DEPARTMENT OF HEALTH AND HUMAN SERVICES

NATIONAL INSTITUTES OF HEALTH

NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

 162nd Meeting of the

NATIONAL ADVISORY COUNCIL ON ALCOHOL ABUSE AND ALCOHOLISM

February 9, 2023

The National Advisory Council on Alcohol Abuse and Alcoholism (NIAAA) convened its 162nd meeting at 12:45 p.m. on Thursday, February 9, 2023, via Zoom videoconference and NIH Webcast. The Council met in closed session from 11:00 a.m. to 11:21 a.m. for a presentation of the NIAAA Board of Scientific Counselors (AABSC) Report by Dr. CeCe Hillard, a member of the NIAAA Board of Scientific Advisors, and from 11:30 a.m. to 12:09 p.m. to review grant applications and cooperative agreements. Dr. Philippe Marmillot, Acting Director of the Office of Extramural Activities, presided over the Council’s review 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. The closed session recessed at 12:09 p.m.

Council Members Present:

Nancy Barnett, Ph. D.
Jill B. Becker, Ph.D.
Andrew MacGregor Cameron, M.D., Ph.D.
Christopher S. Carpenter, Ph.D.
Christina Chambers, Ph.D, MPH 
Constance M. Horgan, Sc.D.
Rhonda Jones-Webb, Ph.D.
Beth Kane-Davidson, LCADC, LCPC
David Kareken, Ph.D.
Charles H. Lang, Ph.D.
Mary E. Larimer, Ph.D.
Michael J. Lewis, Ph.D.
Laura E. Nagy, Ph.D.
Laura O’Dell, Ph.D.
Scott J. Russo, Ph.D.
Katie Witkiewitz, Ph.D.

NIAAA Director and Chair: George F. Koob, Ph.D.

NIAAA Deputy Director: Patricia Powell, Ph.D.

Acting Executive Secretary: Ranga V. Srinivas, Ph.D.

Senior Staff: Vicki Buckley, M.B.A.; David Goldman, M.D.; Ralph Hingson, Sc.D.; M. Katherine Jung, Ph.D.; Raye Litten, Ph.D.; David Lovinger, Ph.D.; Phillipe Marmillot, Ph.D.; Antonio Noronha, Ph.D.; and Bridget Williams-Simmons, Ph.D.

Other Attendees at the Open Session

Approximately 200 people observed the meeting, including representatives from constituency groups, liaison organizations, NIAAA staff, and members of the general public.

 Call to Order

NIAAA Director Dr. George F. Koob, called the open session of the Council meeting to order at 12:45 p.m. on Thursday, February 9, 2023. Council members and NIAAA senior staff introduced themselves.

Director’s Report

Dr. Koob highlighted key recent NIAAA activities, referring to the written Director’s Report, which was distributed to Council members.

Fiscal Year (FY) 2022 Budget. On December 29, 2022, the President signed the Consolidated Appropriations Act of 2023. NIH received a total of $47.7 billion, a $2.5 billion (or 5.5 percent) increase above the Fiscal Year (FY) 2022 level. NIAAA received $595.3 million, a $21.66 million (or 3.8 percent) increase over FY22. NIAAA estimates it will support 728 Research Project Grants this fiscal year. The preparation of the FY24 President’s Budget is underway.

Retirement of Dr. Abraham Bautista. Dr. Koob expressed his deep appreciation for Dr. Bautista who retired from his position as the Director of the Office of Extramural Activities (OEA) after 20 years of Federal Service. Dr. Marmillot is the Acting OEA Director.

 NIAAA Leadership Recruitment. NIAAA is recruiting for the following leadership positions:

• Director, Office of Extramural Activities: The search for a permanent director is in the early stages.
• Scientific Director, Intramural Research Program: Three candidates recommended by the search committee gave a talk about their research as well as their vision for the intramural program. Feedback was solicited from all NIAAA staff. After a final interview stage, NIAAA hopes to have a selection made over the next few weeks.
• Scientific Diversity Officer: Pre-recruitment outreach efforts for this position are underway; NIAAA anticipates that the official announcement will open in the next few weeks.

NIAAA Funding Opportunities. Dr. Koob announced the following NIAAA-issued new Funding Opportunity Announcement (FOA):  

• Research Opportunities for New and "At-Risk" Investigators to Promote Workforce Diversity (PAR-22-181). NIAAA is participating in an FOA to support R01 grant applications from New Investigators and At-Risk Investigators from diverse backgrounds, including those from groups underrepresented in the health-related sciences.

A full list of FOAs may be found in the NIAAA Director’s Report.

NIAAA Data Management and Sharing Policy in Effect. In January 2023, the final NIH Policy for Data Management and Sharing (NOT-OD-21-013) went into effect. The policy promotes transparency and accountability in research by setting a minimum set of expectations for data management and sharing. Among the notable changes:

• Most applications are required to include a Data Management and Sharing Plan.
• Data should be shared no later than the time of an associated publication or the end of the award period, whichever comes first.
• Awards will no longer have a 2-year embargo period before data are shared with the public.

NIAAA has published two related Notices that describe information to be included in the Data Management and Sharing Plan (NOT-AA-23-001) and update the NIAAA Data Archive sharing requirements for human subjects research (NOT-AA-23-002).

