Association between IgE levels and asthma severity among African American, Mexican, and Puerto Rican patients with asthma

Article Outline

• Abstract
• Methods
  • Study participants
  • Asthma questionnaire
  • IgE measurements
  • Pulmonary function tests
  • Statistical analysis
• Results
  • Subject characteristics
  • Comparison of asthma severity and clinical outcomes among subjects high and low IgE
• Discussion
• Acknowledgment
• Appendix. Supplementary data
• References
• Copyright

Background

High levels of IgE are associated with asthma. Whether higher levels of IgE are associated with more severe asthma is still unclear.

Objective

To determine whether IgE is associated with asthma severity among Latino and African American subjects with asthma.

Methods

We assessed lung function and asthma severity among African American, Mexican, and Puerto Rican patients with asthma with high IgE levels (≥100 IU/mL; n = 492) and compared these values to those of patients with asthma with low IgE levels (<100 IU/mL; n = 247). We also examined IgE as a continuous variable among these groups.

Results

Patients with asthma with high IgE had a lower mean FEV₁ (87.6 ± 17.1, percent of predicted) than patients with asthma with low IgE (91.5 ± 17.0; P = .031). Regardless of race and ethnicity, baseline FEV₁, forced expiratory flow, and FEV₁/forced vital capacity were lower among subjects with high IgE than among subjects with low IgE (P = .031, P < .0001, P = .0001, respectively). In addition, 54.7% of patients with asthma with high IgE had been previously hospitalized, compared with 44.1% of patients with asthma with low IgE (odds ratio, 1.33; 95% CI, 1.04-1.71).

Conclusion

Higher IgE is associated with lower baseline lung function and more severe asthma among these populations.

Clinical implications

Among patients with asthma from 3 ethnically distinct groups, total IgE levels are inversely correlated with baseline lung function and asthma severity.

Key words: Asthma, IgE, African Americans, Mexicans, Puerto Ricans, allergy

Abbreviations used: ANCOVA, Analysis of covariance, BMI, Body mass index, ETS, Environmental tobacco smoke, FEF_25-75, Forced expiratory flow at 25% to 75% of forced vital capacity, FVC, Forced vital capacity, GALA, Genetics of Asthma in Latino Americans, ICU, Intensive care unit, MFI, Median family income, OR, Odds ratio, SAGE, Study of African Americans, Asthma, Genes and Environments, SES, Socioeconomic status

IgE is an antibody subclass implicated in airway inflammation and allergic reactions. High levels of IgE are associated with asthma in both adults and children.¹, ², ³, ⁴, ⁵ IgE also may play a role in modulating the severity of asthma, because previous studies have found associations between high IgE levels and greater asthma severity,⁶, ⁷, ⁸, ⁹ airway hyperresponsiveness,¹⁰ and lower baseline lung function.¹¹

In 1989, Burrows et al³ demonstrated an association between high total serum IgE and asthma prevalence, independent of skin test reactivity to common allergens, in a study population of 2657 children and adults. Since then, several reports have suggested a relation between IgE level and asthma severity. In a study conducted by de Marco et al,¹² IgE was a strong predictor of moderate-to-severe asthma among 856 European adult patients with asthma. In The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study, higher total IgE was associated with the degree of asthma severity among younger subjects with difficult-to-treat or severe asthma.⁷ In fact, therapeutic monoclonal anti-IgE antibodies have been shown to reduce exacerbations and steroid requirements in patients with allergy and asthma;¹³, ¹⁴, ¹⁵ however, the underlying mechanism behind the relation between IgE and asthma is not yet clearly understood. Identifying clinical differences between subjects with asthma with high and low IgE levels may help to clarify the regulatory mechanisms that account for the underlying pathogenesis of asthma and high IgE.

IgE levels have also been shown to vary among different ethnic groups. In a study of 569 African American and European American children in suburban Detroit, African American children had the higher IgE levels.¹¹ Asthma prevalence and severity vary significantly among ethnic groups. Although asthma affects 5% to 7% of the US population,¹⁶ a disproportionate number of those with asthma are ethnic minorities, particularly African Americans and Puerto Ricans, who also have the highest morbidity and mortality rates from asthma in the United States.¹¹, ¹⁷, ¹⁸, ¹⁹, ²⁰, ²¹, ²² The role of IgE in the pathogenesis of asthma and in modulating its severity still remains unknown, particularly in those minority populations most affected by the disease.

