African American Controls Research Articles

Variants in the β-globin locus are associated with pneumonia in African American children

In African American adults, the strongest genetic predictor of pneumonia appears to be the A allele of rs334, a variant in the β-globin gene which in homozygous form causes sickle cell disease (SCD). No comparable studies have been done in African American children. We performed genome-wide association analyses of 482 African American children with documented pneumonia and 2048 African American controls using genotypes imputed from two reference panels: 1000 Genomes (1KG) (which contains rs334) and TOPMed (does not contain rs334). Using 1KG imputed genotypes, the most significant variant was rs334 (A allele (OR = 2.76 (2.21-3.74), p=5.9x10-19); using TOPMed imputed genotypes the most significant variant was rs2226952, found in the β-globin locus control region (G allele (OR =2.14 (1.78-2.57), p = 5.1x10-16). After conditioning on rs334, the most strongly associated variant in the β-globin locus was rs33930165, (allele T, 1KG: OR=4.09 (2.29-7.29), p=1.7x10-6; TOPMed: OR=3.58 (2.18-5.90), p=4.7x10-7), which as a compound heterozygote with rs334 A allele can cause SCD. To compare the power of different sample sets we developed a way to estimate the power of sample sets with different sample sizes, genotype arrays and imputation platforms. Our results suggest that in African American children the strongest genetic determinants of pneumonia are those that increase the risk of SCD.

Vitamin D receptor polymorphisms and associated miRNAs in the development of breast cancer in African American women

Breast cancer (BCa) is a prevalent form of cancer in women, exhibiting varying rates and distribution across different ethnic groups. Among these groups, African American (AA) women have the highest incidence of BCa and the lowest levels of Vitamin D (VD). Numerous studies have explored the connection between variations in the VDR gene and BCa risk, particularly in different populations, but research on the AA population remains limited. Epigenetic modifications, including specific microRNAs (miRNAs), can influence gene expression without altering the genetic code and have been implicated in cancer initiation and progression. Our hypothesis suggests that VDR gene variations may increase BCa risk in AA women and that changes in miRNA expression profiles could contribute to BCa development. Using data from the 1000 Genome Project, we identified five VDR gene variants with significant frequency differences between AA and European-American (EA) populations. We genotyped 404 African American BCa cases and controls for five variants using TaqMan® assays. SNPstats assessed their association with BCa risk. The rs1544410 variant’s recessive model (A/A) showed a decreased BCa risk in AA (odds ratio 0.33, 95% CI: 0.15–0.73, p-value 0.0041). Conversely, the rs2853563 variant’s recessive model (A/A) was linked to an increased BCa risk (odds ratio 4.04, 95% CI: 1.49–10.95, p-value 0.0022). We investigated miRNA expression influenced by VD in HCC1806 Triple-Negative Breast Cancer (TNBC) cell lines with the A/A allele for rs2853563. nCounter® Nanostring technology assessed miRNA profiles after calcitriol treatment. Our results indicated that calcitriol treatment led to reduced expression of six miRNAs, four of which are associated with tumor suppression in the presence of the AA genotype in TNBC cell lines. These findings suggest that specific VDR genotypes could have a potential effect on the miRNAs expression which could potentially serve as markers for cell proliferation in TNBC.

Lower Prevalence of Asymptomatic Alzheimer's Disease Among Healthy African Americans.

Alzheimer's disease (AD) is believed to be more common in African Americans (AA), but biomarker studies in AA populations are limited. This report represents the largest study to date examining cerebrospinal fluid AD biomarkers in AA individuals. We analyzed 3,006 cerebrospinal fluid samples from controls, AD cases, and non-AD cases, including 495 (16.5%) self-identified black/AA and 2,456 (81.7%) white/European individuals using cutoffs derived from the Alzheimer's Disease Neuroimaging Initiative, and using a data-driven multivariate Gaussian mixture of regressions. Distinct effects of race were found in different groups. Total Tauand phospho181-Tau were lower among AA individuals in all groups (p < 0.0001), and Aβ42 was markedly lower in AA controls compared with white controls (p < 0.0001). Gaussian mixture of regressions modeling of cerebrospinal fluid distributions incorporating adjustments for covariates revealed coefficient estimates for AA race comparable with 2-decade change in age. Using Alzheimer's Disease Neuroimaging Initiative cutoffs, fewer AA controls were classified as biomarker-positive asymptomatic AD (8.0% vs 13.4%). After adjusting for covariates, our Gaussian mixture of regressions model reduced this difference, but continued to predict lower prevalence of asymptomatic AD among AA controls (9.3% vs 13.5%). Although the risk of dementia is higher, data-driven modeling indicates lower frequency of asymptomatic AD in AA controls, suggesting that dementia among AA populations may not be driven by higher rates of AD. ANN NEUROL 2024;96:463-475.

