The 107th meeting of the National Advisory Council on Aging (NACA) was convened on Tuesday, May 19, 2009, at 3:00 p.m. in Building 31, Conference Room 10, National Institutes of Health (NIH), Bethesda, Maryland. Dr. Richard J. Hodes, Director, National Institute on Aging (NIA), presided.
In accordance with the provisions of Public Law 92–463, the meeting was closed to the public on Tuesday, May 19, from 3 p.m. to 5 p.m. for the review, discussion, and evaluation of grant applications in accordance with the provisions set forth in Sections 552(b)(c)(4) and 552(b)(c)(6), Title 5, U.S. Code and Section 10(d) of Public Law 92–463.1 The meeting was open to the public on Wednesday, May 20, from 8 a.m. to 1:15 p.m.
Dr. Lisa Berkman
Dr. Dale Bredesen
Dr. Kenneth Brummel-Smith
Dr. Peggye Dilworth-Anderson
Dr. Carl Eisdorfer
Dr. Lawrence M. Friedman
Dr. Mary Ganguli
Dr. S. Michal Jazwinski
Dr. Sundeep Khosla (May 19)
Dr. Andrea LaCroix
Dr. Victor Molinari
Dr. John C. Morris
Dr. Gerald Schatten
Ms. June Simmons (May 19)
Dr. James P. Smith
Dr. Susan L. Swain
Dr. Lennart Mucke
Ms. Orien Reid
Ex Officio Participants:
Dr. James Burris, Department of Veterans Affairs (May 17-18)
Absent Ex Officio Participants:
Ms. Lori Gerhard, U.S. Administration on Aging
Dr. Kenneth G. Pugh, National Naval Medical Center
The Council Roster, which gives titles, affiliations, and terms of appointment, is appended to these minutes as attachment A.
In Addition to NIA Staff, Other Federal Employees Present:
Dr. Carolyn Clancy, Agency for Healthcare Research and Quality
Dr. Joel Kupersmith, Department of Veterans Affairs
Dr. Nancy Miller, Office of Science Policy, National Institutes of Health (NIH)
Dr. Elizabeth Nabel, National Heart, Lung and Blood Institute, NIH
Dr. Laurent Taupenot, Center for Scientific Review, NIH
Members of the Public Present:
Dr. Kim Acquaviva, George Washington University/Friends of NIA
Mr. James Appleby, Gerontological Society of America
Dr. Elliott Fisher, Dartmouth Institute for Health Policy and Clinical Practice
Dr. Michela Gallagher, Johns Hopkins University
Ms. Christy Gilmour, American Academy of Orthopedic Surgeons
Ms. Linda Harootyan, Gerontological Society of America
Dr. Darlene Howard, Georgetown University
Dr. Perry Kirkham, Purdue University
Ms. Pat Kobor, American Psychological Association
Dr. Rose M. Li, Rose Li and Associates, Inc.
Dr. Frances McFarland Horne, Rose Li and Associates, Inc.
Dr. Arlan Richardson, University of Texas Health Sciences Center
Mr. David Scalzitti, American Physical Therapy Association
Dr. Mary Tinetti, Yale University School of Medicine
Dr. Abe Walston, PPD, Inc.
Ms. Naomi Webber, Research Councils UK
This portion of the meeting was closed to the public, in accordance with the determination that it concerned matters exempt from mandatory disclosure under Sections 552(b)(c)(4) and 552(b)(c)(6), Title 5, U.S. Code and Section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. Appendix).2
A total of 1244 applications requesting $1,267,916,839 for all years underwent initial review. The Council recommended 647 awards for a total of $808,513,939 for all years. The actual funding of the awards recommended is determined by the availability of funds, percentile ranks, priority scores, and program relevance.
Dr. Hodes welcomed members to the open session of the 107th NACA meeting and called the meeting to order at 8:02 a.m on Wednesday, May 20, 2009.
Dr. Hodes acknowledged Dr. Rebecca Ferrell, of the Scientific Review Branch, and Mr. Kevin Kinsella, of the Division of Behavioral and Social Research, as new staff members and welcomed Mr. James Appleby, the new Executive Director of the Gerontological Society of America. He also circulated the February–May 2009 compilation of media coverage for NIA.
Dr. Hodes reported that the fiscal year (FY) 2009 Omnibus Appropriation Act funds the National Institutes of Health (NIH) at $1 billion over the FY2008 level, representing a 3.2 percent increase. This includes a 2.7 percent increase for the NIA. These increases are still subinflationary, adding to the total accrued decrease in real buying power. The appropriation also makes permanent the Public Access Provision, which requires that research supported by the NIH be made accessible to the public.
The President’s FY2010 budget includes a request of $31 billion for NIH, an increase of $443 million, or 1.4 percent, above the FY2009 level. This includes an approximately $12 million increase to $1.09 billion for the NIA. The FY2010 budget request calls for more than $6 billion for cancer research across the NIH in the first year of an 8-year strategy to double cancer research by FY2017. This request represents an increase of $268 million, or 5 percent, over the FY2009 level of funds devoted to cancer research. All NIH Institutes and Centers (ICs), including the NIA, with investments in cancer research will participate in planning how to use these funds.
