Race/ethnicity-stratified fine-mapping of the MHC locus reveals genetic variants associated with late-onset asthma.

Introduction: Asthma is a chronic disease of the airways that impairs normal breathing. The etiology of asthma is complex and involves multiple factors, including the environment and genetics, especially the distinct genetic architecture associated with ancestry. Compared to early-onset asthma, little is known about genetic predisposition to late-onset asthma. We investigated the race/ethnicity-specific relationship among genetic variants within the major histocompatibility complex (MHC) region and late-onset asthma in a North Carolina-based multiracial cohort of adults. Methods: We stratified all analyses by self-reported race (i.e., White and Black) and adjusted all regression models for age, sex, and ancestry. We conducted association tests within the MHC region and performed fine-mapping analyses conditioned on the race/ethnicity-specific lead variant using whole-genome sequencing (WGS) data. We applied computational methods to infer human leukocyte antigen (HLA) alleles and residues at amino acid positions. We replicated findings in the UK Biobank. Results: The lead signals, rs9265901 on the 5' end of HLA-B, rs55888430 on HLA-DOB, and rs117953947 on HCG17, were significantly associated with late-onset asthma in all, White, and Black participants, respectively (OR = 1.73, 95%CI: 1.31 to 2.14, p = 3.62 × 10-5; OR = 3.05, 95%CI: 1.86 to 4.98, p = 8.85 × 10-6; OR = 19.5, 95%CI: 4.37 to 87.2, p = 9.97 × 10-5, respectively). For the HLA analysis, HLA-B*40:02 and HLA-DRB1*04:05, HLA-B*40:02, HLA-C*04:01, and HLA-DRB1*04:05, and HLA-DRB1*03:01 and HLA-DQB1 were significantly associated with late-onset asthma in all, White, and Black participants. Conclusion: Multiple genetic variants within the MHC region were significantly associated with late-onset asthma, and the associations were significantly different by race/ethnicity group.

Social determinants of health associated with COVID-19 severity during pregnancy: a multinational cohort study (in the International Registry of Coronavirus Exposure in Pregnancy).

BACKGROUND: The COVID-19 pandemic has caused morbidity and mortality, particularly among vulnerable populations. We aimed to assess social and demographic characteristics associated with COVID-19 severity among symptomatic participants during pregnancy. METHODS: The International Registry of Coronavirus Exposure in Pregnancy is a multinational, longitudinal observational cohort study of adult participants tested for SARS-CoV-2 or who received clinical diagnosis of COVID-19 during pregnancy (NCT04366986). Disease severity status of mild, moderate, or severe was determined based on symptoms and healthcare utilization. Stratified by current versus recent pregnancy at enrollment, univariate mixed-effects logistic regression modeling was used to characterize association between social and demographic characteristics with COVID-19 severity, using a cumulative mixed effect model with country as a random effect. RESULTS: The odds of developing more severe COVID-19 (odds ratio [95% confidence interval]) were higher among participants with lower socioeconomic status (poor: 2.72 [2.01,3.69]; lower-middle class: 2.07 [1.62,2.65] vs wealthy), among participants with lower educational attainment (high school: 1.68 [1.39,2.03]; < high school (1.77 [1.25,2.51] vs graduate education). Participants over 25 years of age had lower odds of severe COVID-19 versus participants < 25 years (25-34: 0.69 [0.56,0.85]; 35-50: 0.62 [0.48,0.80]). Employment in food services was also associated with increased odds of more severe COVID-19, whereas employment in healthcare and within home, and primiparity were associated with lower severity. CONCLUSIONS: Findings suggest that employment setting and economic status have strong associations with COVID-19 severity, which warrants considering social determinants of health in the context of assessing risk factors of more severe COVID-19 during pregnancy. TRIAL REGISTRATION: IRCEP was registered with the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) [EUPAS37360] and clinicaltrials.gov [NCT04366986].

Vicarious structural racism and infant health disparities in Michigan: The Flint Water Crisis.

