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February 13, 2018 Advisory Board Meeting Summary Minutes

Department of Health and Human Services
Public Health Service
National Institutes of Health
John E. Fogarty International Center for Advanced Study in the Health Sciences

Eighty-seventh Meeting of the Advisory Board
Minutes of Meeting
February 13, 2018

The Advisory Board met in the Stone House, Building 16, NIH Campus, 9000 Rockville Pike, Rockville, Maryland, at 9:00 a.m., Roger I. Glass, Chair, presiding.

Members Present

ROGER I. GLASS, M.D., Ph.D., Chair
GRETCHEN L. BIRBECK, M.D., M.P.H., Member
JANINE AUSTIN CLAYTON, M.D., Ex Officio Member
ROBERT EINTERZ, M.D., Member
GREGORY GERMINO, M.D., Ex Officio Member
KING HOLMES, PhD, MD, AB, Member
VIKAS KAPIL, D.O., M.P.H., Ex Officio Member
JOHN T. MONAHAN, Member
J. STEPHEN MORRISON, Ph.D., Member

Also Present

Kristen Weymouth, Executive Secretary
Nalini Anand, FIC
Geetha Bansal, FIC
Blythe Beecroft, FIC
Rick Berzon, NIMHD
Seetha Bhagavan, CSR
Kevin Bialy, FIC
Maureen Black, University of Maryland
Michele Bloch, NCI
Joel Breman, FIC
Ken Bridbord, FIC
Stacey Chambers, NINDS
Michael Cheetham, NIBIB
Lois Cohen, NIDCR
Myron Cohen, UNC
Dexter Collins, FIC
Jim Curran, Emory University
Anna Ellis, FIC
Robert Eiss, FIC
Paul Gaist, OAR
George Herrfurth, FIC
Christine Jessup, FIC
Flora Katz, FIC
Peter Kilmarx, FIC
Lydia Kline, FIC
Linda Kupfer, FIC
Vesna Kutlesic, NICHD
Marya Levintova, FIC
Christopher Lynch, NIDDK
George Mensah, NHLBI
Kathy Michels, FIC
Mark Miller, FIC
Amit Mistry, FIC
Claudia Moy, NINDS
Jackie Officer, FIC
Olugbenga Ogedegbe, NYU
Shannon Pearce, FIC
Vivian Pinn, FIC
Shana Potash, FIC
Ann Puderbaugh, FIC
Junnaid Razzak, FIC
Josh Rosenthal, FIC
Katrina Serrano, OD/ORWH
Lana Shekim, NIDCD
David Spiro, FIC
Leandra Stubbs, NIMH/DAR
Myra Thomas, FIC
Cecile Viboud, FIC
Judy Wasserheit, University of Washington
Makeda Williams, NIAID
Amber Wilson, OAR
Mary Wilson, Havard
Mitch Wolfe, CDC
Sanah Zia, NICHD

Director’s Update and Discussion of Current and Planned FIC Activities

Dr. Roger Glass, Chairman of the Fogarty International Center (FIC) Advisory Board, called the meeting to order at 9:04 a.m. He welcomed members as well as representatives from different ICs. He noted that FIC has come a long way from last year’s zeroed-out budget, and he attributes this to improved communication of FIC’s message and support from Congress, grantees, enthusiasts, former alumni, and Advisory Board members. Something he thinks is often overlooked is that 80% of FIC grants go to US institutions, and 100% support partnerships with U.S. institutions and investigators. These grants support the U.S.’s future in global health research. As diseases know no boundaries, so the benefits of research can know no boundaries.

FIC is celebrating its 50th year and will be holding its 50th Anniversary Symposium on May 1, 2018. Dr. Glass thanked Ann Puderbaugh and her team for their work in advertising this anniversary. Dr. Glass welcomed the Advisory Board’s four new members: Drs. Gretchen Birbeck, Robert Bollinger, Robert Einterz, and John Monahan. He then thanked Drs. King Holmes, Steve Morrison, Joe Kolars, and Wafaa El-Sadr for staying beyond their tenure as members to help support the Board.

Peter Kilmarx, Deputy Director of FIC, spoke about a presentation at the 2017 Grand Challenges Annual Meeting that discussed bringing in members of the African diaspora to help strengthen African research and development.

