Review
doi: 10.1111/iji.12155
Next generation sequencing: considering the ethics S. Davey
Summary This review article discusses some of the ethical challenges posed by next generation sequencing (NGS), both in the clinical and research setting. Concerns such as how to deal with unexpected results apply equally to conventional techniques. However, these incidental findings are far more likely with the use of NGS and whole genome sequencing. Whilst the lines of responsibility are better defined in the clinical environment, disclosure of such findings in the research setting is less clear. Recruitment of volunteers for public biobank research, in particular, also raises questions regarding consent and confidentiality.
Introduction Next generation sequencing (NGS) is a revolution in sequencing technology, developed since the ‘first generation’ Sanger sequencing method which has dominated for decades (Metzker, 2010). Producing less than 3 mega bases a day, Sanger sequencing was fundamental to completing the human genome project; this project provided the impetus for the development of novel methods to increase the speed, accuracy and throughput of sequencing, whilst also reducing costs (Liu et al., 2012). Next generation sequencing is also known as massively parallel sequencing due to an adaptation of ‘shotgun sequencing’ used in Sanger technology. Genomic DNA is fragmented, and the short DNA templates generated are ligated to specific adapters and read randomly along the entire genome by NGS technologies. These short reads are subsequently assembled and aligned to a reference genome; the accuracy of sequencing is determined by the ‘coverage’, that is the number of times each base in any one position is represented and length of contiguous sequence (Zhang et al., 2011).
H&I Department, NHS Blood and Transplant, London, UK Received 28 June 2014; revised 17 August 2014; accepted 25 September 2014 Correspondence: Sue Davey, H&I Department, NHS Blood and Transplant, Charcot Road, London NW9 5BG, UK. Tel: +44 20 89572997; Fax: +44 20 89572717; E-mail: [email protected]
© 2014 John Wiley & Sons Ltd International Journal of Immunogenetics, 2014, 41, 457–462
The potential uses for NGS are vast, due to its ability to rapidly sequence large regions of a genome at relatively low cost, when compared to conventional Sanger sequencing (Zhang et al., 2011). The technology is continually evolving and improving, considered by many to be driven by the race towards the $1000 genome (Hayden, 2014). However, this technological advancement brings with it many challenges, not least from an ethical position.
Clinical use of NGS The use of NGS for clinical purposes was first reported towards the end of the last decade and includes applications such as the diagnosis of inherited disorders, investigation of complex disease and assisting in treatment protocols for cancer by tumour profiling (Ayuso et al., 2013). Future routine uses are predicted to include pharmacogenetics and tissue matching (Wright et al., 2011). Indeed, HLA typing using NGS is already being explored by a number of institutions (Gabriel et al., 2014). Some of the ethical issues around NGS are not new and apply equally to testing by conventional methods for the clinical diagnosis of genetic disorders (van El et al., 2013). Generally, clinical investigation of suspected genetic disease involves ‘phenotype to genotype’ testing, where a patient’s clinical presentation initiates gene analysis to determine the cause (Facio et al., 2012). This may involve a targeted approach to sequencing, where a specific region of the genome is interrogated to identify genetic variants that produce the phenotype under investigation. Alternatively, a wider search for mutations may be performed using whole genome sequencing (WGS) or whole exome sequencing (WES), which has the advantage of defining all mutations, reducing the need for multiple tests when the initial investigations prove uninformative (Ayuso et al., 2013). Utilizing an untargeted approach has been shown to be clinically informative. For example, a group in Manchester reported the impact of using NGS for the investigation of inherited forms of blindness. Their study included a patient whose atypical presentation of retinal degeneration was found to be caused by multiple mutations of a gene not normally associated with the disorder, resulting in an
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alternative diagnosis (O’Sullivan et al., 2012). However, scrutiny of larger portions of the genome is likely to require time consuming analysis and may lead to an increase of unexpected findings (van El et al., 2013).