Building on nascent literature examining the health-related effects of vicarious structural racism, we examined indirect exposure to the Flint Water Crisis (FWC) as a predictor of birth outcomes in Michigan communities outside of Flint, where residents were not directly exposed to lead-contaminated water. Using linear regression models, we analyzed records for all singleton live births in Michigan from 2013 to 2016, excluding Flint, to determine whether birth weight (BW), gestational age (GA), and size-for-gestational-age (SzGA) decreased among babies born to Black people, but not among babies born to White people, following the highly publicized January 2016 emergency declaration in Flint. In adjusted regression models, BW and SzGA were lower for babies born to both Black and White people in the 37 weeks following the emergency declaration compared to the same 37-week periods in the previous 3 years. There were no racial differences in the association of exposure to the emergency declaration with BW or SzGA. Among infants born to Black people, GA was 0.05 weeks lower in the 37-week period following the emergency declaration versus the same 37-week periods in the previous 3 years (95% CI: -0.09, -0.01; p = 0.0177), while there was no change in GA for infants born to White people following the emergency declaration (95% CI: -0.01, 0.03; p = 0.6962). The FWC, which was widely attributed to structural racism, appears to have had a greater impact, overall, on outcomes for babies born to Black people. However, given the frequency of highly publicized examples of anti-Black racism over the study period, it is difficult to disentangle the effects of the FWC from the effects of other racialized stressors.

A Phenome-Wide Association Study (PheWAS) of COVID-19 Outcomes by Race Using the Electronic Health Records Data in Michigan Medicine.

BACKGROUND: We performed a phenome-wide association study to identify pre-existing conditions related to Coronavirus disease 2019 (COVID-19) prognosis across the medical phenome and how they vary by race. METHODS: The study is comprised of 53,853 patients who were tested/diagnosed for COVID-19 between 10 March and 2 September 2020 at a large academic medical center. RESULTS: Pre-existing conditions strongly associated with hospitalization were renal failure, pulmonary heart disease, and respiratory failure. Hematopoietic conditions were associated with intensive care unit (ICU) admission/mortality and mental disorders were associated with mortality in non-Hispanic Whites. Circulatory system and genitourinary conditions were associated with ICU admission/mortality in non-Hispanic Blacks. CONCLUSIONS: Understanding pre-existing clinical diagnoses related to COVID-19 outcomes informs the need for targeted screening to support specific vulnerable populations to improve disease prevention and healthcare delivery.

Low-Dose ATG/GCSF in Established Type 1 Diabetes: A Five-Year Follow-up Report.

Previously, we demonstrated low-dose antithymocyte globulin (ATG) and granulocyte colony-stimulating factor (GCSF) immunotherapy preserved C-peptide for 2 years in a pilot study of patients with established type 1 diabetes (n = 25). Here, we evaluated the long-term outcomes of ATG/GCSF in study participants with 5 years of available follow-up data (n = 15). The primary end point was area under the curve (AUC) C-peptide during a 2-h mixed-meal tolerance test. After 5 years, there were no statistically significant differences in AUC C-peptide when comparing those who received ATG/GCSF versus placebo (P = 0.41). A modeling framework based on mean trajectories in C-peptide AUC over 5 years, accounting for differing trends between groups, was applied to recategorize responders (n = 9) and nonresponders (n = 7). ATG/GCSF reponders demonstrated nearly unchanged HbA1c over 5 years (mean [95% CI] adjusted change 0.29% [-0.69%, 1.27%]), but the study was not powered for comparisons against nonresponders 1.75% (-0.57%, 4.06%) or placebo recipients 1.44% (0.21%, 2.66%). These data underscore the importance of long-term follow-up in previous and ongoing phase 2 trials of low-dose ATG in recent-onset type 1 diabetes.

A phenome-wide association study (PheWAS) of COVID-19 outcomes by race using the electronic health records data in Michigan Medicine.

