DEPARTMENT OF HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
NATIONAL ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES ADVISORY COUNCIL
MINUTES OF THE 100th MEETING
February 4th, 2020
8:30 a.m. to 3:00 p.m.
I. CALL TO ORDER
The 100th meeting of the National Arthritis and Musculoskeletal and Skin Diseases Advisory Council (NAMSAC) was held on February 4, 2020, at the National Institutes of Health (NIH) Campus, Building 35, Conference Rooms 620/630. The meeting was chaired by Dr. Robert H. Carter, Acting Director, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS).
Council members present:
Ms. Karen M. Ball, President and CEO, The Sturge-Weber Foundation
Dr. Joan M. Bathon, Professor and Chief of the Division of Rheumatology, Columbia University College of Physicians and Surgeons
Dr. Jill P. Buyon, Director, Division of Rheumatology, Department of Medicine, New York School of Medicine, and Director, NYU Lupus Center
Dr. Elizabeth H. Chen, Professor, University of Texas Southwestern Medical Center
Mr. Vincent Del Gaizo, patient advocate and founding member and past chair, Friends of Childhood Arthritis and Rheumatology Research Alliance
Dr. Michael Econs, Glenn W. Irwin, Jr., Professor of Endocrinology and Metabolism; Director, Division of Endocrinology and Metabolism; and Professor of Medicine and Medical and Molecular Genetics, Indiana University School of Medicine
Dr. Said A. Ibrahim, Vice Chair for Strategy and Development and Chief, Division of Healthcare Delivery Science and Innovation, Department of Healthcare Policy and Research, Weill Cornell Medicine
Dr. Judith A. James, Chair and Member, Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation
Dr. Ethan A. Lerner, Associate Professor of Dermatology, Massachusetts General Hospital
Ms. Rosemary J. Markoff, Co-Chair, Scleroderma Foundation National Advocacy Committee
Mr. William J. Mulvihill, The Mulvihill Advisory Group
Dr. Anthony Oro, Eugene and Gloria Bauer Professor of Dermatology, Associate Director and Professor, Center for Definitive and Curative Medicine, Department of Dermatology, Stanford University School of Medicine
Dr. Stephen J. Tapscott, Professor, Fred Hutchinson Cancer Research Center
Dr. Jennifer J. Westendorf, Margaret Amini Professor of Orthopaedic Regenerative Medicine Research, Mayo Clinic
Dr. Michael J. Yaszemski, Professor, Orthopaedic Surgery and Biomedical Engineering, Mayo Clinic
Staff and Guests
The following NIAMS staff and guests attended:
Dr. Nandini Arunkumar
Mr. Greg Lavine
Mr. Doug Fesler, American Society of Bone and Mineral Research
Dr. Laurie Goodyear, Joslin Diabetes Center, Harvard Medical School
Dr. Susan Gregurick, NIH Associate Director for Data Science; Director, NIH Office of Data
Dr. Charles Helmick, Centers for Disease Control and Prevention (CDC) Arthritis Program
II. CONSIDERATION OF MINUTES
A motion was made, seconded, and passed to approve the minutes of the 99th NAMSAC meeting, held on September 10, 2019.
III. FUTURE COUNCIL MEETING DATES
Future Council meetings are currently planned for the following dates:
June 9, 2020
September 1, 2020
January 26, 2021
May 18, 2021
August 31, 2021
IV. DIRECTORS REPORT
Dr. Carter began by noting that the day’s gathering marks the 100th meeting of the NIAMS Advisory Council. In acknowledgement of this milestone, he gave a brief overview of the history of the Institute. NIAMS was formally established in 1985 via the Health Research Extension Act. However, research on arthritis and musculoskeletal diseases at NIH can be traced back to 1950 and the founding of NIAMS’ predecessor agency, the National Institute of Arthritis and Metabolic Diseases. The first NIAMS Advisory Council meeting was held in 1987. Dr. Carter listed some of the noteworthy Council members from the first roster and some of its initial focus areas.
FY 2020 Budget
Dr. Carter updated the Council on NIAMS’ budgetary situation and outlook. NIH and NIAMS continue to enjoy strong bipartisan support from Congress, which has enabled the agency and its Institutes and Centers (ICs) to receive consistent funding increases over the past few years. NIH received a 5.9% budget increase in the final FY 2020 appropriations bill. A significant portion of this increase was allocated to specific programs and initiatives, such as the BRAIN Initiative, Alzheimer’s research, the Cancer Moonshot, and efforts to address the opioid crisis. NIAMS received a 3.3% budget increase, from $605 million to $625 million. This is a slightly larger increase over the 3.1% bump from FY 2019.