Incidental findings Unexpected variants may not be related to the phenotype under investigation but still have potential significance for the patient. These so-called incidental findings (IF) are more likely with the advent of NGS and WGS; as well as risks for diseases with incomplete penetrance or late onset, 3–5 deleterious recessive genes are carried by the average person (Facio et al., 2012). How to deal with these IF is a topic of much debate. There are several approaches that can be taken by the clinician in response to IF, ranging from full disclosure through to withholding any information over and above the results from the expected findings. Ayuso et al. argue that any findings with clinical use related to the current diagnosis affecting either the patient or their offspring must always be disclosed (Ayuso et al., 2013). However, Townsend and colleagues felt this view was ‘paternalistic’ and contrary to both the current trend towards increased patient autonomy and to the European Convention on Human Rights and Biomedicine. They maintain the right ‘not to know’ cannot be presumed and must be offered and activated by the patient’s explicit choice (Townsend et al., 2014). The counter argument is that, when a patient has agreed to undergo such testing, it would be ethically unacceptable not to use the results clinically, considering both the time taken to perform the investigations and associated costs (Ayuso et al., 2014). How to deal with IF unrelated to the current condition is perhaps less clear. The clinician will need to assess the potential benefits of disclosing the additional findings against possible risks and is likely to depend on the seriousness of the finding and whether prevention or treatment is available. Prior knowledge of the patient and their wishes must also be considered, although duties of beneficence and non-maleficence may result in the doctor overriding a patient’s preference (Hall et al., 2013). As well as health-related concerns, possible negative consequences for the patient with regard to their employment and health or life insurance need to be considered (van El et al., 2013). However, according to the Concordat and Moratorium on Genetics and Insurance, individuals are only required to disclose results from predictive genetic testing when a very restrictive set of criteria apply (HM Government & Association of British Insurers, 2011). Likewise, individuals should take some comfort from protection offered by the Equality Act 2010, although it does not refer to discrimination against genetic disorders per se, unlike the US Genetic Information Nondiscrimination Act. It is important to consider that as
well as the impact on the patient, this type of information may also affect family relationships (Bredenoord et al., 2011). Research suggests that patients sometimes struggle passing on genetic information, when deciding who to tell, what to disclose, how and when; family relationships and communication can be complex (Wiens et al., 2013). Berg et al. proposed categorizing IF into ‘bins’ with a ‘scalable approach’ to their disclosure. The three bins suggested were (i) findings deemed to be ‘clinically actionable’; (ii) those considered ‘clinically valid but not directly actionable’; and (iii) IF of ‘unknown or of no clinical significance’, with each bin including a number of subcategories. It was postulated that this approach may assist the patient and clinician when discussing potential outcomes of tests and options available for disclosing subsequent results (Berg et al., 2011). Both the American College of Medical Genetics and Genomics (ACMG) and the European Society of Human Genetics (ESHG) have recently published recommendations for the reporting of IF as a result of WGS and WES in the clinical setting. The ACMG indicates that the clinician should be responsible for ensuring that comprehensive counselling is offered to the patient both before and after testing, alerting patients to the possibility of IF (Green et al., 2013). The ESHG suggests the use of targeted sequencing or analysis is preferable wherever possible to avoid IF, but indicated that a protocol is required for reporting unsolicited genetic variants when the use of WGS is being considered. They also suggested a need for developing guidelines for informed consent to utilize such techniques (van El et al., 2013). Following a systematic review, Ayuso et al. (2013) have recently published recommendations for the essential information to be included in the informed consent form for the clinical utilization of WGS.
NGS and prenatal genetic diagnosis Recent developments in the ability to test cell-free foetal DNA (cffDNA) for genetic abnormalities may also exploited by NGS. Although only very restricted use of cffDNA for prenatal diagnosis has so far been approved by the American College of Obstetricians and Gynaecologists (Dickens, 2014), it has been demonstrated that obtaining a foetal genome from maternal plasma is possible (Lo et al., 2010). There is concern that the non-invasive nature of cffDNA testing, compared to conventional prenatal testing using amniocentesis or chorionic villus sampling, will result in a higher take-up of antenatal testing. In addition, the potential for foetal WGS with its implications for detecting a wide spectrum of genetic disorders, as well as use for non medical reasons, raises ethical concerns that require discussion (Lo, 2013). An alternative to prenatal testing for genetic disorders is the use of premarital testing and genetic screening. In countries such as Saudi Arabia, couples are
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offered premarital health counselling with the aim to reduce the burden of inherited disease. Counselling is considered particularly important when therapeutic abortion is not tolerated due to religious or cultural reasons (Ibrahim et al., 2013). It is possible that in the future, this type of premarital screening will include NGS technology (Rodriguez-Flores et al., 2014), although all the ethical considerations regarding disclosure of IF will still apply.
NGS in a research setting The use of NGS for clinical purposes is not without controversy but there are clear responsibilities of the clinician for the patient’s welfare and best interests (Hall et al., 2013). In a research setting, disclosure of findings is less clear. Should any genetic data be disclosed, and if so what and by whom? Stjernschantz Forsberg et al. argue that neither anticipated nor IF from biobank research should be returned. They suggest that use of leftover samples for ethically approved research ‘does not come with a duty of beneficence toward specific individuals’ but rather that patients ‘have a duty to contribute to healthcare (by accepting that leftover tissue samples are used explicitly for research)’ (Stjernschantz Forsberg et al., 2010). Rather than using ‘leftover’ samples, the UK Biobank has recruited 500 000 individuals who provided blood, urine and saliva samples specifically for research purposes. However, according to the UK Biobank Ethics and Governance Framework, these participants will also not receive any information about their own results, despite providing detailed personal information and agreeing to have their health monitored. Instead, overall findings will be made available to both ‘participants and the wider community’. The explanation for this policy is that whilst in principle it would be possible to provide results to the research participant (RP), the value of such feedback would be questionable when outside the clinical setting and may be potentially harmful in the absence of appropriate counselling and support (UK Biobank, 2007). Bredenoord et al. performed a literature review of the debate surrounding disclosure of findings from a variety of NGS-based research, ranging from familybased single-gene studies to WGS, biobank research and genome-wide association studies. They comment that such variety of investigations and RPs, which may include both patients and healthy individuals, adds to the complexity of the question of whether to disclose or not (Bredenoord et al., 2011). Disclosure of research results on an ‘aggregate level’ is generally not disputed (Bredenoord et al., 2011). Indeed, the Department of Health’s (DOH, 2005) Research Governance Framework for Health and Social Care stipulates that, once established, findings must be made available to RPs and to those likely to benefit from them. However, there is less agreement
