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Genetic ancestry differences in pediatric asthma readmission are mediated by socioenvironmental factors

  • Tesfaye B. Mersha
    Correspondence
    Corresponding author: Tesfaye Mersha, PhD, Department of Pediatrics-Allergy/Asthma, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45255.
    Affiliations
    Division of Asthma Research, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio

    Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, College of Medicine, Cincinnati, Ohio
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  • Ke Qin
    Affiliations
    Division of Asthma Research, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio

    Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, College of Medicine, Cincinnati, Ohio
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  • Andrew F. Beck
    Affiliations
    Division of General and Community Pediatrics, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio

    Division of Hospital Medicine, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio

    Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, College of Medicine, Cincinnati, Ohio
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  • Lili Ding
    Affiliations
    Division of Biostatistics and Epidemiology, Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio

    Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, College of Medicine, Cincinnati, Ohio
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  • Bin Huang
    Affiliations
    Division of Biostatistics and Epidemiology, Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio

    Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, College of Medicine, Cincinnati, Ohio
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  • Robert S. Kahn
    Affiliations
    Division of General and Community Pediatrics, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio

    Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, College of Medicine, Cincinnati, Ohio
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      Background

      Social and financial hardships, combined with disease managment and environmental factors explain approximately 80% of the observed disparity in asthma-related readmissions between Black and White children.

      Objective

      We sought to determine whether asthma-related readmissions differed by degree of African ancestry and the extent to which such an association would also be explained by socioenvironmental risk factors.

      Methods

      This study used data from a prospective cohort study of 695 Black and White children aged 1 to 16 years with an asthma-related admission. The primary outcome was a similar readmission within 12 months. Each subject’s African ancestry was determined by single nucleotide polymorphisms on a continuous scale ranging from 0 to 1 (0 = no African ancestry; 1 = 100% African ancestry). We also assessed 37 social, environmental, and clinical variables that we clustered into 6 domains (for example, hardship, disease management). Survival and mediation analyses were conducted.

      Results

      A total of 134 children (19.3%) were readmitted within 12 months. Higher African ancestry was associated with asthma readmission (odds ratio 1.11, 95% confidence interval 1.05-1.18 for every 10% increase in African ancestry) with adjustment for age and gender. The association between African ancestry and readmission was mediated by hardship (sβ = 3.42, P < .001) and disease management (sβ = 0.046, P = .001), accounting for >50% of African ancestry’s effect on readmission. African ancestry was no longer significantly associated with readmission (sβ = 0.035, P = .388) after accounting for these mediators.

      Conclusions

      African ancestry was strongly associated with readmission, and the association was mediated by family hardship and disease management. These results are consistent with the notion that asthma-related racial disparities are driven by factors like structural racism and social adversity.

      Graphical abstract

      Key words

      Abbreviations used:

      AUC (Area under the receiver operating characteristic curve), CCHMC (Cincinnati Children’s Hospital Medical Center), CI (Confidence interval), DPVI (Deprivation index), GA (Global ancestry), GCARS (Greater Cincinnati Asthma Risk Study), MEGA (Multi-Ethnic Global Array), OR (Odds ratio), PM (Particulate matter), (Standardized coefficient)
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      References

