RESEARCH UPDATE CONTINUED made. Data from WES can be re-examined as new disease-gene discoveries are made, Dr. Eng adds, while panel testing cannot.
Taking Another Look Such re-examination of genomic data is crucial, says David Goldstein, PhD, Director of the Center for Human Genome Variation at Duke University in Durham, North Carolina. In addition to returning data on known pathogenic mutations for each individual patient, his lab notes suspicious gene mutations not seen in the general population and puts them on a watch list. If new medical literature identifies a mutation on the list as pathogenic, the lab does a subsequent review of that patient’s exome data. “Under no circumstances should you review negative exome data only once,” Dr. Goldstein says. “The pace of discovery is too rapid for a single analysis at one point in time to be sufficient.” An editorial accompanying the Baylor paper also raises the issue of findings with uncertain meaning. Those types of findings can be a major limitation on making a diagnosis using WES, writes Howard J. Jacob, PhD, Director of
Human and Molecular Genetics Center at the Medical College of Wisconsin in Milwaukee, which was among the first centers to offer clinical WES. “Any clinician who has received a clinical laboratory report from an exomesequencing laboratory will have noted that variants of unknown significance constitute the largest category of variants in many reports,” he notes [Jacob, 2013]. Both Dr. Jacob and the study paper’s authors note that many questions remain regarding the effect of WES-identified gene variants on clinical outcomes and the test’s cost-effectiveness, accuracy, yield, and integration into routine medical care. Answering these questions definitively would require an extremely complex prospective study involving a million variants per person and long-term followup periods, Dr. Jacobs adds. But, Dr. Goldstein and Heidi Rehm, PhD, Director, Laboratory for Molecular Medicine Partners Healthcare Center for Personalized Genetic Medicine in Cambridge, Massachusetts, are satisfied that the Baylor study shows WES has clinical value right now.
“Whole-exome sequencing has an impressive yield and can be a useful diagnostic tool that leads to improved understanding of disease and management of patients,” says Dr. Rehm. “As a geneticist, you see families who want to know what comes next. That’s easier to do with a diagnosis. For many patients, this test may get you there.” “Whole-exome sequencing is ready for deployment,” adds Dr. Goldstein. “There will be a whole lot more of it in the future, and it’s likely [that] most sequence data will be from clinical cases, not research.”
References Yang Y, Muzny DM, Reid JG, Bainbridge MN, Willis A, Ward PA, Braxton A, Beuten J, Xia F, Niu Z, Hardison M, Person R, Bekheirnia MR, Leduc MS, Kirby A, Pham P, Scull J, Wang M, Ding Y, Plon SE, Lupski JR, Beaudet AL, Gibbs RA, Eng CM. Clinical whole-exome sequencing for the diagnosis of Mendelian disorders. N Engl J Med 2013; 369:1502-1511. Jacob HJ. Next-generation sequencing for clinical diagnostics. N Engl J Med 2013; 369:1557-1558. DOI: 10.1002/ajmg.a.36385 2014 Wiley Periodicals, Inc.
SCREENING UPDATE WHO SHOULD CONTROL GENOMIC DATA? Researchers advocate putting patients in charge of their own results
I
ndividuals should select which genomic test results they want and change their preferences as they see fit, say genetic researchers at the University of Washington in Seattle. In a paper published in Genetics in Medicine, the authors advocate a major shift in how patients, research subjects, and healthcare providers think about data from genomic sequencing, and who should manage it. Rather than viewing data as test results to be returned and dispensed by healthcare providers and researchers, data should be regarded as a trove of information that patients can
x
access anytime, the researchers contend [Yu et al, 2013]. The authors view geneticists not as gatekeepers, but as professionals who translate and interpret genomic results patients may want to know at various times in their lives. For example, someone who has a risk variant for cystic fibrosis or breast cancer may not want this information as a teenager or young adult, but may feel differently as they get older, the paper points out. “It’s important to give people a choice,” says Holly Tabor, PhD, a coauthor of the paper and Assistant
Professor, Department of Pediatrics at the University of Washington. “They should be able to decide what they want according to values they hold at different points in time.”
