Deep learning predicts DNA methylation regulatory variants in the human brain and elucidates the genetics of psychiatric disorders.

There is growing evidence for the role of DNA methylation (DNAm) quantitative trait loci (mQTLs) in the genetics of complex traits, including psychiatric disorders. However, due to extensive linkage disequilibrium (LD) of the genome, it is challenging to identify causal genetic variations that drive DNAm levels by population-based genetic association studies. This limits the utility of mQTLs for fine-mapping risk loci underlying psychiatric disorders identified by genome-wide association studies (GWAS). Here we present INTERACT, a deep learning model that integrates convolutional neural networks with transformer, to predict effects of genetic variations on DNAm levels at CpG sites in the human brain. We show that INTERACT-derived DNAm regulatory variants are not confounded by LD, are concentrated in regulatory genomic regions in the human brain, and are convergent with mQTL evidence from genetic association analysis. We further demonstrate that predicted DNAm regulatory variants are enriched for heritability of brain-related traits and improve polygenic risk prediction for schizophrenia across diverse ancestry samples. Finally, we applied predicted DNAm regulatory variants for fine-mapping schizophrenia GWAS risk loci to identify potential novel risk genes. Our study shows the power of a deep learning approach to identify functional regulatory variants that may elucidate the genetic basis of complex traits.

A multimodal deep learning model to infer cell-type-specific functional gene networks.

BACKGROUND: Functional gene networks (FGNs) capture functional relationships among genes that vary across tissues and cell types. Construction of cell-type-specific FGNs enables the understanding of cell-type-specific functional gene relationships and insights into genetic mechanisms of human diseases in disease-relevant cell types. However, most existing FGNs were developed without consideration of specific cell types within tissues. RESULTS: In this study, we created a multimodal deep learning model (MDLCN) to predict cell-type-specific FGNs in the human brain by integrating single-nuclei gene expression data with global protein interaction networks. We systematically evaluated the prediction performance of the MDLCN and showed its superior performance compared to two baseline models (boosting tree and convolutional neural network). Based on the predicted cell-type-specific FGNs, we observed that cell-type marker genes had a higher level of hubness than non-marker genes in their corresponding cell type. Furthermore, we showed that risk genes underlying autism and Alzheimer's disease were more strongly connected in disease-relevant cell types, supporting the cellular context of predicted cell-type-specific FGNs. CONCLUSIONS: Our study proposes a powerful deep learning approach (MDLCN) to predict FGNs underlying a diverse set of cell types in human brain. The MDLCN model enhances prediction accuracy of cell-type-specific FGNs compared to single modality convolutional neural network (CNN) and boosting tree models, as shown by higher areas under both receiver operating characteristic (ROC) and precision-recall curves for different levels of independent test datasets. The predicted FGNs also show evidence for the cellular context and distinct topological features (i.e. higher hubness and topological score) of cell-type marker genes. Moreover, we observed stronger modularity among disease-associated risk genes in FGNs of disease-relevant cell types. For example, the strength of connectivity among autism risk genes was stronger in neurons, but risk genes underlying Alzheimer's disease were more connected in microglia.

Genome-wide DNA methylation investigation of glucocorticoid exposure within buccal samples.

AIM: Glucocorticoids play a major role in regulating the stress response, and an imbalance of glucocorticoids has been implicated in stress-related disorders. Within mouse models, CpGs across the genome have been shown to be differentially methylated in response to glucocorticoid treatment, and using the Infinium 27K array, it was shown that humans given synthetic glucocorticoids had DNA methylation (DNAm) changes in blood. However, further investigation of the extent to which glucocorticoids affect DNAm across a larger proportion of the genome is needed. METHODS: Buccal samples were collected before and after synthetic glucocorticoid treatment in the context of a dental procedure. This included 30 tooth extraction surgery patients who received 10 mg of dexamethasone. Genome-wide DNAm was assessed with the Infinium HumanMethylationEPIC array. RESULTS: Five CpGs showed genome-wide significant DNAm changes that were >10%. These differentially methylated CpGs were in or nearest the following genes: ZNF438, KLHDC10, miR-544 or CRABP1, DPH5, and WDFY2. Using previously published datasets of human blood gene expression changes following dexamethasone exposure, a significant proportion of genes with false-discovery-rate-adjusted significant CpGs were also differentially expressed. A pathway analysis of the genes with false-discovery-rate-adjusted significant CpGs revealed significant enrichment of olfactory transduction, pentose and glucuronate interconversions, ascorbate and aldarate metabolism, and steroid hormone biosynthesis pathways. CONCLUSION: High-dose synthetic glucocorticoid administration in the setting of a dental procedure was significantly associated with DNAm changes within buccal samples. These findings are consistent with prior findings of an influence of glucocorticoids on DNAm in humans.

