Minutes of the 136th Meeting of the NATIONAL ADVISORY COUNCIL ON ALCOHOL ABUSE AND ALCOHOLISM
-
DEPARTMENT OF HEALTH AND HUMAN SERVICES
NATIONAL INSTITUTES OF HEALTH
NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
Minutes of the 136th Meeting of the
NATIONAL ADVISORY COUNCIL ON ALCOHOL ABUSE AND ALCOHOLISM
June 4–5, 2014
The National Advisory Council on Alcohol Abuse and Alcoholism (NIAAA) convened for its 136th meeting at 5:00 p.m. on June 4, 2014, at NIAAA headquarters in Rockville, Maryland. The Council met in closed session for a review of grant applications and a Merit Award extension. The meeting recessed at 6:20 p.m. Dr. Abraham Bautista, Director-Office of Extramural Activities, presided over the closed session, which, in accordance with the provisions of Sections 552b(C)(6), Title 5, U.S.C., and 10(d) of Public Law 92-463, excluded the public for the review, discussion, and evaluation of individual applications for Federal grant-in-aid funds. Dr. George Koob, Director, NIAAA, reconvened the Council in closed session on June 5 at 8:15 a.m. for the NIAAA Board of Scientific Counselors’ Report, presented by Dr. Tatiana Foroud. That meeting concluded at 8:50 a.m., and Dr. Koob convened the Council in open session at 9:10 a.m.
Council Members Present:
NIAAA Director and Chair: George F. Koob, Ph.D.
Andrea Barthwell, M.D.
Carol A. Casey, Ph.D.
Linda L. Chezem, J.D.
Fulton T. Crews, Ph.D.
Suzanne M. de la Monte, M.P.H., M.D.
Marianne L. Fleury
Hon. Joseph Thomas Flies-Away, J.D., M.P.A.
Andres G. Gil, Ph.D.
Paul J. Gruenewald, Ph.D.
Craig J. McClain, M.D.
Robert O. Messing, M.D.
Patricia E. Molina, M.D., Ph.D.
Adolf Pfefferbaum, M.D.
Rajita Sinha, Ph.D.
NIAAA Deputy Director: Kenneth R. Warren, Ph.D.
Executive Secretary: Abraham P. Bautista, Ph.D.
Senior Staff: Vivian Faden, Ph.D.; Ralph Hingson, Sc.D., M.P.H.; Robert Huebner, Ph.D.; Keith Lamirande; Gary Murray, Ph.D.; Antonio Noronha, Ph.D.; Patricia Powell, Ph.D.
Chair, NIAAA Board of Scientific Counselors: Tatiana Foroud, Ph.D.
Other Attendees at the Open Sessions:
Approximately 50 observers attended the open session, including representatives from constituency groups, liaison organizations, NIAAA staff, and members of the general public.
Call to Order and Introductions
Dr. George Koob called the open session of the Council meeting to order at 9:10 a.m. on Thursday, February 5, 2014, and Council members introduced themselves.
Director’s Report
Dr. Koob highlighted key recent Institute activities, referring to the written Director’s Report.
- NIAAA budget. NIAAA’s Fiscal Year (FY) 2014 budget amounted to $444.9 million, and the President has proposed a FY 2015 NIAAA budget of $446.0 million. NIAAA has seen a small but steady increase in research project grants and anticipates continuing that trajectory. The total NIH budget for FY 2014 amounted to $29.9 billion, which was $1 billion more than the prior year, and reflects an approximate 50% restoration of the 4.7 % sequestration enacted upon the FY 2013 appropriation. The President has requested a FY 2015 NIH budget of $30.4 billion, a 0.1% increase over the FY 2014 enacted level.
- Honors and awards. NIAAA has presented a number of prestigious awards in recent months. For the first time, in the same year women received both the Keller Award and the Mendelson Award: Dr. Edith Sullivan presented the 18th Annual Mark Keller Honorary Lecture, and Dr. Bernice Porjesz delivered the 6th Annual Jack Mendelson Honorary Lecture. In addition, L’Oreal presented its Woman of the Year Award to a NIAAA grantee, Dr. Brigitte Kieffer. NIAAA’s Dr. David Lovinger and Dr. Kenneth Warren both have earned NIH Director’s Awards. In addition, the Research Society on Alcoholism will present its Lifetime Achievement Award to Dr. Warren. The Society of Biological Psychiatry has named Dr. Andrew Holmes as recipient of the 2014 A.E. Bennett Award.
