Goal 3: Advance Translational Research

Supporting large cohort studies over many years

How do we support large cohort studies over many years in terms of retention of subjects, manpower, funding, and appropriate outcome tools?

Submitted by (@nhlbiforumadministrator)

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 : Research Advocacy Committee, American Thoracic Society

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Goal 2: Reduce Human Disease

Data from regulatory studies a barrier to evidence-based medicine

Alignment of regulatory, healthcare, and research arms of the government is poor. There is a need to improve the design, quality and usefulness of data from regulatory studies to address major clinical questions and also to facilitate scientific inquiry. This is a barrier to evidence based medicine and improved treatments.

Submitted by (@societyforvascularsurgery)

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

Name of idea submitter and other team members who worked on this idea : Society for Vascular Surgery

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Goal 3: Advance Translational Research

Next Stage of COPD Discovery

1) Refinement of COPD subphenotypes for therapeutics, diagnostics and mechanistic interrogation. The NIH should encourage a strong focus on a) rigorous, mechanistically-reinforced definitions (chronic bronchitis, emphysema (with and without obstruction), frequent exacerbators, combined pulmonary fibrosis and emphysema) and 2) the development and optimization of animal model systems that replicate the different subphenotypes. ...more »

Submitted by (@lungmatbio1)

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

Details on the impact of addressing this CQ or CC :

If we could develop less costly and time consuming cell and animal models of COPD that reflect meaningful subphenotypes, we would be able to not only probe basic mechanism but also have reliable test platforms for candidate therapies.

There is typically a major obstacle between the acquisition of big data from observational disease cohorts, often broad but superficial, and the translation of these findings to basic discovery efforts. The clinical researchers speak a different language than the basic investigators and traversing this chasm with grant enticements might prove helpful.

Feasibility and challenges of addressing this CQ or CC :

This would require some suspension of the classic mechanistic, hypothesis driven proposals to develop these research tools.

There would need to be some reconstruction of study sections to permit these combined clinical-basic grants. The translational PPG was in keeping with this but should be reinforced with smaller grant programs such as RO1 level grants.

Name of idea submitter and other team members who worked on this idea : lungmatbio1

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Goal 3: Advance Translational Research

Translational Cardiovascular Medicine

There is a need for the NHLBI to catalyze the development of tools and shared data resources to facilitate mechanistic studies in a human model system. This includes the ability to culture human cardiac tissue, as well as generate a resource to systematically characterize and catalog the epigenome and histone marks associated with the transcriptome in normal and diseased heart tissues.

Submitted by (@stacey.rentschler)

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 in-depth characterization of complex cellular systems is often beyond the scope and capability of individual investigators working in isolation. The NHLBI research community lacks a shared tissue-specific systems biology framework resource that would accelerate the progress of individual, investigator-initiated research.

 

The Human Genome Project and subsequent sequencing projects are characterizing the structural architecture of the human genome, but the biological significance of the human genome and the characterization of functional elements that mediate gene-environment interactions and influence tissue-specific gene expression remain to be further defined.

Feasibility and challenges of addressing this CQ or CC :

Advances in the ability to culture adult human cardiac tissue for prolonged periods while maintaining normal electrical and mechanical function will enable testing of novel therapeutics to treat cardiovascular disease. Tissue-specific epigenetic modification of nucleic acids and dynamic changes in the histone code and chromatin remodeling are important determinants of the transcriptome within heart tissue. Advances in the ability to perform genome-wide analyses in human cardiac tissues to assess dynamic changes in the histone code and chromatin remodeling will enable comparison between normal and disease states.

Name of idea submitter and other team members who worked on this idea : Stacey Rentschler and colleagues, Washington University in St. Louis

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Goal 2: Reduce Human Disease

International epidemiological studies with huge contrast

Well-conducted international epidemiological studies with huge contrast of disease outcome and risk factor exposure will provide clues to disease prevention that cannot be obtained by studies solely within the US.

Submitted by (@akirasekikawa)

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 Seven Countries study in the 1960’s noted a 5-fold difference in CHD between the US and Japan; the low CHD in Japan was largely attributed to very low levels of total cholesterol. Since studies of migrant Japanese to the US in the 1970’s show marked increase in CHD, exposure to more Westernized lifestyle in Japan would cause total cholesterol to rise and CHD to increase. Surprisingly, age-adjusted CHD mortality declined by >50% both in the US and Japan for the past 5 decades. The decline in CHD mortality in the US is attributed to changes in risk factors (decline in total cholesterol, BP, smoking) and improved treatment, whereas Japanese experienced continuous and marked rise in total cholesterol by 50 mg/dl during the past 5 decades. This is despite higher levels of BP and smoking, especially in men, similar levels of lipids and diabetes.

