3

Patient Care and Health Decisions

Important Points Highlighted by the Individual Speakers

  • Nurse practitioners, specialists, genetic counselors, social workers, and researchers compose a team that may be used to take a shared decision approach to genomic testing when gene panel results do not provide enough information to make a diagnosis.
  • Individual patient preferences, accessibility, coverage, and reimbursement are all taken into consideration when deciding whether to order genetic and genomic testing.
  • Taking a large gene-panel approach to sequencing may cost less than sequencing genes individually and provides an opportunity to collect more information faster; however, obtaining extra information that may not have clinical relevance can make clinical decision making more complicated.
  • Identifying a process for producing consistent, reliable, and easy to understand genetic and genomic testing reports will enable patients to have greater trust in the information and how it is used for disease diagnosis and treatment.
  • When little evidence exists for deciding when to obtain genetic or genomic data, a traditional approach of collecting family history and physical examination information can be used to inform the choice.


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3 Patient Care and Health Decisions Important Points Highlighted by the Individual Speakers • Nurse practitioners, specialists, genetic counselors, social work- ers, and researchers compose a team that may be used to take a shared decision approach to genomic testing when gene panel results do not provide enough information to make a diagnosis. • Individual patient preferences, accessibility, coverage, and re- imbursement are all taken into consideration when deciding whether to order genetic and genomic testing. • Taking a large gene-panel approach to sequencing may cost less than sequencing genes individually and provides an oppor- tunity to collect more information faster; however, obtaining extra information that may not have clinical relevance can make clinical decision making more complicated. • Identifying a process for producing consistent, reliable, and easy to understand genetic and genomic testing reports will en- able patients to have greater trust in the information and how it is used for disease diagnosis and treatment. • When little evidence exists for deciding when to obtain genetic or genomic data, a traditional approach of collecting family history and physical examination information can be used to inform the choice. 31

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32 GENOME SEQUENCE INFORMATION IN HEALTH CARE DECISIONS The clinic can be thought of as an interface where patients and clini- cians convene for discussing the use of using genomic information to inform clinical decisions, said Gregory Feero, research director at the Maine–Dartmouth Family Medicine Residency program. For example, he said, it can be difficult for both clinicians and the most informed pa- tients to sort through evidence related to genomic testing and to make decisions based on the available information. Feero asked the audience to consider that most patients will not be seen at large academic medical centers and that implementing these processes for evidence evaluation and making decisions about health could be even more challenging at smaller hospitals and clinics around the country. The accessibility of se- quencing technologies also depends on its coverage by health insurance companies and on the affordability of what is not covered, as patients are increasingly more responsible for paying for their health care. GENETIC TESTING IN A CARDIOLOGY CLINIC In her work as a nurse practitioner with a specialization in genetics, Kathleen Hickey, an assistant professor of nursing and a family/adult nurse practitioner in the Division of Cardiology at Columbia University, is usually the first member of the health care team to interact with patients and families who have inherited cardiac disease. Cardiomyopathy—a group of disease characterized by enlarged heart muscle that can weaken over time and pump blood less efficiently—can be inherited, as is the case with hypertrophic cardiomyopathy, for which 50 to 60 percent of pro- bands have a mutation in one of several genes involved in the sarcomere (Cirino and Ho, 2008). A team-based approach is beneficial to diagnosing and treating car- diomyopathy patients. For example, Hickey said, during a cardiology visit a patient may encounter team members who are collecting a three- generation pedigree, asking targeted questions to detect the signs and symptoms of genetic conditions, providing counseling and education, working to support the patient and the patient’s family, and monitoring treatment. Nurse practitioners can be part of that team. They can order tests, including electrocardiograms, echocardiograms, and genetic test- ing, within the scope of their practice. Nurse practitioners play a key role in helping individuals understand the complex language of genomics,

