Inside AJHG: A Chat with Elizabeth Wright

Posted By: Sara Cullinan, PhD, Deputy Editor, AJHG

Each month, the editors of The American Journal of Human Genetics interview an author of a recently published paper. This month we check in with Elizabeth Wright to discuss her paper ‘Practical and ethical considerations of using the results of personalized DNA ancestry tests with middle-school-aged learners’.

Elizabeth Wright, PhD
Elizabeth Wright (photo courtesy Dr. Wright)

AJHG: What prompted you to start working on this project?

Elizabeth: I could give you a long answer about being a former middle school science teacher and what drove me to get a PhD in Science Education, but simply put, I am committed to finding ways for each and every student to see themselves connected to science and each other, and supporting teachers in that work.

AJHG: What about this paper/project most excites you?

Elizabeth: I am equally thrilled and cautious about having adolescents use their own personal DNA to explore who they are genetically, genealogically/socioculturally, and intentionally. We are not all of one thing and none of another. We can use what we know about pieces of ourselves to imagine something new and amazing. We can reveal these pieces of ourselves to our families and friends and see how we are connected to each other and the grander tree of life.

AJHG: Thinking about the bigger picture, what implications do you see from this work for the larger human genetics community?

Elizabeth: In the previous question I mentioned a bit about what thrills me. I am cautious because the privacy issues surrounding over-the-counter, direct-to-consumer DNA testing are monumental, and ever-shifting. It is both exciting and nerve-wrecking to ask, and watch, young scholars to embark on this intellectual journey. The engagement and electricity in the classroom when young scientists encounter themselves in new and unique ways keeps me going.

AJHG: What advice do you have for trainees/young scientists?

Elizabeth: I think the most important thing I would say is: you belong here. You belong in science. Your voice, your experiences, your viewpoint are all incredibly important. If you feel left out or unwelcome, create your own community and persevere because you are going to change things.

AJHG: And for fun, tell us something about your life outside of the lab.

Elizabeth: I’m a Red Sox season ticket holder and I love the game of baseball. I’ve been to baseball games in 27 different MLB parks, and 3 AAA baseball parks. Also, I love Orangetheory Fitness! Base-Push-All Out, that’s good advice.

Elizabeth Wright, PhD, is a postdoctoral fellow in the Jablonski laboratory at Pennsylvania State University.

Inside AJHG: A Chat with Alan Beggs

Posted By: Sara Cullinan, PhD, Deputy Editor, AJHG

Each month, the editors of The American Journal of Human Genetics interview an author of a recently published paper. This month we check in with Alan Beggs to discuss his paper ‘Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project’.

Several members of the BabySeq research team
Several members of the BabySeq research team, including (L to R) Katie Dunn, Casie Genetti, Ingrid Holm, Alan Beggs, Robert Green, and Pankaj Agrawal. (courtesy of Dr. Beggs)

AJHG: What prompted you to start working on this project? 

Alan: It is well established that genomic sequencing of individuals with a likely genetic disease has clear and recognized benefits that easily outweigh the risks and costs.  However, we are just beginning to appreciate the potential benefits and costs of prospectively sequencing healthy individuals. There is a lot of hope around the prospects for disease prediction, presymptomatic diagnosis, carrier detection, pharmacogenomics and other potential benefits of genomic sequencing, and an equal amount of concern around the risks of misuse of genetic information, misinterpretation of probabilistic results or negative personal impacts such as anxiety, increased family stress or loss of trust that such information might engender.

The NIH Newborn Sequencing In Genomic medicine and public HealTh (NSIGHT) program was conceived to explore the implications, challenges, and opportunities of genomic sequencing in the newborn period. Together with our colleagues here in Boston, and in Houston, Robert Green and I designed the BabySeq Project to experimentally measure the medical, behavioral, and economic outcomes by prospectively sequencing both healthy and sick newborns and then following the consequences of returning results to them, their physicians and to their medical records.

AJHG: What about this paper/project most excites you? 

