Goal 3: Advance Translational Research

Genome Profiling

There is a need to facilitate the integration of genomic and epigenomic profiling into drug discovery efforts by using genomic methods to sequence and analyze blood disease subtypes.

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Despite the important information that has been generated from sequencing studies in various blood disorders, for many hematologic disease subtypes, the limited scope of sequencing and the insufficient number of cases sequenced has prevented researchers from gaining truly useful insights. Whole-genome sequencing of large numbers of samples, with an emphasis on poorly studied and rare entities, is required to fully define the landscape of genetic changes underlying the development of blood diseases. Further, genetic and epigenetic alterations that drive hematologic diseases and the extent to which normal cells are distinct from malignant cells needs to be more broadly elucidated since many blood diseases, including hematopoietic cancers, disturb epigenetic regulators. The knowledge gained from understanding these processes and integrating genomic and epigenomic profiles could provide additional precision medicine opportunities and guide drug discovery efforts.

Name of idea submitter and other team members who worked on this idea : Alice Kuaban on behalf of the American Society of Hematology

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16 down votes
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Goal 1: Promote Human Health

Epigenetics and Genomics

There is a need to target epigenetic mechanisms as new treatment options for hematologic disorders.

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Advances in the field of epigenetics and the understanding of various epigenetic mechanisms has provided a completely new ensemble of therapeutic targets for treating hematologic disorders – both non-malignant and malignant. These mechanisms have enormous implications for understanding the molecular underpinnings of the normal orderly development of hematologic disorders. Although one of the greatest challenges in effectively treating hematologic disorders is the diversity of molecular abnormalities that underlie a disease, there are a number of common threads emerging, including alterations in proteins that function through epigenetic mechanisms. Additional research focusing on epigenetic alterations and emerging targets is needed to identify the role of such proteins in the development of hematologic disorders in order to design potential targeted treatments to counter their effects. This research will further lay the groundwork for precision medicine, and will help to provide more insight on potentially critical determinants of responsiveness to therapeutic regimens.

Name of idea submitter and other team members who worked on this idea : Alice Kuaban on behalf of the American Society of Hematology (ASH)

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-2 net votes
13 up votes
15 down votes
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Goal 2: Reduce Human Disease

Predictors of Sickle Cell Disease Severity

Can better predictors of disease severity such as specific biomarkers and/or genetic polymorphisms be identified so as to help understand the course and progression of sickle cell disease in various patients?

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

The high clinical variability in sickle cell disease (SCD) and the lack of sufficient data to help understand and or predict the course of an individual’s disease warrants the identification of better predictors of disease severity. The identification of predictors of disease severity, such as biomarkers, will be vital in the management and treatment of SCD, especially since more recently several plasma biomarkers and certain genetic polymorphisms have been proposed to influence specific clinical outcomes, including stroke, sickle cell nephropathy, and survival. Furthermore, studies of biomarkers or genetic markers in the context of clinical drug trials may be helpful in predicting response rates, thus allowing for more personalized therapeutic decisions.

Name of idea submitter and other team members who worked on this idea : Alice Kuaban on behalf of the American Society of Hematology (ASH)

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58 net votes
76 up votes
18 down votes
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Goal 2: Reduce Human Disease

Using Genomics to Predict Response to Weight Loss Interventions

Weight loss in response to interventions (both short term and long term maintenance) varies widely between individuals. What is the optimal use of the current molecular arsenal (genomics, metabolomics, expression arrays, etc.) to accurately predict individuals that will respond favorably to specific weight loss strategies?

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Addressing this CC would enable targeted prevention and treatment strategies based on genotype.

Feasibility and challenges of addressing this CQ or CC :

The rapid development of high throughput genomic sequencing and large scale molecular marker assays has led to a lower cost that makes this approach currently feasible. This coupled with large scale computational efforts to manipulate, store and analyze Big Data make the present the ideal time to embark on a focused precision medicine initiative addressing one of the most important US health problems.

Name of idea submitter and other team members who worked on this idea : NHLBI Staff

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27 down votes
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Goal 3: Advance Translational Research

Genome Profiling

What structural changes need to be implemented in the health-care community in order to support the use of genomic information in clinical trials and drug development for hematologic diseases?

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

In various blood disorders, including hematologic malignancies, there are both inherited and somatic genetic alterations that contribute to predisposition, transformation, disease progression, responsiveness to therapy, and treatment complications. The presence of such genetic alterations underscore the need for the identification of rare but traceable mutations as well as the integration of such genomic information into clinical trials. By implementing a few structural changes in the healthcare sector, a clinical trial infrastructure can be established that accounts for proper application of sequencing technology. Some examples include the creation of genome diagnostic networks that address accrual of sufficient patients, procurement of suitable tumor/non-tumor material for sequencing, as well as pharmacodynamic and correlative biology studies in hematologic diseases.