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PATIENT CARE AND HEALTH DECISIONS 33 Hickey said. “Nurse practitioners are often the ones to hear a lot of addi- tional details from patients, such as episodes where a patient passed out but did not think it was important enough to tell a physician.” In the Cardiac Electrophysiology Clinic at Columbia University Medical Center, clinical assessment findings inform decisions to order genetic testing for disease diagnosis. For example, a microarray panel for gene variants associated with hypertrophic obstructive cardiomyopathy would be ordered for a patient with echocardiogram findings of left ven- tricular hypertrophy along with reported episodes of syncope, or fainting. Other targeted panels (e.g., Brugada Syndrome or Long QT syndrome) are ordered for patients with characteristic changes on electrocardio- grams (e.g., a prolonged QT interval) and associated family histories. In Hickey’s current practice, targeted panels are preferred to whole-exome sequencing; however, next-generation sequencing is a future considera- tion, particularly in cases where targeted panels do not provide insight on a diagnosis. In one case, an otherwise healthy woman in her mid-20s suffered an out-of-hospital cardiac arrest despite having no family history of cardiac problems. The patient’s electrocardiogram, echocardiogram, and other test results were unremarkable, as was a genetic panel for sudden cardiac arrest arrhythmia. “She was young, she was planning her wedding, and she wanted answers as to why she had this cardiac arrest,” Hickey said. A “roundtable-type discussion” was held between the patient and her health care team, which consisted of a cardiac electrophysiologist, a ge- netic counselor, a social worker, and sometimes a basic scientist, and the decision was made jointly that whole-exome sequencing should be the next step. Whole-exome sequencing revealed a rare variant, and after database searches in the United States, Europe, and elsewhere, the team identified two other individuals with the same variant who were diag- nosed with idiopathic ventricular fibrillation. “That helped us in her care management,” Hickey said, and the patient underwent placement of an automatic internal cardiac defibrillator. GENETIC TESTING IN A CANCER CLINIC A large-scale project at the University of Michigan is sequencing tumor and germline dyads as part of the CSER consortium, said Jessica Everett, clinical instructor of internal medicine and a genetic counselor in the Cancer Genetics Clinic at the University of Michigan Comprehensive

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34 GENOME SEQUENCE INFORMATION IN HEALTH CARE DECISIONS Cancer Center. Cancer may seem to include a limited number of condi- tions, but in fact it is extremely complex, Everett said. Over the past 9 years at the University of Michigan Health System, almost 3,000 new patients have been seen with 21 different conditions in 15 different la- boratories, and 3,800 individual genetic tests have been performed, creat- ing a significant amount of data to sort through. Other CSER-funded projects include the Baylor College of Medicine’s BASIC3 or Baylor Advancing Sequencing into Childhood Cancer Care which explores the use of blood and tumor exome sequencing for newly diagnosed pediatric patients with solid tumors (Parsons et al., 2013). Next-generation sequencing, including the use of large gene panels, is “a game changer” with both positive and negative considerations for use in clinical practice, Everett said (Robson, 2014). Next-generation sequencing requires the evaluation of risks, benefits, and limitations for each patient. However, it can be less costly than previous approaches, because testing individual genes over time could cumulatively cost more than $25,000, while a large gene panel may cost about $5,000 total. An- other advantage of next-generation sequencing is that it can get results in much less time than a step-wise testing approach. “A panel gives you the ability to do everything faster,” Everett said. Furthermore, this large-scale approach can generate additional clini- cally useful information compared with earlier approaches. For example, a family could carry additional mutations or exhibit mosaicism, which next-generation sequencing can identify. This may be especially helpful for patients who are on a diagnostic odyssey. Other benefits of next-generation sequencing in cancer include the promise of expanded knowledge of phenotypes for a given mutation, bet- ter understanding of the clinical utility of lower penetrance or less stud- ied genes, and generation of data for research and discovery without added cost. Everett also described some of the limitations of using panels in can- cer genetics. Identifying mutations where clinical utility is unclear can complicate risk assessment and clinical recommendations. Furthermore, she said, data generated for research on a small scale needs to be shared in order to be useful to others. DECIDING WHEN TO USE LARGE-SCALE SEQUENCING Emory University’s Medical Genetics Clinic has about 1,500 visits per year, with about 30 new patients per week, said Michael Gambello,

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PATIENT CARE AND HEALTH DECISIONS 35 section chief of the Division of Medical Genetics at the Emory School of Medicine. About 85 percent of the patients in the Medical Genetics Clin- ic at Emory are pediatric, and 15 percent adult, and most of the clinic’s cases involve rare diseases. Indications include developmental delay, autism, and a family history of genetic disease. Typical questions asked by parents and patients include What’s wrong with my child or with me? What caused it? What can be done about it? More broadly, from a re- search perspective, the study of rare diseases can be thought of as a chance to implement tools and procedures that will later be used in appli- cations of genomic medicine to much larger populations, Gambello said. It is clear that whole-exome sequencing can help identify the genes involved in Mendelian disorders. For example, a particular genetic disor- der may involve so many genes that it is better to use a broad test (i.e., a microarray test panel) than one that focuses on just a few suspect genes. While large-scale sequencing can be used in this situation, there is little evidence to provide guidance on its first-time use in the clinic, Gambello said. He teaches his students that clinical reasoning and a targeted ap- proach is good medicine. “We do a family history, we do a physical ex- amination, and we make a differential diagnosis, which is the mainstay of medicine,” he said. “Then we decide what test is likely to make a di- agnosis.” In deciding whether to do large-scale sequencing, Gambello largely follows the ACMG guidelines (ACMG Board of Directors, 2012), which recommend such testing when: • A condition is likely genetic, but no specific genetic test is available. • A condition is a genetic disorder, but so many genes are involved that it is better to test many. • A condition is likely genetic, but targeted tests have not yielded a diagnosis. • A fetus likely has a genetic disorder, but targeted tests have not yielded a diagnosis. As an example, Gambello described a pediatric patient with a movement disorder that was likely genetic. Targeted tests did not yield a diagnosis, so the team decided to use whole-exome sequencing. The se- quencing results revealed a nonsense mutation in a novel gene called NGLY1. A group at Duke University had reported a patient with a similar variant a year earlier, and serendipity led to a connection with a Stanford