National Conference on Alcohol and Other Substance Use in Women and Girls. In October 2022, NIAAA and the Interagency Work Group on Drinking and Drug Use in Women and Girls hosted the virtual “National Conference on Alcohol and Other Substance Use in Women and Girls: Advances in Prevention, Treatment, and Recovery,” attended by more than 400 people. The conference featured plenary lectures by Dr. Koob, National Institute on Drug Abuse (NIDA) Director Dr. Nora Volkow, and National Institute of Mental Health (NIMH) Director Dr. Joshua Gordon. In addition to highlighting the importance of reducing stigma and other health barriers, the conference featured panel sessions, including:

• Overview of Harmful Alcohol and Other Substance Use in Women and Adolescent Girls
• Model Programs for Mothers with Alcohol Use Disorder and Other Substance Use Disorders

• Children with Prenatal Substance Exposure

 Virtual Forum on COVID-19 Research. In January 2023, NIAAA held a virtual forum featuring NIAAA-supported grantees conducting COVID-19-related research. The purpose of the forum was to share progress on COVID-19 supplements and grants that NIAAA supported during the pandemic. Thirty-six

presentations across 6 scientific sessions focused on:

• Effects of the COVID-19 pandemic on alcohol use
• Pathophysiological impact of alcohol on COVID-19 outcomes
• Impacts of COVID-19 stress on alcohol consumption, neural vulnerabilities, and mental health
• Effects of COVID-19 and alcohol-related health outcomes
• HIV/AIDS and other factors
• Health Services

Update: Alcohol-Related Deaths Continued to Increase During the Pandemic. Research by Dr. Aaron White, Senior Scientific Advisor to Dr. Koob, revealed that the number of death certificates listing alcohol as the primary cause or a contributing factor jumped by 25 percent from 2019-2020 and by another 10 percent in 2021, following two decades of roughly 2.5 percent per year increases.

 Public Awareness: Dry January. NIAAA participated in more than 60 media interviews and a “Dry January” Satellite Media tour discussing behaviors during the holidays that may be signs of a problem with alcohol and the benefits of Dry January.

 Provider Awareness: Healthcare Professional’s Core Resource (HPCR) on Alcohol. NIAAA continues to promote the HPCR through multiple efforts, including outreach to organizations, academic leaders, and health plans. HPCR is now designated an American College of Academic Addiction Medicine Recommended Educational Activity, as well as an American Board of Addiction Medicine Recognized Activity for Certification of Diplomates. In December 2022, NIAAA hosted a webinar that included a discussion of how the HPCR can support people in recovery.

Research Highlights. Dr. Koob presented highlights of alcohol-related research studies that represent the breadth of NIAAA-supported research.

“Spironolactone as a Potential New Pharmacotherapy for Alcohol Use Disorder: Convergent Evidence from Rodent and Human Studies” was published in Molecular Psychiatry (2022 Nov; 27(11):4642–4652. doi.org/10.1038/s41380-022-01736-y) by M Farokhnia, CT Rentsch, V Chuong, A McGinn, SK Elvig, EA Douglass, JE Sanfilippo, RCN Marchette, BJ Tunstall, DA Fiellin, GF Koob, AC Justice, L Leggio, and LF Vendruscolo. Evidence suggests that spironolactone, a nonselective mineralocorticoid receptor (MR) antagonist, modulates alcohol seeking and consumption. In this study, the effects of spironolactone were tested in a mouse model of alcohol drinking (drinking-in-the-dark) and in a rat model of alcohol dependence (vapor exposure). In addition, the association between spironolactone receipt for at least 60 continuous days and change in self-reported alcohol consumption was investigated in humans using electronic health records from the U.S. Department of Veterans Affairs. Spironolactone dose-dependently reduced the intake of sweetened or unsweetened alcohol solutions in male and female mice. It also dose-dependently reduced operant alcohol self-administration in dependent and nondependent male and female rats. In humans, a greater reduction in alcohol consumption was observed among those who received spironolactone, compared to controls. The largest effects were among those who reported hazardous/heavy episodic alcohol consumption at baseline and those exposed to the higher doses, ≥ 50 mg/day ,of spironolactone. These convergent findings across rodent and human studies demonstrate that spironolactone reduces alcohol use and support the hypothesis that this medication may be further studied as a novel pharmacotherapy for alcohol use disorder (AUD).

“Acetate Reprograms Gut Microbiota During Alcohol Consumption” was published in Nature Communications (2022 Aug 8; 13(1):4630. doi: 10.1038/s41467-022-31973-2. PMID: 35941112; PMCID: PMC9359997) by C Martino, LS Zaramela, B Gao, M Embree, J Tarasova, SJ Parker, Y Wang, H Chu, P Chen, KC Lee, DD Galzerani, JM Gengatharan, A Lekbua, M Neal, R Knight, H Tsukamoto, CM Metallo, B Schnabl, and K Zengler. Altered gut microbiota and intestinal bacterial overgrowth (dysbiosis) can be found in patients with alcohol-related liver disease. In this study, mouse models were used to investigate the metabolic impacts of alcohol consumption on the gut microbiota. Investigators found that acetate, a by-product of alcohol metabolism, diffused from circulation into the intestine where it provided a source of energy for bacterial growth. Investigators also found that there is no evidence of ethanol metabolism by gut microbiota ex vivo under anaerobic conditions.  Studies aimed at isolating deleterious effects of alcohol on the microbiome will need to carefully consider these acetate effects from the data set in order to understand the gut microbiota changes that are causal for deleterious effects of alcohol consumption.

“Genome-wide Association Study for Circulating FGF21 in Patients with Alcohol Use Disorder: Molecular Links Between the SNHG16 Locus and Catecholamine Metabolism” was published in Molecular Metabolism (2022 Sep; 63:101534. doi: 10.1016/j.molmet.2022.101534. Epub 2022 Jun 22. PMID: 35752286; PMCID: PMC9270258) by MF Ho, C Zhang, I Moon, L Wei, B Coombes, J Biernacka, M Skime, DS Choi, M Frye, K Schmidt, K Gliske, J Braughton, Q Ngo, C Skillon, M Seppala, T Oesterle, V Karpyak, H Li, and R Weinshilboum. Circulating plasma levels of fibroblast growth factor 21 (FGF21) are associated with recent alcohol and chronic consumption and injection of FGF21 was shown to reduce alcohol intake in mice in previous research. The present study identified genetic variants associated with FGF21 levels and evaluated their functional role in AUD. One variant, located 5’ of the SNHG16 gene on chromosome 17, was associated with plasma FGF21 levels and with AUD risk. Knockdown of SNHG16 in HepG2 cells resulted in increased FGF21 levels and decreased expression and enzyme activity for COMT, an enzyme that is involved in catecholamine metabolism. Alcohol induced FGF21 production in iPSC-derived brain organoids, which was blocked by AUD treatments. These results suggest that theSNHG16-FGF21 axis could be a potential pharmaceutical target for the treatment of AUD.