There has been less pressure to increase the base budget for the NIH in light of funds received from the American Recovery and Reinvestment Act (ARRA). ARRA aims to disburse funds as quickly as possible to stimulate the economy, create and preserve jobs, and advance biomedical research. A total of $10.4 billion has been allocated to the NIH, with the majority of those funds, about $7.4 billion, going to the ICs. This funding includes $273 million above the usual appropriation to NIA, to be used in FY2009 and FY2010 to fund existing peer-reviewed applications, trans-NIH funding opportunity announcements (FOA), NIA-specific FOAs, and administrative supplements. Dr. Hodes cautioned that the NIA will limit the amount of funds for administrative supplements and will continue to rely heavily on the peer-review process for assessing scientific merit. He briefly reviewed ARRA funding opportunities at the NIH.
Under ARRA, the NIH also receives $400 million of a total of $1.1 billion allocated for comparative effectiveness research (CER). NIH activities in this regard include participation on the Federal Coordinating Committee, participation in the Stakeholders Meeting of the Institute of Medicine CER Priority-Setting Committee, creation of an NIH CER committee and subcommittees that will interact with the Agency for Healthcare Research and Quality (AHRQ) and the Department of Veterans Affairs (VA). NIH also has created the NIH Fingerprinting Subcommittee to quantify NIH’s existing investment in CER. The $400 million in funds will be used to support CER-specific topics within mechanisms such as the NIH Challenge and Grand Opportunities (“GO grants”). Federal sites will be established for the public to monitor how these and other ARRA funds are used (see http://recovery.nih.gov ).
Dr. Hodes noted the major emphasis on transparency and the intense burden on NIH staff to ensure quick disbursement of ARRA funds. In response to questions from Dr. Gerald Schatten about post-award reporting requirements, Dr. Hodes noted that ARRA requires quarterly, not annual reports, and Dr. Robin Barr reported that negotiation was ongoing about the timing of these reports, as university administrations are concerned that requirements for reports at the beginning of the month are incompatible with their accounting systems.
Dr. Hodes closed by reporting on the HBO documentary, The Alzheimer’s Project, which represents part of NIA’s efforts to communicate with the public. This documentary represents a 2-year effort and includes four films, 15 supplemental films, and a book. The Alzheimer’s Project informs the public about human, emotional, and societal issues related to Alzheimer’s disease (AD), as well as about important areas of research. More than 5,000 screening kits and discussion guides have been distributed and an estimated 3,000 screenings held in communities nationwide.
September 22–23, 2009 (Tuesday and Wednesday)
January 26–27, 2010 (Tuesday and Wednesday)
May 25–26, 2010 (Tuesday and Wednesday)
September 21–22, 2010 (Tuesday and Wednesday)
The minutes of the January 2009 meeting were considered. A motion was made, seconded, and passed unanimously to approve the minutes.
Dr. Peggye Dilworth-Anderson acknowledged the Senate confirmation of Dr. Yvette Roubideaux as head of the Indian Health Service. Dr. Roubideaux is an alumna of the NIA Summer Institute directed by Dr. J. Taylor Harden, and has worked with the NIA-supported Research Center for Minority Aging Research in Colorado. Dr. Dilworth-Anderson cited Dr. Roubideaux as a success story in NIA’s multipronged approach to supporting minority training and research in aging. She then reported on two presentations heard by the task force on the previous day.
In one presentation, Ms. Arlene Jackson discussed the NIA Summer Trainee in Aging Research (STAR) program. This intramural summer program aims to provide an optimal learning environment for students to enhance their interest in training and biomedical research dedicated to aging. The program draws from a diverse population and supports approximately 60 students, ages 16 years or older, who are enrolled in high school or an accredited college. Activities include weekly lectures on various aspects of health and behavioral sciences; a workshop on grantsmanship and presentation preparation; and poster day at the NIA and NIH. STAR program alumni compete in national poster competitions and are included as coauthors on publications. Some students return to the STAR program in subsequent summers. Traditional and social networking methods help track alumni, and an evaluation component examines the seminar topics offered, the quality of students’ laboratory and mentoring experiences, their participation in Poster Day, and suggestions for improvement. Alumni include 28 Ph.D. students, a postdoctoral fellow, an M.D. candidate focused on cardiology, and a student with a B.S. in materials science.
In another presentation, Dr. Michele Evans described the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) Study. This study examines differences in health related to race and socioeconomic status; other contextual variables such as environment, biology, and culture; biologic mechanisms; and potential early biomarkers. All these factors have been associated with age-related health disparities, but the mechanisms behind the disparities are multipronged and contain many root causes. Dr. Evans’ presentation summarized the HANDLS study design and methods, accrual, analyses approach, and the many people involved in the study.
Dr. Dilworth-Anderson closed her presentation by drawing attention to a Web-based toolbox—the Health Disparities Resource Persons Network—and encouraged Council members and young investigators to contact Dr. Harden about participation in the network. She also reported on the Task Force’s discussion of funding opportunities in support of minority aging and training.
