Implications of Race Adjustment in Lung-Function Equations.

BACKGROUND: Adjustment for race is discouraged in lung-function testing, but the implications of adopting race-neutral equations have not been comprehensively quantified. METHODS: We obtained longitudinal data from 369,077 participants in the National Health and Nutrition Examination Survey, U.K. Biobank, the Multi-Ethnic Study of Atherosclerosis, and the Organ Procurement and Transplantation Network. Using these data, we compared the race-based 2012 Global Lung Function Initiative (GLI-2012) equations with race-neutral equations introduced in 2022 (GLI-Global). Evaluated outcomes included national projections of clinical, occupational, and financial reclassifications; individual lung-allocation scores for transplantation priority; and concordance statistics (C statistics) for clinical prediction tasks. RESULTS: Among the 249 million persons in the United States between 6 and 79 years of age who are able to produce high-quality spirometric results, the use of GLI-Global equations may reclassify ventilatory impairment for 12.5 million persons, medical impairment ratings for 8.16 million, occupational eligibility for 2.28 million, grading of chronic obstructive pulmonary disease for 2.05 million, and military disability compensation for 413,000. These potential changes differed according to race; for example, classifications of nonobstructive ventilatory impairment may change dramatically, increasing 141% (95% confidence interval [CI], 113 to 169) among Black persons and decreasing 69% (95% CI, 63 to 74) among White persons. Annual disability payments may increase by more than $1 billion among Black veterans and decrease by $0.5 billion among White veterans. GLI-2012 and GLI-Global equations had similar discriminative accuracy with regard to respiratory symptoms, health care utilization, new-onset disease, death from any cause, death related to respiratory disease, and death among persons on a transplant waiting list, with differences in C statistics ranging from -0.008 to 0.011. CONCLUSIONS: The use of race-based and race-neutral equations generated similarly accurate predictions of respiratory outcomes but assigned different disease classifications, occupational eligibility, and disability compensation for millions of persons, with effects diverging according to race. (Funded by the National Heart Lung and Blood Institute and the National Institute of Environmental Health Sciences.).

Race and Ethnicity in Pulmonary Function Test Interpretation: An Official American Thoracic Society Statement.

Current American Thoracic Society (ATS) standards promote the use of race and ethnicity-specific reference equations for pulmonary function test (PFT) interpretation. There is rising concern that the use of race and ethnicity in PFT interpretation contributes to a false view of fixed differences between races and may mask the effects of differential exposures. This use of race and ethnicity may contribute to health disparities by norming differences in pulmonary function. In the United States and globally, race serves as a social construct that is based on appearance and reflects social values, structures, and practices. Classification of people into racial and ethnic groups differs geographically and temporally. These considerations challenge the notion that racial and ethnic categories have biological meaning and question the use of race in PFT interpretation. The ATS convened a diverse group of clinicians and investigators for a workshop in 2021 to evaluate the use of race and ethnicity in PFT interpretation. Review of evidence published since then that challenges current practice and continued discussion concluded with a recommendation to replace race and ethnicity-specific equations with race-neutral average reference equations, which must be accompanied with a broader re-evaluation of how PFTs are used to make clinical, employment, and insurance decisions. There was also a call to engage key stakeholders not represented in this workshop and a statement of caution regarding the uncertain effects and potential harms of this change. Other recommendations include continued research and education to understand the impact of the change, to improve the evidence for the use of PFTs in general, and to identify modifiable risk factors for reduced pulmonary function.

Racial/ethnic differences in eligibility for asthma biologics among pediatric populations.

BACKGROUND: Asthma is a heterogeneous disease. Clinical blood parameters differ by race/ethnicity and are used to distinguish asthma subtypes and inform therapies. Differences in subtypes may explain population-specific trends in asthma outcomes. However, these differences in racial/ethnic minority pediatric populations are unclear. OBJECTIVE: We investigated the association of blood parameters and asthma subtypes with asthma outcomes and examined population-specific eligibility for biologic therapies in minority pediatric populations. METHODS: Using data from 2 asthma case-control studies of pediatric minority populations, we performed case-control (N = 3738) and case-only (N = 2743) logistic regressions to quantify the association of blood parameters and asthma subtypes with asthma outcomes. Heterogeneity of these associations was tested using an interaction term between race/ethnicity and each exposure. Differences in therapeutic eligibility were investigated using chi-square tests. RESULTS: Race/ethnicity modified the association between total IgE and asthma exacerbations. Elevated IgE level was associated with worse asthma outcomes in Puerto Ricans. Allergic asthma was associated with worse outcomes in Mexican Americans, whereas eosinophilic asthma was associated with worse outcomes in Puerto Ricans. A lower proportion of Puerto Ricans met dosing criteria for allergic asthma-directed biologic therapy than other groups. A higher proportion of Puerto Ricans qualified for eosinophilic asthma-directed biologic therapy than African Americans. CONCLUSIONS: We found population-specific associations between blood parameters and asthma subtypes with asthma outcomes. Our findings suggest that eligibility for asthma biologic therapies differs across pediatric racial/ethnic populations. These findings call for more studies in diverse populations for equitable treatment of minority patients with asthma.