“COVID-19 Pandemic-related Changes in Utilization of Telehealth and Treatment Overall for Alcohol Use Problems” was published in Alcohol: Clinical and Experimental Research (2022 Dec; 46(12):2280-2291. doi: 10.1111/acer.14961. Epub 2022 Dec 17. PMID: 36527427) by VA Palzes, FW Chi, VE Metz, C Campbell, C Corriveau, and S Sterling. This study investigated the impact of the COVID-19 pandemic on alcohol treatment utilization and potential disparities. Investigators analyzed electronic health record and claims data from Kaiser Permanente Northern California for adults with alcohol use problems during pre-COVID-19 (March-December 2019) and COVID-19 onset (March- December 2020). Findings indicated that treatment initiation increased during the COVID-19 onset period and treatment engagement and retention also increased during COVID-19 onset, with the greatest increase among patients aged 35-49 years who initiated treatment via telehealth The transition to telehealth may have attracted individuals who have historically underutilized care for alcohol use problems, particularly younger and healthier adults, without exacerbating pre-pandemic racial and ethnic disparities. Further, greater odds of treatment engagement were observed during pandemic onset and did not vary by age group, race, and ethnicity.

“College Students’ Virtual and In-person Drinking Contexts During the COVID-19 Pandemic“ was published in Alcohol: Clinical and Experimental Research (2022 Nov; 46(11):2089-2102. doi: 10.1111/acer.14947. Epub 2022 Dec 1. PMID: 36454103; PMCID: PMC9720698) by BA Hultgren, KN Smith-LeCavalier, JR Canning, AE Jaffe, IS Kim, VI Cegielski, TA Garcia, and ME Larimer. Although college drinking decreased at the onset of the pandemic, this study sought to identify a more nuanced understanding of changes in drinking contexts and the risks conferred by each context. Secondary analyses were performed on screening data from a large clinical trial assessing a college student drinking intervention. Participants across six cohorts reported on their frequency of drinking. Findings indicated that the proportion and frequency of drinking outside the home increased and was most consistently associated with more alcohol-related consequences. However, drinking at home was not without risks. More specifically, drinking home alone was associated with abuse/dependence, personal, social, hangover, and social media consequences; drinking home with others virtually was associated with abuse/dependence and social consequences; drinking home with others in-person was associated with drunk texting/dialing. Future prevention and intervention efforts may benefit from considering approaches specific to different drinking contexts.

Council Discussion: Dr. Witkiewitz inquired if the NIAAA intramural research program was following up on the findings about spironolactone presented in the Research Highlights; Dr. Koob responded that NIAAA is continuing basic research studies to examine the interactions of steroids with AUD. He asked Dr. Goldman about the status of a clinical trial on spironolactone by intramural PI Dr. Lorenzo Leggio, together with Dr. Mehdi Farokhnia and other members of Dr. leggio’s lab. Dr. Goldman responded that the study has gone through scientific review and should currently be before the Institutional Review Board (IRB). Dr. Koob noted that NIAAA has a contract mechanism in the Division of Treatment and Recovery (DTR) for three types of research, available on a first-come, first-served basis: Alcohol-drug interaction studies in humans, critical for approval of Phase II trials by the Food and Drug Administration (FDA); human laboratory studies; and multi-site clinical trials. DTR has completed two successful clinical trials to date, one testing a vasopressin 1B antagonist and the other for varenicline. Dr. Lewis asked if there is a list of the articles reviewed in the Research Highlights. Dr. Srinivas said they may be found in the Director’s Report that is available on the NIAAA website. Dr. O’Dell commented that spironolactone is being used for the treatment of hypertension and heart failure; she asked if this use advanced the study of this drug for the treatment of AUD. Dr. Koob responded that current use of the spironolactone is off label, despite it being widely used. He noted that it took 15 years for naltrexone and 17 years for acamprosate to become FDA-approved drugs from the date of their first animal studies. In lieu of waiting 17 years for a novel drug to get into the clinic, the alcohol field is trying to use existing medications that might be helpful. Dr. Goldman commented on the advantage of quick FDA approval for an Investigational New Drug (IND) application to study an existing drug like spironolactone where safety data already exists and the disadvantage, as with naltrexone, that the pharmaceutical company is not motivated to promote the drug. Dr. Koob noted that there are licensing and profitability issues that affect the viability of medications.

Partnership Opportunities for NIAAA and the All of Us Research Program

Dr. Koob introduced Dr. Geoffrey S. Ginsburg, Chief Medical and Scientific Officer for the NIH All of Us Research Program. The goal of All of Us is to accelerate health research and medical breakthroughs to make precision medicine possible for everyone by:

• Nurturing partnerships for decades with at least a million participants who reflect the diversity of the United States
• Delivering one of the largest, richest biomedical datasets that is broadly available and secure, and
• Catalyzing an ecosystem of communities, researchers, and funders who make All of Us an indispensable part of health research.

Participants. Over 372,000 participants are enrolled (as of December 2022). More than 50 percent are non-White, including significant numbers of Black and Latin individuals; Asians are currently underrepresented. A large majority (80 percent) are from groups that are underrepresented in biomedical research, e.g., rural communities, people with disabilities, and younger individuals.

Data Sources. Primary data streams in the program include surveys (e.g., lifestyle, access to care, medical history); physical measurements (e.g., height, weight, blood pressure, heart rate); electronic health records (EHRs); genomics (whole genome sequences and genotyping arrays); and wearables (physical activity and heart rate). Every participant is also asked to donate a biosample; there are roughly 420,000 biosamples and 10 million aliquots in the All of Us biobank.

