American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 166C:15–23 (2014)
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Implementing Individualized Medicine into the Medical Practice KONSTANTINOS N. LAZARIDIS, TAMMY M. McALLISTER, DUSICA BABOVIC-VUKSANOVIC, SCOTT A. BECK, MITESH J. BORAD, ALAN H. BRYCE, ASHER A. CHANAN-KHAN, MATTHEW J. FERBER, RAFAEL FONSECA, KILEY J. JOHNSON, ERIC W. KLEE, NORALANE M. LINDOR, JENNIFER B. McCORMICK, ROBERT R. McWILLIAMS, ALEXANDER S. PARKER, DOUGLAS L. RIEGERT-JOHNSON, CAROLYN R. ROHRER VITEK, KIMBERLY A. SCHAHL, CLOANN SCHULTZ, KEITH STEWART, GEORGE C. THEN, ERIC D. WIEBEN, AND GIANRICO FARRUGIA
There is increasing recognition that genomic medicine as part of individualized medicine has a defined role in patient care. Rapid advances in technology and decreasing cost combine to bring genomic medicine closer to the clinical practice. There is also growing evidence that genomic-based medicine can advance patient outcomes, tailor therapy and decrease side effects. However the challenges to integrate genomics into the workflow involved in patient care remain vast, stalling assimilation of genomic medicine into mainstream medical practice. In this review we describe the approach taken by one institution to further individualize medicine by offering, executing and interpreting whole exome sequencing on a clinical basis through an enterprise-wide, standalone individualized medicine clinic. We present our experience designing and executing such an individualized medicine clinic, sharing lessons learned and describing early implementation outcomes. © 2014 Wiley Periodicals, Inc. KEY WORDS: genomic medicine; whole exome sequencing; individualized medicine clinic; personalized medicine
How to cite this article: Lazaridis KN, McAllister TM, Babovic-Vuksanovic D, Beck SA, Borad MJ, Bryce AH, Chanan-Khan AA, Ferber MJ, Fonseca R, Johnson KJ, Klee EW, Lindor NM, McCormick JB, McWilliams RR, Parker AS, Riegert-Johnson DL, Rohrer Vitek CR, Schahl KA, Schultz C, Stewart K, Then GC, Wieben ED, Farrugia G. 2014. Implementing individualized medicine into the medical practice. Am J Med Genet Part C Semin Med Genet 166C:15–23.
Disclosures: Dr. R. Fonseca has received a patent for the prognostication of multiple myeloma based on genetic categorization of the disease. He has received consulting fees from Medtronic, Otsuka, Celgene, Genzyme, BMS, Lilly, Onyx, Binding Site, Millennium and AMGEN. He also has sponsored research from Cylene and Onyx. K.N. Lazaridis M.D. is a Consultant Hepatologist and the Enterprise Director of the Mayo Individualized Medicine Clinic. His research work focuses on the genetics of cholestatic liver diseases. T.M. McAllister, M.S. is the Operations Manager for the Clinomics Translational and Bioethics Infrastructure programs within the Center for Individualized Medicine. D. Babovic-Vuksanovic, M.D. is a Clinical Geneticist and Chair of Department of Medical Genetics at Mayo Clinic. She has expertise in neurofibromatosis, dysmorphology and a variety of hereditary disorders. S.A. Beck is the Administrator of the Center for Individualized Medicine. He works in partnership with Dr. Farrugia to direct the Center's activities. M.J. Borad, M.D. is an Assistant Professor of Medicine in the Division of Hematology/Oncology at Mayo Clinic in Arizona. His work is focused on clinical applications of Next Generation sequencing for cancer patients. A.H. Bryce, M.D. is an oncologist at Mayo Clinic in Arizona. He is director of the genomic oncology service. A.A. Chanan-Khan is the chair of Hematology at Mayo Clinic in Florida and Assistant Director Arizona for the Center for Individualized Medicine. M.J. Ferber Ph.D. DABMG is a Clinical Molecular Geneticist at the Mayo Clinic. He is the Director of the Clinical Genome Sequencing Laboratory, and Co-director of the Individualized Medicine Clinomics Program. R. Fonseca M.D. is a Professor of Medicine and Chair of Medicine at Mayo Clinic in Arizona. He has an interest in tumor genomics, primarily as it relates to the treatment of myeloma and related conditions. K.J. Johnson, M.S., C.G.C. is a certified genetic counselor in the Center for Individualized Medicine at Mayo Clinic. Her work involves whole exome sequencing for diagnostic odyssey and oncology patients for the Center's Individualized Medicine Clinic and helping those patients understand genomic medicine and how it applies to their care. E.W. Klee, Ph.D., works as an Assistant Professor of Medical Informatics in the Departments of Health Sciences Research and Laboratory Medicine and Pathology, at the Mayo Clinic, Rochester, Minnesota. His expertise is in the bioinformatics of next generation sequencing with a focus on the clinical implementation of this technology.
ß 2014 Wiley Periodicals, Inc.
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INTRODUCTION The completion of the first human genome sequence in 2003 created much anticipation and promise among scientists, health care providers, media, and the public [Green et al., 2011]. This promise, however, did not result in immediate and tangible changes in standard medical care. While the media continued to anticipate and the public waited, genomic research progressed. Over the last few years impressive strides have been made to this effect. In recent years, emerging evidence suggests a
In recent years, emerging evidence suggests a rapidly growing expectation to incorporate genomic medicine into individualized patient care. rapidly growing expectation to incorporate genomic medicine into individualized patient care [Manolio et al.,
2013]. The promise of genomic medicine, as one part of individualized care, is to enable medical practitioners to make better clinical decisions through an
The promise of genomic medicine, as one part of individualized care, is to enable medical practitioners to make better clinical decisions through an improved informed process.
improved informed process. The anticipated results are to improve targeted therapies, reduce side-effects, increase prevention and prediction of disease, enable earlier disease intervention, reduce healthcare costs and improve patient outcomes. Despite the numerous benefits, the challenges to integrate genomics into patient care are vast. While rapid advances in technology and decreasing cost combine to bring genomic medicine
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closer to the clinical practice, significant barriers continue to stall assimilation in mainstream medical practice. Variable access and standardization of technology, education, reimbursement, regulation, evidence-based clinical validity, and evolving ethical dilemmas continue to provide challenges [Chan and Ginsburg, 2011; Burton et al., 2012; Farrugia and Weinshilboum, 2013; McCarthy et al., 2013]. Responding to this clinical need, in 2012 Mayo Clinic launched the current Center for Individualized Medicine (CIM) charging it to discover and integrate the latest genomic and clinical sciences into personalized care for all patients. As a “hybrid” center with research and clinical responsibilities, CIM’s goal is to promote rapid translation of research into personalized clinical care and to create genomic medicine mechanisms that are instantly diffusible and applicable across Mayo Clinic’s multiple, geographically dispersed campuses. Thus, one CIM initiative, the Individualized Medicine (IM) Clinic, was created to overcome barriers of translating next generation sequencing into the medical practice—to establish a model uniting the clinical expertise of
N.M. Lindor, M.D. is a medical geneticist with a longstanding interest and expertise in the recognition and management of hereditary predisposition to cancer. More recently she has been involved with exploring the integration and translation of the nextgen-based molecular diagnostics to clinical practice. J.B. McCormick, Ph.D., M.P.P is an Assistant Professor of Biomedical Ethics at the Mayo Clinic. Her work focuses the ethical, legal, and social implications of genetics and genomic translational research. R.R. McWilliams, M.D. is an Associate Professor of Oncology at Mayo Clinic and Chair of the Genomic Tumor Board. His research work focuses on the genetics of pancreatic cancer. A.S. Parker, Ph.D. is an Associate Professor of Epidemiology and Urology and an Associate Director for the Mayo Center for Individualized Medicine. His research focuses on developing biomarkers for genitourinary cancers and exploring genetic and environmental risk factors for these cancers. D.L. Riegert-Johnson, M.D. works as a medical geneticist and gastroenterologist at Mayo Clinic Florida. He trained at the Mayo Clinic in Rochester and Johns Hopkins. C.R. Rohrer Vitek, M.S. is the Education Program Manager in the Center for Individualized Medicine. Her work and research interests include development of provider and patient education to support implementation of genomic medicine into practice. K.A. Schahl is a certified genetic counselor in the Center for Individualized Medicine at Mayo Clinic. Her work involves whole exome sequencing for diagnostic odyssey and oncology patients for the Center's Individualized Medicine Clinic and helping those patients understand genomic medicine and how it applies to their care. C.G. Schultz works as the senior project manager in the Center for Individualized Medicine at Mayo Clinic. K. Stewart, M.B., Ch.B. is a hematology oncologist at Mayo Clinic Arizona and an Associate Dean for Research. G. C. Then, MBA, works as a Principal Health Systems Engineering Analyst at the Division of Systems and Procedures in Mayo Clinic, Rochester. His area of focus is work process design and improvement. E.D. Wieben, Ph.D. is a Professor and Chair Emeritus of Biochemistry and Molecular Biology at Mayo Clinic. He currently directs the Medical Genome Facility at Mayo. G. Farrugia, M.D. is a Gastroenterologist and the Director for the Mayo Clinic Center for Individualized Medicine. Grant sponsor: Cylene; Grant sponsor: Onyx. *Correspondence to: Gianrico Farrugia, M.D., Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail: [email protected] DOI: 10.1002/ajmg.c.31387 Article first published online in Wiley Online Library (wileyonlinelibrary.com): 10 March 2014
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Figure 1. The Individualized Medicine Clinic as a Mechanism for Diffusion of Genomic Medicine. The clinical practice expertise in phenotyping patient disease is merged with genotyping tools and expertise within the IM Clinic.
numerous subspecialties in phenotyping diseases and disorders with new tools of genomic medicine (Fig. 1). The IM Clinic opened to patients on September 30, 2012. In this article, we present our experience designing and executing an enterprise-wide IM Clinic, sharing lessons learned and describing early implementation outcomes.