- NIAAA staff transitions. Ms. Aurelia Higginbotham has joined NIAAA as a Travel Specialist in the Office of the Director; Ms. Laurie Rosenblatt has joined the Ethics and Management Analysis Branch as a Management Analyst; and Dr. Gene-Jack Wang will serve as Senior Medical Staff Clinician with the Laboratory of Neuroimaging. Dr. Page Chiapella, Dr. Cherry Lowman, Capt. David T. George, M.D., and Dr. Lorraine Gunzerath recently retired from federal service. Dr. Bridget Williams-Simmons has been appointed Chief, Science Policy Branch. Dr. Patricia Powell has been appointed NIAAA’s Associate Director for Scientific Initiatives and will also serve also as Chief of Staff. Dr. Markus Heilig has accepted a position in Sweden as Director, Center for Social and Affective Neuroscience, and Dr. David Goldman will serve as Acting Clinical Director for NIAAA. Lastly, Ms. Monique Hill moved to the National Institute of Neurological Disorders and Stroke as a Committee Management Specialist.
- Funding opportunities. Dr. Koob highlighted several new notice of funding opportunities (NOFO) issued by NIAAA. This includes a program announcement (PA) soliciting applications that focus on the mechanisms of behavior change in the treatment of alcohol use disorders and another PA on alcohol-induced effects on tissue injury and repair. Dr. Koob stated that NIAAA will not consider grant applications that propose standard efficacy trials of widely-studied and well-characterized medications, such as naltrexone, topiramate, acamprosate, varenicline, ondansetron, gabapentin, baclofen, and disulfiram on alcohol-dependent subjects. However, he emphasized that our work should continue to focus on new and highly innovative areas.
- Research highlights and accomplishments. Dr. Koob highlighted a number of newly published studies, notably research on imaging, frontal cortex, stress access, deep-brain stimulation, and others—topics anticipated to be part of NIAAA’s portfolio in the coming years.
- New rules. Dr. Koob described NIH’s new policy on resubmission of any A1 applications that do not reach the fundable score by submitting the same application as an A0. NIAAA also is piloting a new policy on biosketch content, which extends the page limit to five pages and emphasizes the key investigators’ personal statement and contributions to the advancement of science in their respective fields.
- Review: Best practices. Dr. Koob reported that chairs of all study sections that conduct reviews within NIAAA convened in May 2014 and came to consensus on two dozen principles to guide future NIAAA reviews. These principles include, for example, greater weight placed on innovation than on approach; liberal discussion of positive and negative attributes; prohibition of ad hominems; adequate time for appropriate review; review by the NIAAA Director of nominations of regular study section members, who should be experienced, tenured researchers typically funded by NIH; encouragement of program staff to attend review meetings; and emphasis on CRAN (Collaborative Research on Addiction at NIH) projects; updating of scores and critiques following discussion; specific guidance to study sections on review criteria; and addressing potential biases against alcohol research at the Center for Scientific Review (CSR). Dr. Koob also debunked the urban legend that success rates for R21 grants are greater than other grant programs; R01s have equal or better chances for success.
- New initiatives. NIAAA initiatives on the horizon include a College Drinking Intervention Matrix, a decision-support system to help colleges and universities select appropriate strategies for alcohol intervention. NIAAA has begun work on a “comprehensive factoid compendium” that will feature facts and statistics about the scope of alcohol misuse. A Biosensor Initiative will be engaged to develop a small, wearable transdermal device to provide data on alcohol consumption in real time. The multi-agency National Longitudinal Study of Neurodevelopmental Consequences of Substance Use is being developed tostudy the impact of alcohol and drug use on the developing human brain.
