AADR submits comments on inclusion of pediatric research in All of Us Research Program

AADR has submitted comments in response to request for public input on the inclusion of pediatric research in the All of Us Research Program, formerly the Precision Medicine Initiative. Currently, children are excluded from the All of Us Research Program, along with prisoners and adults who are unable to give consent. The Child Enrollment Scientific Vision Working Group of All of Us requested input on the types of research questions that could be answered with the enrollment of children. AADR submitted the following comments in response:

Question 1
What are the most critical short-, medium-, and long-term precision medicine research questions that could be addressed by the inclusion of pediatric populations in the All of Us Research Program?

Short term (0-5 years)

Orofacial clefts affect 1/700 live births and are associated with environmental, dietary and genetic factors. Future studies should integrate genetics with cleft phenotypes, identify and describe the contribution of candidate genes and describe the interaction between genetic and environmental risk factors (Parker SE et al. 2010. Birth Defects Res A Clin Mol Teratol. 88(12):1008-16; Dixon MJ et. 2011. Nat Rev Genet. 12(3): 167-178; Li C et al. 2017. JDR 96(11): 1184 – 1191). Childhood dental caries remain a public health concern marked by pronounced health disparities. There is evidence of heritability of dental caries but few known associated loci (e.g., ACTN2) and polymorphisms (Stanley BO. 2014. JDR 93(7):626-32). The strength of the evidence supporting these associations is limited due to small sample sizes and reliance on candidate-gene study designs. Researchers currently do not understand the magnitude and the mode of influence of these loci and polymorphisms on caries risk in children (Divaris K. 2017. Dent Clin N Am. 619-625), especially in the context of environmental factors like fluoride exposure (Shaffer JR et al. 2015. Hum Genet. 134(2):159-67). Understanding the composition and function of the oral microbiome in health and disease will also help investigators precisely dissect the etiology of caries on an individual level and lead to more effective preventive and therapeutic modalities.

Medium (5-10 years)

In 5-10 years, All of Us could help scientists understand the genetic, lifestyle and environmental factors that contribute to oral health disparities in children and that are not completely explained by differences in socioeconomic status. A better understanding of the biological underpinning of oral and craniofacial conditions in children can help explain how social deprivation and other upstream factors can have such profound impact on multiple, clinical oral health endpoints. For example, All of Us could help elucidate the impact of genetics and epigenetics (a mechanism that may illuminate previously uncharacterized links between social factors, environmental exposures and biological or clinical outcomes) on intermediate oral and craniofacial phenotypes such as tooth anatomy, salivary factors, the oral microbiome as well as directly on oral disease susceptibility (Divaris K. 2016. JDR 95(3):248-254).

Long (more than 10 years)

Understanding how oral health and disease develop over time requires longer follow-up periods than what is typically feasible with a research project grant. The inclusion of pediatric research in All of Us will enable longitudinal studies of oral and craniofacial health among large, population-based samples. Gaps in knowledge that need to be addressed include the impact of craniofacial developmental diseases, such as cleft lip/palate and enamel hypomineralization and hypoplasia, on susceptibility to or exacerbation of other diseases; common risk factors between oral and other diseases leading to common prevention and treatment strategies; the quantification of risk for certain oral diseases like dental caries (Divaris K. 2016. JDR 95(3):248-254); caries progression from ages 0-18; and oral health across the lifespan. The health of children with complex medical conditions or with cancer can be further compromised when they have untreated caries lesions. The development of effective means for the prevention or management dental caries among this and other pediatric populations with special health care needs is critical.

All of Us should collect and bank saliva and other biological specimens (e.g., plaque) to enable genetic and microbiome analyses, as well as studies on how salivary factors change from infancy over the life course. Saliva collection methods for valid downstream omics (e.g., genomics, microbiomics and proteomics) analyses in very young children need to be studied.

