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Predictive and Precision Medicine with Genomic Data Clinical Chemistry 66:1 Q&A 33–41 (2020) Predictive and Precision Medicine with Genomic Data 1* Moderator: Linnea M. Baudhuin Downloaded from https://academic.oup.com/clinchem/article-abstract/66/1/33/5688834 by Brigham & Women's Hospital user on 21 January 2020 Experts: Leslie G. Biesecker,2 Wylie Burke,3 Eric D. Green,4 and Robert C. Green5,6,7 Genome and exome analyses have become instrumental in Biesecker). Each of us cur- establishing genetic diagnoses for critically ill newborns and rently has a major leader- in cases of previous diagnostic dilemmas. Genome and ex- ship role: one as the Direc- ome sequencing of presumably healthy individuals is now tor of NHGRI (E.D. gaining traction. The roll-out of genomic medicine to the Green) and one as the cur- generally healthy population offers a new opportunity to rent President of the Amer- provide insights into the current and future healthcare of ican Society of Human individuals and their families. Indeed, numerous projects Genetics (L.G. Biesecker). such as Geisinger’s MyCode Initiative, the National Hu- From these collective van- man Genome Research Institute (NHGRI)’s8 ClinSeq®, tage points, we have a and the various Genomes2People research projects at broad view of genomics Brigham Health and Harvard Medical School are investi- research and the imple- mentation of genomic medicine—a landscape that in- gating the use of genome sequencing for apparently healthy cludes developing technologies, understanding genome individuals. However, there are many scientific and ethical structure and function, identifying disease genes, imple- questions about the benefits, harms, and costs of this ap- menting genomic-based clinical tests, and designing pre- proach. Here, we explore the opportunities and challenges cision therapies on the basis of new genetic and of utilizing genomic data for predictive, precision, and per- genomic knowledge. Having started our medical and sonalized medicine with several experts in the field. research careers before the Human Genome Project, we both find ourselves in awe of the enormous ad- Please describe your involvement in genomic medicine. vances in genomics and genetics witnessed in our ca- Leslie Biesecker and Eric reers, including those leading to changes in medical Green: We are leaders in practice; these have exceeded what we would have pre- genetics and genomics re- dicted when we first became involved in the field. search, working at the NHGRI at the NIH for Wylie Burke: Iama over a quarter century. medical geneticist and aca- Our collective research ef- demic researcher. My work forts and expertise include focuses on the ethical and both the basic science of policy implications of the genomics [including par- use of genomics in medi- ticipation in the Human cine and public health. Genome Project (E.D. Green)] and translational genetics and genomics re- Robert Green: I am a medi- search (L.G. Biesecker). We are both medically cal geneticist who sees pa- trained: one as a clinical pathologist (E.D. Green) and tients and conducts research one as a pediatrician and medical geneticist (L.G. in preventive genomics. I 1 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN; 2 Chief * Address correspondence to this author at: Mayo Clinic, 200 First St. SW, Rochester, MN and Senior Investigator, Medical Genomics and Metabolic Genetics, National Human 55905. Fax 507-284-9758; e-mail [email protected]. Genome Research Institute, National Institutes of Health, Bethesda, MD; 3 Professor Received October 8, 2019; accepted October 24, 2019. Emeritus, Department of Bioethics and Humanities, University of Washington, Seattle, © 2019 American Association for Clinical Chemistry WA; 4 Director, National Human Genome Research Institute, National Institutes of 8 Nonstandard abbreviations: NHGRI, National Human Genome Research Institute; PRSs, Health, Bethesda, MD; 5 Professor, Harvard Medical School, Boston, MA; 6 Geneticist, polygenicriskscores;HbA1C,glycohemoglobin;SNP,single-nucleotidepolymorphism; Department of Medicine, Brigham and Women’s Hospital, Boston, MA; 7 Director, EHR, electronic health record; ClinGen, Clinical Genome. Genomes2People Research Program, Brigham and Women’s Hospital, Boston, MA. 33 Q&A have been fascinated with especially as it relates to presumably healthy the question of whether ge- individuals? netic information can be Wylie Burke: Current observations indicate that exome/ used to predict and prevent genome sequencing can sometimes resolve a diagnostic di- Downloaded from https://academic.oup.com/clinchem/article-abstract/66/1/33/5688834 by Brigham & Women's Hospital user on 21 January 2020 disease in a safe and cost- lemma for patients who have findings that do not allow a