Testing Whether Protective Parenting is a Causal Mediator of Intervention Effects on Decreased Delinquency Using a Randomized Prevention Trial

Protective parenting practices, including parental monitoring and establishing nurturing and supportive rules, are thought to affect the risk of children’s involvement in delinquency. However, there has yet to be any direct test of this hypothesis using experimental data designed to test causality better. Data from 346 Black couples with an 11-year-old child were assigned randomly to Protecting Strong African American Families (ProSAAF) intervention or control condition. Results from traditional mediation models, causal mediation analysis, and the complier analysis indicated that the intervention had a significant indirect effect on youth delinquent behaviors and that effects on protective parenting mediated this effect. The results demonstrated that ProSAAF, which is designed to promote family communication, is effective in deterring delinquent behaviors among Black Americans who reside in resource-scarce communities by enhancing parenting practices.

Parkinson Disease Genetics Extended to African and Hispanic Ancestries in the VA Million Veteran Program.

Nearly all genetic analyses of Parkinson disease (PD) have been in populations of European ancestry. We sought to test the ability of a machine learning method to extract accurate PD diagnoses from an electronic medical record (EMR) system, to see whether genetic variants identified in European populations generalize to individuals of African and Hispanic ancestries, and to compare the rates of PD across ancestries. A machine learning method using natural language processing was applied to EMRs of US veterans participating in the VA Million Veteran Program (MVP) to identify individuals with PD. These putative cases were vetted via blind chart review by a movement disorder specialist. A polygenic risk score (PRS) of 90 established genetic variants whose genotypes were imputed from a customized Axiom Biobank Array was evaluated in different case groups. The EMR prediction scores had a distinct trimodal distribution, with 97% of the high group and only 30% of the middle group having a credible diagnosis of PD. Using the 3,542 cases from the high group matched 4:1 to controls, the PRS was highly predictive in individuals of European ancestry (n = 3,137 cases; OR = 1.82; p = 8.01E-48), and nearly identical effect sizes were seen in individuals of African (n = 184; OR = 2.07; p = 3.4E-4) and Hispanic ancestries (n = 221; OR = 2.13; p = 3.9E-6). The PRS was much less predictive for the 2,757 European ancestry cases who had an ICD code for PD but for whom the machine learning method had a lower confidence in their diagnosis. No novel ancestry-specific genetic variants were identified. Individuals with African ancestry had one-quarter the rate of PD compared with European or Hispanic ancestries aged 60-70 years and one half the rate in the 70-80 years age range. African American cases had a higher proportion of their DNA originating in Europe compared with African American controls. Machine learning can reliably classify PD using data from a large EMR. Larger studies of non-European populations are required to confirm the generalizability of PD risk variants identified in populations of European ancestry and the increased risk coming from a higher proportion of European DNA in African Americans.

Association of Cerebral Hemodynamics and Anemia on Processing Speed in Adults with Sickle Cell Disease.

Compared to healthy controls, adult patients with Sickle Cell Disease (SCD) are anemic, and therefore have higher cardiac output and Cerebral Blood Flow (CBF) to maintain brain oxygenation. They also demonstrate comparatively more cognitive deficits due to either overt strokes or silent cerebral ischemia. However, there are few correlative studies between CBF and cognitive deficits, specifically processing speed in SCD. Such studies are important to develop biomarkers of central brain processing and ischemia for diagnosis, prognosis, and evaluating the effectiveness of potential interventions. This pilot cross-sectional study tested the hypotheses that adults with SCD and elevated CBF demonstrate lower central brain processing speed than controls on average and that CBF is inversely correlated with processing speed. We conducted a pilot cross-sectional study to assess the relation-ships between CBF, central brain processing speed, and hemoglobin levels in asymptomatic adults with SCD and controls from an urban academic medical center. MRI acquisitions at 3T consisted of 2D phase-contrast quantitative arteriograms (Qflow) of the bilateral internal carotid and vertebral arteries and 3D pseudo-continuous arterial spin labeling (pCASL) of the brain. Participants were patients with SCD (hemoglobin [Hb]SS, [Hb] SBetaThal°, or [Hb]SC) aged 22-52 years of African American descent (N=7) or community controls (Hb AA) (n=3). Processing speed was assessed as an in-direct functional marker of ischemia using a recommended test from the NIH Toolbox for Assessment of Neurological and Behavioral Function, the Pattern Comparison Processing Speed Test. t-tests were used to compare means of CBF, hemoglobin, and cognition between SCD patients and healthy controls. Among SCD patients only multivariate correla-tions were used to evaluate relationships between brain perfusion in specific brain regions vs. processing speed and CBF. The significance level was set at p≤0.05. Adults with SCD reported higher CBF compared to healthy con-trols (72.15±28.90 vs. 47.23±12.30 ml/min/100g, p=0.04), and lower hemoglobin concentration (8.64±2.33 vs. 13.33±0.58, p=0.001). Heart rate in SCD patients was higher than in controls (86.29±1.37 vs. 74.00±2.10, p=0.04). Patients with SCD demonstrated lower processing speed (96.14±21.04 vs.123±13.74, p=0.02) than controls. Among adult patients with SCD, perfusion in specific regions of the brain showed an inverse relationship with processing speed, as did whole-brain CBF (p=0.0325). These findings, although from a small sample, lend a degree of validity to the claim that processing speed is slower in people with SCD than in controls and that CBF is significantly higher in SCD patients com-pared to controls. The results also lend credence to the finding that the degree of processing speed deficiencies among adults with SCD is correlated with the degree of elevated CBF, which is known to correspond with the degree of anemia associated with SCD.