DESIGNING THE INDIVIDUALIZED MEDICINE CLINIC An informal survey of genomic offerings in academic institutions suggests a common “silo” approach towards the introduction of genomics into patient care, where most efforts were spearheaded by one particular individual, group or department. Translating individualized medicine into the practice “is as much a cultural and political exercise within a given institution as a scientific one” [Manolio et al., 2013]. There are benefits to being positioned within an established department, including having buy-in from department heads and avoiding the significant effort required to create an infrastructure for the clinic. However, fully functioning multi-disciplinary IM Clinic integrating genomics requires focused and multi-faceted expertise—
perhaps larger than a single department can provide. Based on Mayo Clinic’s team-based model, CIM created a multi-disciplinary, multi-site, committee—the IM Clinic Work Group—to oversee the process of creating the IM Clinic. The Work Group positioned the IM Clinic within CIM, and recruited physicians from across the institution’s departments to contribute expertise. Unaffiliated, the IM Clinic processes were created de novo and designed for the ideal patient encounter, transcending the limits of a single medical, surgical or pathology specialty. Institutional bio-banking, genome sequencing, and bioinformatics infrastructure, along with a subset of information technology and bioethics resources, were aligned under CIM to facilitate infrastructure coordination and prioritization.
INITIAL OFFERINGS OF THE INDIVIDUALIZED MEDICINE CLINIC Abundant literature describes how molecular characterization [McCarthy et al., 2013], genome-wide association studies [Manolio, 2010], and structural variation [Stankiewicz and Lupski, 2010] are helping to elucidate the genomic influences on cancer [Stratton et al., 2009] and complex diseases
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[McCarthy et al., 2013], and reveal effective treatments [Dietz, 2010]. Given this, after considering the likelihood of actionable clinical results, the cost associated with the process and the ethical, legal and social aspects, two services were selected for initial implementation. The first, for patients with advanced cancer who fail standard therapy (or where no proven standard therapy exists) and fit specific tumor and life expectancy criteria, employs comparison of normal and tumor DNA to identify causative or contributing mutations and, subsequently, allows targeted therapy based on genomic information. The second service being for patients with a suspected genetic condition for whom previous genetic testing did not reveal an etiology (i.e., diagnostic odyssey), uses Whole Exome Sequencing (WES) to reveal the variant(s) responsible for the patient’s disease and proposes potential treatments. This step-wise approach to service line development permitted flexible planning, resource maximization, and expedited IM Clinic operations in a short period of time between conception and offering the relevant clinical services. Furthermore, we believe that the initial experiences gained will be instrumental to the development of additional service lines with broader clinical applicability (i.e., prevention genomics, subscription genomics, etc.).
COMPONENTS AND ROLES OF THE INDIVIDUALIZED MEDICINE CLINIC In a pilot project of this magnitude, it is essential to have a group of champions able to affect change-convincing skeptics and maneuvering organizational hurdles [Manolio, 2010]. Broad representation of experts from across Mayo Clinic, to ensure wide-ranging input during the translational phase of the IM Clinic, was essential to defining the unique professional components necessary in the IM Clinic and, subsequently, the processes for each. While each service line requires a slightly different work flow and professional skills, a common infrastructure
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was built to accommodate the basic IM Clinic function. Representatives from IT, bioinformatics, bioethics, patient access management, education, revenue cycle, operations and the research sequencing facilities joined the IM Clinic Work Group to design the structures and processes implemented across all Mayo Clinic campuses. IM Consultation: IM Clinic Consultants As is customary at Mayo Clinic, every patient is assigned a lead physician (i.e., consultant) to oversee and coordinate his/her healthcare. For the IM Clinic, interested physicians across many subspecialties act as an IM Consultant and are assigned to lead care for patients referred to the IM Clinic. For the cancer service, these are medical oncologists or hematologists. Diagnostic Odyssey patients are assigned an IM Consultant from General Internal Medicine, Medical Genetics or a subspecialty department, according to the patient’s main symptoms or physical findings. Clinical departments represented in the IM Clinic services currently include Medical Genetics, Oncology, Hematology, Dermatology, Pharmacology, Neurology, Ophthalmology, Gastroenterology, Hepatology, Cardiology, Rheumatology, Pediatrics, General Internal Medicine, and Family Practice. The assigned IM Consultant reviews the initial consult request for appropriateness; evaluates the patient; coordinates genetic and financial counseling, sample collection, surgery (if needed), and laboratory activities; presents the case and results at expert board meetings; and relays advice for next steps to the patient or the referring physician. Genomic Counseling: CIM Genetic Counselors Genomic medicine is a complex discipline. Patients, often well-prepared and seeking new options for treatment, are often still unaware of basic genetic principles, and information WES can and cannot yet provide [Haga et al.,
2012; Levin et al., 2012]. Vocabulary alone can overwhelm patients. Patients must be informed about the potential risks and ramifications created by genomic data [Weil, 2002]. The IM Clinic process was designed to allow for the time necessary for faceto face visits between the CIM Genetic Counselors and the patient (and family) in a “genomic counseling” session. In this session, genetic counselors define and explain vocabulary and concepts; talk explicitly about different lab tests and their potential results and risks; and apply a shared decision-making model to help the patient select the categories of genomic results to be returned. CIM Certified Genetic Counselors collaborated with the Center for
The IM Clinic process was designed to allow for the time necessary for face-to face visits between the CIM Genetic Counselors and the patient (and family) in a “genomic counseling” session. In this session, genetic counselors define and explain vocabulary and concepts; talk explicitly about different lab tests and their potential results and risks; and apply a shared decision-making model to help the patient select the categories of genomic results to be returned.