Dr. Glass was happy to announce that his nomination for the 2017 Hilton Humanitarian Prize—awarded by the International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b)—won. Dr. Glass received the Ida S. Scudder Humanitarian Oration in October 2017 for his work in developing a dollar a dose rotavirus vaccine in India. The vaccine is pre-qualified for the World Health Organization (WHO) and will eventually go out to the global market. Quarraisha and Salim Abdool Karim received the Lifetime Achievement Award from the Institute for Human Virology in October 2017.

FIC hosted the Nigerian Minister of Health, Isaac Adewole, in October 2017. Nigeria has introduced a 1% tax on industry profits to use for research. Other countries are designing similarly innovative ways to raise research money. The Brain Disorders Network Meeting was one of FIC’s most successful ventures into the Chronic Disease Initiative (CDI). The CDI has provided over 150 small grants, which led to over 30 R01s in developing countries. Dr. Glass thanked Kathy Michels for hosting the Network Meeting.

Dr. Kilmarx discussed the National Academies of Sciences, Engineering, and Medicine (NASEM) Study on Improving Quality of Health Care Globally. NIH is a co-sponsor of the study and has recommended a focus on research as an important tool for improving health care quality. One of the FIC’s roles is to energize ICs to participate in NASEM studies such as this.

Dr. Steve Morrison discussed a documentary by the Center for Strategic and International Studies (CSIS) that he directed titled The New Barbarianism. The film’s main focus is the surge in deliberate violence directed towards the health and humanitarian sectors across multiple open-ended conflicts. Resolutions aimed at documenting and preventing this violence are not working, and the film explores which steps should be taken to facilitate a solution. This documentary has generated a lot of international interest in the topic.

FIC has had four Fogarty at 50 events since its last meeting in areas that aren’t traditionally associated with global health. One event was an FIC session at a meeting of the American Neurological Association. Dr. Gretchen Birbeck, who attended the meeting, said that the international sessions had many attendants. Other events include sessions at the American Society of Tropical Medicine and Hygiene (ASTMH). Dr. Barbara Sina, Deputy Director of the FIC Division of International Training and Research, described these sessions. Dr. Glass attended the American Heart Association symposium, which included a presentation on global cardiology. Presentations like this are seeding the next generation of cardiologists to think on a global scale.

In November 2017, Dr. Glass spoke at a House of Representatives Foreign Affairs Committee hearing on an FIC-sponsored study of Alzheimer’s disease in Colombia. This study has developed a cohort that can be used to find biomarkers of and test new therapies for Alzheimer’s disease. This study exemplifies the value of investing in global health research.

Coalition for African Research and Innovation (CARI): Rob Eiss, Senior Advisor to the Director, FIC; Lydia Kline, Science Policy Analyst, FIC

FIC has been pushing programs to increase funding for research and training in Africa. The Directors of the NIH, Alliance for Accelerating Excellence in Science in Africa, Wellcome Trust, and the President of Global Health for the Bill & Melinda Gates Foundation have partnered to form the Coalition for African Research & Innovation (CARI). Lydia Kline explained that CARI was launched a year ago at the World Economic Forum, and aims to help develop innovative, African-led biomedical research enterprises. The focus may be expanded to include non-communicable diseases (NCDs) and changing microbial threats. CARI recently held a planning meeting in Nairobi in order to receive input from African experts on how to best facilitate improved African-led research and innovation. This meeting had 43 representatives from 12 countries across Africa. The group as a whole was supportive of CARI and gave provided ideas on how to operationalize its concept.

One such idea is to create an East African Centers of Excellence program, as having interested East African countries come together and form a hub of different centers of innovation could raise East Africa as a hotspot of biomedical innovation in the world. CARI would work with the African Development Bank in this initiative. Another idea is to collaborate with the World Bank’s International Vaccine Task Force (IVTF) and develop a regional concept to apply for IVTF funding. A third idea is to hold an African philanthropy forum to bring together African philanthropists and venture capitalists to hear implementable ideas from different scientists that can be funded.