Abstract C020: Identification of metabolic and molecular mechanisms contributing to ER+ cancer disparities using a machine-learning pipeline

Abstract Background: African American (AA) women are less likely to develop breast cancer but when they do, their mortality rates are 40% higher compared to Non-Hispanic White (NHW) women. This disparity is particularly striking among ER+ breast cancer cases. The purpose of this study is to examine whether there are racial differences in metabolic and molecular pathways typically activated in patients with ER+ positive breast cancer. Methods: We collected plasma from AA and NHW cases and controls to conduct an untargeted metabolomics analysis using gas chromatography-mass spectrometry (GC-MS) to identify metabolites that are possibly altered in the different race groups. Statistical methods combined with multiple feature selection and prediction models were employed to identify race-specific altered metabolic signatures. This was followed by the identification of altered metabolic pathways with a focus on AA patients with breast cancer. The clinical significance of the findings was further examined in the PanCancer Atlas breast cancer data set. Results: We identified differential metabolic signatures between NHW and AA patients. In AA patients, we observed disturbed amino acid metabolism, while fatty acid metabolism was significant in NHW patients. By mapping these metabolites to genes, this study identified significant relations with regulators of metabolism such as methionine adenosyltransferase 1A (MAT1A), DNA Methyltransferases, Histone methyltransferases for AA individuals, and Fatty acid Synthase (FASN) and Monoacylglycerol lipase (MGL) for NHW individuals. Specific histone methyltransferase NELFE was overexpressed and associated with poor survival exclusively in AA individuals. Conclusion: We employ a comprehensive and novel approach that integrates multiple machine learning methods, and statistical methods, coupled with human functional pathway analyses. This metabolic profile of serum samples might be used to assess risk progression in AA individuals with ER+ breast cancer. To our knowledge, this is a novel finding that describes metabolic alterations in AA breast cancer and emphasizes a potential biological basis for breast cancer health disparities. Citation Format: Ashlie Santaliz Casiano, Zeynep Madak-Erdogan, Dhruv Meta, Jonna Frasor, Garth Rauscher, Kent Hoskins. Identification of metabolic and molecular mechanisms contributing to ER+ cancer disparities using a machine-learning pipeline [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C020.

A Novel Protective locus significantly reduces the ApoEε4 risk for Alzheimer’s Disease in individuals of African Ancestry.

AbstractBackgroundAfrican ancestry populations have a lower risk for developing Alzheimer disease (AD) from ApoEε4 compared to other populations. Understanding this mechanism of protection could lead new therapeutic insights for AD. Our goal is to identify areas of the genome that interact with ApoEε4 in African ancestry that result in the lowered risk for developing AD in this population.MethodsWe performed association analyses using a logistic regression model with ApoEε4 allele as an interaction term and adjusted for genome‐wide ancestry, age, and sex. Discovery analysis included imputed SNP data from 1,850 African American (AA) individuals with AD and 4,331 AA controls. We performed replication analysis on whole‐genome sequenced (WGS) data from 1) 63 Ibadan (Nigerian) AD individuals and 648 Ibadan controls; 2) WGS 273 Puerto Rican (PR) AD individuals and 275 PR controls; and 3) SNPs imputed from 8,463 non‐Hispanic White (NHW) AD individuals and 11,365 NHW controls.ResultsWe identified a significant interaction with the ApoE ε4 allele and the SNP rs10423769_A allele, that reduces the odds ratio for AD risk from 7.2 for ApoEε4/ε4 without the A allele to 2.1 for allele ApoEε4/ε4 carriers with at least one A allele. rs10423769 (frequency = 0.11 in AA, NHW= 0.003) is located approximately 2 megabases distal to ApoE, in a large cluster of pregnancy specific beta‐1 glycoproteins on chromosome 19 and lies within a long noncoding RNA, ENSG00000282943. rs10423769 is reported to be a splicing QTL (sQTL) for TMEM145, whose highest brain expression is in the cerebellum. This interaction analysis was identified in the discovery AA dataset (β=‐0.54, SE=0.12,p‐value=7.50x10‐6), and this finding was replicated in both the Ibadan (β = ‐1.32,SE = 0.52,p‐value = 1.15x10‐2) and PR (β=‐1.27,SE=0.64,p‐value=4.91x10‐2) datasets while it trended but was not significant in the NHW dataset.ConclusionThis study identified a new African‐ancestry specific locus that reduces the risk effect of ApoEε4 for developing AD by approximately 75%. The genes lying near this protective locus suggest potential new protective mechanisms for AD development.

