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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. RESEARCH NEEDS AND GENOMIC MEDICINE CIRCA 2011
  5. NHGRI CONSULTATIONS AND MEETINGS ON GENOMIC MEDICINE
  6. NHGRI PROGRAMS IN GENOMIC MEDICINE
  7. SUMMARY
  8. REFERENCES

The National Human Genome Research Institute, in close collaboration with its research community, is pursuing an ambitious research agenda to facilitate and promote the implementation of genomics in clinical care. Since 2011, research programs utilizing next-generation sequencing in the management of cancer and other multigenic conditions, workup of undiagnosed conditions, and evaluation of disorders of the newborn period have been initiated, along with projects identifying clinically actionable variants and exploring the ethical and social implications of reporting these findings. Several genomic medicine symposia and other consultations have helped to shape these research initiatives and develop educational materials for physicians and others working to implement the use of genomic findings in clinical care. These efforts provide a valuable complement to the highly successful basic genomics research enterprise that has at last enabled the transition of genomics from the bench to the bedside. © 2014 Wiley Periodicals, Inc.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. RESEARCH NEEDS AND GENOMIC MEDICINE CIRCA 2011
  5. NHGRI CONSULTATIONS AND MEETINGS ON GENOMIC MEDICINE
  6. NHGRI PROGRAMS IN GENOMIC MEDICINE
  7. SUMMARY
  8. REFERENCES

In 2011, the National Human Genome Research Institute (NHGRI) published an updated strategic vision for the future of genomics research [Green and Guyer, 2011], proposing an ambitious research agenda that would facilitate and promote the implementation of genomics in clinical care (i.e., “genomic medicine”). This vision is framed around five research domains, three of which reflect fundamental technologic and basic science pursuits that together will advance our understanding of the role of the human genome in health and disease. While these three research domains—investigating genome structure, genome biology, and the (genomic) biology of disease—have long been (and will continue to be) key components of the Institute's core mission, the 2011 strategic vision described two additional domains focused on genomics research aiming to advance the science of medicine and to improve the effectiveness of healthcare. Together, these last two research domains represent a concerted effort to apply genomics for improving the prevention, diagnosis, and treatment of human disease.

RESEARCH NEEDS AND GENOMIC MEDICINE CIRCA 2011

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. RESEARCH NEEDS AND GENOMIC MEDICINE CIRCA 2011
  5. NHGRI CONSULTATIONS AND MEETINGS ON GENOMIC MEDICINE
  6. NHGRI PROGRAMS IN GENOMIC MEDICINE
  7. SUMMARY
  8. REFERENCES

Although a handful of genomic applications were already in clinical practice in 2011 (e.g., the use of specific tumor mutations in cancer treatment and HLA testing prior to abacavir use [Green and Guyer, 2011]), it was incontrovertibly clear that considerable research would be needed to capitalize on new genomic discoveries for implementing genomic medicine. Among the needed studies were those demonstrating the generalizability of genomic findings across populations and clinical settings (as well as potential interactions of genomic variants with other conditions or treatments) and those generating evidence of the efficacy of using genomic information for clinical care. Such studies typically require vast numbers of patients to identify those with particular genomic variants and conditions of interest; this can be done efficiently by leveraging established biorepositories that are linked with electronic medical records (EMRs). It is notable that the latter situation is also ideal for rapidly acting on genomic findings once they are confirmed. By 2011, the value of using EMRs for assessing phenotypes (“electronic phenotyping”) had been demonstrated [Denny et al., 2010; Ritchie et al., 2010], but many questions remained about integrating genomic information into EMRs, maintaining patient privacy, and providing computerized decision support for practicing healthcare professionals.

Although a handful of genomic applications were already in clinical practice in 2011 (e.g., the use of specific tumor mutations in cancer treatment and HLA testing prior to abacavir use [Green and Guyer, 2011]), it was incontrovertibly clear that considerable research would be needed to capitalize on new genomic discoveries for implementing genomic medicine.

