Megan Allyse

Non-invasive prenatal testing: a review of international implementation and challenges

Noninvasive prenatal genetic testing (NIPT) is an advance in the detection of fetal chromosomal aneuploidies that analyzes cell-free fetal DNA in the blood of a pregnant woman. Since its introduction to clinical practice in Hong Kong in 2011, NIPT has quickly spread across the globe. While many professional societies currently recommend that NIPT be used as a screening method, not a diagnostic test, its high sensitivity (true positive rate) and specificity (true negative rate) make it an attractive alternative to the serum screens and invasive tests currently in use. Professional societies also recommend that NIPT be accompanied by genetic counseling so that families can make informed reproductive choices. If NIPT becomes more widely adopted, States will have to implement regulation and oversight to ensure it fits into existing legal frameworks, with particular attention to returning fetal sex information in areas where sex-based abortions are prevalent. Although there are additional challenges for NIPT uptake in the developing world, including the lack of health care professionals and infrastructure, the use of NIPT in low-resource settings could potentially reduce the need for skilled clinicians who perform invasive testing. Future advances in NIPT technology promise to expand the range of conditions that can be detected, including single gene disorders. With these advances come questions of how to handle incidental findings and variants of unknown significance. Moving forward, it is essential that all stakeholders have a voice in crafting policies to ensure the ethical and equitable use of NIPT across the world.

Not-so-incidental findings: the ACMG recommendations on the reporting of incidental findings in clinical whole genome and whole exome sequencing.

The issue of incidental findings in genomics research has been contentious, particularly in whole genome sequencing (WGS) and whole exome sequencing (WES). An incidental or secondary finding has generally been defined as ‘a finding concerning an individual research participant that has potential health or reproductive importance and is discovered in the course of conduct – but is beyond the aims of the study.’ [1]. However, as WGS and WES increasingly enter the clinical realm, these concerns are extended to individually relevant findings that are unrelated to the clinical purpose of sequencing. In May 2012, the American College of Medical Genetics and Genomics (ACMG) released a policy statement on Points to Consider in the Clinical Application of Genomic Sequencing in which they cautioned that ‘when interpreting secondary findings, or results that are generated in the course of screening asymptomatic individuals, it is critical that the standards for what is reportable be high to avoid burdening the health care system and consumers with what could be very large numbers of false positive results’ [2]. As a result, ACMG convened a working group to offer recommendations on handling incidental findings in clinical sequencing. The Working Group on Incidental Findings in Clinical Exome and Genome Sequencing of the ACMG (‘the Working Group’) published its Recommendations for Reporting of Incidental Findings in Clinical Exome and Genome Sequencing (‘the recommendations’) in March 2013 [3]. On the one hand, the recommendations take seriously the need to focus incidental findings on only those findings with clear clinical utility and actionable results. They provide a stringently curated list of specific variants that they believe rise to the level of clinical obligation to report. On the other hand, the zeal with which these variants were selected apparently encouraged the Working Group towards recommendations that depart significantly from existing practice and policy. First, they suggest that rather than reporting findings that are incidental to the purpose of the clinical sequencing as ordered, clinical sequencing laboratories have an obligation to seek out actively the variants as listed in the recommendations and include these findings in the clinical report. Second, they do not recommend considering patient preferences in reporting results. That is, all patients (or their guardians) should receive all recommended results whether they desire the information or not. This recommendation specifically includes sequencing on children. Although we support the desire of the Working Group to honor beneficence by providing patients with information that may affect their future health, we find these recommendations challenging from both an ethical and a practical perspective. Not only do they redefine incidental findings in a problematic manner, but the implication that individual autonomy should be over-ridden by physicians for the patient’s ‘own good’ is weakly supported in modern clinical ethics.

Cell‐free fetal DNA testing: a pilot study of obstetric healthcare provider attitudes toward clinical implementation

To provide a preliminary assessment of obstetric healthcare provider opinions surrounding implementation of cell‐free fetal DNA testing.

Noninvasive Prenatal Testing Goes Global

Noninvasive prenatal genetic testing is becoming available worldwide, but many practical and ethical challenges in the developing world should be considered. Noninvasive prenatal genetic testing is becoming available worldwide—particularly in low- and middle-income countries—but practical and ethical challenges must be overcome.

Best ethical practices for clinicians and laboratories in the provision of noninvasive prenatal testing.

The goal of this study is to provide an ethical framework for clinicians and companies providing noninvasive prenatal testing using cell‐free fetal DNA or whole fetal cells.