Racial differences in the association of body mass index and ovarian cancer risk in the OCWAA Consortium.

Obesity disproportionately affects African American (AA) women and has been shown to increase ovarian cancer risk, with some suggestions that the association may differ by race. We evaluated body mass index (BMI) and invasive epithelial ovarian cancer (EOC) risk in a pooled study of case-control and nested case-control studies including AA and White women. We evaluated both young adult and recent BMI (within the last 5 years). Associations were estimated using multi-level and multinomial logistic regression models. The sample included 1078 AA cases, 2582 AA controls, 3240 White cases and 9851 White controls. We observed a higher risk for the non-high-grade serous (NHGS) histotypes for AA women with obesity (ORBMI 30+= 1.62, 95% CI: 1.16, 2.26) and White women with obesity (ORBMI 30+= 1.20, 95% CI: 1.02, 2.42) compared to non-obese. Obesity was associated with higher NHGS risk in White women who never used HT (ORBMI 30+= 1.40, 95% CI: 1.08, 1.82). Higher NHGS ovarian cancer risk was observed for AA women who ever used HT (ORBMI 30+= 2.66, 95% CI: 1.15, 6.13), while in White women, there was an inverse association between recent BMI and risk of EOC and HGS in ever-HT users (EOC ORBMI 30+= 0.81, 95% CI: 0.69, 0.95, HGS ORBMI 30+= 0.73, 95% CI: 0.61, 0.88). Obesity contributes to NHGS EOC risk in AA and White women, but risk across racial groups studied differs by HT use and histotype.

Blood glutamine synthetase signaling in alcohol use disorder and racial disparity

As of 2018, 14.4 million adults ages 18 and older in the U.S had alcohol use disorder (AUD). However, only about 8% of adults who had AUD in the past year received treatment. Surveys have also shown racial disparities regarding AUD treatments. Thus, it is imperative to identify racial disparities in AUD patients, as it may indicate a specific underlying pathophysiology in an AUD subpopulation. To identify racial disparity in AUD, we enrolled 64 cohorts, including 26 AUD participants and 38 healthy controls, from Northwest Louisiana using community-based enrollment. Then, we used psychometric scales to assess alcohol drinking patterns and measured blood metabolites change using LC-MS/MS. Alcohol-related scales from the questionnaires did not differ between the Caucasian AUD participants and African-American AUD participants. From blood metabolomics analyses, we identified that 6 amino acids were significantly different by AUD status and or race. Interestingly, Caucasian AUD participants had a higher glutamate metabolism mediated by glutamine synthetase (GS). The correlation between blood glutamate/glutamine ratio and GS activity was only significant in the Caucasian AUD group whereas no changes were observed in African-American AUD group or controls. Taken together, our findings from this sample population demonstrate that blood GS is a potential biomarker associated with Caucasian AUD, which is an important step towards the application of a new pharmacological treatment for AUD.

Genetic Analysis in African American Children Supports Ancestry-Specific Neuroblastoma Susceptibility.

Neuroblastoma is rarer in African American (AA) children compared with American children of European descent. AA children affected with neuroblastoma, however, more frequently develop the high-risk form of the disease. We have genotyped an AA cohort of 629 neuroblastoma cases (254 high-risk) and 2,990 controls to investigate genetic susceptibility to neuroblastoma in AAs. We confirmed the known neuroblastoma susceptibility gene BARD1 at genome-wide significance in the subset of high-risk cases. We also estimated local admixture across the autosomal genome in the AA cases and controls and detected a signal at 4q31.22 where cases show an increase in European ancestry. A region at 17p13.1 showed increased African ancestry in the subgroup of high-risk cases with respect to intermediate- and low-risk cases. Using results from our published European American (EA) genome-wide association study (GWAS), we found that a polygenic score that included all independent SNPs showed a highly significant association (P value = 1.8 × 10-73) and explained 19% of disease risk variance in an independent EA cohort. In contrast, the best fit polygenic score (P value = 3.2 × 10-11) in AAs included only 22 independent SNPs with association P value < 2.75 × 10-6 in the EA GWAS, and explained 2% of neuroblastoma risk variance. The significance of the polygenic score dropped rapidly with inclusion of additional SNPs. These findings suggest that several common variants contribute to risk of neuroblastoma in an ancestry-specific fashion. This work supports the need for GWAS to be performed in populations of all races and ethnicities.