Dr. Carter discussed the interim FY 2020 funding plan for the Institute which was recently posted to the NIAMS website. NIAMS’ budget increases have not kept pace with increases of funds committed to noncompeting research project grants (RPGs), which has led to fewer funds available for new grants in recent years. Part of this budget tightening can be traced back to the smaller grants from the sequestration era coming off the books, which were mostly replaced by full five-year commitments. The Institute has been working to improve this situation. For example, last year all R01s paid past the 12th percentile of the payline were one- to two-year R56 awards. That said, the Institute continually strives to increase funds available for new and competing grants, including options such as limiting funds traditionally kept aside for hardship cases later in the fiscal year.
Dr. Carter noted recent personnel changes at the NIH level. Dr. Ned Sharpless has returned to his role of Director of the National Cancer Institute (NCI) after serving as Acting Commissioner of the Food and Drug Administration (FDA) for seven months. Dr. Susan Gregurick is the new NIH Associate Director for Data Science and Director of the NIH Office of Data Science Strategy. Dr. Joshua Denny has been named Chief Executive Officer of the All of Us Research Program. Dr. Martha Somerman has stepped down as Director of the National Institute for Dental and Craniofacial Research (NIDCR). Dr. Larry Tabak, a previous NIDCR Director, will serve as Acting Director until Dr. Somerman’s permanent replacement is identified.
Dr. Carter updated the Council on the progress of personnel searches for openings in NIAMS leadership. The search for a permanent Director is ongoing and the Institute hopes to have an announcement by the end of the year. The new Director of the NIAMS Extramural Research Program and the Intramural Program Clinical Director should be announced in the coming weeks. The position of NIAMS Executive Officer remains open. Dr. Carter acknowledged the hard work and valuable service of the individuals who have been serving in those roles on an acting basis, in some cases for well over a year. NIAMS is also looking for new Extramural Medical Officers and a Chief Grants Management Officer, and Dr. Carter asked for the Council’s help in identifying potential candidates.
At the NIAMS level:
- Dr. James Witter has retired after 25 years of federal service. Dr. Witter was NIAMS’ sole Extramural Medical Officer.
- Mr. Andrew Jones is retiring as Chief Grants Management Officer after 30 years of federal service. Mr. Erik Edgerton will serve as Acting Chief Grants Management Officer.
Highlights of Selected Recent Scientific Advances
Dr. Carter presented two exciting scientific publications by research teams including two members of the NIAMS Advisory Council, Dr. Michael Econs and Dr. Stephen Tapscott.
- Dr. Econs led a team that recently published an article called “Oral Iron Replacement Normalizes Fibroblast Growth Factor 23 (FGF23) in Iron-Deficient Patients with Autosomal Dominant Hypophosphatemic Rickets (ADHR)” in the Journal of Bone and Mineral Research (JBMR). In humans and mice with the ADHR mutation, iron deficiency results in increased intact FGF23 concentrations and hypophosphatemia. The clinical trial found that oral iron repletion normalized FGF23 and phosphate levels in symptomatic, iron-deficient ADHR subjects. The study concluded the standard approach to ADHR should include recognition, treatment, and prevention of iron deficiency. Dr. Carter highlighted this trial as a great example of research leading to treatment; in this case, a cheap and easily accessed treatment.
- Dr. Tapscott worked on a study by Bradley et al. whose findings were published in Developmental Cell in an article called “DUX4 Suppresses MHC Class I to Promote Cancer Immune Evasion and Resistance to Checkpoint Blockage.” This study looked at the DUX4 gene, which is one of the genetic drivers of facioscapulohumeral muscular dystrophy, a rare disorder, but also now associated with a number of more common solid tumor cancers. DUX4 can prevent cancer cells from being recognized and destroyed by the immune system. This study found that cancers can escape immune surveillance by reactivating a normal developmental pathway and identify a therapeutically relevant mechanism of cell-intrinsic immune evasion. Dr. Carter emphasized this study as example of unexpected and important findings that can result from broad funding strategies.
High Profile NIAMS-Supported Projects
Dr. Carter next discussed important research projects and consortia that are supported by NIAMS. The Back Pain Consortium (BACPAC) Research Program is part of the larger Helping to End Addiction Long-term (HEAL) Initiative, which was established to combat the opioid epidemic. The HEAL Initiative has been appropriated $945 million and BACPAC has been earmarked $150 million. BACPAC’s role will be to examine biomedical mechanisms of chronic lower back pain within a biopsychosocial context by using interdisciplinary methods and exploring innovative technologies. The Consortium recently had a kickoff meeting and has established ten working groups. The program has set aside funding for urgent funding needs. Dr. Carter noted one such funding opportunity that NIAMS has issued to support BACPAC by encouraging researchers to provide data-driven evidence regarding effective mechanisms for reducing reliance on opioids while maintaining quality of life.