Also by 2011, rapid advances in “next-generation” DNA sequencing technologies were being applied to difficult clinical problems, such as uncovering mutations underlying Mendelian syndromes [Ng et al., 2010; Lindhurst et al., 2011] and optimizing management of patients with rare disorders [Bainbridge et al., 2011]. Exome and genome sequencing was beginning to be used in the workup of patients with undiagnosed conditions [Worthey et al., 2011; St. Hilaire et al., 2011], but the feasibility of such approaches outside of highly specialized centers and their generalizability to broader categories of patients remained unclear. Such extensive genomic characterization also raised challenging issues relating to data sharing, informed consent, and the reporting of incidental genomic findings unrelated to the index condition but with potential implications for clinical care. Finally, the potential of genome sequencing to augment or even replace the standard approaches to screen for hereditary diseases in newborns raised numerous questions about efficacy, feasibility, and psychosocial impact that had yet to be fully formulated, let alone addressed [National Human Genome Research Institute, ].

At the same time, genomic analyses of tumors (by genotyping and/or sequencing methods) were becoming relatively common in the clinical setting [Dias-Santagata et al., 2010], but few medical centers were otherwise actively engaged in implementing genomic medicine. Some early clinical genomic successes were occurring in isolation, seemingly without strong means to disseminate their expertise or to develop common knowledgebases and other infrastructure [Manolio et al., 2013]. There appeared to be considerable motivation to develop implementation strategies that built upon the lessons learned by the early adopters, yet a robust forum for facilitating such development and dissemination was lacking. Meanwhile, most physicians and other healthcare professionals were largely unaware of genomic advances that might be relevant to their patients and were generally intimidated by the rapidly emerging discipline of genomic medicine, with few feeling competent to use genomics in their practice [Feero and Green, 2011].

Most physicians and other healthcare professionals were largely unaware of genomic advances that might be relevant to their patients and were generally intimidated by the rapidly emerging discipline of genomic medicine, with few feeling competent to use genomics in their practice [Feero and Green, 2011].

NHGRI CONSULTATIONS AND MEETINGS ON GENOMIC MEDICINE

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. RESEARCH NEEDS AND GENOMIC MEDICINE CIRCA 2011
  5. NHGRI CONSULTATIONS AND MEETINGS ON GENOMIC MEDICINE
  6. NHGRI PROGRAMS IN GENOMIC MEDICINE
  7. SUMMARY
  8. REFERENCES

Shortly after publishing its 2011 strategic vision, NHGRI embarked on a series of consultations with other NIH Institutes and Centers to identify genomic medicine projects related to disease prevention, diagnosis, or treatment that were nearly ready for implementation. Despite great enthusiasm for clinical applications of genomics, most Institutes/Centers identified projects falling more in the realm of NHGRI's “biology of disease” domain (Table I). Relatively few projects involved examining the impact of using individual patients' genomic information in their medical care (NHGRI's “science of medicine” domain), and almost none focused on demonstrating the utility of genomics for actually improving the care of patients (NHGRI's “effectiveness of healthcare” domain). This fifth domain encompasses much of what is referred to as “implementation research”—the study of methods that promote the systematic uptake of proven interventions into routine clinical care [Eccles et al., 2012]. Of note, one project in this realm supported early on by NHGRI involved the targeted sequencing of 84 pharmacologically important genes by the Electronic Medical Records and Genomics (eMERGE) network (see below).

Table I. Disease-Related Genomics Research Across Three NHGRI Research Domains
NHGRI domainBiology of diseaseScience of medicineEffectiveness of healthcare
Common RubricDiscovery researchClinical validationClinical implementation
General GoalDemonstrate genotype–phenotype associationsAssess outcomes after using genomic information to direct clinical careDemonstrate improved healthcare with the use of genomic information
Specific ExamplesIdentify persons at increased risk of disease based on their genomic variantsEvaluate clinician and patient satisfaction with care after receipt of genomic informationEducate clinicians and patients in clinical use of genomic information
Find all variants related to given phenotype or diseaseAssess impact of reporting incidental findings on health behaviors, healthcare utilization, and psychological well-beingDevelop clinical informatics systems for reporting results of genomic analyses and providing decision support
Characterize variation in genes known to be related to disease or treatment responseIdentify causes of rare or undiagnosed diseasesEvaluate impact of using genomic variant information to individualize treatment
Characterize phenotypic variation and effect modifiers in carriers of specific variantsIdentify sources and susceptibilities of infectious agentsIncorporate genomic information into electronic medical records that can follow patients across care systems and throughout lifespan
Classify patients into subgroups with differing prognosis or treatment response (molecular taxonomy)Compare genome sequencing to enzymatic and other assays for modifiable metabolic disorders in newbornsDefine clinically actionable genomic variants and disseminate that information and its relevant evidence base
 Reclassify intermediate risk patients into high- and low-risk categories where differential interventions available 
 Validate drug targets and develop improved therapeutic agents 

