National Advisory Council on Alcohol Abuse and Alcoholism

Summary of the 108th Meeting

February 2-3, 2005

The National Advisory Council on Alcohol Abuse and Alcoholism convened for its 108th meeting at 5:30 p.m. on February 2, 2005, at the Fishers Lane Conference Center in Rockville, Maryland, in a closed session, and again at 8:30 a.m. on February 3 in a closed meeting. The Council convened in open session at 9:30. Dr. Tina Vanderveen presided over the closed review of grant summary statements on February 2; Dr. George Kunos presented the Board of Scientific Counselors Report at the February 3 closed session; and Dr. Ting-Kai Li, Director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), presided over the open session on February 3.

In accordance with the provisions of Sections 552b(C)(6), Title 5, U.S.C. and 10(d) of Public Law 92-463, the meeting on February 2 was closed to the public for the review, discussion, and evaluation of individual applications for Federal grant-in-aid funds.

Council Members Present:

Cheryl J. Stephens Cherpitel, M.P.H., Dr.P.H.
Howard J. Edenberg, Ph.D.
Victor M. Hesselbrock, Ph.D.
Joannes B. Hoek, Ph.D.
Gail A. Jensen, Ph.D.
Mack C. Mitchell, M.D.
Stephanie S. O'Malley, Ph.D.
Kenneth J. Sher, Ph.D.
Alan C. Swann, M.D.
Boris T. Tabakoff, Ph.D.
Hope Taft
Robert E. Taylor, M.D., Ph.D.
Hidekazu Tsukamoto, D.V.M., Ph.D.

Ex-Officio Council Member Present: Richard T. Suchinsky, M.D.

Chairperson: Ting-Kai Li, M.D.

Executive Secretary: Karen P. Peterson, Ph.D.

Council Assistants:
Faye Calhoun, D.P.A., M.S., Mark Goldman, Ph.D., Ralph W. Hingson, Sc.D., M.P.H., Bob Huebner, Ph.D., George Kunos, M.D., Ph.D., Stephen Long, Howard Moss, M.D., Antonio Noronha, Ph.D., Tina Vanderveen, Ph.D., Kenneth R. Warren, Ph.D., Mark Willenbring, M.D., Samir Zakhari, Ph.D.

Other Attendees on February 3, 2005

Approximately 100 additional observers attended the open session, including representatives from constituency groups, liaison organizations, NIAAA staff, and members of the general public.

Call to Order of the Closed Session, February 2, 2005

Dr. Tina Vanderveen, Director, Office of Extramural Activities, called the closed session of the 108th meeting of the Council to order at 5:30 p.m. on February 2, 2005, for consideration of grant applications. Dr. Vanderveen reviewed procedures for reviewing grant summary statements and reminded Council members of regulations pertaining to conflict of interest and confidentiality. Members absented themselves from the discussion and evaluation of applications from their own institutions and in situations involving any real, apparent, or potential conflict of interest. The closed session adjourned at 6:50 p.m.

Call to Order of the Closed Session, February 3, 2005

Dr. Ting-Kai Li, Director, NIAAA, called to order the closed session at 8:30 a.m., during which Dr. Kunos presented the Board of Scientific Counselors Report.

Call to Order of the Open Session and Introductions, February 3, 2005

Dr. Li called the open session to order on February 3, 2005, at 9:35 a.m. and welcomed participants to NIAAA's new quarters and conference center. Dr. Li introduced new members of the Council, Drs. Cherpitel, Hesselbrock, Hoek, Mitchell, and Tsukamoto, and all members then introduced themselves.

Director's Report

Referring to the published "Director's Report," Dr. Li highlighted the following Institute activities:

• Budget. In December 2004 NIAAA received its FY2005 appropriation of $438 million, a 2.3 percent increase over FY2004. The President's budget request for the National Institutes of Health (NIH) for FY2006 was not known at the time of the Council meeting.

• Director's activities. In addition to seminars and lectures presented to professional societies and academic health centers, Dr. Li gave a presentation at the U.S.-China Science and Technology Joint Commission Meeting on alcohol use disorders. As an outcome action item, NIAAA will establish a collaboration with the Chinese Academy of Science to engage in joint research and training programs. In addition, Dr. Li spoke at a White House Leadership Conference on Medical Education in Substance Abuse, giving NIAAA's perspective on how to support education in the health professions. Ongoing communication will take place among various Federal agencies to advance the issue.

• NIAAA staff update. Dr. Li announced Dr. Moss's appointment as the new NIAAA Associate Director for Education and Career Development and acknowledged the retirement of Roberta Wilhelm, Chief, Contracts Management Branch, and the departure of Barbara Smothers, Ph.D., who has accepted the directorship of the Division of Extramural Affairs in the National Institute of Nursing Research.

• Research Priority Emphasis and Core Support Teams. These teams represent active ways of reviewing NIAAA's portfolio and eliciting input from Council members through the Council's Extramural Advisory Board. Dr. Li congratulated Lisa Neuhold on having edited Human Brain Proteome.