Robert Eiss continued that CARI is a timely initiative because African governments have pledged to invest 1% of their countries’ GDP into research and development (R&D). Governments have also initiated the Science, Technology and Innovation Strategy for Africa 2024 (STISA 2024), a cross-continental strategic plan that features biomedical research as one of five priorities. CARI is working to think creatively about how to best leverage these commitments and has commissioned the London School of Economics (LSE) to do a series of case studies of countries that have moved forward with innovation systems. Another CARI-supportive idea is for the NIH to implement a cross-continental flagship in Africa that would enlist the support of African governments and the private sector. Mr. Eiss referenced H3Africa as inspiration. There is an anticipated influx of product trial investment in Africa over the next five years, which could be a good opportunity to build clinical and translational science capacity in Africa. NIH has formed two working groups to explore these ideas and develop more.

Continuation of Director’s Update and Discussion of Current and Planned FIC Activities

Dr. Glass thanked Dr. Judy Wasserheit for her work with the Afya Bora Consortium at the University of Nairobi. Kenyan institutions and the NIH have collaborated for 30 years. In 2017, there were 139 NIH grants in Kenya from a diverse set of ICs. Representatives from different ICs flew to Kenya for a meeting on January 22, 2018. Unfortunately, due to a U.S. government shutdown, these representatives had to fly back to the U.S. before this meeting occurred. Although the representatives were able to meet their counterparts and collaborators, they were unable to participate in the meeting or conduct any site visits. Due to interest from the representatives, work is being done to restage this meeting for next year.

Dr. Glass shared bits of the presentation that he was going to make at this meeting. Over the past 20 years, the amount of NIH grants per year and IC involvement in Kenya has risen, and the focus on HIV has decreased to include other topics. These new partnerships helped create a fivefold rise in medical literature publications, of which NIH IC research represent about 20%. Databases showing institutional and individual co-authorship networks can be analyzed to show the patterns of the spread of knowledge within Kenya. Medical research and HIV interventions have also helped raise life expectancy in Kenya. Dr. Glass asked members to encourage grantees to apply for grants with the African Association for Health Professions Education and Research and the Health-Professional Education Partnership Initiative. Applications for both are due March 28, 2018.

Both of the winners for the Prince Mahidol awards in basic science or global health were NIH grantees or researchers. Dr. Eric Green accepted the award for the Human Genome Project, and Drs. John Robbins, Rachel Schneerson, Porter Anderson, and Mathu Santosham received the award for work on the Hib vaccine. Dr. Glass discussed different FIC grantees that he met at the Prince Mahidol Award Conference.
NIH’s World RePORT recently released its new data for 2017. This data covers all of NIH’s investments in global health. NIH is working to incorporate other databases into this website, which allows research to be looked up by topic and/or country.

In light of its 50th anniversary, Dr. Glass asked where the Center should be going for the next 10, 20, or 50 years. Drs. Paul Drain and King Holmes recently wrote an article for Clinical Infectious Diseases detailing FIC’s accomplishments and exploring possible priorities for the next 50 years. Dr. Glass believes that FIC can make a huge impact by investing in current partnerships and training fellows to be future leaders. Dr. Holmes said that anti-microbial resistance (AMR) is an area that many people want FIC to prioritize.

FIC members will be participating in panels at the Consortium for Universities for Global Health (CUGH) conference from March 16-18, 2018. On May 1st, 2018, FIC will be holding its 50th Anniversary Symposium. The symposium’s sessions will bring together IC directors and global health grantees, and will cover topics such as NCDs, HIV/AIDS research, and global mental health research.

Last year, FIC was zeroed out in the White House’s proposed budget. However, FIC has been given funding in the White House’s 2019 proposed budget.

The next FIC Advisory Board meeting will be April 30-May 1, 2018, and the subsequent meeting is scheduled for September 6-7, 2018. Dr. Glass thanked Junaid Razzak for his work in developing global emergency medicine sessions for the upcoming American Society of Emergency Medicine meeting.

Center for Global Health Studies (CGHS) Update: Nalini Anand, Director, Division of Science Policy, Planning and Evaluation (DISPPE); Director, CGHS; Dr. Rachel Sturke, Deputy Director, DISPPE; Dr. Amit Mistry, Senior Scientist, DISPPE

Nalini Anand presented on FIC’s Center for Global Health Studies (CGHS). CGHS does not work with grants but does work with the grants division to complement their actions. CGHS works to convene different ICs around concrete global health challenges.