In parallel, NHGRI also consulted and facilitated collaborations with the external research community by convening a series of “Genomic Medicine Meetings” (Table II), developed with the guidance and leadership of the Genomic Medicine Working Group of the National Advisory Council on Human Genome Research [ Human Genome Research Institute a]. The first meeting in June 2011 laid to rest any doubts about whether there existed a critical mass of researchers actively engaged in genomic medicine implementation; representatives of 20 groups attended this first meeting on short notice and on their own funds. Commonalities and duplications across efforts became readily apparent, including similar obstacles encountered and solutions developed, often quite independently. A summary of these efforts and the major lessons learned by early adopters was published as an “implementation roadmap” [Manolio et al., 2013], and plans were made to facilitate collaborations and to address the critical need for a consensus process to identify clinically actionable genomic variants.

Table II. NHGRI Genomic Medicine Meetings and Related Workshops
MeetingDatesEmphasisProductsMeeting URL
Genomic Medicine Symposium [Manolio et al., 2013]June 29, 2011Academic medical centersImplementation roadmap [Manolio et al., 2013], ClinAction workshophttps://www.genome.gov/27547270
ClinAction WorkshopDecember 2–3, 2011Methods for identifying clinically actionable variantsRFA HG-12-016, Clinically Relevant Genetic Variants Resource; ClinGen Consortium [Ramos et al., 2014]http://www.genome.gov/27546546
Genomic Medicine IIDecember 5–6, 2011Pilot demonstration projectsRFAs HG-12-006 and -007, Genomic Medicine Pilot Demonstration Projects; IGNITE Consortiumhttps://www.genome.gov/27546373
Genomic Medicine IIIMay 3–4, 2012Working with laboratories and payersPayers' meetinghttps://www.genome.gov/27548693
Payers' meetingOctober 24, 2012Potential for collaborative researchPhysician education workgroup is preparing a summary of lessons learned about the problems encountered by clinicians in the pre- and post-analytic phases of genetic test ordering 
Genomic Medicine IVJanuary 28–29, 2013Physician education in genomicsInter-Society Coordinating Committee for Practitioner Education in Genomics (ISCC), [ Human Genome Research Institute b], approval for AJMG Seminars issue devoted to Implementation of Genomic Medicinehttps://www.genome.gov/27552294
Genomic Medicine VMay 28–29, 2013Working with federal stakeholdersExploratory implementation project in collaboration with VA and military medical serviceshttps://www.genome.gov/27553865
Inter-Society Coordinating CommitteeSeptember 19–20, 2013Physician competencies, use cases, educational materials, and collaborations with specialty boardsResources developed by ISCC will be posted on NHGRI Genetics and Genomics Competency Center (G2C2) and NHGRI Global Genetics and Genomics Community (G3C) websites; White Paper [Manolio and Murray, in press].http://www.g-2-c-2.org/index.php and http://www.g-3-c.org/en/ http://www.genome.gov/27555775
Genomic Medicine VIJanuary 8–9, 2014Developing international collaborations  
Genomic Medicine VII (proposed)September, 2014Working with industry?  
Genomic Medicine VIII (proposed)June, 2015   

