DCM Research Project

An overview of how the DCM Consortium and our current studies fit together

DCM Consortium

A Multisite Investigator Group for DCM Research

Precision Medicine Study

A DCM Consortium Study funded by the National Institutes of Health in 2015

DCM Discovery Study

Our DCM study since 1993; initially know as the FDC Study (1993-2013) and DCM Study (2013-2015)

 

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.

 

 

Collaborating Sites

DCM Consortium

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.

WHAT IS PRECISION MEDICINE?
Precision medicine, most simply, is when clinical medicine uses or leverages genetic and genomic knowledge for risk prediction and intervention.  The National Institute of Health defines precision medicine as “an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person”.  Our work on the genetic contributors to DCM will expand precision medicine for cardiology.

SCIENTIFIC SUMMARY OF THE PRECISION MEDICINE STUDY
The Project Description, a brief summary contained in the submitted NIH application, is provided here. Note the numbers of probands and family members have been increased due to supplemental funding from the NHGRI.

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.

 

NHGRI HISPANIC SUPPLEMENT TO THE PRECISION MEDICINE STUDY
The DCM Precision Medicine Study receives its main funding from the National Heart Lung and Blood Institute (NHLBI). However, we have been fortunate to receive supplemental funding from the National Human Genome Research Institute (NHGRI), which will enable us to add 100 probands of Hispanic ethnicity and their 200 family members to the 600 probands and 1200 family members of both European and African ancestry already planned for the study.
PRECISION MEDICINE STUDY PERSONNEL of the October 2014 NIH Application
We recognize the following personnel for their help and support, all of whom included NIH Biosketches in the October 2014 NIH application.

Name Affiliation Study Role
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

PRECISION MEDICINE STUDY FUNDING
Our funding comes from the National Institutes of Health (NIH), a part of the United States federal government dedicated to biomedical research of human health and disease.

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.

Precision Medicine Study Communication Tools

other tools you can use to help communicate with your family members about DCM genetic risk and invite them to participate in our study:

 

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.