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on whether individual RP should receive feedback on their own genetic data (Bredenoord et al., 2011). In an anonymized study, this should not be possible, although it has been argued that true anonymity is unfeasible in a study of this nature. Bohannon reported that researchers were able to guess the identities of DNA donors by applying an algorithm to genomes from a database and the use of genealogy websites, which raises concerns about genetic data security (Bohannon, 2013). Anonymous studies would also deny researchers valuable clinical data that would be required for genotype to phenotype research hypotheses often tested by NGS (Facio et al., 2012; Black et al., 2013). Where it is possible to identify a RP, the question might be whether disclosure should be active or passive, that is at the specific request of the RP (Bredenoord et al., 2011). Participants do have a right to know information held about them, in accordance with the Data Protection Act 2010, and researchers would therefore be legally bound to provide such information on request. However, providing results to all participants, particularly in large studies, may be logistically difficult and prohibitively expensive. Black et al. suggest the need for a funding mechanism in support of disclosure protocols in biobank research, particularly if disclosure is required by law. Estimated costs and management of disclosure could be incorporated into grant applications to ensure appropriate funding was made available (Black et al., 2013). Bredenoord et al. (2011), argue that disclosure, particularly for very large studies, would put an ‘untenable burden on research infrastructure’, requiring trained personnel to impart such data; most researchers will not have the skills required to communicate to the participant. Even if the profession could support the increase in demand, genetic counsellors may not be the most appropriate communicators in some instances, for example in the case of ex-paternity (Black et al., 2013). An added encumbrance for biobank research, in particular, could be the commitment to disclosure many years after enrolment to the study (Bredenoord et al., 2011). It is important to consider the validity of any findings obtained in a research environment; confirmatory testing or further investigation may be required from an accredited laboratory as a result of an IF in genetic research. This is likely to have financial implications for further study if not financed from clinical budgets (Bredenoord et al., 2011). In the current economic climate, priorities have to be given to genetic testing even within the clinical setting to where there is a demonstrable health-related need; not all genetic tests can be funded (Rogowski et al., 2014). The alternative of funding by the RPs themselves could lead to inequities on the basis of those who are able to afford this service (Bredenoord et al., 2011). Once a decision has been made to feedback data, the scope of disclosure must be considered. An argu-
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ment in favour of limiting genetic research results returned to RP to only life saving information is that disclosure ‘promotes therapeutic misconception’ and may risk researchers over stating the benefits of participation (Bredenoord et al., 2011). Townsend and Cox investigated the reasons why people participated in health research. Motivation to participate in the studies appeared mainly to access health information or health services. Twenty-five of the 39 participants took part in respective research for health gains due to their own chronic disease or because they considered the study as a means to monitor their own health and/or prevent the development of disease. Some also volunteered to participate to access services that were difficult to access or unavailable to them otherwise. This was despite the fact that RPs were aware that the main purpose of the research was to acquire new knowledge (Townsend & Cox, 2013). An ongoing collaborative ‘INTERVAL’ study, set up the NHSBT and the Universities of Cambridge and Oxford to study the frequency of blood donation by 50 000 blood donors, will also involve NGS to study the impact genes have on regulation of blood cells. The organizers are keen to point out to RP that there will be no direct benefit to them and, like UK Biobank, there are no plans to feedback any results from genetic tests (NHSBT, 2012a). This comes with the caveat that RP will be informed of results from bloodbased tests performed as part of the study that have an immediate impact on their healthcare, such as a high platelet count or presence of cells indicative of leukaemia (NHSBT, 2012b). Oxford Biobank, recruiting volunteers from the Oxfordshire area, has taken a slightly different approach indicating that, with the consent of the RP, key blood results and health indicators such as blood pressure will be disclosed to both them and their general practitioner (Oxford Biobank, 2013a). However, they also do not allow access to any genetic data generated from the RP’s samples (Oxford Biobank, 2013b). In complete contrast, the Personal Genome Project (PGP) not only provides the RP with all genetic data generated, but also makes this data publically available one month following disclosure to the RP (Personal Genome Project, 2014). However, as well as indicating the unlikelihood of any personal benefit from participation, PGP very clearly highlights the risks associated with such a disclosure policy. They point out that, albeit unlikely, publically available sequences might be used maliciously; for example, DNA could be synthesized and planted at a crime scene. Data might also accurately or inaccurately reveal a disease or trait or an enhanced risk of their development (Personal Genome Project, 2013). Such a revelation may be potentially harmful for the RP, with psychological consequences including stress and anxiety. John Laurerman gave a personal account of his experience when faced with the discovery that his own genome carried a variant linked to a myeloprolifera-
tive disorder, following sequencing by the PGP at Harvard University. He recounted the spectrum of emotions and uncertainty he felt before coming to terms with the results (Lauerman, 2012). The PGP also emphasizes other risks associated with full disclosure of genetic testing such as the potential for unexpected knowledge of genealogical characteristics including relationships or ancestry (Personal Genome Project, 2013). This may have particular significance for certain ethnic groups where findings may be contrary to their own history or myths (Bredenoord et al., 2011). Concerns have been raised that genetic research may exacerbate stigmatization and discrimination experienced by some ethnic groups in Africa, highlighting perceived differences used to promote ethnic conflict (Wright et al., 2013).