        • Nurmagambetov T.
        • Kuwahara R.
        • Garbe P.
        The economic burden of asthma in the United States, 2008-2013.
        Ann Am Thorac Soc. 2018; 15: 348-356
        • Zahran H.S.
        • Bailey C.M.
        • Damon S.A.
        • Garbe P.L.
        • Breysse P.N.
        Vital signs: asthma in children—United States, 2001-2016.
        MMWR Morb Mortal Wkly Rep. 2018; 67: 149-155
        • Akinbami L.J.
        • Simon A.E.
        • Rossen L.M.
        Changing trends in asthma prevalence among children.
        Pediatrics. 2016; 137: 1-7
        • Adejare A.A.
        • Gautam Y.
        • Madzia J.
        • Mersha T.B.
        Unraveling racial disparities in asthma emergency department visits using electronic healthcare records and machine learning.
        J Asthma. 2020;
        • Pacheco C.M.
        • Ciaccio C.E.
        • Nazir N.
        • Daley C.M.
        • DiDonna A.
        • Choi W.S.
        • et al.
        Homes of low-income minority families with asthmatic children have increased condition issues.
        Allergy Asthma Proc. 2014; 35: 467-474
        • Karlsen S.
        • Nazroo J.Y.
        Relation between racial discrimination, social class, and health among ethnic minority groups.
        Am J Public Health. 2002; 92: 624-631
        • Mersha T.B.
        • Abebe T.
        Self-reported race/ethnicity in the age of genomic research: its potential impact on understanding health disparities.
        Hum Genomics. 2015; 9: 1
        • Beck A.F.
        • Huang B.
        • Auger K.A.
        • Ryan P.H.
        • Chen C.
        • Kahn R.S.
        Explaining racial disparities in child asthma readmission using a causal inference approach.
        JAMA Pediatr. 2016; 170: 695-703
        • Mersha T.B.
        Mapping asthma-associated variants in admixed populations.
        Front Genet. 2015; 6: 292
        • Gautam Y.
        • Ghandikota S.
        • Chen S.
        • Mersha T.B.
        PAMAM: power analysis in multiancestry admixture mapping.
        Genet Epidemiol. 2019; 43: 831-843
        • Willer C.J.
        • Schmidt E.M.
        • Sengupta S.
        • Peloso G.M.
        • Gustafsson S.
        • Kanoni S.
        • et al.
        Discovery and refinement of loci associated with lipid levels.
        Nat Genet. 2013; 45: 1274-1283
        • Beecham A.H.
        • Patsopoulos N.A.
        • Xifara D.K.
        • Davis M.F.
        • Kemppinen A.
        • et al.
        • International Multiple Sclerosis Genetics Consortium (IMSGC)
        Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.
        Nat Genet. 2013; 45: 1353-1360
        • Yeager M.
        • Orr N.
        • Hayes R.B.
        • Jacobs K.B.
        • Kraft P.
        • Wacholder S.
        • et al.
        Genome-wide association study of prostate cancer identifies a second risk locus at 8q24.
        Nat Genet. 2007; 39: 645-649
        • Torgerson D.G.
        • Ampleford E.J.
        • Chiu G.Y.
        • Gauderman W.J.
        • Gignoux C.R.
        • Graves P.E.
        • et al.
        Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations.
        Nat Genet. 2011; 43: 887-892
        • Kumar R.
        • Seibold M.A.
        • Aldrich M.C.
        • Williams L.K.
        • Reiner A.P.
        • Colangelo L.
        • et al.
        Genetic ancestry in lung-function predictions.
        N Engl J Med. 2010; 363: 321-330
        • Auger K.A.
        • Teufel 2nd, R.J.
        • Harris 2nd, J.M.
        • Gay J.C.
        • Del Beccaro M.A.
        • Neuman M.I.
        • et al.
        Children’s hospital characteristics and readmission metrics.
        Pediatrics. 2017; 139e20161720
        • Sills M.R.
        • Hall M.
        • Colvin J.D.
        • Macy M.L.
        • Cutler G.J.
        • Bettenhausen J.L.
        • et al.
        Association of social determinants with children’s hospitals’ preventable readmissions performance.
        JAMA Pediatr. 2016; 170: 350-358
        • VanderWeele T.J.
        Mediation analysis: a practitioner’s guide.
        Annu Rev Public Health. 2016; 37: 17-32
        • Beck A.F.
        • Moncrief T.
        • Huang B.
        • Simmons J.M.
        • Sauers H.
        • Chen C.
        • et al.
        Inequalities in neighborhood child asthma admission rates and underlying community characteristics in one US county.
        J Pediatr. 2013; 163: 574-580
        • Howrylak J.A.
        • Spanier A.J.
        • Huang B.
        • Peake R.W.
        • Kellogg M.D.
        • Sauers H.
        • et al.
        Cotinine in children admitted for asthma and readmission.
        Pediatrics. 2014; 133: e355-e362
        • Spanier A.J.
        • Beck A.F.
        • Huang B.
        • McGrady M.E.
