Abstract
Background:
The American Thoracic Society recently recommended that race- and ethnicity-specific predicted equations for spirometry be replaced with race-neutral equations. This change could have implications for asthma management.
Objective:
To examine the effect of race-specific vs. race-neutral spirometry reference equations on the resultant guideline-directed asthma therapy in a study population with a high proportion of Black children.
Methods:
We pooled and harmonized data from 2,076 children and adolescents across 4 Inner-City Asthma Consortium studies which had all used a computer-asssisted algorithm for asthma medication management. The asthma control level was re-calculated, first using the percent predicted FEV1 values derived from the 2012 race-specific equations and then using those derived from the GLI Global race-neutral equations. The calculated control level then determined the recommendation for treatment step changes.
Results:
Among urban Black children not already at the highest recommended inhaled corticosteroid doses, 18% would have been assigned a higher medication step at study entry when using the race-neutral rather than race-specific reference equations to assess asthma control. A very small number of children in other race or ethnicity groups had a recommendation for a higher medication step.
Conclusion:
The transition to the use of race-neutral values for measures of lung function has the potential to reduce racial bias in diagnosing and treating asthma.
Keywords: asthma, spirometry, reference equations, race, Black
Capsule summary:
Among urban Black children not already at the highest recommended inhaled corticosteroid doses, 18% would have been assigned a higher medication step when using the race-neutral rather than race-specific reference equations to assess asthma control.
Introduction
The American Thoracic Society recently recommended that race and ethnicity-specific predicted equations for spirometry be replaced with race-neutral equations.1 In 4 Inner-City Asthma Consortium (ICAC) studies, conducted between 2002 and 2015, spirometry percent of predicted measures were used to assess asthma control and then calibrate recommended asthma controller medication use with a computer-assisted algorithm.2 Our objective for this analysis was to examine the effect of race-specific vs. race-neutral spirometry reference equations on the resultant guideline-directed asthma therapy in a study population with a high proportion of Black children.
We pooled data from 2,076 children and adolescents across 4 ICAC studies: Asthma Control Evaluation (ACE): a Biomarker-Based Approach to Improving Asthma Control3; Inner-City Anti-IgE Therapy for Asthma (ICATA)4; Preventative Omalizumab or Step-up Therapy for Severe Fall Exacerbations (PROSE)5; and Asthma Phenotypes in the Inner-City (APIC).6
All 4 studies used a similar approach to standardize asthma management by applying guidelines-based asthma care for all study participants. At study entry, questionnaire responses regarding asthma symptoms and recent exacerbations, along with spirometry percent of predicted measurements, were determined and entered into a computer algorithm to calculate the level of asthma control. This assessment of asthma control was then used to recommend whether the participant’s currently prescribed asthma controller medication should be maintained or stepped up.2 (At the initial study screening visit, when study staff assumed the participants’ asthma care, treatment was not allowed to be stepped down).
For the current comparisons, the GLI race-specific (2012)7 and GLI Global race-neutral (2022)8 spirometry equations were applied across the studies to compare assessment of asthma control and potential need for treatment adjustments. The asthma control level was calculated, first using the percent predicted FEV1 values derived from the 2012 race-specific equations and then using those derived from the GLI Global race-neutral equations, along with the symptom and exacerbation components of the control level (see Table E1 in the Online Repository). The calculated control level then determined the recommendation for treatment step changes (see Table E2 in the Online Repository for treatment step definitions).
Results and Discussion
Eligibility for all 4 ICAC studies required residence in urban areas with high rates of households below the poverty level. In our analysis population across all 4 studies, 61.8% of the children self-identified as Black, 29.7% identified as Hispanic, and 8.5% named other races/ethnicities, including White and multiple races. The participants ranged in age from 6 to 20 with a mean age of 11.5 years. Fifty-eight percent were male and 42% were female. Characteristics by study are shown in Table 1.
Table 1.