Here, we compare and contrast clinical characteristics among 739 adults and children with asthma with high IgE levels (≥100 IU/mL) and low IgE levels (<100 IU/mL) of African American, Mexican, and Puerto Rican ethnicity. Mexicans and Puerto Ricans with asthma were recruited as a part of the Genetics of Asthma in Latino Americans (GALA) study, a comprehensive study initiated to understand better the clinical, genetic, and environmental differences in asthma severity among these ethnic groups. African Americans with asthma were recruited as part of the Study of African Americans, Asthma, Genes and Environments (SAGE), an ongoing case-control study of genetic and environmental factors associated with asthma among African Americans, who, like Puerto Ricans, have disproportionately high asthma prevalence, morbidity, and mortality in the United States.²³, ²⁴

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Methods 

Study participants 

Study participants were from the following ethnic groups: Puerto Rican, Mexican, and African American ethnicity. As part of the GALA study, Mexican subjects with asthma were recruited from the San Francisco Bay Area, California and Mexico City, Mexico, and Puerto Rican subjects with asthma were recruited from New York City and Puerto Rico.²⁵ African Americans with asthma were recruited from the San Francisco–Bay Area as part of SAGE. All subjects with asthma were recruited from community clinics and hospitals, and recruitment was standardized across all centers. Eligible subjects were between the ages of 8 and 40 years, had physician-diagnosed asthma or had greater than 12% bronchodilator responsiveness, and had experienced 2 or more episodes of asthma symptoms (wheezing, coughing, and/or shortness of breath) in the previous 2 years. Subjects were enrolled into the study only if both biological parents and all biological grandparents were identified as Puerto Rican (for the New York City and Puerto Rico sites), Mexican (for the San Francisco and Mexico City, Mexico, sites), or African American (for the San Francisco site). Ethnicity was self-reported using standardized questions. Physicians who were bilingual and bicultural and who specialized in asthma were present at all interviews. Local institutional review boards approved all studies, and all subjects provided written, age-appropriate informed consent or assent.

Asthma questionnaire 

Trained interviewers administered a modified version of the 1978 American Thoracic Society–Division of Lung Diseases epidemiology questionnaire,²⁶ which gathers comprehensive information related to medical and social history, environmental exposures, and asthma symptoms. Socioeconomic information was available for the San Francisco site and was determined using the Federal Financial Institutions Examination Council's Geocoding/Mapping System for subjects with complete street addresses. To assign socioeconomic status, we used the Federal Financial Institutions Examination Council's Geocoding/Mapping System to classify subjects into 1 of 4 US Census 2000 tract income levels: low, moderate, middle, and upper. These categories were based on the median family household income of the census tract for that year. Classifications are based on the census tract's median family income (MFI), divided by the median family income of the metropolitan area in which the tract is located, or MFI %. If the MFI % < 50%, then the income level is low. If the MFI % ≥50% and <80%, then the income level is moderate. If the MFI % ≥80% and <120%, then the income level is middle. If the MFI % ≥120%, then the income level is upper.²⁷

The level of asthma severity was determined by a global severity classification that used information gathered from questionnaire and spirometry data. All subjects were classified as having either mild or moderate-to-severe asthma on the basis of 4 criteria:

Subjects were classified as mild if they met criterion 1 and no others and were classified as moderate-to-severe if they met any of criteria 2, 3, or 4, regardless of whether they met criterion 1. Subjects who did not meet any of the criteria were not included. Patients classified as mild in this study correspond to the National Asthma Education and Prevention Program classification of mild intermittent asthma, and those classified as moderate-to-severe fit into the mild, moderate, and severe-persistent classifications.

IgE measurements 

Total plasma IgE was measured in duplicate for all 739 subjects with asthma by using Uni-Cap technology (Pharmacia, Kalamazoo, Mich). Subjects were classified as having high IgE if their total IgE level was greater than or equal to 100 IU/mL. Subjects were classified as having low IgE if their total IgE level was less than 100 IU/mL.

Pulmonary function tests 

Spirometry was conducted on all patients according to American Thoracic Society standards.²⁸ Subjects with asthma were instructed to withhold their bronchodilator medications for at least 8 hours before pulmonary function tests. After initial spirometry, albuterol was administered through a spacer device from a standard metered dose inhaler: 180 μg (2 puffs) for subjects <16 years old and 360 μg (4 puffs) for subjects ≥16 years old. Repeat spirometry was then performed 15 minutes after albuterol administration. Pulmonary function tests are expressed as a percentage predicted by using age- and race-adjusted prediction equations.²⁹ Bronchodilator responsiveness (Δ FEV₁) to albuterol is reported as percent change in FEV₁ after albuterol administration (post-FEV₁ in liters minus pre-FEV₁ in liters, times 100, divided by pre-FEV₁ in liters).

