Committing to genomic answers for all kids: Evaluating inequity in genomic research enrollment.

PURPOSE: Persistent inequities in genomic medicine and research contribute to health disparities. This analysis uses a context-specific and equity-focused strategy to evaluate enrollment patterns for Genomic Answers for Kids (GA4K), a large, metropolitan-wide genomic study on children. METHODS: Electronic health records for 2247 GA4K study participants were used to evaluate the distribution of individuals by demographics (race, ethnicity, and payor type) and location (residential address). Addresses were geocoded to produce point density and 3-digit zip code maps showing local and regional enrollment patterns. Health system reports and census data were used to compare participant characteristics with reference populations at different spatial scales. RESULTS: Racial and ethnic minoritized and populations with low-income were underrepresented in the GA4K study cohort. Geographic variation demonstrates inequity in enrollment and participation among children from historically segregated and socially disadvantaged communities. CONCLUSION: Our findings illustrate inequity in enrollment related to both GA4K study design and structural inequalities, which we suspect may exist for similar US-based studies. Our methods provide a scalable framework for continually evaluating and improving study design to ensure equitable participation in and benefits from genomic research and medicine. The use of high-resolution, place-based data represents a novel and practical means of identifying and characterizing inequities and targeting community engagement.

The safety of asthma medications during pregnancy and lactation: Clinical management and research priorities.

Asthma is one of the most common underlying diseases in women of reproductive age that can lead to potentially serious medical problems during pregnancy and lactation. A group of key stakeholders across multiple relevant disciplines was invited to take part in an effort to prioritize, strategize, and mobilize action steps to fill important gaps in knowledge regarding asthma medication safety in pregnancy and lactation. The stakeholders identified substantial gaps in the literature on the safety of asthma medications used during pregnancy and lactation and prioritized strategies to fill those gaps. Short-term action steps included linking data from existing complementary study designs (US and international claims data, single drug pregnancy registries, case-control studies, and coordinated systematic data systems). Long-term action steps included creating an asthma disease registry, incorporating the disease registry into electronic health record systems, and coordinating care across disciplines. The stakeholders also prioritized establishing new infrastructures/collaborations to perform research in pregnant and lactating women and to include patient perspectives throughout the process. To address the evidence gaps, and aid in populating product labels with data that inform clinical decision making, the consortium developed a plan to systematically obtain necessary data in the most efficient and timely manner.

Identification of Presymptomatic and Asymptomatic Cases Using Cohort-Based Testing Approaches at a Large Correctional Facility-Chicago, Illinois, USA, May 2020.

BACKGROUND: Coronavirus disease 2019 (COVID-19) continues to cause significant morbidity and mortality worldwide. Correctional and detention facilities are at high risk of experiencing outbreaks. We aimed to evaluate cohort-based testing among detained persons exposed to laboratory-confirmed cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in order to identify presymptomatic and asymptomatic cases. METHODS: During 1-19 May 2020, 2 testing strategies were implemented in 12 tiers or housing units of the Cook County Jail, Chicago, Illinois. Detained persons were approached to participate in serial testing (n = 137) and offered tests at 3 time points over 14 days (day 1, days 3-5, and days 13-14). The second group was offered a single test and interview at the end of a 14-day quarantine period (day 14 group) (n = 87). RESULTS: 224 detained persons were approached for participation and, of these, 194 (87%) participated in ≥1 interview and 172 (77%) had ≥1 test. Of the 172 tested, 19 were positive for SARS-CoV-2. In the serial testing group, 17 (89%) new cases were detected, 16 (84%) on day 1, 1 (5%) on days 3-5, and none on days 13-14; in the day 14 group, 2 (11%) cases were identified. More than half (12/19; 63%) of the newly identified cases were presymptomatic or asymptomatic. CONCLUSIONS: Our findings highlight the utility of cohort-based testing promptly after initiating quarantine within a housing tier. Cohort-based testing efforts identified new SARS-CoV-2 asymptomatic and presymptomatic infections that may have been missed by symptom screening alone.

Network Characteristics and Visualization of COVID-19 Outbreak in a Large Detention Facility in the United States - Cook County, Illinois, 2020.

