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Abstract. Introduction:. Mu opioid receptor gene (OPRM1) variant rs1799971 introduces a CpG site, which may influence DNA methylation (DNAm) and opioid/pain outcomes. Objectives:. In this nested analysis, we investigated both OPRM1 A118G genotype and promoter/immediate downstream blood DNAm sequencing data for associations with opioid effects and chronic postsurgical pain (CPSP) in a surgical cohort. Methods:. Prospectively recruited opioid naïve patients undergoing Nuss procedure or spinal fusion with rs1799971 genotypes (Illumina arrays), DNAm (next generation enzymatic methylation sequencing at Chr6:154,039,209-154,039,803) and outcomes—opioid analgesia (integrated opioid use + pain over postoperative days 0 and 1 normalized to surgery type), safety—respiratory depression (RD) in high opioid use groups, and CPSP (Numerical Rating Scale >3/10 2-12 months postsurgery)—were included. Linear and logistic regression were performed to test genetic and epigenetic associations, adjusted for sociodemographics, cell types, and analgesics. Results:. In this cohort (N = 112; 15.3 ± 2.0 years, 50% female, 83% White, 55% had CPSP, 13% had RD), DNAm at Chr6:154039216-154039217 was associated with CPSP (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.00-1.57; P = 0.03), Chr6:154039661-154039662 with acute integrated pain (β = −20.9, 95% CI, −40.70 to −1.10, P = 0.04), Chr6:154039520-154039521 (OR, 1.49; 95% CI, 1.09-2.03; P = 0.01), and Chr6:154039571-154039572 (OR, 1.47; 95% CI, 1.08-2.01; P = 0.02) with RD. Significant CpG sites were located in Repressed Polycomb chromatin states. Genotype was not associated with DNAm or outcomes. Conclusion:. Our analyses support OPRM1 DNAm as predictors of acute and chronic pain/opioid outcomes in children after painful surgery. Study limitations included absent GG genotype, low sequencing coverage, and lack of correction for multiple testing.

The most recognised role of vitamin D in the body is for calcium absorption, and sufficiency is defined as a vitamin D blood serum level greater than 20 ng/mL (50 nmol/L). In growing children, hypovitaminosis D is associated with bone and muscle weakness, fractures, and osteoporosis. Burns patients are at a greater risk of low vitamin D levels due to lack of ultraviolet rays reaching the skin during prolonged hospital admission and sun avoidance post-burn injury. This study aimed to identify any individual, seasonal or burn injury characteristics in paediatric patients that were associated with low total vitamin D levels. Three different vitamin D metabolites were analysed to identify if, and where, in the synthesis pathway any insufficiencies may be occurring. Liquid Chromatography Mass Spectrometry (LCMS) was used to concurrently assess vitamin D3 (25OHD3 or Calcifediol), its epimer (3epi-25(OH)D3), and its precursor Pre Vitamin D3 (Cholecalciferol), in the plasma from 193 Australian paediatric burn patients, compared to 46 healthy controls. The results indicated that 61 % of healthy controls and up to 76 % of all burn patients had below normal clinical ranges of Total 25OHD3 (25(OH)D3 + 3epi-25(OH)D3). However, there were no significant differences between patient groups (control, acute, scarring, and reconstructive). The season of sample collection contributed significantly to total vitamin D levels but patients who were undergoing reconstructive surgery 1–17 years post-burn had consistently low vitamin D levels across all seasons. Routine screening, dietary monitoring, and potential supplementation of vitamin D in the burns population is recommended as it may impact recovery, growth and development of the child post-burn.

Summary: Caspase recruitment domain family member 14 (CARD14) and its variants are associated with both atopic dermatitis (AD) and psoriasis, but their mechanistic impact on skin barrier homeostasis is largely unknown. CARD14 is known to signal via NF-κB; however, CARD14-NF-κB signaling does not fully explain the heterogeneity of CARD14-driven disease. Here, we describe a direct interaction between CARD14 and MYC and show that CARD14 signals through MYC in keratinocytes to coordinate skin barrier homeostasis. CARD14 directly binds MYC and influences barrier formation in an MYC-dependent fashion, and this mechanism is undermined by disease-associated CARD14 variants. These studies establish a paradigm that CARD14 activation regulates skin barrier function by two distinct mechanisms, including activating NF-κB to bolster the antimicrobial (chemical) barrier and stimulating MYC to bolster the physical barrier. Finally, we show that CARD14-dependent MYC signaling occurs in other epithelia, expanding the impact of our findings beyond the skin.