Statistical analysis 

To investigate the relation between IgE and asthma severity, we evaluated several indicators of asthma severity, including normalized baseline lung function tests (FEV₁, FEV₁/forced vital capacity [FVC], forced expiratory flow at 25% to 75% of forced vital capacity [FEF_25-75]); drug responsiveness (Δ FEV₁, Δ FEV₁/FVC, Δ FEF_25-75); asthma severity level (moderate-to-severe vs mild); daily symptoms (binary); nocturnal symptoms (binary); wheezing (binary); chest tightness (binary); use of controller medication (single binary variable for use of any of the following: steroids, long-acting β₂-agonists, leukotriene antagonists, theophylline, or cromolyn sodium); steroid medication (binary); allergic reaction to pets, mold, and dust (3 binary variables: 1 = runny or stuffy nose, shortness of breath, chest tightness, coughing, or wheezing after exposure, 0 = no reaction); previous hospitalization (binary); intensive care unit (ICU) visits (binary, 1 = has had previous visit to ICU, 0 = has not had visit to ICU); and previous intubation (binary). Environmental tobacco smoke (ETS) exposure was available for subjects under age 13 years. ETS exposure was determined to be present if 1 or both parents or any other person in the household reported smoking during the first 2 years of the life of a child with asthma and absent if the answer was no. Besides lung function tests and severity levels, these variables were derived from yes/no questions from the standardized questionnaire.

For continuous variables, an ANOVA and an analysis of covariance (ANCOVA) were performed to examine differences in clinical characteristics of asthma severity between subjects with asthma with high IgE and low IgE levels overall, within each ethnic group, and for the subset of all subjects <18 years. IgE was entered into the model as a binary variable (1= IgE ≥ 100 IU/mL; 0 = IgE < 100 IU/mL). Covariates in these models included age, sex, race, socioeconomic status (SES), log-transformed body mass index (BMI), and age at disease onset. For binary variables, logistic regression was performed including race, age, sex, BMI, and age at disease onset as covariates in the model. For the subset of subjects under age 18, sex, race, SES, log-transformed BMI, and age at disease onset were included as covariates.

Last, we tested for associations between IgE and indicators of asthma severity by entering IgE as a log-transformed continuous variable into logistic regression models for binary outcomes and multiple linear regression models for continuous outcomes. P values expressed for continuous variables are from ANCOVAs unless specifically noted. STATA V.8 statistical analysis software was used for this analysis (STATA, College Station, Tex).

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Results 

Subject characteristics 

Overall characteristics for the complete GALA and SAGE cohorts are described elsewhere (Naqvi M, et al, unpublished data, 2005).¹⁷, ²⁵ In the present analysis, we analyzed a total of 739 patients with asthma (492 with high IgE and 247 with low IgE) who had complete information for IgE, asthma severity, and other variables, including BMI, age, sex, disease onset, and parental histories of asthma and allergies, as described in Methods. No significant differences were noted in drug response, severity level, and other measures of baseline lung function between subjects who were included in this analysis and those who were excluded.

Table I describes characteristic of patients with asthma with high (≥100 IU/mL) and low (<100 IU/mL) IgE levels. Through univariate regression, African Americans were more prevalent in the group with low IgE (P < .001) than in the group with high IgE. Earlier age at onset was associated with high IgE (P = .013). As expected, hay fever was associated with high IgE (P < .0001). Sex, age, and BMI were not independently associated with high IgE. Parental histories of asthma, eczema, and hay fever were not significantly associated with high IgE.

Table I. Characteristics of subjects with asthma with high and low IgE levels

	Subjects with IgE ≥100 IU/mL (n = 492)	Subjects with IgE <100 IU/mL (n = 247)	P value∗
	(% or mean ± SD)
Race/ethnicity
Mexican	40.2	29.2	<.001
Puerto Rican	32.9	22.7	<.001
African American	26.8	48.2	—
Subject characteristics
Age (y)	16.3 ± 8.0	17.3 ± 9.5	.129
Male sex	52.8	45.7	.069
BMI	24.3 ± 6.9	25.2 ± 7.5	.148
SES	2.01 ± .8	2.11 ± .85	.237
Breast-fed	56.1	54.9	.834
ETS exposure	30	26.7	.529
Age at asthma onset	5.8 ± 7.6	7.4 ± 8.6	.013
Eczema	35.2	32.8	.510
Hay fever	84.9	71.7	<.001
Maternal history
Asthma	34.4	29.8	.217
Eczema	10.1	6.3	.095
Hay fever	27.8	32.8	.171
Paternal history
Asthma	23.4	24.1	.845
Eczema	7.5	8.4	.697
Hay fever	24.7	22.6	.556

After adjustment for age, sex, BMI, and age at asthma onset, African Americans had significantly lower IgE levels (mean, 285.9 IU/mL) than did Mexicans and Puerto Ricans (mean, 472.9 IU/mL and 460.2 IU/mL, respectively; P < .0001). Adjusted logistic regression analysis showed that Puerto Ricans and Mexicans were more likely to have high IgE levels than were African Americans (odds ratio [OR], 2.46; 95% CI, 1.6-3.7; and OR, 2.68; 95% CI, 1.82-3.94, respectively). Table E1 (see this article's Online Repository at www.jacionline.org) summarizes IgE levels and subject characteristics stratified by race.