Dr. John Morris discussed two meetings and three Requests for Applications (RFA) proposed for concept clearance, which the Working Group discussed the previous day. The Council also reviewed a change to the Statement of Understanding.
Dr. Chhanda Dutta, of the Division of Geriatrics and Clinical Gerontology, reported on a meeting held to update a 1998 guide on exercise and physical activity. Future plans include potential collaborations to evaluate the guide’s usefulness, a possible Spanish-language translation, and perhaps an exercise video. The Working Group discussed opportunities to collaborate with area agencies on aging and with commercial enterprises such as Nintendo Wii-Fit. A motion to endorse the NIA activities promoting exercise and physical activity was forwarded, seconded, and unanimously approved.
Dr. Tony Phelps, of the Division of Neuroscience, proposed a conference to be held June 15, 2009, in Bethesda, cosponsored by the Alzheimer’s Association, to review diagnostic criteria for mild cognitive impairment (MCI) and dementia. If a revision to the diagnostic criteria is found to be warranted, a larger meeting would be held in the future. The working group agreed on the need to accelerate research on the detection of dementia and to recognize that MCI itself might represent a stage of the disease process. A motion was made, seconded, and unanimously approved to approve the meeting proposal as outlined.
Dr. Erica Spotts, of the Division of Behavioral and Social Research (DBSR), presented a proposed RFA to examine the interplay between early genetic and environmental factors and their effects on health and behavior later in life. This concept, based on recommendations from a 2008 DBSR review, would encourage existing family and twin studies to pool resources to examine relevant questions. The RFA is expected to yield multidisciplinary measures, promote harmonization of measures, and attract investigators new to aging research. A motion to approve the RFA concept was forwarded, seconded, and passed unanimously.
Dr. Mahadev Murthy, of the Division of Aging Biology (DAB), presented a proposed RFA focused on the biology of aging in invertebrates to support the development of models to explore genes and pathways in aging research, and to attract leading researchers in these fields to enter aging research. The working group held considerable discussion of the potential for added value over what has already been learned with existing models, such as C. elegans. During Council discussion, Dr. Schatten observed that the RFA would offer an opportunity to explore invertebrates that might be more useful than nematodes and fruit flies in studying plasticity. He recommended reviewing the small number of projects funded with support from the Division of Comparative Medicine, National Center for Research Resources. On the other hand, Dr. Dale Bredesen expressed concerns about potential loss of focus, the uncertainty that additional models would add value in terms of plasticity and regeneration, and the need to develop new models in light of current budget constraints. Dr. Bredesen stressed the importance of continuing to support and use models that have so far yielded a large amount of information. A motion was made and seconded to approve the RFA concept. The motion passed with one abstention.
Dr. Jonathan King, of DBSR, presented a proposed RFA on healthy aging and behavioral economic analyses. Dr. King noted current difficulties in promoting behavior change, even when such change is clearly in an individual’s best interest. This RFA would support research on behavioral economic tools that could encourage actions to improve health. During Council discussion, Dr. King clarified that although adherence to medication is an obvious example to study, behaviors such as maintenance of physical activity or dietary changes and response to stressors are also of interest. To provide context, Dr. Hodes described an ongoing, NIH-wide initiative focused on behavior change that has garnered support from 17 ICs and the Office of Behavioral and Social Science Research. This RFA would further position the NIA to participate in this broader effort. In response to concerns from Dr. Eisdorfer regarding use of the term “behavioral economics,” Dr. King indicated that the behavioral economic standpoint would focus on specific choices and the use of incentive structures. Dr. Richard Suzman, DBSR Director, added that this term appropriately captures the Division’s interest in applying models that have been applied conventionally to financial decisions to lifestyle issues. DBSR has commissioned reports from the National Academies’ Committee on National Statistics and the Institute of Medicine on the cost-effectiveness and efficacy of behavioral interventions, with particular emphasis on health and lifestyle. A motion to approve the RFA concept was made, seconded, and unanimously passed.
Dr. Barr reminded the Council that the Statement of Understanding between the NIA and NACA allows the NIA to expedite actions and report on them at later Council meetings. Because there is insufficient time between the September Council meeting and the funding of applications responding to ARRA initiatives before the end of the fiscal year, the NIA requested a change to the Statement of Understanding to permit early concurrence of the ARRA applications to expedite the award process. A motion was made whereby “NIA staff may expedite award of applications submitted in response to the American Recovery and Reinvestment Act of 2009 initiatives provided that they raise no policy or scientific concerns. Council members will provide second-level review either electronically or by fax before the Council meets.” The motion was seconded and passed unanimously.
Dr. S. Michal Jazwinski, chair of the DAB review committee, provided an initial report that covered the focus and organization of the review, major determinations, and challenges. He thanked the NIA leadership and staff for providing materials for the review, and for their candor and collegiality.
The DAB review committee formed six subcommittees focused on each of the three DAB branches (Genetics and Cell Biology; Aging Physiology; and Biological Resources), the Nathan Shock Centers, training, and interdisciplinary and translational research. The DAB review committee met May 17-18, 2009, to consider the Division’s response to the last quadrennial review, to review the subcommittee reports, to formulate additional areas of inquiry, to interview the NIA Director and DAB staff, and to outline the draft committee report.