NIAMS co-leads the Molecular Transducers of Physical Activity Consortium (MoTrPAC), which is funded through the NIH Common Fund. MoTrPAC was created to perform preliminary characterization of the range of molecular transducers that underlie the effects of physical activity in humans. The program's goal is to study the molecular changes that occur during and after exercise, and ultimately to advance the understanding of how physical activity improves and preserves health. An early part of the initiative was to produce animal data on these subjects, which Dr. Laurie Goodyear will present later in the meeting.
Dr. Carter next gave an update on the Accelerating Medicines Partnership (AMP) for rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Data acquisition for single cells transcription profiling of the synovial cells from RA patients is now complete for Phase 2. This is a major milestone for the program. The Advisory Council previously created a work group to look at the AMP RA/SLE program and identify lessons learned regarding how the network developed its processes and procedures and how AMP can serve as model for other large interdisciplinary research projects. Dr. Judith James will present the findings of the work group later in the meeting.
Dr. Carter also made the Council aware of an upcoming NIAMS roundtable to be held on March 11th on subset analysis in clinical studies. Most clinical trials funded by NIAMS use traditional randomized clinical trial designs, which measure the difference in average outcome between participants assigned to one intervention or another. However, it would be more clinically useful to understand who would likely benefit more from, or be harmed by, either intervention. This can be addressed, to some extent, by stratification, but at a significant increase in costs and requiring pre-specification. The roundtable will gather input as to how clinical studies can be designed to identify groups of individuals that are more likely to benefit from or be harmed by a given intervention in order to better inform clinical care.
All of these partnerships and collaborations benefit greatly from the work of the NIAMS Coalition in raising awareness and publicizing funding opportunities. Dr. Carter invited Ms. Colleen Dundas, from the Science Communications and Outreach Branch, to discuss NIAMS’ efforts to better leverage the NIAMS Coalition in its outreach efforts regarding funding opportunities. Ms. Dundas gave a brief overview of the NIAMS Coalition. Founded over 20 years ago, the coalition is comprised of over 95 national professional and voluntary organizations and is led by a 12-member steering committee. The coalition and its member organizations are key Institute partners and they serve as the voice of the patients and providers whom the Institute serves. NIAMS reached out to the coalition to ask for its input on how the Institute can better communicate its funding opportunities. The NIAMS Coalition’s recommendations fell into four general areas: concise and simplified messaging, easy to share formatting, additional communication methods (e.g., infographics, videos, surveys, etc.), and increased opportunities for collaboration and interaction. NIAMS is in the process of developing an action plan to address these topics going forward. This action plan will be part of an Institute-wide strategic outreach plan to improve communication. The plan will clarify specific goals, identify audience segments for targeted outreach, determine key metrics to measure success and gaps, and prioritize action. Ms. Dundas encouraged the Advisory Council to provide feedback to the Science Communications and Outreach Branch.
Key Issues at NIH
Dr. Carter briefed the Council on the NIH Advisory Committee to the Director (ACD)’s anti-harassment activities. ACD Working Group on Changing the Culture to End Sexual Harassment recently published a report called “Changing the Culture to End Sexual Harassment.” Overall, the Working Group’s report’s overarching objectives were increasing transparency and accountability in reporting of professional misconduct, especially sexual harassment; establishing mechanisms for restorative justice; and creating system-wide change to ensure safe, diverse, and inclusive research environments. The report included a number of recommendations and Dr. Carter mentioned a few as examples. Advisory Council members were encouraged to review the findings and recommendations of the report.
Dr. Carter also provided an update on the activities of the ACD Working Group on Artificial Intelligence. The Working Group’s report had eight key recommendations over the cross-cutting themes of people, data, and ethics.
The ACD recently approved and finalized the details of the Stephen I. Katz Award, developed in honor of the late NIAMS Director. The award is an investigator-initiated R01 for early-stage investigators (ESIs). The application must propose a new research direction with no preliminary data. The award will provide for 5-years of funding.
Another focus area at NIH in recent months has been improving chances for advancement and career opportunities for women in science. Dr. Carter presented a graph showing a drastic difference between the number of woman PhDs and the number of those with assistant professorships as compared to men. Part of this disparity can be attributed to the difficulties that young women with families face starting a research career. On recommendation of the ACD, NIH has posted two Notices of Special Interest (NOSI) funding supplements to help address and retain scientists at this life stage.
V. NIH’S STRATEGIC VISION FOR DATA SCIENCE: ENABLING A FAIR-DATA ECOSYSTEM
Dr. Carter introduced Dr. Susan Gregurick, NIH Associate Director for Data Science and Director of the Office of Data Science Strategy, to update the Council on the NIH’s strategic vision for data science.
In order to ground the discussion in a topic area relevant to NIAMS’ research purview, Dr. Gregurick began by discussing current research challenges in the study of osteoporosis. Osteoporosis affects approximately 9 million adults in the United States, and while a significant number of genetic loci have been associated with the disease, identifying the genes responsible has proven difficult. Integrating genomic-wide association studies (GWAS) with other data sources, such as eQTLs, epigenetic data, and other relevant molecular measurements from osteoclasts and osteoblasts could help pinpoint causative genes. However, finding and integrating these datasets has historically been cost-prohibitive, inefficient, and impractical.