Informed consent for research The above discussion affirms the importance of obtaining informed consent in research studies, particularly when using NGS technology for WGS. The Declaration of Helsinki was developed by the Word Medical Association in 1964 (revised 2008), providing a statement of principles on which medical research involving human subjects, material or data should be founded. This underlies the 13 key principles of Good Clinical Practice, one of which refers to the need to obtain ‘freely given informed consent’ (Vijayananthan, 2008). Whilst these guidelines relate specifically to clinical trials, the principles have been adopted by the DOH Research Governance Framework for Health and Social Care, which provides governance for both clinical and non-clinical research (DOH, 2005). The concern with many studies using NGS and WGS, however, is whether fully informed consent is possible. Consent for biobank research is often what is termed ‘broad consent’; but Is this informed consent if the donor has not been given details of the specific research project(s) for which their sample will be used? The Human Tissue Authority advocate requesting generic consent for research to avoid the need for future consent, with the caveat that the consent is valid (Human Tissue Authority, 2014); a person needs to understand what is being done and aware of any associated risks. In 2006, Wendler analysed 30 studies reporting views of individuals on consent for research with their biological samples. He reported that most people endorse ‘one-time general consent’ for use of their samples for research and that there was no reason to believe they also want to decide what projects these samples are used for (Wendler, 2006). However, the risk exists that a RP discover they have been included in a study with which they strongly disagree. Therefore, research organizers, including biobanks, need to ensure an option for withdrawal exists (Helgesson, 2012). Whilst it might be possible to withdraw samples from future studies, Facio et al., argue that, when enrolling in ‘hypothesis-generating’ research, the
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RP needs to understand that it might lead to subsequent research projects, with ongoing communication and consent. They also indicate that RP who are uncomfortable with disclosure of results from such studies should ‘be encouraged to decline enrolment’ (Facio et al., 2012).
Summary Over the coming years, the use of NGS in both a clinical and a research environment is likely to expand significantly, particularly the use of WGS. It is apparent that further debate is required, including public engagement, to develop clear guidelines for both clinicians and researchers when developing protocols for consent from their respective patients and participants. Education of the public on the implications of genetic disclosure will also be important; it can be argued that qualified disclosure will facilitate this (Bredenoord et al., 2011).
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Green, R.C., Berg, J.S., Grody, W.W., Kalia, S.S., Korf, B.R., Martin, C.L. et al. (2013) ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genetics in Medicine, 15, 1. Hall, A., Hallowell, N. & Zimmern, R. (2013) Managing Incidental and Pertinent Findings from WGS in the 100,000 Genomes Project. PHG Foundation, Cambridge, UK. ISBN 978-1-907198-12-0 Hayden, E.C. (2014) Technology: the $1,000 genome. Nature, 507, 294. Helgesson, G. (2012) In defence of broad consent. Cambridge Quarterly of Healthcare Ethics, 21, 40. HM Government & Association of British Insurers (2011) Concordat and moratorium on genetics and insurance. https:// www.gov.uk/government/uploads/system/uploads/attachment_ data/file/216821/Concordat-and-Moratorium-on-Genetics-andInsurance-20111.pdf [Accessed on 11 December 2013]. Human Tissue Authority (2014) Code of Practice 1. Consent: The fundamental principles. http://www.hta.gov.uk/_db/ _documents/Code_of_practice_1_Consent.pdf [Accessed on 11 October 2014]. Ibrahim, N.K., Bashawri, J., Al Bar, H., Al Ahmadi, J., Al Bar, A., Qadi, M., Milaat, W. & Feda, H. (2013) Premarital screening and genetic counselling program: knowledge, attitude, and satisfaction of attendees of governmental outpatients clinics in Jeddah. Journal of Infection and Public Health, 6, 41. Lauerman, J. (2012) Harvard mapping my DNA turns scary as threatening gene emerges. Bloomberg. 15 February. http:// www.bloomberg.com/news/2012-02-15/harvard-mappingmy-dna-turns-scary-as-threatening-gene-emerges.html [Accessed on 10 December 2013]. Liu, L., Li, Y., Li, S., Hu, N., He, Y., Pong, R., Lin, D., Lu, L. & Law, M. (2012) Comparison of next-generation sequencing systems. Journal of Biomedicine and Biotechnology, 251364, 1. Lo, Y.M.D. (2013) Non-invasive prenatal testing using massively parallel sequencing of maternal plasma DNA: from molecular karyotyping to fetal whole-genome sequencing. Reproductive BioMedicine Online, 27, 593. Lo, Y.M.D., Chan, K.C., Sun, H., Chen, E.Z., Jiang, P., Lun, F.M. et al. (2010) Maternal plasma DNA sequencing reveals the genome-wide genetic and mutational profile of the fetus. Science Translational Medicine, 2, 61ra91. Metzker, M.L. (2010) Sequencing technologies – the next