The reviewers determined that DAB has responded positively to many of the recommendations from the prior (2005) review, and made often remarkable progress despite declining funds in real dollars. The committee echoed the previous review finding that outcome measures are lacking to gauge success, and it encouraged DAB to collect such information to aid in future reviews. The review committee also noted continuing challenges, relative to other NIA Divisions, such as low and declining funding, as well as fewer funded program projects (P01), translational supplements, and fellowships (F32). The DAB review committee expressed astonishment that these challenges persist in light of the many major breakthroughs in the fundamental biology of aging.
Dr. Jazwinski summarized the committee’s recommendations to the DAB and NIA leadership:
The review committee commended Dr. Felipe Sierra for his creative leadership in the short time he has directed the Division, as well as the exceptionally committed staff. The committee applauded the interactive and dynamic nature of DAB, acknowledged the challenges associated with implementing ARRA requirements, and suggested that this is a time for improved communication and rational distribution of discretionary funds to increase morale. Formal training in management also was suggested.
The final review report will be presented to Council at the September meeting. During Council discussion, Dr. Hodes raised three points to be addressed in the final report: (1) the tradeoff between increasing discretionary funds and funding applications within the payline; (2) the balance between the need for interdisciplinary research and the perspective that the R01 mechanism should be the first priority for investigator-initiated research; and (3) the tension between calling for a broad strategic plan and the finding that DAB’s areas are too broad. In response to questions from Dr. Schatten, Dr. Hodes discussed the balance between discretionary and program funds.
Dr. Hodes introduced the symposium by noting that the quality of the Nation’s health care will be enhanced by comparative effectiveness research (CER). NIH emphasis on CER has been ongoing since summer 2008. Although there is wide agreement among policymakers, health plan managers, employers, drug and device manufacturers, and professional associations that more CER is needed, perspectives about details differ. Many definitions have been proposed for CER, but Dr. Hodes referred to the one posted by the U.S. Office of Management and Budget (OMB):
Comparative effectiveness research is the conduct and synthesis of systematic research comparing different interventions and strategies to prevent, diagnose, treat and monitor health conditions. The purpose of this research is to inform patients, providers, and decision-makers, responding to their expressed needs, about which interventions are most effective for which patients under specific circumstances. To provide this information, comparative effectiveness research must assess a comprehensive array of health-related outcomes for diverse patient populations. Defined interventions compared may include medications, procedures, medical and assistive devices and technologies, behavioral change strategies, and delivery system interventions. This research necessitates the development, expansion, and use of a variety of data sources and methods to assess comparative effectiveness.
Systematic research methods can include randomized controlled trials, meta-analyses, and other types of deliberate and orderly research.
Dr. Hodes emphasized that to be useful over the long term, the definition of CER must be flexible. After reminding the Council of the budget allocations under ARRA and summarizing the many formal planning activities in which the NIH is involved, he highlighted CER issues relevant to aging:
Following Dr. Hodes’ overview, the Council heard four short presentations, then engaged the panel in discussion.
Dr. Mary Tinetti, of the Yale University School of Medicine, began by explaining that one aim of the Medicare Modernization Act was to improve the quality, effectiveness, and efficiency of health care delivered through Medicare, Medicaid, and the State Children’s Health Insurance Program. However, it is not clear how this improvement can occur without the inclusion of services and treatments given to the more than half of Medicare beneficiaries who have at least two chronic diseases or conditions. Older adults with multiple conditions are the largest users of health care and medical treatments, but little is known about the effectiveness (and harm) of their care. This lack of evidence arises partly because older adults are often excluded from most clinical trials. Moreover, trials and observational studies that do include older adults with multiple morbidities focus on the benefit for only one disease or one set of disease outcomes. The most effective treatments for patients with multimorbidities are not known, and treatment that is effective for one disease might prove harmful for other conditions or the patient. Thus multimorbidity should be a focus of CER.
CER in older adults should include comparisons of “usual care” versus “disease-guideline-based care” and of net benefit versus harm, rather than focusing solely on benefits. The research should include key subgroups, for example classified by disease burden, because harms and benefits likely vary according to patient characteristics. Importantly, CER must assess and compare universal outcomes, which are health outcomes that are important to patients and represent outcomes through which all disease-specific outcomes exert an effect. These outcomes can be classified into the domains of symptoms and impairments, function or disability, and survival.
Dr. Tinetti described study designs in which guidelines-based care is compared with “usual” or “less aggressive” care for disease pairs or multiple diseases. Such studies could compare disease-specific and universal outcomes and examine innovative models of care, treatment algorithms driven by patients’ priorities, and single interventions that benefit several diseases. Although these studies could be designed as observational studies or randomized, controlled trials, they would require large, representative sample populations with multiple conditions, as well as descriptive and prognostic data on subgroups, longitudinal data on disease-specific and universal outcomes, and data on treatments to be compared. Potential study populations can be derived from the Medicare Current Beneficiary Survey, the Medicare Expenditure Panel Survey, and integrated systems with electronic medical records (EMRs), such as Group Health, Kaiser, and the VA. Key comparisons would include more versus fewer drugs, behavioral versus drug interventions, and models versus disease guidelines.