Characteristics of participants included in the analysis, by study and overall.
| ACE N=529 | ICATA N=386 | APIC N=685 | PROSE N=476 | Total N=2,076 | |
|---|---|---|---|---|---|
| Study Site | |||||
| Baltimore | 51 (9.6%) | - | 127 (18.5%) | - | 178 (8.6%) |
| Boston | 55 (10.4%) | 30 (7.8%) | 87 (12.7%) | 53 (11.1%) | 225 (10.8%) |
| Chicago | 55 (10.4%) | 50 (13.0%) | 80 (11.7%) | 48 (10.1%) | 233 (11.2%) |
| Cincinnati | - | - | 62 (9.1%) | 57 (12.0%) | 119 (5.7%) |
| Cleveland | 67 (12.7%) | 40 (10.4%) | - | - | 107 (5.2%) |
| Dallas | 52 (9.8%) | 66 (9.6%) | 64 (16.6%) | 54 (11.3%) | 236 (11.3%) |
| Denver | 48 (9.1%) | 61 (8.9%) | 69 (17.9%) | 74 (11.6%) | 252 (12.1%) |
| Detroit | - | - | 75 (11.0%) | 51 (10.7%) | 126 (6.1%) |
| New York | 59 (11.2%) | 56 (14.5%) | 78 (11.4%) | 53 (11.1%) | 246 (11.9%) |
| St. Louis | 53 (10.0%) | - | - | - | 53 (2.6%) |
| Tucson | 54 (10.2%) | 27 (7.0%) | - | - | 81 (3.9%) |
| Washington, DC | 35 (6.6%) | 50 (13.0%) | 49 (7.2%) | 86 (18.1%) | 220 (10.6%) |
| Sex | |||||
| Male | 279 (52.7%) | 226 (58.6%) | 397 (58.0%) | 302 (63.4%) | 1204 (58.0%) |
| Female | 250 (47.3%) | 160 (41.4%) | 288 (42.0%) | 174 (36.6%) | 872 (42.0%) |
| Self-reported Race and Ethnicity | |||||
| Black | 336 (63.5%) | 230 (59.6%) | 440 (64.2%) | 277 (58.2%) | 1283 (61.8%) |
| Hispanic | 120 (22.7%) | 144 (37.3%) | 191 (27.9%) | 161 (33.8%) | 616 (29.7%) |
| Mixed/Other | 73 (13.8%) | 12 (6.7%) | 54 (7.9%) | 38 (8.0%) | 177 (8.5%) |
| Age in Years (mean, sd) | 14.4 (2.1) | 10.9 (3.5) | 10.7 (3.0) | 9.8 (2.9) | 11.5 (3.4) |
By applying race-neutral measures of lung function, the mean FEV1 percent predicted value was reduced from 92.1% to 81.9% (10.2 percentage points) in Black children. This difference compared to 3.4 percentage points in Hispanic children and 2.8 percentage points in children who reported mixed or other races/ethnicities (Table 2). This corresponds to a reduction in the FEV1 z-score in Black children of −0.8 (or most of a standard deviation) which was a significantly greater reduction compared to the change in Hispanic or Mixed/Other children (p < 0.001; Figure 1). This observation of a significant change in Black children only was the same across age groups and for both boys and girls.
Table 2.
Change in Mean (SD) Percent Predicted FEV1 with Race-Neutral Reference Equations by Self-Identified Race and Ethnicity
| Black (N=1283) | Hispanic (N=616) | Mixed/Other (N=177) | |
|---|---|---|---|
| FEV1 (liters) at Screening Visit | 2.1 (0.8) | 2.3 (0.9) | 2.4 (0.9) |
| GLI Race-Adjusted Percent Predicted | 92.1 (17.3) | 102.5 (17.8) | 95.8 (15.7) |
| GLI Race-Neutral Percent Predicted | 81.9 (15.5) | 99.1 (17.2) | 93.0 (15.7) |
| Percentage Point Difference | −10.2 (2.9) | −3.4 (2.6) | −2.8 (2.3) |
Figure 1. Reduction in Percent Predicted FEV1 Z-scores using the GLI Race-Neutral Reference Equations by Self-Identified Race and Ethnicity.
Panel A shows the FEV1 percent predicted z-score using race-specific and race-neutral reference equations by self-identified race and ethnicity. Panel B shows that the reduction in FEV1 z-score was significantly larger in Black children than in Hispanic or Mixed/Other children (linear model of the change from using race-specific to race-neutral spirometry reference equations, with race as a predictor and adjusting for each participant’s race-specific FEV1 z-score value).
One-fourth of the Black children moved to a higher (worse) control level category using the race-neutral equations with 13% being assigned to a higher medication step (p<0.001 vs. non-Black children; Table 3). Children already on Step 5 therapy (combination therapy equivalent to 500mcg fluticasone plus 50mcg salmeterol twice daily) could not be assigned to a higher step in these studies, because this would require the use of ICS doses greater than FDA approved levels. When children (n=572) that started at Step 5 were removed from the analysis, 18% of the Black children would have been assigned a higher medication step using the raceneutral equations to assess asthma control. In contrast, only 2-3% of the Hispanic or Mixed/Other children would have had a medication step-up recommended. We also examined an increase from Step 5 to a theoretical Step 6, as these children could be candidates for a step-up to biologic therapy under current treatment guidelines. Table 3 shows that a larger percentage of Black children at Step 5 would be recommended for a higher level of treatment compared to other groups.