generation. Nature Reviews Genetics, 11, 31. NHSBT (2012a) A Study of Blood Donation Frequency: Information Leaflet. Available from: http://www.intervalstudy. org.uk/wp-content/blogs.dir/27/files/2012/04/INTERVAL_ STUDY-OF-BLOOD-FREQ_v8.pdf [14 October 2013]. NHSBT (2012b) INTERVAL Study Consent form (Study Copy). http://www.intervalstudy.org.uk/wp-content/blogs.dir/ 27/files/2011/11/Study-consent-V4.1-25.04.pdf [14 October 2013]. O’Sullivan, J., Mullaney, B.G., Bhaskar, S.S., Dickerson, J.E., Hall, G., O’Grady, A., Webster, A., Ramsden, S.C. & Black, G.C. (2012) A paradigm shift in the delivery of services for diagnosis of inherited retinal disease. Journal of Medical Genetics, 49, 322. Oxford Biobank (2013a) Oxford Biobank: Information Leaflet. http://www.oxfordbiobank.org.uk/wp-content/uploads/2012/ 06/OBB-Patient-Information-Sheet-Web-Version-1.1-25-92013.pdf [Accessed on 16 January 2014]. Oxford Biobank (2013b) Consent form: Oxford Biobank. http:// www.oxfordbiobank.org.uk/wp-content/uploads/2013/11/ OBB-consent-form-Version-1.1-25-9-2013.pdf [Accessed on 16 January 2014]. Personal Genome Project (2014) Informed Consent Form for Enrolment http://www.personalgenomes.org/static/docs/
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harvard/PGP_Consent_2014-02-18_online.pdf [Accessed on 1 February 2014]. Rodriguez-Flores, J.L., Fakhro, K., Hackett, N.R., Salit, J., Fuller, J., Agosto-Perez, F. et al. (2014) Exome sequencing identifies potential risk variants for Mendelian disorders at high prevalence in Qatar. Human Mutation, 35, 105. Rogowski, W.H., Grosse, S.D., Schmidtke, J. & Marckmann, G. (2014) Criteria for fairly allocating scare health-care resources to genetic tests: which matters most?. European Journal of Human Genetics, 22, 25. Stjernschantz Forsberg, J., Hansson, M.G. & Eriksson, S. (2010) Changing perspectives in biobank research: from individual rights to concerns about public health regarding the return of results. European Journal of Human Genetics, 17, 1544. Townsend, A. & Cox, S.M. (2013) Accessing health services through the back door: a qualitative interview study investigating reasons why people participate in health research in Canada. BMC Medical Ethics, 14, 40. Townsend, A., Rousseau, F., Friedman, J., Adam, S., Lohn, Z. & Birch, P. (2014) Autonomy and the patient’s right ‘not to know’ in clinical whole-genomic sequencing. European Journal of Human Genetics: EJHG, 22, 6. UK Biobank (2007) UK Biobank Ethics and Governance Framework v3.0 October 2007. http://www.ukbiobank.ac.uk/
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© 2014 John Wiley & Sons Ltd International Journal of Immunogenetics, 2014, 41, 457–462
doi: 10.1111/iji.12155
Next generation sequencing: considering the ethics S. Davey
Summary This review article discusses some of the ethical challenges posed by next generation sequencing (NGS), both in the clinical and research setting. Concerns such as how to deal with unexpected results apply equally to conventional techniques. However, these incidental findings are far more likely with the use of NGS and whole genome sequencing. Whilst the lines of responsibility are better defined in the clinical environment, disclosure of such findings in the research setting is less clear. Recruitment of volunteers for public biobank research, in particular, also raises questions regarding consent and confidentiality.
Introduction Next generation sequencing (NGS) is a revolution in sequencing technology, developed since the ‘first generation’ Sanger sequencing method which has dominated for decades (Metzker, 2010). Producing less than 3 mega bases a day, Sanger sequencing was fundamental to completing the human genome project; this project provided the impetus for the development of novel methods to increase the speed, accuracy and throughput of sequencing, whilst also reducing costs (Liu et al., 2012). Next generation sequencing is also known as massively parallel sequencing due to an adaptation of ‘shotgun sequencing’ used in Sanger technology. Genomic DNA is fragmented, and the short DNA templates generated are ligated to specific adapters and read randomly along the entire genome by NGS technologies. These short reads are subsequently assembled and aligned to a reference genome; the accuracy of sequencing is determined by the ‘coverage’, that is the number of times each base in any one position is represented and length of contiguous sequence (Zhang et al., 2011).
H&I Department, NHS Blood and Transplant, London, UK Received 28 June 2014; revised 17 August 2014; accepted 25 September 2014 Correspondence: Sue Davey, H&I Department, NHS Blood and Transplant, Charcot Road, London NW9 5BG, UK. Tel: +44 20 89572997; Fax: +44 20 89572717; E-mail: [email protected]
© 2014 John Wiley & Sons Ltd International Journal of Immunogenetics, 2014, 41, 457–462
The potential uses for NGS are vast, due to its ability to rapidly sequence large regions of a genome at relatively low cost, when compared to conventional Sanger sequencing (Zhang et al., 2011). The technology is continually evolving and improving, considered by many to be driven by the race towards the $1000 genome (Hayden, 2014). However, this technological advancement brings with it many challenges, not least from an ethical position.