Correctional and detention facilities have been disproportionately affected by coronavirus disease 2019 (COVID-19) because of shared space and movement of staff members and detained persons within facilities (1,2). During March 1-April 30, 2020, at Cook County Jail in Chicago, Illinois, >900 COVID-19 cases were diagnosed across all 10 housing divisions, representing 13 unique buildings.† Movement within the jail was examined through network analyses and visualization, a field that examines elements within a network and the connections between them. This methodology has been used to supplement contact tracing investigations for tuberculosis and to understand how social networks contribute to transmission of sexually transmitted infections (3-5). Movements and connections of 5,884 persons (3,843 [65%] detained persons and 2,041 [35%] staff members) at the jail during March 1-April 30 were analyzed. A total of 472 (12.3%) COVID-19 cases were identified among detained persons and 198 (9.7%) among staff members. Among 103,701 shared-shift connections among staff members, 1.4% occurred between persons with COVID-19, a percentage that is significantly higher than the expected 0.9% by random occurrence alone (p<0.001), suggesting that additional transmission occurred within this group. The observed connections among detained persons with COVID-19 were significantly lower than expected (1.0% versus 1.1%, p<0.001) when considering only the housing units in which initial transmission occurred, suggesting that the systematic isolation of persons with COVID-19 is effective at limiting transmission. A network-informed approach can identify likely points of high transmission, allowing for interventions to reduce transmission targeted at these groups or locations, such as by reducing convening of staff members, closing breakrooms, and cessation of contact sports.

Closing the gap: Understanding African American asthma knowledge and beliefs.

BACKGROUND: African American children are disproportionately affected by asthma (13% vs 8% non-Hispanic white Americans) and experience 30% higher asthma-related deaths than whites. Knowledge regarding asthma and asthma treatment among African Americans has been postulated as a potential contributor to this observed health disparity. Compared with the amount of studies on asthma, few investigations provide insight into the baseline knowledge and beliefs of African Americans regarding asthma. OBJECTIVE: Assess knowledge and beliefs regarding asthma symptoms, diagnosis, treatment, prognosis, and stigmas in a general community sample of African Americans. METHODS: Using community-based participatory research techniques, we developed and implemented a cross-sectional survey to explore asthma knowledge and beliefs among African American adults in a Midwestern city. RESULTS: Among the 158 African American adults who completed the survey, general asthma knowledge was good, with awareness of the genetic contribution to asthma and general asthma symptomatology (eg, 92% aware of nighttime cough as a symptom). However, asthma-related misconceptions were also revealed. Thirty-three percent of respondents were concerned about addiction to asthma medication, and 60% of respondents believed that inhaled corticosteroids were dangerous or did not know. CONCLUSION: This study reveals important insights into asthma knowledge and beliefs among African Americans that may be used to address disparities in asthma outcomes in this population.

Population pharmacokinetic/pharmacodynamic modeling of histamine response measured by histamine iontophoresis laser Doppler.

The epicutaneous histamine (EH) test is the current gold standard method for the clinical evaluation of allergic conditions. However, the EH method is limited in providing an objective and qualitative assessment of histamine pharmacodynamic response. The histamine iontophoresis with laser Doppler (HILD) monitoring method, an alternative method, allows a fixed dose of histamine to be delivered and provides an objective, continuous, and dynamic measurement of histamine epicutaneous response in children and adults. However, due to the high sampling frequency (up to 40 Hz), the output files are usually too cumbersome to be directly used for further analysis. In this study, we developed an averaging algorithm that efficiently reduces the HILD data in size. The reduced data was further analyzed and a population linked effect pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the local histamine response. The model consisted of a one-compartment PK model and a direct-response fractional maximum effect (Emax) model. The parameter estimates were obtained as follows: absorption rate constant (ka), 0.094/min; absorption lag time (Tlag), 2.72 min; partitioning clearance from local depot to systemic circulation (CLpar), 0.0006 L/min; baseline effect (E0), 13.1 flux unit; Emax, 13.4; concentration at half maximum effect (EC50) 31.1 mg/L. Covariate analysis indicated that age and race had significant influence on Tlag and EC50, respectively.