Question 2

What are the key gaps in current pediatric study designs that might be appropriate for All of Us to address through the enrollment of children (for example, preconception studies, sibling studies)? 

All of Us should enroll families and follow these family cohorts over time. Children are subject to the behaviors, environment and resources of their caregivers, e.g., caregiver oral health literacy is associated with the oral health status of the child (Vann WF et al. JDR. 89(12):1395-400).  Maternal periodontitis treatment may improve low birth weight, but the evidence is low quality (Iheozor-Ejiofor Z et al. 2017. Cochrane. (6)) due to study sizes and possibly treatment intervention at the end of the first trimester versus preconception.

All of US should include community-based participants, i.e., individuals enrolled regardless of health or disease status. Oral and craniofacial research has relied on case-control study designs or clinic-based samples, but these designs are subject to numerous biases.

All of Us should enroll racially/ethnically diverse children from younger age groups. Precision oral health studies (e.g., genome-wide association studies) have been mostly conducted in children of European decent and have included few children under the age of 6, the cutoff age for early childhood caries. Many studies of oral diseases have also been conducted in small cohorts or clinical (care-seeking) samples. A larger, diverse pool of community-based (not necessarily care-seeking or clinic-attending) participants can alleviate previous challenges with low statistical power, validity, reproducibility and generalizability (Divaris. 2017. Dent Clin N Am. 619-625).

Question 3
What are the research resources that the inclusion of children into the All of Us Research Program could potentially generate (for example: registries, databases, or innovative methods)?

The data generated from All of Us will enable the refinement, validation and ultimately improvement of current caries risk assessment tools (Divaris K. 2016. JDR 95(3):248-254) and the generation of more precise algorithms for the prediction of disease occurrence, time to disease development, and disease severity as well as methodologies in genetics and social and behavioral research. The dental research community will greatly benefit from using samples stored in biobanks for future research. The inclusion of pediatric research in All of Us will enable hypothesis generation and testing for future research. It is expected that the availability of such rich biorepositories (offering opportunities for ‘deep phenotyping’) and other big data sources (allowing ‘wide’ research explorations) will accelerate scientific discovery and the potential for translation of research findings to meaningful, individual and population health-improving solutions in the oral and craniofacial domain.


AADR Comment on Prenatal Fluoride Exposure Study in Mexico

AADR Comment on “Prenatal Fluoride Exposure and Cognitive Outcomes in Children at 4 and 6–12 Years of Age in Mexico” by Bashash, M. et al. in Environmental Health Perspectives published online September 19, 2017

The findings reported by Bashash et al. add to the scientific literature on associations between fluoride exposure and cognitive outcomes. Their epidemiologic study using 299 mother-child pairs in Mexico examined maternal urinary fluoride levels, as a proxy measure of pre-natal fluoride exposure, and two measures of cognitive outcomes in their children at age 4 and 6 -12 years. Their findings must be taken into context with previous studies, including the New Zealand Dunedin longitudinal study that did not find an association between fluoridated water and IQ.

It is also important to note that Bashash et al. used data from a longitudinal birth cohort study in Mexico (ELEMENT) originally designed to examine how environmental exposures to metals and other chemicals affect pregnant women and children, and not to examine the specific relationship between fluoride exposure and cognitive development. The current study is examining samples of urine from two cohorts, the first to investigate prenatal lead exposure (1997-2001) and the second, the effect of calcium supplementation (2001-2006). As an examination of fluoride was not part of the original study design, there are no data on total fluoride intake by the pregnant mothers or their children, other than the fact that Mexico does not have community water fluoridation. Exposure to fluoride would be from naturally occurring in water supplies, fluoridated salt, and other dietary and environmental sources.

Some places in Mexico with high concentrations of naturally-occurring fluoride in water also have high concentrations of arsenic, a known neurotoxin. As the authors noted, information regarding the study population’s exposure to arsenic or other environmental toxins was not available, and therefore, could not be ruled out as a confounding variable. Given such lack of exposure data, among other limitations clearly cited by the authors, the results should not alter current policy recommendations on the use of fluorides for caries prevention.