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36 GENOME SEQUENCE INFORMATION IN HEALTH CARE DECISIONS researcher, which resulted in a study of eight patients with NGLY1 defi- ciency, which affects an endoplasmic reticulum–associated degradation pathway and is associated with neurological dysfunction (Enns et al., 2014). “That certainly has ended the diagnostic odyssey for this family,” Gambello said. “Has it given us any insight into how to treat this disor- der? No, it hasn’t. But we have a lot of people thinking about this disor- der now, and maybe there will be treatment soon.” A PATIENT’S PERSPECTIVE Many questions surround the variants that are revealed—or, in some cases, not revealed—by next-generation sequencing. A basic question is what is known and how reliable that knowledge is. Neuroscientist Amy Hower described how she gained a better understanding of how patients comprehend and process information during a diagnostic odyssey when she and her parents underwent whole-exome sequencing to see if she could find the underlying cause of her cardiomyopathy with ventricular tachycardia after exhausting all other options. “The decision is not just about my health,” she said, “but if I want to have children, it could affect the life and the health of my children.” Surprisingly, Hower said, se- quencing turned up several candidate genes. However, because most of the variants were novel, they were not clearly actionable. “Because fur- ther functional testing would be needed in order to assign definitive cau- sation, . . . I am at the beginning of my search.” There were also limitations to how much Hower thought she could trust the information. For example, Hower knew through newborn screening that she has the most common variant for cystic fibrosis as a carrier, but that variant was not uncovered by sequencing. Sequencing can have trouble detecting insertions and deletions and clearly cannot find everything, Hower observed, but she was also told that the top three hits from her sequencing information would be Sanger confirmed, yet according to her laboratory report, only the first two were. When her ge- netic counselor checked with the laboratory, the lab said that all three were confirmed. “If the report was that wrong,” she asked, “then can I trust what was done?” The report also left Hower uncertain about how the top three hits were selected. Another concern was that it was difficult or impossible to interpret from the report itself some aspects of how the test was done. As a scien- tist, she was at an advantage compared to most patients, few of whom

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PATIENT CARE AND HEALTH DECISIONS 37 may be able to understand the report at this level, Hower acknowledged. The information contained in the report should be written as a material and methods section of a well-written peer-reviewed journal article, she suggested. There were other findings concerning Hower that were unreported, such as a frameshift or splice site mutation in a gene now known to be related to the disease. “A splice site mutation in a gene that is expressed in the heart, and expressed in the right pathways to possibly cause the problems that I have, would probably be . . . a better candidate than two of the three that I got back,” she said. But that information was not rou- tinely provided to her physician (although it could be requested), so it was more difficult to personally weigh in on that information, she said. Also unreported were unknown variants in known genes, the parameters for defining relevance, and the actual coverage of the sequencing. Additionally, in order for her physician to receive the raw data, Hower was asked to waive her rights to receive any raw data herself. Be- cause she did not agree with this approach, the wording of the consent was altered after discussion. DISCUSSING RESULTS WITH PATIENTS Concerning how and to what extent the results of next-generation sequencing should be discussed with patients, Hickey said that, in order to put genetic results in context, she and her colleagues try to relate the results to a patient’s condition and family history. Rather than relaying an entire panel of results gene by gene, they provide a general overview. In some cases, however, patients have done research, read the scientific literature, and want to know about detailed results, and for such patients the best approach may be to review the results of individual genes. “We try to make it very individualized,” she said. Everett noted that she has a tendency to group genes into bins when returning results to patients. She and her colleagues provide more infor- mation about genes known to be highly penetrant and less information about genes that may have less to do with cancer. She and her colleagues also tend to do less talking at the beginning and more talking later as pa- tients have more questions. Gambello pointed out that money is one of the reasons for talking less at the beginning. “Money is time, and we’ve not talked once about paying for all this genetic counseling,” he said. “That’s an issue that we