Innovation and CIM’s Community Advisory Board, to create tools, specifically for the IM Clinic, to help patients make decisions about incidental findings that they may or may not want to learn for this testing. Counselors also discuss testing costs and coordinate insurance authorization. The genetic counselor
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often becomes the patient’s main point of contact. Sample Acquisition: Surgeons, Pathology, and Laboratory Medicine Tumor tissue quality and quantity are essential to high-quality test results. Necessary sample requirements for the sequencing tests ordered for IM Clinic patients differ in volume, form and destination laboratory. Because Mayo Clinic’s Department of Laboratory Medicine does not yet offer WES clinically, standard laboratory preparatory processes were not in place to accommodate the orders for cancer tissue preparation for DNA sequencing. IM Clinic Pathology leaders designed new workflow processes routing appropriate samples to external CLIA and Mayo laboratories. Expert Review Boards: Inter-Department Expertise In the post-genome era, a major challenge for physicians is interpretation of genomic data and results [Stanek et al., 2012]. With this being key to learning and translating genomic medicine into the practice, the IM Clinic Work Group designed a genomicsfocused expert board for each service line (Genomic Tumor Board [GTB] and Genomic Odyssey Board [GOB] for service line one and two, respectively) to act as a clinical interpretation team; assisting the patient’s physician with results, potential treatment options and access to therapies. As IM Clinic patients’ test results are returned to the IM Consultant, the expert boards convene weekly for an in-person and video conference across all Mayo campuses to discuss results and formulate recommendations and/or action plans. These multidisciplinary boards encourage wide participation and exchange of experience, drawing genomic medicine experts from across the institution, including standing members from Anatomic Pathology, Molecular Genetics, Clinical Genome Sequencing
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Laboratory, Hematopathology, Medical Genome Facility (research), bioinformatics and biomedical ethics. Joining to provide focused, multi-disciplinary attention to each individual case, disease-oriented specialists (as warranted) and the referring physician are also invited to participate in case discussions. All patient material is de-identified for discussion. Multi-site video-conferencing allows the boards to share laboratory reports, databases, and other materials that enable collaboration without regard to patient or board member location. Following case discussions, the board chair enters one unified clinical note in the electronic health record summarizing the group’s deliberations and recommendations. Infrastructure Support: IT and Electronic Data Systems Integrating genomic medicine into practice requires consideration of multiple practice management IT systems, that is, electronic health records (EHR), ordering and appointment scheduling systems. Genomic medicine cuts across specialties and divisions and is not easily compartmentalized in the EHR. Documentation in the EHR remains unchanged, that is, categorized within the applicable division following the home department of the IM Consultant. Electronic appointment orders were created for internal and affiliated practice health care providers. A standardized approach to the clinical workflow and naming convention was developed. As with all laboratory tests, the raw data file (.BAM file) is placed in a centralized, tiered storage environment where it remains accessible for future use. An underlying database houses all of the genetic variants for IM Clinic patients, facilitating reanalysis as medical knowledge evolves. Infrastructure Support: Bioethics Numerous ethical, legal, and social issues (ELSI) unique to genomic medicine require careful attention [Wright Clayton, 2003]. How to treat “inciden-
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tal findings” and convey the concepts of variants and risks to patients are among the topics to consider. The goal of the IM Clinic is to lead the translation of genomic medicine into standard clinical practice. To accomplish this in an ethically and socially responsible way, members of the Biomedical Ethics program were integrated upfront into IM Clinic infrastructure. Tracking nationally debated genomic-based medicine topics, bioethicists provided insight on ELSI concerns to both expert boards, and have been engaged in research studies pertinent to the IM Clinic, helping design the protocols and executing the patient informed consent process. To continually improve IM Clinic services, the Biomedical Ethics program has launched an ELSI study, tracking patients’ hopes, concerns and expectations as well as clinicians’ experiences, concerns in meeting the needs of patients and barriers faced in implementing genomics into practice. Infrastructure Support: Research Sequencing Facility and Bioinformatics Analytics Team The analysis and interpretation of WES data is complicated. To facilitate our understanding of the challenges and requirements in establishing this process internally, all patients seen in the IM Clinic are offered WES clinically (through a collaborative CLIA certified and College of American Pathologists accredited laboratory) and through the IM Clinic research protocol. The internally generated research data is initially processed through our DNA sequencing workflow, including Novoalign for sequence re-alignment and GATK (following best-practices) for recalibration, realignment, and germline variant calling. Subsequent to this analysis, endpoint specific processes are executed to identify and classify mutations in a service line specific manner, including using an integrated and multi-algorithmic solution for calling somatic variants in tumor samples and using a complementary three-track process for classifying mode-of-inheritance specific
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mutations for the diagnostic odyssey cases. Finally, an extensive set of annotations is used to provide context to the sample-specific mutations and facilitate the prioritization of the data for review by the research analysis teams and selection of actionable findings. Ultimately, findings from the research study are compared back to the actionable mutations reported by the clinical send-out and used to validate and refine the methodologies enacted. As such, this dual track approach (one clinical, the other research) is aiding in our development of a completely internalized clinical process. The IM Clinic research protocol allows for exome data generation in our research Medical Genome Facility and subsequent analysis by an IM Clinicsponsored research team focused on establishing an approach that would provide a clinical interpretation of the results. One for each service line, the analysis teams consist of experts from multiple disciplines, including clinical molecular genetics, genetic counseling, medical genetics, bioinformatics, biostatistics, and cancer biology. The teams are charged with reviewing each case and identifying what analyses and contextual information is required in order to interpret the results. The analysis teams also review the quality of data generated for each case, identify a list of highinterest mutations, provide short interpretative summaries of these variants, and pass the information on to the GTB and GOB for further consideration and review. Infrastructure Support: Education Education and communication are required to translate genomic medicine to the rest of the practice [Guttmacher et al., 2007; Feero and Green, 2011] and to patients [Green et al., 2011]. To address this, CIM’s Education Program created training materials, daily operational checklists for IM Consultants and scheduling staff, and collaborated with IM Clinic leaders to create educational presentations and operational instructions for both internal and external referring physicians.
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To create effective genomically focused patient educational materials for the IM Clinic, collaborations were set up between genetic counselors, the Mayo Clinic Center for Innovation, the institution’s patient education department and other Mayo Clinic writers. The goal is to make innovative, helpful genomic medicine materials in the form of workbooks, pamphlets, videos and animations available in the practice and via the IM Clinic webpage (http:// mayoresearch.mayo.edu/center-for-individualized-medicine/individualizedmedicine-clinic.asp). Infrastructure Support: Revenue Cycle Current reimbursement systems do not yet address using genomic medicine in the practice [Guttmacher et al., 2010]. When the IM Clinic opened, reimbursement for genomic services was hard to predict without CPT billing recognition of whole exome and other next generation sequencing laboratory tests. This situation will persist while codes and recognition of the services are slowly incorporated into national plans. Within these limits, revenue cycle representatives and Certified Genetic Counselors have worked to assist patients to achieve pre-authorization or commitment for payment from insurance providers on a case-by-case basis. On average, about
half of our patients get at least partial coverage.
PATIENTS SEEN IN THE IM CLINIC Instead of establishing a separate appointment scheduling and reception infrastructure, the IM Clinic partnered with various divisions to build access and in-take models. The Departments of Oncology and Medical Genetics incorporated existing members of allied staffs into the triaging, scheduling and in-take coordinating of IM Clinic patients. This required slight modifications of standard department processes to accommodate the IM Clinic patient flow. Patient Access Management incorporated decision trees to triage patients requesting “individualized medicine” and other commonly used “personalized medicine” terms. After the patient appointment request, the patient workflow (Fig. 2) is executed. Details of the service lines’ processes diverge slightly to accommodate the varied needs of the patients. Cancer Service Line Patient Flow Once a request is received for the cancer service line, a clinical Oncologist or Hematologist serving as the IM Clinic Consultant reviews it to determine if entry criteria are met. As part of this
Figure 2. Basic Individualized Medicine Clinic Workflow. The figure illustrates the process from the initial patient referral through patient care visits within the IM Clinic, sample procurement and testing, discussion, and recommendations by the Genomic Board culminating with the patient follow up.
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process, imaging, pathology and pertinent medical history are made available to the IM Consultant. The patient is enrolled in the IM Clinic if he/she has a tumor that can be excised or biopsied, can tolerate the procedure, has failed standard therapy and has a life expectancy likely to extend beyond 12 weeks. The patient meets with the IM Consultant, who discusses the concept of genomic testing in order to define a new therapy. Information about specific DNA tests, risks and expectations, basic costs and result timelines are also discussed. If the patient agrees to genomic testing, the IM Consultant contacts the IM Clinic Pathologist to discuss the tissue requirements and determines which tests should be ordered based on the patient’s status and tissue availability. The standard clinical order is an array CGH (turn-around time approximately 3 weeks), a cancer-gene panel (covering approx. 200 genes with results in approximately 3 weeks) and WES (results returned in approximately 15 weeks). Additionally, though not required, patients are also offered the opportunity to participate in the IM Clinic research protocol, where our research facility performs RNA sequencing and WES. This protocol serves multiple purposes including as a quality control measure to validate the results of external labs, to interrogate the value of RNA sequencing in predicting clinical outcomes, and to test new compare new sequencing platforms as they become available. Approximately 40% of patients have chosen to participate in the research in addition to the clinical services. After tissue priorities and plans are discussed, the IM Consultant orders a consult with a surgeon when applicable (tissue excision) and orders the Genomic Counseling session. The patient then meets the CIM Certified Genetic Counselor for basic genomic education, explanation of the specific testing and our partner-lab consent forms. The counselor guides the patient (and family) through a shared decision-making process that includes the social and ethical considerations of DNA sequencing, test costs and
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insurance coverage issues. They also have the opportunity to meet with a financial counselor if necessary. A bioethics representative meets the patient to offer enrollment in the IM Clinic research study as well as the IM Clinic ELSI study. The patient continues with a surgery consult, phlebotomy and tissue acquisition. Standard tumor pathology analysis is performed, followed by DNA extraction and delivery to the sequencing laboratories. Given the significant difference in turn-around time for array CGH and gene panel assays compared to WES, all results are discussed as they become available. As test results are returned to the IM Consultant over the course of about 15 weeks, the patient’s case is discussed at the weekly Genomic Tumor Board (GTB) meeting. GTB members interpret test results in light of clinical findings and discuss potential actionable treatment options. This information is provided to the patient’s primary oncologist by the IM Consultant allowing discussion of potential next treatment steps. A summary clinical note is created for the treating clinician. Diagnostic Odyssey Service Line Patient Flow Consult requests made for Diagnostic Odyssey patients prompt a CIM Certified Genetic Counselor to contact the patient and collect pedigree information (if not already available). Additionally, the Counselor reviews the medical record and provides case details to the IM Consultant who presents the case at the weekly expert board meeting. Board members discuss how likely the patient is to benefit from WES. At the fore of these discussions are considerations of costs, patient medical and family histories, likelihood of success and meaningful applicability of findings from WES versus other genetic tests, and patient expectations. Presently little data exist to inform this decision, and there is always a tension between recommending continuation of conventional diagnostics versus proceeding with WES. Current limitations of the technology (i.e., “whole” exome really refers to about 85% coverage) means that cover-
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age for suspect genes may less than ideal or limited, as compared to an existing panel of potential candidate genes. Given the cost differential between some of the existing single gene or small panel tests and WES, these considerations are critical. On the other hand, when no CLIA validated single gene tests exist, yet the literature suggests genes as possible candidates, WES provides opportunities for diagnostic odyssey patients and their families to find an answer they often desperately seek. A further tension exists when the phenotype of the patients is ill-defined, thus likely attributable to a complexity of gene–gene, gene–protein, and gene– environment interactions. However, by articulating where coverage is low versus high we can create algorithms to replace a typical series of single gene tests ordered for certain differential diagnoses with WES. The extra data in WES may reveal more than the single genes tests elucidate, in particular when the initial phenotyping is incomplete. This underscores the importance of tracking the clinical presentations with the testing outcomes so that someday this type of triage is more evidence-based. If the consensus of the board is that there may be benefit from WES, the patient is enrolled as an IM Clinic patient. Whenever possible, additional family members are selected to create a genetically informative trio to test.
