Effects of depression and stress on oral self-care among perinatal women in Appalachia: A longitudinal study.

OBJECTIVES: Oral health during the perinatal period and beyond affects the health and well-being of women and their offspring. Oral self-care behaviours can maintain or improve oral health; depression or stress during the perinatal period may compromise these behaviours. The aim of the study was to investigate the independent and combined effects of depression and stress on oral self-care behaviours of perinatal women in Appalachia, given the high burden of oral disease in this region. METHODS: A total of 1172 women in the first or second trimester of pregnancy were enrolled in the Center for Oral Health Research in Appalachia, cohort 2 (COHRA2) in West Virginia or Pittsburgh, Pennsylvania. Participants completed the Center for Epidemiological Studies Depression Scale, Perceived Stress Scale-10, and self-report items about oral self-care behaviours (i.e. toothbrushing and flossing) during pregnancy and five times in the 2+ years following birth. A Generalized Estimating Equation approach was used to analyse the longitudinal data. RESULTS: Maternal depression and stress were independently negatively related to toothbrushing and flossing frequency. These findings for toothbrushing were more pronounced in those with high levels of depression and high levels of stress, so there were both independent and combined effects. Frequency of toothbrushing and flossing stayed constant over time, so time was not associated with outcomes. About three-fourths of the sample reported toothbrushing levels that are consistent with established guidelines (i.e. two times daily), but almost half of the participants had very low levels of flossing (i.e. once or less a week). CONCLUSION: Interventions targeting stress and depression throughout the perinatal period might be helpful in improving oral self-care behaviours and oral health among women in Appalachia, in addition to the benefit of decreasing emotional distress.

Custom Biomedical FAIR Data Analysis in the Cloud Using CAVATICA.

The historically fragmented biomedical data ecosystem has moved towards harmonization under the findable, accessible, interoperable, and reusable (FAIR) data principles, creating more opportunities for cloud-based research. This shift is especially opportune for scientists across diverse domains interested in implementing creative, nonstandard computational analytic pipelines on large and varied datasets. However, executing custom cloud analyses may present difficulties, particularly for investigators lacking advanced computational expertise. Here, we present an accessible, streamlined approach for the cloud compute platform CAVATICA that offers a solution. We outline how we developed a custom workflow in the cloud, for analyzing whole genome sequences of case-parent trios to detect sex-specific genetic effects on orofacial cleft risk, which required several programming languages and custom software packages. The approach involves just three components: Docker to containerize software environments, tool creation for each analysis step, and a visual workflow editor to weave the tools into a Common Workflow Language (CWL) pipeline. Our approach should be accessible to any investigator with basic computational skills, is readily extended to implement any scalable high-throughput biomedical data analysis in the cloud, and is applicable to other commonly used compute platforms such as BioData Catalyst. We believe our approach empowers versatile data reuse and promotes accelerated biomedical discovery in a time of substantial FAIR data.

Maternal perceptions of assisting preschool-aged children with toothbrushing.

BACKGROUND: Parent-led toothbrushing with fluoride toothpaste is part of an evidence-based strategy to prevent caries in children. There is a gap in the literature regarding perceptions of how and when to assist a child with toothbrushing from the maternal perspective. METHODS: A qualitative cross-sectional study was conducted with participants in North and North Central Appalachia to examine maternal perceptions of when and how to assist with toothbrushing. From 2018 through 2022, 301 mothers of children aged 3 through 5 years volunteered to participate in semistructured interviews from a more extensive parent study (Center for Oral Health Research in Appalachia cohort). The qualitative data were transcribed, coded, and analyzed using Nvivo software, Version 12 (QSR International). The data were analyzed using grounded theory, constant comparative method, and template analysis. RESULTS: A total of 301 mothers were interviewed for this study; 156 (52%) lived in West Virginia and 145 (48%) lived in Pittsburgh, Pennsylvania. Four main themes emerged: (1) assisting with child toothbrushing, (2) ceasing to provide assistance with child toothbrushing, (3) lacking recommendations from dental care professionals on child toothbrushing, and (4) adhering to recommendations from dental care professionals on child toothbrushing assistance. CONCLUSIONS: Understanding the factors that influence how parents brush their children's teeth and the information they receive to guide daily dental hygiene behavior for children is essential in developing effective interventions for preventing caries in children. PRACTICAL IMPLICATIONS: These insights can improve child toothbrushing quality through improved oral hygiene education, recommendations, terminology, and policies from the dental community.

Genome-wide study of gene-by-sex interactions identifies risks for cleft palate.