 All of Us has approximately 100,000 whole genome sequences and 165,200 genotyping arrays. Because of the program’s emphasis on diversity, analysis of this data revealed almost 600 million unique variants that have never been seen before in publicly available genomic datasets. This genetic data can also be paired with phenotyping data obtained from the All of Us surveys, wearables, and EHRs.

Researcher Diversity. Over 3,750 researchers across a wide range of roles and career stages are participating in All of Us; about 50 percent of these individuals identify as non-White. Data agreements have been established with 440 institutions, mostly nonprofits and academic institutions, including Historically Black Colleges and Universities (HBCUs) and Hispanic-Serving Institutions (HSIs).

Researcher Workbench. A Researcher Workbench with over 3,000 active studies is available at ResearchAllofUs.org. Data access levels include a public tier which allows aggregated participant data and summary statistics, with identifiers removed; a registered tier available to registered researchers which allows access to curated, individual-level data, a variety of research tools to conduct a wide range of studies, and new data, including initial Social Determinants of Health (SDoH) data and COVID-19 EHR data; and a controlled tier in which registered users with amended institutional agreements can access all of the data in the registered tier plus expanded demographic data, genomic data, CRAM files which enable capabilities such as custom genomic variant evaluation and visualization, and intensity files (iDat) for custom array analyses beyond variants. Thus, the Workbench provides individual researchers with the capacity to carry out sophisticated studies at low cost. For example, one postdoctoral fellow conducted a genome-wide association study (GWAS) in the workspace to examine Type 2 diabetes in a cohort of approximately 20,000 individuals utilizing 23 million single-nucleotide polymorphisms (SNPs) for a total cost of $37. All Workbench users start with a $300 credit that could fund up to ten GWAS applications.

Scientific Framework. The Scientific Roadmap for All of Us identifies areas of research for the program and will ultimately drive the funding opportunities that become available. The overarching goal of the program is advancing precision health and medicine through risk assessment, diagnosis, and treatment for all. The foundation for the roadmap is the Researchers Workbench where the datasets reside. In addition to the five core data types described above, the Workbench will also provide access to rich phenotyping data drawn from the biosamples, including immune/clinical assays, metabolomics, and targeted proteomics; importation of imaging and ECGs; and expansion of digital health data from wearables and other technologies. Finally, a toolbox of novel methods to analyze the multi-dimensional All of Us data will be included. The roadmap also considers factors such as SDoH that modify health outcomes. These “drivers and exposures” include lifestyles, substances, and behavioral health; environment; health equity; and genetics and biology. They drive health outcomes in focus areas such as common and rare health conditions, maternal and child health, and healthy aging and resilience across the lifespan.  All of Us also has a commitment to return results to the participants and to understand the downstream impacts of those results on individual and population health. Finally, All of Us will work closely with NIH Institutes and Centers (ICs), companies, health care systems, payers, and policy makers to effectively translate the Workbench findings into tangible benefits for society and population health.

Alcohol-Related Data Availability. The All of Us dataset contains approximately 16,000 people with alcoholism, alcohol abuse, alcohol dependence, or other alcohol-related conditions, based on EHR data. To date, 26 questions related to alcohol have been included in the All of Us lifestyle surveys, e.g., “How often did you have a drink in the past year?”; “On a typical day when you drink, how many drinks do you have?” There are currently 22 active research projects addressing alcohol in the Researcher’s Workbench, including machine learning to identify individuals at risk for AUD, association of AUD with health-related quality of life, and whole genome associations with AUD.

Partnership Opportunities and Ancillary Studies. In 2022, All of Us supported Administrative Supplements to Advance Precision Medicine Using the All of Us Research Program’s Data (NOT-PM-22-002), making awards to 25 (of 33) eligible applications selected for funding across 15 Institutes, Centers, and Offices (ICOs), including NIAAA.

All of Us has recently published the following FOAs:

• Small Grants involving 27 ICs and a $4.75 million total shared investment:
  • R03: Analyze data in the Researcher Workbench, using standard tools and methods (RFA-PM-23-002)
  • R21: Develop and use new tools to analyze data in the Researcher Workbench and make new tools broadly available (RFA-PM-23-001)
• Notice of Special Interest: Administrative Supplements to Promote Workforce Diversity to Enhance the Use of the All of Us Research Program’s Data (NOT-PM-22-005)
• All of Us Research Participant and Partner Services Center due March 20 (OTA-23-002)

A Research Opportunity Announcement (ROA) will be published in February 2023:

• All of Us Center for Linkage and Acquisition of Data (NOT-PM-23-002)

By 2026, All of Us has established the following goals:

• Enroll 1 million participants who reflect the diversity of the U.S., cover the lifespan, and have shared all baseline elements. Of these participants, 500,000 are actively engaged in the program.
• Expand data available for 1 million participants to include surveys, health data streams, a whole genome sequence, environmental data, and physical measures.
• Launch ancillary studies as a core and scalable capability, expanding the cohort and delivering phenotypic, lifestyle, environmental, and biologic data.
• Establish a diverse global community of 10,000 researchers productively using All of Us
• Incorporate participant return of value into data collections and assess its impact, including return of information to participants on genomics and EHR.

Partnership opportunities for NIAAA may be found in ancillary studies. An “ancillary study” expands the All of Us dataset by adding new data for all or a subset of participants by generating data from existing or new biospecimens; by collecting information directly from participants, and/or adding participants beyond the current recruitment audience; and by pursuing novel scientific objectives in alignment with the goals outlined in the All of Us Scientific Roadmap. Current examples of ancillary studies include a COVID serology study (biospecimen use to generate new data); Exploring the Mind (re-contact of participants for custom surveys, wearables, etc.); and Nutrition for Precision Health (embedded studies). Ancillary studies range in complexity, from observational studies to randomized clinical trials.

