The DCM Research Project
An Overview of how the DCM Consortium and our current studies fit together.
The DCM Research Project encompasses all of the DCM research activities, studies, information, and related resources. Please see Our History for more detail of the development of the DCM Research Project and What We’ve Accomplished for the evolution of our research studies.
The DCM Research Project was started in 1993, first named the Familial Dilated Cardiomyopathy Research Project, with the singular focus to gather very large families with multiple individuals affected with DCM. Such very large families are exceptionally helpful for gene discovery. This was particularly the case with the linkage analysis and gene mapping methods available in the 1990s. The high value of such families remains even though our discovery approaches now include exome and genome sequencing.
From 1993 – 2013, the research study of the Project was entitled “The Familial Dilated Cardiomyopathy (FDC) Study.” This name was changed in 2013 to “The DCM Study.” Please see Our History for more detail. With the new Precision Medicine study in 2015 and the expansion of the website, this ongoing study is now named “The DCM Discovery Study.”
By the mid-2000’s, based on studies from our group and others, it became clear that familial DCM had a genetic basis even though only a fraction of genetic cause of FDC had been identified. Based on our preliminary data 2004-2008 (summarized in 2009), we developed the hypothesis that all DCM, whether familial or non-familial, had a genetic basis. It also became clear that to test this hypothesis we would need a much larger cohort of DCM patients and families. For this reason Dr Hershberger created the DCM consortium concept in late 2008, and from 2009-2011 recruited 5 sites and wrote research applications to fund a major DCM discovery study. Please see Our History for more detail. Once at the Ohio State University in 2012, Dr Hershberger placed renewed emphasis on testing this general hypothesis. With the availability of exome and genome sequencing, and the rapid emergence of precision medicine (see What is Precision Medicine), the DCM Consortium was expanded again and the Precision Medicine Study was conceived and developed from 2013-2015.
The DCM Consortium
DCM CONSORTIUM OVERVIEW
The DCM Consortium is a multisite investigator group to conduct research studies focused on the genetics and genomics of DCM, including discovery, mechanisms of disease, genetic epidemiology, clinical genetics, and precision medicine and its related questions of behavioral and implementation science. The Consortium was developed independently of any specific study or funding source, and was also designed to be active prior to and following funding and completion of any specific study. The DCM Consortium is currently conducting one study, The Precision Medicine Study. Additional studies focused on DCM genetics and genomics can be considered for development, funding and conduct.
DCM CONSORTIUM CONTRACT
Dr Ray Hershberger, conceived and designed the DCM Consortium and placed this into contract language while at the University of Miami (UM) in 2009-2010, with legal assistance provided by the UM Clinical Trials office. The contract defines the relationships between the sponsoring institutions, Dr Hershberger, and the Site PI’s. The contract was modified slightly for OSU.
RATIONALE FOR THE DCM CONSORTIUM AND CRITERIA FOR SELECTION OF SITES
The DCM Consortium was formed so that recruitment potential would be large enough over a 2-3 year period that DCM studies could be designed that would be competitive for NIH funding within the usual 5 year NIH funding time frame.
DCM Consortium sites are selected based upon the experience and expertise of the site PI and their local collaborators, the structure and stability of site’s heart failure and DCM programs, access to racially and ethnically diverse DCM patients, numbers of DCM patients available for study, and willingness, ability, and success of the site to promptly process and approve contractual and regulatory documents.
The number of sites is based upon the size of the cohort needed to achieve the scientific goals of the study of interest. For example, in the original (parent) Precision Medicine Study, funded by the NHLBI, 11 sites were sufficient. With the NHGRI supplement to the Precision Medicine Study, one or more sites, enriched in DCM patients of Hispanic ethnicity, will be added.
