7

The Future of Genomics in Precision Health Care

The final session of the workshop considered what genomics in health care will look like in the coming decades and how the field might get there (summarized in Box 7-1) and concluded with reflections on the highlights of each session presented by Christa Martin, chief scientific officer, Geisinger, and professor and director, Autism & Developmental Medical Institute (summarized in Box 7-2).

ACHIEVING WIDESPREAD ADOPTION OF GENOMICS IN CLINICAL CARE

David Ledbetter, professor, University of Florida College of Medicine-Jacksonville, and former chief scientific officer at Geisinger, highlighted possible actions to help achieve the vision of embedding genomics into clinical practice to advance the delivery of precision care.

Removing Key Obstacles

The Cost of Genome Sequencing

In the future, the cost of genome sequencing and analysis will become more affordable and have faster turnaround times for clinicians, Ledbetter said. Although talk of “the $100 to $200 genome” can dominate conversations, Ledbetter reminded participants the $200 genome announced by Illumina is essentially the list price of the reagents used. As discussed by Ashley (Chapter 2), the cost of sequencing a genome has decreased signifi-

cantly, but there are significant capital equipment costs and separate costs associated with analysis of the results that cannot be forgotten. A clinical diagnostic whole genome test still costs several thousand dollars today, Ledbetter said. Costs can be reduced with volume and batching, and he predicted that a whole genome sequence could be in the range of $500 in the coming years. A question for consideration, he said, is, “How cheap does it have to get?” He suggested comparing the value of a whole genome sequence, which would likely be done once in a person’s lifetime, to that of other medical testing such as magnetic resonance imaging.

Sequenced Once, Analyzed Repeatedly

Today, knowing which genetic test to order for a patient can be very complicated, and physicians often order a single gene test and/or a gene panel. “Genome sequencing will become the universal genetic test,” Ledbetter predicted. He suggested that, in the next 5 to 10 years, an individual’s genome will be sequenced once, via a single test with a single CPT code, and then it will be reanalyzed as needed. Whole genome sequencing can also overcome some of the shortcomings of other methods in detecting repeat expansion disorders, such as fragile X syndrome (Ibañez et al., 2022).

In addition, turnaround times for whole genome sequencing and analysis will be 24 to 72 hours, Ledbetter predicted. Historically, the lack of urgency by genetics professionals in returning genetic test results has been counterproductive, negatively affecting their clinical usefulness and clinicians’ perceptions of their value. For example, in the 1980s it took 6 weeks to receive the results of amniocentesis chromosome analysis, which Ledbetter described as an unnecessary delay. The work of Kingsmore and colleagues in returning whole genome sequencing results to the NICU in 50 hours has demonstrated the potential utility of whole genome sequencing for clinical care (Saunders et al., 2012).

Multiple Opportunities for Genome Sequencing

Genome sequencing will be done at various points across the life span, Ledbetter said. For example, whole genome sequencing can be done for preconception screening in place of expanded carrier screening of parents, and for prenatal screening, using cell-free DNA or fetal cells, he said. As one example, he noted a health system in Israel that is considering offering free whole genome sequencing to couples in a preconception setting as an incentive for delivering at their hospital instead of their competitors’ hospital. As another example, Ledbetter said that for many patients with cancer, it is now recommended that germline sequencing be done concurrently with tumor sequencing, and the sequences compared to aid with interpretation.

There are a variety of pilot programs launching to study the use of whole genome sequencing for newborn screening. Ledbetter mentioned the GUARDIAN program in the United States,¹ which is planning to enroll 100,000 newborns, and another program to be launched in 2023 by Genomics England that he said plans to sequence genomes for 100,000 newborns per year. As discussed above, the ability to rapidly return whole genome sequencing results for patients in the NICU has been demonstrated. Ledbetter said that whole genome sequencing for all undiagnosed disease patients in the NICU and pediatric intensive care unit could save lives and reduce the length of the patient’s hospital stay. In addition, Ledbetter said that some payers, including Geisinger, are now covering trio exome sequencing² as a more efficient alternative to chromosome microarray for patients with autism spectrum disorder and other pediatric neurodevelopmental disorders.

A question for the future is how often the interpretation of one’s genome should be updated (e.g., reinterpret variants, check against updates to the ClinVar database). Ledbetter suggested that a person’s annual physical exam could coincide with an annual genome checkup. An additional challenge for the future may be equity of access to genomic advances. One participant suggested that organic implementation could lead to more inequity in the health system because only those individuals who live near systems that have invested in genomics will have access. Ledbetter agreed that it will be a challenge, but he noted that the population primarily served by Geisinger is disadvantaged by multiple criteria (e.g., predominantly of low socioeconomic status with an increased incidence of health problems such as obesity and diabetes).