Rachel Sturke discussed the CGHS’s Adolescent HIV Prevention and Treatment Implementation Science Alliance (AHISA). AHISA held implementation science training on January 17-19, 2017 in Johannesburg. This training was developed through an FIC supported collaboration between UNC and the University of Witwatersrand and was funded by the Center for Global Health Studies. Fourteen AHISA teams were represented at this training, including NIH-funded PIs and in-country partners. Many AHISA members are interested in more training. Potential next steps include holding train-the-trainer training and a research priority setting exercise. AHISA’s purpose is to bring together funded PIs, policymakers, and program implementers to move implementation science in adolescent HIV prevention and treatment forward. Dr. Sturke said that NIH can still build capacity in implementation science, even among implementation scientists. Dr. Wilson asked if funders have asked for AHISA to be expanded. Dr. Sturke said that AHISA has applied to expand its network but that she has not heard of demand from funders. Dr. Wasserheit asked if there are thoughts to bring ministry-level policymakers into AHISA’s future trainings. She commented that it would be useful to discuss implementation science as a future priority for FIC. Dr. Sturke responded that the goal is to further hone and adapt the training and bring it to ministries.

Amit Mistry presented on CGHS’s newest project, Health Research in Humanitarian Crises. The goals of this project are to explore ways to catalyze more and better research during humanitarian crises and to encourage uptake of research and evidence into humanitarian policy and practice. To inform this project, CGHS consulted with researchers, NGOs, UN agencies, and US government agencies, and formed a planning committee composed of several researchers from the US and from low- and middle-income country (LMIC) institutions. This project is initially taking a broad look across different humanitarian crises in order to identify important cross-cutting issues. Areas of interest include: research methodologies, implementation science, research capacity, humanitarian-researcher partnerships, and the inclusion of communities and affected populations in research. CGHS will be holding a small workshop in April 2018 to share learning, identify gaps, and consider what would be the most appropriate deliverable for this project.

CGHS will soon be conducting a 5-year review in order to understand past successes and to create priorities for the future. The review will inform FIC, NIH partners, and future partners. Dr. Glass thanked Ms. Anand and the rest of the CGHS team for their work.

Pakistan Biosecurity Initiative Update: Dr. David Spiro, Director, Division of International Epidemiology and Population Studies (DIEPS)

Dr. David Spiro presented on a recent Pakistan Biological Safety Association (PBSA) meeting. Since 2014, FIC and PBSA have partnered to develop a biosafety and biosecurity training program throughout Pakistan. People across Pakistan attended this meeting and associated biosafety and biosecurity trainings. The training is country and region-specific and is rapidly growing in popularity. A national biosafety training center will be built in Islamabad over the next year.

FIC Communications Update: Ann Puderbaugh, Communications Director, FIC

Ann Puderbaugh spoke about FIC’s communication activities and priorities. FIC is always working to expand its community, explore new platforms, and develop new content and resources. Website traffic did level off during FIC’s period of funding uncertainty but fortunately is now back on track. FIC produces the Global Health Matters newsletter as well as Funding News, a weekly e-product that provides global health highlights from the NIH Guide. FIC’s total subscriber base is now 53,000. Total email subscribers continue to grow by about 15% each year. FIC provides annual updates on CGHS programs and achievements. During the period of budget uncertainty, FIC updated internal and external stakeholders with positive developments. FIC has been able to reach a different audience through social media and is therefore working to improve its visuals for these platforms. FIC has developed a searchable database of current grants and new printable fact sheets with targeted messaging, both of which can be found on FIC’s website. Content commemorating FIC’s 50th anniversary is still in development. Future plans include rebuilding the FIC website and making improvements for mobile users. Ms. Puderbaugh thanked her team for their work.