- Director’s goals. Dr. Koob enumerated a series of goals to guide work under his leadership: FDA approval of medications for treatment of alcoholism, implementation of effective behavioral treatments for alcohol use disorders, implementation of effective prevention strategies for adolescent drinking, implementation of effective prevention strategies for drinking during pregnancy, elimination of alcohol-related HIV pathology, establishment of effective treatments for fetal alcohol spectrum disorder (FASD), development of effective treatments for alcoholic liver disease, appropriate treatment of comorbidities associated with alcoholism, successful recruitment of young investigators to the alcohol field, elimination of disparities in the alcohol field, and equal pay for women and minorities in the alcohol field.
CRAN Update
Dr. Peggy Murray, Director, Global Alcohol Research Program, NIAAA, presented highlights of activities associated with Collaborative Research on Addiction at NIH (CRAN), the entity that represents the “functional merger” of NIAAA, National Institute on Drug Abuse (NIDA), and National Cancer Institute (NCI). CRAN recently received an overwhelming response to its request for applications on using social media to understand and address substance use and addiction. CRAN will focus considerable attention on a new longitudinal study of the effects of psychoactive substances on the developing brain. An expert panel met in May 2014 to develop recommendations on the framework of a study of alcohol and drug exposure and its neurodevelopmental effects as an initial step in designing a possible initiative. NIAAA will present the design at the Society for Neuroscience meeting in November 2014. The CRAN committee plans to release an NOFO in 2015.
Dr. Murray described collaborative expert panel discussions, noting that greater consensus was reached than anticipated. Topics included the study sample, neuroimaging data collection, substance use data and biospecimen collection, psychosocial/psychometric/psychiatric and other measures of substance use, and neurocognitive tasks. Overarching themes included data sharing/harmonization and ethics. NIAAA’s extensive previous work on certificates of confidentiality and lessons from the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) study informed the conversation. Dr. Murray noted general buy-in among the panelists, but acknowledged that the challenge to secure funds remains.
Dr. Adolph Pfefferbaum, Director, Neuroscience Program, Center for Health Sciences, SRI International, identified lessons from the NCANDA experience. He stated that early results show large across-subject variance but small longitudinal trajectory variance for individuals. The main dependent variable will be change in the developmental trajectory with exposure to illicit drugs and alcohol.
Concept Clearance
Dr. Changhai Cui, Program Director, Division of Neuroscience and Behavior, NIAAA, presented two concepts regarding novel approaches to understanding disease mechanisms, including human induced pluripotent stem cell (iPSC) based approaches and molecular imaging approaches. Dr. Cui explained that iPSC-based approach would permit a broad assessment of cellular alterations associated with patient disease phenotypes, advance understanding of the contributions of genetic alterations to disease, and facilitate the understanding of pharmacogenetic mechanisms of treatments. She also explained that the iPSC-based approach offers a research platform to study the disease phenotype at the cellular level with patients’ genetic information in human-specific cell biology.
Though many alcohol targets have been identified in recent years, knowledge is lacking about how these targets are modulated in vivo. Molecular imaging approaches will help to fill in this gap. Dr. Cui explained that in vivo molecular-imaging approaches, such as PET imaging, would allow the examination of the role of targets at molecular and cellular level. It will also facilitate the understanding of target and compounds interaction, and the evaluation of the efficacy of the drug - target interaction in vivo. Currently, there are no effective PET imaging ligands for certain important alcohol targets.
Discussion. Dr. Fulton Crews identified potential limitations of in-vitro strategies. Dr. Pfefferbaum stated that because development of PET ligands is difficult, a strong hypothesis for a specific neurotransmitter system would be needed, along with the commitment for a large allocation of funds. Dr. Koob observed that NIDA has considerable interest in PET ligands and stated that the Institute will continue to pursue this area of inquiry. Dr. Sinha concurred that, despite caveats, NIAAA should pursue PET imaging.
Violence and Health Research at the National Institutes of Health
Dr. Peggy Murray stated that NIAAA’s robust violence research portfolio on epidemiology, etiology, and treatment, has given the Institute the lead on many NIH violence activities. These activities include, among others, basic research; a variety of studies on victimization and on environment factors; studies on the epidemiology and effects of alcohol treatment on partner violence, etiology of alcohol aggression, and suicide; and drinking that follows victimization and drinking that follows exposure to violence. Prevention approaches to alcohol-related violence under study include binge-drinking intervention, cue recognition training, emergency room brief intervention, bystander intervention, land-use zoning to de-cluster alcohol outlets, and environmental alterations in bars.