The AADR concurs with Bashash et al. that the ability to extrapolate their findings to how exposures may impact general populations is limited given the lack of data on fluoride exposure and fluoride pharmacokinetics during pregnancy. The authors conclude that their findings must be confirmed in other populations. The AADR agrees with the authors that these findings reinforce the need for additional research.

AADR notes that fluoride has been an important tool in reducing the prevalence of dental caries in the United States. Specifically, the Centers for Disease Control and Prevention named community water fluoridation one of the top 10 public health achievements of the 20th century. Other fluoride interventions include the application of topical fluorides including fluoride varnish, the use of fluoride supplements and fluorides in toothpaste. As a result, caries prevalence in children has been reduced dramatically as has the number of older adults with total tooth loss in the United States.

Senate appropriations committee approves $2 bil NIH increase for FY 2018

Today, the Senate Appropriations Committee approved a $2 billion increase in the budget of the National Institutes of Health (NIH) to $36.1 billion for FY 2018. If enacted, this would constitute a 6% increase over FY 2017. The Senate spending bill includes $400 million for the BRAIN initiative, a $140 million increase; $290 million for the All of Us Research Program, a $60 million increase; and increases to to every NIH institute and center, according to the Senate Appropriations press release. Importantly, the bill also prohibits capping indirect costs at 10%.

Earlier this summer, the House Appropriations Committee approved a spending bill that only provided an additional $1 billion – a 3% increase. The National Institute for Dental and Craniofacial Research (NIDCR) received a $6 million increase in this bill, only a 1.6% increase over FY 2017 levels.

Update: The Senate Appropriations Committee has released the bill text. The spending bill provides for an additional $14 million over FY 2017 for NIDCR, which is a 3% increase over FY 2017.

AADR submits comments on NIDCR FY 2019 proposed research initiatives

AADR has provided input on the National Institute of Dental and Craniofacial Research’s (NIDCR’s) Proposed Research Initiatives for FY 2019. Each year, NIDCR solicits input from its stakeholders as the institute decides on which areas to focus research efforts for future fiscal years. The research themes outlined in the request for comment will be used to guide research initiatives for FY 2019 but do not fully capture the entire research portfolio of NIDCR. Instead these initiatives serve as research goals for the institute and can be further developed into funding opportunities. The proposed initiatives are:

  • Advancing Our Understanding of Enamel Development
  • Basic and Translational Research on HIV and AIDS-Related Pathogens in the Oral Cavity
  • Bioinformatics/Data Science Jumpstart for Dental, Oral, and Craniofacial Diseases
  • Biological Factors Underlying Dental, Oral, and Craniofacial Health Disparities
  • Biology of Aging in Dental, Oral, and Craniofacial Tissues
  • Dental Practice-Based Research Networks
  • FaceBase 3 – Bioinformatics and Data Management Hub
  • Precision Imaging of Oral Lesions
  • Understanding Gene-Environment Interactions in Dental, Oral, and Craniofacial Diseases

In its letter to NIDCR Director, Dr. Martha J. Somerman, AADR strongly supported the proposed initiatives. AADR also urged NIDCR to incentivize collaboration between researchers and provided additional feedback on the proposed initiatives on enamel development, HIV/AIDS and precision imaging of oral lesions. To view the full comments, please click here.

AADR joins over 100 organizations to oppose cuts to indirect costs

AADR joined over 100 organizations to oppose the 20% cut to the National Institutes of Health (NIH) budget and the reduction in NIH support for indirect research costs proposed in President Trump’s FY18 budget request. From the letter:

Conducting high-quality medical research for our country carries expenses, including essential costs for maintenance and development of state-of-the-art labs, utilities such as precision climate control, security protections for handling dangerous chemicals, proper disposal of hazardous waste, and personnel to support required administrative and compliance work, among others. It simply is not possible to carry out medical research without incurring such expenses, and NIH support for F&A helps offset a portion of these real research costs.