Recent advances in artificial intelligence (AI) have led to the development of tools that could help bridge these gaps. In particular, machine learning has great potential to help scientists utilize and make sense of the vast quantities of data being generated by modern science. Machine learning is becoming increasingly attractive for its ability to analyze these massive datasets and identify features of interest that may have mechanistic or diagnostic value. There are several hurdles that must be overcome, however, before machine learning can be utilized in an efficient and productive manner. The datasets involved must be of a certain size and quality to be useful for current machine learning applications. Datasets often have to be transferred across networks or to the cloud, which can take time and money. Staff must be trained or hired to develop and implement new algorithms and machine learning applications often require access to specialized hardware in order to run analysis software.
NIH’s data science strategy is based upon the FAIR principles: data must be Findable, Accessible, Interoperable, and Reusable. Dr. Gregurick has found that most researchers understand these principles, but there is some confusion about how to put them into practice. Researchers often have difficulty prioritizing dataset annotation and curation, which is sometimes seen as burdensome and time-consuming. Researchers need to understand how to select the appropriate metadata to help make it easy to access for future users of the data, and they have to be made aware of the appropriate places to store their data for long-term access.
Dr. Gregurick walked through examples of how an efficient and well-designed database that takes advantage of machine learning can revolutionize the way biomedical research is conducted. NIH’s Strategic Plan for Data Science was designed to create the environment where that research is possible. The strategic plan encompasses goals across five categories: data infrastructure; modernized data ecosystem; data management, analytics, and tools; workforce development; and stewardship and sustainability. Dr. Gregurick reviewed NIH’s long history of supporting public access to research results. NIH is currently in the final stages of developing a new Data Management and Sharing Policy. The policy will require NIH-funded researchers who conduct studies resulting in the generation of scientific data to submit a data management plan. The plans must describe how the scientific data will be managed and which data will be shared. NIH strongly encourages that researchers use open access data sharing repositories as a first choice. Dr. Gregurick briefly noted potential repositories that can be used which adhere to the FAIR principles. One such example, particularly for datasets that lack an appropriate existing repository, is the NIH Figshare generalist repository pilot. The pilot allows researchers to attach licenses, embargos, metadata, and unique identifiers for data citation.
Dr. Gregurick next described the NIH Science and Technology Research Infrastructure for Discovery, Experimentation, and Sustainability (STRIDES) Initiative, which is a partnership with industry leaders to provide a cloud-based repository and machine learning computing platform. This initiative will utilize Google Cloud technology and will be more appropriate for larger studies involving big datasets and many collaborators. STRIDES also provides access to professional and technical support services and access to training programs for research. The initiative is available to all NIH-funded researchers at discounted pricing. NIH researchers have already moved over 30 petabytes of data to the STRIDES cloud, including the NHLBI Framingham Heart Study, the All of Us Research Program, and the NCI Genomic Data Commons, among many others. NIH is also working to create a single sign-on across all NIH data resources to facilitate easier access for researchers and to conform to industry standards.
Perhaps the most difficult challenge for the data science community is making data interoperable. NIH will be attempting to leverage Fast Healthcare Interoperability Resources (FHIR) standard, which enables electronic healthcare data exchange through an application programming interface (API). An API is a specified set of protocols and data standards that establish the ground rules by which one information system directly communicates with another. Software developers can then connect their program to another computer through a FHIR API to transmit electronic health data. NIH is encouraging researchers to explore the use of the FHIR standard to capture, integrate, and exchange clinical data for research purposes and to enhance capabilities to share research data. NIH is currently funding two pilot initiatives regarding the use of the FHIR standard. One will be focused on increasing the availability of high-quality standardized phenotypic information for genomic research by extracting relevant data from EHRs (Electronic Health Records) via FHIR. The second will develop and test tools and resources that enable researchers to extract clinical data from an EHR and map the data to the FHIR standard in order to be deposited in FHIR servers.
Finally, NIH and the Office of Data Science are working to enhance the biomedical workforce with data science specialists. The office supports a program called Coding it Forward, which awards 10 undergraduate fellowships. The fellows spent 10 weeks at NIH combining their computational expertise with hands-on experience on biomedical data-related challenges. One student developed machine learning models to predict migration paths and morphology of fibroblast cells in the extracellular medium. NIH also will be funding the Data and Technology Advancement (DATA) National Service Scholar Program, which will bring five fellows on one- to two-year national service sabbaticals to tackle high-impact data science and technology projects.