Among study participants for whom SES data were available (Mexicans and African Americans in the continental United States), no association was found between SES and IgE by univariate logistic regression (P > .05), nor did SES vary significantly between Mexican and African American populations (P > .05). Because of these findings and the unavailability of comparable SES data among Puerto Ricans, SES was not used as a covariate in our models.

Comparison of asthma severity and clinical outcomes among subjects high and low IgE 

Mean values for lung function and drug responsiveness among subjects with asthma with high and low IgE levels are shown in Table II. Mean lung function tests for individual ethnic groups are shown in Table E2 (see this article's Online Repository at www.jacionline.org). After adjusting for ethnic background, age, sex, BMI, and age of disease onset, participants with high IgE had significantly lower lung function than did those with low IgE. Participants with high IgE had lower baseline values of FEV₁, FEF_25-75, and FEV₁/FVC, percent of predicted, than did those with low IgE (P = .031, P < .0001, P = .0001, respectively). In addition, a greater proportion of subjects with high IgE had baseline FEV₁ < 80% of predicted than did those with low IgE (P = .021). With regard to IgE levels, the same trends in FEV₁, FEF_25-75, and FEV₁/FVC and higher proportion of participants with baseline FEV₁ < 80% of predicted regarding IgE levels were seen in each ethnic group. Multiple linear regression confirmed that baseline FEV₁, FEF_25-75, and FEV₁/FVC, percent of predicted, were all associated with higher IgE (continuous and log-transformed) both before and after adjustment for covariates (P = .007, P < .001, P = .001, respectively). Bronchodilator drug responsiveness was not associated with IgE levels in our study population.

Table II. Comparison of lung function between subjects with asthma with high and low IgE levels

Clinical characteristics and outcomes of participants, stratified by IgE levels, are shown in Table III. Clinical characteristics for individual ethnic groups are shown in Table E3 (see this article's Online Repository at www.jacionline.org). Presented ORs are from logistic regression analysis, using the binary severity indicator as the outcome variable. Subjects were classified as having mild asthma or moderate-to-severe asthma, as described in Methods, with 72.2% of those with high IgE having moderate-to-severe asthma compared with 65.6% of those with low IgE. Logistic regression using IgE as a continuous log-transformed variable showed that IgE was associated with moderate-to-severe asthma before and after adjusting for race and ethnicity, age, sex, BMI, and age at disease onset (OR, 1.39; 95% CI, 1.08-1.8). In addition, 54.7% of subjects with asthma with high IgE had been previously hospitalized, compared with 44.1% of those with low IgE (OR, 1.33; 95% CI, 1.04-1.71). Intubations and ICU visits did not differ between subjects with high IgE and low IgE, although we had little power to detect such associations given the low proportions of each. Other indicators of severity, however, including medication use, nocturnal symptoms, daily symptoms, wheezing, and chest tightness, did not vary significantly between subjects with high and low IgE. Finally, as expected, subjects with asthma with high IgE were more likely to have had an allergic reaction to pets than those with low IgE (59.4% and 40.8%, respectively; OR, 1.90; 95% CI, 1.48-2.43).

Table III. Clinical characteristics and outcomes among subjects with asthma with high and low IgE

Outcome variable	Subjects with IgE ≥100 IU/mL (n = 492)	Subjects with IgE <100 IU/mL (n = 247)	Adjusted OR∗	95% CI		P value
	(Percent)
Asthma severity
Moderate-to-severe asthma	72.2	65.6	1.39	1.08	1.80	.011
Diurnal asthma symptoms	54.8	51.5	1.18	0.93	1.50	.172
Nocturnal asthma	47	51.5	1.05	0.82	1.35	.681
Symptoms and medication
Wheezing	83.1	92.3	1.05	0.77	1.44	.750
Chest tightness	83.1	93.4	0.98	0.71	1.34	.890
Controller medication	64.2	59.1	1.21	0.96	1.55	.108
Steroid medication	57.3	54.2	1.21	0.95	1.53	.119
Allergic reactions
Pets	59.4	40.8	1.90	1.48	2.43	<.0001
Mold	75	76.1	1.02	0.78	1.33	.898
Dust	91.1	87.4	1.38	0.95	2.01	.095
Hospitalization
Hospitalization	54.7	44.1	1.33	1.04	1.71	.023
Intubation	3.7	7.3	0.71	0.41	1.20	.200
ICU	11.7	11	1.37	0.92	2.03	.120