Effectiveness on Early Childhood Caries of an Oral Health Promotion Program for Medical Providers.

OBJECTIVES: To assess an oral health promotion (OHP) intervention for medical providers' impact on early childhood caries (ECC). METHODS: We implemented a quasiexperimental OHP intervention in 8 federally qualified health centers that trained medical providers on ECC risk assessment, oral examination and instruction, dental referral, and fluoride varnish applications (FVAs). We measured OHP delivery by FVA count at medical visits. We measured the intervention's impact on ECC in 3 unique cohorts of children aged 3 to 4 years in 2009 (preintervention; n = 202), 2011 (midintervention; n = 420), and 2015 (≥ 4 FVAs; n = 153). We compared numbers of decayed, missing, and filled tooth surfaces using adjusted zero-inflated negative binomial models. RESULTS: Across 3 unique cohorts, the FVA mean (range) count was 0.0 (0), 1.1 (0-7), and 4.5 (4-7) in 2009, 2011, and 2015, respectively. In adjusted zero-inflated negative binomial models analyses, children in the 2015 cohort had significantly fewer decayed, missing, and filled tooth surfaces than did children in previous cohorts. CONCLUSIONS: An OHP intervention targeting medical providers reduced ECC when children received 4 or more FVAs at a medical visit by age 3 years.

Absence of Fluoride Varnish-Related Adverse Events in Caries Prevention Trials in Young Children, United States.

INTRODUCTION: Fluoride varnish is an effective prevention intervention for caries in young children. Its routine use in clinical care is supported by meta-analyses and recommended by clinical guidelines, including the US Preventive Services Task Force (B rating). This report is the first prospective systematic assessment of adverse events related to fluoride varnish treatment in young children. METHODS: We determined the incidence of adverse events related to fluoride varnish treatment in 3 clinical trials on the prevention of early childhood caries, conducted under the auspices of the Early Childhood Caries Collaborating Centers, an initiative sponsored by the National Institute of Dental and Craniofacial Research. Each trial incorporated use of fluoride varnish in its protocol and systematically queried all children's parents or legal guardians about the occurrence of acute adverse events after each fluoride varnish treatment. RESULTS: A total of 2,424 community-dwelling, dentate children aged 0 to 5 years were enrolled and followed for up to 3 years. These children received a cumulative total of 10,249 fluoride varnish treatments. On average, each child received 4.2 fluoride varnish treatments. We found zero fluoride varnish-related adverse events. CONCLUSION: Fluoride varnish was not associated with treatment-related adverse events in young children. Our findings support its safety as an effective prevention intervention for caries in young children.

A Community-Based Oral Health Intervention in Navajo Nation Head Start: Participation Factors and Contextual Challenges.

Successful interventions require consistent participation by intended recipients. We utilized mixed methods to describe participation of 518 parent-child dyads enrolled in a randomized cluster trial of a 2-year oral health intervention for Head Start (HS) families across Navajo Nation delivered by native Community Oral Health Specialists (COHS). We quantitatively assessed factors that contributed to participation and qualitatively examined barriers and strategies. The intervention offered fluoride varnish (FV) and oral health promotion (OHP) activities for two cohorts (enrolled in 2011, N = 286, or 2012, N = 232) of children in the HS classrooms and OHP for parents outside the classroom. Child participation was good: FV: 79.7 (Cohort 1) and 85.3 % (Cohort 2) received at least 3 of 4 applications; OHP: 74.5 (Cohort 1) and 78.4 % (Cohort 2) attended at least 3 of 5 events. Parent participation was low: 10.5 (Cohort 1) and 29.8 % (Cohort 2) attended at least three of four events. Analysis of survey data found significant effects on parent participation from fewer people in the household, Cohort 2 membership, greater external-locus of control, and a greater perception that barriers existed to following recommended oral health behaviors. Qualitative analysis of reports from native field staff, COHS, community members, and the research team identified barriers (e.g., geographic expanse, constraints of a research trial) and suggested strategies to improve parent participation (e.g., improve communication between COHS and parents/community). Many challenges to participation exist when conducting interventions in rural areas with underserved populations. Working with community partners to inform the development and delivery of interventions is critical.