• Reorganization. NIAAA's new Office of Extramural Activities is directed by Dr. Vanderveen.

Progress of NIAAA over Past Two Years: Vision and Goals for the NIAAA--2003 and Beyond

Dr. Li presented an overview of NIAAA's history since 1973, when it became an autonomous institute within ADAMHA and whose mission marginally included research. In 1992 NIAAA moved to NIH, with substance abuse services and other functions transferred to the Substance Abuse and Mental Health Services Administration (SAMHSA). NIAAA's budget is less than $0.5 billion, but the problem that alcohol causes to citizens and society is large. A Journal of the American Medical Association (JAMA) report identifies alcohol as the third actual cause of death, after tobacco use and poor diet and physical inactivity. Dr. Li noted that alcohol consumption also contributes to other causes of death, including death by automobiles and firearms.

In order to plan for the future, it was necessary to look at the distinctive features of alcohol metabolism and its effects on the body. Alcohol is metabolized quickly in the body to carbon dioxide (CO2) and water, and alcohol contributes to caloric intake; (2) large between-individual differences exist, with half this variation attributable to genetics; and (3) common and unique aspects of alcohol metabolism and mechanisms of toxicity exist in different organ systems. The action of alcohol on behavior is biphasic, with lower concentrations stimulating behavior and higher concentrations inhibiting behavior. The crossover point is important and the curve is steep, which relates to acute intoxication and death. All three compounds-alcohol, and its primary metabolites acetaldehyde and acetate-in their respective concentrations in the body are psychoactive (stimulatory, inhibitory, or both). Alcohol affects multiple molecular targets in the brain that are sensitive to differences in the concentration of the substances. Genetic contributions to alcoholism are known, and NIAAA's research portfolio has identified alcohol-specific and alcohol-nonspecific genes shared with other mental disorders, personality traits, and other phenotypes.

Planning for future research involves considering the strengths and opportunities of NIAAA's portfolio. Strengths include alcohol pharmacogenetics, including good human and animal research models; excellent animals for the study of genes, pathways and networks, and gene-environment (GxE) interactions; good epidemiology with longitudinal general population studies (for example, the National Epidemiologic Survey on Alcohol and Related Conditions, NESARC); and treatments that include behavioral and pharmacological therapies.

NIAAA's vision and mission for 2003 and beyond are to support and promote the best science on alcohol and health for the benefit of all citizens, using multidisciplinary and transdisciplinary approaches to increase the understanding of both normal and abnormal biological functions and behaviors relating to alcohol use; improve the diagnosis, prevention, and treatment of alcohol use disorders or diseases; and enhance the quality of health care. NIAAA has five research emphasis teams: underage drinking, medications development, GxE interactions as etiology of risk, mechanisms of alcohol action and injury, and mechanisms of behavioral change.

The NESARC epidemiology database will be used to address basic questions in alcohol research, including the trajectory of alcohol use disorders. NESARC data indicate that a majority of people with active dependence are in the 18-to-25 age range, making that group a clear target population for prevention and treatment activities. Early onset of alcohol and other drug problems, as well as co-occurring disorders, is seen in this population.

An example of a translational research opportunity is the characterization of the ontogeny of alcohol-associated changes in an effort to address gender differences in response to alcohol. Large differences exist in alcohol response to different conditions between, for example, genetically selected animals and animals without a genetic predisposition.

Dr. Li stated that NIAAA's realignment interweaves the Institute staff's administrative and scientific functions in order to promote interdisciplinary research, promote creativity and foster multidisciplinary approaches, and strengthen the scientific career development of Institute staff. A matrix model has been proposed for the five research divisions, with cross-cutting research emphasis teams and infrastructure teams reflecting research priorities that were part of NIAAA's 2002 strategic plan. The goal is to stimulate the transdisciplinary intellectual development of science and its integration into the day-to-day administration of NIAAA's research portfolio, at the same time providing increased opportunities for staff advancement.

Successful new trans-NIH and -Departmental initiatives since 2003 include collaborative research with NIDA on the genetics of alcoholism (COGA), NESARC, and (with NCI, NIDA) tobacco research centers (T-TURCS); with NCCAM, on alternative therapies for alcohol and drug abuse; with NICHD, on alcohol, SIDS, and stillbirth; and with the Department of Justice, on enforcing underage drinking laws. NIAAA is discussing clinical trials with the Department of Veterans Affairs. Another NIAAA goal is evidence-based outreach to develop common definitions and measures. The Council has developed guidelines for moderate and binge drinking, and has provided recommendations for screening and brief interventions. Dr. Li acknowledged NIAAA staff contributions and recruitment to top leadership positions. Having completed a formative assessment to foster the realignment process, the Institute will begin mentoring efforts and leadership training.