effective manner, and I am determined to try to answer specific diagnosis but are suggestive of a genetic disorder. In this question using experi- a public health context (that is, for screening in individuals mental methods and em- who are not known to have a genetic disorder), such testing pirical data. Although ethi- could identify rare individuals with treatable monogenic dis- cists have repeatedly drawn orders, such as Lynch syndrome. The risks cannot be fully attention to legitimate but determined because information about the outcomes of largely hypothetical concerns that patients and re- such testing is currently limited and does not involve long- search participants would experience great distress, term follow-up. However, it is clear that such testing gener- misunderstand their results, suffer mistreatment by ates many results of uncertain clinical significance and has the potential to provide misleading information about mul- uninformed physicians, and utilize excessive amounts tifactorial conditions. Studies document inconsistencies in of medical resources, we have pursued the answers to how different laboratories interpret variants, as well as in- these questions in rigorously designed, often random- stances of clinically significant variant reclassification. Vari- ized, controlled experimental trials. ant interpretation is more difficult in unselected populations Preventive genomics was first legitimized within (as opposed to patients with symptoms or a suggestive fam- mainstream medicine in 2013 when Les Biesecker and ily history) because we lack population-based data on the I co-led the ACMG (American College of Medical natural history and the range of penetrance for most Men- Genetics and Genomics) Working Group that recom- delian conditions. Overall, genome/exome sequencing cur- mended opportunistic screening of a minimum set of rently lacks the specificity that is traditionally required for genes. I am also helping design the return of unantic- tests used in screening programs. The risks to patients in- ipated findings in our Harvard Partners Biobank, in clude overdiagnosis, unnecessary medical follow-up, and re- the Google/Verily Baseline Project, and in the All of sulting iatrogenic harm, a “cascade effect” well documented Us Research Program. And having been recently in other areas of medical practice. As a result, the cost to awarded NIH funding, we will soon be returning un- patients and the healthcare system could be substantial. The anticipated genomic results to participants in 2 of the potential benefits of the use of exome/genome sequencing as world’s most iconic long-term epidemiology studies: a screening tool do not outweigh the considerable potential the predominantly European-American Framingham for risks and costs. Instead, more focused approaches to Heart Study and the all African-American Jackson genomic screening are needed. Heart Study. Our Genomes2People Research Program has led Robert Green: It is important when talking about both many of the first federally funded clinical trials to assess risks and benefits of sequencing healthy individuals to the medical, behavioral, and economic impact of ge- make distinctions between those that are more and less nomic sequencing in healthy adults (the MedSeq Proj- likely to occur, and to consider the spectrum of risks and ect), newborns (the BabySeq Project), the active duty benefits alongside other types of testing that we perform military (the MilSeq Project), and among healthy early in the practice of medicine. The field of genomic medi- adopters all over the world that have sought out elective cine has been unnecessarily hampered by “genetic excep- sequencing (the PeopleSeq Consortium). These studies tionalism” wherein we have applied one set of rules and all indicate that sequencing healthy individuals is less standards for genomic testing results and another set for risky, more informative, and less expensive than was pre- test results in other medical domains. For example, the viously thought. We have also recently established the field of radiology has been dealing with unanticipated world’s first Preventive Genomics Clinics at Brigham and findings in indication-based studies for decades and has Women’s Hospital, where healthy adults and children simply created a series of protocols to guide clinicians can have predispositional genome sequencing for risk as- within their specialty. Similarly, we screen adults for low- sessment and preventive care as a clinical service and then probability events in medicine all the time, because we elect to be followed longitudinally in a research protocol believe that surveillance and/or orthogonal testing can for health outcomes. result in health benefits. With this in mind, the potential risks of sequencing
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