Collaboration Between Medical Providers and Dental Hygienists in Pediatric Health Care.

UNLABELLED: Basic preventive oral services for children can be provided within the medical home through the collaborative care of medical providers and dental hygienists to expand access for vulnerable populations. BACKGROUND: Because dental caries is a largely preventable disease, it is untenable that it remains the most common chronic disease of childhood. Leveraging the multiple visits children have with medical providers has potential to expand access to early preventive oral services. Developing interprofessional relationships between dental providers, including dental hygienists, and medical providers is a strategic approach to symbiotically expand access to dental care. Alternative care delivery models that provide dental services in the medical home expand access to these services for vulnerable populations. The purpose of this article is to explore 4 innovative care models aimed to expand access to dental care. METHODS: Current activities in Colorado and around the nation are described regarding the provision of basic preventive oral health services (eg, fluoride varnish) by medical providers with referral to a dentist (expanded coordinated care), the colocation of dental hygiene services into the medical home (colocated care), the integration of a dental hygienist into the medical care team (integrated care), and the expansion of the dental home into the community setting through telehealth-enabled teams (virtual dental home). Gaps in evidence regarding the impacts of these models are elucidated. CONCLUSION: Bringing preventive and restorative dental services to the patient both in the medical home and in the community has potential to reduce long-standing barriers to receive these services, improve oral health outcomes of vulnerable patients, and decrease oral health disparities.

Validation of a pediatric oral health-related quality of life scale in Navajo children.

BACKGROUND: American Indian (AI) children experience the highest rates of early childhood caries (ECC) in the USA, yet no tool has been validated to measure the impact of ECC on their oral health-related quality of life (OHRQoL). OBJECTIVE: To validate a pediatric OHRQoL scale in a preschool, rural, reservation-based AI population. METHODS: In 2011 and 2012, we measured the OHRQoL of AI children attending Head Start in Navajo Nation with the 12-item preschool version of the pediatric oral health-related quality of life (POQL) scale administered to their parents/caregivers. Parents/caregivers also reported their children's subjective oral health status (OHS) and oral health behavior adherence. Concurrently, calibrated dental examiners measured the children's decayed, missing, and filled tooth surfaces (dmfs). Validation was assessed with internal reliability and convergent and divergent validity testing and exploratory factor analyses. RESULTS: We measured the outcomes in 928 caregiver-child dyads. All children were AI and in preschool [mean (SD) child age was 4.1 (0.5) years]. The majority of children had experienced decay [dmfs: 89 %, mean (SD): 21.5 (19.9)] and active decay [any ds: 70 %, mean (SD): 6.0 (8.3)]. The mean (SD) overall POQL score was 4.0 (9.0). The POQL scale demonstrated high internal consistency reliability (Cronbach alpha = 0.87). Convergent validity of the POQL scale was established with highly significant associations between POQL and caries experience, OHS, and adherence to oral health behaviors (all ps < 0.0001). CONCLUSIONS: The POQL scale is a reliable and valid measure of OHRQoL in preschoolers from the Navajo Nation.

Does oral health goal setting during medical visits improve parents' oral health behaviors?