The DCM Consortium is based at The Ohio State University. Ray Hershberger MD has organized the DCM Consortium and is the overall Principal Investigator. The site Principal Investigators (PI’s) are cardiologists with special expertise in DCM, heart failure and in most cases advanced therapies including ventricular assist devices and cardiac transplantation.
|INSTITUTION||SITE PRINCIPAL INVESTIGATOR|
|Ohio State University, Columbus||Garrie Haas, MD|
|University of Maryland, Baltimore||Stephen Gottlieb, MD|
|Stanford University, Palo Alto, CA||Euan Ashley, MD|
|Cleveland Clinic, Cleveland, OH||Wilson Tang, MD|
|Medstar Health Research Institute, Washington, DC||Mark Hofmeyer, MD|
|University of Pennsylvania, Philadelphia||Anjali Owens, MD|
|Louisiana State University, New Orleans||Frank Smart, MD|
|Inova Heart and Vascular, Fairfax, VA||Palak Shah, MD|
|University of Michigan, Ann Arbor||Keith Aaronson, MD|
|Massachusetts General Hospital, Boston||Christopher Newton-Cheh, MD|
|Emory University, Atlanta||Alanna Morris, MD|
|University of Southern California, Los Angeles||Martin Cadeiras, MD|
|INSTITUTION||SITE PRINCIPAL INVESTIGATOR|
|Tufts University, Boston, MA||Gordon Huggins, MD|
|University of Washington, Seattle||Daniel Fishbein, MD|
|Methodist Hospital, Houston||Barry Trachtenberg, MD|
|South Miami Heart Center, Miami, FL||Javier Jimenez, MD PhD|
|University of Mississippi Medical Center, Jackson||Charles Moore, MD|
|University of Arizona, Tuscon||Nancy Sweitzer, MD|
|University of Nebraska Medical Center, Omaha||Brian Lowes, MD PhD|
|Washington University, St Louis, MO||Greg Ewald, MD|
|New York University Lagone Medical Center, New York City||Steven Pan, MD PhD|
|Drexel University, Philadelphia, PA||Howard Eisen, MD|
|University of Alabama, Birmingham||Salpy Pamboukian, MD|
Expansion of the Consortium. Cardiovacular faculty at academic heart failure/transplant sites with access to DCM patients who have interest in joining the DCM Consortium for current or future studies are encouraged to contact Dr Hershberger.
Precision Medicine Study
A DCM Consortium Study funded by the National Institutes of Health in 2015.
The Precision Medicine Study is a research study to test the general hypothesis that most of dilated cardiomyopathy (DCM) of unknown cause, otherwise meeting a formal diagnosis for idiopathic dilated cardiomyopathy (IDC), has an underlying genetic basis regardless of whether it has been categorized as familial or non-familial DCM. For those not familiar with the DCM or IDC terms, please see our Frequently Asked Questions.
Dilated cardiomyopathy of unknown cause (DCM), known clinically as idiopathic dilated cardiomypathy, is the most common cardiomyopathy and is the leading cause of heart transplantation. By our estimates DCM affects approximately one million individuals, and so has a major impact on US public health. DCM is commonly asymptomatic until very late in its course when it causes heart failure, disability, and death. Because of its clinical course, any means to identify patients at risk for DCM or to detect DCM in its asymptomatic phase could provide enormous opportunity for intervention to extend lives and prevent late-stage disease. Within this paradigm precision medicine for DCM could greatly impact health care outcomes and costs. Recent advances in DCM genetics have introduced these possibilities, but unresolved questions of familial recurrence risk, genetic etiology, racial differences, and family-based screening must be addressed to move ahead. Our central hypothesis, based on our published studies, states that DCM has substantial genetic basis. For this study we hypothesize that: (a) 35% of probands of both European and African ancestry (EA/AA) will be classified as familial in a cohort recruited in a multicenter US consortium and given explicit recommendations and assistance to achieve the clinical screening of relatives; (b) approximately 40% of DCM probands, whether categorized as familial or non-familial, or as EA or AA, will have pathogenic or likely pathogenic variants in genes previously implicated in DCM; and (c) a tailored intervention to help DCM probands communicate DCM risk to their family members will improve the uptake and impact of necessary clinical and genetic testing. To test these hypotheses, we propose to: (1) estimate and compare the frequencies of EA and AA DCM probands classified as having familial DCM; (2) estimate and compare the proportions of probands with an identifiable genetic cause of DCM in groups defined by proband classification (familial/non-familial) and ancestry (EA/AA); and (3) evaluate the impact of a randomized intervention to aid and direct family communication on participation of at-risk family members in clinical screening and appropriate follow-up surveillance for DCM. These aims will be accomplished by recruiting a cohort of 1200 DCM probands (600 EA and 600 AA), performing cardiovascular clinical screening of 2400 family members, performing genetic testing of probands and affected family members by exome sequencing, returning genetic results, and randomizing probands to an intervention to improve family communication regarding DCM risk. Proving these hypotheses would be transformative for the field: rather than viewing DCM as only a clinical diagnosis, we would understand DCM as a genetic disease that should be managed using genetic diagnostic and family-based preventive strategies. Our study results would make precision medicine for DCM a reality.