Dr. James asked Dr. Gregurick if she expects NIH to be looking for a part-time data manager to be included in future R01 applications to assist in the data sharing process. Dr. Gregurick said NIH will expect that grant applications take into account data management, and NIH will work to provide support to make the process easier to manage, but she does not expect NIH to mandate a dedicated data management team member. Dr. James also asked what will happen to third party-housed projects when the grant funding expires. Dr. Gregurick said NIH cannot absorb those costs and it will be up to the PI and the home institution to decide how to handle the data after the grant has ended.
Dr. Econs asked how these programs will handle confidentiality, particularly regarding rare diseases where patients oftentimes struggle to maintain anonymity. Dr. Gregurick said NIH is starting to explore advanced encryption methods, such as homomorphic encryption and differential privacy. In the meantime, all NIH-sponsored programs will adhere to existing data privacy and consent rules for each dataset.
Dr. Anthony Oro asked about connecting phenotypes and creating a shared language across datasets. Dr. Gregurick said the NIH has been working on this issue for some time and strongly encourages the use of common data elements. NIH is currently working to map the common data elements to the FHIR system.
VI. CDC ARTHRITIS, LUPUS, AND PAIN ACTIVITIES AND POTENTIAL FOR PARTNERSHIPS
Dr. Carter welcomed Dr. Charles Helmick, the Scientific Lead for the CDC’s Arthritis Program, to present to the Council on the CDC’s arthritis, lupus, and pain efforts.
Dr. Helmick first gave the Council a general overview of the CDC’s mission. The CDC is generally known for its work on prevention and control of infectious disease, foodborne pathogens, environmental health, and emerging health risks in the U.S. and around the globe. The CDC has a large chronic disease program as well: the National Center for Chronic Disease Prevention and Health Promotion’s last budget was $1.2 billion.
The CDC’s Arthritis Program began in 1999 and its FY 2020 is $11 million. The program takes a public health approach to musculoskeletal disorders and rheumatic conditions. The public health approach looks at what determines the health of a population. CDC research on the social determinants of health has found that medical care only accounts for about 25 percent of population health. The remaining 75 percent is determined by social or societal characteristics, health behaviors, and genetics. Public health is a broad, interdisciplinary field that includes the government public health infrastructure, academia, community, employers, and the media. At the CDC the public health approach includes surveillance, risk factor identification, evaluation of potential interventions, and response implementation.
The Arthritis Program has two major ongoing goals: 1) quantifying the population burden of arthritis, and 2) identifying interventions to make the population healthier. One of the ways the population burden is evaluated is by looking at prevalence. A CDC study conducted from 2013 to 2015 found that 54 million adults had arthritis, or 22.7 percent of the adult population. About 43.5 percent of that group, or 22.7 million adults, reported having arthritis-attributable activity limitations. Using this data, the CDC has made prevalence projections, based on Census data, which indicate that 78 million adults will have arthritis by the year 2040. Another way to assess population burden is by looking at cost impacts. A CDC-funded 2013 study found the cost burden nationwide to be $304 billion for that year; $140 billion in medical costs and $164 billion in earnings losses. CDC has also funded studies on severity. One study conducted in partnership with state agencies on state-specific data found a median of 30 percent of adults with arthritis experience severe joint pain across the states (ranging from 20.8 percent in Colorado to 45.3 percent in Mississippi).
Public health burden can be measured by disability rates. A CDC study on disability causes found arthritis/rheumatism and back and spine problems to be the two most common causes of disability in the U.S. For work-related disability, those categories are two of the top three causes, with back and neck problems the number one cause. CDC studies have shown that arthritis is a common comorbid condition in Americans with other health issues. One study found that 31 percent of individuals with obesity, 47 percent of people with diabetes, and 49 percent of individuals with heart disease also suffer from arthritis. People with these conditions are 1.5, 1.7, and 1.9 times more likely to have arthritis than people without the condition, respectively. This is an important finding because physical activity is a common treatment recommendation for obesity, diabetes, and heart disease, and people with arthritis frequently have related barriers to physical activity. Dr. Helmick argued that addressing arthritis-related barriers to activity could help improve many other conditions along with the arthritic pain.
Dr. Helmick also discussed quality of life and longitudinal studies funded by the CDC. The Johnston County Osteoarthritis Project began in 1991 and provided some of the first credible osteoarthritis estimates for the African American population. Data from this study have also helped produce lifetime risk estimates. For example, this study suggests nearly 1 in 2 adults may develop knee osteoarthritis by age 85.
The CDC public health approach also looks at opportunities for interventions to address gaps not being addressed elsewhere. For example, CDC has found that interventions based on physical activity and self-management education for arthritis are known to be beneficial and recommended, but these interventions rarely exist in practice because these are difficult to offer in the clinic. To address this gap, CDC works to promote clinic-community linkages so that patients can be connected with community providers that offer these courses.