 

COPD is the fourth leading cause of death in the US, of which singular important risk factor is smoking. Rates of cigarette smoking in men in Japan have been 20-30% higher than in men in the US for the past 5 decades. Yet, it is known that COPD mortality in men in Japan is internationally very low: less than a half of the US. First step is to compare the prevalence of COPD with standardized methods between the US and Japan and if COPD prevalence in Japan is much lower than in the US, elucidating some factors responsible for the low COPD rates in Japan might lead to novel preventive ways for this important disease.

Feasibility and challenges of addressing this CQ or CC :

Though both the US and Japan have well-established cohort studies, key methods are not generally standardized which makes the comparison difficult. Moreover, standardization of methods is limited by its cost.

Name of idea submitter and other team members who worked on this idea : Akira Sekikawa

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Goal 3: Advance Translational Research

NEW INFRASTRUCTURE FOR CLINICAL RESEARCH IN SLEEP AND CIRCADIAN DISORDERS

Much of the current clinical research on sleep and circadian research depends on cohorts designed for other purposes. While this has been helpful, such studies have limitations. These limitations are related to availability of in-depth phenotyping data and questions as to whether individuals identified in population studies are equivalent to those who present clinically with specific disorders. These concerns could ...more »

Submitted by (@jnoel0)

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

Details on the impact of addressing this CQ or CC :

Sleep and circadian disorders are extremely common. For many of these we know little about the natural history, whether different subgroups exist and effects of current therapies. Thus, developing specific registries for common sleep and circadian disorders would provide a basis for addressing these questions.

 

For some aspects, e.g., studies of inadequate sleep, impact of snoring and circadian disruption, would be facilitated by developing a specific sleep/circadian cohort with in-depth phenotyping. This strategy has worked extremely well in other areas, e.g., cardiovascular disease. The lack of this type of cohort for sleep and circadian disorders is a barrier to progress in this area. The high prevalence of these disorders and their known public health significance argue that development of such a cohort would be a game changer and accelerate progress in this new area of medicine.

 

Such a cohort could address several compelling questions:

 

a. What is the natural history of short sleep across the lifespan?

b. What is the impact of snoring? Does it lead, as has been proposed, to vibration injury to carotid arteries with accelerated vessel wall damage?

c. Are there different subtypes of individuals with the different sleep and circadian disorders?

d. What is the natural history of shift-workers and what types of shifts lead to increased risk for cardiovascular disease?

Feasibility and challenges of addressing this CQ or CC :

Problems with sleep and circadian rhythm and the relevant disorders are common. There are multiple accredited sleep centers for clinical purposes in the United Sates. They use common phenotyping platforms that could be the basis of some aspects of addressing this critical challenge. Moreover, most CTSA programs have a sleep study component. There are patient support groups for sleep apnea, insomnia, restless legs syndrome and narcolepsy. Thus, these groups could be marshaled to help in this effort. There is already a Sleep Research Network that was founded by the field itself. It is currently based on volunteer effort and there are no resources to support it. It could be the basis for future activities in this area.

Name of idea submitter and other team members who worked on this idea : Sleep Research Society

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Goal 3: Advance Translational Research

Substituting scientific-medical insight before profit in drug development

Since the Pure Food and Drug Act of 1906 and the rise of the FDA, the US federal government has directly inserted itself into medical research, primarily from a business perspective. The Orphan Drug Act of 1983 monetarily incentivized the process for rare diseases, but for ultra-rare diseases of < 1,000 patients, it does not work. Successful drugs for rare diseases have enormous price tags to compensate their development ...more »

Submitted by (@mtothbsf)

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

Details on the impact of addressing this CQ or CC :

By harnessing the vast resources of US biomedical research and biomedical researchers, many of whom were trained with NIH funding, the US can more effectively translate scientific discoveries into clinical benefit--many treatments for many diseases using many PIs. While the monetary profit incentive has been a vital aspect of pharmaceutical development over the last 50 years, in this era of personalized medicine it may not be as relevant. The individual PI with a good idea and sound scientific background may hold the key to a cure for a rare or personal disease, but is prevented from translating this because of ignorance, lack of institutional support, or the need for substantial capital investment to perform a proper clinical study. The FDA could recalibrate its requirements for clinical studies to allow even a single PI to test their idea economically, and perhaps offer the funding to do it properly. It should not go unnoticed that by understanding and treating a specific rare disease, the medical world may use this knowledge to better understand and treat diseases that affect larger numbers of people. For example, understanding or treating heart failure in a specific rare disease, may offer benefits to the larger group of heart failure patients.

Feasibility and challenges of addressing this CQ or CC :

Meeting this challenge will require a major rethinking of the traditional FDA approach of drug development and testing in humans at least for the non-profit or single PI scenario. For ultra-rare diseases of < 1,000 individuals there seems little hope that the for-profit sector would choose to be involved. For that reason and to take advantage of the enormous biomedical research resources the the US federal government has sponsored though the NIH, the US could advance translational research and usher in an era of true "personalized medicine'.

Name of idea submitter and other team members who worked on this idea : Matthew J. Toth, PhD, Science Director, Barth Syndrome Foundation Inc.