Comparison Between the 2021 USPSTF Lung Cancer Screening Criteria and Other Lung Cancer Screening Criteria for Racial Disparity in Eligibility

In 2021, the US Preventive Services Task Force (USPSTF) broadened its age and smoking pack-year requirement for lung cancer screening. To compare the 2021 USPSTF lung cancer screening criteria with other lung cancer screening criteria and evaluate whether the sensitivity and specificity of these criteria differ by race. This study included 912 patients with lung cancer and 1457 controls without lung cancer enrolled in an epidemiology study (INHALE [Inflammation, Health, Ancestry, and Lung Epidemiology]) in the Detroit metropolitan area between May 15, 2012, and March 31, 2018. Patients with lung cancer and controls were 21 to 89 years of age; patients with lung cancer who were never smokers and controls who were never smokers were not included in these analyses. Statistical analysis was performed from August 31, 2020, to April 13, 2021. The study assessed whether patients with lung cancer and controls would have qualified for lung cancer screening using the 2013 USPSTF, 2021 USPSTF, and 2012 modification of the model from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCOm2012) screening criteria. Sensitivity was defined as the percentage of patients with lung cancer who qualified for screening, while specificity was defined as the percentage of controls who did not qualify for lung cancer screening. Participants included 912 patients with a lung cancer diagnosis (493 women [54%]; mean [SD] age, 63.7 [9.5] years) and 1457 control participants without lung cancer at enrollment (795 women [55%]; mean [SD] age, 60.4 [9.6] years). With the use of 2021 USPSTF criteria, 590 patients with lung cancer (65%) were eligible for screening compared with 619 patients (68%) per the PLCOm2012 criteria and 445 patients (49%) per the 2013 USPSTF criteria. With the use of 2013 USPSTF criteria, significantly more White patients than African American patients with lung cancer (324 of 625 [52%] vs 121 of 287 [42%]) would have been eligible for screening. This racial disparity was absent when using 2021 USPSTF criteria (408 of 625 [65%] White patients vs 182 of 287 [63%] African American patients) and PLCOm2012 criteria (427 of 625 [68%] White patients vs 192 of 287 [67%] African American patients). The 2013 USPSTF criteria excluded 950 control participants (65%), while the PLCOm2012 criteria excluded 843 control participants (58%), and the 2021 USPSTF criteria excluded 709 control participants (49%). The 2013 USPSTF criteria excluded fewer White control participants than African American control participants (514 of 838 [61%] vs 436 of 619 [70%]). This racial disparity is again absent when using 2021 USPSTF criteria (401 of 838 [48%] White patients vs 308 of 619 [50%] African American patients) and PLCOm2012 guidelines (475 of 838 [57%] White patients vs 368 of 619 [60%] African American patients). This study suggests that the USPSTF 2021 guideline changes improve on earlier, fixed screening criteria for lung cancer, broadening eligibility and reducing the racial disparity in access to screening.

Abstract IA-40: CDKN2A germline rare coding variants and risk of pancreatic cancer in minority populations

Abstract Performing genetic epidemiology studies in underrepresented populations is challenging, but is extremely important in order to understand how cancer impacts differing populations, This can then allow more tailored and nuanced management of persons at risk. Our group at Mayo Clinic encountered some interesting preliminary findings regarding CDKN2A, but given small numbers of subjects in our registry, we needed to partner with other collaborators to have enough statistical power to make sense of the findings and generate a publishable result. This talk will focus on the means of doing this, the importance of team-based science across centers, and future opportunities. Background: Pathogenic germline mutations in the CDKN2A tumor suppressor gene are rare and associated with highly penetrant familial melanoma and pancreatic cancer in non-Hispanic whites. WeTo date, the prevalence and impact of CDKN2A rare coding variants (RCV) in racial minority groups remain poorly characterized. We examined the role of CDKN2A RCVs on the risk of pancreatic cancer among minority subjects. Methods: We performed a case-control study of germline mutations in CDKN2A among patients with incident pancreatic cancer and controls, focused on underrepresented minority populations. We sequenced CDKN2A in 220 African American pancreatic cancer cases, 900 noncancer African American controls, and 183 Nigerian controls. RCV frequencies were determined for each group and compared with that of 1,537 Non-Hispanic White patients with pancreatic cancer. Odds ratios (OR) and 95% confidence intervals (CI) were calculated for both a case–case comparison of RCV frequencies in African Americans versus Non-Hispanic Whites, and case–control comparison between AA cases versus noncancer AA controls plus Nigerian controls. Smaller sets of Hispanic and Native American cases and controls also were sequenced. Race/ethnicity categorization was from self-report. Results: One novel missense RCV and one novel frameshift RCV were found among AA patients: 400G&amp;gt;A and 258_278del. RCV carrier status was associated with increased risk of pancreatic cancer among AA cases (11/220; OR, 3.3; 95% CI, 1.5–7.1; P ¼ 0.004) compared with African American and Nigerian controls (17/1,083). Further, African American cases had higher frequency of RCVs: 5.0% (OR, 13.4;95%CI, 4.9–36.7; P &amp;lt; 0.001) compared with Non-Hispanic White cases (0.4%). Conclusions: CDKN2A RCVs are more common in African Americans than in Non-Hispanic White patients with pancreatic cancer and associated with moderately increased pancreatic cancer risk among African Americans. Citation Format: Robert McWilliams. CDKN2A germline rare coding variants and risk of pancreatic cancer in minority populations [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr IA-40.