One of CDC’s long-term projects in arthritis has been on raising the visibility of the condition. In recent years, the CDC has been attempting to include more arthritis reports in its Morbidity and Mortality Weekly Report. Arthritis has also become more of a priority in the Health People strategic goals that are announced by the Department of Health and Human Services on a decadal basis.
Dr. Helmick next discussed the growing visibility of pain as a health issue in the United States, an issue deeply connected to arthritis and musculoskeletal diseases. This issue came to the fore in the public consciousness in recent years in light of the opioid epidemic. Dr. Helmick traced the federal response back to the 2011 Institute of Medicine Report “Relieving Pain in America,” which helped galvanize the disparate stakeholders to come together and create a unified response. The report called for a cultural transformation in the way pain is understood, assessed, and treated. It also identified a clear role for public health responses and called for better data to monitor incidence and prevalence. More recently, the 2016 National Pain Strategy and the 2017 Interagency Pain Research Coordinating Committee, among other federal activities, set out a population health strategy for pain research. One of CDC’s first steps in this process was to conduct a prevalence study. This study was conducted in 2018 and found that 50 million adults suffer from chronic pain, or 21 percent of the adult population, and 20 million of those experience high-impact chronic pain (8 percent of the adult population). More recent federal efforts include the HEAL Initiative, discussed by Dr. Carter earlier, and the White House-directed National Roadmap on Health Research and Development to Stem the Opioid Crisis.
Dr. Helmick concluded by discussing how this greater attention on pain can help the field of arthritis research. Firstly, growing attention to pain in general means growing attention to pain as an important health outcome. As noted above, arthritis and musculoskeletal conditions are a leading cause of pain in America and one of the most commonly cited reasons for opioid prescription. Therefore, reducing prescribed opioids means addressing arthritis pain management. Dr. Helmick noted several topic areas for potential partnerships between CDC and NIAMS, such as continuing CDC’s work raising visibility and awareness, expanding underused interventions, further research on comorbidities, and funding of secondary analyses and longitudinal studies, among others
Dr. Gayle Lester, Director, Division of Extramural Research, identified the Johnston County study as one area ripe for collaboration from the Institute’s perspective.
Dr. Jill Buyon asked about data availability and integration, particularly related to the CDC’s lupus work. Dr. Helmick said he learned a lot from Dr. Gregurick’s presentation earlier in the meeting and CDC is looking at ways to improve data sharing. He noted that some of the data in question is owned by state health departments so their permission will have to be sought as part of the process.
Dr. Ibrahim noted that the latest CDC study on knee replacements was in 2009 and that might be an area for renewed research.
VII. MoTrPAC ANIMAL DATA: A BRIEF OVERVIEW WITH SOME SUPRISING RESULTS
Dr. Carter introduced Dr. Laurie Goodyear, Senior Investigator, Joslin Diabetes Center, to deliver the presentation.
Dr. Goodyear began by giving an overview of the MoTrPAC (Molecular Transducers of Physical Activity Consortium). It is well-established that regular physical activity has many salutary effects on human health and wellbeing. Indeed, it could be argued that exercise is the most important form of preventive medicine available to the human population. The consortium was established to study how this process works at molecular level in order to advance the understanding of how physical activity and exercise improve and preserve health. MoTrPAC is a six-year program and represents the largest targeted NIH investment of funds into the mechanisms of how physical activity improves health and prevents disease.
NIH identified several objectives for the MoTrPAC program:
- Enable and encourage research to define the mechanisms underlying the health benefits of physical activity
- Provide measurable outcomes to enable the use of a physical activity intervention in basic and clinical studies of health and disease
- Provide novel molecular definitions for fitness and exercise response
- Provide predictors for the health response to physical activity
- Generate novel, testable mechanistic hypotheses regarding normal human physiology and disease.
The program will collect tissue from both humans and animals and conduct a broad array of chemical and multi-omics analyses at sites across the country. The goal is to produce large scale datasets to ultimately inform integrative analyses for discoveries. The human portion will consist of approximately 2,000 healthy participants providing blood, muscle, and adipose tissue. The primary role of the animal studies will be to enable tissue collection from organs and time courses that cannot be acquired from the human population for practical and ethical reasons.
Dr. Goodyear presented the preliminary results of the animal model analyses. MoTrPAC funded these animal studies through the Preclinical Animal Study Sites (PASS) program. The participating research teams were tasked with producing multi-omics data across the sub-domains of genomics and transcriptomics, proteomics, and metabolomics. There are currently three active PASS sites located at the University of Iowa, the University of Florida, and Dr. Goodyear’s lab at the Joslin Diabetes Center.
Dr. Goodyear first described the phase of the study model for animal tissue collection. Phase 1 consists of acute exercise, or response to a single session, and training exercise to look at responses to a series of exercise sessions. The teams set up a complex series of time points to delineate a specific process and targets for these sessions and the subsequent tissue collection. The Phase 1 study consisted of Fischer 344 rats, both males and females, with treadmill exercise across two ages: 6 months and 18 months. After the exercise sessions, tissue samples were collected from 19 organ/body sites.
