Goal 1: Promote Human Health

Epigenetics and Genomics

There is a need to investigate hemoglobin biosynthesis in order to develop novel approaches to treat sickle cell disease, thalassemia, and other anemias.

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

Details on the impact of addressing this CQ or CC :

Studies on epigenetic mechanisms have extraordinary promise for the development of transformative therapeutic approaches for non-malignant hematologic disorders, however, limited progress has been made in advancing therapies to counteract the often crippling complications of these conditions. In the case of sickle cell disease, an ensemble of proteins has been implicated in mediating the epigenetic repression of gamma-globin expression, raising the possibility that antagonizing the actions of these proteins to increase gamma-globin expression may be a useful treatment strategy. However, in certain cases, some of these proteins are deemed “undruggable,” based on their structural attributes. There is a critical need to identify druggable components of the multi-step epigenetic mechanisms as well as develop better models and assays that will more effectively identify modulators of “undruggable” proteins. Given the rich proteome and improved technologies available today, studies of proteomics, metabolomics, and regulatory RNAs are likely to reveal promising translational avenues. In addition, approaches to modifying the expression of the components of this pathway are underway using developing gene therapy strategies, such as viral vectors and/or gene editing can quickly advance therapy in sickle cell disease and β-thalassmia.

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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62 up votes
20 down votes
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Goal 3: Advance Translational Research

Implementation Science to Improve Care in Sickle Cell Disease

There are approximately 100,000 individuals living with sickle cell disease in the US, however study after study has shown that many lack access to the few existing evidence based interventions such as hydroxyurea. We need to investigate novel ways to increase acess to hematology care and disease modifying therapies.

Submitted by (@amy.sobota)

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

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12 net votes
14 up votes
2 down votes
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Goal 2: Reduce Human Disease

Systems Approaches to "Phenosimilar" Diseases

There are diverse diseases that share similar features. For example, many chronic airways diseases (chronic aspiration, ciliary dyskinesia, some COPD) "phenocopy" cystic fibrosis in terms of infectious agents, mucus clearance problems, progressive loss of lung function, etc. Use multiplatform "omics" approaches and Big Data bioinformatics to identify common nodes for therapeutic targeting. Other examples: emphysema and ...more »

Submitted by (@jhagood)

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

Details on the impact of addressing this CQ or CC :

may be able to target multiple diseases with new or repurposed therapies. Might narrow down the broad array of potential "high value" targets to study.

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4 net votes
12 up votes
8 down votes
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Goal 1: Promote Human Health

Origins of early disease

Defining the origins of early disease.

Submitted by (@nhlbiforumadministrator)

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

Details on the impact of addressing this CQ or CC :

While we are fully supportive of the recent emphasis on patient‐centered outcomes and implementation science, we are also reminded of the critical importance of investigating underlying mechanisms of pulmonary, critical care and sleep disorders. Recent discoveries have created exciting progress in the areas of cystic fibrosis, pulmonary hypertension, pulmonary fibrosis, and biological therapies in asthma. Only through further efforts to elucidate underlying mechanisms are new therapeutic approaches likely to emerge. Promoting further academic‐industry interactions are likely to yield benefits, which will ultimately lead to improvements in the health of our nation.

Name of idea submitter and other team members who worked on this idea : Research Advocacy Committee, American Thoracic Society

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3 net votes
3 up votes
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Goal 2: Reduce Human Disease

Interstitial Lung Disease

Does the treatment of gastroesophageal reflux disease improve outcomes in patients with IPF?

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 :

There are preliminary data to support the treatment of gastroesophageal

reflux (GER), in particular surgical treatment with laparoscopic fundoplication, as a disease modifying therapy for IPF. Many providers are prescribing medication or recommending surgery for GER in patients with IPF. Full disclosure, this compelling question submitter has submitted a UM1 grant application to study this question in a phase II clinical trial that is currently pending review.