Global Health Priorities Now and in the Future

Dr. Glass asked participants to brainstorm innovations and priorities that FIC can pursue in the next 10, 20, and 50 years. Dr. Myron Cohen said that FIC should focus more on collaborating with industry. Industry can play an important role in helping to develop and train human capital, which in turn would save FIC money. Dr. Robert Einterz believes that FIC is already on the right track and that there are opportunities to bring up more sustainable, collaborative, and entrepreneurial academic partnerships. FIC should prioritize universal health coverage by leveraging its network of universities to develop more effective and efficient healthcare delivery systems. John Monahan said that FIC should work to cultivate a network of innovators around the world, both by creating new partnerships and by investing in current partnerships. FIC should remember that it is publically funded and continue to promote the value of global health research to that public. Dr. Vikas Kapil said that FIC should explore partnerships with international institutions in order to promote population health and implementation science. Dr. Kapil also said that FIC should keep in mind public health challenges that contribute to NCDs, such as air pollution.

Dr. Gregory Germino said that FIC should foster communication between U.S. and international institutions in the area of diabetes and chronic kidney disease research. Dr. Olugbenga Ogedegbe said that FIC should invest in building research capacity efficiently and wisely. Interregional collaboration should be emphasized and the focus should be broadened beyond diseases. Dr. Janine Clayton said that FIC should develop a framework for facilitating partnerships that moves beyond facilitating communication. She believes FIC’s richest resource is its community and network of trainees. FIC should also prioritize research around maternal morbidity, mortality, and health. Maternal health should be viewed as a predictor of future health for women. Discussions around NCDs should also include maternal health. Dr. James Curran believes that FIC is headed in a good direction for the next 10 years and would rather focus on priorities for the next 20-50 years. He said that in order to maintain dominance in biomedical science in an increasingly post-American world, FIC may need to leverage international partnerships and become less dependent on U.S. government funding. Dr. Mary Wilson said that due to the rise of urbanization, FIC should focus on research to create safe and healthy urban environments. Dr. Steve Morrison said that FIC should consider focusing on fixing its chronic weaknesses, which include problems with funding, branding, and a lack of champions. He agreed that FIC should continue to brand itself as an essential part of forging international partnerships in areas of global health, and said that FIC should explore funding and leadership support from both Congress and the NIH.

Dr. Gretchen Birbeck said that FIC should reach out to small and emerging programs to help develop cohesive ideas around curricula and framework in order to address the issue of well-intentioned but ill-prepared students doing global health work. Dr. King Holmes encouraged members to read Disease Control Priorities 3, which focuses on practical actions for health in LMICs. He discussed NASEM’s recent study titled “Global Health and the Future Role of the United States.” This study has 14 recommendations, some of which include: improving international emergency response coordination, combating AMR, building public health capacity in LMICs, improving digital health infrastructure, and optimizing resources through smart financing. Dr. Holmes believes that another priority should be to confront and treat hepatitis C, for which there is now treatment. Dr. Judy Wasserheit recommended that FIC focus less on disease- and population-specific targets and focus more on how to work with countries and implement evidence-based best practices through a research and evaluation lens. She recommended that FIC explore how it could incentivize U.S. universities to approach international and domestic partnerships differently. She said that in many places, there will need to be a shift from acute episodic care to chronic care. FIC should examine how to approach systems of primary healthcare, which will be the entry point. Finally, she said that FIC should explore how the rise of technology and robots will affect global healthcare jobs. Dr. Glass said that FIC is exploring the idea of industry partnerships. By partnering with companies, researchers can get funding to create innovative products and services. Dr. Glass thanked everyone for their thoughtful ideas and guidance and looks forward to continuing these important discussions.

Malnutrition and Enteric Disease Study (MAL-ED) Session
Dr. Stacey Knobler, Scientific Program Director, Division of International Epidemiology and Population Studies (DIEPS)