The association of environmental, meteorological, and pollen count variables with asthma-related emergency department visits and hospitalizations in the Bronx.

Objective: To better understand how meteorological variables, air quality variables, and pollen counts collectively contribute to asthma-related emergency department visits (AREDV) and asthma-related hospitalizations (ARH) among pediatric and adult patients in the New York City borough of the Bronx. Methods: The numbers of daily adult and pediatric AREDV and ARH from 2001 to 2008 were obtained from three Bronx hospitals. After removing outliers, interpolating missing data, and standardizing variable values by scaling the data using z-scores, data were analyzed using Spearman rank tests and linear regression models for the full year and each season. Results: There were a total of 42,065 AREDV and 1,664 ARH at both Bronx hospitals. With the exception of a spring peak in AREDVs, AREDVs and ARHs follow a cyclical pattern, climbing in the fall, plateauing in the winter, dropping in the spring, and reaching a low in the summer. Among the 11 air quality, meteorological, and pollen count variables, temperature and tree pollen made the greatest contribution to AREDV with scaled coefficients of -0.337 and 0.311 respectively; equating to an additional AREDV for every 5.0-unit decrease in temperature and an additional AREDV for every 186.0-unit increase in tree pollen. These two variables were confirmed to have independent associations with AREDV prior to the data interpolation. Grass pollen was also found to have a relatively large contribution to AREDV during the summer with a scaled coefficient of 0.314, equating to an additional AREDV for every 2.3-unit increase in grass pollen. Conclusion: There are distinct peaks of increased AREDVs that are closely associated with increased tree pollen counts in the spring and decreasing temperatures in the fall. Early anticipation of these air quality, meteorological, and pollen factor changes based on ongoing surveillance could potentially guide clinical practice and minimize AREDVs in the Bronx.

Epigenetic patient stratification via contrastive machine learning refines hallmark biomarkers in minoritized children with asthma.

Identifying and refining clinically significant patient stratification is a critical step toward realizing the promise of precision medicine in asthma. Several peripheral blood hallmarks, including total peripheral blood eosinophil count (BEC) and immunoglobulin E (IgE) levels, are routinely used in asthma clinical practice for endotype classification and predicting response to state-of-the-art targeted biologic drugs. However, these biomarkers appear ineffective in predicting treatment outcomes in some patients, and they differ in distribution between racially and ethnically diverse populations, potentially compromising medical care and hindering health equity due to biases in drug eligibility. Here, we propose constructing an unbiased patient stratification score based on DNA methylation (DNAm) and utilizing it to refine the efficacy of hallmark biomarkers for predicting drug response. We developed Phenotype Aware Component Analysis (PACA), a novel contrastive machine-learning method for learning combinations of DNAm sites reflecting biomedically meaningful patient stratifications. Leveraging whole-blood DNAm from Latino (discovery; n=1,016) and African American (replication; n=756) pediatric asthma case-control cohorts, we applied PACA to refine the prediction of bronchodilator response (BDR) to the short-acting ß2-agonist albuterol, the most used drug to treat acute bronchospasm worldwide. While BEC and IgE correlate with BDR in the general patient population, our PACA-derived DNAm score renders these biomarkers predictive of drug response only in patients with high DNAm scores. BEC correlates with BDR in patients with upper-quartile DNAm scores (OR 1.12; 95% CI [1.04, 1.22]; P=7.9 e-4) but not in patients with lower-quartile scores (OR 1.05; 95% CI [0.95, 1.17]; P=0.21); and IgE correlates with BDR in above-median (OR for response 1.42; 95% CI [1.24, 1.63]; P=3.9e-7) but not in below-median patients (OR 1.05; 95% CI [0.92, 1.2]; P=0.57). These results hold within the commonly recognized type 2 (T2)-high asthma endotype but not in T2-low patients, suggesting that our DNAm score primarily represents an unknown variation of T2 asthma. Among T2-high patients with high DNAm scores, elevated BEC or IgE also corresponds to baseline clinical presentation that is known to benefit more from biologic treatment, including higher exacerbation scores, higher allergen sensitization, lower BMI, more recent oral corticosteroids prescription, and lower lung function. Our findings suggest that BEC and IgE, the traditional asthma biomarkers of T2-high asthma, are poor biomarkers for millions worldwide. Revisiting existing drug eligibility criteria relying on these biomarkers in asthma medical care may enhance precision and equity in treatment.