Additional meetings in December 2011 addressed the latter two topics, leading to the release of several NHGRI funding solicitations and ultimately the funding of two new consortia, the Clinical Genomics Resource (ClinGen) [Ramos et al., 2014] and Implementing Genomics into Clinical Practice (IGNITE) Network (see below). Later meetings focused on issues relevant to laboratories and payers (May 2012), professional societies (January 2013), and federal agencies (May 2013). Each of these led to follow-up discussions regarding potential collaborative research projects with payers and/or with multiple federal healthcare providers. The fourth meeting was particularly productive, with the professional societies urging NHGRI to establish and co-lead an Inter-Society Coordinating Committee on Practitioner Education in Genomics (ISCC) that would facilitate the efforts of professional societies in developing and sharing genomics educational materials and standards for physicians and other health practitioners [Manolio et al., 2013; Manolio and Murray, in press; Human Genome Research Institute b]. The ISCC has already empanelled several working groups to develop competencies, use cases, and accessible educational products for use across multiple disciplines and professional organizations. A sixth genomic medicine meeting to explore potential international collaborations in genomic medicine is planned for January 2014. Subsequent meetings focusing on other key stakeholder groups and topics are anticipated to be held roughly every 9 months. Other tangible products of these meetings, such as a potential large collaborative project across multiple federal healthcare providers, are currently in development.

NHGRI PROGRAMS IN GENOMIC MEDICINE

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. RESEARCH NEEDS AND GENOMIC MEDICINE CIRCA 2011
  5. NHGRI CONSULTATIONS AND MEETINGS ON GENOMIC MEDICINE
  6. NHGRI PROGRAMS IN GENOMIC MEDICINE
  7. SUMMARY
  8. REFERENCES

Three research programs already in progress in 2011 readily lent themselves to extension into genomic medicine implementation studies: NHGRI's Electronic Medical Records and Genomics (eMERGE) network [McCarty et al., 2011], NHGRI's genome sequencing program [ Human Genome Research Institute c], and the NIH Undiagnosed Diseases Program [Gahl et al., 2012]. The eMERGE network was established in 2007 to explore how best to use biorepositories linked with EMRs in genomics research projects. Having demonstrated the research value of such biorepositories [Denny et al., 2010; Ritchie et al., 2010], eMERGE was poised to explore the use of genomic information for clinical care as it prepared for its second phase [ Human Genome Research Institute d]. Ten projects were funded in 2011–2012 to continue eMERGE's efforts in electronic phenotyping and genomic discovery research, while also expanding into genomic medicine implementation studies. These projects included pilot studies examining genome sequencing in the workup of undiagnosed diseases, the effects of returning high-risk CFH, HFE, and FVL variants on physician and patient behaviors, and genomic versus clinical risk assessments in managing coronary disease and hypertensive nephropathy.

The eMERGE network was established in 2007 to explore how best to use biorepositories linked with EMRs in genomics research projects. Having demonstrated the research value of such biorepositories [Denny et al., 2010; Ritchie et al., 2010], eMERGE was poised to explore the use of genomic information for clinical care as it prepared for its second phase [ Human Genome Research Institute d].

As noted above, in 2012 eMERGE proposed initiating a collaborative project in pharmacogenomics with the National Institute of General Medical Sciences. The resulting eMERGE-PGx program involves assessing 9,000 patients for genomic variants in 84 genes known to be important in the response to drug therapy through the Pharmacogenomics Research Network []. A select number of Clinical Laboratory Improvement Act (CLIA)-validated variants with well-established clinical implications—as defined by programs such as the Clinical Pharmacogenetics Implementation Consortium (CPIC [Relling and Klein, 2011])—are being reported to clinicians and integrated into these patients' EMRs with appropriate clinical decision support to assess the impact of this genomic information on clinical decision-making.

Established in 2008, the NIH Undiagnosed Diseases Program (UDP) seeks to establish diagnoses for patients who remain undiagnosed after exhaustive medical workups and to discover new disorders and insights into disease mechanisms [ Institutes of Health a]. By 2011, the UDP had established diagnoses in nearly a quarter of the evaluated patients and identified several new disorders, but the transferability of the program and expertise outside the unique setting the NIH Clinical Center and Intramural Research Program was unclear. NHGRI has since worked with the other NIH Institutes and Centers through the NIH Common Fund to expand the UDP into a multi-center Undiagnosed Diseases Network, which will involve the establishment of several new clinical sites and core facilities [ Institutes of Health b]. Funding for this program should begin in early Fiscal Year 2014.

In 2008, the NIH Undiagnosed Diseases Program (UDP) seeks to establish diagnoses for patients who remain undiagnosed after exhaustive medical workups and to discover new disorders and insights into disease mechanisms [ Institutes of Health a]. By 2011, the UDP had established diagnoses in nearly a quarter of the evaluated patients and identified several new disorders, but the transferability of the program and expertise outside the unique setting the NIH Clinical Center and Intramural Research Program was unclear.