MAL-ED is funded by the Bill and Melinda Gates Foundation, and explores the interaction between malnutrition, enteric diseases, and their influence on cognitive development. Although there have been significant advances in reducing mortality and morbidity in children under five in most of the developing world, there is still a significant gap in the extent to which these children are achieving their full potential. MAL-ED’s initial goal was to find out what was contributing to this gap by answering this question: how do various and potentially synergistic environmental exposures early in life conspire to continue to affect subsequent growth and development outcomes in children in LMICs? MAL-ED had eight different field sites, which represent geographic and cultural diversity as well as different rates of mortality due to diarrhea at the start of the study. MAL-ED is an observational, prospective birth cohort study that utilized harmonized protocol, SOPs, and data collection forms. MAL-ED relied on local laboratory capacity and has helped build an enhanced platform for child development studies at these different sites. Centralized data management allowed for rigorous quality control procedures to be implemented both at the sites and at the FIC Data Coordinating Center. Enrollment was staggered so as to capture potential seasonal effects. Phase 1 of MAL-ED consisted of twice-a-week surveillance of enrollees for the first 24 months of life. Phase 2 consisted of monthly follow-up visits monitoring development from 36 to 60 months of life. These two phases provided data that allows researchers to understand how early exposures have the potential to significantly impact people later in life. MAL-ED has fostered lots of successful collaboration. Dr. Knobler thanked the 110 global co-investigators and 2,000 children and families involved in MAL-ED as well as the Gates Foundation.

Dr. Dennis Lang, Foundation for NIH

Dr. Lang discussed some of the surprising microbiology findings in MAL-ED. Using classical techniques, researchers found a high amount of pathogens in children’s non-diarrheal stool samples, which means that although these children may have looked healthy, they were carrying around a huge burden of enteric pathogens. Pathogens examined include bacteria, enteric viruses, and parasites. Researchers examined over 40 different pathogens. The Gates Foundation also awarded a grant to Dr. Eric Houpt from UVA to examine these samples using a real-time polymerase chain reaction (PCR) assay with TaqMan technology. The PCR assay showed the presence of several enteric viruses that were not prevalent in the findings from the classical techniques. When non-diarrheal stools were compared between children in Bangladesh and children in Virginia, pathogens were found in both. However, the magnitude of the pathogens found in the Bangladeshi children’s stools was about eightfold. The sample size for this comparison was small. Dr. Lang believes there is an opportunity to research what normal, non-diarrheal stool consists of in different populations, including healthy ones. This data currently does not exist.

MAL-ED data shows that, across all 8 sites, a pathogen was first detected in children’s stools within the first six or seven months of life. Many children were found to be infected within one month of life. However, despite these pathogens, many children (particularly in South Africa and Brazil) don’t get diarrhea. The data shows that the pathogen burden in these children does not decrease with age, which indicates that the children are developing immunities to these pathogens.

Researchers explored the effects of pathogens that are not recognized in any known illness symptom. MAL-ED hypothesized that damage to the intestine may contribute to longer-term negative effects on nutrition, growth, immune response to oral vaccines, cognitive development, et cetera. Many children were found to be carrying around an undetected pathogen burden. However, these negative effects could be caused by more than this undetected pathogen burden. For example, chemical pollutants and disruption of the intestinal tract’s helpful microbiome could be contributors. Dr. Lang emphasized the following take-home messages: 1) MAL-ED found early and frequent infections with enteric pathogens, many of which are asymptomatic; 2) there are frequent co-infections; 3) enteropathogen detection results from MAL-ED standard assays and TaqMan are largely similar, with some expected differences; 4) most diarrheal episodes were of short duration; and 5) enteropathogens pose a significant and previously unrecognized threat to child health in LMICs, which suggests the need for a multi-faceted approach to reduce exposure. Dr. Lang suggested potential future studies with MAL-ED data and samples, such as examining antibiotic resistance of bacterial pathogens and measuring immune response to infection.

Dr. Laura Caulfield, Johns Hopkins University

Dr. Caulfield discussed the relationship between nutrition, enteropathogens, gut function, and growth in the first two years of life. Researchers have known for some time that malnutrition results from the single and combined effects of poor diets and high morbidity. There is an increasing body of evidence showing that enteropathogens outside of diarrheal experiences and exposure to certain pathogens can negatively impact the growth velocity of children. MAL-ED was interested in evaluating the effects of enteropathogens, diarrhea, and poor dietary intake on the growth velocity of children and whether exposure to specific pathogens matters. It was also interested in exploring whether gut dysfunction mediates these effects and helps explain the relationship between enteropathogens, poor dietary intakes, and differential outcomes in children. Data across MAL-ED sites generally shows a growth faltering as compared to the WHO standards.