The All of Us vision for ancillary studies includes:

1. Proactive Planned Partnerships – Establish a pipeline of future ancillary study partnerships that align with the Scientific Roadmap, beginning with NIH Institutes and Centers and expanding to other partners, such as external organizations, communities, and individual investigators.
2. React to requests (initially from ICOs and later from outside) – Develop and apply a transparent prioritization process for proposed ancillary studies ideas, guided by the program’s Scientific Roadmap.
3. Pilot and Scale – Validate scientific approach and test feasibility of proposed ancillary study. Then, enable scalable operations with a funding structure that reduces or relieves the cost burden on All of Us.
4. Grow All of Us participant trust and value - Harmonize ancillary studies into existing All of Us brand to create a seamless participant experience.
5. Enhance All of Us resources – Integrate new data, data types, biosamples, and tools and training to enable innovative research.

Synergy between NIAAA and All of Us. Data from All of Us will allow NIAAA to examine the relationship between alcohol use, health conditions, and genetics to define an integrated perspective more deeply on the impact of alcohol on health than has previously been described. Advantages of working with the All of Us Research Program include:

• Substance use is included in All of Us
• Substance use is on the All of Us Scientific Priorities Roadmap as a focus area.
• Inclusion of broadly diverse populations of participants
• Data on social determinants of health and linkages to environmental data over time
• Multidimensional data to describe an integrated perspective on “whole person health” (biological, behavioral, social, environmental) across the lifespan, and
• Acceleration of NIAAA research and rapid hypothesis testing without the need to build individual cohorts.

Discussion: Dr. Koob commented that he serves on the “brain trust” for All of Us; Dr. Laura Kwako is NIAAA’s representative to the program. He suggested Dr. Ginsburg’s presentation would be valuable to give at a Research Society on Alcoholism meeting. Dr. Kareken asked Dr. Ginsburg to elaborate on the availability of imaging and cognitive testing data. Dr. Ginsburg responded that the program is exploring the types of imaging data that are available from the ICs and hopes to import some of that data into the program. Currently, All of Us is focusing on natural language processing to represent imaging. Five types of cognitive testing data is being used in the Exploring the Mind ancillary study protocol; the first cognitive testing will be completed on 400 participants in the coming weeks. Eventually, All of Us hopes to scale the five cognitive tests to the entire cohort. Dr. Witkiewitz noted that NIAAA is adopting terms such as AUD rather than stigmatizing ones such as “alcoholism” that appeared in Dr. Ginsburg’s presentation. He replied that the data he presented were extracted from existing ICD-10 coding. He encouraged Council members to change the conversation so that widespread changes in terminology can occur. Dr. Witkiewitz concurred, noting that ICD-11 has adopted “harmful alcohol use” and “alcohol dependence” as its alcohol-related codes to replace previous, stigmatizing language. Dr. Becker asked if there is equal participation of men and women in All of Us research. Dr. Ginsburg said that there are currently more women than men in the cohort. Dr. Becker inquired if data are identified by sex or gender, noting that self-reported gender identity is preferred. Dr. Ginsburg pointed to the alcohol-related data, noting that they show sex assigned at birth, age, and source of data. There is also information available on other ways people identify sex and gender which is not available on the publicly facing platform for privacy reasons but can be accessed by researchers with permission. Dr. Horgan asked Dr. Ginsburg to expand on the role of health systems and payers on the Scientific Roadmap. She also asked if there are plans to merge outside databases that impact systems of care with the All of Us databases. Dr. Ginsburg responded that All of Us is creating a translation work group to do outreach to potential partner organizations who can translate All of Us research into health services. The program’s goal is to be strategic and aggressive in translating its findings. Dr. Horgan inquired further about how All of Us plans to use health services-related data present in electronic health records to further its work. Dr. Ginsburg responded that All of Us’s surveys are collecting SDoH data, as well as extensive health care access data that will provide insight into the challenges for moving research into the healthcare system.

Council Member Presentation: Alcohol Biosensors: State of the Science, Opportunities, and Future Directions

Dr. Koob introduced Dr. Nancy Barnett (Brown University) who summarized the current status of alcohol biosensors. Her presentation addressed goals for passive alcohol sensing, features of available technology, and anticipated advances.

Goals for Passive Alcohol Sensing. Dr. Barnett identified the following goals for passive alcohol sensing devices:

• Acceptability to wearer
• Validity for:
  • Any drinking
  • Heavy drinking
  • Blood Alcohol Concentration (BAC) in real time (both peak and at a specific time)
  • Total alcohol exposure (Number of drinks)
• Alcohol episode characteristics
• Reliability
  • Between devices
  • Between individuals
  • Over time
• Wireless Data Collection and Tools for Data Interpretation

Features of Available Technology/Acceptability. Dr. Barnett focused her presentation on two commercially available sensors that are currently available and provide transdermal alcohol content (TAC): SCRAM® and BACtrack Skyn™. SCRAM sensors are locked onto the ankle and are commonly used by individuals court-ordered to wear them. They are uncomfortable and stigmatizing to wear, but advantageous in having a long battery life, being water resistant, and requiring little interaction from the user to sync. They provide observations every 30 minutes, which may be insufficient for research purposes. In contrast, the Skyn sensor is worn on the wrist and is not unattractive. However, they must be removed for charging every few days and for bathing, and they require active syncing by the user. Skyn sensors provide observations every 20 seconds. Although SCRAM sensors have been used successfully in prior research, the Skyn sensor has higher acceptability than the SCRAM sensor for research purposes.

Validity.  Both SCRAM and Skyn sensors provide TAC level, temperature, and time stamps. SCRAM data is fairly clean, and the company provides an indication when the wearer meets the SCRAM company criteria for a drinking episode, which is generally too stringent for research or clinical purposes (because false positives are not acceptable as they would send the court-ordered wearer to jail). Adjustments have successfully been made to these criteria by Dr. Barnett and others to make the SCRAM more useful for research. In contrast, Skyn data show sharp peaks, a lot of up and down fluctuations from point to point, and values below zero when displayed visually. Therefore, researchers need to develop methods to effectively analyze the data. Currently, the data can’t simply be downloaded and immediately reported.