Please click here for the full text of the letter sent to Mick Mulvaney, Director of the Office of Management and Budget, and Dr. Tom Price, Secretary of the Department of Health and Human Services.

Trump releases R&D priorities for FY19

President Trump has released his research and development (R&D) priorities for FY19 in a memo from Office of Management and Budget (OMB) Director Mick Mulvaney to executive agency heads. The memo specifically mentions the aging population, the opioid crisis and research that leads to “more efficient and effective healthcare” as top health research priorities. The memo also prioritizes STEM education and workforce development for all Americans, specifically mentioning women and other underrepresented groups.

This is President Trump’s first memo outlining his scientific priorities. The Obama administration’s first memo on science and technology was similarly light on specifics but included more detailed initiatives in subsequent years, such as the BRAIN Initiative, combating antibiotic resistance and the Precision Medicine Initiative. However, the memo is in stark contrast to President Trump’s FY17 and FY18 budget proposals, which each proposed severe cuts to the National Institutes of Health (NIH) and other health agencies.

Other priorities outlined in the memo do give cause for concern. First, the emphasis on budget neutrality would make it virtually impossible to grow the biomedical research enterprise. The Trump administration has previously targeted indirect, or facilities and administration, costs as a means of shrinking the NIH’s budget, and these costs may be targeted again. Second, the memo emphasizes reducing duplicative efforts across federal agencies. While this is not a new idea, it is concerning in the context of the previously proposed reorganization of NIH that would also move the Agency for Healthcare Research and Quality (AHRQ) into the NIH. Finally, the memo emphasizes the role of the federal government in basic and early-stage research and that of the private sector in late-stage, applied research, specifically stating agencies should “identify existing R&D programs that could progress more efficiently through private sector R&D, and consider their modification or elimination where Federal investment is no longer needed or appropriate”. Basic research is often the focus of federal research investments and applied research is taken up by the private sector, but in the context of President Trump’s previous budget proposals, this may indicate that the Trump administration still aims to shrink the federal research budget to make room for other priorities. Ultimately, the research community will have to wait until the release of the President’s FY19 budget proposal to fully understand how the Trump administration envisions translating these priorities into federal R&D investments going forward.

AADR will continue to monitor both formal and informal indications of the Trump administration’s federal R&D priorities and intentions and continue to engage and educate members of Congress on the importance of providing robust funding for biomedical research. Please continue to monitor the Government Affairs and Science Policy blog for how members can be engaged in these efforts.


FDA delays deeming rule deadlines; focuses on regulating nicotine

Food and Drug Administration (FDA) Commissioner Dr. Scott Gottlieb has unveiled changes in tobacco regulatory policy in addition to a new plan to reduce the addictive potential of combustible cigarettes.

In 2016, the “deeming rule” extended the regulatory authority of the FDA to all previously unregulated tobacco products. These products included e-cigarettes, cigars, hookah and pipe tobacco. The deeming rule brought newly regulated products under the provisions of the Tobacco Control Act of 2009, such as placing health warnings on packages and advertisements; prohibited the sale of newly regulated tobacco products to consumers under the age of 18; and required products on the market after February 15, 2007 to receive marketing authorization from FDA, among other regulations.

With the Commissioner’s new announcement, the deadline for submission of approval applications is extended until August 8, 2021 for combustible products and until August 8, 2022 for noncombustible products such as e-cigarettes. However, this new announcement does not affect other provisions such as the age restriction or the requirement for warning labels.

Commissioner Gottlieb also announced the Comprehensive Approach to Nicotine and Tobacco, which is a plan to reduce the concentration of nicotine in cigarettes to a “non-addictive level”. The goal is to reduce the addictive potential of cigarettes to enable current cigarette smokers to quit, reduce the likelihood that youth who experiment with cigarettes will become addicted, and shift cigarette smokers who still crave nicotine to less toxic products. This plan is only directed at reducing the nicotine concentration in cigarettes.