Summary: Genetic testing with exome sequencing and genome sequencing is increasingly offered to infants and children with cardiovascular diseases. However, the rates of positive diagnoses after genetic testing within the different categories of cardiac disease and phenotypic subtypes of congenital heart disease (CHD) have been little studied. We report the diagnostic yield after next-generation sequencing in 500 patients with CHD from diverse population subgroups that were enrolled at three different sites in the Clinical Sequencing Evidence-Generating Research consortium. Patients were ascertained due to a primary cardiovascular issue comprising arrhythmia, cardiomyopathy, and/or CHD, and corresponding human phenotype ontology terms were selected to describe the cardiac and extracardiac findings. We examined the diagnostic yield for patients with arrhythmia, cardiomyopathy, and/or CHD and phenotypic subtypes of CHD comprising conotruncal defects, heterotaxy, left ventricular outflow tract obstruction, septal defects, and “other” heart defects. We found a significant increase in the frequency of positive findings for patients who underwent genome sequencing compared to exome sequencing and for syndromic cardiac defects compared to isolated cardiac defects. We also found significantly higher diagnostic rates for patients who presented with isolated cardiomyopathy compared to isolated CHD. For patients with syndromic presentations who underwent genome sequencing, there were significant differences in the numbers of positive diagnoses for phenotypic subcategories of CHD, ranging from 31.7% for septal defects to 60% for “other”. Despite variation in the diagnostic yield at each site, our results support genetic testing in pediatric patients with syndromic and isolated cardiovascular issues and in all subtypes of CHD.

Parents’ emotions after their child’s burn might be influenced by the injury circumstances or demographic characteristics of the patient and family. Parents’ post-traumatic stress symptoms and their child’s distress may interact and affect emotional states. The psychosocial outcomes of parents were measured using the Impact of Event Scale-Revised, the CARe Burn Scale, and the Post-traumatic Growth Inventory-Brief. The psychosocial quality of life outcomes of the pediatric burn patients were measured using the Pediatric Quality of Life Inventory (PedsQL). Regression analysis was used to assess the relationship between patient psychosocial quality of life and the related parent scores. A total of 48 patients and parents participated, with 36 giving full data at 12 months. Parental post-traumatic stress symptoms were initially high, settling by six months, although outliers remained. Parents reported higher IESR scores if their child was female, if they felt helpless at the time of the incident, and if a language other than English was spoken in the home. Parents’ scores of their child’s psychosocial function were similar to their child’s self-scores. Parents who perceived poorer emotional functioning in their child reported higher IESR scores.

Introduction: There is significant unexplained variability in behavioral and executive functioning after pediatric traumatic brain injury (TBI). Prior research indicates that there are likely genetic contributions; however, current research is limited. The purpose of this study is to use a systems biology informed approach to characterize the genomic signature related to behavioral and executive functioning ∼12 months after moderate through severe TBI in children.Methods: Participants were from two prospective cohorts of children with severe TBI (Cohort #1) and moderate-severe TBI and an orthopedic injury (OI) group (Cohort #2). Participants included 196 children (n = 72 and n = 124 total from each respective cohort), ranging in age between 0–17 years at the time of injury. In total, 86 children had severe TBI, 49 had moderate TBI, and 61 had an OI. Global behavioral functioning assessed via the Child Behavior Checklist and executive function assessed via the Behavioral Rating Inventory of Executive Function at ∼ 12 months post injury served as outcomes. To test for a genomic signature, we compared the number of nominally significant (p < 0.05) polymorphisms associated with the outcomes in our systems biology identified genes to a set 10,000 permutations using control genes (e.g., not implicated by systems biology). We used the ToppFun application from Toppgene Suite to identify enriched biologic processes likely to be associated with behavioral and executive function outcomes.Results: At 12 months post injury, injury type (TBI vs OI) by polymorphism interaction was significantly enriched in systems biology selected genes for behavioral and executive function outcomes, suggesting these genes form a genomic signature. Effect sizes of the associations from our genes of interest ranged from .2–.5 for the top 5% of variants. Systems biology analysis of the variants associated with the top 5% effect sizes indicated enrichment in several specific biologic processes and systems.Discussion: Findings indicate that a genomic signature may explain heterogeneity of behavioral and executive outcomes after moderate and severe TBI. This work provides the foundation for constructing genomic signatures and integrating systems biology and genetic information into future recovery, prognostic, and treatment algorithms.