OBJECTIVES: The Rocky Mountain Network for Oral Health (RoMoNOH) promotes the delivery of preventive oral health services (POHS) to children receiving care at community health centers (CHCs) in Arizona, Colorado, Montana, and Wyoming. One POHS is oral health goal setting (OHGS). This study aimed to evaluate the effect of OHGS during medical visits on parent/caregiver-reported oral health behaviors (OHBs). METHODS: The RoMoNOH implementation team trained CHC healthcare providers in POHS, including caries risk assessment, oral health education, fluoride varnish application, dental referrals, and parent/caregiver oral health engagement. To promote parents' oral health engagement, healthcare providers were trained in motivational interviewing (MI) with OHGS at medical visits. To evaluate the impact of MI with OHGS on parent/caregiver OHBs, a healthcare team member invited parents/caregivers to complete a baseline survey after their medical visits. The evaluation team sent a follow-up survey after 10-14 days. The surveys measured parents/caregivers' goals, confidence in goal attainment, OHBs, and sociodemographics; the follow-up survey also measured OHGS attainment. Improvement in parent/caregiver-reported OHBs was tested with a paired t-test and unadjusted and adjusted multiple linear regression. RESULTS: In total, 426 parents/caregivers completed the baseline survey; 184 completed both surveys. OHBs, including toothbrushing frequency, stopping bed bottles, drinking tap water, and brushing with fluoride toothpaste improved over the evaluation interval. After adjusting for covariates, brushing with fluoride toothpaste (p = 0.01), drinking tap water (p = 0.03), and removing bed bottles (p = 0.03) improved significantly. CONCLUSION: MI with OHGS with parents/caregivers during medical visits has potential to improve OHBs on behalf of their children.

Differences in the Oral Health of Children with Medical Complexity.

OBJECTIVES: Children with medical complexity (CMC), a subgroup of children with special health care needs (CSHCN) with the most serious medical conditions and disabilities, are at risk for negative effects from poor oral health. CSHCN have high rates of poor oral health including cavities. This study aimed to compare oral health status between CMC and CSHCN. METHODS: This was a cross-sectional analysis of the 2016-17 National Survey of Child Health data. CMC and CSHCN were identified using validated algorithms. The primary outcome was oral health status; secondary outcomes included dental service use. Bivariate analyses compared prevalence and service use by medical complexity status. Multivariable logistic regression assessed oral health outcomes by complexity, adjusting for influencing variables. RESULTS: Of 16,178 CSHCN ages 1-17 years, 6% were CMC and 94% were non-CMC CSHCN. Compared to CSHCN, CMC had a higher prevalence of fair/poor teeth conditions (19% vs 9%; p<0.001) and higher odds for fair/poor teeth conditions after adjusting for socioeconomic factors (aOR: 1.54; 95% CI: 1.01-2.34). There was no statically significant difference between groups when assessing cavities, toothache, or receipt of most preventive dental services. CONCLUSION: 1 in 5 CMC are reported by caregivers as having poor oral health including cavities, despite high rates of receiving preventive dental services. After adjusting for socioeconomic factors, medical complexity remained associated with fair or poor teeth conditions. Understanding potentially modifiable targets could further help families of CMC prioritize dental needs and potentially reduce negative effects on overall health.

Genome-wide DNA methylation analysis in female veterans with military sexual trauma and comorbid PTSD/MDD.

BACKGROUND: Military sexual trauma (MST) is a prevalent issue within the U.S. military. Victims are more likely to develop comorbid diseases such as posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). Nonetheless, not everyone who suffers from MST develops PTSD and/or MDD. DNA methylation, which can regulate gene expression, might give us insight into the molecular mechanisms behind this discrepancy. Therefore, we sought to identify genomic loci and enriched biological pathways that differ between patients with and without MST, PTSD, and MDD. METHODS: Saliva samples were collected from 113 female veterans. Following DNA extraction and processing, DNA methylation levels were measured through the Infinium HumanMethylationEPIC BeadChip array. We used limma and bump hunting methods to generate the differentially methylated positions and differentially methylated regions (DMRs), respectively. Concurrently, we used Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome to find enriched pathways. RESULTS: A DMR close to the transcription start site of ZFP57 was differentially methylated between subjects with and without PTSD, replicating previous findings and emphasizing the potential role of ZFP57 in PTSD susceptibility. In the pathway analyses, none survived multiple correction, although top GO terms included some potentially relevant to MST, PTSD, and MDD etiology. CONCLUSION: We conducted one of the first DNA methylation analyses investigating MST along with PTSD and MDD. In addition, we found one DMR near ZFP57 to be associated with PTSD. The replication of this finding indicates further investigation of ZFP57 in PTSD may be warranted.

How many molecular layers of polar solvent molecules control chemistry? The concept of compensating dipoles.