BACKGROUND: We perform a phenome-wide scan to identify pre-existing conditions related to COVID-19 susceptibility and prognosis across the medical phenome and how they vary by race. METHODS: The study is comprised of 53,853 patients who were tested/positive for COVID-19 between March 10 and September 2, 2020 at a large academic medical center. RESULTS: Pre-existing conditions strongly associated with hospitalization were renal failure, pulmonary heart disease, and respiratory failure. Hematopoietic conditions were associated with ICU admission/mortality and mental disorders were associated with mortality in non-Hispanic Whites. Circulatory system and genitourinary conditions were associated with ICU admission/mortality in non-Hispanic Blacks. CONCLUSIONS: Understanding pre-existing clinical diagnoses related to COVID-19 outcomes informs the need for targeted screening to support specific vulnerable populations to improve disease prevention and healthcare delivery.

Use of metabolic syndrome severity to assess treatment with vitamin E and pioglitazone for non-alcoholic steatohepatitis.

BACKGROUND AND AIM: Non-alcoholic steatohepatitis (NASH), which can lead to liver failure, requires liver biopsies to follow and is difficult to treat. Our goal was to assess metabolic syndrome (MetS) severity as a predictor of treatment success and a marker of response. METHODS: We assessed data from the Pioglitazone, Vitamin E, or Placebo for NASH Study, in which individuals with biopsy-confirmed NASH were randomized to receive pioglitazone, vitamin E, or placebo for 96 weeks. We assessed associations of a sex-specific and race/ethnicity-specific MetS severity Z-score (MetS-Z) at baseline and 48 weeks with biopsy-determined endpoint of NASH resolution at 96 weeks. RESULTS: Baseline MetS-Z was inversely associated with odds of NASH resolution (odds ratio [OR] per 1 SD of MetS-Z: 0.47, 95% confidence interval [CI] 0.28, 0.79). Decrease in MetS-Z during initial 48-week intervention was greatest for pioglitazone treatment (effect size: -0.31, 95% CI -0.15, -0.48) and for vitamin E tended toward being greater for those with versus without NASH resolution (-0.18 vs -0.05). Overall, 48-week change in MetS-Z was associated with NASH resolution (OR per 1-SD change: 0.53, 95% CI 0.33, 0.85), although this was attenuated in models that included transaminases, which remained linked to treatment success (OR by change-in-aspartate aminotransferase Z-score: 0.38, 95% CI 0.19, 0.76). CONCLUSIONS: Individuals with more severe metabolic derangement at baseline were less likely to exhibit NASH resolution, suggesting that individuals may have a threshold of MetS severity beyond which successful treatment is unlikely. As an integrated marker of metabolic abnormalities, MetS-Z was correlated with successful treatment, although transaminases were a more consistent marker of NASH resolution.

Electronic decision support and diarrhoeal disease guideline adherence (mHDM): a cluster randomised controlled trial.

BACKGROUND: Acute diarrhoeal disease management often requires rehydration alone without antibiotics. However, non-indicated antibiotics are frequently ordered and this is an important driver of antimicrobial resistance. The mHealth Diarrhoea Management (mHDM) trial aimed to establish whether electronic decision support improves rehydration and antibiotic guideline adherence in resource-limited settings. METHODS: A cluster randomised controlled trial was done at ten district hospitals in Bangladesh. Inclusion criteria were patients aged 2 months or older with uncomplicated acute diarrhoea. Admission orders were observed without intervention in the pre-intervention period, followed by randomisation to electronic (rehydration calculator) or paper formatted WHO guidelines for the intervention period. The primary outcome was rate of intravenous fluid ordered as a binary variable. Generalised linear mixed-effect models, accounting for hospital clustering, served as the analytical framework; the analysis was intention to treat. The trial is registered with ClinicalTrials.gov (NCT03154229) and is completed. FINDINGS: From March 11 to Sept 10, 2018, 4975 patients (75·6%) of 6577 screened patients were enrolled. The intervention effect for the primary outcome showed no significant differences in rates of intravenous fluids ordered as a function of decision-support type. Intravenous fluid orders decreased by 0·9 percentage points for paper electronic decision support and 4·2 percentage points for electronic decision support, with a 4·2-point difference between decision-support types in the intervention period (paper 98·7% [95% CI 91·8-99·8] vs electronic 94·5% [72·2-99·1]; pinteraction=0·31). Adverse events such as complications and mortality events were uncommon and could not be statistically estimated. INTERPRETATION: Although intravenous fluid orders did not change, electronic decision support was associated with increases in the volume of intravenous fluid ordered and decreases in antibiotics ordered, which are consistent with WHO guidelines. FUNDING: US National Institutes of Health.