Abstract Insulin‐like growth factor (IGF) binding proteins (IGFBPs) are a family of growth factor modifiers, some of which are known to be independently associated with pulmonary arterial hypertension (PAH) survival. IGF factor binding protein 7 (IGFBP7) is a unique low‐affinity IGFBP that, independent of IGF, stimulates prostacyclin production. This study proposed to establish associations between IGFBP7 and PAH severity and survival, using enrollment and longitudinal samples. Serum IGFBP7 levels were significantly elevated in patients with PAH compared to controls. After adjusting for age and sex, logarithmic increases in IGFBP7 were associated with a 20 m shorter six‐minute walk distance (6MWD; p

Abstract Chemotherapy‐induced nausea and vomiting (CINV) is commonly experienced by patients receiving antineoplastic agents prior to hemopoietic stem cell transplant (HSCT). Ondansetron, a 5‐HT3 antagonist metabolized by CYP2D6, is an antiemetic prescribed to treat short‐term CINV, but some patients still experience uncontrolled nausea and vomiting while taking ondansetron. Adult CYP2D6 ultrarapid metabolizers (UMs) are at higher risk for CINV due to rapid ondansetron clearance, but similar studies have not been performed in pediatric patients. We performed a retrospective chart review of 128 pediatric HSCT recipients who received ondansetron for CINV prevention and had CYP2D6 genotyping for 20 alleles and duplication detection. The number of emetic episodes for each patient was collected from the start of chemotherapy through 7 days after HSCT. The average age of the cohort was 6.6 years (range: 0.2–16.7) and included three UMs, 72 normal metabolizers, 47 intermediate metabolizers, and six poor metabolizers. Because UMs are the population at risk for inefficacy, we describe the course of treatment for these three patients, as well as the factors influencing emesis: chemotherapy emetogenicity, diagnosis, and duration of ondansetron administration. The cases described support guidelines recommending non‐CYP2D6 metabolized antiemetics (e.g., granisetron) when a patient is a known CYP2D6 UM, but pediatric studies with a larger sample of CYP2D6 UMs are needed to validate our findings.

Abstract Low‐dose methotrexate (MTX) is an immunosuppressant used to treat inflammatory bowel disease (IBD). SLCO1B1 genetic variation has been associated with delayed MTX clearance and increased toxicity. The purpose of this study was to evaluate the association between SLCO1B1 genetic variation and MTX‐induced nausea in children with IBD. We performed a single center retrospective chart analysis of 278 patients who were prescribed MTX for IBD. Two hundred two patients had banked DNA and were genotyped for three SLCO1B1 single nucleotide polymorphisms (SNPs; rs4149056, rs2306283, and rs11045819). Diplotypes were determined by combining the SNPs into *1, *4, *5, *14, *15, and *37 alleles. Incidence of nausea was abstracted from clinician notes. Prescriptions and demographics were extracted from the medical record. The cohort was 69.8% boys, 89.1% White, and 87.6% had a diagnosis of Crohn’s disease with a mean age of 16.0 (± 3.8) years. MTX‐induced nausea was noted in 34% of the cohort. MTX‐induced nausea was associated with the number of reduced‐function *15 alleles (p = 0.034) and occurred 2.26 times more often in patients with at least one *15 allele who did not initiate MTX treatment with concomitant ondansetron (p = 0.034). MTX‐induced nausea was significantly independently associated with SLCO1B1 diplotype (p = 0.006) after controlling for MTX dose group and concomitant ondansetron. Our data demonstrate that the SLCO1B1 *15 allele is associated with MTX‐induced nausea in pediatric patients with IBD. Additionally, *15 allele carriers could benefit from a dose reduction of MTX to reduce exposure and treatment initiation with concomitant ondansetron to reduce nausea.

Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory disease with a complex underlying genetic etiology. Here, the authors identify a series of rare variants in DSP and PPL in multiplex families with EoE and uncover a pathogenic role for desmosomal dysfunction in EoE.

Environmental factors can lead to disease and health disparities when the places where people live, learn, work, play and pray are burdened by social inequities. Non-formal programs that explicitly connect local environmental exposures and human health could be of great value to communities at greatest risk. The purpose of this work was to co-create relevant and engaging education with youth and community stakeholders of all ages that more explicitly emphasizes the link between the local environment and community members’ health through a hands-on community science experience. Our experiences helped strengthen our community-academic partnership and establish a route to create and tailor informal programming to meet local needs *and* engage people in community science with academic partners. We generated two distinctly different community science neighborhood audit tools designed to differently engage our community partners and inform community participants of their local environments and its role on their health. Through community meetings, we garnered critical insight from our stakeholders. While neither of the tools and accompanying data collected were deemed to be scientifically generalizable, our ongoing and future work has benefited from important lessons learned from their creation and sharing.