Genetic Variation along the Histamine Pathway in Children with Allergic versus Nonallergic Asthma.

Histamine is an important mediator in the pathogenesis of asthma. Variation in genes along the histamine production, response, and degradation pathway may be important in predicting response to antihistamines. We hypothesize that differences exist among single-nucleotide polymorphisms (SNPs) in genes of the histamine pathway between children with allergic versus nonallergic asthma. Children (7-18 yr of age; n = 202) with asthma were classified as allergic or nonallergic based on allergy skin testing. Genotyping was performed to detect known SNPs (n = 10) among genes (HDC, HNMT, ABP1, HRH1, and HRH4) within the histamine pathway. Chi square tests and Cochran-Armitage Trend were used to identify associations between genetic variants and allergic or nonallergic asthma. Significance was determined by P < 0.05 and false-positive report probability. After correction for race differences in genotype were observed, HRH1-17 TT (6% allergic versus 0% nonallergic; P = 0.04), HNMT-464 TT (41% allergic versus 29% nonallergic; P = 0.04), and HNMT-1639 TT (30% allergic versus 20% nonallergic; P = 0.04) were overrepresented among children with allergic asthma. Genotype differences specifically among the African-American children were also observed: HRH1-17 TT (13% allergic versus 0% nonallergic; P = 0.04) and HNMT-1639 TT (23% allergic versus 3% nonallergic; P = 0.03) genotypes were overrepresented among African-American children with allergic asthma. Our study suggests that genetic variation within the histamine pathway may be associated with an allergic versus nonallergic asthma phenotype. Further studies are needed to determine the functional significance of identified SNPs and their impact on antihistamine response in patients with asthma and allergic disease.

Genetic variation within the histamine pathway among patients with asthma--a pilot study.

OBJECTIVE: Histamine is an important mediator in the pathophysiology of asthma. We have previously reported that HRH1 is differentially expressed among those with asthma compared to those without asthma. Single histamine-related genes have also been associated with asthma. We aimed to evaluate known single nucleotide polymorphisms (SNPs) in genes along the histamine biotransformation and response pathway, and determine their association with asthma and HRH1 mRNA expression. METHODS: We enrolled children and adults (n = 93) with/without asthma who met inclusion/exclusion criteria. Genotyping was performed for nine known SNPs in the HDC, HRH1, HRH4, HNMT and ABP1 genes. HRH1 mRNA expression was determined on RNA from buccal tissue. General linear model, Fisher's exact test and Chi-square test were used to determine differences in allele, genotype and haplotype frequency between subjects with and without asthma and differential HRH1 mRNA expression relative to genotype. Statistical significance was determined by p < 0.05. RESULTS: No difference was observed in genotype/allele frequency for the nine SNPs between subjects with and without asthma. The HNMT-1639C/-464C/314C/3'UTRA haplotype was more frequently observed in those without asthma than those with asthma (p = 0.03). We also observed genetic differences relative to race and gender. HNMT 314 genotype CT was more frequent in males with asthma compared to those without asthma (p = 0.04). CONCLUSIONS: Histamine pathway haplotype was associated with a diagnosis of asthma in our cohort but allele and genotype were not. Subgroup evaluations may also be important. Further studies are needed to determine the potential biological/clinical significance of our findings.

The impact of skin color and tone on histamine iontophoresis and Doppler flowmetry measurements as a pharmacodynamic biomarker.