Dr. Murray discussed NIAAA’s role in NIH’s violence and health research. NIAAA provides support to the Institute of Medicine’s ongoing Forum on Global Violence Prevention, an ongoing impartial setting for the exchange of evidence-based, multidisciplinary information that involves scientists, policymakers, and diverse other stakeholders. NIAAA also leads an initiative on the health determinants, consequences, and prevention of violence, particularly violence involving firearms. The presidentially mandated initiative spans 10 Institutes, Centers, and Offices, as well as private funders and advocacy organizations. Using the World Health Organization’s definition of violence, the initiative incorporates basic neuroscience and basic behavioral research in addition to clinical and translational studies; intervention development at the individual, family, and community levels; efficacy trials of interventions; and research to identify effective dissemination and implementation. In the first round NIAAA received the second highest number of applications submitted for funding consideration under this initiative.
Discussion. Judge Linda Chezem commended NIH on the broad and basic nature of its firearms research, and noted the importance of also examining violence perpetrated in the absence of firearms. She suggested seeking input from the Department of Justice. Dr. Crews endorsed research in this area and inquired whether genetics plays a role in violence. Dr. David Goldman responded that heritability data supports the hypothesis that genes contribute to violence.
Presentation of Council Operating Procedures
Council members unanimously approved NIAAA’s Operating Procedures for Institute Staff Actions for Administrative Supplements and Time Extensions.
Consideration of Minutes of the February 2014 Council Meeting and Future Meeting Dates
Council members unanimously approved the minutes of the NIAAA Council meeting held February 4–5, 2014, and of the Joint Council meeting with NIDA and NCI held on February 4.
NIAAA has scheduled a Council meeting for September 10–11, 2014. In 2015 the Joint Council meeting (NIAAA, NIDA, and NCI) will take place on February 4, and the NIAAA Council will meet February 4–5, June 10–11, and September 16–17. In 2016 the NIAAA Council will meet February 3–4, June 8–9, and September 14–15.
Repurposing a Ghrelin Receptor Antagonist for Alcoholism:
An NIH-Academia-Industry T1 Project
Dr. Lorenzo Leggio, Chief and Clinical Investigator, Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, Laboratory of Clinical and Translational Studies (LCTS), NIAAA and NIDA, described his work in the development of novel medications for treatment of alcohol use disorders, especially ghrelin (growth hormone–releasing factor). Dr. Leggio stated that early animal research demonstrated that ghrelin increased appetite and food intake, and subsequent animal and human research repeatedly identified other functions.
Dr. Leggio’s 2006 study found a positive, significant correlation between ghrelin levels and alcohol craving, and that year another group found that ghrelin increases alcoholic reward, locomotor activity, and increases alcohol intake. The opposite effects were found by using either a ghrelin receptor antagonist or knock-out mice for the receptor. Independent groups have replicated these findings. Clinical studies have shown consistently that, compared to healthy controls, alcoholic patients who are active drinkers have lower ghrelin levels compared to controls, while abstinent alcoholic patients have higher levels.
In the absence of a longitudinal approach, Dr. Leggio conducted a 12-week study that found that abstinent individuals had a trajectory different from that of active-drinking alcoholic patients. Baseline levels of ghrelin were different between the two groups, and ghrelin levels correlated with alcoholic craving. To bridge a large translation gap in moving from animals to humans, the investigators conducted a proof-of-concept, human laboratory study by administering a pharmacological ghrelin infusion as a challenge to non-treatment-seeking, alcohol-dependent heavy drinkers. The researchers found a significant ghrelin effect in increasing alcohol craving at the highest dose, compared to placebo and lower dose.
In summary, both human and animal studies suggest ghrelin involvement in alcohol craving, indicating that manipulating ghrelin signaling may lead to new treatment targets for alcoholism. Several approaches currently are underway or under consideration to modify ghrelin signaling.