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38 GENOME SEQUENCE INFORMATION IN HEALTH CARE DECISIONS need to deal with, because we talk about spending all this time with these patients, and then, of course, none of our administrators want to pay for it. That’s something to consider.” Gambello also drew an analogy with prescribing pharmaceuticals, when physicians do not discuss with a pa- tient every single possible adverse effect of a drug. “In some respects, we are finding ourselves in a similar situation,” he said. “I don’t know what the answer is, but there are only so many hours in a day, and I think you have to do the best you can.” Hower reported that she was generally pleased with how the findings deemed most important by the laboratory were reported, despite her qualms about some aspects of that reporting. She added that she would not expect her physician to go through the results gene by gene. But she did say that she would like the results to be accessible, especially be- cause additional research may reveal a variant in a new light. Health Literacy Studies have shown that many patients have a relatively poor under- standing of cancer genomics (Pellegrini et al., 2012). For example, Everett said, among breast cancer patients at French cancer centers who were interviewed about treatment decision making, only 20 of 37 had some understanding or knowledge of genomic testing. Among these, half thought that genomic testing referred to or included constitutional or germline analysis, she said. Gambello agreed that patient understanding depends heavily on the level of education of the patient. Most patients do not ask the kinds of questions Hower described in her talk, he said, but some do. Gambello said that his patients tend to want all of the information generated in hope of coming to a diagnosis. Laboratory consent forms play an im- portant role in these interactions because they help with the delivery of results to patients and parents. In Gambello’s clinic, almost all of the pa- tients and parents have wanted the information, although he has not yet had to deal much with the return of incidental findings. Hickey’s practice serves the diverse population of New York City, and the patients in that practice have various levels of health literacy and come from a wide variety of socioeconomic backgrounds. Access to care is an overarching issue, as is health literacy as it applies to patients’ abil- ity to comprehend complex genetic information. “Most patients, in a pe- riod of about 30 minutes or so, are completely saturated with information that we’re providing,” she said. Patients receive a general information

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PATIENT CARE AND HEALTH DECISIONS 39 guide to take with them, available in both English and Spanish, which defines some general terms. Patients also have access to online resources. Patient Preferences It is difficult to elicit patient preferences about the disclosure of se- quencing results without biasing their responses about which genomic information they would like to receive, Everett said. “Our personal atti- tudes about whether or not we think that information is valuable almost certainly color our interactions.” One way to gauge the effects of these interactions would be to ask patients once information has been disclosed to them whether they would change their decisions in light of what they have learned. Additionally, Everett continued, the biggest distinction pa- tients seem to make in deciding how much information to receive is whether something can be done on the basis of a genetic finding. Con- sent forms are helpful, but often they do not provide any context for the decisions that need to be made. In that respect, patients who have experi- ence with a condition from someone else in their family have more back- ground than patients who do not. The University of Michigan project received CSER funding in 2013 to address these issues. Most people ad- just to the information they receive, Everett said. “They learn to cope with these diagnoses and work with them.” Even when people are given a prognosis that they are at increased risk of Alzheimer’s disease, they “do pretty well with that information,” she said. In their Michigan Oncology Sequencing Center project, Everett and her colleagues are studying patient preferences concerning the return of results (Roychowdhury et al., 2011). Cancer patients who have advanced or refractory disease and who are eligible for clinical trials will undergo whole-genome sequencing of their tumors and whole-exome sequencing of both tumor and germline DNA. The team takes a four-generation ped- igree and then discusses the sequencing of the cancer genome and the germline, including the reasons for doing both. The team also responds to patient questions about family history or the testing process, discusses consent for the return of results, and reviews a flexible informed consent default plan for return of results. Of the 167 patients who enrolled through April 2013, almost all of them said that they wanted to receive germline findings, Everett said. Slightly fewer people want the infor- mation in a pediatric context, a finding that needs more study. The findings from germline testing are separated into bins for disclo- sure, Everett said. Previously reported pathogenic mutations in high pen-