Dr. Tinetti closed her presentation by acknowledging that effectiveness for older adults with multimorbidity would likely be the most complex area of CER. However, this complexity is inherent in the problem itself, not in the research. Because multimorbidity is the core of geriatric care, ignoring this question can result in harmful, expensive care of unclear benefit.
Dr. Elliott Fisher, of the Dartmouth Institute for Health Policy and Clinical Practice, sees current public and policy interest in CER as largely motivated by rapidly rising health care costs, and the expectation that CER is key to achieving savings and improving the quality of U.S. health care. However, the failure to think clearly about the role of the local delivery system will result in a missed opportunity for realizing improvements. In considering CER and its potential impact on spending and quality, Fisher distinguishes three broad categories of evidence:
An assessment of regional spending on discrete, biologically targeted interventions in the United States suggests that higher-spending regions are less likely to deliver interventions that are known to work. The same is true for discretionary interventions such as hip or knee replacements. This has several implications for outcomes: (1) Patients in higher-spending regions do not necessarily receive better care, (2) mortality rates in older populations appear to be slightly worse, and (3) physicians report less capacity to care for patients.
In summarizing what has been learned about potential explanations for these differences, Dr. Fisher noted that evidence is an important but limited influence on clinical decision making, that physicians practice within a local context that powerfully influences their decision making, that “more” is not necessarily better, and that continued growth is not affordable. Enough is known about some principles to begin putting them into practice. For example, it is apparent that problems in organizational context, performance measures, and the payment system must be addressed. However, there is much left to learn. For example, little is known about the factors underlying differences in spending across communities or across academic medical centers.
In summarizing implications for policy, Dr. Fisher pointed to contextual factors that will influence the effectiveness and cost of interventions, and in the current, unfettered payment system, savings are unlikely to arise from targeted interventions, as reduced use in one group will coincide with increased use by another population. Thus a narrow focus on biologically targeted interventions will ignore opportunities for improving both the quality and costs of care. Investment in infrastructure, including a strong measurement component, is needed for both performance measurement and CER, and CER should be defined broadly to include biologically targeted interventions, care models, and delivery system interventions.
Dr. Carolyn Clancy, Director of the Agency for Healthcare Research and Quality (AHRQ), began by referencing findings from the 2008 National Healthcare Quality and Disparities Reports, including indications that although overall quality of care is improving, many areas of disparities are the same or worsening. About 39 percent of non-institutionalized, older adults rated their health as good, although many older adults had at least one chronic condition. Dr. Clancy emphasized the need to define what is meant by “success” for patients with multiple chronic illnesses. She also described the potential impact of CER, including the enhancement of information on services that improve quality, safety, and effectiveness and the use of that information to assist participants in their decision making.
AHRQ has received an FY2009 appropriation of $50 million for CER, an increase of $20 million from FY2008, as well as $300 million in funds from ARRA. Its Effective Health Care Program, established about 5 years ago as part of the Medicare Prescription Drug, Improvement, and Modernization Act, includes synthesis of evidence on treatment effectiveness, research networks to develop new scientific knowledge and address gaps, and a strong role in translating and communicating information arising from these activities. AHRQ plans to expand this infrastructure and capacity to accommodate CER, conduct prospective studies that include underrepresented populations, hold a symposium on CER methods, and increase investments in innovative, broad dissemination and translation.
CER might not save money in the short run but could improve the value of health interventions in the long run. Dr. Clancy noted that the information emerging from CER is necessary, but not sufficient. It alone will not make policy or health care decisions, and it cannot tell physicians how to practice medicine. However, CER will give patients a tool to weigh information and make the best decisions, and it will provide opportunities to identify what is now known and where research is needed.
Dr. Clancy expects that public-private partnerships will be needed to further encourage CER. Although there appears to be little opposition to CER, some are worried about how it will be used, and are concerned, for example, that CER results will be used to deny care to someone who might have benefited from a particular intervention or that CER will discourage innovation. Issues of ethics, transparency, priority setting, and sufficiency of evidence will need to be addressed, and patients should be engaged as partners at the local and national levels.
Dr. Joel Kupersmith shared the experiences of the Department of Veterans Affairs (VA), which has engaged in CER for 20 to 30 years. The VA’s research mission includes discovering knowledge and creating innovations to advance health and care of veterans and the nation. The VA offers numerous advantages for CER, including its large health care system comprising 5.5 million patients per year, 7.8 million enrollees, and 153 medical centers, 117 with Federalwide assurances for research. The VA system uses EMRs, and its research community involves 3,000 researchers and funds 2,100 projects per year, including cooperative studies, health services research, and rehabilitation studies. Dr. Kupersmith described the process for funding research projects and provided examples, including CER studies showing when and how best to perform a colonoscopy, a comparison of laboratory-based and home evaluation of sleep apnea, and comparisons of optimized versus usual care.