Testing the Proposal The authors are testing their proposal with the website my46.org, developed at the University of Washington and named in reference to the 46 chromosomes in most human cells. The website, which is currently being used only for research purposes, allows patients and their families to indicate the particular genetic
Reaction “I think this paper is spot on,” says Misha Angrist, PhD, Assistant Professor of the Practice, Institute for Genome Sciences and Policy at Duke University in Durham, North Carolina. “Giving individuals access to information derived from their own bodies that they’ve subsidized with their tissue, time, and tax dollars seems the least one can do.” Dr. Angrist says returning results related to mutations that carry risk of treatable diseases is a good first step. “That said, the notion of what’s actionable is
fluid,” she adds. “Keeping up with those changes will require vigilance, resources, and a change in culture,” she adds. “There’s something to be said for sharing responsibility for stewardship of genomic data among researchers, physicians, and patients/ research participants.” “The Washington group should be congratulated Through websites such as my46.org, patients are able to learn for developing and testing about and manage their genomics testing results. these educational tools [on my46.org],” says Armand Antommaria, compelling and likely warrant patient– MD, PhD, Director of the Ethics Center provider interaction,” says Dr. Biesecker. at Cincinnati Children’s Hospital Medical “This tool is for the other 99.9% of Center (CCHMC) in Ohio. But low health findings.” He notes that ACMG guidelines literacy in the general population may were created in part to avoid situations in be a barrier to effectively implementing which providers would need to explain a the scenario described in the paper, Dr. vast amount of genetic data to patients. Tools like my46.org “could be useful Antommaria contends. “My sense from talking to members for those nonmedically compelling of the genetics community is that it takes results,” adds Dr. Biesecker. He finds the time and considerable effort to explain website and proposal exciting because they represent an alternative to face-togenome sequencing results,” he says. The proposal doesn’t address the face, patient–provider interactions, which complexity of decision making, especially he sees as an impractical time to discuss for children, adds Cindy Prows, MSN, the volume of information potentially Genetics Clinical Nurse Specialist in the revealed by genomic sequencing. Dr. Biesecker envisions that labs will Division of Human Genetics at CCHMC. She describes discussing genomic review genomic results for mutations sequencing with the hospital’s family from the ACMG list, and physicians will resource advocacy group. “Members had deliver worrisome results to patients in a hard time deciding what they would person. If there are none, patients can be want to know about themselves and many referred to a resource like my46.org, then couldn’t come to decisions about learning bring questions to a genetics professional. Although this approach may result in their kids’ adult-onset disorders,” Ms. patients burdening the healthcare system Prows recalls. with medically insignificant findings, Dr. Biesecker adds that it also “may Connection With ACMG Guidelines? The ACMG incidental findings guidelines, allow patients to focus and direct what’s which support returning test results important to them.” related to mutations that carry risk of treatable diseases, and the University of Reference Washington proposal aren’t necessarily Yu JH, Jamal SM, Tabor HK, Bamshad MJ. Selfguided management of exome and wholeat odds, says Leslie G. Biesecker, MD, the genome sequencing results: Changing the results guidelines’ senior author and Chief of return model. Gen Med 2013;15:684-690. the National Human Genome Research Institute’s Genetic Diseases Research DOI: 10.1002/ajmg.a.36386 2014 Wiley Periodicals, Inc. Branch in Bethesda, Maryland. “The guidelines refer to a tiny proportion of results that are medically LDprod | Shutterstock.com
test result they want, while offering healthcare providers more detailed, technical information. The portal also features short summaries of disorders associated with particular mutations in plain language and online educational resources for patients and families. Additionally, the website will offer some audio instruction in genetics to accompany written information, so that people can learn by both hearing and seeing, Dr. Tabor notes. “People can learn at home at their own pace,” she adds. “They can use online tools as long and as often as they want. That’s better than trying to put all the genetics education on the counselor.” Educational tools aren’t meant to replace genetic counselors, Dr. Tabor emphasizes, but they can lift the burden of basic explanations so counselors can focus on patients’ and families’ specific situations, she explains. The authors have assembled a cohort of 150 patients to study use of the website in various settings. To date, half of the patients have obtained genomic test results from the website, while the remainder received results from genetic counselors. The researchers will study how much patients understand, with whom they share information, and how the website can be improved. The researchers will also study how my46.org returns results from targeted clinical testing, and examine how the website can be used to share information relevant to particular types of tests and conditions, says Dr. Tabor.