Going forward, the FDA will seek public comment on the risks, benefits and unintended consequences of lowering the level of nicotine in cigarettes. The FDA will also seek public comment about how flavors attract youth to tobacco products and how flavors may influence how adults switch from cigarettes to less harmful “forms of nicotine delivery”.

In the Commissioner’s public statement, he also said that during this initiative, the FDA will consider whether to exempt premium cigars from regulation.

How you can help

AADR will alert members when the FDA publishes requests public for comment on these issues. In the meantime, please send Science Policy Analyst Seun Ajiboye (sajiboye@iadr.org) information regarding the following as well as any other relevant information:

  • Previous research or public health experience with nicotine reduction in cigarettes
  • “Non-addictive” levels of nicotine in cigarettes
  • Unintended consequences of this initiative, especially regarding youth, vulnerable populations and health disparities.

FDA Comprehensive Approach to Nicotine and Tobacco Resources

AADR, research community encourages Congress to raise spending caps

The American Association for Dental Research joined over 200 organizations in a letter to House and Senate leaders encouraging them to raise the defense and non-defense spending caps established under the 2011 Budget Control Act. The letter also encourages Congress to override sequestration, which will return in 2018. This will significantly hamper scientific research. From the letter:

Whether the challenge before us is fiscal, economic, health or security-related, Americans do not acquiesce to threats, we end them. Our nation must not block its own path by forsaking strategic investments. We urge you to forge another bipartisan budget deal that increases the spending caps and overrides sequestration, setting the stage for a safe, prosperous and healthy future.

The Coalition for Health Funding provides a helpful explanation of sequester here. AADR will continue to follow the FY18 appropriations process and provide updates. Please continue to follow the Government Affairs and Science Policy blog for developments.

AADR opposes tobacco policy riders in agriculture appropriations bill

The American Association for Dental Research joined with over 50 organizations to oppose tobacco policy riders in the House of Representatives Agriculture Appropriations Bill that would weaken tobacco regulation. Specifically, section 752 of the bill would exempt large and premium cigars from oversight by the Food and Drug Administration (FDA) and could provide a loophole for other tobacco products to escape regulation. Section 753 would exempt tobacco products on the market before a certain date from FDA oversight and weaken the ability of the FDA to remove non-compliant tobacco products from market. Both would weaken the deeming rule that extended the FDA’s regulatory authority to all tobacco products.

During House appropriations committee markup of the bill, an amendment was offered to strike section 753. That amendment was voted down, and the House appropriations bill was approved with the two provisions. The Senate version of the bill, however, does not include either provision.

AADR will continue to track the tobacco policy riders during the appropriations process. Please continue to check the Government Affairs and Science Policy blog for updates.

AADR joins 63 organizations to support CDC OSH

The American Association for Dental Research joined 63 other organizations to support the Centers for Disease Control and Prevention (CDC) Office on Smoking and Health (OSH). In letters sent to both the House and the Senate, health and research organizations requested $210 million in appropriations for CDC OSH, citing the financial and public health burden of tobacco use. The letter also opposed President Trump’s proposal to eliminate the office. From the letters:

OSH plays a critical role in reducing the death and disease caused by tobacco by funding activities that help to prevent youth from starting to use tobacco and help adult tobacco users to quit. For example, OSH funds the highly successful national media campaign, Tips from Former Smokers. This media campaign has motivated about five million smokers to make a quit attempt, helped approximately 500,000 smokers to successfully quit, and saved at least 50,000 people from premature death since its inception in 2012. The campaign is highly cost-effective with a cost of just $393 per year of life saved, far below the $50,000 that is an accepted benchmark for cost-effective public health programs.

AADR will continue to monitor the appropriations process and provide updates as they become available.