Dr. Mark Egli, chair of the committee on the formative assessment, reported that some scientific divisions and Institute offices have been realigned, and seven new transdisciplinary teams have been created with current staff. Work is ongoing to define the functions of those teams and to refine the definition of and establish operating procedures for how the offices and divisions work. The evaluation revealed the dedication and commitment among NIAAA staff to promoting alcohol research science and achieving the overall public health mission of the Institute.

Discussion. Mrs. Taft commended NIAAA on its reorganization, which has made the Institute more understandable.

National Children's Study

Duane Alexander, M.D., Director, National Institute on Child Health and Human Development, (NICHD), stated that NICHD was created in 1962. Within its mission are the following goals: to improve outcomes of pregnancy by ensuring that all children are born healthy and wanted; to ensure that people are able to have the children they want when they want them; to ensure that women don't suffer adverse consequences from the reproductive process; and to see that children can grow up healthy and reach adulthood free of disease and disability and able to achieve their full potential. NICHD's budget is just over $1.2 billion. NICHD collaborates with NIAAA on projects involving peptides that show a neuroprotective effect, particularly among mice, in preventing fetal alcohol syndrome (FAS). NICHD also is experimenting with small peptides with a protective effect against hypoxic ischemic encephalopathy in newborns with Down Syndrome. In addition, the National Institute on Aging is interested in certain peptides as a possible intervention in Alzheimer's disease. Animal toxicology studies to determine dosage and safety are underway prior to work with humans. Extramural collaboration includes a study on the relationship of alcohol to sudden infant death syndrome (SIDS) and stillbirth, D.C. Infant Mortality/Morbidity Initiative, and a potentially expanded role with the Leadership to Keep Children Alcohol Free.

NICHD's National Children's Study (NCS) involves broad collaboration across agencies, including NIAAA and most other NIH Institutes. With a planned national representative sample cohort of 100,000 families recruited over 4 years before and during pregnancy and followed through age 21, the NCS aims to understand basic underlying contributions of environmental factors to children's health and development.

The 2000 President's Task Force on Environmental Health and Safety Risks to Children looked at broadly defined environmental exposures to children that have adverse impacts on their health and development. The task force agreed on the need for a prospective longitudinal cohort study because children are particularly vulnerable to environmental exposures. Children's behaviors expose them to harmful substances that increase their risks. In addition, children's metabolism differs from that of adults. Exposure to certain agents, including alcohol prenatally, has been documented as hazardous. The varying effects of prenatal alcohol exposure need to be studied in a longitudinal cohort study. The long-term effects on children from exposure to such factors as pesticides, violence, and violence in the media are unknown. High-burden conditions with suspected environmental contribution include learning disabilities, autism, diabetes, asthma, birth defects, and premature birth, but existing research is too limited in size and scope to answer questions. Dr. Alexander asserted that the need is clear for a large cohort followed over time, looking at each substance of interest in terms of other co-exposures to determine whether interaction plays a role.

Under the Children's Health Act of 2000, NICHD took the lead in organizing a consortium of Federal agencies to plan, develop, and implement a prospective cohort study from birth to adulthood, looking at the effects of chronic and intermittent exposures from the environment on children's health and development. Congress has not yet funded the study, and NICHD has used its own funds for planning, with support from the Centers for Disease Control, Environmental Protection Agency, and NIH. Dr. Peter Scheidt leads a small staff to work on the study.

Study tasks include the longitudinal study of children, their families, and the environment. The study is national in scope, and is hypothesis driven, with a broadly defined environment (chemical, physical, behavioral, social, and cultural). The study covers a range of environmental exposures and less common outcomes, and the covered exposure period begins in pregnancy or before. In addition, the study design includes gene-environment interactions; state-of-the-art technology for tracking, measurement, and data management; a consortium of multiple agencies; extensive public-private partnerships; and a national resource and data source for future studies. Data will be made available to investigators at short intervals for testing their own hypotheses.

The NCS is guided by an advisory committee and has received input from 22 working groups. In addition, hypotheses have been developed; a contract mechanism is to be used, with a universal core protocol; a sampling strategy has been devised; a center-based strategy would be engaged to recruit subjects; and an Interagency Coordinating Committee has been constituted. Since 2000, NICHD has sponsored 27 scientific workshops, 12 pilot studies, and 9 scientific reviews. Over 2,500 people have been involved in contributing to scientific development of the study.

The multiple hypotheses necessary for framing the study will assure answers to "big-issue" questions. In addition, these hypotheses are required for costly elements of the study and are important for child health and development. The hypotheses have reasonable scientific rationale, require a large sample size, involve measurable elements with a study of this size, and require longitudinal follow-up. More than 20 hypotheses have been accepted for the study. The NCS will look at such big-issue disorders as autism, diabetes, stillbirth, birth defects, learning disabilities, obesity, asthma, behavioral disorders, schizophrenia, and other outcomes. Priority environmental exposures include the physical environment, chemical exposures, biological environment, genetics, and the psychosocial milieu. Priority outcomes include pregnancy outcome, neurodevelopment and behavior, injury, asthma, and obesity and physical development. Some effects will be observable immediately and others delayed.