Alan: Although thousands of both healthy and sick individuals have undergone genomic sequencing by now, BabySeq represents one of the first prospective, randomized controlled trials of sequencing for which disease detection was not a primary goal. By enrolling newborn participants regardless of their medical status we can achieve one of the less biased comparisons within a human population. Although our sample size is modest, we were surprised to find in the sequencing arm that 9.4% of the infants, including ten of 127 healthy newborns, harbored what we considered to be a monogenic disease risk alleles, in other words, genetic variants that are predicted to cause disease using current best practices for determining disease-gene association and variant interpretation. Such a high rate of predicted genetic morbidity suggests either that we currently underestimate genetic contributions to common disorders such as heart disease or cancer, or that our variant predictions of pathogenicity or assumed disease gene penetrances are over estimated.

I think the randomized controlled aspect of this study is something else that excites me. It is providing an important opportunity for Amy McGuire and her team at Baylor to more rigorously assess the psychological and social implications of having genomic information at an early age. Funding permitting, we aim to follow the BabySeq families in both the sequenced and control arms well beyond the one-year follow-up surveys currently in progress, and I expect that we will be able to provide some hard data to address some of the concerns surrounding potential negative implications of learning genetic information.

AJHG: Thinking about the bigger picture, what implications do you see from this work for the larger human genetics community?

Alan: This is a difficult question to answer!  Of course, just about everyone who has interviewed me has asked whether I think sequencing of newborns will become standard of care. The first point I make is that, for the foreseeable future at least, we absolutely do not view this as a replacement for traditional newborn screening, which targets a carefully chosen group of treatable diseases using tests with well-established and high degrees of sensitivity and specificity.

There is no question in my mind that rapid genomic testing is indicated for newborns with undiagnosed medical conditions that may have a genetic basis, and it is gratifying to see that geneticists and neonatologists are rapidly adopting this, and that third part payers are finally starting to come around and reimburse for this. Although I’m confident the data will eventually show that the risks of newborn sequencing in healthy infants are acceptably low, the benefits will be harder to establish and are likely to be uneven: most newborns will not have immediately actionable findings, but identification of carrier states will occasionally lead to identification of couples at-risk for future pregnancies, and presymptomatic diagnosis of even untreatable conditions such as Duchene muscular dystrophy, will help some families avoid having affected children in the future. Occasionally, and with increasing frequency, an early diagnostic finding will lead to potentially life saving interventions or surveillance, as in the case of the families we identified with variants for hereditary cancer syndromes. As our understanding of disease-gene associations and variant interpretation improves, more and more children will stand to benefit from such information.

The newborn period is a hectic and disruptive time for new families, so I think genomic sequencing for healthy babies is more likely to be eventually offered in late infancy or early childhood, much like many vaccinations are offered today. Before this happens though, it will be up to us, the professional genetics community, to engage with our colleagues, legislators, third party payers, and most importantly the public, in a discussion to determine when the broader societal benefits justify the risk and the costs, and to ensure that genetic information is protected to avoid misuse and discrimination.

AJHG: What advice do you have for trainees/young scientists?

Alan: Follow your heart and pursue the questions that excite you, but be mentally flexible and look for opportunities to work with outstanding scientists who will appreciate and support your efforts. Early in my postdoctoral career, my advisor passed away suddenly and I was faced with a career-altering dilemma. I was fortunate to find an outstanding new mentor in Dr. Lou Kunkel, and my career path shifted abruptly to focus on neuromuscular disease, and eventually genetics and genomics of rare diseases.  Science, and society, are constantly evolving, so put aside your preconceived notions of what “should” or “will” happen, and follow the data and opportunities wherever they lead.

AJHG: And for fun, tell us something about your life outside of the lab.

Alan: I like learning about new things, so I tend to be a generalist with broad interests who enjoys tinkering and trying different things. I’m not an expert in any one area, but I’ve dabbled in woodworking, I like repairing broken things, from dishwashers to lawnmowers (YouTube is great for that!), and I’ve got a killer fish tank at home. I also love to be outdoors, and I’m just as happy raking leaves, cleaning my gutters, or shoveling snow in the middle of the night as I am kayaking or skiing.

A longtime ASHG member, Alan Beggs, PhD, is Director of The Manton Center for Orphan Disease Research at Boston Children’s Hospital and the Sir Edwin and Lady Manton Professor of Pediatrics at Harvard Medical School. 

How Companies Can Safeguard Consumer Genetic Data

Guest Post By: Carson Martinez, Future of Privacy Forum

Consumers’ interest in accessing their genetic information has boomed, as companies bring increasingly affordable consumer genetic and personal genomic testing services to market. With more testing services available than ever before, it is estimated that more than 12 million consumers have signed up in recent years to explore the insights that can be drawn from their genes.