Genetic variants in KIF3A are associated with atopic dermatitis (AD). Here, the authors identify two AD-risk alleles that show high methylation resulting in lower KIF3A expression. Mice with epidermis-specific loss of Kif3a show disrupted skin barrier homeostasis and increased AD susceptibility.

Currently available noninvasive markers for assessing disease severity and mortality risk in pulmonary arterial hypertension (PAH) are unrelated to fundamental disease biology. Endostatin, an angiostatic peptide known to inhibit pulmonary artery endothelial cell migration, proliferation and survival in vitro, has been linked to adverse haemodynamics and shortened survival in small PAH cohorts. This observational cohort study sought to assess: 1) the prognostic performance of circulating endostatin levels in a large, multicentre PAH cohort; and 2) the added value gained by incorporating endostatin into existing PAH risk prediction models. Endostatin ELISAs were performed on enrolment samples collected from 2017 PAH subjects with detailed clinical data, including survival times. Endostatin associations with clinical variables, including survival, were examined using multivariable regression and Cox proportional hazards models. Extended survival models including endostatin were compared to null models based on the REVEAL risk prediction tool and European Society of Cardiology/European Respiratory Society (ESC/ERS) low-risk criteria using likelihood ratio tests, Akaike and Bayesian information criteria and C-statistics. Higher endostatin was associated with higher right atrial pressure, mean pulmonary arterial pressure and pulmonary vascular resistance, and with shorter 6-min walk distance (p

Summary: Bicuspid aortic valve (BAV) with ∼1%–2% prevalence is the most common congenital heart defect (CHD). It frequently results in valve disease and aorta dilation and is a major cause of adult cardiac surgery. BAV is genetically linked to rare left-heart obstructions (left ventricular outflow tract obstructions [LVOTOs]), including hypoplastic left heart syndrome (HLHS) and coarctation of the aorta (CoA). Mouse and human studies indicate LVOTO is genetically heterogeneous with a complex genetic etiology. Homozygous mutation in the Pcdha protocadherin gene cluster in mice can cause BAV, and also HLHS and other LVOTO phenotypes when accompanied by a second mutation. Here we show two common deletion copy number variants (delCNVs) within the PCDHA gene cluster are associated with LVOTO. Analysis of 1,218 white individuals with LVOTO versus 463 disease-free local control individuals yielded odds ratios (ORs) at 1.47 (95% confidence interval [CI], 1.13–1.92; p = 4.2 × 10−3) for LVOTO, 1.47 (95% CI, 1.10–1.97; p = 0.01) for BAV, 6.13 (95% CI, 2.75–13.7; p = 9.7 × 10−6) for CoA, and 1.49 (95% CI, 1.07–2.08; p = 0.019) for HLHS. Increased OR was observed for all LVOTO phenotypes in homozygous or compound heterozygous PCDHA delCNV genotype comparison versus wild type. Analysis of an independent white cohort (381 affected individuals, 1,352 control individuals) replicated the PCDHA delCNV association with LVOTO. Generalizability of these findings is suggested by similar observations in Black and Chinese individuals with LVOTO. Analysis of Pcdha mutant mice showed reduced PCDHA expression at regions of cell-cell contact in aortic smooth muscle and cushion mesenchyme, suggesting potential mechanisms for BAV pathogenesis and aortopathy. Together, these findings indicate common variants causing PCDHA deficiency play a significant role in the genetic etiology of common and rare LVOTO-CHD.

Abstract Background Group 1 pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recent therapeutic advances. Pathogenic remodeling of pulmonary arterioles leads to increased pulmonary pressures, right ventricular hypertrophy, and heart failure. Mutations in bone morphogenetic protein receptor type 2 and other risk genes predispose to disease, but the vast majority of non-familial cases remain genetically undefined. Methods To identify new risk genes, we performed exome sequencing in a large cohort from the National Biological Sample and Data Repository for PAH (PAH Biobank, n = 2572). We then carried out rare deleterious variant identification followed by case-control gene-based association analyses. To control for population structure, only unrelated European cases (n = 1832) and controls (n = 12,771) were used in association tests. Empirical p values were determined by permutation analyses, and the threshold for significance defined by Bonferroni’s correction for multiple testing. Results Tissue kallikrein 1 (KLK1) and gamma glutamyl carboxylase (GGCX) were identified as new candidate risk genes for idiopathic PAH (IPAH) with genome-wide significance. We note that variant carriers had later mean age of onset and relatively moderate disease phenotypes compared to bone morphogenetic receptor type 2 variant carriers. We also confirmed the genome-wide association of recently reported growth differentiation factor (GDF2) with IPAH and further implicate T-box 4 (TBX4) with child-onset PAH. Conclusions We report robust association of novel genes KLK1 and GGCX with IPAH, accounting for ~ 0.4% and 0.9% of PAH Biobank cases, respectively. Both genes play important roles in vascular hemodynamics and inflammation but have not been implicated in PAH previously. These data suggest new genes, pathogenic mechanisms, and therapeutic targets for this lethal vasculopathy.