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Goal 3: Advance Translational Research

Vascular Anomalies

Vascular anomaly research is currently making exciting advances but discovery is hampered by lack of funding and collaborative prospective studies

Submitted by (@paula.mobberleyschuman)

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

Name of idea submitter and other team members who worked on this idea : Dr. Denise M Adams and Paula Mobberley-Schuman, MS

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Goal 3: Advance Translational Research

NIH should promote, rather than deter “fast-track” translational research projects

In the current environment, NIH reviewers actually deter, rather than promote, progress on proposed pre-clinical animal research that is most likely to rapidly translate into clinical breakthroughs in the short term. Scientists should be allowed to focus on critical missing information (roadblocks) needed to accelerate a promising treatment to clinical trials. For instance, at the NHLBI there is currently no study section ...more »

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 :

Yes, large animal studies may often be desirable too. But, the comprehensive information needed can be dramatically accelerated by using small rodents (e.g. by increased “n” and shorter lifespan). Then and if necessary, more focused large animal studies can be used more judiciously before commencing human trials. If a proposed, well-designed, translational study has identified a promising new treatment and the PI seeks to collect critical information to set the stage for clinical trials, he/she should be given the chance to conduct this research instead of being directed toward many years of collecting mechanistic data for something that is ready to move toward clinical study. Later, we can prop our feet on the desk and leisurely design those mechanistic studies knowing that more people are surviving, rather than dying. Rome burns while we play!

Feasibility and challenges of addressing this CQ or CC :

Can be done now by simply fast-tracking studies that may truly accelerate improvements in patient outcomes. Knowing that is works is more important than how it works from the patient standpoint.

Name of idea submitter and other team members who worked on this idea : Anthony Martin Gerdes

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Goal 3: Advance Translational Research

NHLBI Cohort Populations for T4 Implementation Research

How best can NHLBI observational cohorts be utilized to study observational T4 Implementation Research among both general and vulnerable US populations?

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 :

• Would help identify key factor associated with successful implementation that could be studied in interventional T4 implementation research

• Result would refine implementation strategies and health and social policy aimed to reduce heart, lung, blood, sleep diseases and conditions

• Builds on excellent established platform of research with high quality outcomes in well characterized study populations over long term follow-up.

Feasibility and challenges of addressing this CQ or CC :

• Big data is developing methods to link large data sets from national, state, and community level surveys – surveys that can define exposures to various policies and interventions in place, time, and population.

• A family of high quality cohorts are available for ancillary observation studies

• Collection of community level and more broad policy level exposures is feasible through data already collected and through potentially new data collection.

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

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Goal 3: Advance Translational Research

Cohort studies and clinical trials in vascular disease

Utilization of well characterized cohort studies and clinical trials to conduct ancillary scientific studies on pathophysiology, responses to treatment, and identify new ways to predict and treat disease. Restore the Ancillary Studies mechanism. Improved biobanks and data sharing platforms are needed. Facilitate public-private partnerships.

Submitted by (@societyforvascularsurgery)

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

Name of idea submitter and other team members who worked on this idea : Society for Vascular Surgery

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Goal 3: Advance Translational Research

The Investigator's Catch-22: How Can NHLBI Help?

The Critical Challenge is to determine how NHLBI can continue to foster the translational research necessary to allow our researchers to further develop their NHLBI-funded basic science discoveries. Researchers can't readily get a "typical" grant to perform the preclinical and early clinical translational IND-enabling research, and also can't yet attract private sector support without having done the work to "de-risk" ...more »

Submitted by (@nhlbiforumadministrator1)

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

Details on the impact of addressing this CQ or CC :

Ensuring that NHLBI-funded researchers have the means to further develop promising research discoveries will ensure that NHLBI continues to fulfill its Mission. Providing funding or resources to move basic science discoveries from the lab towards the clinic can expand the research environments, opportunities, and collaborations available to NHLBI investigators and lead to potential new therapies for heart, lung, and blood diseases.

Feasibility and challenges of addressing this CQ or CC :

Just as research project itself can take years, if not decades, to accomplish, so too can a cultural shift in our extramural research community. While one may have a different understanding of what constitutes "translational" research depending upon his or her vantage point, in reality it is bi-directional (from bench to bedside and back to bench) and offers possibilities for a wide range of researchers. Engaging established basic scientists in translational research can open new opportunities to them, and younger researchers are likely more familiar and well-poised for new research paradigms and collaborative efforts such as those afforded by the translational development process.

Basic discovery science is appropriately the backbone of the NHLBI extramural research program. But, for any basic science discovery to have a meaningful impact on human health, it must be "translated from the bench to the bedside." These next steps in translation involve a tremendous amount of research that is not amenable to hypothesis-driven grant mechanisms like an R01 or P01. Without access to funding support for early-stage translational work, investigators can be stymied and NHLBI-funded basic science discoveries can languish.

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

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