Characteristics Associated With Racial/Ethnic Disparities in COVID-19 Outcomes in an Academic Health Care System.

Importance: Black patients are overrepresented in the number of COVID-19 infections, hospitalizations, and deaths in the US. Reasons for this disparity may be due to underlying comorbidities or sociodemographic factors that require further exploration. Objective: To systematically determine patient characteristics associated with racial/ethnic disparities in COVID-19 outcomes. Design, Setting, and Participants: This retrospective cohort study used comparative groups of patients tested or treated for COVID-19 at the University of Michigan from March 10, 2020, to April 22, 2020, with an outcome update through July 28, 2020. A group of randomly selected untested individuals were included for comparison. Examined factors included race/ethnicity, age, smoking, alcohol consumption, comorbidities, body mass index (BMI; calculated as weight in kilograms divided by height in meters squared), and residential-level socioeconomic characteristics. Exposure: In-house polymerase chain reaction (PCR) tests, commercial antibody tests, nasopharynx or oropharynx PCR deployed by the Michigan Department of Health and Human Services and reverse transcription-PCR tests performed in external labs. Main Outcomes and Measures: The main outcomes were being tested for COVID-19, having test results positive for COVID-19 or being diagnosed with COVID-19, being hospitalized for COVID-19, requiring intensive care unit (ICU) admission for COVID-19, and COVID-19-related mortality (including inpatient and outpatient). Medical comorbidities were defined from the International Classification of Diseases, Ninth Revision, and International Classification of Diseases, Tenth Revision, codes and were aggregated into a comorbidity score. Associations with COVID-19 outcomes were examined using odds ratios (ORs). Results: Of 5698 patients tested for COVID-19 (mean [SD] age, 47.4 [20.9] years; 2167 [38.0%] men; mean [SD] BMI, 30.0 [8.0]), most were non-Hispanic White (3740 patients [65.6%]) or non-Hispanic Black (1058 patients [18.6%]). The comparison group included 7168 individuals who were not tested (mean [SD] age, 43.1 [24.1] years; 3257 [45.4%] men; mean [SD] BMI, 28.5 [7.1]). Among 1139 patients diagnosed with COVID-19, 492 (43.2%) were White and 442 (38.8%) were Black; 523 (45.9%) were hospitalized, 283 (24.7%) were admitted to the ICU, and 88 (7.7%) died. Adjusting for age, sex, socioeconomic status, and comorbidity score, Black patients were more likely to be hospitalized compared with White patients (OR, 1.72 [95% CI, 1.15-2.58]; P = .009). In addition to older age, male sex, and obesity, living in densely populated areas was associated with increased risk of hospitalization (OR, 1.10 [95% CI, 1.01-1.19]; P = .02). In the overall population, higher risk of hospitalization was also observed in patients with preexisting type 2 diabetes (OR, 1.82 [95% CI, 1.25-2.64]; P = .02) and kidney disease (OR, 2.87 [95% CI, 1.87-4.42]; P < .001). Compared with White patients, obesity was associated with higher risk of having test results positive for COVID-19 among Black patients (White: OR, 1.37 [95% CI, 1.01-1.84]; P = .04. Black: OR, 3.11 [95% CI, 1.64-5.90]; P < .001; P for interaction = .02). Having any cancer was associated with higher risk of positive COVID-19 test results for Black patients (OR, 1.82 [95% CI, 1.19-2.78]; P = .005) but not White patients (OR, 1.08 [95% CI, 0.84-1.40]; P = .53; P for interaction = .04). Overall comorbidity burden was associated with higher risk of hospitalization in White patients (OR, 1.30 [95% CI, 1.11-1.53]; P = .001) but not in Black patients (OR, 0.99 [95% CI, 0.83-1.17]; P = .88; P for interaction = .02), as was type 2 diabetes (White: OR, 2.59 [95% CI, 1.49-4.48]; P < .001; Black: OR, 1.17 [95% CI, 0.66-2.06]; P = .59; P for interaction = .046). No statistically significant racial differences were found in ICU admission and mortality based on adjusted analysis. Conclusions and Relevance: These findings suggest that preexisting type 2 diabetes or kidney diseases and living in high-population density areas were associated with higher risk for COVID-19 hospitalization. Associations of risk factors with COVID-19 outcomes differed by race.