The SCRAM’s ability to identify drinking is good at levels above 1-2 drinks; sensitivity increases with the number of drinks consumed.

In one evaluation of the validity of the devices with laboratory-controlled administration of alcohol, breath alcohol concentration (BrAC) measurements were consistent across individuals, but both SCRAM and Skyn measures were more variable between persons. Both devices show a delay in detecting alcohol intake compared to breath or blood measures. This delay varies, and ranges from 30 minutes to as long as 3-4 hours, making it difficult to say when drinking actually began. In other lab studies, peak TAC highly correlated with peak BrAC (rs = .60-.99) and the total area under the BrAC and TAC curves were highly correlated (rs = .60 -.91). In field studies, self-reported drinks per episode correlated with TAC area under the curve (AUC) (rs =.70-.94). In an article in Alcoholism: Clinical and Experimental Research (2021) that showed the potential for TAC information to predict other outcomes, MA Russell, RJ Turrisi, and JM Smyth reported that peak TAC, AUC, faster TAC rise, and faster TAC fall were positively associated with day-level consequences, both total number and specific individual consequences. Thus, the sensors can provide a level of utility that is not available from BrAC.

In summary, the sensors’ validity is strongest for detecting heavy drinking; good for detecting any drinking, total alcohol exposure, and alcohol episode characteristics; and somewhat less good for peak blood alcohol concentration (BAC) and BAC at a specific time.

Reliability. Sensors have demonstrated reliability of data between devices, between different people, and over time. It is expected that this reliability will continue to improve in the future as the versions of devices progress and become more stable.

Data Collection and Interpretability. Ideally, data from sensors should be transmitted quickly and wirelessly, and both Skyn and SCRAM have this capability. One issue however with the interpretation of the sensor data is that one must differentiate between consumed alcohol and environmental confounders, such as the use of hand sanitizers or a spilled drink, that appear as high TAC levels. The SCRAM system provides warnings and excludes these interferents, but no such guidance is available for the Skyn. To try to develop rules for excluding these environmental interferents in Skyn data, Dr. Barnett’s team asked respondents to report when they used hand sanitizer and when they drank. After comparing the sanitizer results with the sensor data, the team was able to develop criteria that eliminated 90 percent of the interference characteristics; these criteria need further finetuning to increase accuracy.

A second problem with the Skyn TAC data is that most cases will have missing data, e.g., when the user removes the sensor to bathe or to charge the device or in the event of a malfunction. Thus, there is a need to train participants in the use of the device to increase compliance. A second type of missing data is hidden invalid data, e.g., times when the user is not wearing the sensor, but the device remains on. The temperature readings should be able to help with this, as temperature will be lower when the sensor is not being worn. However, temperature cutoffs are challenging to establish because they vary by person, time of day, and season, but it is important to do so because the researcher needs to be able to exclude any TAC data as not valid. Since the SCRAM is locked on, it is not removed by the user, and if it is cut off, it has sensors that can identify that this has happened.

In summary, available alcohol sensors provide good acceptability, validity, and reliability. Each of these characteristics have improved over time and continue to improve. Nonetheless, there are some drawbacks to using sensors for research:

• Data processing is tedious; there is a need to develop a standardized approach for processing data.
• There are no criteria for detecting alcohol use in field data with the Skyn device; there is a need for reliable criteria for identifying consumed alcohol in field observations that excludes interferents and identifies invalid data.

• TAC and BrAC are not equivalent. Discrepancies vary, making it challenging to predict BrAC from the sensor data. Therefore, there is a need to translate TAC to BrAC.

Dr. Barnett’s team has developed a Transdermal Alcohol Sensor Macro (TASMAC) that works as a macro in Excel to process SCRAM data. It has recently been revised to work with Skyn data as well and this new version has additional features including allowing the user to set the criteria for detecting drinking episodes; incorporating researcher uploaded event-level data including BrAC, drinks, and known interferents; summarizes TAC data; and enables visualization of episodes at either the day- or episode-level. Eventually, Dr. Barnett and her colleagues hope to create a platform that people using the device for self-change or treatment can use to see what their alcohol consumption looks like.

Published research on transdermal alcohol sensors has exploded in the past 2-3 years. Dr. Barnett shared two recent studies. The first, a 2022 article by T Ariss, CE Fairbairn, and N Bosch (Alcoholism: Clinical and Experimental Research), applied machine learning approaches to convert TAC to BrAC in a large-scale laboratory sample. These researchers found that the newest version of Skyn demonstrated a substantially lower rate of error than earlier models and that real-time estimates of BrAC from TAC were very close (within 0.007 of true BAC readings in the laboratory and within 0.019 of true BrAC readings in the field). The second study, from Dr. Susan Luczak’s laboratory at the University of Southern California, was published in Alcohol (2019). It presents a mathematical, population-based approach for estimating BRaC from TAC data, rather than the individual calibration approach that was previously needed. These findings move the field forward by standardizing data interpretation of sensor-derived data.

Anticipated Advances. There are new transdermal sensors in development, including one that is undergoing some testing but is not yet available widely for purchase. Other promising approaches include the use of microneedles, optical spectroscopy, smartphone sensors to detect gait changes during drinking episodes, and patches, tattoos, saliva ring, and smart glasses. For example, a recent article reported on a wearable microneedle array of sensors that monitored biomarkers such as alcohol and glucose in real time, with data capture and visualization via a smartphone app. Most of these new approaches are still in the developmental stage. Also in the pipeline are Driver Alcohol Detection Systems for Safety (DADSS) that may detect a driver’s alcohol use via breath or touch sensors built into the car; if alcohol is detected, built-in locks will prevent the car from working.

One of the areas that requires additional work is the use of sensors as an adjunct to AUD treatment and with clinical populations. Dr. Barnett’s team and others have tested the use of sensors in contingency management for reducing alcohol use. There is also strong potential for helping those who are not in treatment to self-monitor their alcohol use, as well as in “just in time” interventions for AUD treatment and short-term monitoring in medical or other clinical settings where alcohol interferes with a condition or treatment (e.g., pre- or post-surgery).