Current Missed Opportunities

Ledbetter highlighted two missed opportunities that are affecting efforts to implement and integrate genomics into clinical care.

Lost Genomes

Although trio genome sequencing is now being done (and reimbursed by many payers) for diagnosis of NICU patients and pediatric neurodevelopmental disorders, Ledbetter explained that “the parental genomes are just used for reference to interpret the variant of the child.” There is no further interpretation of the parental genomes, which he said could be used to inform parents of their own potential health risks or for pharmaco-

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¹ See https://guardian-study.org/ (accessed January 20, 2023).

² Trio exome sequencing is used to identify genetic alterations by sequencing not only the patient, but also their parents (Hebert et al., 2022).

genomics, for example. Further, he said the child’s genome is only used to address the acute diagnostic question. These “lost genomes” are not retained, or are stored and forgotten, when they could be made available for interpretation and to inform care throughout the life span of the child and the parents.

The United States Lags on Implementation

Although the development of genomic technology is advancing rapidly in the United States, the country lags far behind the UK in the implementation of genomics in care, Ledbetter said. For example, the UK NHS and Genomics England launched the 100,000 Genomes Project in 2013 to study the role of genes in rare diseases and cancer. In 2022, the UK NHS and the Our Future Health program announced a 5-million-participant clinical study of the role of polygenic risk scores in preventing common adult diseases. The UK NHS established Health Education England, Ledbetter noted, which is dedicated to health care workforce training, including educating clinicians about genomics.

Genomics England and other initiatives are evidence of the political will in the UK for the implementation of genomics in health care, Wordsworth said, and certainly having a single health care system helps. However, she added, the success can also be attributed to the significant support and effort from academics, clinicians, and others who are eager to see genomics implemented. “A lot of the work that has been done has been done in people’s spare time just to help the initiative move forward,” she said.

Ledbetter suggested that the roundtable could convene a workshop in London, inviting leaders of the UK NHS and the leadership of NIH, CMS, and the U.S. Department of Health and Human Services (HHS). He acknowledged that the United States and UK have very different payment systems but said that HHS needs to bring NIH and CMS together to discuss what evidence CMS needs NIH to generate to support CMS coverage of whole genome sequencing for the desired range of circumstances.

GENOMICS AT PROVIDENCE: A VISION FOR THE FUTURE

As an example of how organizations are looking to realize the promise of genomics in precision care, Amy Compton-Phillips, president and chief clinical officer at Press Gainey, presented an overview of the vision for genomics at Providence, a community-based health care organization.³

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³ Compton-Phillips was president of clinical care at Providence until September 2022, joining Press Gainey in October 2022, just prior to the workshop. She spoke from her experience at Providence.

Providence believes “Genomics can be a gateway to creating whole-person care and wellness by improving prevention, early diagnosis, and treatment,” she said. The goal at Providence is to accelerate the translation of evidence-based genomics from research to practice, embedding genomics innovation into patient care.

Pathways to Using Genomics in Clinical Practice

The Providence Genomics Lab was established in 2014, around the time that next-generation sequencing of tumors was beginning to be used to guide cancer treatment decisions. With philanthropic funding, Providence acquired Illumina sequencing instrumentation and has expanded over time to provide deep tumor sequencing services to all 52 Providence hospitals in multiple western U.S. states as part of its GenOmic Cancer Profiling program. A virtual tumor board was established to ensure that all clinicians were able to use the sequencing data provided to inform their treatment decisions.

Providence has been integrating genomic screening tools at the point of care where individuals would be most interested in being screened. For example, the CARE program uses online or phone-based surveys to identify women coming in for mammography who might also benefit from genetic testing for increased risk of breast cancer. Compton-Phillips said this program has been highly effective and has thus far identified about 60,000 women as high risk. Of those who were then sent for BRCA gene testing, about 26,000 were positive.

Providence is also expanding to provide liquid biopsy services using the Galleri multicancer early detection blood test. A study is under way to conduct 5,000 tests in the primary care setting. There are many questions to be answered before this approach can be widely implemented, Compton-Phillips said. For example, if a patient’s liquid biopsy indicates they are at risk for colon cancer, but they already had a colonoscopy last year, what actions should be taken (e.g., another colonoscopy, CT scan, or wait)?