In a unique design based on advice from the community, the NCS merges a national representative probability sample based on births and a convenience sample recruited by centers of excellence. Ninety-six representative study locations across the U.S. and eight vanguard sites have been selected. The NCS will issue solicitations for centers that will then propose recruitment of the sample from the 96 locations, most of which are located in areas close to an academic health center of a university or hospital. A proposed schedule of visits by subjects has been determined, including a hoped-for 25 percent to be recruited pre-pregnancy to serve as a control group, to look at difficulty in becoming pregnant in relationship to environmental exposures, and to recruit a population using assisted reproductive technology and infertility clinics.

Contracts are in place for the scientific support program and information technology development. Initial funding will be awarded in FY2005 for the data coordinating center and vanguard centers. Contracts will be let later for sample repository and laboratory services contractors. Modifications to the protocol are expected, and a final protocol will be developed. New funds amounting to approximately $2.5 billion are required to conduct the study over its 25-year course, and NICHD is working to provide education about the importance of the study in discussions with public and private partners on funding various portions of the study. The database will be made available to investigators frequently, with much analysis conducted under grants by investigators. If the study is launched on schedule, initial data should be available by 2010. Dr. Alexander asserted that with a reduction of 3 percent in the prevalence of such conditions as asthma, birth defects, learning disabilities, and other primary outcomes, savings of 100 times more than the total 25-year cost would accrue to the U.S. health care system.

The pilot study and methods of development work are nearly complete. While hypotheses are not quite final, the study design has been published. In September 2005 vanguard centers will be selected; by FY2006 the final protocol will be complete; investigators will enroll first participants in 2007; pregnancy outcomes will be available in 2010; and analysis will go forward through 2030.

In terms of funding status, $13 million was allocated in FY2005, which is sufficient to begin the study, although $27 million was sought. About $2.5 billion will be needed over 24 years. Peaks of $220-230 million are expected during recruitment and children's early years, and then maintenance costs are anticipated at about $95 million annually. The study's website is http://nationalchildrensstudy.gov. As proposed, the study is unprecedented in size, scope, and complexity. It uses new methodologies and can answer important questions about environmental influences on children's health and development. The study enjoys broad-based support from advocacy groups, the scientific community, and industry, all of which are needed to convince Congress of the value of the study. The study holds value for FAS and for age of onset of alcohol intake, once information is collected during the teen years on the physical, environmental, psychosocial, family, and community environments.

Discussion. Dr. Sher mentioned the need for more frequent assessments in the teen years regarding alcohol and substance abuse. Dr. Alexander noted that if resources are available, that would be advantageous to the field. Dr. Hingson suggested using state-by-state samples that reflect differences in the components of alcohol and tobacco laws and other environmental policies. Dr. Alexander responded that data from multiple sites in several larger states can be incorporated in the sample. He stated also that genetic material will be taken from parents, children, and siblings. Dr. Edenberg questioned how the NCS might relate to the Genome Research Institute's proposed larger study, AEGIS. Dr. Alexander stated that NICHD is discussing the benefits of sharing resources with the Institute, but that AEGIS will recruit in a different manner. Dr. Tabakoff noted the benefits of conducting a transgenerational study that includes the children of the cohort. Dr. Alexander responded that some people question why the study will extend for such a long period of time and others ask why it is necessary to stop it. Congress mandated a study until the onset of adulthood, but he stated his hope that people will see the value of continuing the study beyond this point.

Overview of SIDS and the PASS Network

Hannah C. Kinney, M.D., Harvard Medical School, and Steering Committee Chairman, PASS (Prenatal Alcohol, SIDS, and Stillbirth) Research Network, discussed research related to adverse prenatal outcomes and morbidity associated with prenatal alcohol exposure, in particular SIDS and stillbirth. Unexplained stillbirth is the leading cause of infant mortality in the United States at 6 per 1,000 live births annually. A public health campaign in the 1990's recommended that infants sleep on their backs, which resulted in a 50 percent reduction in the SIDS rate within 2 years. In more than 75 percent of infant deaths, babies are found face down. In 75 percent of infant deaths, babies are between two and four months old. These observations suggest to researchers that SIDS results from babies' inability to expel CO2 when in compromised positions, and that developmental mechanisms are involved. Many risk factors found in studies to be linked with SIDS suggest that SIDS originates in utero. Risk factors include maternal alcohol drinking and smoking during pregnancy as well as prematurity. Additional risk factors include over-bundling and infection. Subtle abnormalities in respiration, upper airway control, autonomic function, and sleeping/waking patterns have been found in infants who subsequently die of SIDS, suggesting a failure in homeostatic control mechanisms, particularly in babies with compromised sleeping positions.