|Study Principal Investigator, Collaborating Investigators and Consultants|
|Ray Hershberger, MD||Ohio State University||Principal Investigator|
|Ana Morales, MS, LGC||Ohio State University||Collaborating Investigator|
|Daniel Kinnamon, PhD||Ohio State University||Collaborating Investigator|
|Amy Sturm, MS LGC||Ohio State University||Collaborating Investigator|
|Soledad Fernandez, PhD||Ohio State University||Collaborating Investigator|
|Julie Gastier-Foster, PhD||Nationwide Children’s Hospital||Collaborating Investigator|
|Euan Ashley, MD||Stanford University||Collaborating Investigator|
|Colleen Caleshu, MS CGC||Stanford University||Collaborating Investigator|
|Gordon Huggins, MD||Tufts University, Boston||Collaborating Investigator|
|Deborah Nickerson, PhD||University of Washington||Collaborating Investigator|
|Michael Dorschner, PhD||University of Washington||Collaborating Investigator|
|Wylie Burke, MD PhD||University of Washington||Collaborating Investigator|
|Deborah Bowen, PhD||University of Washington||Collaborating Investigator|
|Gail Jarvik, MD PhD||University of Washington||Consultant|
|Carlos Bustamante, PhD||Stanford University||Consultant|
|Eden Martin, PhD||University of Miami||Consultant|
|Heidi Rehm, PhD||Harvard Medical School||Consultant|
|Clinical Site Principal Investigators (PI’s) and Other Significant Contributors (OSC’s)|
|Wilson Tang, MD||Cleveland Clinic||Consortium Site PI|
|Randall Starling, MD||Cleveland Clinic||Consortium Site OSC|
|Barry Trachtenberg, MD||Methodist Hospital, Houston||Consortium Site PI|
|Guha Ashrith, MD||Methodist Hospital, Houston||Consortium Site OSC|
|Arvind Bhimaraj, MD||Methodist Hospital, Houston||Consortium Site OSC|
|Jerry Estep, MD||Methodist Hospital, Houston||Consortium Site OSC|
|Javier Jimenez, MD PhD||South Miami Hosp, Miami||Consortium Site PI|
|Hakop Hrachian, MD||South Miami Hosp, Miami||Consortium Site OSC|
|Euan Ashley, MD||Stanford University||Consortium Site PI|
|Matthew Wheeler, MD PhD||Stanford University||Consortium Site OSC|
|Garrie Haas, MD||Ohio State University||Consortium Site Co-PI|
|Ayesha Hasan, MD||Ohio State University||Consortium Site Co-PI|
|William Abraham, MD||Ohio State University||Consortium Site OSC|
|Phillip Binkley, MD||Ohio State University||Consortium Site OSC|
|Brent Lampert, MD||Ohio State University||Consortium Site OSC|
|Jennifer Host, ANP||Ohio State University||Consortium Site OSC|
|Sakima Smith, MD||Ohio State University||Consortium Site OSC|
|Gordon Huggins, MD||Tufts University, Boston||Consortium Site PI|
|David DeNofrio, MD||Tufts University, Boston||Consortium Site OSC|
|Michael Kiernan, MD||Tufts University, Boston||Consortium Site OSC|
|Stephen Gottlieb, MD||University of Maryland||Consortium Site PI|
|Charles Moore, MD||University of Mississippi||Consortium Site PI|
|Robert Long, MD||University of Mississippi||Consortium Site OSC|
|Matthew deShazo, MD||University of Mississippi||Consortium Site OSC|
|Anjali Owens, MD||University of Pennsylvania||Consortium Site PI|
|Susan Brozena, MD||University of Pennsylvania||Consortium Site OSC|
|Thomas Cappola, MD||University of Pennsylvania||Consortium Site OSC|
|Kenneth Margulies, MD||University of Pennsylvania||Consortium Site OSC|
|Rhondalyn McLean, MD||University of Pennsylvania||Consortium Site OSC|
|J. Eduardo Rame, MD||University of Pennsylvania||Consortium Site OSC|
|Anjali Vaidya, MD||University of Pennsylvania||Consortium Site OSC|
|Joyce Wald, DO||University of Pennsylvania||Consortium Site OSC|