Dr. Leggio also described his current work under a major new NCATS (National Center for Advancing Translational Sciences) grant program to accelerate therapeutic development through collaborative research involving NIH, academia, and pharmaceutical companies. Dr. Leggio’s grant involves collaborative efforts among NIAAA/NIDA, NIH’s Clinical Center, University of Rhode Island, and Pfizer to study a ghrelin receptor antagonist originally developed by Pfizer to treat Type II diabetes. This preclinical and clinical research aims to assess medication/alcohol interactions and pharmacodynamics/pharmakinetics to ensure safety, and to initiate a proof-of-concept study to examine early efficacy outcomes related to behavior and neuroimaging. An additional exploratory aim of the research focuses on the effects of alcohol on craving.
Discussion. Dr. Koob stated that NIAAA anticipates conducting additional collaborative studies in the future under the NCATS model. In response to questions from Council members, Dr. Leggio stated that this research explores food intake during inpatient stays; safety considerations played no role in Pfizer choosing not to pursue ghrelin research; and Pfizer informs the project on safety concerns. Dr. Joanne Fertig added that all the pharmaceuticals in the NCATS program failed for efficacy, but not for safety. All regulatory work has been completed, giving NCATS researchers a head start of about 18 months.
Characterizing Environments and their Interactions with Genes
Dr. Kenneth J. Sher, Curators’ Distinguished Professor of Psychological Sciences, University of Missouri, described two NIAAA-sponsored workshops on research issues related to the interaction of genes and environment (GxE). In January 2013, participants in the “Challenges and Opportunities in GxE Research: Creating Consensus Recommendations for Guidelines” workshop reviewed issues related to statistical analysis, selection of candidate environments and genes, replication, and publication. Based upon the discussion, recommendations were proposed to improve research quality, particularly on issues surrounding publication and replicability.
A large body of literature relates to GxE interaction, which represents a special case of well-established principle in psychology (sometimes referred to as person X situation interaction and aptitude X treatment interaction). The basic hypothesis is that substantial variation in a phenotype is explained by the interaction of both individual differences in susceptibility and environment beyond the additive effects of these variables. Moreover, strong evidence for GxE on alcohol-related outcomes has been generated in biometric studies on twins, convincingly demonstrating that heritability estimates of twins varies as a function of environmental conditions. Approximately a decade ago there was considerable excitement on the promise of candidate gene X environment (cGxE) research owing to some high profile reports in leading scientific journals. However, apparent problems in replicating many of these findings have called many of these findings into question, and along with it, the value of cGxE research as currently implemented. Beyond the problem of replication itself are additional questions about the ability to nominate the most relevant candidate genes because in some areas of research, important genetic variants discovered in genome-wide association studies (GWAS) had not been on anyone’s a priori candidate lists. Additionally, GWAS has revealed that for most complex disorders, most single gene effects are of very modest magnitude, and although possible, it seems implausible that cGxE effects would be substantially larger.
Workshop discussions on how best to conduct GxE research centered on challenges posed, for example, by the multidisciplinary and opportunistic nature of the research, and conceptual models that have not always been well developed. Participants also discussed certain technical issues that represent barriers to GxE research. Participants considered data pooling and integrative data analysis to be appropriate approaches to explore. They generally agreed that best practice in cGxE research involves more rigorous research conduct and transparent reporting, new approaches to identify new candidate genes, evaluation of the promise of the Genome-Wide Environment Interaction Studies (GWEIS) and polygenic score approaches to help identify critical GxE processes, and experimental studies (both in the lab and in pharmacogenetic drug trials) to test specific underlying mechanisms.
In December 2012 a diverse panel of experts convened for a workshop on “Establishing a Taxonomy of Alcohol-Related Environmental Exposures on Associated Alcohol Use and Consequences.” Panelists’ expertise included use of mobile technology, economic policy, pharmacogenomics, social network analysis, ethnography, and computational approaches, among other areas. Dr. Sher explained that environments can have a range of general and specific effects, and work along different pathways. Critical points for consideration included the current lack of an envirome—a systematically organized framework or taxonomy to study a full range of relevant environmental exposures. Developing a comprehensive, scientifically based framework could help identify environmental risk factors for development of problematic alcohol use and its consequences, and to identify targets for preventive interventions.