The Aberdeen Area Infant Mortality Study in Northern Plains Indians found prenatal alcohol exposure to be a risk factor for SIDS. A large Danish study found a link between stillbirth and prenatal alcohol consumption. In a South African study, placental abruption, the most common cause of stillbirth in Western Cape Province, is linked to alcohol use during pregnancy.

The mission of the PASS Research Network is to perform community-based studies on the role of prenatal alcohol exposure in the risk for SIDS, stillbirth, and FAS. The goal is to reduce fetal and infant morbidity and mortality in communities at risk for prenatal alcohol exposure. The PASS Network's Safe Passage is a prospective study in two phases. Phase I extends from 2003 to 2006 for development of hypotheses and protocols (completed), and pilot/feasibility studies should begin in April 2005. Phase II, 2006-2011, involves full-scale, hypotheses-driven studies. The overall hypothesis is that prenatal alcohol exposure increases risk for unexplained stillbirth from 20 weeks to birth and for SIDS during the first 12 postnatal months. The study will look at the mechanism that determines the link for prenatal alcohol exposure to FAS, SIDS, and/or stillbirth.

A major hypothesis involves the serotonergic system of the brain and specifically the neurotransmitter serotonin, as a potential link in the spectrum of disorders associated with prenatal alcohol exposure. Evidence comes from Boston's Children's Hospital for serotonin abnormalities in SIDS, such as hypoplasia of the caudal region of the arcuate nucleus. The serotonergic system is involved in homeostatic control and upper airway control, and mediates the sympathetic autonomous nervous system; the baroreceptor reflex also is influenced by the serotonergic system. Dr. Kinney stated that the Aberdeen study found that prenatal alcohol exposure, whether or not the infant died of SIDS, is associated with a decrease in serotonin binding. The serotonergic caudal domain hypothesis offers possible explanations for unexplained stillbirth or SIDS. This hypothesis states that the caudal serotonergic domain dysfunction affects a variety of homeostatic mechanisms. In a vulnerable infant, prenatal alcohol is an exposure factor.

In infants with prenatal alcohol effects, a wide range of alterations in autonomic control, EEG, and sleep/waking patterns are recorded. In the Aberdeen study, Fifer, Myers, Ten Fingers, and Youngman find neonatal alterations in heart-rate response to head tilt and in heart-rate variability in subjects exposed to prenatal alcohol. This result indicates that prenatal alcohol has an effect on the development of the autonomic nervous system, and in particular on a reflex modulated by the serotonergic system.

The PASS Network's underlying hypothesis is that some unexplained stillbirth is etiologically similar to SIDS. Both involve sudden death unexplained by autopsy, and they share common risk factors, such as maternal smoking during pregnancy. Recent research shows that increased alpha-fetoprotein in mothers in the second trimester is a risk factor for both SIDS and unexplained stillbirth, that SIDS begins in utero, and that a two-fold increased risk for SIDS exists if a prior stillbirth occurs in the same mother. Matturri has found that arcuate nucleus abnormalities occur in unexplained stillbirth, as they do in SIDS. PASS researchers believe that FAS is a complex problem in part of the rostral serotonergic system, whose cell bodies are in the midbrain and pons and project to the forebrain to influence cognition and affective behavior. In animal models of prenatal alcohol exposure, Zhou and colleagues have shown that when serotonin is disrupted, abnormality and incomplete formation of the cortex occur. This work will prompt the search for subtle abnormalities in FAS that were not investigated before. The findings suggest that serotonin impacts the development of the cortex in utero and that alcohol can cause cortical abnormalities. PASS researchers hypothesize that prenatal alcohol exposure adversely affects the development of the serotonergic system in the caudal and rostral domains, but whether FAS, SIDS, or stillbirth occurs depends, at least in part, on the extent that one brain-stem system is affected relative to the other. In addition, the researchers seek to understand whether the timing or quantity of the alcohol exposure or other moderators determine the pattern of involvement of the caudal versus rostral systems. In other words, PASS will look at the fact that a particular disorder is due to differences in environmental and/or genetic factors.

The PASS Network is conducting both prospective and retrospective studies at clinical sites in the Northern Plains and in Cape Town, South Africa, which are areas with high rates of SIDS and FAS. The prospective study will follow 12,000 pregnancies through the end of the first year. The Cape Town population is Cape Colored, a group of mixed ancestry that historically tended to the vineyards, was paid for their labor in part with alcohol, and continues to be a community saturated with alcoholism. The study will include a developmental biology and pathology center, a data coordinating and analysis center, and program officers at NICHD and NIAAA. A steering committee and data safety monitoring board will guide the study. The unique multidisciplinary study focuses on a human problem with human biology and human pathology. The study offers an unprecedented opportunity to define in humans the genetic and environmental interactions that influence prenatal alcohol toxicity, effects of prenatal alcohol toxicity at different doses on the placenta, brain development, physiological development, autonomic nervous system and neurobehavioral development, potential links between SIDS and unexplained stillbirth, and the effects of prenatal alcohol exposure on the risks for stillbirth and SIDS.