The phenotypical manifestations of asthma among children are diverse and exhibit varying responses to therapeutic interventions. There is a need to develop objective biomarkers to improve the characterization of allergic and inflammatory responses relevant to asthma to predict therapeutic treatment responses. We have previously investigated histamine iontophoresis with laser Doppler flowmetry (HILD) as a potential surrogate biomarker that characterizes histamine response and may be utilized to guide the treatment of allergic and inflammatory disease. We have identified intra-individual variability of HILD response type among children and adults with asthma and that HILD response type varied in association with racial classification. As laser Doppler flowimetry may be impacted by skin color, we aimed to further validate the HILD method by determining if skin color or tone is associated with observed HILD response type differences. We conducted an observational study utilizing quantification of skin color and tone obtained from photographs of the skin among participants during HILD assessments via the RGB color model. We compared RGB values across racial, ethnic, and HILD response type via the Kruskal-Wallis test and calculated Kendall rank correlation coefficient to evaluate the relationship between RGB composite scores and HILD pharmacodynamic measures. We observed that RGB scores differed among racial groups and histamine response phenotypes (p < 0.05). However, there was a lack of correlation between the RGB composite score and HILD pharmacodynamic measures (r values 0.1, p > 0.05). These findings suggest that skin color may not impact HILD response variations, necessitating further research to understand previously observed differences across identified racial groups.

Understanding Health Equity in Patient-Reported Outcomes.

Patient-reported outcomes (PROs) are measures of patients' health that are conveyed directly by individual patients. These measures serve as instruments to evaluate the impact of interventions on any aspect of patients' health, from specific symptoms to broader quality of life indicators. However, their effectiveness relies on capturing relevant factors accurately. Whereas they are commonly used in clinical trials, PROs extend their influence across health care settings, informing clinicians, health care payers, regulators, and administrators to guide quality improvement and reimbursement decisions. Neglecting health equity considerations in PRO development and implementation widens health disparities, leading to biased interpretations, medical mismanagement, and poor health outcomes among marginalized groups. To foster equitable health care, efforts must focus on considering the values of underrepresented populations in PRO design, addressing barriers to completion, enhancing representation in research, providing cultural competency training for clinicians, and allocating research funding to support health equity research. By addressing these issues, advances can be made toward fostering inclusive, equitable health care for all individuals.

Detecting gene expression in buccal mucosa in subjects with asthma versus subjects without asthma.

BACKGROUND: Differences in mRNA expression for inflammatory markers have been observed between subjects with asthma vs. controls and in relation to corticosteroid response. However, these studies utilized methods (e.g., bronchoscopy) that are too invasive to be used routinely in children and in the clinic. The primary purpose of this study was to determine the feasibility of obtaining RNA of adequate quantity and quality from buccal mucosa of children and adults for gene expression studies. Secondly, this study aimed to determine whether gene expression patterns in buccal mucosa are similar to those that have been observed in respiratory epithelium. METHODS: We enrolled 94 subjects with and without asthma between 5 and 54 years of age. Relative gene expression in buccal mucosa was determined with quantitative RT-PCR for the following genes: CCL2, EDN1, FKBP5, IL8, IFNAR2, NFKB1, RELA, SERPINB2, DENND1B, HRH1, ICAM1, ORMDL3, NR3C1, CLCA1, CRHR1, MUC5B, FCER2, POSTN, GAPDH, PPIA. RESULTS: mRNA Expression of the following genes was detected in buccal mucosa: CCL2, EDN1, FKBP5, IL8, IFNAR2, NFKB1, RELA, SERPINB2, DENND1B, HRH1, ICAM1, ORMDL3, NR3C1, GAPDH, PPIA. HRH1 was differentially expressed in adults with asthma vs. controls (p = 0.04), and EDN1 was differentially expressed in children with asthma vs. controls 12-18 years old (p = 0.03). A similar trend for HRH1 was observed in children 12-18 years old. CONCLUSIONS: Buccal mucosa sampling is a reliable method for detecting changes in gene expression in patients with asthma. This non-invasive technique may serve as a valuable tool for diagnosing asthma and evaluating therapeutic response.

Mixed modeling and sample size calculations for identifying housekeeping genes.