Dr. Sher highlighted environmental aspects of research conducted on college student drinking. For example, class schedules impact on alcohol intake levels; extreme binge drinking is a common ritual at 21st birthday celebrations; alcohol drinkers often self-segregate in social networks; and alcohol outlet density moderates the influence of campus-based prevention programs. Developmental exposures—such as early ethanol exposure; early trauma, abuse, and neglect; peers and parenting; and others—have effects as well. Dr. Sher suggested that the body of knowledge developed by occupational and environmental health scientists may be useful in GxE studies, particularly in helping to gauge actual exposure to the environment using biomarkers and other indexes.
Workshop participants observed that considerable underutilized, archived environmental data are available to inform ongoing GxE studies; measurement schemes are often inconsistent among studies that impede replication; and certain issues hamper measuring phenotypes. New endophenotypic approaches have the potential to serve as the foundation for personalized medicine.
There are a number of critical issues that surround research on environmental exposures. These include: (1) the durability of effects (i.e., distinguishing environmental processes that confer long-term effects on dispositions from those that operate situationally to promote expression of a disposition on a given occasion), (2) exposure specificity (e.g., does the exposure have broad effects on self-regulation or is it specific to alcohol?) , (3) multidimensionality of some environments (i.e., many environments are complex and different aspects of the environment can each have specific effects), (4) developmental specificity (i.e., the developmental timing of exposures; the exposure may be most critical at certain periods of life), (5) co-occurring and correlated exposures (i.e., is the “candidate” exposure the critical variable or is it spuriously associated with another exposure that is the active environmental agent?), and establishing causation (i.e., ruling out noncausal mechanisms such as certain forms of gene-environment correlation). In future work it will be important to recognize the range of environmental influence and to coordinate research addressing multiple levels of influence; promote common measurement approaches while at the same time not stifle innovation; promote usability and access to archival, aggregate environmental data; and recognize the need for labor-intensive approaches and technical expertise since many measures of the environment in current research relies on imprecise self-report assessments.
Discussion. To Judge Joseph Flies-Away’s question about environmental effects on populations and societies, Dr. Sher responded that assessing the important impact of environmental factors on groups is considered to be another level of analysis beyond impacts on individuals.
Council Member Round Table
Dr. Koob noted that Council members have questioned aspects of the grant review process, and NIAAA has proceeded to address those issues. In anticipation of new NIAAA efforts to recruit tenured professors to review sections, Dr. Andrea Barthwell urged NIAAA to support diversity in study sections, in particular to include reviewers affiliated with comparatively less-resource-rich institutions, such as Historically Black Colleges and Universities. Dr. Bautista stated that NIAAA is working to enhance diversity of all types in study sections. Dr. Koob asserted the need for reviewers who have worked with younger people and who can serve as role models on the NIAAA study sections. He stated that he has met with the chairs of all NIAAA study sections. Dr. Patricia Molina suggested that Dr. Koob consider personally addressing each study section as it congregates on the first day if its review meeting. She also suggested emphasizing to the peer review panels the serious responsibility that they hold. Ms. Mimi Fleury thanked Dr. Koob for participating in the reinvigorated Friends of NIAAA’s educational event the previous month and for NIAAA’s designation of prevention as a priority. Dr. Koob asserted the importance of efforts to raise NIAAA’s visibility and the Institute’s contribution to public health.
Public Comment
Gen. Arthur T. Dean, Chairman and CEO, Community Anti-Drug Coalitions of America (CADCA), explained that CADCA, a global nongovernmental organization that represents more than 5,000 U.S. coalitions, ranks underage drinking and excessive alcohol use as top challenges. A long-time ally of NIAAA on alcohol issues, CADCA provides training and technical assistance to the organization’s local coalitions.
Adjournment
The meeting adjourned at 12:50 p.m.
CERTIFICATION
I hereby certify that, to the best of my knowledge, the foregoing minutes are accurate and complete.
/s/
George F. Koob, Ph.D.
Director
National Institute on Alcohol Abuse and Alcoholism
and
Chairperson
National Advisory Council on Alcohol Abuse and Alcoholism
/s/
Abraham P. Bautista, Ph.D.
Director
Office of Extramural Activities
and
Executive Secretary
National Advisory Council on Alcohol Abuse and Alcoholism