In addition to clinical trials, EMR analysis offers immediate results and less cost. However, care must be taken in the kinds of randomization and instruments used, particularly if care decisions are made not for clinical reasons but rather for reasons such as delays in accepting drugs on the formulary list. Dr. Kupersmith presented examples of EMR analyses, such as a diabetes cohort database that showed no differences in mortality among oral anti-diabetic drugs, a comparison of obesity care practices, prescription strategies for non-steroidal anti-inflammatory drugs, and a comparison of treatments for heart failure.
The VA has two mechanisms for implementation and translation. The Quality Enhancement Research Initiative (QUERI) aims to implement and translate evidence-based clinical practices and research findings systematically into routine care. QUERI has been used, for example, in implementing collaborative care for depression and in vaccinating against influenza and pneumococcus in patients with spinal cord injuries. The VA Evidence Synthesis Program involves a policy-oriented synthesis of evidence to inform medical practice and health systems planning. Recent topics have included drug management of benign prostate hyperplasia and the incorporation of osteoporosis in guidelines on screening male veterans. Dr. Kupersmith acknowledged that despite these approaches, cultural issues do manifest themselves because many doctors practice both in the VA and in university practice plans. In addition, not everything is translated immediately to care. Dr. Kupersmith concluded his presentation by stating that the VA is operationally ready for CER and will participate in discussions with NIH.
Discussion turned next to the issue of integrating measures of outcomes with those of patients’ values. Dr. Kupersmith pointed out that personalized therapy is not limited to genomics and that research most likely would evolve into short-term, randomized, controlled trials followed by longer-term analyses of complex databases with information on demographics, patients’ values, and comorbidities to determine what might be best for individuals. This could be combined with an examination of the cultural approaches of both patient and physician. Participants also suggested investigating expectations and cohort effects.
Dr. Hodes stated that the NIH has relied primarily on investigator-initiated research, but that it now should proactively consider strategies in which NIH will not be the only entity involved. Dr. Kupersmith noted the need to encourage the clinical establishment to play a larger role. Drs. Schatten and Tinetti added that mathematicians, statisticians, and data managers also should be included, and Dr. Lisa Berkman commented that CER should include studies of prevention interventions outside the medical system (i.e., tobacco taxation).
Infrastructure was also discussed. Dr. Tinetti suggested that the NIA, the Food and Drug Administration (FDA), the VA, and other Federal agencies could push for the infrastructure needed to accommodate CER. These agencies could call for more clinical data, but they also could require universal outcomes. As medicine moves toward using EMRs, Federal agencies could require that certain components and universal outcomes be included in the EMR. Dr. Fisher commented that CER infrastructure also should include disease-specific measures in a flexible way. Legal and privacy issues should be considered in terms of tracking patients over time, and registries should be built in a way that captures not only individual attributes, but also community and social supports.
Dr. Mary Ganguli, whose institution has used an EMR system for years, called for the development of a nationwide, uniform system of EMRs that are compatible across institutions. She pointed out that EMR systems presently involve time-consuming steps and that so-called enhancements typically create more problems. Dr. Kupersmith noted problems between the VA and Department of Defense (DoD) systems, arising from differences in the way these agencies approach research. Dr. Andrea LaCroix also cautioned that analytic methods used with the EMR cannot account for complex outcomes or confounding by indication. Dr. Fisher agreed with the importance of a universal record, and he noted that consensus had not yet been reached on the attributes needed to convert the EMR from its current electronic version of the paper record to a form that will support registry and database development and that can be used as research tools. Health Insurance Portability and Accountability Act (HIPAA) compliance also must be considered. Dr. Kupersmith commented that the VA EMR is user-friendly because users have been involved in its development.
Participants also discussed the need for cultural changes. For example, the research community should find ways, in addition to the medical literature, to communicate among its members. Dr. Victor Molinari suggested that increased communication among physicians might be difficult within a payment system where 15-minute appointments barely allow physicians enough time with patients. Dr. Fisher agreed that changing this model of care would require altering the payment system so that appointments are more value based. However, efforts could begin with determining how to obtain the best outcomes at reasonable costs, then tackling ways to encourage physicians to work together in teams.
Dr. Hodes mentioned training as an obvious area for intervention. Dr. Dilworth-Anderson added that training should focus not only on clinicians, but also on researchers and communities. For example, members of the community could be trained to become research participants, and researchers could be trained on mixed methods and community participatory research.
Drs. Richard Suzman and Marie Bernard noted the importance of CER but pointed out that resources are finite and that the NIA and NIH must consider how best to focus their efforts. Opportunities for collaboration among Federal agencies were discussed. For example, the VA collaborates with several NIH ICs, with AHRQ, and with some overseas institutions. Dr. Hodes noted the willingness to collaborate, but he also mentioned barriers inherent in records and patient confidentiality.
Also discussed was studying patients with multiple morbidities. Dr. Brummel-Smith raised the practical research problem that datasets might start out large, but as more comorbidities are added, the number of available patients declines considerably. The addition of demographic requirements decreases that number even further, leaving a dataset with small research samples. The new push toward CER could support the development of large, nationally representative datasets. Dr. LaCroix added that many good research applications have been rejected because of tension between basic scientists, geriatricians, and epidemiologists regarding comorbidities. For example, a mouse strain could not be generated to harbor several diseases.