Dr. Goodyear focused her presentation on the acute exercise portion of Phase 1. She briefly described the details of the acute exercise, including how it was managed and conducted. One early finding was greatly increased plasma lactate concentration across both age groups and genders post-exercise, indicating that the model was successfully exercising the animals. Tissues were collected at several time points post-exercise in order to study length of activity effects: half an hour, one hour, four hours, seven hours, 24 hours, and 48 hours. For the training exercise arm, rats were exercised for up to eight weeks, with samples taken at one, four, and eight weeks.
Dr. Goodyear reviewed the 19 tissues that were collected in the study and discussed the collection process. The process started almost immediately post-exercise when the rat was transferred to the collection room and anesthetized for blood removal and euthanized for tissue collection, processing, and storage. This process was very complex given the number of tissues being collected and required eight or nine researchers for each collection session. A standard dissection order was established across the PASS sites to make the process as efficient as possible. Across all three sites, samples were collected from 432 rats for a total of 10,464 blood and tissue samples. The samples were sent to the central storage site at the University of Vermont and then distributed to the various analysis teams across the country.
Dr. Goodyear next presented some of the multi-omics data being produced at the MoTrPAC research sites, known as chemical analysis sites (CAS). Multi-omics techniques utilized in these analyses provide information on DNA composition and structure and quantify gene transcription, protein expression and modification, and metabolite concentration. Ultimately, the goal is to integrate the data produced by the CAS analyses in order to help predict response to exercise, identify novel pathways or signals that mediate adaptations to exercise, and to discover mechanisms by which exercise cures, prevents, or alleviates disease.
For genomics and transcriptomics, a team at Stanford University is using ATAC-sequencing and RNA-sequencing on the acute exercise samples and has nearly completed this process. One notable preliminary finding is that the majority of differentially expressed genes are shared across multiple tissues. The team found that 39 genes are differentially expressed due to acute exercise and these genes are found in 14 tissue sites. The team also found that these globally responsive genes are enriched for pathways known to be involved in disease, including pathways of heat shock response, mitogen-activated protein kinase (MAPK) signaling, apoptosis, circadian rhythms, bone growth, and immune response such as TNF-alpha.
A CAS team at Pacific Northwest National Laboratory is conducting proteomics analysis. This team collects tryptic peptides from the tissues to conduct whole proteome, phosphoproteome, and acetylome analyses. These analyses are used to look at the effect of exercise on muscle. For the acute exercise samples, the team found modest changes in protein levels and more immediate changes in phosphopeptides that soon return to baseline post-exercise. However, preliminary analysis of the exercise training study samples indicates significant remodeling of the global muscle proteome with endurance exercise.
Dr. Goodyear next presented the work of a CAS team at Duke University on targeted metabolomics. This team conducted a number of different strategies to determine metabolite abundance in the samples. Dr. Goodyear highlighted one noteworthy finding regarding the effect of exercise on serum ketone concentrations. The analysis showed that serum ketones continue to increase after exercise until food is provided. These results indicate that refraining from eating post-exercise may be a way to support elevated ketone levels. Another metabolomics team at Mayo Clinic is looking at acylcarnitines, which are carriers that transport long chain fatty acids into the mitochondria for oxidation. High concentrations of acylcarnitines are associated with
diabetes, and there is an ongoing debate as to whether high levels of acylcarnitines are inflicting or reflecting diabetes. The CAS team has found that acute exercise increases acylcarnitines in the rat models. Long chain species increase immediately after exercise, whereas short chain species peak 30 minutes later. These results would not support a role for acylcarnitines mediating skeletal muscle insulin resistance. Dr. Goodyear also presented data from untargeted metabolomics analysis in the arena of lipidomics from a CAS team at Georgia Tech.
Dr. Goodyear concluded her presentation by expressing her excitement at the work MoTrPAC has produced thus far and will continue to produce going forward as data integration begins across human and animal models.
Dr. Bathon commented that joint tissue would have been another valuable tissue collection site for these studies. Dr. Goodyear concurred and said that the team would have liked to collect from many more sites but the program was limited by cost concerns.
Dr. Ibrahim asked how the team chose the 30-minute exercise duration. Dr. Goodyear said the team was aiming for a moderate to high intensity exercise that the rats of both age groups were able to complete consistently.
Dr. Jennifer Westendorf asked if any data validation has been conducted, particularly on the protein data. Dr. Goodyear said that has not been done yet.
Dr. Oro asked if any thought had been put in to connecting aging phenotypes, or ageotypes, with exercise analyses. Dr. Goodyear said current analyses are focused on the 6-month old animals but the program hopes to find funding for in-depth analysis of the 18-months samples in the future. Dr. Oro also asked about MoTrPAC’s data aggregation and organization strategy. Dr. Goodyear said the data management strategy is out of her purview, but the program does have a bioinformatics team to spearhead this effort.