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Like the cancer service line, the patient and family members see the Certified Genetic Counselor for the Genomic Counseling session with similar goals. Lab orders for clinical WES (results returned in approximately 15 weeks) for the patient and the rest of the trio are submitted. Additionally, the patient is asked to participate in the IM Clinic research protocol that performs WES of all members of the trio. As test results are returned to the IM Consultant, the patient’s case is discussed at the weekly GOB meeting. Members of the GOB interpret test results in light of clinical findings and discuss potential therapy options. Patients are offered follow-up appointments with the IM Consultant and genetic counselor to review the results.
VALUE OF THE IM CLINIC AND LESSONS LEARNED As the cost of WES continues to decline, global experience and expertise in sequencing and genomic medicine increases, and sequencing tests become more accurate and sensitive, WES is entering clinical patient care [Chan and Ginsburg, 2011]. At Mayo Clinic, CIM’s IM Clinic provides the translation of genomic medicine to the clinical practice by bringing together multifaceted genomic experts and providing necessary infrastructure (Fig. 3).
Figure 3. Value of the IM Clinic. The IM Clinic demonstrates a mechanism for applying genomic medicine in the clinical practice—leveraging infrastructure created by CIM and bringing together multi-faceted genomic experts.
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Providing genomic counseling, coordination of insurance and sample acquisition, bioinformatic strategies, expert
At Mayo Clinic, CIM’s IM Clinic provides the translation of genomic medicine to the clinical practice by bringing together multifaceted genomic experts and providing necessary infrastructure (Fig. 3). Providing genomic counseling, coordination of insurance and sample acquisition, bioinformatic strategies, expert review boards, research options and genomic education, the IM Clinic demonstrates a
mechanism for applying genomic medicine to the clinical practice. review boards, research options and genomic education, the IM Clinic demonstrates a mechanism for applying genomic medicine to the clinical practice. At the time of this submission, the IM Clinic has been operating for just over 1 year and has seen approximately 60 patients per service line. Several original notions have been confirmed and other lessons have been learned that were not apparent until we became operational. First, dissociation of the IM Clinic from a single clinical department has turned out to have several advantages, as it allowed a degree of nimbleness and innovation that would not be readily achieved through existing departmental structures. The basis for the conceptual
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framework used focused models of care that could be easily tested and quickly modified—responding both to rapid advancement in the clinical laboratory offerings, and to changes in preferences of the health care providers as they gain expertise in using genomic data for patients—scaling up or down in response. This approach not only provides flexibility to react to the needs posed by the clinical practice, but allows development of more permanent structures once proven to be applicable, affordable, and valuable. In addition, CIM as a hybrid center has access, contacts and resources throughout research, education and the practice that can be quickly pulled together to design new processes responding to new ideas and new findings. Second, very significantly, we demonstrated that setting up the IM Clinic was not unlike setting up a new medical department, requiring a considerable investment in the infrastructure required to make the clinic work. Involving IT
Figure 4. Ongoing Implementation Challenges. After initial design and implementation, CIM continues to work on resolving challenges in translating genomic medicine to the practice. The figure describes several categories of these issues, which include turnaround time, billing issues, scalability, and education.
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and logistical expertise are essential elements to make the clinic work efficiently, allowing seamless utilization of the EHR, electronic orders, and systems for storage and retrieval of the resulting exomic data. Third, we confirmed that though patients are coming to us with some genetic knowledge, and with a high-risk tolerance, when it comes to genomic findings even well-educated patients require thoughtful conversations with Certified Genetic Counselors and genome-educated clinicians. We also learned that patients want materials ahead of time and materials to take home with them. Electronic education opportunities need to be further explored. A fourth lesson is the already well recognized need to have billing codes for genomic lab services established and recognized by payers. The landscape of coding and reimbursement for laboratory services continues to shift, making it difficult to anticipate what out-ofpocket expense patients might incur and what revenue impact it may have on CIM. A fifth lesson is the need to continue nurturing relations with other relevant departments. Even when buy-in is obtained, the rapidly changing landscape and unexpected issues require constant communication. For instance continual interactions between the Department of Laboratory Medicine and Pathology and CIM is required to set the priority of developing in-house Next Generation Sequencing tests needed by the IM Clinic patients versus other revenuegenerating tests. Sixth, we believe that broader availability of genomic medicine is possible with the proper integration of these services across diverse clinical sites. For clinical practices sharing a unified ordering system and electronic health record, this interaction can take place with a referral to IM Clinic from existing divisions and departments. Moreover, point-of-care learning can be used to
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create care process models for addressing consultations on genomic medicine. For clinical practices that do not share an ordering system and/or an electronic health record this interface can take place with the development of an e-consult mechanism along with means of secure distribution of medical records and conference/video interaction of the patient, referring health care provider with the staff of the IM Clinic. Additional outstanding issues remain (Fig. 4). Hurdles, such as (i) the scalability of genomic counseling, analytics and expert boards, (ii) how to expand beyond the initial offerings, (iii) how to reduce the turn-around time for clinical WES, and (iv) how to move into Whole Genome Sequencing, must be addressed for continued improvement and effective translation.
CONCLUSION In this review, we describe our approach to offer, execute and interpret WES on a clinical basis. Appreciation by health care providers and patients of potential benefits of exomic/genomic sequencing has advanced more quickly than expected. Accordingly, we propose that the Mayo IM Clinic model can be successfully replicated at other institutions willing and able to provide required resources and dedicated personnel.
ACKNOWLEDGMENTS We would like to thank the patients for their participation, and acknowledge the support of James L. and Donna K. Barksdale, Everett J. and Jane M. Hauck, George M. Eisenberg Foundation for Charities, and Mayo Foundation.
REFERENCES Burton H, Cole T, Lucassen AM. 2012. Genomic medicine: Challenges and opportunities for physicians. Clin Med 12:416–419. Chan IS, Ginsburg GS. 2011. Personalized medicine: Progress and promise. Annu Rev Genomics Hum Genet 12:217–244.