The Puerto Rican Infant Metagenomic and Epidemiologic Study of Respiratory Outcomes (PRIMERO): Design and Baseline Characteristics for a Birth Cohort Study of Early-life Viral Respiratory Illnesses and Airway Dysfunction in Puerto Rican Children.

Epidemiologic studies demonstrate an association between early-life respiratory illnesses (RIs) and the development of childhood asthma. However, it remains uncertain whether these children are predisposed to both conditions or if early-life RIs induce alterations in airway function, immune responses, or other human biology that contribute to the development of asthma. Puerto Rican children experience a disproportionate burden of early-life RIs and asthma, making them an important population for investigating this complex interplay. PRIMERO, the Puerto Rican Infant Metagenomics and Epidemiologic Study of Respiratory Outcomes , recruited pregnant women and their newborns to investigate how the airways develop in early life among infants exposed to different viral RIs, and will thus provide a critical understanding of childhood asthma development. As the first asthma birth cohort in Puerto Rico, PRIMERO will prospectively follow 2,100 term healthy infants. Collected samples include post-term maternal peripheral blood, infant cord blood, the child's peripheral blood at the year two visit, and the child's nasal airway epithelium, collected using minimally invasive nasal swabs, at birth, during RIs over the first two years of life, and at annual healthy visits until age five. Herein, we describe the study's design, population, recruitment strategy, study visits and procedures, and primary outcomes.

Race/Ethnicity and Clinical Prediction Algorithms for Childhood Asthma.

In 1985, the United States Department of Health and Human Services released the Report of the Secretary's Task Force on Black & Minority Health.1 The landmark report showed that persistent health disparities accounted for excess mortality among ethnic and racial minoritized groups. Since this report was published, many efforts have been made to improve clinical outcomes between White and non-White populations. Despite almost 40 years of knowledge, we continue to experience drastic racial or ethnic inequities in common medical conditions.

Race- and Ethnicity-Based Spirometry Reference Equations: Are They Accurate for Genetically Admixed Children?

BACKGROUND: Variation in genetic ancestry among genetically admixed racial and ethnic groups may influence the fit of guideline-recommended spirometry reference equations, which rely on self-identified race and ethnicity. RESEARCH QUESTION: What is the influence of genetic ancestry on the fit of race- and ethnicity-based spirometry reference equations in populations of genetically admixed children? STUDY DESIGN AND METHODS: Cross-sectional fit of guideline-recommended race- and ethnicity-based spirometry reference equations was evaluated in healthy control participants from case-control studies of asthma. Anthropometry, blood samples, and spirometric measurements were obtained for 599 genetically admixed children 8 to 21 years of age. Genetic ancestry was estimated using genome-wide genotype data. Equation fit, measured as a mean z score, was assessed in self-identified African American (n = 275) and Puerto Rican (n = 324) children as well as genetic ancestry-defined strata of each population. RESULTS: For African American children, African American-derived equations fit for predicting FEV1 and FVC in those with an African ancestry more than the median (81.4%-100.0%), whereas composite equations for "other/mixed" populations fit for predicting FEV1 and FVC in those with African ancestry at or less than the median (30.7%-81.3%). For Puerto Rican children with African ancestry at or less than the median (6.4%-21.3%), White-derived equations fit both FEV1 and FVC, whereas for those with African ancestry more than the median (21.4%-87.5%), White-derived equations fit the FEV1 and the composite equations fit the FVC. INTERPRETATION: Guideline-recommended spirometry reference equations yielded biased estimates of lung function in genetically admixed children with high variation of African ancestry. Spirometry could benefit from reference equations that incorporate genetic ancestry, either for more precise application of the current equations or the derivation and use of new equations.

Genetic Determinants of Telomere Length in African American Youth.

Telomere length (TL) is associated with numerous disease states and is affected by genetic and environmental factors. However, TL has been mostly studied in adult populations of European or Asian ancestry. These studies have identified 34 TL-associated genetic variants recently used as genetic proxies for TL. The generalizability of these associations to pediatric populations and racially diverse populations, specifically of African ancestry, remains unclear. Furthermore, six novel variants associated with TL in a population of European children have been identified but not validated. We measured TL from whole blood samples of 492 healthy African American youth (children and adolescents between 8 and 20 years old) and performed the first genome-wide association study of TL in this population. We were unable to replicate neither the 34 reported genetic associations found in adults nor the six genetic associations found in European children. However, we discovered a novel genome-wide significant association between TL and rs1483898 on chromosome 14. Our results underscore the importance of examining genetic associations with TL in diverse pediatric populations such as African Americans.