Sustainability was discussed briefly. Dr. Lawrence Friedman pointed out that keeping CER sustainable will require funding sources beyond the Department of Health and Human Services (DHHS) and ARRA. Tapping industry and various funding sources will facilitate balanced information emerging from this research.
The Free Radical Theory of Aging has become the predominant theory to explain aging at the molecular level. This theory states that oxidative damage increases with age, resulting in loss of cellular function and increased pathology and aging. Almost all the large body of research supporting this theory over the past five decades has been correlative -- oxidative damage does appear to increase with age, and animal models with increased life span show less damage and increased resistance to oxidative stress.
Prior to the advent of genetic technology, which allowed investigators to alter the expression of antioxidant enzymes, direct evidence showing that oxidative damage/stress alters aging was limited. Because of their role in detoxifying free radicals and reactive oxygen species, such enzymes can alter the sensitivity of the organism to oxidative stress and the levels of oxidative damage in cells and tissues.
Around 2000, several reports showed that overexpressing an antioxidant enzyme in fruit flies increased their lifespan. Dr. Arlan Richardson, of the University of Texas Health Science Center, presented similar research in mice, examining the effects of reducing or enhancing the antioxidant defense system. He and his colleagues have found that mice deficient in methionine sulfoxide reductase (MsrA) have shorter life spans and that mice heterozygous for copper-zinc superoxide dismutase (CuZnSOD) show a large amount of oxidative damage and die primarily of a liver cancer not normally observed. Surprisingly, mouse strains engineered to overexpress various antioxidant enzymes all show resistance to oxidative stress, but they show no differences in life span. Dr. Richardson pointed out that these studies were conducted under optimal husbandry, in which the levels of stress and infection had been reduced, and also that the studies included a number of mice sufficient to see a 10 percent difference. He argued that the Free Radical Theory of Aging should be reconsidered.
Dr. Richardson also discussed notable exceptions. Rats overexpressing CuZnSOD exhibit about a 10 percent difference in life span, and end-of-life pathology for these mice shows significantly reduced cancer deaths and a higher number of deaths of undetermined cause. This rat strain was created in a Sprague-Dawley background. Sprague-Dawley rats tend to become obese, suggesting that increased adiposity results in increased stress; that life span effects in a “clean” environment might not be the same as life span effects in a “dirty” environment; and that alterations in the antioxidant defense system might affect “health span” in addition to life span. Dr. Richardson and his colleagues are now studying the effects of manipulating the tendency toward obesity in both rats and mice.
A second exception involves the naked mole rat, which lives 10 times longer than mice and does not show signs of cancer at death, as mice do. Yet surprisingly, naked mole rats show more oxidative damage than do mice, particularly on proteins. Typically, oxidative damage to proteins results in misfolding, which could lead to neurodegeneration. Studies of liver extracts show an increased tendency toward protein misfolding and aggregation in extracts from mice and a reduced tendency in extracts from naked mole rats. These results suggest that cell environment might not decrease the amount of oxidative damage in species evolved to live longer, but it could reduce the downstream effects of such damage.
Discussion focused primarily on a dirty environment versus a clean one. Dr. Jazwinski noted that the dirty environment is closer to a natural one but that using this as a model for human aging might depend on populations under study. Dr. Richardson also acknowledged that the natural environment changes and that typical experiments, which control environment, will not yield information about the natural environment. He stressed the importance of conducting experiments in clean environments, but added that more stressful environments should be considered. Dr. Richardson also noted that researchers usually stop studying mice after they reach 28 months of age; more research is needed on what happens to very old mice.
Episodic memory deficits have been documented as an important and early-detected risk factor for dementia, and are a hallmark of Mild Cognitive Impairment (MCI), a diagnostic entity often regarded as a preclinical phase of AD. Many studies have reported functional changes in the medial temporal lobe (MTL) of MCI and AD cases. In contrast with studies reporting reduced hippocampal activity during memory tasks in mild AD cases, other studies have shown that MCI patients exhibit a pattern of “hyperactivity” in the hippocampus/parahippocampal region during memory encoding tasks. These changes in functional activity have been linked to both the current level of impairment and the development of future impairments. However, the actual source of the hyperactive signals is not known.
Recently, animal models of age-related memory impairment have offered some insight into the neural mechanisms potentially underlying this hyperactivity. In a well-characterized population of outbred rats, those with memory impairment in spatial cognition and recollection during recognition judgments exhibit a failure to encode novel information while navigating similar environments, shifting instead to using familiar information. This “rigidity” in the encoding of new information is localized to the CA3 region of the hippocampus and might arise from impairment in pattern separation, or the ability to store similar representations in a distinct, non-overlapping fashion. It is important to note that episodic memory, recollection, and source memory all place strong demands on pattern separation. In addition to encoding failures, CA3 neurons in this animal model exhibit excess activity.
