodosRESUMO
BACKGROUND: The use of Next Generation Sequencing such as Whole Genome Sequencing (WGS) is a promising step towards a better understanding and treatment of neurological diseases. WGS can result into unexpected information (incidental findings, IFs), and information with uncertain clinical significance. In the context of a Genome Canada project on 'Personalized Medicine in the Treatment of Epilepsy', we intended to address these challenges surveying neurologists' opinions about the type of results that should be returned, and their professional responsibility toward recontacting patients regarding new discovered mutations. METHODS: Potential participants were contacted through professional organizations or direct invitations. RESULTS: A total of 204 neurologists were recruited. Fifty nine percent indicated that to be conveyed, WGS results should have a demonstrated clinical utility for diagnosis, prognosis or treatment. Yet, 41% deemed appropriate to return results without clinical utility, when they could impact patients' reproductive decisions, or on patients' request. Current use of targeted genetic testing and age of patients influenced respondents' answers. Respondents stated that analysis of genomics data resulting from WGS should be limited to the genes likely to be relevant for the patient's specific medical condition (69%), so as to limit IFs. Respondents felt responsible to recontact patients and inform them about newly discovered mutations related to the medical condition that triggered the test (75%) for as long as they are following up on the patient (55%). Finally, 53.5% of the respondents felt responsible to recontact and inform patients of clinically significant, newly discovered IFs. CONCLUSION: Our results show the importance of formulating professional guidelines sensitive to the various - and sometimes opposite - viewpoints that may prevail within a same community of practice, as well as flexible so as to be attuned to the characteristics of the neurological conditions that triggered a WGS.
Assuntos
Revelação/ética , Sequenciamento de Nucleotídeos em Larga Escala/ética , Neurologia/ética , Guias de Prática Clínica como Assunto , Adulto , Canadá , Criança , Revelação/normas , Feminino , Genoma Humano , Humanos , Masculino , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/genética , Neurologia/estatística & dados numéricos , Responsabilidade Social , Inquéritos e QuestionáriosAssuntos
Revelação/ética , Responsabilidade pela Informação/legislação & jurisprudência , Aconselhamento Genético/ética , Testes Genéticos/ética , Sequenciamento de Nucleotídeos em Larga Escala/ética , Predisposição Genética para Doença/prevenção & controle , Humanos , Obrigações Morais , Papel ProfissionalRESUMO
In the era of next-generation sequencing, it is essential to collect and understand the patient outcomes that result from this new technology. One critical determinant of these is the process by which individuals first decide whether and how to pursue genome sequencing. In this perspective article, we examine the literature on adult patient decision-making in genome sequencing and identify current research gaps to address. Several studies have explored the motivations and concerns of patients undergoing sequencing; less attention has been paid to those who decline sequencing or to individuals from lower socioeconomic groups. Many factors that might play a role in the decision to pursue or decline sequencing, including trust, family dynamics and barriers to access, have yet to be explored fully. Future research that captures the experience of the wider population will produce a more generalizable understanding of the clinical, psychosocial, and economic outcomes of pursuing or declining sequencing.
Assuntos
Análise de Sequência de DNA/ética , Sequenciamento Completo do Genoma/ética , Mapeamento Cromossômico/ética , Tomada de Decisões/ética , Genoma/ética , Conhecimentos, Atitudes e Prática em Saúde , Sequenciamento de Nucleotídeos em Larga Escala/ética , Humanos , Achados Incidentais , Consentimento Livre e Esclarecido/ética , Medição de RiscoRESUMO
In recent years, high-throughput sequencing techniques have been developed for cancerology and many clinical trials are currently structured around biomarkers that can guide specific treatment choices. This approach is characteristic of precision medicine, which is actually a concept initiated several decades ago with, for example, retinoic acid in promyelocytic leukemia. This paper will review the different types of molecular alterations and « -omics ¼ biological analyses, bioinformatics tools, coupled drug/biomarkers already validated, the ethical issues of whole genomic sequencing of an individual as part of an inclusion in a clinical trial and finally the first results of precision medicine trials. The AcSé crizotinib program, supported by the Inca (french Cancer National Institute), is emblematic of a success of this personalized medicine illustrated by 4 points: the discovery of a cohort of patients with lung cancer with a ROS1 rearrangement characteristic of a sensitivity to crizotinib, a rapid availability of this innovation through the implementation of a temporary recommendation for use (ANSM), the obtention of a conditional marketing authorization by the pharmaceutical industry and finally, financial assumption of responsibility by French social security (HAS), despite preliminary and non-comparative data. In the case of cancers refractory to standard chemotherapy, and regarding our system of access to drugs illustrated by the PROFILER clinical trial, this approach allows the access to a therapeutic drug targeting specific biomarkers only in 7% of patients included. This does not bode well for efficient treatment and even less for survival. Allowing patients to be included in trials that identify molecular targets by molecular screening, and not being able to propose the drug of interest is a traumatic event for those patients who live in the hope of an immediate future. In refractory disease we must rethink precision medicine in a more humanistic vision for our patients and not only in a dimension of medico-industrial promotion. The implementation of a new multi-drug/multi-molecular target program could address this issue.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Medicina de Precisão/métodos , Biomarcadores Tumorais/genética , Ensaios Clínicos como Assunto , Biologia Computacional , Crizotinibe , Aprovação de Drogas , Rearranjo Gênico , Sequenciamento de Nucleotídeos em Larga Escala/ética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Terapia de Alvo Molecular/métodos , Neoplasias/genética , Medicina de Precisão/ética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/genética , Proteômica , Proteínas Proto-Oncogênicas/genética , Pirazóis/uso terapêutico , Piridinas/uso terapêuticoAssuntos