MAL-ED utilized a piecewise cumulative spline model to evaluate the effects of enteropathogens and dietary intakes on growth velocity over time. This model accounts for changes in growth velocity over time and time-specific influences on growth, and can be used to show persistent and cumulative effects. Data from the British Medical Journal (BMJ) indicates that reducing the pathogen burden in non-diarrheal stools from high to low could result in improvements in size at 24 months of age. MAL-ED findings show that enteropathogen exposure negatively impacts the growth of involved children and the burden of disease is underestimated globally. Markers of gut dysfunction were not identified as key mediators affecting growth, although there is evidence of a relationship between gut dysfunction and growth. A dietary pattern involving breastfeeding, the regular inclusion of animal milks, and a higher protein density from complementary foods positively affected the children’s growth overall. However, results don’t show protein deficiency to be the problem. Rather, higher protein content tends to be evidence for a higher-quality diet. MAL-ED is currently working to understand indicators of gut function and whether they mediate the association between micronutrient intake and micronutrient status. MAL-ED is also working to evaluate nutrient components and systemic inflammation in order to identify an anti-inflammatory diet. MAL-ED data can be used to characterize dietary factors as they relate to gut microbiomes. Future studies also include examining how early exposures affect growth beyond age 5.

Dr. Laura Murray-Kolb, Penn State University

Dr. Murray-Kolb presented on the MAL-ED data on early-life risk factors and later cognitive development, specifically from birth to 24 months. MAL-ED followed best practice guidelines for assessing child development by assessing multiple domains and using multiple sources. Data was collected on children’s global development, language skills, motor development, socio-emotional skills, and home environment. Maternal depressive symptoms and cognitive skills were also assessed. The study addressed whether early life enteropathogen burden is related to child cognitive development at 24 months of age. MAL-ED researchers hypothesized that repeated early-life enteric infections would negatively impact cognitive development and that children with a lower weight at MAL-ED enrollment would be more susceptible to the negative consequences of enteric infections. Researchers worked to account for factors in child development beyond biological factors.

Researchers found that maternal reasoning ability was directly and positively related to child cognitive development at 24 months of age and that enteropathogen detection was directly and negatively related. Hemoglobin concentration and vitamin B6 and folate intakes were found to be positively related to child cognitive development and illness was found to be negatively related. Meat, fish, and poultry protein intake was found to be negatively related to cognitive development at 24 months, which researchers plan to investigate further. Illness was found to have the biggest negative impact on child cognitive development. Researchers found that the effects of pathogen exposure were at least partially mediated by illness and hemoglobin concentration. Children with a lower weight at enrollment were found to be more vulnerable to environmental influences on cognitive development; however, children of all weights can be negatively affected. Researchers found that factors other than enteropathogens are more strongly associated with child cognition; therefore, inventions should not only target enteropathogens.

MAL-ED researchers would like to examine associations between the microbiome and child development outcomes. The different MAL-ED sites have expressed interest in continuing to follow up on these children if the funding is available. Researchers would like to assess the children at 10-12 years of age and collect other outcome variables.

Discussion
Lead Discussant: Dr. Maureen Black, University of Maryland
IC Discussants: NINDS, NICHD, NIAID, and others

Dr. Black discussed the context of child development in 2018. There have been major advances in child development in terms of neuroscience, epidemiology, and more. A current challenge in the field is how to measure child development. Research has found that children need nurturing care early in life. Nurturing care includes health, nutrition, responsive caregiving, opportunities for early learning, and protection from environmental threats. WHO has developed an early childhood action network, which is in the process of launching nurturing care as part of the World Health Assembly this year. There is an increasing global emphasis on examining children ages 0 to 3. In this context, MAL-ED is a global treasure and one of a kind.

Dr. Nina Schor, Deputy Director of NINDS, spoke next. She expressed amazement that all this data was collected despite language, dialect, and literacy barriers. She said that in the early years of life, the main changes in a child’s brain have to do with myelination and connectivity. She commented on the complexity of the data and was curious about the possible impact of cultural views and perceptions of illness on child development. Dr. Glass asked if using an imaging or functional test would help link together verbal tests of cognition development. Dr. Schor responded that an imaging test has the potential to do this.