Dr. Michela Gallagher, of Johns Hopkins University, discussed her studies using high-resolution functional magnetic resonance imaging (fMRI) to examine humans with amnestic MCI during performance of a task that taxes pattern separation. As reported elsewhere for typical recognition memory tasks, MCI patients performed just as well as controls on “new” and “repeat” items. However, they were selectively impaired on similar (but not identical) items, which place heavier demands on pattern separation than do new or identically repeated items. Although the fMRI data showed increases in several hippocampal subregions in MCI patients, only the left CA3/dentate gyrus showed hyperactive blood oxygen level-dependent (BOLD) activity when pattern separation was heavily taxed. Dr. Gallagher and colleagues also observed a correlation between increased BOLD activity in this region and decreased behavioral pattern separation activities.
Along with evidence from electrophysiological recordings in rats and animal microimaging studies, Dr. Gallagher’s study indicates that hippocampal hyperactivity is likely part of a dysfunctional network. In light of results from previous studies in the rat, it is likely that a shift in the control of CA3 activity results in a shift from the ability to separate new inputs during a task to the completion of a task based on familiar information previously learned.
Aside from questions about details of Dr. Gallagher’s studies, discussion focused on implications for distinguishing normal aging from pathologic aging. Although aging is still the biggest risk factor for AD, little is known about the transition from aging into AD. Dr. Gallagher also noted that pathologic aging is a progressive condition and that the observations from her studies might provide a correlate of aging that causes memory impairment but not necessarily progression to pathologic deterioration.
The open session of the 107th meeting of the National Advisory Council on Aging was adjourned at 1:15 p.m. on May 20, 2009. The next meeting is scheduled for September 22 and 23, 2009.
I hereby certify that, to the best of my knowledge, the foregoing minutes and attachments are accurate and complete.3
Richard J. Hodes, M.D.
Chairman, National Advisory Council on Aging
Director, National Institute on Aging
Prepared by Robin Barr, D.Phil.
With assistance by Rose Li and Associates, Inc.
NATIONAL ADVISORY COUNCIL ON AGING
NATIONAL INSTITUTE ON AGING
(Terms end December 31) (*WGoP Member)
Richard J. Hodes, M.D.
Director, National Institute on Aging
National Institutes of Health
Lisa F. Berkman, Ph.D. (2012)
Director and Professor
Harvard School of Public Health
Dept of Society, Human Development, and Health, and Dept of Epidemiology
Dale E. Bredesen, M.D. (2011)
Professor, Director & CEO
Buck Institute for Age Research
Kenneth V. Brummel-Smith, M.D. (2009)
Professor and Chair
Department of Geriatrics
Florida State University College of Medicine
Peggye Dilworth-Anderson, Ph.D. (2010)
Professor, Health Policy & Management
Associate Director, Aging and Diversity/ Institute on Aging
University of North Carolina, Chapel Hill
Chapel Hill, NC
Carl Eisdorfer, Ph.D., M.D. (2009)
Knight Professor and Director
Center on Aging
University of Miami
Lawrence M. Friedman, M.D. (2009)
*Mary Ganguli, M.D., M.P.H. (2009)
Professor of Psychiatry, Neurology, and Epidemiology
Department of Psychiatry
University of Pittsburgh
*S. Michal Jazwinski, Ph.D., (2010)
Department of Medicine
Tulane University Health Sciences Center
New Orleans, LA
*Sundeep Khosla, M.D. (2010)
Professor, Endocrine Research Unit
Division of Endocrinology, Metabolism, & Nutrition
Mayo Clinic College of Medicine
Andrea Z. LaCroix, Ph.D., M.P.H. (2012)
Fred Hutchison Cancer Research Center
Women’s Health Initiative Clinical Coordinating Center
Victor Molinari, Ph.D. (2012)
University of South Florida
Department of Aging and Mental Health
*John C. Morris, M.D. (2009)
Washington University School of Medicine
St. Louis, MO
Lennart Mucke, M.D. (2012)
Director and Professor of Neuroscience
Gladstone Institute of Neurological Disease
University of California, San Francisco
San Francisco, CA
Orien Reid (2010)
Chairman, Alzheimer's Disease International
President, Consumer Connection
*Gerald P. Schatten, Ph.D. (2009)
Professor, Pittsburgh Development Center
Magee-Womens Research Institute
University of Pittsburgh
June Simmons (2012)
Chief Executive Officer
Partners in Care Foundation
San Fernando, CA
James P. Smith, Ph.D. (2012)
Department of Labor and Population
Santa Monica, CA
Susan L. Swain, Ph.D. (2011)
President and Director
Saranac Lake, NY
Department of Health and Human Services
Hubert H. Humphrey Building
Francis S. Collins, M.D., Ph.D.
National Institutes of Health
Public Health Service
James F. Burris, M.D.
Geriatrics & Extended Care Strategic Healthcare Group
Department of Veterans Affairs
Director, Office of Planning & Policy Development
U.S. Administration on Aging, DHHS
Kenneth G. Pugh, M.D.
Commander, MC, U.S. Navy
Department of Medicine
National Naval Medical Center
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