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Dietz HC. 2010. New therapeutic approaches to Mendelian disorders. N Engl J Med 363: 852–863. Farrugia G, Weinshilboum RM. 2013. Challenges in implementing genomic medicine: The Mayo Clinic Center for Individualized Medicine. Clin Pharmacol Ther 94:204– 206. Feero WG, Green ED. 2011. Genomics education for health care professionals in the 21st century. J Am Med Assoc 306:989–990. Green ED, Guyer MS, National Human Genome Research I. 2011. Charting a course for genomic medicine from base pairs to bedside. Nature 470:204–213. Guttmacher AE, Porteous ME, McInerney JD. 2007. Educating health-care professionals about genetics and genomics. Nat Rev Genet 8:151–157. Guttmacher AE, McGuire AL, Ponder B, Stefánsson K. 2010. Personalized genomic information: Preparing for the future of genetic medicine. Nat Rev Genet 11:161– 165. Haga SB, O’Daniel JM, Tindall GM, Lipkus IR, Agans R. 2012. Survey of US public attitudes toward pharmacogenetic testing. Pharmacogenomics J 12:197–204. Levin E, Riordan S, Klein J, Kieran S. 2012. Genetic counseling for personal genomic testing: Optimizing client uptake of post-test telephonic counseling services. J Genet Counsel 21:462–468. Manolio TA. 2010. Genomewide association studies and assessment of the risk of disease. N Engl J Med 363:166–176. Manolio TA, Chisholm RL, Ozenberger B, Roden DM, Williams MS, Wilson R, Bick D, Bottinger EP, Brilliant MH, Eng C, Frazer KA, Korf B, Ledbetter DH, Lupski JR, Marsh C, Mrazek D, Murray MF, O’Donnell PH, Rader DJ, Relling MV, Shuldiner AR, Valle D, Weinshilboum R, Green ED, Ginsburg GS. 2013. Implementing genomic medicine in the clinic: The future is here. Genet Med 15:258– 267. McCarthy JJ, McLeod HL, Ginsburg GS. 2013. Genomic medicine: A decade of successes, challenges, and opportunities. Sci Transl Med 5:189sr4. Stanek EJ, Sanders CL, JohansenTaber KA, Khalid M, Patel A, Verbrugge RR, Agatep BC, Aubert RE, Epstein RS, Frueh FW. 2012. Adoption of pharmacogenomic testing by US physicians: Results of a nationwide survey. Clin Pharmacol Ther 91:450– 458. Stankiewicz P, Lupski JR. 2010. Structural variation in the human genome and its role in disease. Annu Rev Med 61:437–455. Stratton MR, Campbell PJ, Futreal AP. 2009. The cancer genome. Nature 458:719– 724. Weil J. 2002. Genetic counselling in the era of genomic medicine. EMBO Rep 3:590–593. Wright Clayton E. 2003. Ethical, legal, and social implications of genomic medicine. N Engl J Med 349:562–569.
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Implementing Individualized Medicine into the Medical Practice KONSTANTINOS N. LAZARIDIS, TAMMY M. McALLISTER, DUSICA BABOVIC-VUKSANOVIC, SCOTT A. BECK, MITESH J. BORAD, ALAN H. BRYCE, ASHER A. CHANAN-KHAN, MATTHEW J. FERBER, RAFAEL FONSECA, KILEY J. JOHNSON, ERIC W. KLEE, NORALANE M. LINDOR, JENNIFER B. McCORMICK, ROBERT R. McWILLIAMS, ALEXANDER S. PARKER, DOUGLAS L. RIEGERT-JOHNSON, CAROLYN R. ROHRER VITEK, KIMBERLY A. SCHAHL, CLOANN SCHULTZ, KEITH STEWART, GEORGE C. THEN, ERIC D. WIEBEN, AND GIANRICO FARRUGIA
There is increasing recognition that genomic medicine as part of individualized medicine has a defined role in patient care. Rapid advances in technology and decreasing cost combine to bring genomic medicine closer to the clinical practice. There is also growing evidence that genomic-based medicine can advance patient outcomes, tailor therapy and decrease side effects. However the challenges to integrate genomics into the workflow involved in patient care remain vast, stalling assimilation of genomic medicine into mainstream medical practice. In this review we describe the approach taken by one institution to further individualize medicine by offering, executing and interpreting whole exome sequencing on a clinical basis through an enterprise-wide, standalone individualized medicine clinic. We present our experience designing and executing such an individualized medicine clinic, sharing lessons learned and describing early implementation outcomes. © 2014 Wiley Periodicals, Inc. KEY WORDS: genomic medicine; whole exome sequencing; individualized medicine clinic; personalized medicine
How to cite this article: Lazaridis KN, McAllister TM, Babovic-Vuksanovic D, Beck SA, Borad MJ, Bryce AH, Chanan-Khan AA, Ferber MJ, Fonseca R, Johnson KJ, Klee EW, Lindor NM, McCormick JB, McWilliams RR, Parker AS, Riegert-Johnson DL, Rohrer Vitek CR, Schahl KA, Schultz C, Stewart K, Then GC, Wieben ED, Farrugia G. 2014. Implementing individualized medicine into the medical practice. Am J Med Genet Part C Semin Med Genet 166C:15–23.
Disclosures: Dr. R. Fonseca has received a patent for the prognostication of multiple myeloma based on genetic categorization of the disease. He has received consulting fees from Medtronic, Otsuka, Celgene, Genzyme, BMS, Lilly, Onyx, Binding Site, Millennium and AMGEN. He also has sponsored research from Cylene and Onyx. K.N. Lazaridis M.D. is a Consultant Hepatologist and the Enterprise Director of the Mayo Individualized Medicine Clinic. His research work focuses on the genetics of cholestatic liver diseases. T.M. McAllister, M.S. is the Operations Manager for the Clinomics Translational and Bioethics Infrastructure programs within the Center for Individualized Medicine. D. Babovic-Vuksanovic, M.D. is a Clinical Geneticist and Chair of Department of Medical Genetics at Mayo Clinic. She has expertise in neurofibromatosis, dysmorphology and a variety of hereditary disorders. S.A. Beck is the Administrator of the Center for Individualized Medicine. He works in partnership with Dr. Farrugia to direct the Center's activities. M.J. Borad, M.D. is an Assistant Professor of Medicine in the Division of Hematology/Oncology at Mayo Clinic in Arizona. His work is focused on clinical applications of Next Generation sequencing for cancer patients. A.H. Bryce, M.D. is an oncologist at Mayo Clinic in Arizona. He is director of the genomic oncology service. A.A. Chanan-Khan is the chair of Hematology at Mayo Clinic in Florida and Assistant Director Arizona for the Center for Individualized Medicine. M.J. Ferber Ph.D. DABMG is a Clinical Molecular Geneticist at the Mayo Clinic. He is the Director of the Clinical Genome Sequencing Laboratory, and Co-director of the Individualized Medicine Clinomics Program. R. Fonseca M.D. is a Professor of Medicine and Chair of Medicine at Mayo Clinic in Arizona. He has an interest in tumor genomics, primarily as it relates to the treatment of myeloma and related conditions. K.J. Johnson, M.S., C.G.C. is a certified genetic counselor in the Center for Individualized Medicine at Mayo Clinic. Her work involves whole exome sequencing for diagnostic odyssey and oncology patients for the Center's Individualized Medicine Clinic and helping those patients understand genomic medicine and how it applies to their care. E.W. Klee, Ph.D., works as an Assistant Professor of Medical Informatics in the Departments of Health Sciences Research and Laboratory Medicine and Pathology, at the Mayo Clinic, Rochester, Minnesota. His expertise is in the bioinformatics of next generation sequencing with a focus on the clinical implementation of this technology.
ß 2014 Wiley Periodicals, Inc.
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INTRODUCTION The completion of the first human genome sequence in 2003 created much anticipation and promise among scientists, health care providers, media, and the public [Green et al., 2011]. This promise, however, did not result in immediate and tangible changes in standard medical care. While the media continued to anticipate and the public waited, genomic research progressed. Over the last few years impressive strides have been made to this effect. In recent years, emerging evidence suggests a
In recent years, emerging evidence suggests a rapidly growing expectation to incorporate genomic medicine into individualized patient care. rapidly growing expectation to incorporate genomic medicine into individualized patient care [Manolio et al.,
2013]. The promise of genomic medicine, as one part of individualized care, is to enable medical practitioners to make better clinical decisions through an
The promise of genomic medicine, as one part of individualized care, is to enable medical practitioners to make better clinical decisions through an improved informed process.