Clinical use of NGS The use of NGS for clinical purposes was first reported towards the end of the last decade and includes applications such as the diagnosis of inherited disorders, investigation of complex disease and assisting in treatment protocols for cancer by tumour profiling (Ayuso et al., 2013). Future routine uses are predicted to include pharmacogenetics and tissue matching (Wright et al., 2011). Indeed, HLA typing using NGS is already being explored by a number of institutions (Gabriel et al., 2014). Some of the ethical issues around NGS are not new and apply equally to testing by conventional methods for the clinical diagnosis of genetic disorders (van El et al., 2013). Generally, clinical investigation of suspected genetic disease involves ‘phenotype to genotype’ testing, where a patient’s clinical presentation initiates gene analysis to determine the cause (Facio et al., 2012). This may involve a targeted approach to sequencing, where a specific region of the genome is interrogated to identify genetic variants that produce the phenotype under investigation. Alternatively, a wider search for mutations may be performed using whole genome sequencing (WGS) or whole exome sequencing (WES), which has the advantage of defining all mutations, reducing the need for multiple tests when the initial investigations prove uninformative (Ayuso et al., 2013). Utilizing an untargeted approach has been shown to be clinically informative. For example, a group in Manchester reported the impact of using NGS for the investigation of inherited forms of blindness. Their study included a patient whose atypical presentation of retinal degeneration was found to be caused by multiple mutations of a gene not normally associated with the disorder, resulting in an
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alternative diagnosis (O’Sullivan et al., 2012). However, scrutiny of larger portions of the genome is likely to require time consuming analysis and may lead to an increase of unexpected findings (van El et al., 2013).
Incidental findings Unexpected variants may not be related to the phenotype under investigation but still have potential significance for the patient. These so-called incidental findings (IF) are more likely with the advent of NGS and WGS; as well as risks for diseases with incomplete penetrance or late onset, 3–5 deleterious recessive genes are carried by the average person (Facio et al., 2012). How to deal with these IF is a topic of much debate. There are several approaches that can be taken by the clinician in response to IF, ranging from full disclosure through to withholding any information over and above the results from the expected findings. Ayuso et al. argue that any findings with clinical use related to the current diagnosis affecting either the patient or their offspring must always be disclosed (Ayuso et al., 2013). However, Townsend and colleagues felt this view was ‘paternalistic’ and contrary to both the current trend towards increased patient autonomy and to the European Convention on Human Rights and Biomedicine. They maintain the right ‘not to know’ cannot be presumed and must be offered and activated by the patient’s explicit choice (Townsend et al., 2014). The counter argument is that, when a patient has agreed to undergo such testing, it would be ethically unacceptable not to use the results clinically, considering both the time taken to perform the investigations and associated costs (Ayuso et al., 2014). How to deal with IF unrelated to the current condition is perhaps less clear. The clinician will need to assess the potential benefits of disclosing the additional findings against possible risks and is likely to depend on the seriousness of the finding and whether prevention or treatment is available. Prior knowledge of the patient and their wishes must also be considered, although duties of beneficence and non-maleficence may result in the doctor overriding a patient’s preference (Hall et al., 2013). As well as health-related concerns, possible negative consequences for the patient with regard to their employment and health or life insurance need to be considered (van El et al., 2013). However, according to the Concordat and Moratorium on Genetics and Insurance, individuals are only required to disclose results from predictive genetic testing when a very restrictive set of criteria apply (HM Government & Association of British Insurers, 2011). Likewise, individuals should take some comfort from protection offered by the Equality Act 2010, although it does not refer to discrimination against genetic disorders per se, unlike the US Genetic Information Nondiscrimination Act. It is important to consider that as
well as the impact on the patient, this type of information may also affect family relationships (Bredenoord et al., 2011). Research suggests that patients sometimes struggle passing on genetic information, when deciding who to tell, what to disclose, how and when; family relationships and communication can be complex (Wiens et al., 2013). Berg et al. proposed categorizing IF into ‘bins’ with a ‘scalable approach’ to their disclosure. The three bins suggested were (i) findings deemed to be ‘clinically actionable’; (ii) those considered ‘clinically valid but not directly actionable’; and (iii) IF of ‘unknown or of no clinical significance’, with each bin including a number of subcategories. It was postulated that this approach may assist the patient and clinician when discussing potential outcomes of tests and options available for disclosing subsequent results (Berg et al., 2011). Both the American College of Medical Genetics and Genomics (ACMG) and the European Society of Human Genetics (ESHG) have recently published recommendations for the reporting of IF as a result of WGS and WES in the clinical setting. The ACMG indicates that the clinician should be responsible for ensuring that comprehensive counselling is offered to the patient both before and after testing, alerting patients to the possibility of IF (Green et al., 2013). The ESHG suggests the use of targeted sequencing or analysis is preferable wherever possible to avoid IF, but indicated that a protocol is required for reporting unsolicited genetic variants when the use of WGS is being considered. They also suggested a need for developing guidelines for informed consent to utilize such techniques (van El et al., 2013). Following a systematic review, Ayuso et al. (2013) have recently published recommendations for the essential information to be included in the informed consent form for the clinical utilization of WGS.