COVID-19 outcomes, risk factors and associations by race: a comprehensive analysis using electronic health records data in Michigan Medicine.

IMPORTANCE: Blacks/African-Americans are overrepresented in the number of COVID-19 infections, hospitalizations and deaths. Reasons for this disparity have not been well-characterized but may be due to underlying comorbidities or sociodemographic factors. OBJECTIVE: To systematically determine patient characteristics associated with racial/ethnic disparities in COVID-19 outcomes. DESIGN: A retrospective cohort study with comparative control groups. SETTING: Patients tested for COVID-19 at University of Michigan Medicine from March 10, 2020 to April 22, 2020. PARTICIPANTS: 5,698 tested patients and two sets of comparison groups who were not tested for COVID-19: randomly selected unmatched controls (n = 7,211) and frequency-matched controls by race, age, and sex (n = 13,351). Main Outcomes and Measures: We identified factors associated with testing and testing positive for COVID-19, being hospitalized, requiring intensive care unit (ICU) admission, and mortality (in/out-patient during the time frame). Factors included race/ethnicity, age, smoking, alcohol consumption, healthcare utilization, and residential-level socioeconomic characteristics (SES; i.e., education, unemployment, population density, and poverty rate). Medical comorbidities were defined from the International Classification of Diseases (ICD) codes, and were aggregated into a comorbidity score. RESULTS: Of 5,698 patients, (median age, 47 years; 38% male; mean BMI, 30.1), the majority were non-Hispanic Whites (NHW, 59.2%) and non-Hispanic Black/African-Americans (NHAA, 17.2%). Among 1,119 diagnosed, there were 41.2% NHW and 37.4% NHAA; 44.8% hospitalized, 20.6% admitted to ICU, and 3.8% died. Adjusting for age, sex, and SES, NHAA were 1.66 times more likely to be hospitalized (95% CI, 1.09-2.52; P=.02), 1.52 times more likely to enter ICU (95% CI, 0.92-2.52; P=.10). In addition to older age, male sex and obesity, high population density neighborhood (OR, 1.27 associated with one SD change [95% CI, 1.20-1.76]; P=.02) was associated with hospitalization. Pre-existing kidney disease led to 2.55 times higher risk of hospitalization (95% CI, 1.62-4.02; P<.001) in the overall population and 11.9 times higher mortality risk in NHAA (95% CI, 2.2-64.7, P=.004). CONCLUSIONS AND RELEVANCE: Pre-existing type II diabetes/kidney diseases and living in high population density areas were associated with high risk for COVID-19 susceptibility and poor prognosis. Association of risk factors with COVID-19 outcomes differed by race. NHAA patients were disproportionately affected by obesity and kidney disease.

Postnatal pediatric systemic antibiotic episodes during the first three years of life are not associated with mode of delivery.

BACKGROUND: Delivery by cesarean section (C-section) is associated with adverse short-term and long-term infant outcomes. Given that antibiotics during early life are prescribed for infant outcomes that are more likely among c-section deliveries, we hypothesized that postnatal antibiotic exposure will be greater among c-section infants compared to vaginally delivered infants. OBJECTIVE: The aim of this paper was to evaluate if mode of infant delivery was associated with patterns of systemic antibiotic exposure in children during their first three years. METHODS: Pediatric electronic health records from UFHealth, 2011 to 2017 were reviewed. We included singleton, term infants (37-42 weeks gestation) with a birth weight ≥ 2500 grams, with documented mode of delivery and well visits on record. Infants with a neonatal intensive care unit stay were excluded. Both oral and intravenous antibiotics for a 10-day duration were classified as a single episode. The primary outcome was antibiotic episodes in the first three years of life, and a sub-analysis was performed to compare broad-spectrum versus narrow-spectrum antibiotic exposures. RESULTS: The mean number of antibiotic episodes in 4,024 full-term infants was 0.34 (SD = 0.79) and 24.1% of infants had at least one antibiotic episode. Penicillins were the most prescribed antibiotic in children 0-1 years (66.9%) and cephalosporins were the most common antibiotic prescribed for children 1-3 years (56.2%). We did not detect a meaningful or significant rate ratio (RR) between mode of delivery and overall antibiotic episodes 1.14 (95% CI 0.99, 1.31), broad-spectrum episodes 1.19 (95% CI 0.93, 1.52, or narrow-spectrum episodes 1.14 (95% CI 0.97, 1.34). CONCLUSION: Our results do not support the hypothesis that postnatal antibiotic exposure was greater among infants delivered by cesarean section compare to infants delivered vaginally during the first three years of life.