Discussion. Dr. O'Malley indicated the need to disseminate the information to individuals at risk and their health care providers. Dr. Kinney stated that at the end of the Aberdeen study, researchers presented and explained findings to tribal councils and disseminated the information throughout the community. Dr. Calhoun reported that in December 2004, the Surgeon General reissued the announcement that drinking during pregnancy is hazardous. Dr. Warren noted that information on adverse effects of alcohol on pregnancy is not well known, despite the initial advisory having been issued 24 years ago. Dr. Marion Willinger stated that the Aberdeen study demonstrated the binge-drinking risk in the Northern Plains and highlighted the importance of NICHD partnering with NIAAA to develop public health messages based on data. Dr. Willinger noted that NICHD has targeted an outreach campaign toward American Indian/Alaska Natives regarding the risks of binge drinking and SIDS. Dr. Li questioned why the rate of binge drinking decreased in the control group. Dr. Willinger responded that once many women knew they were pregnant, they tried to stop drinking, but during the first semester no data were provided to the community that would have explained the decrease. To Mrs. Taft's question about sharing this information with SAMHSA-funded state FAS prevention initiatives, Dr. Calhoun stated that NIAAA could work with SAMHSA to disseminate additional information. Mrs. Taft observed that broadening the spectrum of issues would galvanize people to pay attention to them. Dr. Kinney stated that the Aberdeen study is the first in the SIDS literature to link prenatal alcohol exposure with SIDS, and it is hoped that the PASS study will replicate the findings. She asserted that the PASS Network researchers believe the information is applicable to all populations. Dr. Mitchell suggested looking at potential interactions between alcohol and folic acid. Dr. Kinney stated that diet is an important part of the study and welcomed input on other factors to investigate. Drs. Tabakoff and Kinney discussed serotonin receptors. Dr. Kinney stated that the study is looking at whether there is actual loss of serotonergic neurons. Dr. Tabakoff responded that the location makes them seem like dendritic autoreceptors. Dr. Kinney stated that serotonin has been shown to be a trophic factor that affects synaptic genesis and cell number proliferation. Dr. Sher asked about the feasibility of measuring autonomic imbalance noninvasively. Dr. Kinney stated that the PASS Network will look at heart rate variability and movement in the fetus at a variety of time points. The goal is to identify children preterm at high risk. Dr. Taylor questioned whether any changes in nicotinic receptors have been detected. Dr. Kinney stated that one of the neurotransmitter systems studied was the nicotinic system. The Children's Hospital dataset found no differences between SIDS and controls in nicotinic binding, but PASS will look at the issue to determine any effects of nicotine on the development of the serotonergic system. Dr. Taylor suggested that the effects may be related to different subtypes of nicotinic receptors.

Update: NIH Roadmap for Medical Research

Dr. Dushanka Kleinman, Associate Director for Roadmap Coordination and Deputy Director of the National Institute of Dental and Craniofacial Research, presented an update on progress on the Roadmap for Medical Research at NIH. The Roadmap is a series of initiatives aimed at contributing to enhancements in the way NIH does research and in the benefit to the public, and is a new way of doing business that crosses individual Institutes' missions. Goals are to accelerate basic research discoveries and give researchers tools to do that, to address roadblocks to the barriers, and to move science into practice.

In focused discussions on research gaps, barriers, solutions, collaborations, and priorities, more than 300 experts developed three major themes: new pathways to discovery; research teams of the future; and re-engineering the clinical research enterprise. Twenty-eight initiatives were selected on the basis of priority and ability to move the science forward. In FY2004 NIH funded 196 projects, predominantly extramural, that started development on new tools and technologies, provided training, supported planning and feasibility studies and research policy analysis, and tested new approaches to clinical research and support.

The New Pathways to Discovery theme addresses a range of technologies and approaches that are tools for investigators and that will open new doors, such as a network of molecular libraries screening centers, development of probes for cellular imaging, and screening assay development. In 2005 solicitations will be issued to increase this capacity for the broader research community. Another initiative is the funding to date (with more to come) of four National Centers for Biomedical Computing focused on software development by teams of computer scientists and basic and clinical researchers who are collaborating to analyze massive amounts of data using a variety of content areas as models. One planned initiative is a PA that would allow RO1 investigators to use the centers' resources for their own investigations.

Under the Research Teams of the Future theme, one group is looking at ways of conducting high-risk research, such as the NIH Director's Pioneer Award (NDPA). Another focus is on interdisciplinary research, in an effort to establish workforce and institutional capacity and to interest disciplines in coming together and evolving into new disciplines through team science. Interdisciplinary Research Exploratory Centers (P20s) will be funded for three years to develop capacity for interdisciplinary research; for example, the team at the Carolina Center for Exploratory Genetic Analysis is looking at the combined expertise of experimental geneticists, quantitative experts in statistics and biostatistics, and computer scientists for such endeavors as family linkage studies and susceptibility to alcohol addiction. While the Roadmap looks at general resources, scientists build capacity and institutional infrastructure and policies, bring people together, and work within models of disease and conditions. The NIH Roadmap website, http://nihroadmap.nih.gov, shows all supported research and opportunities.