        • Drotar D.D.
        • Peake R.W.
        • et al.
        Family hardships and serum cotinine in children with asthma.
        Pediatrics. 2015; 135: e416-e423
        • Beck A.F.
        • Huang B.
        • Simmons J.M.
        • Moncrief T.
        • Sauers H.S.
        • Chen C.
        • et al.
        Role of financial and social hardships in asthma racial disparities.
        Pediatrics. 2014; 133: 431-439
        • Piccolo R.S.
        • Subramanian S.V.
        • Pearce N.
        • Florez J.C.
        • McKinlay J.B.
        Relative contributions of socioeconomic, local environmental, psychosocial, lifestyle/behavioral, biophysiological, and ancestral factors to racial/ethnic disparities in type 2 diabetes.
        Diabetes Care. 2016; 39: 1208-1217
        • Balavarca Y.
        • Weigl K.
        • Thomsen H.
        • Brenner H.
        Performance of individual and joint risk stratification by an environmental risk score and a genetic risk score in a colorectal cancer screening setting.
        Int J Cancer. 2020; 146: 627-634
        • Park S.K.
        • Tao Y.
        • Meeker J.D.
        • Harlow S.D.
        • Mukherjee B.
        Environmental risk score as a new tool to examine multi-pollutants in epidemiologic research: an example from the NHANES study using serum lipid levels.
        PLoS One. 2014; 9e98632
        • Biagini Myers J.M.
        • Schauberger E.
        • He H.
        • Martin L.J.
        • Kroner J.
        • Hill G.M.
        • et al.
        A pediatric asthma risk score to better predict asthma development in young children.
        J Allergy Clin Immunol. 2019; 143: 1803-1810.e2
        • Brokamp C.
        • LeMasters G.K.
        • Ryan P.H.
        Residential mobility impacts exposure assessment and community socioeconomic characteristics in longitudinal epidemiology studies.
        J Expo Sci Environ Epidemiol. 2016; 26: 428-434
        • Brokamp C.
        • Jandarov R.
        • Hossain M.
        • Ryan P.
        Predicting daily urban fine particulate matter concentrations using a random forest model.
        Environ Sci Technol. 2018; 52: 4173-4179
        • Ryan P.H.
        • LeMasters G.K.
        • Biswas P.
        • Levin L.
        • Hu S.
        • Lindsey M.
        • et al.
        A comparison of proximity and land use regression traffic exposure models and wheezing in infants.
        Environ Health Prespect. 2007; 115: 278-284
        • Auger K.A.
        • Kahn R.S.
        • Davis M.M.
        • Beck A.F.
        • Simmons J.M.
        Medical home quality and readmission risk for children hospitalized with asthma exacerbations.
        Pediatrics. 2013; 131: 64-70
        • Brokamp C.
        • Beck A.F.
        • Goyal N.K.
        • Ryan P.
        • Greenberg J.M.
        • Hall E.S.
        Material community deprivation and hospital utilization during the first year of life: an urban population-based cohort study.
        Ann Epidemiol. 2019; 30: 37-43
        • DeWan A.T.
        • Egan K.B.
        • Hellenbrand K.
        • Sorrentino K.
        • Pizzoferrato N.
        • Walsh K.M.
        • et al.
        Whole-exome sequencing of a pedigree segregating asthma.
        BMC Med Genet. 2012; 13: 95
        • Auton A.
        • Brooks L.D.
        • Durbin R.M.
        • Garrison E.P.
        • Kang H.M.
        • et al.
        • 1000 Genomes Project Consortium
        A global reference for human genetic variation.
        Nature. 2015; 526: 68-74
        • Alexander D.H.
        • Novembre J.
        • Lange K.
        Fast model-based estimation of ancestry in unrelated individuals.
        Genome Res. 2009; 19: 1655-1664
        • Bang H.
        • Edwards A.M.
        • Bomback A.S.
        • Ballantyne C.M.
        • Brillon D.
        • Callahan M.A.
        • et al.
        Development and validation of a patient self-assessment score for diabetes risk.
        Ann Intern Med. 2009; 151: 775-783
        • MacKinnon D.P.
        Introduction to statistical mediation analysis.
        Taylor & Francis/Lawrence Erlbaum, New York2008
        • Rosseel Y.
        Lavaan: an R package for structural equation modeling.
        J Stat Softw. 2012; 48: 1-36
        • Kline R.B.
        Principles and practice of structural equation modeling.
        3rd ed. Guilford Press, New York2011
        • Weiss S.
        Environmental risk factors in childhood asthma.
        Clin Exp Allergy. 1998; 28: 29-34
        • Beck A.F.
        • Huang B.
        • Kercsmar C.M.
        • Guilbert T.W.
        • McLinden D.J.
        • Lierl M.B.
        • et al.
        Allergen sensitization profiles in a population-based cohort of children hospitalized for asthma.