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Carson Martinez, Future of Privacy Forum (courtesy Ms. Martinez).

With many of these genetic testing services, individuals can share their genetic data with academic researchers or pharmaceutical researchers, and after reviewing an informed consent notice on potential risks, many choose to participate. By providing the research community the ability to analyze significantly larger and more diverse range of genetic data, individuals have helped researchers discover important breakthroughs in biomedical research, healthcare, and personalized medicine.

If consumers are to safely share this information, the sensitive details revealed by genetic data need to be safeguarded by companies. Genetic data is one of the most intimate types of information, as it may be used to identify predispositions and potential risk for future medical conditions, and may reveal information about and even implicate an individual’s family members, including future generations. And as we have seen in recent cases like the Golden State Killer, it also can be used as a powerful investigative tool by law enforcement.

Although laws such as the Genetic Information Nondiscrimination Act of 2008 protect against discriminatory uses of genetic data by employers and health insurers, consumers also need to be certain that companies will respect the privacy of their genetic data and give them strong controls over how it is used and shared.

With this in mind, I and other speakers will be discussing the privacy of personal genetic information at the ASHG 2018 Policy Luncheon, taking place Thursday, October 18.

As a think tank focused on helping chief privacy officers navigate privacy challenges and incorporate ethical data practices, the Future of Privacy Forum (FPF) believes that emerging technologies like consumer genetic tests are valuable, but that protecting individual privacy is core to the success of any industry. In this nascent industry, there is a need for strong guidelines.

To that end, FPF together with 23andMe, Ancestry, Helix and other leading consumer genetic testing companies released Privacy Best Practices for Consumer Genetic Testing Services this summer to develop a policy framework for the collection, use, and sharing of consumer genetic data.

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Privacy best practices for consumer genetic testing services (Courtesy Ms. Martinez).

Incorporating input from a wide range of stakeholders including the Federal Trade Commission, genetics experts, and privacy and consumer advocates, the document:

  • sets forward consumer rights to access and delete their genetic data;
  • requires informed consent for sharing genetic data for research;
  • bans the sharing of genetic data with third parties (such as employers, insurance companies, and educational institutions) without express consent;
  • requires valid legal process for disclosing genetic data to law enforcement; and
  • requires notice and consent for material changes to the policy and transfer of ownership, among others.

The Best Practices is supported by: Ancestry, 23andMe, Helix, MyHeritage, Habit, African Ancestry, FamilyTreeDNA, and Living DNA.

Carson Martinez is a Health Policy Fellow at the Future of Privacy Forum and leads FPF’s Health Privacy Project. To learn more about the Best Practices, attend the Policy Luncheon at the ASHG 2018 Annual Meeting in San Diego.

FDA Takes Steps to Advance Genomics Technology, Encourage NGS-based Test Innovation

Guest Post: Laura M. Koontz, PhD, U.S. Food and Drug Administration 

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Laura M. Koontz, PhD, U.S. Food and Drug Administration (courtesy Dr. Koontz)

Genomics is advancing at an unprecedented pace, a fact that will come as no surprise to members of ASHG who work on the front lines of this exciting field. Over the past few years, the FDA has been working with stakeholders from across the genomics community, including ASHG, with the goal of applying our regulatory authorities to genomics in ways that encourage innovation and ensure that tests provide accurate and meaningful results to patients. Recently, we announced two new FDA Guidances on next generation sequencing (NGS)-based in vitro diagnostics that are intended to encourage further development of these powerful tests and enable more efficient regulatory review by FDA.

The first guidance, “Use of Public Human Genetic Variant Databases to Support Clinical Validity for Genetic and Genomic-Based In Vitro Diagnostics,” describes an approach where test developers may rely on clinical evidence from FDA-recognized public databases to support clinical claims for their tests and provide assurance of the accurate clinical evaluation of genomic test results. Using FDA-recognized databases will provide test developers with an efficient path for marketing clearance or approval of a new test. Further, FDA believes that this guidance will encourage crowdsourcing of NGS evidence generation, curation, and data sharing, advancing the development of high quality precision medicine treatments and diagnostics.