The theme of Re-engineering the Clinical Research Enterprise reflects the need to deal with policies and harmonization regarding human subject research as well as issues related to informatics and clinical research networks. The theme spans the full spectrum of the conduct and impact of research. Examples include establishing a national electronic clinical trials information database capacity and funding an inventory of research networks to identify best practices to be discussed at a forthcoming conference. Dr. Kleinman noted that more than 500 networks have been identified to date. NIH hopes to link clinical research networks with local physicians, nurse practitioners, and dentists to form communities of research, in an effort both to improve recruitment of patients for clinical trials and to move science more quickly into practice. This project is at the stage of feasibility study, and in FY2006, models will be pilot tested. Multidisciplinary clinical research career development involves training together individuals from different disciplines to develop leaders in clinical research who can work across disciplines effectively. Seven training opportunities were funded for FY2005.

In response to concerns about public trust in the context of research, Dr. Zerhouni initiated the NIH Public Trust Initiative. Among the FY2006 initiatives will be nanomedicine; the nanomedicine group is reviewing concept papers funded in FY2004 for Nanomedicine Development Centers and is developing an initial solicitation for centers to be funded in FY2005. Roadmap funding is expected to be stable at not more than 1 percent of the total NIH budget.

Discussion. Dr. Hoek mentioned the need for opportunities for Ph.D. investigators to play leadership roles. Dr. Kleinman responded that the key role of basic Ph.D. scientists in clinical research is being looked at and encouraged in regional translational research centers, and possibly in short-term training programs. Dr. Tabakoff asked for comment on the Neuroscience Blueprint Initiative and its relationship with the NIH Roadmap. Dr. Kleinman responded that that initiative is an ongoing, multi-IC collaboration. The way NIH needs to do business in the future requires collaborations to address common needs, and discussion continues among NIH leadership to support efforts that develop common resources for the research community at large. Dr. Kleinman explained that Roadmap funding is predominantly from Institute and Center funds, with some Building 1 funds, and that NIH has not yet addressed expanding funding sources. The evaluation component of the Roadmap will provide information on outcomes. Dr. Edenberg observed that recognition for multiple investigators in interdisciplinary research is an issue. Dr. Kleinman stated that the charge to P20s is to explore institutional barriers, including recognition and promotion issues within and across departments. A committee at NIH is looking at its own databases to determine how to document investigators beyond the primary investigator in the context of emerging team science. Policy has been changed to eliminate fiscal constraints to institutions working together.

Compliance with NIH Policy on Inclusion Guidelines

Dr. Karen P. Peterson, Executive Secretary, National Advisory Council on Alcohol Abuse and Alcoholism, noted the need for the Council to approve guidelines mandated by the NIH Revitalization Act of 1993 that aim to ensure that women and minorities are included in all clinical research. She described a variety of ways by which compliance is ensured, including: review by the Scientific Review Group; language in Program Announcements (PAs) and Requests for Applications (RFAs) involving human subjects on NIH's inclusion policy; guidance from program officials to help applicants put together the proper plan for subjects in their protocols; and instruction of study section members by scientific review administrators regarding the policy. Other efforts to ensure compliance include discussion of noncompliance by program officials with applicants and remediation of applicants' plans, extramural staff training, posting of inclusion guidelines on the Institute website, and periodic demonstration sessions.

Dr. Peterson presented comparison enrollment data through FY2003 to Council members. She explained that in FY2001 reporting categories expanded, including separating the Asian group to Asian American/Pacific Islander, adding a "more than one race" option, and enabling ethnicity coding as Hispanic or non-Hispanic. Newly enrolling projects must use the newer format that reports ethnicity as well as racial categories, and projects initiated prior to FY2001 can use either the old or new form. Using U.S. census data for comparison, Dr. Peterson demonstrated that NIAAA approximates the breakdowns for various races and ethnicities in NIAAA studies.

The Council voted unanimously to certify NIAAA compliance with NIH's policy of inclusion of women and minorities in clinical studies for the reporting period through FY2003.

Discussion. Dr. Carmen Richardson responded to a question from Dr. Sher that NIH policy is to include children in studies, as appropriate, but the number of children is not tracked. Dr. Sher suggested the usefulness of tracking data on the number of children in studies.