Dr. Curran asked if MAL-ED plans to follow enrollees to adulthood. He asked if MAL-ED would recommend any interventions for the factors that are adversely connected to growth and cognitive development. Dr. Caulfield responded that in light of the finding that enteropathogens found in non-diarrheal stool affect both growth and cognitive development, researchers need to think of ways to reduce that exposure. She referenced studies that explored interventions, such as improved complementary feeding and reduced exposure to enteropathogens through improvement of the hygienic environment. Unfortunately, these studies didn’t find an impact. Researchers need to discover how to approach improved hygiene as an effective intervention against enteropathogen exposure. Although improved complementary feeding does show a positive impact on growth and development, the results are too low given the amount of effort put into this intervention. MAL-ED needs to examine how to improve breastfeeding practices and the protein density of children’s diets from non-breast milk foods. Dr. Curran asked about widespread antibiotic distribution as an intervention. Dr. Caulfield responded that MAL-ED data indicates that many people have access to antibiotics and that this is a possible intervention. However, data showed that diarrheal episodes with no known antibiotic treatment had a negative impact on children’s growth.

Dr. Wasserheit asked if MAL-ED plans to look at the exceptionally positive cases in the cohort. Dr. Murray-Kolb responded that one idea is to cluster the children based on different characteristics. The overall goal is to explore optimal development for any given child, and so both positive and negative cases need to be examined. Dr. Glass asked about the possibility of collecting data on these children past age 5. Dr. Black said that researchers need to follow up on these children past the age of 5 in order to fully understand the interaction of the negative and positive effects of different factors. Dr. Glass asked Dr. Vesna Kutlesic, Director of the Office of Health Equity at NICHD, if NICHD has followed other cohorts like the MAL-ED cohort. He asked if NICHD finds the MAL-ED cohort useful to study. Dr. Kutlesic responded that NICHD’s primary cohort only follows children for the first month of life. She thinks MAL-ED is a unique cohort and supports learning about long-term outcomes.

Dr. Christopher Lynch, Director of the Office of Nutrition Research at NIDDK, asked if MAL-ED collected samples of human milk. Dr. Lynch referenced studies that associate certain hormones in breast milk with healthy GI tract function. Dr. Caulfield responded that MAL-ED didn’t collect milk samples. However, sites that interfaced with the NIH Human Microbiome Project did collect fecal and milk samples from the mothers. MAL-ED collected blood and/or saliva samples from mothers for potential use in future DNA studies. Dr. Lynch asked if MAL-ED found any correlations between child growth and a country’s fortification and supplementation practices. Dr. Caulfield responded that MAL-ED did create food composition tables for each site. By and large, the children were not exposed to a broad variety of public health programs.

Dr. Glass asked if MAL-ED provides any evidence that supports the need for aggressive interventions to prevent development stunting. Dr. Murray-Kolb responded that current analyses do not strongly support the idea that addressing stunting will automatically improve child cognitive development. Dr. Holmes asked if MAL-ED looked at the immune response of children based on their feeding patterns and how this would affect their response to vaccines. Dr. Lang responded that research is currently being done that examines this question. Ms. Knobler said that so far, the data doesn’t support the conventional idea that there are significant differences between oral and parenteral administration of vaccines. Dr. Caulfield said that MAL-ED has shown a light on the complexity of the relationship between breast milk and biomarkers of children’s gut health.

Dr. Maria Giovanni, Director of the Office of Genomics and Advanced Technologies at NIAID, commented on the importance of the complexity of the dataset and advocated for more predictive analyses to be done on that dataset. Dr. Shahida Baqar, Program Officer for the Enteric and Hepatic Diseases Branch of NIAID, said that surveillance needs to be done with the understanding that diarrheal disease can be caused by more than one pathogen at a time. Dr. Lang agreed and commented that pathogens can interact to create results that are different from those of any of the pathogens by themselves.

Closing Comments

Dr. Glass summarized the day’s meeting and thanked members for their ideas and thoughts. He said that although the funding has run out for the initial study in MAL-ED, the collected samples and data are incredibly valuable for future studies. Creating an inventory of the samples and data would make it more accessible to different ICs. He thanked members and participants for their work.

Adjourn

There being no other comments, Dr. Glass adjourned the meeting at 2:59 p.m.