Structural birth defects affect 3-4% of all live births and, depending on the type, tend to manifest in a sex-biased manner. Orofacial clefts (OFCs) are the most common craniofacial structural birth defects and are often divided into cleft lip with or without cleft palate (CL/P) and cleft palate only (CP). Previous studies have found sex-specific risks for CL/P, but these risks have yet to be evaluated in CP. CL/P is more common in males and CP is more frequently observed in females, so we hypothesized there would also be sex-specific differences for CP. Using a trio-based cohort, we performed sex-stratified genome-wide association studies (GWAS) based on proband sex followed by a genome-wide gene-by-sex (GxS) interaction testing. There were 13 loci significant for GxS interactions, with the top finding in LTBP1 (RR=3.37 [2.04 - 5.56], p=1.93x10 -6 ). LTBP1 plays a role in regulating TGF-B bioavailability, and knockdown in both mice and zebrafish lead to craniofacial anomalies. Further, there is evidence for differential expression of LTBP1 between males and females in both mice and humans. Therefore, we tested the association between the imputed genetically regulated gene expression of genes with significant GxS interactions and the CP phenotype. We found significant association for LTBP1 in cell cultured fibroblasts in female probands (p=0.0013) but not in males. Taken altogether, we show there are sex-specific risks for CP that are otherwise undetectable in a combined sex cohort, and LTBP1 is a candidate risk gene, particularly in females.

DeepFace: Deep-learning-based framework to contextualize orofacial-cleft-related variants during human embryonic craniofacial development.

Orofacial clefts (OFCs) are among the most common human congenital birth defects. Previous multiethnic studies have identified dozens of associated loci for both cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP). Although several nearby genes have been highlighted, the "casual" variants are largely unknown. Here, we developed DeepFace, a convolutional neural network model, to assess the functional impact of variants by SNP activity difference (SAD) scores. The DeepFace model is trained with 204 epigenomic assays from crucial human embryonic craniofacial developmental stages of post-conception week (pcw) 4 to pcw 10. The Pearson correlation coefficient between the predicted and actual values for 12 epigenetic features achieved a median range of 0.50-0.83. Specifically, our model revealed that SNPs significantly associated with OFCs tended to exhibit higher SAD scores across various variant categories compared to less related groups, indicating a context-specific impact of OFC-related SNPs. Notably, we identified six SNPs with a significant linear relationship to SAD scores throughout developmental progression, suggesting that these SNPs could play a temporal regulatory role. Furthermore, our cell-type specificity analysis pinpointed the trophoblast cell as having the highest enrichment of risk signals associated with OFCs. Overall, DeepFace can harness distal regulatory signals from extensive epigenomic assays, offering new perspectives for prioritizing OFC variants using contextualized functional genomic features. We expect DeepFace to be instrumental in accessing and predicting the regulatory roles of variants associated with OFCs, and the model can be extended to study other complex diseases or traits.

Whole genome sequencing identifies associations for nonsyndromic sagittal craniosynostosis with the intergenic region of BMP2 and noncoding RNA gene LINC01428.

Craniosynostosis (CS) is a major birth defect resulting from premature fusion of cranial sutures. Nonsyndromic CS occurs more frequently than syndromic CS, with sagittal nonsyndromic craniosynostosis (sNCS) presenting as the most common CS phenotype. Previous genome-wide association and targeted sequencing analyses of sNCS have identified multiple associated loci, with the strongest association on chromosome 20. Herein, we report the first whole-genome sequencing study of sNCS using 63 proband-parent trios. Sequencing data for these trios were analyzed using the transmission disequilibrium test (TDT) and rare variant TDT (rvTDT) to identify high-risk rare gene variants. Sequencing data were also examined for copy number variants (CNVs) and de novo variants. TDT analysis identified a highly significant locus at 20p12.3, localized to the intergenic region between BMP2 and the noncoding RNA gene LINC01428. Three variants (rs6054763, rs6054764, rs932517) were identified as potential causal variants due to their probability of being transcription factor binding sites, deleterious combined annotation dependent depletion scores, and high minor allele enrichment in probands. Morphometric analysis of cranial vault shape in an unaffected cohort validated the effect of these three single nucleotide variants (SNVs) on dolichocephaly. No genome-wide significant rare variants, de novo loci, or CNVs were identified. Future efforts to identify risk variants for sNCS should include sequencing of larger and more diverse population samples and increased omics analyses, such as RNA-seq and ATAC-seq.

Risk of Postpartum Dental Caries: Survival Analysis of Black/African American and White Women in Appalachia.