        Ann Am Thorac Soc. 2015; 12: 376-384
        • Newman N.C.
        • Ryan P.H.
        • Huang B.
        • Beck A.F.
        • Sauers H.S.
        • Kahn R.S.
        Traffic-related air pollution and asthma hospital readmission in children: a longitudinal cohort study.
        J Pediatr. 2014; 164: 1396-1402.e1
        • Neophytou A.M.
        • White M.J.
        • Oh S.S.
        • Thakur N.
        • Galanter J.M.
        • Nishimura K.K.
        • et al.
        Air pollution and lung function in minority youth with asthma in the GALA II (Genes-Environments and Admixture in Latino Americans) and SAGE II (Study of African Americans, Asthma, Genes, and Environments) studies.
        Am J Respir Crit Care Med. 2016; 193: 1271-1280
        • Choudhry S.
        • Burchard E.G.
        • Borrell L.N.
        • Tang H.
        • Gomez I.
        • Naqvi M.
        • et al.
        Ancestry–environment interactions and asthma risk among Puerto Ricans.
        Am J Respir Crit Care Med. 2006; 174: 1088-1093
        • Baye T.M.
        • Kovacic M.B.
        • Myers J.M.B.
        • Martin L.J.
        • Lindsey M.
        • Patterson T.L.
        • et al.
        Differences in candidate gene association between European ancestry and African American asthmatic children.
        PLoS One. 2011; 6e16522
        • Forno E.
        • Celedón J.C.
        Asthma and ethnic minorities: socioeconomic status and beyond.
        Curr Opin Allergy Clin Immunol. 2009; 9: 154
        • Litonjua A.A.
        • Carey V.J.
        • Weiss S.T.
        • Gold D.R.
        Race, socioeconomic factors, and area of residence are associated with asthma prevalence.
        Pediatr Pulmonol. 1999; 28: 394-401
        • Thakur N.
        • Oh S.S.
        • Nguyen E.A.
        • Martin M.
        • Roth L.A.
        • Galanter J.
        • et al.
        Socioeconomic status and childhood asthma in urban minority youths. The GALA II and SAGE II studies.
        Am J Respir Crit Care Med. 2013; 188: 1202-1209
        • Thakur N.
        • Martin M.
        • Castellanos E.
        • Oh S.S.
        • Roth L.A.
        • Eng C.
        • et al.
        Socioeconomic status and asthma control in African American youth in SAGE II.
        J Asthma. 2014; 51: 720-728
        • Moncrief T.
        • Beck A.F.
        • Olano K.
        • Huang B.
        • Kahn R.S.
        Routinely sleeping away from home and the association with child asthma readmission.
        J Community Health. 2014; 39: 1209-1215
        • Klinnert M.D.
        • Kaugars A.S.
        • Strand M.
        • Silveira L.
        Family psychological factors in relation to children’s asthma status and behavioral adjustment at age 4.
        Fam Process. 2008; 47: 41-61
        • Nyenhuis S.M.
        • Krishnan J.A.
        • Berry A.
        • Calhoun W.J.
        • Chinchilli V.M.
        • Engle L.
        • et al.
        Race is associated with differences in airway inflammation in patients with asthma.
        J Allergy Clin Immunol. 2017; 140: 257
        • Wang J.
        • Visness C.M.
        • Calatroni A.
        • Gergen P.J.
        • Mitchell H.E.
        • Sampson H.A.
        Effect of environmental allergen sensitization on asthma morbidity in inner-city asthmatic children.
        Clin Exp Allergy. 2009; 39: 1381-1389
        • Gruchalla R.S.
        • Pongracic J.
        • Plaut M.
        • Evans III, R.
        • Visness C.M.
        • Walter M.
        • et al.
        Inner city asthma study: relationships among sensitivity, allergen exposure, and asthma morbidity.
        J Allergy Clin Immunol. 2005; 115: 478-485
        • Spira-Cohen A.
        • Chen L.C.
        • Kendall M.
        • Sheesley R.
        • Thurston G.D.
        Personal exposures to traffic-related particle pollution among children with asthma in the South Bronx, NY.
        J Expo Sci Environ Epidemiol. 2010; 20: 446-456
        • Margolis H.G.
        • Mann J.K.
        • Lurmann F.W.
        • Mortimer K.M.
        • Balmes J.R.
        • Hammond S.K.
        • et al.
        Altered pulmonary function in children with asthma associated with highway traffic near residence.
        Int J Enrivon Health Res. 2009; 19: 139-155
      1. Archer DN. ‘White Men’s Roads Through Black Men’s Homes’: Advancing Racial Equity Through Highway Reconstruction. Vanderbilt Law Review 1259 (2020), NYU School of Law, Public Law Research Paper No. 20-49.

        • Luria C.J.
        • Sitarik A.R.
        • Havstad S.
        • Zoratti E.M.
        • Kim H.
        • Wegienka G.R.
        • et al.
        Association between asthma symptom scores and perceived stress and trait anxiety in adolescents with asthma.
        Allergy Asthma Proc. 2020; 41: 210-217