Background Pediatric cardiomyopathy is a genetically heterogeneous disease with substantial morbidity and mortality. Current guidelines recommend genetic testing in children with hypertrophic, dilated, or restrictive cardiomyopathy, but practice variations exist. Robust data on clinical testing practices and diagnostic yield in children are lacking. This study aimed to identify the genetic causes of cardiomyopathy in children and to investigate clinical genetic testing practices. Methods and Results Children with familial or idiopathic cardiomyopathy were enrolled from 14 institutions in North America. Probands underwent exome sequencing. Rare sequence variants in 37 known cardiomyopathy genes were assessed for pathogenicity using consensus clinical interpretation guidelines. Of the 152 enrolled probands, 41% had a family history of cardiomyopathy. Of 81 (53%) who had undergone clinical genetic testing for cardiomyopathy before enrollment, 39 (48%) had a positive result. Genetic testing rates varied from 0% to 97% between sites. A positive family history and hypertrophic cardiomyopathy subtype were associated with increased likelihood of genetic testing (P=0.005 and P=0.03, respectively). A molecular cause was identified in an additional 21% of the 63 children who did not undergo clinical testing, with positive results identified in both familial and idiopathic cases and across all phenotypic subtypes. Conclusions A definitive molecular genetic diagnosis can be made in a substantial proportion of children for whom the cause and heritable nature of their cardiomyopathy was previously unknown. Practice variations in genetic testing are great and should be reduced. Improvements can be made in comprehensive cardiac screening and predictive genetic testing in first‐degree relatives. Overall, our results support use of routine genetic testing in cases of both familial and idiopathic cardiomyopathy. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01873963.

ObjectivesIncorporation of genetic factors in psychosocial/perioperative models for predicting chronic postsurgical pain (CPSP) is key for personalization of analgesia. However, single variant associations with CPSP have small effect sizes, making polygenic risk assessment important. Unfortunately, pediatric CPSP studies are not sufficiently powered for unbiased genome wide association (GWAS). We previously leveraged systems biology to identify candidate genes associated with CPSP. The goal of this study was to use systems biology prioritized gene enrichment to generate polygenic risk scores (PRS) for improved prediction of CPSP in a prospectively enrolled clinical cohort.MethodsIn a prospectively recruited cohort of 171 adolescents (14.5 ± 1.8 years, 75.4% female) undergoing spine fusion, we collected data about anesthesia/surgical factors, childhood anxiety sensitivity (CASI), acute pain/opioid use, pain outcomes 6–12 months post-surgery and blood (for DNA extraction/genotyping). We previously prioritized candidate genes using computational approaches based on similarity for functional annotations with a literature-derived “training set.” In this study, we tested ranked deciles of 1336 prioritized genes for increased representation of variants associated with CPSP, compared to 10,000 randomly selected control sets. Penalized regression (LASSO) was used to select final variants from enriched variant sets for calculation of PRS. PRS incorporated regression models were compared with previously published non-genetic models for predictive accuracy.ResultsIncidence of CPSP in the prospective cohort was 40.4%. 33,104 case and 252,590 control variants were included for association analyses. The smallest gene set enriched for CPSP had 80/1010 variants associated with CPSP (p < 0.05), significantly higher than in 10,000 randomly selected control sets (p = 0.0004). LASSO selected 20 variants for calculating weighted PRS. Model adjusted for covariates including PRS had AUROC of 0.96 (95% CI: 0.92–0.99) for CPSP prediction, compared to 0.70 (95% CI: 0.59–0.82) for non-genetic model (p < 0.001). Odds ratios and positive regression coefficients for the final model were internally validated using bootstrapping: PRS [OR 1.98 (95% CI: 1.21–3.22); β 0.68 (95% CI: 0.19–0.74)] and CASI [OR 1.33 (95% CI: 1.03–1.72); β 0.29 (0.03–0.38)].DiscussionSystems biology guided PRS improved predictive accuracy of CPSP risk in a pediatric cohort. They have potential to serve as biomarkers to guide risk stratification and tailored prevention. Findings highlight systems biology approaches for deriving PRS for phenotypes in cohorts less amenable to large scale GWAS.