Dr. Lerner asked Dr. Goodyear where she would take the program if funding concerns were off the table. Dr. Goodyear said she would conduct analysis of all the samples, which currently is not feasible with current funding levels. Other interesting research pathways would include looking at resistance exercise and comparing and contrasting various exercise regimes.
VIII. AMP LESSONS LEARNED WORKING GROUP
Dr. James began by updating the Council on the work of the Accelerating Medicines Partnership (AMP) in Rheumatoid Arthritis and Lupus (RA/Lupus). The AMP is a public-private partnership between the NIH, FDA, biopharmaceutical companies, and non-profits to transform the current model for developing new diagnostics and treatments by identifying and validating promising biological targets for therapeutics. The ultimate goal of AMP is to increase the number of new diagnostics and therapies for patients and reduce the time and cost of developing them.
The goals of the AMP RA/Lupus program are to define disease-specific biological pathways to identify relevant drug targets for the treatment of RA, lupus and related autoimmune diseases. The program also aims to develop an enhanced systems-level understanding of gene expression and signaling in target tissues and cells of affected organs and blood. Finally, AMP hopes to create a unique and novel infrastructure that uses a collaborative interdisciplinary team science approach to test high impact ideas. Over 200 individuals across 40 different institutions are actively involved in the AMP RA/Lupus program.
Dr. James briefly reviewed the research phases of the program, starting with method development and technology selection, through development of a disease-specific expression profile of tissue cells to establish feasibility, and finally patient characterization. The program is currently in the final stage, Phase II, and Dr. James reported that it has exceeded enrollment targets for its cohorts. Across all phases, over 500 RA and lupus patients have been enrolled and tens of thousands of samples collected across all cohorts. Phase II will consist of RNA-sequencing and ATAC-sequencing analyses, among others.
Dr. James discussed multiple publications that came out of Phase I research, including a paper by Zhang et al. in Nature Immunology looking at cells and expression molecules in RA and osteoarthritis synovium; and a paper by Der et al., also in Nature Immunology, focused on tubular interferon scores in lupus nephritis patients versus other populations.
Dr. James next reviewed the composition and charge of the Council’s AMP Lessons Learned Working Group. The working group was tasked with reviewing data and providing summaries of findings and themes to the NIAMS Council focused on the program’s goal of fostering interdisciplinary team science. What are the lessons learned from AMP that NIAMS should consider in future efforts to support interdisciplinary team science projects? Dr. James briefly touched on the working group’s meeting schedule and evaluation methodology, including qualitative and quantitative components.
Dr. James presented the Working Groups’ interim progress report. The quantitative analysis included two RFAs to review the publications resulting from the AMP RA/Lupus program. These reviews found 90 publications connected to the program, 9 of which came directly from the core AMP network. Overall, the publications scored very high, above the 90th percentile, on relevance to the program goals. Dr. James also discussed data comparing AMP publications to other NIH high risk, high reward grant programs for public impact, as well as data on journal impact rankings and content analysis. The working group also evaluated the AMP RA/Lupus program’s outreach and dissemination efforts. Scientific data is made available to the research community through dbGaP and ImmPort. Outreach to stakeholder organizations, nonprofit partners, and the international research community has also increased in recent years.
Finally, Dr. James discussed the working group’s next steps for the coming months. The working group will meet to review the qualitative responses and compile and further analyze the accumulated data. The working group will then draft its white paper on lessons learned and present the final report, with themes and suggestions, to the NIAMS Council later in 2020.
Dr. Westendorf asked if the program ever hopes to produce GWAS data, which generally requires much larger cohorts of participants. Dr. James said all the subjects will be genotyped and the program is mainly looking to run eQTL analysis, which is more appropriate for smaller populations, as well as ATAC-seq and immune receptor repertoire analyses. Council members were generally enthused about the work of the AMP program itself and the working group’s in-depth and detailed evaluation of the program.
IX. NIAMS COLLABORATIONS WITH NCI’S CANCER MOONSHOT PROGRAM
This portion of the meeting occurred during closed session.
X. SPECIAL ACTIONS
This portion of the meeting occurred during closed session.
The 100th National Arthritis and Musculoskeletal and Skin Diseases Advisory Council met on February 4, 2020. 15 council members attended in person. En bloc concurrence was unanimously approved for 712 primary and 238 secondary applications. The total cost requested in year -01 for all applications was $375,212,197.
The 100th National Arthritis and Musculoskeletal and Skin Diseases Advisory Council adjourned at 3:00 p.m. Proceedings of the public portion of this meeting are recorded in this summary.
I hereby certify that, to the best of my knowledge, the foregoing summary and attachments are accurate and complete.
Robert H. Carter, M.D