The second guidance, “Considerations for Design, Development, and Analytical Validation of Next Generation Sequencing (NGS)–Based In Vitro Diagnostics (IVDs) Intended to Aid in the Diagnosis of Suspected Germline Diseases,” discusses FDA’s considerations for analytical validation of NGS-based tests intended to help diagnose suspected germline diseases. The Agency believes the analytical validation recommendations laid out in this guidance could spur the creation of consensus standards for NGS-based tests that will be developed by the community and potentially recognized by FDA. Moreover, the guidance articulates FDA’s belief that NGS tests for germline diseases could potentially be classified in class II (moderate risk)  based on conformance to the recommendations in this guidance or to standards that address these recommendations, which would allow FDA to consider exempting them from premarket review.

The Agency believes these guidances will provide test developers with a more efficient path to market, improving FDA’s ability to protect public health by ensuring these tests provide accurate and meaningful results, while at the same time speeding patient access to NGS assays by lowering barriers to innovation. And importantly, the guidances will help to give patients, payers, researchers, and clinicians greater confidence that NGS platforms can reliably be used to inform critical treatment decisions and improve patient outcomes.

To learn more about these two guidances, please join the FDA for a webinar on Thursday, May 24, from 2:00-3:30 p.m. U.S. Eastern Time.

Laura Koontz, PhD, is a member of the Personalized Medicine Staff in the Center for Devices and Radiological Health at the U.S. Food and Drug Administration. She has a PhD in Molecular Biology and Genetics and was the 2012-2013 ASHG-NHGRI Genetics & Public Policy Fellow.

Following the Path of ASHG’s Statement on Pediatric Genetic Testing

Posted By: Cara Cavanaugh, MSc, Cell Press

What happens to a paper once it is published? After the research is over, the proofs are reviewed, and the paper is out in the world, how is it used and by whom?

To answer these questions, we traced the post-publication trajectory of ASHG’s position statement, “Points to Consider: Ethical, Legal, and Psychosocial Implications of Genetic Testing in Children and Adolescents.” The statement was published in The American Journal of Human Genetics (AJHG) in 2015 and was an update from two decades earlier. Following the history of the paper since its publication shows us the reach that an ASHG position statement can have over three years.

About the Position Statement

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Published in 2015, the statement has been cited by a variety of sources, including academic, legal, and public discourse.

The position statement gives recommendations for when and why families should decide to perform genetic tests on children and adolescents. “We felt that it was timely to update the statement across a range of issues,” says first author Jeffrey Botkin, MD, MPH, a professor and chief of the Division of Medical Ethics and Humanities at the University of Utah. “Our primary focus was genetically testing children for adult-onset conditions when there is no intervention during childhood. There hasn’t been a lot of research on the impact of such testing because folks felt that it was unethical under any context. We wanted to soften the perceived stance that such testing should never be conducted and have the position of the society be a little more flexible. We recognize that there may be circumstances when such testing might be appropriate for the child and family. We also wanted to encourage more research on these issues.”

Academic Citations and Public Conversation

Since its publication, the position statement is one of the top downloaded papers in AJHG’s history, with over 5,000 downloads as of 2018. After publication, to make the content more accessible to readers, ASHG created infographics that explain the issues and intricacy around childhood genetic testing. The paper has been cited by Genetics in Medicine, Pediatrics, Blood, Nature Reviews Genetics, and more than 80 other academic titles.

The statement has also been cited outside of the scientific research context. For example, it has impacted legal academic discourse. In one 2016 paper, Sénécal et al. discuss the legal approaches to healthcare decisions for minors in the European Journal of Human Genetics to the ASHG position statement as a “more nuanced approach” to how genetic testing should be pursued. They praise the statement for advising that physicians should inform families of all genetic testing options, even if the family has decided not to pursue any tests. Another paper by Otero in the European Journal of Health Law uses the position statement in a narrower context, specifically to analyze European and Spanish legal frameworks. These papers are just two of several examples of how one position statement from scientists can contribute to legal analysis internationally.

In addition to the academic studies discussed above, the position paper was also featured in the mainstream media. It gained coverage in NPR, VICE, and Pacific Standard. Exposure in these news sources helped engender public conversations online about the ethics of genetic testing in children.

What’s Next?

This paper shows the broad reach the ASHG community has in important societal and cultural issues of our time. As genetic testing appears more frequently in the news and becomes increasingly controversial, especially with products like direct-to-consumer genetic testing kits, it is imperative that we fully debate and consider how this could affect children and adolescents. ASHG policy statements, like the one published in 2015, provide us with long-lasting resources for continuing those discussions.