Background: Biobanks can accelerate research by providing researchers with samples and data. However, hospital-based recruitment as a source for controls may create bias as who comes to the hospital may be different from the broader population.Methods: In an effort to broadly improve the quality of research studies and reduce costs and challenges associated with recruitment and sample collection, a group of diverse researchers at Cincinnati Children's Hospital Medical Center led an institution-supported initiative to create a population representative pediatric “Greater Cincinnati Childhood Cohort (GCC).” Participants completed a detailed survey, underwent a brief physician-led physical exam, and provided blood, urine, and hair samples. DNA underwent high-throughput genotyping.Results: In total, 1,020 children ages 3–18 years living in the 7 county Greater Cincinnati Metropolitan region were recruited. Racial composition of the cohort was 84% non-Hispanic white, 15% non-Hispanic black, and 2% other race or Hispanic. Participants exhibited marked demographic and disease burden differences by race. Overall, the cohort was broadly used resulting in publications, grants and patents; yet, it did not meet the needs of all potential researchers.Conclusions: Learning from both the strengths and weaknesses, we propose leveraging a community-based participatory research framework for future broad use biobanking efforts.

Abstract Background Our purpose is to develop a testable biological hypothesis to explain the known increased risk of breast cancer associated with extensive percent mammographic density (PMD), and to reconcile the apparent paradox that although PMD decreases with increasing age, breast cancer incidence increases. Methods We used the Moolgavkar model of carcinogenesis as a framework to examine the known biological properties of the breast tissue components associated with PMD that includes epithelium and stroma, in relation to the development of breast cancer. In this model, normal epithelial cells undergo a mutation to become intermediate cells, which, after further mutation, become malignant cells. A clone of such cells grows to become a tumor. The model also incorporates changes with age in the number of susceptible epithelial cells associated with menarche, parity, and menopause. We used measurements of the radiological properties of breast tissue in 4454 healthy subjects aged from 15 to 80+ years to estimate cumulative exposure to PMD (CBD) in the population, and we examined the association of CBD with the age-incidence curve of breast cancer in the population. Results Extensive PMD is associated with a greater number of breast epithelial cells, lobules, and fibroblasts, and greater amounts of collagen and extracellular matrix. The known biological properties of these tissue components may, singly or in combination, promote the acquisition of mutations by breast epithelial cells specified by the Moolgavkar model, and the subsequent growth of a clone of malignant cells to form a tumor. We also show that estimated CBD in the population from ages 15 to 80+ years is closely associated with the age-incidence curve of breast cancer in the population. Conclusions These findings are consistent with the hypothesis that the biological properties of the breast tissue components associated with PMD increase the probability of the transition of normal epithelium to malignant cells, and that the accumulation of mutations with CBD may influence the age-incidence curve of breast cancer. This hypothesis gives rise to several testable predictions.

Abstract Extensive mammographic density is a strong risk factor for breast cancer, but may also be an indicator of biological age. In this study we examined whether mammographic density is related to blood telomere length, a potential marker of susceptibility to age-related disease. We measured mammographic density by a computer assisted method and blood telomere length using a validated PCR method. Urinary malondialdehyde (MDA), a marker of lipid peroxidation, was measured in 24 hour urine collections. In the 342 women examined telomere length was negatively correlated with age, was lower in postmenopausal compared to premenopausal women and in smokers compared to non-smokers, and was positively correlated with urinary MDA. Telomere length was not associated with percent mammographic density or dense area, before or after adjustment for risk factors and MDA. However, there was a significant interaction between telomere length and MDA in their association with mammographic density. At lower levels of MDA, mammographic density and telomere length were inversely associated; while at high levels of MDA, there was evidence of a J-shaped association between mammographic density and telomere length. Further work is need to replicate these results and to examine the association of mammographic density with age-related chronic disease and mortality.

Abstract Background There is a lack of rigorous research investigating the factors that influence scar outcome in children. Improved clinical decision-making to reduce the health burden due to post-burn scarring in children will be guided by evidence on risk factors and risk stratification. This study aimed to examine the association between selected patient, injury and clinical factors and the development of raised scar after burn injury. Novel patient factors were investigated including selected immunological co-morbidities (asthma, eczema and diabetes type 1 and type 2) and skin pigmentation (Fitzpatrick skin type). Methods A prospective case-control study was conducted among 186 children who sustained a burn injury in Western Australia. Logistic regression was used to explore the relationship between explanatory variables and a defined outcome measure: scar height measured by a modified Vancouver Scar Scale (mVSS). Results The overall correct prediction rate of the model was 80.6%; 80.9% for children with raised scars (>1 mm) and 80.4% for children without raised scars (≤1 mm). After adjustment for other variables, each 1% increase in % total body surface area (%TBSA) of burn increased the odds of raised scar by 15.8% (95% CI = 4.4–28.5%). Raised scar was also predicted by time to healing of longer than 14 days (OR = 11.621; 95% CI = 3.727–36.234) and multiple surgical procedures (OR = 11.521; 1.994–66.566). Conclusions Greater burn surface area, time to healing of longer than 14 days, and multiple operations are independently associated with raised scar in children after burn injury. Scar prevention strategies should be targeted to children with these risk factors.