The extension of the solvent influence of the shell into the volume of a polar medium was examined by means of anti-collinear dipoles on the basis of the E(T)(30) solvent polarity scale (i.e., the molar energy of excitation of a pyridinium-N-phenolatebetaine dye; generally: E(T) =28,591 nm kcal mol(-1)/λmax) where no compensation effects were found. As a consequence, solvent polarity effects are concentrated to a very thin layer of a few thousand picometres around the solute where extensions into the bulk solvent become unimportant. A parallelism to the thin surface layer of water to the gas phase is discussed.

Embedding Dental Hygienists into Medical Care Teams: Implementation and evaluation of a medical-dental integration approach in Colorado.

This case report describes the implementation approach and evaluation of a medical-dental integration (MDI) project in Colorado that embedded dental hygienists (DHs) into 10 medical practice settings. Through the MDI Learning Collaborative, DHs were integrated into primary care medical care practices to provide full-scope dental hygiene care to patients. Dental hygienists were trained to collect quality-improvement metrics on all encounters, including untreated tooth decay, and referred patients with restorative needs to partnering dentists. Cross-sectional, aggregated clinic-level oral health metrics were submitted monthly from 2019-2022. Descriptive statistics were used to describe the population receiving MDI care and interviews were conducted with MDI staff to describe their perspectives on this approach to comprehensive care. A logistic regression model, adjusted for time and practice, compared untreated dental caries in established vs new MDI patient-visits. From 2019-2021, integrated DHs completed 13,458 visits to low-income patients, Medicaid (70%, n=9,421), uninsured (24%, n=3,230), SCHIP (3%, n=404), private (3%, n=404), of various ages: 0-5 (29%, n=3,838), 6-18 (17%, n=2,266), 18-64 (51%, n=6,825), >65 (4%, n=529). A total of 912 visits were provided to pregnant patients. Services included caries risk assessment (n=9,329), fluoride varnish (n=6,722), dental sealants (n=1,391), silver diamine fluoride (n=382), x-rays (n=5,465) and scaling/root-planing (n=2,882). Improvement was found in untreated decay of established vs. new patient-visits in four of the practices. Dental hygienists integrated into medical teams provided full-scope dental hygiene care to patients and expanded access to dental services. Medical-dental integration (MDI) care was variably associated with reduction in untreated decay. Integrating dental hygienists into primary care medical practices has potential to improve oral health-related outcomes, however access to restorative dental care remains a challenge.

Incorporating Oral Health into Pediatric Practice: National Trends 2008, 2012, 2018.

OBJECTIVE: Oral health is a critical component of children's overall health, but past research has found that pediatricians report barriers to implementing oral health into practice. Recently, policies have further delineated the importance of oral health in primary medical care. We sought to determine how pediatricians' practices and perceived barriers related to oral health involvement have changed since 2008. METHODS: There have been 3 nationally representative, cross-sectional, oral-health-focused periodic surveys of US American Academy of Pediatrics (AAP) members who provide health supervision: in 2008 (n = 1104; response rate (rr) = 69%), 2012 (n = 646; rr = 48%), and 2018 (n = 485; rr = 48%). The surveys asked about frequency of performing oral health tasks in children 3 years and younger, self-rated ability to perform these tasks, and attitudes about and barriers to oral health involvement. Predicted values from separate multivariable logistic regression models examined the independent effect of survey year. RESULTS: In 2018, pediatricians reported they were more likely to provide fluoride varnish and dental referrals at a younger age and less likely to complete a caries risk assessment or oral examination. They reported diminished barriers to incorporating oral health into pediatric practice. Other oral health activities, notably the oral screening examination and caries risk assessment, remain underutilized by pediatricians. CONCLUSIONS: From 2008 to 2018, more pediatricians reported performing a range of oral health tasks with fewer reported barriers. Ongoing efforts are needed to increase pediatricians' attention to oral screening examinations and caries risk assessments for all pediatric patients beginning in infancy, and to promote further use of fluoride varnish.

Early Childhood Caries in Indigenous Communities.