Finally, Geno4ME is Providence’s whole genome sequencing program.⁴ The program launched targeting higher-risk populations with a focus on underrepresented populations, Compton-Phillips said. Currently over 2,000 people have been enrolled, about 48 percent of whom identify as a person of color or member of a minority group. A challenge now is returning contextualized information to participants’ primary care providers in a way that is actionable, such as embedding pharmacogenomics information into the EHR. Efforts are under way to launch EHR pharmacogenomics

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⁴ For more information on Geno4ME, see https://www.geno4me.org/en/home (accessed January 5, 2023).

decision support tools, and there is also a hotline number for providers or patients to speak with a medical geneticist.

“We really haven’t harnessed the capacity of the technology yet,” Compton-Phillips said. There are many hurdles to be addressed in adopting genomics into routine care, “but we’re not going to learn how to do it until we start,” she said.

Other Potential Considerations for the Future

Participants raised several other issues to be addressed as genomics is more broadly adopted in the coming years. Maxwell highlighted the need to ensure the necessary computing infrastructure is in place to both store the vast amounts of genomic data and to enable reanalysis. While an individual’s genome sequence is static, the interpretation is dynamic, and there must be capability to reanalyze genomes, she said. Providence is building the tools to support the future of genomics, Compton-Phillips said. Whole genome sequencing at Providence is currently being conducted as implementation research. There is a new tool that facilitates electronic enrollment of participants. A “dynamic e-consent platform” allows participants to select how their data can be used and to update their consent to use their data at any time in the future. Providence has partnered with Microsoft to develop structured data cloud storage that is indexed to enable genomic information to be requeried (Microsoft does not have access to participant data). Following on the comment by Ledbetter, Compton-Phillips said that Providence does requery the patient’s genome as part of their annual physical. She said Providence is hoping that providing cutting-edge genomics as part of primary care will differentiate them in the health care market.

What lessons, Feero asked, from these ongoing efforts to implement DNA sequencing in clinical care could be applied to facilitate more rapid uptake of other molecular diagnostics in the future, such as RNA sequencing, DNA methylation analysis, proteomics, metabolomics, epigenetics, and microbiome analysis? The focus needs to be not only on collecting data but on how to put these data into practice, Compton-Phillips said. Providence is taking an implementation science approach to answering key questions such as how to build trust with communities of color so they share their data, which can then be used to improve their care, she said, or how to share data about genomic variants with clinicians and patients in a meaningful, actionable way. There is still much to be elucidated about what methylation patterns and microbiome profiles mean for an individual’s health, for example. But there are lessons that can be learned now such as how to manage the volumes of molecular data collected for an individual patient and put it in context for their health, Compton-Phillips said.

WORKSHOP REFLECTIONS

Martin summarized her key lessons from each of the panel sessions (Box 7-2). As discussed throughout the workshop, the use of genomic information in clinical care today is primarily reactive, and there are bottlenecks that obstruct access to genomics, Martin said. The hope for the future is for genomic information to be “readily and routinely available and accessible” for use by providers and patients, and there was much discussion about the need for improved integration of genomic data into the EHR in a manner that enables access, interrogation, and sharing. Many of the challenges that impede equitable access to precision health care are not unique from other areas of health care, she said, but the field has not adequately addressed them through education, better resources, or efforts to build trust. Martin highlighted opportunities to integrate genomics into routine clinical care across the life span in areas such as prevention, early detection, clinical diagnosis, treatment, and surveillance.

Recurrent themes across the workshop discussions, as summarized by Martin, included opportunities for

• equitable adoption of genomics at the population level;
• improved education and training of providers and the public;
• less reliance on genetics specialty clinics and greater support for integration of genetics into routine care;
• EHR-integrated clinical decision support tools; and
• engagement of all interested parties in realizing the potential of genomics in precision health care, including patients, their families, providers, payers, the public, and others.

The discussion indicated that the evolution of genetic testing to a single genetic test (a whole genome sequence) could eliminate many of the implementation challenges and barriers discussed by panelists throughout the workshop, but there is still much work to be done to realize the potential of genomic information for the practice of medicine and the delivery of precision health care, Martin said. She reiterated the point by Henley that patients are caught up in a system where valuable time is being wasted having the same discussions year after year, and restated Henley’s appeal that it is time to “stop talking about changing the system” and take the actions needed to actually do it.