Evaluating the Consistency of Gene Sets Used in the Analysis of Bacterial Gene Expression Data

Background Statistical analyses of whole genome expression data require functional information about genes in order to yield meaningful biological conclusions. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) are common sources of functionally grouped gene sets. For bacteria, the SEED and MicrobesOnline provide alternative, complementary sources of gene sets. To date, no comprehensive evaluation of the data obtained from these resources has been performed. Results We define a series of gene set consistency metrics directly related to the most common classes of statistical analyses for gene expression data, and then perform a comprehensive analysis of 3581 Affymetrix gene expression arrays across 17 diverse bacteria. We find that gene sets obtained from GO and KEGG demonstrate lower consistency than those obtained from the SEED and MicrobesOnline, regardless of gene set size. Conclusions Despite the widespread use of GO and KEGG gene sets in bacterial gene expression data analysis, the SEED and MicrobesOnline provide more consistent sets for a wide variety of statistical analyses such data. Increased use of the SEED and MicrobesOnline gene sets in the analysis of bacterial gene expression data may improve statistical power and utility of expression data

Increased risk of asthma at age 10 years for children sensitized to multiple allergens

BACKGROUND: Childhood sensitization patterns have been previously found to be related to variable risk of early life allergic disease in several birth cohorts. OBJECTIVE: To determine whether these risks persist into later childhood. METHODS: In the birth cohort of the Wayne County Health, Environment, Allergy and Asthma Longitudinal Study, previous latent class analysis based on sensitization to 10 allergens found the following 4 early life sensitization patterns at age 2 years: highly sensitized, milk/egg dominated, peanut and inhalant(s), and low to no sensitization. At an age 10 study-specific visit, children were evaluated by an allergist for current asthma and atopic dermatitis through a physical examination and interviews with the child and parent or guardian. Total and specific immunoglobulin E (IgE), spirometry, and methacholine challenge were also completed. RESULTS: Compared with children sensitized to none or 1 allergen, children sensitized to 4 or more food and inhalant allergens at age 2 had the highest risk of current asthma (relative risk [RR], 4.42; 95% confidence interval [CI], 2.58-7.59; P \u3c .001) and bronchial hyperresponsiveness (RR, 1.77; 95% CI, 1.29-2.42; P \u3c .001). In addition, they had the highest levels of total IgE (geometric mean, 800 IU/mL; 95% CI, 416-1536) among the 4 groups. Risk of current atopic dermatitis did not depend on pattern of sensitization but remained increased for children with any sensitization (RR, 2.23; 95% CI, 1.40-3.55; P \u3c .001). No differences in spirometry (forced expiratory volume in 1 second, forced expiratory flow between 25% and 75%, and forced expiratory volume in 1 second/forced vital capacity) were identified. CONCLUSION: The previously reported importance of a specific pattern of sensitization in early life (sensitization to ≥4 inhalant and food allergens) continues to be associated with an increased risk of asthma, bronchial hyperresponsiveness, and high total IgE at age 10 years

Association between prenatal antimicrobial use and offspring attention deficit hyperactivity disorder

BACKGROUND: Gut-brain cross-talk may play an important role in modulating neurodevelopment. Few studies have examined the association between antimicrobials that influence infant gut microbiota assemblage and attention deficit hyperactivity disorder (ADHD). OBJECTIVE: To examine the association between maternal prenatal antimicrobial use and ADHD in offspring at 10 years of age. METHODS: Data are from the Wayne County Health, Environment, Allergy and Asthma Longitudinal Study, a racially and socioeconomically diverse birth cohort in metropolitan Detroit, Michigan. Maternal antimicrobial use was extracted from the medical record. ADHD diagnoses were based on parental report at the 10-year study visit. Poisson regression models with robust error variance were used to calculate risk ratios (RR). Cumulative frequency of exposure to antibiotics, and effect modification were also evaluated. RESULTS: Among the 555 children included in the analysis, 108 were diagnosed with ADHD. During pregnancy, 54.1% of mothers used antibiotics while 18.7% used antifungals. Overall, there was no evidence of an association between prenatal antibiotic exposure and ADHD (RR [95% CI] = 0.98 [0.75, 1.29]), but there was an increased risk of ADHD among those with mothers using 3+ courses of antibiotics (RR [95%CI] = 1.58 [1.10, 2.29]). Prenatal exposure to antifungals was associated with a 1.6 times higher risk of ADHD (RR [95% CI] = 1.60 [1.19, 2.15]). In examining effect modification by child sex for antifungal use, there was no evidence of an association among females (RR [95% CI] = 0.97 [0.42, 2.23]), but among males, prenatal antifungal use was associated with 1.82 times higher risk of ADHD (RR [95% CI] = 1.82 [1.29, 2.56]). CONCLUSIONS: Maternal prenatal antifungal use and frequent prenatal antibiotic use are associated with an increased risk of ADHD in offspring at age 10. These findings highlight the importance of the prenatal environment and the need for careful use of antimicrobials