Normalization of gene expression data using internal control genes that have biologically stable expression levels is an important process for analyzing reverse transcription polymerase chain reaction data. We propose a three-way linear mixed-effects model to select optimal housekeeping genes. The mixed-effects model can accommodate multiple continuous and/or categorical variables with sample random effects, gene fixed effects, systematic effects, and gene by systematic effect interactions. We propose using the intraclass correlation coefficient among gene expression levels as the stability measure to select housekeeping genes that have low within-sample variation. Global hypothesis testing is proposed to ensure that selected housekeeping genes are free of systematic effects or gene by systematic effect interactions. A gene combination with the highest lower bound of 95% confidence interval for intraclass correlation coefficient and no significant systematic effects is selected for normalization. Sample size calculation based on the estimation accuracy of the stability measure is offered to help practitioners design experiments to identify housekeeping genes. We compare our methods with geNorm and NormFinder by using three case studies. A free software package written in SAS (Cary, NC, U.S.A.) is available at http://d.web.umkc.edu/daih under software tab.

Interpretation of food specific immunoglobulin E levels in the context of total IgE.

BACKGROUND: Food specific immunoglobulin E (IgE) (fsIgE) cut points are used in the evaluation of food allergies. Concomitant measurement of total IgE (tIgE) is traditionally not obtained. We anecdotally observed elevations in fsIgE mirroring tIgE increases, which may confound accurate interpretation. OBJECTIVE: To determine whether changes in tIgE were associated with fsIgE and whether predictions of fsIgE could be formulated based on tIgE. METHODS: We studied children younger than 18 years who had both tIgE and fsIgE (egg, n = 136; milk, n = 123; peanut, n = 201; soy, n = 55) obtained simultaneously on 1 or more occasion between January 2008 and February 2011. After institutional review board approval, natural log-transformed (ln) tIgE and fsIgE levels were analyzed using univariate and multivariate regression models to assess associations and predict fsIgE using tIgE and other covariates. RESULTS: Soy IgE levels were strongly correlated (ρ = 0.85, P < .001), whereas egg, milk, and peanut IgE levels were substantially correlated (ρ = 0.69, 0.69, and 0.66, respectively, P < .001) with tIgE. A 1-unit increase in ln(tIgE) was significantly correlated with unit increases in ln(egg IgE) (0.77), ln(milk IgE) (0.84), ln(peanut IgE) (0.87), and ln(soy IgE) (0.89) (P < .001). The ln(tIgE)-based univariate models could predict fsIgE in the validation data with strong (soy) and substantial (egg, milk, and peanut) predictive ability (P < .001). CONCLUSION: Our study found significant and parallel relationships between tIgE and fsIgE levels to egg, milk, peanut, and soy. It underscores the importance of examining fsIgE levels in context of tIgE while making diagnostic and management decisions in children with food allergies.

Genetic variation in the TNFA promoter region and TNFA gene expression in subjects with asthma.

OBJECTIVE: Asthma is a chronic disease that affects millions of people. Messenger RNA (mRNA) expression of specific inflammatory markers has been associated with asthma and corticosteroid response. Tumor necrosis factor-α (TNF-α), a pro-inflammatory cytokine, has been shown to have increased expression in airways of asthmatics and may be related to corticosteroid sensitivity. The purpose of this study was to determine how genetic variants within the promoter region of the TNFA gene differ between subjects with asthma and controls. We also investigated how genetic variation affects gene expression. METHODS: We enrolled 94 subjects between 5 to 54 years of age who met the inclusion and exclusion criteria. TNFA mRNA expression was determined by qRT-PCR on total RNA isolated from the buccal mucosa. Genotyping was performed for TNFA-1031T/C, -857C/T, and -308G/A on genomic DNA isolated from blood with commercially available assays. Gene expression was log-2 transformed and corrected with 2 normalization genes. General linear model, Chi-square test, Fisher's exact test, and Cochran-Mantel-Haenszel test were performed with p < .05. RESULTS: The TNFA-857C/T polymorphism is associated with asthma in this cohort. The TNFA-857 T allele is underrepresented in pediatric subjects with asthma relative to those without asthma (3% and 29% of individuals, respectively, p = .01). Furthermore, a TNFA haplotype combination containing -1031T/-857C/-308G and -1031T/-857T/-308G is associated with lower expression of TNF-α mRNA (p = .01) in pediatric subjects. CONCLUSIONS: Presence of the TNFA-857T allele may be protective in the development of asthma and a haplotype combination that contains the TNFA-857T allele is associated with TNFA expression.