Discussion. Dr. Koob recalled the NIAAA competition for a wearable alcohol sensor that resulted in the BACtrack Skyn device. He commented that he has wanted a Smartwatch that would track alcohol use; Dr. Barnett pointed out Skyn has a band for Apple watches that contains their sensor. Dr. Koob noted that NIAAA invited the SCRAM company to meet with Institute staff. The company said it could not miniaturize the device, which Dr. Barnett agreed would make it more attractive to researchers. He asked if anyone has conducted a head-on-head comparison between timeline/follow-back with one of these devices. Dr. Barnett responded that this comparison is commonly done by ecological momentary assessment (EMA) or daily diary, e.g., asking the individual in the morning about his or her drinking the previous day. This may be more accurate than asking them to report in the alcohol consumption moment. This self-reported data can then be compared to the sensor-derived data. The timeline follow-back, on the other hand, if the timeframe is past-week or past month is difficult to align with sensor data because people forget when and how much they drank on specific occasions during the previous week. Some researchers are now using portable breathalyzers to validate TAC data with “in the moment” testing. Noting the need for more reliable tools, Dr. Koob said that sensors could help researchers to understand the social determinants of drinking and driving. Dr. Barnett commented that we may want to think about these developments in five-year increments: Five years ago, Skyn didn’t exist; five years in the future, there will be more sensing options available, and the field will have become more skilled in data interpretation. 

Concept Clearance. Alcohol-associated Hepatitis (AlcHepNet) Research Programs

Dr. Koob introduced Dr. Peter Gao, Program Director in the Division of Metabolism and Health Effects (DMHE), who sought Council support to continue funding the alcohol-associated hepatitis research programs conducted by AlcHepNet.

Background: Alcohol-associated hepatitis (AH) is one form of alcohol-associated liver disease (AALD). It is a clinical syndrome involving acute and severe liver injury in persons with known AALD or long-term heavy alcohol use. Severe AH (sAH) has a 90-day mortality of up to 30 percent. There are no FDA-approved treatments for AH. Treatment options for sAH are limited to supportive care and corticosteroid therapy. Currently, liver transplant is the only treatment for sAH, but there continues to be a shortage of livers available. AH-related hospitalizations have significantly increased in recent years; both rates of hospitalization and health care costs for AH increased by more than 30 percent between 2002 and 2010, a time period characterized by a concurrent increase in the amount of alcohol consumption. Therefore, there is a dire need for developing safe and effective therapies for patients with sAH.

The Alcoholic Hepatitis Network (AlcHepNet): Established in 2012 and renewed in 2018, the AlcHepNet consists of 10 leading partner institutes that conduct common randomized clinical trials, observational studies, and site-specific translational projects to test new therapies; study the etiology, risk factors, and natural history of AH; discover new diagnostic options; and identify new druggable disease mechanisms.

In 2020, AlcHepNet launched a Phase II multicenter, randomized, double blinded, placebo-controlled clinical trial of anakinra (plus zinc) an interleukin-1 receptor antagonist in patients with severe alcoholic hepatitis. The primary end point in the trial was overall survival at 90 days. The targeted enrollment goal for the study was met; however, the trial was stopped early after a planned interim analysis found higher 90-day overall survival in the prednisone control arm and a higher Incidence of early acute kidney injury (AKI) in the anakinra + zinc treatment arm.

Among AlcHepNet’s accomplishments to date are that it has demonstrated the feasibility of clinical trials in sAH and proved successful patient enrollment; published diagnostic criteria and common data elements for AH clinical trials, thereby contributing to a significant increase in the number of active trails on AH registered at ClinicalTrial.gov (from 4 in 2016 to 23 in 2023); and demonstrated the complexity of alcohol hepatitis treatment.

Importance of AUD Intervention in Recovery from AH. AH patients have two disorders, AUD and liver disease, and both disorders need to be addressed. Research has shown that alcohol rehabilitation significantly reduced 30-day hospital readmission, alcohol relapse, and mortality in AH patients. Yet less than 8 percent of AH patients received alcohol relapse prevention medication. More research is needed on the best ways to address alcohol use in patients with AH. Research gaps include:

• While emerging evidence suggests that treatment for AUD reduces alcohol-associated liver disease, studies are needed to address the effect of AUD treatment on AH outcomes specifically.
• Protocols need to be developed for clinical trials that combine treatment for AUD and AH that include specifics on treatment duration, clinical endpoints, outcome measures, etc.
• Collaborations between hepatologists and addiction medicine specialists are needed to provide optimal care for patients with co-occurring AUD and ALD.
• Studies are needed to assess possible drug-induced hepatotoxicity of medications for AUD in patients with AH.

NIAAA’s Strategy for the Next 5 Years. NIAAA’s vision is to leverage existing AlcHepNet resources to accelerate progress in the treatment of AH, through:

• Multi-center, multi-disciplinary clinical trials designed to study safety and efficacy of interventions/treatments targeting both AUD and AH
• Modernization of trial design, e.g., Adaptive/SMART trial designs, hybrid decentralized trials
• Ensuring data is more Findable, Accessible, Interoperable, and Reusable (FAIR).

To implement this strategy, NIAAA plans to:

• Fund multiple Clinical Centers (U01) with multi-disciplinary team including multiple PIs representing hepatology and addiction at each center.
• Conduct common AUD-AH combined intervention/treatment trials.
• Fund a Data Coordinating Center (U24) – Data Commons, Biorepository, Medical monitoring, Statistical and Logistical Support, and
• Provide up to 5 years of funding.