xi
Taking Another Look Such re-examination of genomic data is crucial, says David Goldstein, PhD, Director of the Center for Human Genome Variation at Duke University in Durham, North Carolina. In addition to returning data on known pathogenic mutations for each individual patient, his lab notes suspicious gene mutations not seen in the general population and puts them on a watch list. If new medical literature identifies a mutation on the list as pathogenic, the lab does a subsequent review of that patient’s exome data. “Under no circumstances should you review negative exome data only once,” Dr. Goldstein says. “The pace of discovery is too rapid for a single analysis at one point in time to be sufficient.” An editorial accompanying the Baylor paper also raises the issue of findings with uncertain meaning. Those types of findings can be a major limitation on making a diagnosis using WES, writes Howard J. Jacob, PhD, Director of
Human and Molecular Genetics Center at the Medical College of Wisconsin in Milwaukee, which was among the first centers to offer clinical WES. “Any clinician who has received a clinical laboratory report from an exomesequencing laboratory will have noted that variants of unknown significance constitute the largest category of variants in many reports,” he notes [Jacob, 2013]. Both Dr. Jacob and the study paper’s authors note that many questions remain regarding the effect of WES-identified gene variants on clinical outcomes and the test’s cost-effectiveness, accuracy, yield, and integration into routine medical care. Answering these questions definitively would require an extremely complex prospective study involving a million variants per person and long-term followup periods, Dr. Jacobs adds. But, Dr. Goldstein and Heidi Rehm, PhD, Director, Laboratory for Molecular Medicine Partners Healthcare Center for Personalized Genetic Medicine in Cambridge, Massachusetts, are satisfied that the Baylor study shows WES has clinical value right now.
“Whole-exome sequencing has an impressive yield and can be a useful diagnostic tool that leads to improved understanding of disease and management of patients,” says Dr. Rehm. “As a geneticist, you see families who want to know what comes next. That’s easier to do with a diagnosis. For many patients, this test may get you there.” “Whole-exome sequencing is ready for deployment,” adds Dr. Goldstein. “There will be a whole lot more of it in the future, and it’s likely [that] most sequence data will be from clinical cases, not research.”
References Yang Y, Muzny DM, Reid JG, Bainbridge MN, Willis A, Ward PA, Braxton A, Beuten J, Xia F, Niu Z, Hardison M, Person R, Bekheirnia MR, Leduc MS, Kirby A, Pham P, Scull J, Wang M, Ding Y, Plon SE, Lupski JR, Beaudet AL, Gibbs RA, Eng CM. Clinical whole-exome sequencing for the diagnosis of Mendelian disorders. N Engl J Med 2013; 369:1502-1511. Jacob HJ. Next-generation sequencing for clinical diagnostics. N Engl J Med 2013; 369:1557-1558. DOI: 10.1002/ajmg.a.36385 2014 Wiley Periodicals, Inc.
SCREENING UPDATE WHO SHOULD CONTROL GENOMIC DATA? Researchers advocate putting patients in charge of their own results
I
ndividuals should select which genomic test results they want and change their preferences as they see fit, say genetic researchers at the University of Washington in Seattle. In a paper published in Genetics in Medicine, the authors advocate a major shift in how patients, research subjects, and healthcare providers think about data from genomic sequencing, and who should manage it. Rather than viewing data as test results to be returned and dispensed by healthcare providers and researchers, data should be regarded as a trove of information that patients can
x
access anytime, the researchers contend [Yu et al, 2013]. The authors view geneticists not as gatekeepers, but as professionals who translate and interpret genomic results patients may want to know at various times in their lives. For example, someone who has a risk variant for cystic fibrosis or breast cancer may not want this information as a teenager or young adult, but may feel differently as they get older, the paper points out. “It’s important to give people a choice,” says Holly Tabor, PhD, a coauthor of the paper and Assistant
Professor, Department of Pediatrics at the University of Washington. “They should be able to decide what they want according to values they hold at different points in time.”