improved informed process. The anticipated results are to improve targeted therapies, reduce side-effects, increase prevention and prediction of disease, enable earlier disease intervention, reduce healthcare costs and improve patient outcomes. Despite the numerous benefits, the challenges to integrate genomics into patient care are vast. While rapid advances in technology and decreasing cost combine to bring genomic medicine
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closer to the clinical practice, significant barriers continue to stall assimilation in mainstream medical practice. Variable access and standardization of technology, education, reimbursement, regulation, evidence-based clinical validity, and evolving ethical dilemmas continue to provide challenges [Chan and Ginsburg, 2011; Burton et al., 2012; Farrugia and Weinshilboum, 2013; McCarthy et al., 2013]. Responding to this clinical need, in 2012 Mayo Clinic launched the current Center for Individualized Medicine (CIM) charging it to discover and integrate the latest genomic and clinical sciences into personalized care for all patients. As a “hybrid” center with research and clinical responsibilities, CIM’s goal is to promote rapid translation of research into personalized clinical care and to create genomic medicine mechanisms that are instantly diffusible and applicable across Mayo Clinic’s multiple, geographically dispersed campuses. Thus, one CIM initiative, the Individualized Medicine (IM) Clinic, was created to overcome barriers of translating next generation sequencing into the medical practice—to establish a model uniting the clinical expertise of
N.M. Lindor, M.D. is a medical geneticist with a longstanding interest and expertise in the recognition and management of hereditary predisposition to cancer. More recently she has been involved with exploring the integration and translation of the nextgen-based molecular diagnostics to clinical practice. J.B. McCormick, Ph.D., M.P.P is an Assistant Professor of Biomedical Ethics at the Mayo Clinic. Her work focuses the ethical, legal, and social implications of genetics and genomic translational research. R.R. McWilliams, M.D. is an Associate Professor of Oncology at Mayo Clinic and Chair of the Genomic Tumor Board. His research work focuses on the genetics of pancreatic cancer. A.S. Parker, Ph.D. is an Associate Professor of Epidemiology and Urology and an Associate Director for the Mayo Center for Individualized Medicine. His research focuses on developing biomarkers for genitourinary cancers and exploring genetic and environmental risk factors for these cancers. D.L. Riegert-Johnson, M.D. works as a medical geneticist and gastroenterologist at Mayo Clinic Florida. He trained at the Mayo Clinic in Rochester and Johns Hopkins. C.R. Rohrer Vitek, M.S. is the Education Program Manager in the Center for Individualized Medicine. Her work and research interests include development of provider and patient education to support implementation of genomic medicine into practice. K.A. Schahl is a certified genetic counselor in the Center for Individualized Medicine at Mayo Clinic. Her work involves whole exome sequencing for diagnostic odyssey and oncology patients for the Center's Individualized Medicine Clinic and helping those patients understand genomic medicine and how it applies to their care. C.G. Schultz works as the senior project manager in the Center for Individualized Medicine at Mayo Clinic. K. Stewart, M.B., Ch.B. is a hematology oncologist at Mayo Clinic Arizona and an Associate Dean for Research. G. C. Then, MBA, works as a Principal Health Systems Engineering Analyst at the Division of Systems and Procedures in Mayo Clinic, Rochester. His area of focus is work process design and improvement. E.D. Wieben, Ph.D. is a Professor and Chair Emeritus of Biochemistry and Molecular Biology at Mayo Clinic. He currently directs the Medical Genome Facility at Mayo. G. Farrugia, M.D. is a Gastroenterologist and the Director for the Mayo Clinic Center for Individualized Medicine. Grant sponsor: Cylene; Grant sponsor: Onyx. *Correspondence to: Gianrico Farrugia, M.D., Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail: [email protected] DOI: 10.1002/ajmg.c.31387 Article first published online in Wiley Online Library (wileyonlinelibrary.com): 10 March 2014
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Figure 1. The Individualized Medicine Clinic as a Mechanism for Diffusion of Genomic Medicine. The clinical practice expertise in phenotyping patient disease is merged with genotyping tools and expertise within the IM Clinic.
numerous subspecialties in phenotyping diseases and disorders with new tools of genomic medicine (Fig. 1). The IM Clinic opened to patients on September 30, 2012. In this article, we present our experience designing and executing an enterprise-wide IM Clinic, sharing lessons learned and describing early implementation outcomes.
DESIGNING THE INDIVIDUALIZED MEDICINE CLINIC An informal survey of genomic offerings in academic institutions suggests a common “silo” approach towards the introduction of genomics into patient care, where most efforts were spearheaded by one particular individual, group or department. Translating individualized medicine into the practice “is as much a cultural and political exercise within a given institution as a scientific one” [Manolio et al., 2013]. There are benefits to being positioned within an established department, including having buy-in from department heads and avoiding the significant effort required to create an infrastructure for the clinic. However, fully functioning multi-disciplinary IM Clinic integrating genomics requires focused and multi-faceted expertise—
perhaps larger than a single department can provide. Based on Mayo Clinic’s team-based model, CIM created a multi-disciplinary, multi-site, committee—the IM Clinic Work Group—to oversee the process of creating the IM Clinic. The Work Group positioned the IM Clinic within CIM, and recruited physicians from across the institution’s departments to contribute expertise. Unaffiliated, the IM Clinic processes were created de novo and designed for the ideal patient encounter, transcending the limits of a single medical, surgical or pathology specialty. Institutional bio-banking, genome sequencing, and bioinformatics infrastructure, along with a subset of information technology and bioethics resources, were aligned under CIM to facilitate infrastructure coordination and prioritization.
INITIAL OFFERINGS OF THE INDIVIDUALIZED MEDICINE CLINIC Abundant literature describes how molecular characterization [McCarthy et al., 2013], genome-wide association studies [Manolio, 2010], and structural variation [Stankiewicz and Lupski, 2010] are helping to elucidate the genomic influences on cancer [Stratton et al., 2009] and complex diseases
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[McCarthy et al., 2013], and reveal effective treatments [Dietz, 2010]. Given this, after considering the likelihood of actionable clinical results, the cost associated with the process and the ethical, legal and social aspects, two services were selected for initial implementation. The first, for patients with advanced cancer who fail standard therapy (or where no proven standard therapy exists) and fit specific tumor and life expectancy criteria, employs comparison of normal and tumor DNA to identify causative or contributing mutations and, subsequently, allows targeted therapy based on genomic information. The second service being for patients with a suspected genetic condition for whom previous genetic testing did not reveal an etiology (i.e., diagnostic odyssey), uses Whole Exome Sequencing (WES) to reveal the variant(s) responsible for the patient’s disease and proposes potential treatments. This step-wise approach to service line development permitted flexible planning, resource maximization, and expedited IM Clinic operations in a short period of time between conception and offering the relevant clinical services. Furthermore, we believe that the initial experiences gained will be instrumental to the development of additional service lines with broader clinical applicability (i.e., prevention genomics, subscription genomics, etc.).
COMPONENTS AND ROLES OF THE INDIVIDUALIZED MEDICINE CLINIC In a pilot project of this magnitude, it is essential to have a group of champions able to affect change-convincing skeptics and maneuvering organizational hurdles [Manolio, 2010]. Broad representation of experts from across Mayo Clinic, to ensure wide-ranging input during the translational phase of the IM Clinic, was essential to defining the unique professional components necessary in the IM Clinic and, subsequently, the processes for each. While each service line requires a slightly different work flow and professional skills, a common infrastructure
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was built to accommodate the basic IM Clinic function. Representatives from IT, bioinformatics, bioethics, patient access management, education, revenue cycle, operations and the research sequencing facilities joined the IM Clinic Work Group to design the structures and processes implemented across all Mayo Clinic campuses. IM Consultation: IM Clinic Consultants As is customary at Mayo Clinic, every patient is assigned a lead physician (i.e., consultant) to oversee and coordinate his/her healthcare. For the IM Clinic, interested physicians across many subspecialties act as an IM Consultant and are assigned to lead care for patients referred to the IM Clinic. For the cancer service, these are medical oncologists or hematologists. Diagnostic Odyssey patients are assigned an IM Consultant from General Internal Medicine, Medical Genetics or a subspecialty department, according to the patient’s main symptoms or physical findings. Clinical departments represented in the IM Clinic services currently include Medical Genetics, Oncology, Hematology, Dermatology, Pharmacology, Neurology, Ophthalmology, Gastroenterology, Hepatology, Cardiology, Rheumatology, Pediatrics, General Internal Medicine, and Family Practice. The assigned IM Consultant reviews the initial consult request for appropriateness; evaluates the patient; coordinates genetic and financial counseling, sample collection, surgery (if needed), and laboratory activities; presents the case and results at expert board meetings; and relays advice for next steps to the patient or the referring physician. Genomic Counseling: CIM Genetic Counselors Genomic medicine is a complex discipline. Patients, often well-prepared and seeking new options for treatment, are often still unaware of basic genetic principles, and information WES can and cannot yet provide [Haga et al.,
2012; Levin et al., 2012]. Vocabulary alone can overwhelm patients. Patients must be informed about the potential risks and ramifications created by genomic data [Weil, 2002]. The IM Clinic process was designed to allow for the time necessary for faceto face visits between the CIM Genetic Counselors and the patient (and family) in a “genomic counseling” session. In this session, genetic counselors define and explain vocabulary and concepts; talk explicitly about different lab tests and their potential results and risks; and apply a shared decision-making model to help the patient select the categories of genomic results to be returned. CIM Certified Genetic Counselors collaborated with the Center for
The IM Clinic process was designed to allow for the time necessary for face-to face visits between the CIM Genetic Counselors and the patient (and family) in a “genomic counseling” session. In this session, genetic counselors define and explain vocabulary and concepts; talk explicitly about different lab tests and their potential results and risks; and apply a shared decision-making model to help the patient select the categories of genomic results to be returned.