|Daniel Fishbein, MD||University of Washington||Consortium Site PI|
|Richard Cheng, MD||University of Washington||Consortium Site OSC|
|Todd Dardas, MD||University of Washington||Consortium Site OSC|
|Wayne Levy, MD||University of Washington||Consortium Site OSC|
|Claudius Mahr, MD||University of Washington||Consortium Site OSC|
|Sofia Masri, MD||University of Washington||Consortium Site OSC|
|April Stempien-Otero MD PhD||University of Washington||Consortium Site OSC|
|Mark Hofmeyer, MD||Washington Hospital Center/MedStar, Washington DC||Consortium Site PI|
For this study we received a grant of $10.7 million from National Heart Lung and Blood Institute (NHLBI) to be disbursed over 5 years (2015 – 2020) assuming satisfactory conduct of the study. The NHLBI is an Institute dedicated to understanding and preventing heart disease and stroke. Additional information regarding the invaluable work of the NHLBI is available.
We have also received $1.7 million in supplemental funding from the National Human Genome Research Institute (NHGRI) with specific emphasis to expand this study to recruit additional patients with DCM and their families who consider themselves of Hispanic ethnicity. Please see the section above NHGRI Hispanic Supplement for additional details.
The DCM Discovery Study
We commenced studying DCM genetics in The Familial Dilated Cardiomyopathy (FDC) Study in 1993. In 2013 the study was renamed The Dilated Cardiomyopathy (DCM) Study until 2015. In 2015 with the new Precision Medicine Study and our need to expand the website, this study has been renamed the DCM Discovery Study.
We accept new families to the Discovery Study. Interested individuals and families with DCM please see Options for Participation. Health care professionals interested in referring patients and families to us please see Referring Patients for Research Purposes.
Discovery has been and remains an essential and central focus of our work. We have always consented participants for long term follow up and for re-contact. In January 2000 we developed an FDC study newsletter to support the DCM Discovery Study.
Please see The DCM Research Project for a brief explanation of all DCM research activities, studies, information, and related resources. Our History provides detail of the development of the DCM Research Project and What We’ve Accomplished explains the evolution of our current research studies, including this DCM Discovery Study.
By 2015 we recruited over 2500 individuals to this DCM Discovery Study. These individuals have contributed greatly to our efforts for discovery and to understand the DCM genetics. All publications prior to 2015 have been from the DCM Discovery Study.
We published a clinical description of the first 304 families in 2008.
In a summary published in 2013 of all individuals recruited to the Discovery study through June 2011, we had identified plausible genetic cause for approximately one-third of the more than 300 families who had undergone sequencing for 16 genes. We have also notified participants, where applicable, of these results.
By mid 2015, exome sequences have been produced for approximately 450 individuals affected with DCM from the Discovery cohort. Analysis is ongoing and publications are in process.
We maintain contact and continue to work on DCM gene discovery for the individuals and families with DCM of this extremely valuable Discovery cohort for whom we have not yet discovered the cause of their DCM.