NGS and prenatal genetic diagnosis Recent developments in the ability to test cell-free foetal DNA (cffDNA) for genetic abnormalities may also exploited by NGS. Although only very restricted use of cffDNA for prenatal diagnosis has so far been approved by the American College of Obstetricians and Gynaecologists (Dickens, 2014), it has been demonstrated that obtaining a foetal genome from maternal plasma is possible (Lo et al., 2010). There is concern that the non-invasive nature of cffDNA testing, compared to conventional prenatal testing using amniocentesis or chorionic villus sampling, will result in a higher take-up of antenatal testing. In addition, the potential for foetal WGS with its implications for detecting a wide spectrum of genetic disorders, as well as use for non medical reasons, raises ethical concerns that require discussion (Lo, 2013). An alternative to prenatal testing for genetic disorders is the use of premarital testing and genetic screening. In countries such as Saudi Arabia, couples are
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offered premarital health counselling with the aim to reduce the burden of inherited disease. Counselling is considered particularly important when therapeutic abortion is not tolerated due to religious or cultural reasons (Ibrahim et al., 2013). It is possible that in the future, this type of premarital screening will include NGS technology (Rodriguez-Flores et al., 2014), although all the ethical considerations regarding disclosure of IF will still apply.
NGS in a research setting The use of NGS for clinical purposes is not without controversy but there are clear responsibilities of the clinician for the patient’s welfare and best interests (Hall et al., 2013). In a research setting, disclosure of findings is less clear. Should any genetic data be disclosed, and if so what and by whom? Stjernschantz Forsberg et al. argue that neither anticipated nor IF from biobank research should be returned. They suggest that use of leftover samples for ethically approved research ‘does not come with a duty of beneficence toward specific individuals’ but rather that patients ‘have a duty to contribute to healthcare (by accepting that leftover tissue samples are used explicitly for research)’ (Stjernschantz Forsberg et al., 2010). Rather than using ‘leftover’ samples, the UK Biobank has recruited 500 000 individuals who provided blood, urine and saliva samples specifically for research purposes. However, according to the UK Biobank Ethics and Governance Framework, these participants will also not receive any information about their own results, despite providing detailed personal information and agreeing to have their health monitored. Instead, overall findings will be made available to both ‘participants and the wider community’. The explanation for this policy is that whilst in principle it would be possible to provide results to the research participant (RP), the value of such feedback would be questionable when outside the clinical setting and may be potentially harmful in the absence of appropriate counselling and support (UK Biobank, 2007). Bredenoord et al. performed a literature review of the debate surrounding disclosure of findings from a variety of NGS-based research, ranging from familybased single-gene studies to WGS, biobank research and genome-wide association studies. They comment that such variety of investigations and RPs, which may include both patients and healthy individuals, adds to the complexity of the question of whether to disclose or not (Bredenoord et al., 2011). Disclosure of research results on an ‘aggregate level’ is generally not disputed (Bredenoord et al., 2011). Indeed, the Department of Health’s (DOH, 2005) Research Governance Framework for Health and Social Care stipulates that, once established, findings must be made available to RPs and to those likely to benefit from them. However, there is less agreement
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on whether individual RP should receive feedback on their own genetic data (Bredenoord et al., 2011). In an anonymized study, this should not be possible, although it has been argued that true anonymity is unfeasible in a study of this nature. Bohannon reported that researchers were able to guess the identities of DNA donors by applying an algorithm to genomes from a database and the use of genealogy websites, which raises concerns about genetic data security (Bohannon, 2013). Anonymous studies would also deny researchers valuable clinical data that would be required for genotype to phenotype research hypotheses often tested by NGS (Facio et al., 2012; Black et al., 2013). Where it is possible to identify a RP, the question might be whether disclosure should be active or passive, that is at the specific request of the RP (Bredenoord et al., 2011). Participants do have a right to know information held about them, in accordance with the Data Protection Act 2010, and researchers would therefore be legally bound to provide such information on request. However, providing results to all participants, particularly in large studies, may be logistically difficult and prohibitively expensive. Black et al. suggest the need for a funding mechanism in support of disclosure protocols in biobank research, particularly if disclosure is required by law. Estimated costs and management of disclosure could be incorporated into grant applications to ensure appropriate funding was made available (Black et al., 2013). Bredenoord et al. (2011), argue that disclosure, particularly for very large studies, would put an ‘untenable burden on research infrastructure’, requiring trained personnel to impart such data; most researchers will not have the skills required to communicate to the participant. Even if the profession could support the increase in demand, genetic counsellors may not be the most appropriate communicators in some instances, for example in the case of ex-paternity (Black et al., 2013). An added encumbrance for biobank research, in particular, could be the commitment to disclosure many years after enrolment to the study (Bredenoord et al., 2011). It is important to consider the validity of any findings obtained in a research environment; confirmatory testing or further investigation may be required from an accredited laboratory as a result of an IF in genetic research. This is likely to have financial implications for further study if not financed from clinical budgets (Bredenoord et al., 2011). In the current economic climate, priorities have to be given to genetic testing even within the clinical setting to where there is a demonstrable health-related need; not all genetic tests can be funded (Rogowski et al., 2014). The alternative of funding by the RPs themselves could lead to inequities on the basis of those who are able to afford this service (Bredenoord et al., 2011). Once a decision has been made to feedback data, the scope of disclosure must be considered. An argu-