Table 3.
Treatment Step Increases with Race-Neutral Reference Equations for Each Step as Determined Using Race-Adjusted Reference Equations by Self-Identified Race and Ethnicity
| Black (N=1283) | Hispanic (N=616) | Mixed/Other (N=177) | Chi-square p-value | |
|---|---|---|---|---|
| Step 0 to Step 1 | 31/84 (37%) | 1/41 (2%) | 0/11 (0%) | <0.001 |
| Step 1 to Step 2 | 36/156 (19%) | 2/100 (2%) | 240 (5%) | <0.001 |
| Step 2 to Step 3 | 27/213 (13%) | 2/103 (2%) | 0/20 (0%) | <0.001 |
| Step 3 to Step 4 | 38/193 (20%) | 3101 (3%) | 1/16 (6%) | <0.001 |
| Step 4 to Step 5 | 36/239 (15%) | 0/112 (0%) | 1/37 (3%) | <0.001 |
| Step 5 to Step 6* | 30/266 (11%) | 3/126 (2%) | 0/41 (0%) | <0.001 |
| Any Increase (% of all children) | 168/1283 (13%) | 8/616 (1%) | 4/177 (2%) | <0.001 |
| Any Increase if Step 6 available (% of all children) | 198/1283 (15%) | 11/616 (2%) | 4/177 (2%) | <0.001 |
|
| ||||
| Any Increase (% of children < Step 5) | 168/921 (18%) | 8/457 (2%) | 4/124 (3%) | <0.001 |
There was not a Step 6 option available in these studies; however, current practice would consider a step up to biologic therapy for these children.
In all 4 studies, after the initial study visit and assumption of asthma management, the participants’ control level and recommended treatment was determined using percent of personal best rather than percent of predicted FEV1. Thus, we were unable to use this type of comparison to assess whether potential under-treatment with controller medications resulted in excess morbidity during study follow-up.
Our study population was well-suited to this analysis because of the high proportion of Black study participants. Importantly, significant changes in percent predicted FEV1 values were found only among the Black children. This is not surprising, given that the race-specific reference equations contain a downward adjustment for the predicted FEV1 in Black children and adults. Nonetheless, our study population was restricted to urban populations in large U.S. cities and these findings may not be generalizable to other populations.
Race-based spirometry reference equations classify some Black children as having “normal” lung function who would be classified as “low” when using race-neutral equations. Our results demonstrate that this misclassification would result in a significant proportion of Black children being treated with lower doses of inhaled corticosteroids when using the race-based equations. While we were unable to conclude that treatment decisions based on race-neutral equations would result in better clinical outcomes, there is a potential for a switch to race-neutral equations to contribute to better asthma control. A recent survey indicates that a majority of academic health centers are currently using race-neutral spirometry reference standards or intend to do so in the near future.9 The transition to the use of race-neutral values for measures of lung function has the potential to reduce racial bias in diagnosing and treating asthma.
Supplementary Material
Clinical Implications:
Race-based spirometry reference equations may misclassify some Black children as having “normal” lung function who would be classified as “low” when using race-neutral equations, potentially contributing to less effective asthma control.
Funding Source:
This project has been funded in whole with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, under Contract/Grant numbers NO1-AI-25496, NO1-AI-25482, HHSN272200900052C, HHSN272201000052I, 1UM1AI114271-01, UM2AI117870, and 1U01AI178772.
Disclosure Statement:
Dr. Jackson reports personal fees from Genentech, Pfizer, Upstream Bio, Sanofi, AstraZeneca, Avillion, GlaxoSmithKline and Areteia as well as grants and personal fees from Regeneron, and OM Pharma outside the submitted work. All other authors report nothing to disclose.
Abbreviations
- ACE
Asthma Control Evaluation
- APIC
Asthma Phenotypes in the Inner-City
- GLI
Global Lung Initiative
- ICAC
Inner-City Asthma Consortium
- ICATA
Inner-City Anti-IgE Therapy for Asthma
- PROSE
Preventative Omalizumab or Step-up Therapy for Severe Fall Exacerbations
Footnotes
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Disclaimer: Dr. Gergen’s co-authorship on this publication does not constitute endorsement by the US National Institute of Allergy and Infectious Diseases or by any other United States government agency.
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