Discussion: Dr. Nagy asked if future research on AUD treatments would focus only on medications or also include cognitive behavioral therapies. Dr Gao responded that interventions for AUD will include both approaches. Dr. Nagy also inquired if translational studies would be simultaneously supported while intervention research was ongoing. Dr. Gao replied that nothing has been decided yet, but the research direction has shifted to clinical research and the translation U01s in the Network may be sunset in the future. However, researchers have alternative funding mechanisms for collaborating with AlcHepNet investigators. Dr. Koob noted that there is also an opportunity for back translation, i.e., evidence from a clinical study can be “moved back” to animal models to validate those models. Dr. Horgan asked how AlcHepNet research can be designed to accommodate what insurance plans view as two separate benefits: a medical benefit and a behavioral health benefit. There are synergies between this kind of research and health services research to get the findings into the real world of the delivery system.

Action: Dr. Witkiewitz publicly endorsed the concept, which was unanimously by supported by the council members in the Chat.

Consideration of September 8, 2022, Council Meeting Minutes

Dr. Lang moved to accept the September 8, 2022, Council minutes, which were approved unanimously by Council.

Council Discussion

Dr. Witkiewitz asked if NIAAA and NIDA were working together to be more explicit in the discussion of harm reduction approaches to addiction. Dr. Koob asked Dr. Litton to comment on NIAAA’s work in treatment and recovery, e.g., in interactions with the FDA on desired outcomes and on continuum of care models. Dr. Litten stated that NIAAA is recommending in the HPCR that NIAAA’s goal is for people to be abstinent or limit their drinking to 1-2 drinks per day. Therefore, NIAAA is focusing on people reducing the amount they drink and has encouraged the FDA to use reduced alcohol consumption as an endpoint in studies. NIAAA has supported some epidemiological studies that indicate people can improve the way they feel and function by reducing their alcohol consumption. Dr. Koob noted the 60 media interviews on Dry January that framed the usefulness of the observance as harm reduction.

Dr. Barnett reported that she has been hearing concerns from researchers whose requests for no-cost extensions have been denied, noting that COVID restrictions are still impacting their work. Dr. Kareken interjected that there has also been a downstream effect of the pandemic, i.e., people are not applying for jobs. Dr. Barnett agreed, noting that there is a shortage of staff to collect data. Dr. Koob asked Dr. Marmillot to look into this issue. If there is a comprehensive answer, Dr. Marmillot will send out an email to Council members. Dr. Barnett also noted that the research community is having problems with the new data sharing requirement. Dr. Koob asked Dr. Powell to respond to this concern. She said that if it’s clinical data, researchers can contact NIAAA Health Scientist Administrator Dr. Dan Faulk for support. She also noted that researchers can get supplements if they need additional help in getting their data uploaded into the NIAAA data archive. She and Dr. Koob both emphasized, however, that currently the goal is simply to develop a plan for data sharing. Dr. Barnett commented that it may not be appropriate to allow public access to complex behavioral or qualitative data. Dr. Kareken commented that the data sharing plan is a great idea in principle, but it’s a complicated issue and require in-person discussions. Dr. Koob responded that the topic can be addressed during the May Council meeting that is expected to be in-person. He also noted that a subgroup to study the issues could be created, if necessary. Dr. Koob urged Council members to not be overly anxious about the data sharing requirement, noting that change always comes with benefits and downsides. He also commented that there will be a change in how ICs and the Center for Scientific Review (CSR) review applications with a bigger emphasis on the significance of the proposed research. He suggested inviting CSR Director Dr. Noni Byrnes to address Council on this topic.

Dr. O’Dell inquired about the status of the diversity workgroup. Dr. Koob responded that the pandemic and NIH’s UNITE initiative with its requirement that ICs develop a Racial and Ethnic Equity Plan (REEP) drew attention away from the workgroup. Now that those efforts are getting more settled, it may be time to re-institute the diversity workgroup. Dr. Williams-Simmons emphasized the importance of having a coordinated effort across diversity initiatives. Dr. Powell noted that NIAAA is recruiting a diversity officer to coordinate all diversity-related initiatives. Dr. Koob observed that mentorship, a key theme of the diversity workgroup, is also beginning to evolve. He encouraged Council members interested in working on these issues to express their interest in serving on a workgroup.

Retiring Advisory Council Members

Dr. George Koob thanked retiring Council members Drs. Jill Becker, Constance Horgan, and Scott Russo, for their contributions and asked them to share their parting thoughts with Council. Dr. Becker explained that she had been tasked with making sure that NIAAA was paying attention to sex differences and the inclusion of both sexes in its work. She expressed her appreciation to Dr. Koob in making this issue a priority at the Institute, noting that increased awareness of the topic can be seen in concept clearances and grant awards since she has served on Council. She passed the torch for reviewing grants to make sure that sex differences have been considered appropriately by the study sections to Dr. O’Dell and encouraged Council members to make sure that sex is a category in data repositories so that sex differences can be systematically examined. Dr. Horgan commented that participation on Council has allowed her to appreciate how important it is to break down professional siloes to find areas of synergy and to address the quality and costs of services by translating basic scientific discoveries to the "real world.” She thanked Dr. Koob and his colleagues who have supported these efforts in health services research. Dr. Russo echoed Dr. Horgan’s comments about the impact of Council on reducing professional siloes. He said he had been surprised by the breadth of NIAAA’s work and the Institute’s willingness to think about alternative in addressing issues. He noted that one way that his experience on Council has influenced him is that he is shifting his own research to alcohol addiction and hoped to continue meeting old Council friends at future professional meetings.

Future Meeting Dates

Dr. Srinivas announced upcoming Council meeting dates for 2023. The next Council meeting on May 9 is expected to be in person. The CRAN Joint Advisory Council will meet on May 10.

Adjournment

Dr. Koob adjourned the meeting at 5:03 p.m.
 

CERTIFICATION  

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

George F. Koob, Ph.D. Director National Institute on Alcohol Abuse and Alcoholism and Chairperson National Advisory Council on Alcohol Abuse and Alcoholism

Ranga V. Srinivas, Ph.D. Executive Secretary National Advisory Council on Alcohol Abuse and Alcoholism