Testing the Proposal The authors are testing their proposal with the website my46.org, developed at the University of Washington and named in reference to the 46 chromosomes in most human cells. The website, which is currently being used only for research purposes, allows patients and their families to indicate the particular genetic
Reaction “I think this paper is spot on,” says Misha Angrist, PhD, Assistant Professor of the Practice, Institute for Genome Sciences and Policy at Duke University in Durham, North Carolina. “Giving individuals access to information derived from their own bodies that they’ve subsidized with their tissue, time, and tax dollars seems the least one can do.” Dr. Angrist says returning results related to mutations that carry risk of treatable diseases is a good first step. “That said, the notion of what’s actionable is
fluid,” she adds. “Keeping up with those changes will require vigilance, resources, and a change in culture,” she adds. “There’s something to be said for sharing responsibility for stewardship of genomic data among researchers, physicians, and patients/ research participants.” “The Washington group should be congratulated Through websites such as my46.org, patients are able to learn for developing and testing about and manage their genomics testing results. these educational tools [on my46.org],” says Armand Antommaria, compelling and likely warrant patient– MD, PhD, Director of the Ethics Center provider interaction,” says Dr. Biesecker. at Cincinnati Children’s Hospital Medical “This tool is for the other 99.9% of Center (CCHMC) in Ohio. But low health findings.” He notes that ACMG guidelines literacy in the general population may were created in part to avoid situations in be a barrier to effectively implementing which providers would need to explain a the scenario described in the paper, Dr. vast amount of genetic data to patients. Tools like my46.org “could be useful Antommaria contends. “My sense from talking to members for those nonmedically compelling of the genetics community is that it takes results,” adds Dr. Biesecker. He finds the time and considerable effort to explain website and proposal exciting because they represent an alternative to face-togenome sequencing results,” he says. The proposal doesn’t address the face, patient–provider interactions, which complexity of decision making, especially he sees as an impractical time to discuss for children, adds Cindy Prows, MSN, the volume of information potentially Genetics Clinical Nurse Specialist in the revealed by genomic sequencing. Dr. Biesecker envisions that labs will Division of Human Genetics at CCHMC. She describes discussing genomic review genomic results for mutations sequencing with the hospital’s family from the ACMG list, and physicians will resource advocacy group. “Members had deliver worrisome results to patients in a hard time deciding what they would person. If there are none, patients can be want to know about themselves and many referred to a resource like my46.org, then couldn’t come to decisions about learning bring questions to a genetics professional. Although this approach may result in their kids’ adult-onset disorders,” Ms. patients burdening the healthcare system Prows recalls. with medically insignificant findings, Dr. Biesecker adds that it also “may Connection With ACMG Guidelines? The ACMG incidental findings guidelines, allow patients to focus and direct what’s which support returning test results important to them.” related to mutations that carry risk of treatable diseases, and the University of Reference Washington proposal aren’t necessarily Yu JH, Jamal SM, Tabor HK, Bamshad MJ. Selfguided management of exome and wholeat odds, says Leslie G. Biesecker, MD, the genome sequencing results: Changing the results guidelines’ senior author and Chief of return model. Gen Med 2013;15:684-690. the National Human Genome Research Institute’s Genetic Diseases Research DOI: 10.1002/ajmg.a.36386 2014 Wiley Periodicals, Inc. Branch in Bethesda, Maryland. “The guidelines refer to a tiny proportion of results that are medically LDprod | Shutterstock.com
test result they want, while offering healthcare providers more detailed, technical information. The portal also features short summaries of disorders associated with particular mutations in plain language and online educational resources for patients and families. Additionally, the website will offer some audio instruction in genetics to accompany written information, so that people can learn by both hearing and seeing, Dr. Tabor notes. “People can learn at home at their own pace,” she adds. “They can use online tools as long and as often as they want. That’s better than trying to put all the genetics education on the counselor.” Educational tools aren’t meant to replace genetic counselors, Dr. Tabor emphasizes, but they can lift the burden of basic explanations so counselors can focus on patients’ and families’ specific situations, she explains. The authors have assembled a cohort of 150 patients to study use of the website in various settings. To date, half of the patients have obtained genomic test results from the website, while the remainder received results from genetic counselors. The researchers will study how much patients understand, with whom they share information, and how the website can be improved. The researchers will also study how my46.org returns results from targeted clinical testing, and examine how the website can be used to share information relevant to particular types of tests and conditions, says Dr. Tabor.
xi