Name of idea submitter and other team members who worked on this idea : ATS Member

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2 net votes
2 up votes
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Goal 1: Promote Human Health

Re-examining Antigenicity of Rare Blood Disease Proteins

What specific roles do protein glycosylation and protein complex formation on stable and activated cellular membranes play in inherent immunogenicity and antibody formation to life-saving therapies for rare blood disorders?

Submitted by (@nhlbiforumadministrator1)

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

Details on the impact of addressing this CQ or CC :

Inhibitory alloantibody formation to critical life-saving therapies impedes effective replacement therapy in up to 30-40% of children and adults with congenital blood diseases, thereby significantly increasing the complications of the underlying disease. For children with hemophilia A, this treatment complication has significantly limited the impact of the last 20 years of therapeutic advances in product efficacy and safety. Discovery science in this area has focused on the relationship between the immune response and treatment circumstances, and the epitope specificity of the targeted immune response. However, this scientific pathway to discovery has not yielded the critical mechanistic data required to inform effective prevention strategies. Recent advances in our understanding of the co-factors for immunogenicity, the biochemistry of coagulation factor complex formation on cellular membranes, glycobiology and gene transfer must now converge to create a potential platform for exploring new paradigms of immunogenicity, and thus leading to new strategies for inducing tolerance to future new therapeutics in hemophilia.

Feasibility and challenges of addressing this CQ or CC :

A recent workshop sponsored by the National Hemophilia Foundation highlighted the threat to novel therapies for hemophilia as well as curative gene therapy from the unsolved problem of replacement protein or gene product antigenicity. However recent advances in our understanding of the co-factors for immunogenicity, the biochemistry of coagulation factor complex formation on cellular membranes, glycobiology and gene transfer, can now converge to create a potential platform for exploring new paradigms of immunogenicity, and thus leading to new strategies for inducing tolerance to future new therapeutic. NHLBI leadership and collaboration with NIAID is needed to bring this combined expertise to bear on the understanding and prevention of this most significant complication of hemophilia therapy.

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

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-20 net votes
6 up votes
26 down votes
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Goal 2: Reduce Human Disease

Implications of Sickle Cell Trait

What are the healthcare implications of sickle cell trait?

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 :

Millions of people in the U.S and throughout the world have sickle cell trait, yet other than its impact on athletes and the recent finding that it may significantly raise the risk of chronic kidney disease, little is known about the trait’s effect on the health of those who carry it. Additional research is needed to further elucidate the implications of sickle cell trait alone, in combination with other genetic tendencies or in response to certain environmental factors. Findings can be used to provide evidence-based clinical guidance for the millions of people who may be affected

Feasibility and challenges of addressing this CQ or CC :

Addressing this question is feasible. Obtaining sufficient long-term data to answer these questions may be challenging.

Name of idea submitter and other team members who worked on this idea : The Sickle Cell Association of New Jersey

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6 net votes
6 up votes
0 down votes
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Goal 2: Reduce Human Disease

Biology of the intact alveolar wall – the new frontier in lung research

HOW DO WE STUDY THE BIOLOGY OF THE INTACT ALVEOLAR WALL IN THE CONTEXT OF LUNG DISEASE AND REPAIR?

Submitted by (@jb3900)

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

Details on the impact of addressing this CQ or CC :

SEE UPLOADED FILE

Feasibility and challenges of addressing this CQ or CC :

SEE UPLOADED FILE

Name of idea submitter and other team members who worked on this idea : JAHAR BHATTACHARYA

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2 net votes
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Goal 2: Reduce Human Disease

Fibrosis Care Center Network and Patient Registry

Complex diseases such as interstitial lung disease and pulmonary fibrosis requires a collaborative effort to effectively characterize, appropriately diagnose, and efficient evaluate novel therapies. Similarly, basic, translational and clinical research in this field requires the integration of clinical phenotypes with biologic specimens. We propose the expanded development of the Care Center Network and Patient Registry ...more »

Submitted by (@gcosgrove)