Genetic and demographic predisposing factors associated with pediatric sleepwalking in the Philadelphia Neurodevelopmental Cohort

ObjectivesSleepwalking is a parasomnia associated with non-rapid eye movement (NREM) sleep and is formally diagnosed using polysomnography (PSG). However, PSG are difficult to perform on children or adolescents due to needed compliance. To understand this condition in youth, few studies have been conducted on a large cohort of youths with a diverse distribution of ages and races to characterize it better in the absence of PSG. The present study aimed to evaluate the prevalence of sleepwalking in youth, as well as associated demographic and genetic characteristics, using questionnaires in a large pediatric cohort. MethodsData from the Philadelphia Neurodevelopmental Cohort (PNC) of 7515 youths aged between 8 and 22 years were used in analyses. Demographic and clinical data, including age, sex, and race, and genetic data from 2753 African American (AA) and 4762 European American (EA) subjects were investigated. The age-wise prevalence of sleepwalking in AA and EA subjects was evaluated. Finally, race-specific genome-wide association (GWAS) analyses of sleepwalking were also performed (N = 155 AA cases and 2598 AA controls; N = 512 EA cases and 4250 EA controls). ResultsLifetime history of sleepwalking correlated with male sex and EA race. A genetic risk locus that reached genome-wide significance was detected at rs73450744 on chromosome 18 in AA, but not EA youth. ConclusionThe present results suggest that male sex, EA race, and genetic factors may be associated with higher rates of sleepwalking among youth. Future studies should consider these variables to advance understanding of the complex pathogenesis of sleepwalking.

Deep learning prediction of attention-deficit hyperactivity disorder in African Americans by copy number variation.

Current understanding of the underlying molecular network and mechanism for attention-deficit hyperactivity disorder (ADHD) is lacking and incomplete. Previous studies suggest that genomic structural variations play an important role in the pathogenesis of ADHD. For effective modeling, deep learning approaches have become a method of choice, with ability to predict the impact of genetic variations involving complicated mechanisms. In this study, we examined copy number variation in whole genome sequencing from 116 African Americans ADHD children and 408 African American controls. We divided the human genome into 150 regions, and the variation intensity in each region was applied as feature vectors for deep learning modeling to classify ADHD patients. The accuracy of deep learning for predicting ADHD diagnosis is consistently around 78% in a two-fold shuffle test, compared with ∼50% by traditional k-mean clustering methods. Additional whole genome sequencing data from 351 European Americans children, including 89 ADHD cases and 262 controls, were applied as independent validation using feature vectors obtained from the African American ethnicity analysis. The accuracy of ADHD labeling was lower in this setting (∼70-75%) but still above the results from traditional methods. The regions with highest weight overlapped with the previously reported ADHD-associated copy number variation regions, including genes such as GRM1 and GRM8, key drivers of metabotropic glutamate receptor signaling. A notable discovery is that structural variations in non-coding genomic (intronic/intergenic) regions show prediction weights that can be as high as prediction weight from variations in coding regions, results that were unexpected.