Innovation and CIM’s Community Advisory Board, to create tools, specifically for the IM Clinic, to help patients make decisions about incidental findings that they may or may not want to learn for this testing. Counselors also discuss testing costs and coordinate insurance authorization. The genetic counselor
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often becomes the patient’s main point of contact. Sample Acquisition: Surgeons, Pathology, and Laboratory Medicine Tumor tissue quality and quantity are essential to high-quality test results. Necessary sample requirements for the sequencing tests ordered for IM Clinic patients differ in volume, form and destination laboratory. Because Mayo Clinic’s Department of Laboratory Medicine does not yet offer WES clinically, standard laboratory preparatory processes were not in place to accommodate the orders for cancer tissue preparation for DNA sequencing. IM Clinic Pathology leaders designed new workflow processes routing appropriate samples to external CLIA and Mayo laboratories. Expert Review Boards: Inter-Department Expertise In the post-genome era, a major challenge for physicians is interpretation of genomic data and results [Stanek et al., 2012]. With this being key to learning and translating genomic medicine into the practice, the IM Clinic Work Group designed a genomicsfocused expert board for each service line (Genomic Tumor Board [GTB] and Genomic Odyssey Board [GOB] for service line one and two, respectively) to act as a clinical interpretation team; assisting the patient’s physician with results, potential treatment options and access to therapies. As IM Clinic patients’ test results are returned to the IM Consultant, the expert boards convene weekly for an in-person and video conference across all Mayo campuses to discuss results and formulate recommendations and/or action plans. These multidisciplinary boards encourage wide participation and exchange of experience, drawing genomic medicine experts from across the institution, including standing members from Anatomic Pathology, Molecular Genetics, Clinical Genome Sequencing
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Laboratory, Hematopathology, Medical Genome Facility (research), bioinformatics and biomedical ethics. Joining to provide focused, multi-disciplinary attention to each individual case, disease-oriented specialists (as warranted) and the referring physician are also invited to participate in case discussions. All patient material is de-identified for discussion. Multi-site video-conferencing allows the boards to share laboratory reports, databases, and other materials that enable collaboration without regard to patient or board member location. Following case discussions, the board chair enters one unified clinical note in the electronic health record summarizing the group’s deliberations and recommendations. Infrastructure Support: IT and Electronic Data Systems Integrating genomic medicine into practice requires consideration of multiple practice management IT systems, that is, electronic health records (EHR), ordering and appointment scheduling systems. Genomic medicine cuts across specialties and divisions and is not easily compartmentalized in the EHR. Documentation in the EHR remains unchanged, that is, categorized within the applicable division following the home department of the IM Consultant. Electronic appointment orders were created for internal and affiliated practice health care providers. A standardized approach to the clinical workflow and naming convention was developed. As with all laboratory tests, the raw data file (.BAM file) is placed in a centralized, tiered storage environment where it remains accessible for future use. An underlying database houses all of the genetic variants for IM Clinic patients, facilitating reanalysis as medical knowledge evolves. Infrastructure Support: Bioethics Numerous ethical, legal, and social issues (ELSI) unique to genomic medicine require careful attention [Wright Clayton, 2003]. How to treat “inciden-
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tal findings” and convey the concepts of variants and risks to patients are among the topics to consider. The goal of the IM Clinic is to lead the translation of genomic medicine into standard clinical practice. To accomplish this in an ethically and socially responsible way, members of the Biomedical Ethics program were integrated upfront into IM Clinic infrastructure. Tracking nationally debated genomic-based medicine topics, bioethicists provided insight on ELSI concerns to both expert boards, and have been engaged in research studies pertinent to the IM Clinic, helping design the protocols and executing the patient informed consent process. To continually improve IM Clinic services, the Biomedical Ethics program has launched an ELSI study, tracking patients’ hopes, concerns and expectations as well as clinicians’ experiences, concerns in meeting the needs of patients and barriers faced in implementing genomics into practice. Infrastructure Support: Research Sequencing Facility and Bioinformatics Analytics Team The analysis and interpretation of WES data is complicated. To facilitate our understanding of the challenges and requirements in establishing this process internally, all patients seen in the IM Clinic are offered WES clinically (through a collaborative CLIA certified and College of American Pathologists accredited laboratory) and through the IM Clinic research protocol. The internally generated research data is initially processed through our DNA sequencing workflow, including Novoalign for sequence re-alignment and GATK (following best-practices) for recalibration, realignment, and germline variant calling. Subsequent to this analysis, endpoint specific processes are executed to identify and classify mutations in a service line specific manner, including using an integrated and multi-algorithmic solution for calling somatic variants in tumor samples and using a complementary three-track process for classifying mode-of-inheritance specific
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mutations for the diagnostic odyssey cases. Finally, an extensive set of annotations is used to provide context to the sample-specific mutations and facilitate the prioritization of the data for review by the research analysis teams and selection of actionable findings. Ultimately, findings from the research study are compared back to the actionable mutations reported by the clinical send-out and used to validate and refine the methodologies enacted. As such, this dual track approach (one clinical, the other research) is aiding in our development of a completely internalized clinical process. The IM Clinic research protocol allows for exome data generation in our research Medical Genome Facility and subsequent analysis by an IM Clinicsponsored research team focused on establishing an approach that would provide a clinical interpretation of the results. One for each service line, the analysis teams consist of experts from multiple disciplines, including clinical molecular genetics, genetic counseling, medical genetics, bioinformatics, biostatistics, and cancer biology. The teams are charged with reviewing each case and identifying what analyses and contextual information is required in order to interpret the results. The analysis teams also review the quality of data generated for each case, identify a list of highinterest mutations, provide short interpretative summaries of these variants, and pass the information on to the GTB and GOB for further consideration and review. Infrastructure Support: Education Education and communication are required to translate genomic medicine to the rest of the practice [Guttmacher et al., 2007; Feero and Green, 2011] and to patients [Green et al., 2011]. To address this, CIM’s Education Program created training materials, daily operational checklists for IM Consultants and scheduling staff, and collaborated with IM Clinic leaders to create educational presentations and operational instructions for both internal and external referring physicians.
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To create effective genomically focused patient educational materials for the IM Clinic, collaborations were set up between genetic counselors, the Mayo Clinic Center for Innovation, the institution’s patient education department and other Mayo Clinic writers. The goal is to make innovative, helpful genomic medicine materials in the form of workbooks, pamphlets, videos and animations available in the practice and via the IM Clinic webpage (http:// mayoresearch.mayo.edu/center-for-individualized-medicine/individualizedmedicine-clinic.asp). Infrastructure Support: Revenue Cycle Current reimbursement systems do not yet address using genomic medicine in the practice [Guttmacher et al., 2010]. When the IM Clinic opened, reimbursement for genomic services was hard to predict without CPT billing recognition of whole exome and other next generation sequencing laboratory tests. This situation will persist while codes and recognition of the services are slowly incorporated into national plans. Within these limits, revenue cycle representatives and Certified Genetic Counselors have worked to assist patients to achieve pre-authorization or commitment for payment from insurance providers on a case-by-case basis. On average, about
half of our patients get at least partial coverage.
PATIENTS SEEN IN THE IM CLINIC Instead of establishing a separate appointment scheduling and reception infrastructure, the IM Clinic partnered with various divisions to build access and in-take models. The Departments of Oncology and Medical Genetics incorporated existing members of allied staffs into the triaging, scheduling and in-take coordinating of IM Clinic patients. This required slight modifications of standard department processes to accommodate the IM Clinic patient flow. Patient Access Management incorporated decision trees to triage patients requesting “individualized medicine” and other commonly used “personalized medicine” terms. After the patient appointment request, the patient workflow (Fig. 2) is executed. Details of the service lines’ processes diverge slightly to accommodate the varied needs of the patients. Cancer Service Line Patient Flow Once a request is received for the cancer service line, a clinical Oncologist or Hematologist serving as the IM Clinic Consultant reviews it to determine if entry criteria are met. As part of this
Figure 2. Basic Individualized Medicine Clinic Workflow. The figure illustrates the process from the initial patient referral through patient care visits within the IM Clinic, sample procurement and testing, discussion, and recommendations by the Genomic Board culminating with the patient follow up.