The potential for clinicians to utilize genome sequence data for the care of their patients is being explored by the Clinical Sequencing Exploratory Research (CSER) consortium, a component of NHGRI's Genome Sequencing Program. CSER aims to investigate the actual use of genomic information in clinical care by defining conditions for which genome sequencing is clinically beneficial and by developing the necessary policies, procedures, and infrastructure to integrate genome-sequence information into the clinical workflow. Nine CSER projects are using exome or genome sequencing for the care of patients with diverse conditions, including several types of cancer, cardiomyopathy, and developmental delay. A related program, the Return of Results Consortium [ Human Genome Research Institute e], is supporting seven studies examining the ethical, legal, and social issues involved in returning genomic research results to study participants and their families.

Another new NHGRI genomic medicine project, conducted jointly with the National Institute of Child Health and Human Development, is building upon successful early CSER experiences to explore the implications and challenges of using genome sequencing in newborns [National Institute of Child Health and Human Development]. Four collaborating projects are acquiring and analyzing genome sequences that considerably expand the scale of data available for analysis in the newborn period; in addition, they are investigating the ethical, legal, and social implications of the possible implementation of genome sequencing as part of newborn medical care.

The two remaining programs mentioned above arose directly from NHGRI's consultations with the biomedical research community. The ClinGen project aims to fill an urgent need for a systematic approach to developing and disseminating consensus information about genomic variants relevant for clinical care, much as the CPIC program does for pharmacogenomics. To date, such efforts have mostly been pursued independently by individual groups, with investigators often evaluating the same assays, assessing the same evidence, and in most cases coming to the same conclusions, all in a highly duplicative fashion within and across sites. ClinGen was established to develop a consensus process for identifying genomic variants that are relevant for clinical care and to incorporate this information into an accessible electronic resource. The rationale for this project is described in another paper in this special issue [Ramos et al., 2014].

The ClinGen project aims to fill an urgent need for a systematic approach to developing and disseminating consensus information about genomic variants relevant for clinical care, much as the CPIC program does for pharmacogenomics.

Lastly, the potential for “early adopter” genomic medicine sites to share their experiences and test the generalizability of their approaches in diverse clinical settings led NHGRI to solicit a series of genomic medicine demonstration projects [ Human Genome Research Institute f]. The recently funded IGNITE network is designed to expand and link existing genomic medicine efforts, develop new collaborative projects in diverse settings and populations, contribute to the evidence base supporting the use of genomic information for clinical care, and share best practices for genomic medicine implementation, diffusion, and sustainability.

SUMMARY

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. RESEARCH NEEDS AND GENOMIC MEDICINE CIRCA 2011
  5. NHGRI CONSULTATIONS AND MEETINGS ON GENOMIC MEDICINE
  6. NHGRI PROGRAMS IN GENOMIC MEDICINE
  7. SUMMARY
  8. REFERENCES

The incorporation of genomic technologies and findings into routine clinical care holds considerable potential for personalizing medical treatments and enhancing the effectiveness of healthcare, but significant potential pitfalls abound. Chief among these is that the use of genomic information may not improve clinical outcomes, and almost certainly will not in every instance. Evidence supporting the utility of genomic information thus needs to be carefully assessed, while at the same time avoiding unreasonable expectations for exhaustive evidence for every genomic variant that may influence human health and disease. Potential misuses of genomic information that cause unnecessary worry, discrimination, increased medical costs, or diverted resources also need to be recognized and avoided. NHGRI expects the systematic set of research programs outlined above, in conjunction with additional future projects now in early design phases, will play key roles in addressing the major questions and barriers associated with genomic medicine implementation. In doing so, these efforts will provide a valuable complement to the highly successful basic research enterprise that has made such genomic advances conceivable.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. RESEARCH NEEDS AND GENOMIC MEDICINE CIRCA 2011
  5. NHGRI CONSULTATIONS AND MEETINGS ON GENOMIC MEDICINE
  6. NHGRI PROGRAMS IN GENOMIC MEDICINE
  7. SUMMARY
  8. REFERENCES
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