Background: Pregnancy is associated with increased risk of caries, but the extent this increase extends into the postpartum period is poorly understood. Study Objective: Describe the epidemiology of dental decay in the postpartum period among Black/African American and White American women and explore associations with potentially modifiable risk factors. Materials and Methods: We analyzed data from 1,131 Black/African American and White women participating in Center for Oral Health Research in Appalachia cohorts. Women were enrolled during the first two trimesters of pregnancy. Calibrated dental professionals completed dental examinations at the prenatal enrollment visit, and 2-month, 1-year, 2-year, and 3-year postpartum visits. Results: Between the prenatal visit and 2-month visit, the incidence of decayed, missing, and filled teeth (DMFT) increase was 6.92/100 person-months, compared to 3.6/100 person-months between the 2-month and 1-year visit. In a multivariate Cox proportional hazard regression predicting incidence of caries up to 3-years postpartum, being younger, having less than college education, a household income <$50,000, smoking cigarettes, a DMFT >0, a very poor or poor Oral hygiene Rating Index, lower salivary pH at enrollment, or frequently drinking 100% juice increased the hazard of new dental caries. Adjusting for race/ethnic group did not affect the direction or magnitude of observed associations. Conclusions: The strong associations of prior DMFT and Oral Rating Index with occurrence of new dental caries postpartum suggests that targeting young women for interventions to improve oral health may be more valuable for reducing caries incidence during pregnancy and in the postpartum period than targeting women only during pregnancy.

netMUG: a novel network-guided multi-view clustering workflow for dissecting genetic and facial heterogeneity.

Introduction: Multi-view data offer advantages over single-view data for characterizing individuals, which is crucial in precision medicine toward personalized prevention, diagnosis, or treatment follow-up. Methods: Here, we develop a network-guided multi-view clustering framework named netMUG to identify actionable subgroups of individuals. This pipeline first adopts sparse multiple canonical correlation analysis to select multi-view features possibly informed by extraneous data, which are then used to construct individual-specific networks (ISNs). Finally, the individual subtypes are automatically derived by hierarchical clustering on these network representations. Results: We applied netMUG to a dataset containing genomic data and facial images to obtain BMI-informed multi-view strata and showed how it could be used for a refined obesity characterization. Benchmark analysis of netMUG on synthetic data with known strata of individuals indicated its superior performance compared with both baseline and benchmark methods for multi-view clustering. The clustering derived from netMUG achieved an adjusted Rand index of 1 with respect to the synthesized true labels. In addition, the real-data analysis revealed subgroups strongly linked to BMI and genetic and facial determinants of these subgroups. Discussion: netMUG provides a powerful strategy, exploiting individual-specific networks to identify meaningful and actionable strata. Moreover, the implementation is easy to generalize to accommodate heterogeneous data sources or highlight data structures.

Syndrome-informed phenotyping identifies a polygenic background for achondroplasia-like facial variation in the general population.

Human craniofacial shape is highly variable yet highly heritable with genetic variants interacting through multiple layers of development. Here, we hypothesize that Mendelian phenotypes represent the extremes of a phenotypic spectrum and, using achondroplasia as an example, we introduce a syndrome-informed phenotyping approach to identify genomic loci associated with achondroplasia-like facial variation in the normal population. We compared three-dimensional facial scans from 43 individuals with achondroplasia and 8246 controls to calculate achondroplasia-like facial scores. Multivariate GWAS of the control scores revealed a polygenic basis for normal facial variation along an achondroplasia-specific shape axis, identifying genes primarily involved in skeletal development. Jointly modeling these genes in two independent control samples showed craniofacial effects approximating the characteristic achondroplasia phenotype. These findings suggest that both complex and Mendelian genetic variation act on the same developmentally determined axes of facial variation, providing new insights into the genetic intersection of complex traits and Mendelian disorders.

Transmission analysis of candidate genes for nonsyndromic oral clefts in Brazilian parent-child triads with recurrence

Cleft lip and/or palate (CL/P) is a major congenital defect with complex etiology, including multiple genetic and environmental factors. Approximately two thirds of the cases are not accompanied by other anomalies and are called nonsyndromic (NS). In the present study, we performed transmission distortion analysis of the MSX1-CA, TGFB3-CA and MTHFR-C677T polymorphisms in 60 parent-child triads, in which the NS-CL/P affected child had at least one affected parent. No association with genes MSX1 or TGFB3 was found, but the results were suggestive of an association of the MTHFR-C677T polymorphism with NS-CL/P.