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40 GENOME SEQUENCE INFORMATION IN HEALTH CARE DECISIONS etrance cancer genes with known clinical utility are disclosed, while al- leles associated with low to moderate cancer risk with an evolving or unknown clinical utility are disclosed only on a case-by-case basis. Mu- tations associated with autosomal recessive conditions are not disclosed, with the exception that all germline findings relevant to the current can- cer are communicated. With support from a Robert Wood Johnson Foundation Nurse Facul- ty Scholar Award, Hickey and colleagues have studied more than 50 pa- tients to find out how they integrated information from cardiac genetic testing into their lives. Overall, they found a positive cardiac genetic di- agnosis did not negatively impact a patient’s well-being as self-reported through a quality-of-life measure (Hickey et al., 2014). Patient preferences are very important, Hower said. “For example, because a result could affect the health of my children, I need an answer within a time frame that would be useful for preconception considera- tion.” Patient preferences also factor into disclosure of information. “My opinion is, it’s the patient’s data, and it should be the patient’s choice,” she said. Furthermore, patients will need access to data if they change health care providers or specialists, if a laboratory goes out of business, or if updates to the data become available, Hower said. Insurance should not cover next-generation sequencing for someone who has no reason for getting it, Hower added. “If the patient preference doesn’t make sense, then the clinician should be free to say so.” Because the data belong to the patient, the patient should be able to decide whether to receive reports of incidental findings, Hower said. “For me personally, I wanted full disclosure because I think it could be useful for preventive care.” The ACMG recommendations support this position, though even more information with frequent updates and ex- pansions would be desirable, she said. With relatively few variants con- firmed through Sanger sequencing, a patient may have to pay for confirmation to be sure about a variant. Finally, a gene may be involved in more than one disease, and if a patient does not receive information about a gene, a secondary connection to a disease could be missed. Hower said that she has leaned toward permitting her genetic infor- mation to be shared, without too much concern over privacy and securi- ty. This is mainly, she said, because “I want an answer, and the more people I release this information to, the more likely I will be able to get useful data. And the more of us who put the data out there, the more use- ful it becomes.”

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PATIENT CARE AND HEALTH DECISIONS 41 Everett observed that many cancer genetics clinics are working with laboratories that may or may not decide to include their information in publicly available databases. Any decision to not share such data is un- fortunate because it is impossible to predict which information might prove critical in figuring out the answers to key questions. It is also important to take patient preferences into account, Hickey said. In her practice, patients participate in the decision making for their treatment, including whether to undergo an invasive therapy such as the implantation of an automatic internal cardiac defibrillator, whether to initiate drug therapies with possible severe adverse effects, whether to receive information on incidental findings, whether to conduct screening of other family members, and whether to join a support group. Other strategies for engaging participants in studies are developing such as dy- namic consent (Kaye et al., 2014). “Knowing our patients and presenting those options to them is critical,” said Hickey. REIMBURSEMENT CONSIDERATIONS Coverage and reimbursement by insurance is “certainly a considera- tion when ordering testing in the clinical setting,” Hickey said. (Reim- bursement issues are covered in more detail in Chapter 5.) For patients who are uninsured, Columbia University determines payment on a case- by-case basis. Targeted cardiac panels can cost more than $3,000 each, and whole-exome sequencing for an individual and two parents is about $9,000, she said. Gambello agreed that reimbursement definitely plays a role in order- ing genomic tests. Sixty percent of the Medical Genetics Clinic patients receive Medicaid, which does not reimburse for whole-exome sequenc- ing. Requests for the exome sequencing of inpatients for consultations are invariably reviewed by the pathology department before they are or- dered. If the tests are deemed to not be required for the acute care of a child’s admission, the requests will be denied. Because of this situation, discussions need to occur more often between the genetics and pathology departments about reasons to order large-scale sequencing, Gambello said. Patient out-of-pocket costs also factor into decisions about which test to order. In some cases, research funds are available to counteract financial limitations. For instance, it may be possible to refer patients to the Cen- ters for Mendelian Genomics at Baylor College of Medicine and Johns

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42 GENOME SEQUENCE INFORMATION IN HEALTH CARE DECISIONS Hopkins University School of Medicine to defray expenses. Waiting just a couple of years could allow prices to drop for whole-exome sequenc- ing. Occasionally, philanthropic support is available. “I have a lot of pa- tients that I would love to do an exome on, and we just don’t have the funding,” Gambello said. Reimbursement did play a role in ordering a whole-exome test, Hower said. She suggested that next-generation sequencing should be covered by insurance for diagnostic purposes, just as smaller or more targeted kinds of sequencing would be covered. “If it’s useful for your health and your life and even your offspring’s life and health,” she said, then it seems like it should be covered. Clinicians will need to continue to evaluate targeted versus large- scale sequencing while also taking into account financial considerations, patient understandings and needs, and evidence-based recommendations, Gambello said. “Most physicians don’t think like geneticists, so if we want these tests to eventually trickle down into general medicine clinics, there need to be evidence-based recommendations.”