Prenatal pet keeping and caregiver-reported attention deficit hyperactivity disorder through preadolescence in a United States birth cohort

BACKGROUND: While the keeping of pets has been shown to protect against childhood allergic disease and obesity, less is known regarding potential associations of prenatal pet keeping and attention deficit hyperactivity disorder (ADHD). We sought to examine the associations between prenatal dog or cat keeping with caregiver-reported ADHD in preadolescents in the Wayne County Health, Environment, Allergy and Asthma Longitudinal Study (WHEALS) birth cohort (N = 1258). METHODS: At an interview with the caregiver at child age 10-12 years, caregivers reported if the WHEALS child had ever been diagnosed with ADHD. Similarly, during an interview with the mother prenatally, pet keeping (defined as dog or cat kept inside ≥1 h/day) was ascertained. Logistic regression models were fit to examine the association of prenatal pet keeping (dog keeping and cat keeping, separately) with ADHD. RESULTS: A subset of 627 children were included in the analyses: 93 who had ADHD and 534 with neurotypical development. After accounting for confounders and loss to follow-up, maternal prenatal dog exposure was associated with 2.23 times (95% CI: 1.15, 4.31; p = 0.017) greater odds of ADHD among boys. Prenatal dog keeping was not statistically significantly associated with ADHD in girls (odds ratio = 0.27, 95% CI: 0.06, 1.12; p = 0.070). Prenatal cat keeping was not associated with ADHD. CONCLUSIONS: In boys, but not girls, maternal prenatal dog keeping was positively associated with ADHD. Further study to confirm these findings and to identify potential mechanisms of this association (e.g., modification of the gut microbiome, exposure to environmental toxicants or pet-related medications) is needed

Evaluating methods for combining rare variant data in pathway-based tests of genetic association

Abstract Analyzing sets of genes in genome-wide association studies is a relatively new approach that aims to capitalize on biological knowledge about the interactions of genes in biological pathways. This approach, called pathway analysis or gene set analysis, has not yet been applied to the analysis of rare variants. Applying pathway analysis to rare variants offers two competing approaches. In the first approach rare variant statistics are used to generate p-values for each gene (e.g., combined multivariate collapsing [CMC] or weighted-sum [WS]) and the gene-level p-values are combined using standard pathway analysis methods (e.g., gene set enrichment analysis or Fisher’s combined probability method). In the second approach, rare variant methods (e.g., CMC and WS) are applied directly to sets of single-nucleotide polymorphisms (SNPs) representing all SNPs within genes in a pathway. In this paper we use simulated phenotype and real next-generation sequencing data from Genetic Analysis Workshop 17 to analyze sets of rare variants using these two competing approaches. The initial results suggest substantial differences in the methods, with Fisher’s combined probability method and the direct application of the WS method yielding the best power. Evidence suggests that the WS method works well in most situations, although Fisher’s method was more likely to be optimal when the number of causal SNPs in the set was low but the risk of the causal SNPs was high

The Burnout Epidemic Within A Viral Pandemic: Impact of a Wellness Initiative

Background: Anesthesiologists are at high risk of developing burnout, a condition which can lead to many deleterious effects for the physician, and far-reaching effects on their patients and hospital systems. The COVID-19 pandemic has presented new challenges that have further exacerbated the risk of burnout in anesthesiologists. It is critical to develop effective strategies to promote well-being and decrease burnout for physicians in this specialty. The purpose of this observational study was to evaluate the impact of a Physician Well-Being Initiative on distress and well-being in anesthesiologists. It was hypothesized that the wellness intervention would promote an improvement in well-being scores. Methods: The Physician Well-Being Initiative was launched in August 2019 in the Department of Anesthesiology, Pain Management and Perioperative Medicine at Henry Ford Hospital in Detroit, Michigan. The Physician Well-Being Initiative was designed to address several of the key factors that improve physician wellness, including 1) a sense of autonomy; 2) positive view of leadership; and 3) flexible schedule opportunities. To assess the impact of the Physician Well-Being Initiative on the well-being and distress scores of participating anesthesiologists, the physicians were emailed the validated Well-Being Index survey at baseline and 3, 6 and 12 months. The Well-Being Index evaluates multiple items of distress in the healthcare setting. The sample size was limited to the 54 anesthesiologists at Henry Ford Hospital. Results: Forty-four of the 54 anesthesiologists completed the baseline questionnaire. A total of 44 physicians answered the questionnaire at baseline, with more male than female physicians (35 males and 7 females) and the majority (17/44) in practice for 5-10 years. Thirty-two physicians completed the survey at 3 and 6 months, and 31 physicians at 12 months after the launch of the Physician Well-Being Initiative. Twenty-one physicians completed the questionnaire at all 4 time points. Although the COVID-19 pandemic started shortly after the 6-month surveys were submitted, results indicated that there was a 0.05 decrease in the Well-Being Index sum score for every 1-month of time (coefficient -0.05, 95% CI -0.01, -0.08, P = 0.013). This study shows that, with the wellness initiative in place, the department was able to maintain and potentially even reduce physician distress despite the concurrent onset of the pandemic. Conclusions: Following the launch of a sustained wellness initiative, this study demonstrates that physician wellness improved with time. This suggests that it takes time for a wellness initiative to have an effect on well-being and distress in anesthesiologists