DNA/análise , Sequenciamento de Nucleotídeos em Larga Escala/tendências , Teoria Quântica , DNA/química , Previsões , Sequenciamento de Nucleotídeos em Larga Escala/ética , Sequenciamento de Nucleotídeos em Larga Escala/instrumentação , Sequenciamento de Nucleotídeos em Larga Escala/métodos , HumanosRESUMO
The nature of next generation sequencing technologies (NGS) results in the generation of large amounts of data and the identification of numerous variants, for some of which the clinical significance may be difficult to ascertain based on our current knowledge. These Variants of Uncertain Significance (VUS) may be identified in genes in which the function is known or unknown and which may or may not be related to the original rationale for sequencing the patient. Little is known about whether laboratories report VUS to clinicians and current guidelines issued by some of the most notable professional bodies do not provide specific recommendations on this point. To address this, 26 interviews were conducted with 27 laboratory personnel, representing 24 laboratories in Europe (12), Canada (5) and Australasia (7) in order to explore their reporting practices. Participants highlighted that the classification of variants is a real challenge despite the presence of classification guidelines. We identified variation in the reporting practices of VUS across the laboratories within the study. While some laboratories limit their reporting to variants that are pathogenic and thought to be causative of the phenotype, more commonly laboratories report VUS when they are identified in genes related to the clinical question. Some laboratories will also report VUS in candidate genes. VUS that are secondary findings are generally not reported. While it is unclear whether uniformity in reporting is desirable, exploring the perspectives of laboratory personnel undertaking these analyses are critical to ensure the feasibility of any future reporting recommendations.
Assuntos
Testes Genéticos/normas , Sequenciamento de Nucleotídeos em Larga Escala/normas , Notificação de Abuso , Mutação/genética , Guias de Prática Clínica como Assunto , Relatório de Pesquisa/normas , Análise de Sequência de DNA/normas , Atitude do Pessoal de Saúde , Australásia , Canadá , Europa (Continente) , Testes Genéticos/ética , Sequenciamento de Nucleotídeos em Larga Escala/ética , Humanos , Análise de Sequência de DNA/éticaRESUMO
This review describes the social and ethical responses to the history of innovations in forensic genetics and their application to criminal investigations. Following an outline of the three recurrent social perspectives that have informed these responses (crime management, due process, and genetic surveillance), it goes on to introduce the repertoire of ethical considerations by describing a series of key reports that have shaped subsequent commentaries on forensic DNA profiling and databasing. Four major ethical concerns form the focus of the remainder of the paper (dignity, privacy, justice, and social solidarity), and key features of forensic genetic practice are examined in the light of these concerns. The paper concludes with a discussion of the concept of "proportionality" as a resource for balancing the social and ethical risks and benefits of the use of forensic genetics in support of criminal justice.
Assuntos
Genética Forense/ética , Genética Forense/legislação & jurisprudência , Impressões Digitais de DNA/ética , Impressões Digitais de DNA/legislação & jurisprudência , Bases de Dados de Ácidos Nucleicos/ética , Bases de Dados de Ácidos Nucleicos/legislação & jurisprudência , Privacidade Genética/ética , Sequenciamento de Nucleotídeos em Larga Escala/ética , Direitos Humanos/legislação & jurisprudência , Humanos , Autonomia PessoalRESUMO
INTRODUCTION: The advent of next-generation sequencing (NGS) has introduced an exciting new era in biomedical research. NGS forms the foundation of current genetic testing approaches, including targeted gene panel testing, as well as more comprehensive whole-exome and whole-genome sequencing. Together, these approaches promise to provide critical insights into the understanding of health and disease. However, with NGS testing come many ethical questions and concerns, particularly when testing involves children. These concerns are especially relevant for children with cancer, where the testing of tumor and germline tissues is increasingly being incorporated into clinical care. Areas covered: In this manuscript, we explore the key ethical considerations related to conducting germline NGS testing in pediatric oncology, focusing on the four main principles of beneficence, non-maleficence, autonomy and justice. Expert commentary: The ethical issues surrounding germline NGS testing are complex and result in part from our limited understanding of the medical relevance of many of the results obtained and poor knowledge of the impacts of testing, both beneficial and detrimental, on patients and their families. In this article we discuss the risks and benefits of germline NGS testing and the arguments for and against such testing in children with cancer.
Assuntos
Ética , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala/ética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias/genética , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , MasculinoRESUMO
Like any true conceptual revolution, next-generation sequencing (NGS) has not only radically changed research and clinical practice, it has also modified scientific culture. With the possibility to investigate DNA contents of any organism and in any context, including in somatic disorders or in tissues carrying complex microbial populations, it initially seemed as if the genetic underpinning of any biological phenomenon could now be deciphered in an almost streamlined fashion. However, over the past recent years, we have once again come to understand that there is no such a thing as great opportunities without great challenges. The steadily expanding use of NGS and related applications is now facing biologists and physicians with novel technological obstacles, analytical hurdles and increasingly pressing ethical questions.