Cara Cavanaugh, MSc, is a Marketing Contractor at Cell Press. She earned a BA in History of Science from Princeton University and a MSc in Science Communication from Dublin City University while on a Fulbright Award.

Behind-the-Scenes: Developing the DNA Day Essay Question

Posted By: Evelyn Mantegani, BA, ASHG Education Coordinator

For teachers and students participating in the DNA Day Essay Contest, each year’s question seems to appear on the website out of thin air. While that would be simpler for us on the Question Committee, it wouldn’t be any fun.

20180118_DNAday-logoOur goal every year is to craft a challenging, thought-provoking, and current question. We often have a hard time narrowing down our choices because of our excitement for the potential answers from students, and turn to a variety of resources to help.

Soon after celebrating DNA Day on April 25, we launch into discussions for the next year’s question. This year’s Question Committee included myself, the rest of the Education Department, our former Genetics & Education Fellow Teresa Ramirez, and our former Executive Vice President Joe McInerney. First, we look over questions from previous years to determine what worked and what didn’t. We consider a question to be less successful if there are fewer submissions or it has a concept too difficult for students to grasp. We then look through a list of potential questions that has been built up in recent years. We pick our favorites, alter some, add on to others, and brainstorm new questions based on what is new in genetics. What follows is weeks of discussion about how to shape our top choices to be both challenging and accessible to high school-aged students around the globe.

This part of the process is often the most difficult, as we try to figure out how to get the wording perfect. When satisfied, we send three pilot questions to a group of teachers to vote and critique via survey. We ask questions like whether students would understand the question prompt and whether they would be interested in the question topic. Our pilot group of teachers are longtime contest participants who have submitted more than four essays each year over the past five years and are from public and private schools, as well as from various states and countries. Based on their vote, our 2018 question, which asks students to argue if consumers should or should not have direct access to predictive genetic testing, was chosen as the winner.

Now that we have finalized the question, we are excited to see the responses. I think this year’s question will be especially thought-provoking because direct-to-consumer genetic testing is becoming increasingly popular and accessible. And now, it’s on to the contest.

ASHG Members: If you would like to participate as a judge in this year’s essay contest, look out for a recruitment email in February. Please keep in mind that you must be a current ASHG member to judge DNA Day essays. If you have any questions, please email dnaday@ashg.org.

Students and Teachers: We are now accepting essay submissions via the DNA Day website. The deadline is March 9.

Evelyn Mantegani, BA, is Education Coordinator at ASHG. For more information on ASHG’s programs for K-12 students and teachers, visit the education website.

New CME Program: Cell-free DNA Testing

Posted by: Karen Hanson, ASHG Health Professional Education Programs Manager

ASHG is proud to announce our newest health professional educational program, “Prenatal cfDNA screening”. In response to rapid developments in prenatal cfDNA technology and concerns about its incorrect use, we developed this program to address a need for genetics education within the OB/GYN community, in collaboration with the Mayo Clinic and with help from colleagues from Kaiser Permanente California.

A needs assessment of this group suggested that their biggest challenges were communicating the fundamentals of prenatal cfDNA screening with patients and helping patients understand screening results. Based on these findings, the new program uses a case-based focus to model patient communication and review the basic science behind cfDNA technology, as well as discuss methods for incorporating this test into clinical practice. Our content was developed and reviewed by a team of experts in the field of prenatal care. The result is a program that includes three online education modules built around pre-test and post-test patient encounters, video case presentations using a standardized patient to demonstrate the integration of cfDNA screening into clinical practice, and point-of-care educational tools.

Above: Health Professional Education Programs Manager Karen Hanson describes ASHG’s genetics education programs for providers.

Similar to our previous educational programming for health professionals, our goal for “Prenatal cfDNA Screening” is to improve the practice of medicine and patient outcomes. We’re hoping that this program helps health professionals improve communication with their patients regarding prenatal screening options in general and prenatal cfDNA screening specifically. To encourage participation, this program is modular, so that each part can be viewed separately at one’s own pace. In addition, it is CME accredited through the Mayo Clinic College of Medicine and Science.

Karen Hanson, MS, MBA, CGC, is Health Professional Education Programs Manager at ASHG. Read more about ASHG’s educational programs for health professionals.