Quantitative Sensory Testing in Children with Sickle Cell Disease

▪Background: Quantitative Sensory Testing (QST) is used in a variety of pain disorders such as arthritis and neuropathic pain syndromes, to characterize pain and predict prognosis and response to specific therapies. QST evaluates sensory function using a set of psychophysical procedures to measure subjective somatosensory responses to various physical stimuli. In Sickle Cell Disease (SCD) the painful vasoocclusive crisis is the most difficult management challenge and factors underlying the transition from acute to chronic pain and the wide interpatient variability in the pain experience are poorly understood. Optimal management for this complex pain syndrome remains unclear despite over three decades of basic and clinical research in the field.In this study, we aimed to duplicate results in the literature documenting altered QST thresholds in SCD and test the reproducibility of results over time to validate QST as a therapeutic endpoint for use in clinical trials evaluating novel preventative pain therapies.Objectives: Primary objectives were to test thermal thresholds in children with SCD versus African American controls and determine consistency over 6 months. Exploratory objectives were to correlate QST with clinical factors and select biomarkers and assess pressure pain thresholds (PPTs).Methods: Fifty-seven SCD and 60 control subjects aged 8-20 years underwent heat (wdt) and cold (cdt) detection and pain (hpt and cpt) threshold testing using a Medoc TSAII. A thermal composite score (TCS) was constructed by averaging the wdt, cdt, hpt, and cpt threshold responses from the testing instrument's starting temperature of 32°C. All participants were tested at baseline and 3 months; SCD subjects were additionally tested at 6 months and blood collected for future biomarker assessment. PPTs were performed using an SBMedic algometer. A single individual performed all QST. Descriptive statistics were computed and covariate-adjusted differences in thresholds within and between groups evaluated over time by mixed effects regression models with random intercepts and linear contrast tests. The intraclass correlation coefficient (ICC) from these models was used to assess within-subject consistency and Spearman's correlation was used to evaluate associations between thresholds and biomarkers. In addition, as a nested pseudo-intervention study, we analyzed a subset of “new” hydroxyurea (HU) users consisting of SCD subjects in whom HU was initiated within a few weeks prior to, or shortly after baseline testing. Significance was set at 0.05.Results: There were no significant differences in mean thermal or PPTs between SCD and control participants at baseline (Table 1) or month 3. QST measurements were consistent in SCD and control subjects for cpt, wdt, hpt and TCS (each ICC>0.55), but not necessarily for cdt (ICC = 0.37). Although generally internally consistent, there was some variability in mean thermal thresholds among SCD subjects over time, but the only significant difference between the 3 and 6 month means was for hpt (+0.67°C; 95% CI 1.15, 0.19). There was no association between mean thermal thresholds and chronic transfusion therapy. The group in whom HU was initiated shortly after baseline testing (n=6) demonstrated significant reductions in all thermal sensitivity and pain threshold measurements following HU initiation (Table 2).Conclusions: In contrast to Brandow's study (Brandow, American Journal Hematology, 2012), which documented thermal hypersensitivity in SCD, we have not demonstrated significant differences in thermal thresholds between SCD and control subjects. This could be due, in part, to differences in body sites used for testing. Results between second and third test sessions were highly consistent, indicating that reliability may improve once subjects have experience with QST. Subjects on whom HU was initiated shortly after baseline testing (new HU users) exhibited progressive and significant decreases in both cold and heat sensitivity from baseline to 6 months, suggesting that thermal testing is sensitive to effective therapy to prevent vasoocclusive pain. These findings are of critical importance to inform the planning of future SCD related clinical trials using QST as an endpoint in the evaluation of preventative pain therapies.Supported by National Institute of General Medical Sciences National Institutes of Health Award P20GM109021 and U54GM104941 [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Genital Powder Use and Risk of Epithelial Ovarian Cancer in the Ovarian Cancer in Women of African Ancestry Consortium.

Genital powder use is more common among African-American women; however, studies of genital powder use and ovarian cancer risk have been conducted predominantly in White populations, and histotype-specific analyses among African-American populations are limited. We used data from five studies in the Ovarian Cancer in Women of African Ancestry consortium. Participants included 620 African-American cases, 1,146 African-American controls, 2,800 White cases, and 6,735 White controls who answered questions on genital powder use prior to 2014. The association between genital powder use and ovarian cancer risk by race was estimated using logistic regression. The prevalence of ever genital powder use for cases was 35.8% among African-American women and 29.5% among White women. Ever use of genital powder was associated with higher odds of ovarian cancer among African-American women [OR = 1.22; 95% confidence interval (CI) = 0.97-1.53] and White women (OR = 1.36; 95% CI = 1.19-1.57). In African-American women, the positive association with risk was more pronounced among high-grade serous tumors (OR = 1.31; 95% CI = 1.01-1.71) than with all other histotypes (OR = 1.05; 95% CI = 0.75-1.47). In White women, a significant association was observed irrespective of histotype (OR = 1.33; 95% CI = 1.12-1.56 and OR = 1.38; 95% CI = 1.15-1.66, respectively). While genital powder use was more prevalent among African-American women, the associations between genital powder use and ovarian cancer risk were similar across race and did not materially vary by histotype. This is one of the largest studies to date to compare the associations between genital powder use and ovarian cancer risk, overall and by histotype, between African-American and White women.

Transcriptional Inflammatory Signatures Differentiate Baseline Health from Acute Pain in Sickle Cell Disease Patients

Severe unpredictable acute pain and chronic daily pain causes significant morbidity for individuals with sickle cell disease (SCD). SCD is shown to be a chronic inflammatory disorder. Regulation of the immune response can potentially modulate the inflammatory impact on pain in SCD. We sought to determine the balance between patients’ inflammatory and immune regulatory response and examine whether this balance changes during acute SCD pain. We conducted a cross sectional analysis involving 3 cohorts: 16 SCD patients in baseline health, 27 SCD patients during acute pain and 45 healthy African American controls. Participant plasma was co-cultured with cryopreserved PBMCs from a healthy donor to induce transcription. We identified transcripts that differentiate SCD patients from healthy controls and retained ones differentially expressed that exhibit a fold change >1.4, ANOVA p-value of

First- and second-degree family history of ovarian and breast cancer in relation to risk of invasive ovarian cancer in African American and white women.

