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.


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