Specific adverse childhood experiences and their association with other adverse childhood experiences, asthma and emotional, developmental and behavioral problems in childhood.

BACKGROUND: Adverse childhood experiences (ACEs) have lifelong health consequences, yet screening remains challenging. Particularly in clinical settings, brief screeners that could lead to comprehensive assessments may be more feasible. We explore how two ACEs (economic hardship, parental/caregiver divorce/separation) are associated with other ACEs, asthma, and emotional, developmental, or behavioral (EDB) problems. METHODS: Using the 2016 National Survey of Children's Health, we assessed the associations between ACEs and asthma and EDB problems and calculated sensitivities, specificities and predictive values. RESULTS: Parents frequently reported 1+ ACEs for their child (50.3%). Individual ACE frequency ranged from 4.2 to 29.6%; all were significantly associated with EDB problems (adjusted odds ratios (aORs): 2.2-5.1) and more ACEs confirmed higher odds. Two ACES (economic hardship, parental/caregiver divorce/separation) co-occurred frequently with other ACEs, having either predicted EDB problems similarly to other ACEs (aORs 1.8; 95% CI 1.4, 2.3) and having both greatly increased odds (aOR 3.8; 95% CI 2.8, 5.2). The negative predictive value of EDB problems associated with citing neither ACE was high (95.7%). Similar trends with asthma were observed. CONCLUSIONS: Economic hardship and caregiver separation are strongly associated with other ACEs, EDB problems and asthma. A brief screener including these ACEs may reduce clinical barriers to broader ACEs screening.

Performance and Impact of a CLIA-waived, Point-of-care Respiratory PCR Panel in a Pediatric Clinic.

BACKGROUND: Laboratory-based respiratory polymerase chain reaction (PCR) panels are rarely used in outpatient pediatric practice due to prolonged turn-around times and cost of medical equipment. The BioFire FilmArray Respiratory Panel EZ (RP EZ) is a Clinical Laboratory Improvement Amendments-waived respiratory pathogen PCR panel which rapidly tests for 14 common respiratory organisms. The aim of this study was to identify the distribution of organisms seen in pediatric clinics and to determine if utilization of this point-of-care test improved disease management, while exploring impact on clinic workflow. METHODS: From January 2018 through January 2019, when clinically appropriate, patients were tested by the RP EZ and/or antigen tests (Clinic A) or antigen test only (Clinic B). Residual samples from Clinic B antigen tests were frozen and later tested on the RP EZ for definitive pathogen identification. Patient data and prescription records were extracted from the electronic health record. RESULTS: A total of 430 patients had RP EZ tests performed, and at least 1 organism was detected in 70.4% of patients. The most common organisms identified were human rhinovirus/enterovirus, influenza, and respiratory syncytial virus. Appropriate treatment occurred for 93.6% of patients when the RP EZ was performed (Clinic A) versus 87.9% of patients who had only antigen tests performed (Clinic B, P = 0.0445). Utilization of RP EZ testing also significantly reduced appointment duration time (48.0 versus 54.9 minutes, P = 0.0009). Three false-positive influenza B results were identified by antigen testing. CONCLUSIONS: A point-of-care PCR panel improved patient care by providing an accurate diagnosis and shortened appointment duration.