The oral health of Indigenous children of Canada (First Nations, Inuit, and Métis) and the United States (American Indian and Alaska native) is a major child health disparity when compared with the general population of both countries. Early childhood caries (ECC) occurs in Indigenous children at an earlier age, with a higher prevalence, and at much greater severity than in the general population. ECC results in adverse oral health, affecting childhood health and well-being, and may result in high rates of costly surgical treatment under general anesthesia. ECC is an infectious disease that is influenced by multiple factors, but the social determinants of health are particularly important. This policy statement includes recommendations for preventive and clinical oral health care for infants, toddlers, preschool-aged children, and pregnant women by primary health care providers. It also addresses community-based health-promotion initiatives and access to dental care for Indigenous children. This policy statement encourages oral health interventions at early ages in Indigenous children, including referral to dental care for the use of sealants, interim therapeutic restorations, and silver diamine fluoride. Further community-based research on the microbiology, epidemiology, prevention, and management of ECC in Indigenous communities is also needed to reduce the dismally high rate of caries in this population.

Correlates of depressive and anxiety symptoms in young adults with spina bifida.

OBJECTIVE: Based on social ecological theory, this study was designed to examine the unique relationships between multi-level ecological factors and psychological symptoms in young adults with spina bifida (SB). METHOD: A sample of 61 individuals with SB, 18-25 years of age, completed standardized self-report measures of attitude toward SB, satisfaction with family functioning, Chronic Care Model (CCM) services, and depressive and anxiety symptoms. A chart review yielded SB clinical data. RESULTS: High rates of depressive and anxiety symptoms were found. Hierarchical regression analysis identified the proximal individual (attitude toward SB) and family (satisfaction with family functioning) factors as more strongly related to depressive symptoms than the distal healthcare system factor (CCM services). Self-reported pain was the only ecological factor associated with anxiety symptoms. CONCLUSIONS: Study findings provide a potential foundation for multi-factor screening of young adults with SB at risk for psychological symptoms.

Validation of Psychosocial Measures Assessing American Indian Parental Beliefs Related to Control over Their Children's Oral Health.

OBJECTIVES: To validate questionnaire items assessing American Indian (AI) parental beliefs regarding control over their children's oral health within the context of psychosocial measures and children's oral health status. METHODS: Baseline questionnaire data were collected as part of a randomized controlled trial (n = 1016) addressing early childhood caries. Participants were AI parents with preschool-age children in the Navajo Nation Head Start program. Questionnaire items assessed parental oral health locus of control (OHLOC) and agreement with beliefs indicating that they were in control of their children's oral health (internal), the dentist was in control (external powerful others), or children's oral health was a matter of chance (external chance). Exploratory factor analysis was conducted, and convergent validity was assessed using linear regression. RESULTS: Parents with more education (p < 0.0001) and income (p = 0.001) had higher scores for internal OHLOC. Higher internal OHLOC scores were associated with higher scores on knowledge (p < 0.0001), perceived seriousness and benefits (p < 0.0001), higher self-efficacy, importance, sense of coherence (p < 0.0001 for all), and lower scores for perceived barriers (p < 0.0001) and distress (p = 0.01). Higher scores for both types of external OHLOC were associated with lower scores on knowledge (p < 0.0001), perceived seriousness (p < 0.0001), and higher scores on perceived susceptibility (p = 0.01 external chance; <0.0001 powerful others) and barriers (<0.0001). Higher scores for external powerful others were associated with lower scores for importance (p = 0.04) and sense of coherence (p = 0.03). Significant associations were not found for OHLOC beliefs and children's oral health status. CONCLUSIONS: Questionnaire items addressing OHLOC functioned in accordance with the theoretical framework in AI participants.

The relationship between DNA methylation in neurotrophic genes and age as evidenced from three independent cohorts: differences by delirium status.

We previously reported the association between DNA methylation (DNAm) of pro-inflammatory cytokine genes and age. In addition, neurotrophic factors are known to be associated with age and neurocognitive disorders. Therefore, we hypothesized that DNAm of neurotrophic genes change with age, especially in delirium patients. DNAm was analyzed using the Illumina HumanMethylation450 or HumanMethylationEPIC BeadChip Kit in 3 independent cohorts: blood from 383 Grady Trauma Project subjects, brain from 21 neurosurgery patients, and blood from 87 inpatients with and without delirium. Both blood and brain samples showed that most of the DNAm of neurotrophic genes were positively correlated with age. Furthermore, DNAm of neurotrophic genes was more positively correlated with age in delirium cases than in non-delirium controls. These findings support our hypothesis that the neurotrophic genes may be epigenetically modulated with age, and this process may be contributing to the pathophysiology of delirium.