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 envisioned impact of an integrated Care Center Network and Patient Registry is to create a resource that:

 

• Informs the understanding of interstitial lung disease (ILD), its epidemiology and natural history;

• Assists to understand treatment patterns associated with optimal outcomes that will inform an emerging standard of care and development of treatment guidelines;

• Facilitates patient and clinician engagement in support of future prospective studies;

• Furthers study of biomarkers and predictors of disease and severity;

• Documents patient experience of living with ILD as described through patient reported outcomes (PRO) including quality of life, functioning, and symptoms;

• Generates new hypotheses and new endpoints in support of future studies;

• Increases awareness of relevant issues and needs among the immediate ILD community;

• Provides the opportunity to promote and inform policies in the larger health care community in support of those with ILD

Feasibility and challenges of addressing this CQ or CC :

With the establishment of collaborations between several partners, we initiated the PFF Care Center Network and Patient Registry in 2014. The Care Center Network and Patient Registry has since expanded to 21 centers regionally dispersed throughout the United States. The challenges of effectively and efficiently investigating the cause, care and treatment of pulmonary fibrosis are predominantly those of organization and integration of effort. Expertise is present throughout the United States. We suggest that with the continued expansion of the Care Center Network and Patient Registry, those challenges will be overcome and the focus of the fibrosis community efforts can be on diligently investigating the diseases that devastatingly affect patients. An integrated repository of well-phenotyped patients and biologic specimens is the first step in Precision Medicine for patients with interstitial lung disease and pulmonary fibrosis.

Name of idea submitter and other team members who worked on this idea : Gregory P. Cosgrove, MD, The Pulmonary Fibrosis Foundation

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Goal 3: Advance Translational Research

EMR virtual registries for rare diseases

Rare disease suffer from poorly organized or unfunded networks of researchers and clinicians. Define cross-platform minimal datasets for EMRs using collaborative grants for researchers and EMR companies

Submitted by (@jhagood)

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

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1 net vote
8 up votes
7 down votes
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Goal 2: Reduce Human Disease

Should clinical primary prevention of ASCVD be guided by subclincal disease or estimated risk?

Current approaches to guiding use of clinical primary prevention interventions, e.g., statins and aspirin, are based on treating patients who exceed a specific risk threshold. The performance of risk estimation is good, but not outstanding, and results from clinical and population studies continue to support the value of new biomarkers. Given the widespread use of preventive therapies, the lack of untreated cohorts is ...more »

Submitted by (@david.goff)

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 size of the US and global population qualifying for treatment with a statin or aspirin for primary prevention of ASCVD is immense. Given the performance of risk estimation, even if risk estimation were universally implemented, patients would be misclassified with the consequence of being under or over treated. If treatment based on presence of subclinical disease is more cost-effective, the benefits of preventive therapies can be enjoyed by larger proportions of our population and more ASCVD can be averted. Given the ionizing radiation, albeit low intensity, associated with CT scanning, it is incumbent on the biomedical research community to document the advantages, if any, of a subclinical disease guided approach to provision of clinical primary prevention services for ASCVD.

Feasibility and challenges of addressing this CQ or CC :

Many people will be concordant for the two methods of guiding provision of therapy, about 65% of middle aged and older adults. That is, many people will be high risk and have subclinical disease and many people will below risk and not have subclinical disease. It is only the discordant people, i.e., high risk people without subclinical disease and low risk people with subclinical disease, who will be informative study participants. Hence, many people will need to be screened to identify the roughly 35% who are discordant, and would be treated differently by the two approaches.

 

People may be unwilling to accept randomization once they know the information about their estimated risk and presence or absence of subclinical disease. If a low participation rate among eligible persons is observed, an even larger population of screenees would be needed.

 

A vanguard phase could provide information about these potential challenges.

Name of idea submitter and other team members who worked on this idea : David Goff, Donald Lloyd-Jones, Phil Greeland.....

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6 up votes
9 down votes
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