Family history (FH) of ovarian cancer and breast cancer are well-established risk factors for ovarian cancer, but few studies have examined this association in African American (AA) and white women by histotype. We assessed first- and second-degree FH of ovarian and breast cancer and risk of epithelial ovarian cancer in the Ovarian Cancer in Women of African Ancestry Consortium. Analyses included 1052 AA cases, 2328 AA controls, 2380 white cases and 3982 white controls. Race-specific odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multilevel logistic regression with adjustment for covariates. Analyses were stratified by histotype (high-grade serous vs others). First-degree FH of ovarian cancer was associated with high-grade serous carcinoma in AA (OR = 2.32, 95% CI: 1.50, 3.59) and white women (OR = 2.48, 95% CI: 1.82, 3.38). First-degree FH of breast cancer increased risk irrespective of histotype in AAs, but with high-grade serous carcinoma only in white women. Associations with second-degree FH of ovarian cancer were observed for overall ovarian cancer in white women and with high-grade serous carcinoma in both groups. First-degree FH of ovarian cancer and of breast cancer, and second-degree FH of ovarian cancer is strongly associated with high-grade serous ovarian carcinoma in AA and white women. The association of FH of breast cancer with high-grade serous ovarian carcinoma is similar in white women and AA women, but may differ for other histotypes.

Abstract PO-180: Genital powder use and risk of epithelial ovarian cancer in the Ovarian Cancer in Women of African Ancestry Consortium

Abstract PURPOSE: To date, the epidemiology of epithelial ovarian cancer (EOC) among African-American women has been severely understudied. It remains unclear to what extent variation in the prevalence of EOC risk factors may explain incidence disparities between African-American and white women. Genital powder use is more common among African-American women; however, studies of genital power use and EOC risk have been conducted predominantly in white populations, and histotype specific analyses among African-American populations are limited. The objective of this study was to evaluate the association between genital powder use and EOC risk among African-American and white women, overall and by histotype. METHODS: We used data from four ovarian cancer case-control studies in the Ovarian Cancer in Women of African Ancestry (OCWAA) consortium: the African American Cancer Epidemiology Study, the Los Angeles County Ovarian Cancer Study, the Cook County Case-Control Study, and the North Carolina Ovarian Cancer Study. Participants included 601 African-American cases, 1,012 African-American controls, 2,225 white cases, and 3,086 white controls who answered questions on genital powder use prior to 2014. The association between genital powder use and EOC risk was estimated using logistic regression. Pooled histotype specific odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using polytomous logistic regression. The population attributable risk (PAR) by race was calculated using the Bruzzi method. RESULTS: The prevalence of reporting ever genital powder use was 66% among African-American women and 44% among white women. African- American women who ever used genital powder were 29% more likely to develop EOC compared to African-American women who reported no use (OR=1.29, 95% CI=0.98-1.71). White women who ever used genital powder were 36% more likely to develop EOC compared to white women reporting no use (OR=1.36, 95% CI=1.12- 1.52). The associations were similar when examined by histotype. Among African- American women, the ORs were 1.29 (95% CI=0.94-1.76) for high grade serous (HGS) and 1.38 (95% CI=0.87-2.19) for non-HGS. For white women, the corresponding ORs were 1.27 (95% CI=1.06-1.52) and 1.21 (95% CI=0.96-1.56), respectively. The PAR for genital powder use was slightly higher, but not statistically significantly different, in African-American women (PAR=10.7, 95% CI=3.7-17.5) compared to white women (PAR=7.8, 95% CI=4.9-10.7). CONCLUSION: While the prevalence of ever genital body powder use was higher among African-American women, the associations between genital powder use and ovarian cancer risk were similar between African-American and white women, and did not materially vary by histotype. Further analyses incorporating additional OCWAA studies and using more refined exposure categories (e.g., frequency and duration of powder use, age at first application) are currently being conducted. Citation Format: Colette P. Davis, Elisa V. Bandera, Traci N. Bethea, Tareq F. Camacho, Charlotte E. Joslin, Anna H. Wu, Alicia Beeghly-Fadiel, Emily K. Cloyd, Patricia G. Moorman, Evan Myers, Heather M. Ochs-Balcom, Lauren C. Peres, Will L. Rosenow, Veronica W. Setiawan, Lynn Rosenberg, Joellen M Schildkraut, Holly R. Harris. Genital powder use and risk of epithelial ovarian cancer in the Ovarian Cancer in Women of African Ancestry Consortium [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-180.