Objectives: To test whether genetic associations with behavioral outcomes after early childhood traumatic brain injury (TBI) are enriched for biologic pathways underpinning neurocognitive and behavioral networks.Design: Cross-sectional evaluation of the association of genetic factors with early (~ 6 months) and long-term (~ 7 years) post-TBI behavioral outcomes. We combined systems biology and genetic association testing methodologies to identify biologic pathways associated with neurocognitive and behavior outcomes after TBI. We then evaluated whether genes/single nucleotide polymorphism (SNPs) associated with these biologic pathways were more likely to demonstrate a relationship (i.e., enrichment) with short and long-term behavioral outcomes after early childhood TBI compared to genes/SNPs not associated with these biologic pathways.Setting: Outpatient research setting.Participants:140 children, ages 3–6:11 years at time of injury, admitted for a TBI or orthopedic injury (OI).Interventions: Not Applicable.Main Outcome Measures: Child behavior checklist total problems T score.Results: Systems biology methodology identified neuronal systems and neurotransmitter signaling (Glutamate receptor, dopamine, serotonin, and calcium signaling), inflammatory response, cell death, immune systems, and brain development as important biologic pathways to neurocognitive and behavioral outcomes after TBI. At 6 months post injury, the group (TBI versus OI) by polymorphism interaction was significant when the aggregate signal from the highest ranked 40% of case gene associations was compared to the control set of genes. At ~ 7 years post injury, the selected polymorphisms had a significant main effect after controlling for injury type when the aggregate signal from the highest ranked 10% of the case genes were compared to the control set of genesConclusions: Findings demonstrate the promise of applying a genomics approach, informed by systems biology, to understanding behavioral recovery after pediatric TBI. A mixture of biologic pathways and processes are associated with behavioral recovery, specifically genes associated with cell death, inflammatory response, neurotransmitter signaling, and brain development. These results provide insights into the complex biology of TBI recovery.

In pediatric patients, the selective serotonin reuptake inhibitors (SSRIs) escitalopram and citalopram (es/citalopram) are commonly prescribed for anxiety and depressive disorders. However, pharmacogenetic studies examining CYP2C19 metabolizer status and es/citalopram treatment outcomes have largely focused on adults. We report a retrospective study of electronic medical record data from 263 youth < 19 years of age with anxiety and/or depressive disorders prescribed escitalopram or citalopram who underwent routine clinical CYP2C19 genotyping. Slower CYP2C19 metabolizers experienced more untoward effects than faster metabolizers (p = 0.015), including activation symptoms (p = 0.029) and had more rapid weight gain (p = 0.018). A larger proportion of slower metabolizers discontinued treatment with es/citalopram than normal metabolizers (p = 0.007). Meanwhile, faster metabolizers responded more quickly to es/citalopram (p = 0.005) and trended toward less time spent in subsequent hospitalizations (p = 0.06). These results highlight a disparity in treatment outcomes with es/citalopram treatment in youth with anxiety and/or depressive disorders when standardized dosing strategies were used without consideration of CYP2C19 metabolizer status. Larger, prospective trials are warranted to assess whether tailored dosing of es/citalopram based on CYP2C19 metabolizer status improves treatment outcomes in this patient population.

Cardiovascular malformations (CVM) are common birth defects (incidence of 2–5/100 live births). Although a genetic basis is established, in most cases the cause remains unknown. Analysis of whole exome sequencing (WES) in left sided CVM case and trio series has identified large numbers of potential variants but evidence of causality has remained elusive except in a small percentage of cases. We sought to determine whether variant segregation in families would aid in novel gene discovery. The objective was to compare conventional and co-segregation approaches for WES in multiplex families. WES was performed on 52 individuals from 4 multiplex families ascertained by probands with hypoplastic left heart syndrome (HLHS). We identified rare variants with informatics support (RVIS, minor allele frequency ≤0.01 and Combined Annotation Dependent Depletion score ≥20) in probands. Non-RVIS variants did not meet these criteria. Family specific two point logarithm of the odds (LOD) scores identified co-segregating variants (C-SV) using a dominant model and 80% penetrance. In families, 702 RVIS in 668 genes were identified, but only 1 RVIS was also a C-SV (LOD ≥ 1). On the other hand, there were 109 non-RVIS variants with LOD ≥ 1. Among 110 C-SV, 97% were common (MAF > 1%). These results suggest that conventional variant identification methods focused on RVIS, miss most C-SV. For diseases such as left sided CVM, which exhibit strong familial transmission, co-segregation can identify novel candidates.