Extramural Advisory Board Update and Gene by Environment Team Interim Report

Dr. Kendall Bryant explained that the Etiology of Risk, Gene, and Environment (ERGE) Team and the Extramural Advisory Board (EAB) produced an initial report of the ERGE team's grant portfolio review. Following comments and guidance from the EAB at an October 2004 meeting, a transcript of that discussion was produced. This transcript summarizes the meeting discussions, identifies issues, and offers preliminary recommendations. EAB members are submitting comments to the ERGE team, which is synthesizing and developing a revised document that identifies short- and long-term goals. An executive summary will be posted on the Institute website for comment. The process was designed to open the discussion to the larger community, within and without NIAAA. The final report is expected to be presented to the Council in May.

Three sets of preliminary issues emerged in the discussions: (1) elaborating the framework for GxE research, including clarifying the structure and organization of the environment and articulating risk mechanisms versus risk factors; (2) identifying phenotypes and endophenotypes, including how to deal with parallel endophenotypes or phenotypes in using animal models better, and how to extend animal models to include human issues that are moderators, such as stress or impulsiveness; and (3) developing strategies and opportunities in the short run to expand the discussion of GxE foci. Specific discussions centered on how to develop consensus environmental assessment techniques, the role of access and analysis of genetic information in this context, and how to share data.

Dr. Zhaoxia Ren described the ERGE team's process. After the last EAB meeting, the ERGE team formed several sub-working groups to focus on identification of opportunities to research integration of animal and human studies, environmental measures, analysis of existing databases, and training to develop cross-disciplinary training for GxE. Sub-working groups are focused on ongoing potential initiatives that address issues in such areas as developing a mechanism for integrative research for animals and humans, to develop NIAAA databases and resources to maximize usage by the scientific community and provide opportunities for secondary analysis. In addition, they will develop a conceptual framework for the structure and organization of the environment for etiology of the risk.

The NIAAA ERGE team has issued a PA to solicit research applications to address GxE interactions in alcohol-related phenotypes and diseases, and an RFA with NIMH to track applications to study GxE environmental effects and epigenesis in depression. The team expects to continue to participate in NIH activities such as the NIH GxE working group and has co-hosted a symposium with the National Institute of Environmental Health Sciences (NIEHS) and the National Human Genome Research Institute (NHGRI) on genetic variations and GxE interactions in human health and disease.

Once the EAB's final recommendations are received, the objectives identified will be revised continually, based on the Institute's research priorities and the EAB's recommendations. Sub-working groups already focus on some objectives, including development of better methodology to assess and measure environmental factors for the development of alcohol use disorders, development of integrative research for identification of phenotypes in animals that are common to humans to address the GxE issue, and development of integrated databases to address GxE issues.

Dr. Kenneth Sher stated that the portfolio review was more difficult than anticipated. In a discussion of etiology, genes, and environment, many subcomponents must be addressed, and it was helpful to have the various perspectives of the people around the table and additional advisors. He stated the need to question the value of the ongoing work in order to identify areas where a revision of strategy should occur. He provided the example that animal models do not involve social behavior, even though some animals are reared in social environments, and the effects of environment are unknown. Therefore, it is important to develop a model of the environment before one can specify it. He stated that outcomes will be specific recommendations presented to the Council for further discussion.

Update of Alcohol Administration Guidelines

Judge Linda Chezem, Chair of the Council Working Group on Guidelines for Alcohol Administration, described progress on the review and revision of guidelines on alcohol administration. The working group is compiling a draft recommendation, which will be submitted in final form to the Council in May.

Future Meeting Dates and Consideration of the September 2004 Minutes

Dr. Peterson noted that the next Council meeting will convene on May 25-26, 2005, at the Fishers Lane Conference Center in Rockville, Maryland. The following meeting will be held on September 14-15, 2005. The Council unanimously accepted the minutes as submitted.

Public Comment

Thelma King Thiel, Chairman and Chief Executive Officer, Hepatitis Foundation, described the foundation's work with schools, health departments, and the Center for Substance Abuse Prevention in training counselors and other professionals, and in developing educational materials. Evaluations have shown a broad lack of information or understanding about the liver, but the foundation's work has been shown to help people change behaviors. Ms. Thiel stated that the foundation would like to collaborate with NIAAA to expand outreach efforts to educate elementary-age children, to give teachers tools to engage people in adopting healthy behaviors, and to bring alcohol abuse and hepatitis under control.

Joan Levy Zlotnick, Ph.D., A.C.S.W., Director, Institute for the Advancement of Social Work Research, highlighted the important contributions that social work researchers can make. She acknowledged NIAAA's work in reaching out to educate the social work community and faculty about alcohol and alcohol abuse, and to encourage training of greater numbers of social work researchers.

Mrs. Taft called on the Council to recognize the contributions of Suzanne Medgyesi-Mitschang, retiring co-chair of Leadership to Keep Children Alcohol Free. Dr. Medgyesi-Mitschang was unanimously praised and thanked by the Council for her outstanding work.

Adjournment

Dr. Li adjourned the meeting at 2:20 p.m.

CERTIFICATION

I hereby certify that, to the best of my knowledge, the foregoing minutes are accurate and complete.

Updated: August 2005