Infant Feeding Practices and Subsequent Dietary Patterns of School-Aged Children in a US Birth Cohort

BACKGROUND: Infant feeding practices are thought to shape food acceptance and preferences. However, few studies have evaluated whether these affect child diet later in life. OBJECTIVE: The study objective was to examine the association between infant feeding practices and dietary patterns (DPs) in school-aged children. DESIGN: A secondary analysis of data from a diverse prospective birth cohort with 10 years of follow-up (WHEALS [Wayne County Health Environment Allergy and Asthma Longitudinal Study]) was conducted. PARTICIPANTS/SETTING: Children from the WHEALS (Detroit, MI, born 2003 through 2007) who completed a food screener at age 10 years were included (471 of 1,258 original participants). MAIN OUTCOME MEASURES: The main outcome was DPs at age 10 years, identified using the Block Kids Food Screener. STATISTICAL ANALYSIS PERFORMED: Latent class analysis was applied for DP identification. Breastfeeding and age at solid food introduction were associated with DPs using a 3-step approach for latent class modeling based on multinomial logistic regression models. RESULTS: The following childhood DPs were identified: processed/energy-dense food (35%), variety plus high intake (41%), and healthy (24%). After weighting for loss to follow-up and covariate adjustment, compared with formula-fed children at 1 month, breastfed children had 0.41 times lower odds of the processed/energy-dense food DP vs the healthy DP (95% CI 0.14 to 1.25) and 0.53 times lower odds of the variety plus high intake DP (95% CI 0.17 to 1.61), neither of which were statistically significant. Results were similar, but more imprecise, for breastfeeding at 6 months. In addition, the association between age at solid food introduction and DP was nonsignificant, with each 1-month increase in age at solid food introduction associated with 0.81 times lower odds of the processed/energy-dense food DP relative to the healthy DP (95% CI 0.64 to 1.02). CONCLUSIONS: A significant association between early life feeding practices and dietary patterns at school age was not detected. Large studies with follow-up beyond early childhood that can also adjust for the multitude of potential confounders associated with breastfeeding are needed

Food insecurity in Detroit: exploring the relationship between patient-reported food insecurity and proximity to healthful grocery stores

Objective: The objective of the current study was to determine if patients of a large health care system in Detroit who self-identify as food insecure live further away from healthy grocery stores compared with food secure patients. Second, we explored whether food insecurity and distance to healthy grocery stores are related to ecological measures of vehicle availability in the area of residence. Design: A secondary data analysis that uses baseline data from a pilot intervention/feasibility study. Setting: Detroit, Michigan, USA. Participants: Patients of Henry Ford Health System were screened for food insecurity to determine eligibility for a pilot intervention/feasibility study (i.e. Henry’s Groceries for Health), conducted through a collaboration with Gleaners Community Foodbank of Southeastern Michigan. Only patients residing in Detroit city limits (including Highland Park and Hamtramck) were included in the secondary analysis. Of the 1,100 patients included in the analysis, 336 (31 %) were food insecure. Results: After accounting for socio-demographic factors associated with food insecurity, we did not find evidence that food insecure patients lived further away from healthier grocery stores, nor was this modified by ecological measures of vehicle access. However, some neighbourhoods were identified as having a significantly higher risk of food insecurity. Conclusions: Food insecure patients in Detroit are perhaps limited by social and political determinants and not their immediate neighbourhood geography or physical access to healthy grocery stores. Future research should explore the complexity in linkages between household socio-economic factors, socio-cultural dynamics and the neighbourhood food environment

Evaluating methods for the analysis of rare variants in sequence data

A number of rare variant statistical methods have been proposed for analysis of the impending wave of next-generation sequencing data. To date, there are few direct comparisons of these methods on real sequence data. Furthermore, there is a strong need for practical advice on the proper analytic strategies for rare variant analysis. We compare four recently proposed rare variant methods (combined multivariate and collapsing, weighted sum, proportion regression, and cumulative minor allele test) on simulated phenotype and next-generation sequencing data as part of Genetic Analysis Workshop 17. Overall, we find that all analyzed methods have serious practical limitations on identifying causal genes. Specifically, no method has more than a 5% true discovery rate (percentage of truly causal genes among all those identified as significantly associated with the phenotype). Further exploration shows that all methods suffer from inflated false-positive error rates (chance that a noncausal gene will be identified as associated with the phenotype) because of population stratification and gametic phase disequilibrium between noncausal SNPs and causal SNPs. Furthermore, observed true-positive rates (chance that a truly causal gene will be identified as significantly associated with the phenotype) for each of the four methods was very low (<19%). The combination of larger than anticipated false-positive rates, low true-positive rates, and only about 1% of all genes being causal yields poor discriminatory ability for all four methods. Gametic phase disequilibrium and population stratification are important areas for further research in the analysis of rare variant data