Early life nutritional imbalances are risk factors for metabolic dysfunctions in adulthood, but the long term effects of perinatal exposure to high versus low protein diets are not completely understood. We exposed C57BL/6J offspring to a high protein/low carbohydrate (HP/LC) or low protein/high carbohydrate (LP/HC) diet during gestation and lactation, and measured metabolic phenotypes between birth and 10 months of age in male offspring. Perinatal HP/LC and LP/HC exposures resulted in a decreased ability to clear glucose in the offspring, with reduced baseline insulin and glucose concentrations in the LP/HC group and a reduced insulin response post-glucose challenge in the HP/LC group. The LP/HC diet group also showed reduced birth and weanling weights, whereas the HP/LC offspring displayed increased weanling weight with increased adiposity beyond 5 months of age. Gene expression profiling of hypothalamus and liver revealed alterations in diverse molecular pathways by both diets. Specifically, hypothalamic transcriptome and pathway analyses demonstrated perturbations of MAPK and hedgehog signaling, processes associated with neural restructuring and transmission, and phosphate metabolism by perinatal protein imbalances. Liver transcriptomics revealed changes in purine and phosphate metabolism, hedgehog signaling, and circadian rhythm pathways. Our results indicate maternal protein imbalances perturbing molecular pathways in central and peripheral metabolic tissues, thereby predisposing the male offspring to metabolic dysfunctions.

Dyslipidemia is a major risk factor for CVD. Previous studies on lipid heritability have largely focused on white populations assessed after the obesity epidemic. Given secular trends and racial differences in lipid levels, this study explored whether lipid heritability is consistent across time and between races. African American and white nuclear families had fasting lipids measured in the 1970s and 22–30 years later. Heritability was estimated, and bivariate analyses between visits were conducted by race using variance components analysis. A total of 1,454 individuals (age 14.1/40.6 for offspring/parents at baseline; 39.6/66.5 at follow-up) in 373 families (286 white, 87 African American) were included. Lipid trait heritabilities were typically stronger during the 1970s than the 2000s. At baseline, additive genetic variation for LDL was significantly lower in African Americans than whites (P = 0.015). Shared genetic contribution to lipid variability over time was significant in both whites (all P < 0.0001) and African Americans (P ≤ 0.05 for total, LDL, and HDL cholesterol). African American families demonstrated shared environmental contributions to lipid variation over time (all P ≤ 0.05). Lower heritability, lower LDL genetic variance, and durable environmental effects across the obesity epidemic in African American families suggest race-specific approaches are needed to clarify the genetic etiology of lipids.

In our ongoing effort to identify genes influencing the biological pathways that underlie the metabolic disturbances associated with obesity, we performed genome-wide scanning in 2,209 individuals distributed over 507 Caucasian families to localize quantitative trait loci (QTLs), which affect variation of plasma lipids. Pedigree-based analysis using a quantitative trait variance component linkage method that localized a QTL on chromosome 7q35-q36, which linked to variation in levels of plasma triglyceride [TG, logarithm of odds (LOD) score = 3.7] and was suggestive of linkage to LDL-cholesterol (LDL-C, LOD = 2.2). Covariates of the TG linkage included waist circumference, fasting insulin, and insulin:glucose, but not body mass index or hip circumference. Plasma HDL-cholesterol (HDL-C) levels were suggestively linked to a second QTL on chromosome 12p12.3 (LOD = 2.6). Five other QTLs with lower LOD scores were identified for plasma levels of LDL-C, HDL-C, and total cholesterol.These newly identified loci likely harbor genetic elements that influence traits underlying lipid adversities associated with obesity.

This paper deals with the reification of the concept of race in biomedical research. It combines philosophical analysis and a quantitative approach to investigate the ways in which the reification fallacy may occur in race research, thereby providing theoretical legitimacy to the misuse of scientific research. It examines the prevalence of obesity in the US and some African countries as an empirical case to guide a conceptual analysis. The paper suggests that, to avoid the reification of race, researchers need to be more aware of the fact that continental genetic clusters do not necessarily correspond to the genotypic partitions of interest in therapeutic reaction or disease etiology, and need to take seriously the phenotypic variability of breeding populations within continents.