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ment in favour of limiting genetic research results returned to RP to only life saving information is that disclosure ‘promotes therapeutic misconception’ and may risk researchers over stating the benefits of participation (Bredenoord et al., 2011). Townsend and Cox investigated the reasons why people participated in health research. Motivation to participate in the studies appeared mainly to access health information or health services. Twenty-five of the 39 participants took part in respective research for health gains due to their own chronic disease or because they considered the study as a means to monitor their own health and/or prevent the development of disease. Some also volunteered to participate to access services that were difficult to access or unavailable to them otherwise. This was despite the fact that RPs were aware that the main purpose of the research was to acquire new knowledge (Townsend & Cox, 2013). An ongoing collaborative ‘INTERVAL’ study, set up the NHSBT and the Universities of Cambridge and Oxford to study the frequency of blood donation by 50 000 blood donors, will also involve NGS to study the impact genes have on regulation of blood cells. The organizers are keen to point out to RP that there will be no direct benefit to them and, like UK Biobank, there are no plans to feedback any results from genetic tests (NHSBT, 2012a). This comes with the caveat that RP will be informed of results from bloodbased tests performed as part of the study that have an immediate impact on their healthcare, such as a high platelet count or presence of cells indicative of leukaemia (NHSBT, 2012b). Oxford Biobank, recruiting volunteers from the Oxfordshire area, has taken a slightly different approach indicating that, with the consent of the RP, key blood results and health indicators such as blood pressure will be disclosed to both them and their general practitioner (Oxford Biobank, 2013a). However, they also do not allow access to any genetic data generated from the RP’s samples (Oxford Biobank, 2013b). In complete contrast, the Personal Genome Project (PGP) not only provides the RP with all genetic data generated, but also makes this data publically available one month following disclosure to the RP (Personal Genome Project, 2014). However, as well as indicating the unlikelihood of any personal benefit from participation, PGP very clearly highlights the risks associated with such a disclosure policy. They point out that, albeit unlikely, publically available sequences might be used maliciously; for example, DNA could be synthesized and planted at a crime scene. Data might also accurately or inaccurately reveal a disease or trait or an enhanced risk of their development (Personal Genome Project, 2013). Such a revelation may be potentially harmful for the RP, with psychological consequences including stress and anxiety. John Laurerman gave a personal account of his experience when faced with the discovery that his own genome carried a variant linked to a myeloprolifera-
tive disorder, following sequencing by the PGP at Harvard University. He recounted the spectrum of emotions and uncertainty he felt before coming to terms with the results (Lauerman, 2012). The PGP also emphasizes other risks associated with full disclosure of genetic testing such as the potential for unexpected knowledge of genealogical characteristics including relationships or ancestry (Personal Genome Project, 2013). This may have particular significance for certain ethnic groups where findings may be contrary to their own history or myths (Bredenoord et al., 2011). Concerns have been raised that genetic research may exacerbate stigmatization and discrimination experienced by some ethnic groups in Africa, highlighting perceived differences used to promote ethnic conflict (Wright et al., 2013).
Informed consent for research The above discussion affirms the importance of obtaining informed consent in research studies, particularly when using NGS technology for WGS. The Declaration of Helsinki was developed by the Word Medical Association in 1964 (revised 2008), providing a statement of principles on which medical research involving human subjects, material or data should be founded. This underlies the 13 key principles of Good Clinical Practice, one of which refers to the need to obtain ‘freely given informed consent’ (Vijayananthan, 2008). Whilst these guidelines relate specifically to clinical trials, the principles have been adopted by the DOH Research Governance Framework for Health and Social Care, which provides governance for both clinical and non-clinical research (DOH, 2005). The concern with many studies using NGS and WGS, however, is whether fully informed consent is possible. Consent for biobank research is often what is termed ‘broad consent’; but Is this informed consent if the donor has not been given details of the specific research project(s) for which their sample will be used? The Human Tissue Authority advocate requesting generic consent for research to avoid the need for future consent, with the caveat that the consent is valid (Human Tissue Authority, 2014); a person needs to understand what is being done and aware of any associated risks. In 2006, Wendler analysed 30 studies reporting views of individuals on consent for research with their biological samples. He reported that most people endorse ‘one-time general consent’ for use of their samples for research and that there was no reason to believe they also want to decide what projects these samples are used for (Wendler, 2006). However, the risk exists that a RP discover they have been included in a study with which they strongly disagree. Therefore, research organizers, including biobanks, need to ensure an option for withdrawal exists (Helgesson, 2012). Whilst it might be possible to withdraw samples from future studies, Facio et al., argue that, when enrolling in ‘hypothesis-generating’ research, the
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RP needs to understand that it might lead to subsequent research projects, with ongoing communication and consent. They also indicate that RP who are uncomfortable with disclosure of results from such studies should ‘be encouraged to decline enrolment’ (Facio et al., 2012).
Summary Over the coming years, the use of NGS in both a clinical and a research environment is likely to expand significantly, particularly the use of WGS. It is apparent that further debate is required, including public engagement, to develop clear guidelines for both clinicians and researchers when developing protocols for consent from their respective patients and participants. Education of the public on the implications of genetic disclosure will also be important; it can be argued that qualified disclosure will facilitate this (Bredenoord et al., 2011).
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