Attitudes towards non-invasive prenatal testing for aneuploidy among US adults of reproductive age

Objective:To determine how adults in the United States view non-invasive prenatal testing using cell-free fetal DNA (cffDNA testing) in order to help estimate uptake.Study Design:A national sample of 1861 US-based adults was surveyed using a validated online survey instrument. The survey was administered by a commercial survey research company. Respondents were randomized to receive a survey about prenatal testing for trisomy 13 and 18 or trisomy 21. Participants were asked to select among testing modalities, including cffDNA testing, and rank the features of testing that they considered most important to decision making.Result:There was substantive interest in the use of cffDNA testing rather than traditional screening mechanisms, with a minority of respondents reporting that they would support the use of both methods in combination. The lower rates of false-negative and false-positive test results and the ability to use the test earlier in the pregnancy were the most highly rated benefits of cffDNA testing. Participants expressed strong support for diagnostic confirmation via invasive testing after a positive result from either screening or cffDNA testing. However, almost one-third of participants reported that they would not endorse the use of either invasive or non-invasive prenatal testing.Conclusion:There appears to be support for uptake of non-invasive prenatal tests. Clinical guidelines should therefore go forward in providing guidance on how to integrate non-invasive methods into the current standard of care. However, our findings indicate that even when accuracy, which is rated by patients as the most important aspect of prenatal testing, is significantly improved over existing screening methods and testing is offered non-invasively, the number of individuals who reported that they would decline any testing remained the same. Attention should therefore be directed at ensuring that the right of informed refusal of prenatal testing is not impacted by new, non-invasive methods.

Cell-free fetal DNA testing for fetal aneuploidy and beyond: clinical integration challenges in the US context

The recent release of new, non-invasive prenatal tests for fetal aneuploidy using cell-free fetal DNA (cffDNA) has been hailed as a revolution in prenatal testing and has triggered significant commercial interest in the field. Ongoing research portends the arrival of a wide range of cffDNA tests. However, it is not yet clear how these tests will be integrated into well-established prenatal testing strategies in the USA, as the timing of such testing and the degree to which new non-invasive tests will supplement or replace existing screening and diagnostic tools remain uncertain. We argue that there is an urgent need for policy-makers, regulators and professional societies to provide guidance on the most efficient and ethical manner for such tests to be introduced into clinical practice in the USA.

Integrating stakeholder perspectives into the translation of cell-free fetal DNA testing for aneuploidy.

BackgroundThe translation of novel genomic technologies from bench to bedside enjoins the comprehensive consideration of the perspectives of all stakeholders who stand to influence, or be influenced by, the translational course. Non-invasive prenatal aneuploidy testing that utilizes cell-free fetal DNA (cffDNA) circulating in maternal blood is one example of an innovative technology that promises significant benefits for its intended end users; however, it is currently uncertain whether it will achieve widespread clinical implementation. We conducted qualitative interviews with 18 diverse stakeholders in this domain, including prospective users of the technology and healthcare personnel, researchers and developers, and experts in social, legal, and regulatory aspects of genetic technology, and a pilot survey of 62 obstetric healthcare providers. Analysis of interview and survey data was combined with a review of the proceedings of a full-day, multidisciplinary conference on the topic and published scientific and ethics literature surrounding this and other relevant technologies.DiscussionWe constructed potential pathways for technological implementation, identified broad stakeholder classes party to these translational processes, and performed a preliminary assessment of the viewpoints and interrelations among these diverse stakeholders. Some of the stakeholders whose priorities are critical to understand and integrate into translation include pregnant women and their families; healthcare providers; scientists, their institutions or companies, and the funding agencies that support them; regulatory and judicial bodies; third-party payers; professional societies; educational systems; disability rights communities; and other representatives from civil society. Stakeholder interviews, survey findings, and conference proceedings add complexity to these envisioned pathways and also demonstrate a paramount need to incorporate an iterative stakeholder analysis early and throughout the translational endeavor. We believe that the translational framework that we have developed will help guide crucial future stakeholder mapping and engagement activities for cffDNA aneuploidy testing and inform novel methods of technology assessment for other developments in the growing field of genomic medicine.SummaryMapping potential pathways for implementation and exploring the attitudes and interrelations of diverse stakeholders may lead to more effective translation of a novel method of prenatal aneuploidy testing.

Too much, too soon?: Commercial provision of noninvasive prenatal screening for subchromosomal abnormalities and beyond.

Too much, too soon?: Commercial provision of noninvasive prenatal screening for subchromosomal abnormalities and beyond

Translating cell-free fetal DNA technology: structural lessons from non-invasive RhD blood typing.

This work was supported by NIH grant P50 HG003389 (Center for Integrating Ethics and Genetic Research). Dr Cho is additionally supported by NIH grant 1 U54 RR024374-01A1 (Stanford Center for Clinical and Translational Education and Research).Disclaimer statementMary E. Norton is a principal investigator on clinical trial NCT0145167, sponsored by Ariosa Diagnostics. The other authors declare no competing interests.