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process, imaging, pathology and pertinent medical history are made available to the IM Consultant. The patient is enrolled in the IM Clinic if he/she has a tumor that can be excised or biopsied, can tolerate the procedure, has failed standard therapy and has a life expectancy likely to extend beyond 12 weeks. The patient meets with the IM Consultant, who discusses the concept of genomic testing in order to define a new therapy. Information about specific DNA tests, risks and expectations, basic costs and result timelines are also discussed. If the patient agrees to genomic testing, the IM Consultant contacts the IM Clinic Pathologist to discuss the tissue requirements and determines which tests should be ordered based on the patient’s status and tissue availability. The standard clinical order is an array CGH (turn-around time approximately 3 weeks), a cancer-gene panel (covering approx. 200 genes with results in approximately 3 weeks) and WES (results returned in approximately 15 weeks). Additionally, though not required, patients are also offered the opportunity to participate in the IM Clinic research protocol, where our research facility performs RNA sequencing and WES. This protocol serves multiple purposes including as a quality control measure to validate the results of external labs, to interrogate the value of RNA sequencing in predicting clinical outcomes, and to test new compare new sequencing platforms as they become available. Approximately 40% of patients have chosen to participate in the research in addition to the clinical services. After tissue priorities and plans are discussed, the IM Consultant orders a consult with a surgeon when applicable (tissue excision) and orders the Genomic Counseling session. The patient then meets the CIM Certified Genetic Counselor for basic genomic education, explanation of the specific testing and our partner-lab consent forms. The counselor guides the patient (and family) through a shared decision-making process that includes the social and ethical considerations of DNA sequencing, test costs and
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insurance coverage issues. They also have the opportunity to meet with a financial counselor if necessary. A bioethics representative meets the patient to offer enrollment in the IM Clinic research study as well as the IM Clinic ELSI study. The patient continues with a surgery consult, phlebotomy and tissue acquisition. Standard tumor pathology analysis is performed, followed by DNA extraction and delivery to the sequencing laboratories. Given the significant difference in turn-around time for array CGH and gene panel assays compared to WES, all results are discussed as they become available. As test results are returned to the IM Consultant over the course of about 15 weeks, the patient’s case is discussed at the weekly Genomic Tumor Board (GTB) meeting. GTB members interpret test results in light of clinical findings and discuss potential actionable treatment options. This information is provided to the patient’s primary oncologist by the IM Consultant allowing discussion of potential next treatment steps. A summary clinical note is created for the treating clinician. Diagnostic Odyssey Service Line Patient Flow Consult requests made for Diagnostic Odyssey patients prompt a CIM Certified Genetic Counselor to contact the patient and collect pedigree information (if not already available). Additionally, the Counselor reviews the medical record and provides case details to the IM Consultant who presents the case at the weekly expert board meeting. Board members discuss how likely the patient is to benefit from WES. At the fore of these discussions are considerations of costs, patient medical and family histories, likelihood of success and meaningful applicability of findings from WES versus other genetic tests, and patient expectations. Presently little data exist to inform this decision, and there is always a tension between recommending continuation of conventional diagnostics versus proceeding with WES. Current limitations of the technology (i.e., “whole” exome really refers to about 85% coverage) means that cover-
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age for suspect genes may less than ideal or limited, as compared to an existing panel of potential candidate genes. Given the cost differential between some of the existing single gene or small panel tests and WES, these considerations are critical. On the other hand, when no CLIA validated single gene tests exist, yet the literature suggests genes as possible candidates, WES provides opportunities for diagnostic odyssey patients and their families to find an answer they often desperately seek. A further tension exists when the phenotype of the patients is ill-defined, thus likely attributable to a complexity of gene–gene, gene–protein, and gene– environment interactions. However, by articulating where coverage is low versus high we can create algorithms to replace a typical series of single gene tests ordered for certain differential diagnoses with WES. The extra data in WES may reveal more than the single genes tests elucidate, in particular when the initial phenotyping is incomplete. This underscores the importance of tracking the clinical presentations with the testing outcomes so that someday this type of triage is more evidence-based. If the consensus of the board is that there may be benefit from WES, the patient is enrolled as an IM Clinic patient. Whenever possible, additional family members are selected to create a genetically informative trio to test.
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Like the cancer service line, the patient and family members see the Certified Genetic Counselor for the Genomic Counseling session with similar goals. Lab orders for clinical WES (results returned in approximately 15 weeks) for the patient and the rest of the trio are submitted. Additionally, the patient is asked to participate in the IM Clinic research protocol that performs WES of all members of the trio. As test results are returned to the IM Consultant, the patient’s case is discussed at the weekly GOB meeting. Members of the GOB interpret test results in light of clinical findings and discuss potential therapy options. Patients are offered follow-up appointments with the IM Consultant and genetic counselor to review the results.
VALUE OF THE IM CLINIC AND LESSONS LEARNED As the cost of WES continues to decline, global experience and expertise in sequencing and genomic medicine increases, and sequencing tests become more accurate and sensitive, WES is entering clinical patient care [Chan and Ginsburg, 2011]. At Mayo Clinic, CIM’s IM Clinic provides the translation of genomic medicine to the clinical practice by bringing together multifaceted genomic experts and providing necessary infrastructure (Fig. 3).
Figure 3. Value of the IM Clinic. The IM Clinic demonstrates a mechanism for applying genomic medicine in the clinical practice—leveraging infrastructure created by CIM and bringing together multi-faceted genomic experts.
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Providing genomic counseling, coordination of insurance and sample acquisition, bioinformatic strategies, expert
At Mayo Clinic, CIM’s IM Clinic provides the translation of genomic medicine to the clinical practice by bringing together multifaceted genomic experts and providing necessary infrastructure (Fig. 3). Providing genomic counseling, coordination of insurance and sample acquisition, bioinformatic strategies, expert review boards, research options and genomic education, the IM Clinic demonstrates a
mechanism for applying genomic medicine to the clinical practice. review boards, research options and genomic education, the IM Clinic demonstrates a mechanism for applying genomic medicine to the clinical practice. At the time of this submission, the IM Clinic has been operating for just over 1 year and has seen approximately 60 patients per service line. Several original notions have been confirmed and other lessons have been learned that were not apparent until we became operational. First, dissociation of the IM Clinic from a single clinical department has turned out to have several advantages, as it allowed a degree of nimbleness and innovation that would not be readily achieved through existing departmental structures. The basis for the conceptual
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framework used focused models of care that could be easily tested and quickly modified—responding both to rapid advancement in the clinical laboratory offerings, and to changes in preferences of the health care providers as they gain expertise in using genomic data for patients—scaling up or down in response. This approach not only provides flexibility to react to the needs posed by the clinical practice, but allows development of more permanent structures once proven to be applicable, affordable, and valuable. In addition, CIM as a hybrid center has access, contacts and resources throughout research, education and the practice that can be quickly pulled together to design new processes responding to new ideas and new findings. Second, very significantly, we demonstrated that setting up the IM Clinic was not unlike setting up a new medical department, requiring a considerable investment in the infrastructure required to make the clinic work. Involving IT
Figure 4. Ongoing Implementation Challenges. After initial design and implementation, CIM continues to work on resolving challenges in translating genomic medicine to the practice. The figure describes several categories of these issues, which include turnaround time, billing issues, scalability, and education.
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and logistical expertise are essential elements to make the clinic work efficiently, allowing seamless utilization of the EHR, electronic orders, and systems for storage and retrieval of the resulting exomic data. Third, we confirmed that though patients are coming to us with some genetic knowledge, and with a high-risk tolerance, when it comes to genomic findings even well-educated patients require thoughtful conversations with Certified Genetic Counselors and genome-educated clinicians. We also learned that patients want materials ahead of time and materials to take home with them. Electronic education opportunities need to be further explored. A fourth lesson is the already well recognized need to have billing codes for genomic lab services established and recognized by payers. The landscape of coding and reimbursement for laboratory services continues to shift, making it difficult to anticipate what out-ofpocket expense patients might incur and what revenue impact it may have on CIM. A fifth lesson is the need to continue nurturing relations with other relevant departments. Even when buy-in is obtained, the rapidly changing landscape and unexpected issues require constant communication. For instance continual interactions between the Department of Laboratory Medicine and Pathology and CIM is required to set the priority of developing in-house Next Generation Sequencing tests needed by the IM Clinic patients versus other revenuegenerating tests. Sixth, we believe that broader availability of genomic medicine is possible with the proper integration of these services across diverse clinical sites. For clinical practices sharing a unified ordering system and electronic health record, this interaction can take place with a referral to IM Clinic from existing divisions and departments. Moreover, point-of-care learning can be used to
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create care process models for addressing consultations on genomic medicine. For clinical practices that do not share an ordering system and/or an electronic health record this interface can take place with the development of an e-consult mechanism along with means of secure distribution of medical records and conference/video interaction of the patient, referring health care provider with the staff of the IM Clinic. Additional outstanding issues remain (Fig. 4). Hurdles, such as (i) the scalability of genomic counseling, analytics and expert boards, (ii) how to expand beyond the initial offerings, (iii) how to reduce the turn-around time for clinical WES, and (iv) how to move into Whole Genome Sequencing, must be addressed for continued improvement and effective translation.
CONCLUSION In this review, we describe our approach to offer, execute and interpret WES on a clinical basis. Appreciation by health care providers and patients of potential benefits of exomic/genomic sequencing has advanced more quickly than expected. Accordingly, we propose that the Mayo IM Clinic model can be successfully replicated at other institutions willing and able to provide required resources and dedicated personnel.
ACKNOWLEDGMENTS We would like to thank the patients for their participation, and acknowledge the support of James L. and Donna K. Barksdale, Everett J. and Jane M. Hauck, George M. Eisenberg Foundation for Charities, and Mayo Foundation.
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