Name of idea submitter and other team members who worked on this idea : Alice Kuaban on behalf of the American Society of Hematology (ASH)

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22 up votes
11 down votes
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Goal 3: Advance Translational Research

Genetics and Genomics of Heart Disease

Identification of new genetic/genomic variants and risk genes often opens a new window to explore the fundamental molecular mechanisms underlying a disease and to develop new methods and strategies for diagnosis and treatment. Existing genomic variants and/or mutations explain only 10% to 20% heritability of common heart diseases. Much remains to be done in this important area. However, most genetic projects are discovery-driven ...more »

Submitted by (@wangq2)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Identification of new genetic/genomic variants and risk genes often opens a new window to explore the fundamental molecular mechanisms underlying a disease and to develop new methods and strategies for diagnosis and treatment. Existing genomic variants and/or mutations explain only 10% to 20% heritability of common heart diseases. Much remains to be done in this important area. However, most genetic projects are discovery-driven and not hypothesis-driven, so that finding in this area has been extremely low. We recommend that genetics and genomics should be placed as a strong priority for NIH funding for the coming years.

Feasibility and challenges of addressing this CQ or CC :

Feasible

Name of idea submitter and other team members who worked on this idea : Qing Kenneth Wang

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Goal 3: Advance Translational Research

Genome Profiling

How can proper infrastructure be designed to host sequencing data from hematologic diseases so as to enable its efficient interpretation and use in clinical care?

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Accurate and consistent analysis of genetic data is crucial for both basic research and clinical applications, however, the complexity of sequence mutations in several blood disorders as well as the immense amounts of raw data produced during the sequencing and analysis process, make accurate bioinformatics analysis a challenge. Furthermore, the lack of consistency in the analysis of the non-coding genome and variations in correlating this information with transcriptional and epigenetic data pose an additional challenge in obtaining a comprehensive portrait of various hematologic diseases. To overcome these challenges, content-rich portals that can offer cost-effective and regulated access to raw genomic data for interrogating and sharing sequencing results without compromising patient privacy must be designed. Also, the biologic and clinical relevance of genetic alterations found in these portals must be reliable and sufficiently comprehensive in order to foster proper interpretation.

Name of idea submitter and other team members who worked on this idea : Alice Kuaban on behalf of the American Society of Hematology (ASH)

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10 up votes
18 down votes
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Goal 3: Advance Translational Research

Durable gene activity map at the individual level

A durable gene activity map of the individual to understand when certain gene sets are on vs off or dysfunctional over an individual’s lifetime as one way of guiding the precision of medicine for that patient. It would need to be person portable and universally exportable and interpretable across all of the EHRs.

Submitted by (@greg.martin)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Name of idea submitter and other team members who worked on this idea : Society of Critical Care Medicine Executive Committee/Council

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3 up votes
1 down votes
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Goal 3: Advance Translational Research

Genomics in transfusion medicine

How can RBC genomics be utilized to improve outcomes with transfusion?

Submitted by (@barbarak)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Prevention of alloimmunization with transfusion

Improved understanding of RBC epitope diversity

Feasibility and challenges of addressing this CQ or CC :

Utilize advances in genomics medicine to better understand impact of transfusion and to improve outcomes.

Limited donor pool, particularly in minority populations, presents challenges

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Goal 3: Advance Translational Research

Molecular determinants of vascular wall development and aneurysm formation that can be used as markers for early diagnosis

To increase the potential of translating basic research discoveries into the clinic, there is a need to discover molecular biomarkers that confer risk for aneurysms and vascular dissections. The creation of a nation-wide biorepository of well-defined tissue and plasma samples along with research utilizing these tissue samples employing state-of-the art proteomics, genomics and development of appropriate mouse models will ...more »

Submitted by (@dstrickland)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

The challenge is the coordination of all components of the Project (i.e. development of a national biorepository along with coordination of proteomics and genomics analysis as well as proof of concept in animal models).

Feasibility and challenges of addressing this CQ or CC :

This process is not feasible via the R01 funding mechanisms. The feasibility of addressing this critical challenge is excellent provided adequate resources are provided.

Name of idea submitter and other team members who worked on this idea : Dudley Strickland and Selen Catania Muratoglu

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5 net votes
7 up votes
2 down votes
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