To address the possible confounding effects of differences between childhood and adult allergic asthma, we repeated the analysis on the subset of children with asthma under age 18 years (n = 526). Among this group, children with IgE ≥ 100 IU/mL (n = 354) still had lower lung function than did children with IgE < 100 IU/mL (n = 172) after adjustment for the covariates listed in Methods. Specifically, the children with high IgE had lower mean baseline FEV₁, FEF_25-75, and FEV₁/FVC (89.2 ± 15.7, 69.5 ± 25.7, 89.2 ± 10.9, respectively) than did children with low IgE (93.1 ± 16.9, 78.6 ± 28.0, 93.0 ± 11.3, respectively). These differences were significant after adjustment for confounders by ANCOVA (P = .032, P = .002, P = .004, respectively). Among children with asthma and high IgE levels, a significantly higher proportion of subjects reported an allergic reaction to pets than among those with asthma and low IgE levels (58.2% and 38.2%, respectively; OR, 2.20; 95% CI, 1.49-3.25). ETS information was available for children <13 years of age. Incorporating ETS into this group, we found that subjects with low IgE levels had significantly higher levels of FEF_25-75 and FEV₁/FVC (P = .011 and P = .044, respectively.) As in adults, no association was found between IgE levels and bronchodilator drug responsiveness.

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Discussion 

The results of our analysis demonstrate an association between high IgE levels and asthma severity among Mexican, Puerto Rican, and African American patients with asthma. These findings remain significant after accounting for differences in race/ethnicity, age, sex, BMI, and age of asthma onset, and also after stratification of patients with asthma into children and adults. Although asthma has already been shown to be associated with serum IgE levels,¹, ², ³ our results expand on previous findings by demonstrating that higher IgE levels are correlated with lower lung function and more severe asthma. In addition, these findings are notable among Mexican, Puerto Rican, and African American subjects with asthma, high-risk populations that are often understudied. To our knowledge, this is the first and largest investigation of IgE and asthma severity (defined by questionnaire and spirometry) conducted specifically among 3 US minority populations.

Previous studies examining IgE, asthma characteristics, and lung function have shown an association between severity and IgE in adults and children⁷; however, one of the limitations of these evaluations is the lack of standardization of asthma classification. Our study used formal lung function studies (in addition to physician assessment and symptom scores) in all patients and, as such, offers objective and reproducible severity classification, as demonstrated in multiple previous studies.³⁰, ³¹, ³²

Our study found an association between lower baseline lung function and IgE levels among subjects with asthma in 3 minority populations, as well as associations with moderate-to-severe asthma and hospitalizations for asthma. In conjunction with the established relationship between IgE and asthma phenotype, these findings suggest a relationship between IgE and severity level that is related to asthma pathology. We are aware of only 1 previous study that has attempted to examine this relationship. An epidemiologic longitudinal study performed by Annesi et al⁸ specifically examined FEV₁ and methacholine reactivity in a cohort of 310 French adult men in a 5-year period. They found a decline in FEV₁ was associated with IgE in nonsmokers (P = .03) and in exsmokers (P = .06). Although this study does demonstrate a relationship between IgE and lung function, their population included both subjects with and without asthma. In addition, this study did not assess such a relationship in children with asthma.

In our study, African American subjects were older than subjects in the other 2 groups. Although our models were adjusted for age, this age difference may account for the skewed proportion of African American asthmatics with low IgE. To further adjust for age differences, we stratified subjects into adults (≥18 years) and children (<18 years). We found that subjects with asthma with high IgE still had significantly lower lung function than those with low IgE, as shown by 3 separate indexes, regardless of age group. Although our findings thereby lost significance, the same trends regarding lower lung function and IgE remained when ethnic groups were examined individually.

In addition to asthma severity, we also compared asthma-related characteristics among racial/ethnic groups. We found that African American patients with asthma had significantly lower IgE levels and were less likely to have high IgE levels compared with both Puerto Rican and Mexican patients with asthma, even after adjustment for race, age, sex, BMI, and age at asthma onset. Although there have been few studies that directly compare IgE levels and asthma-related traits across racial/ethnic groups, Joseph et al¹¹ demonstrated that, among children in suburban Detroit, African Americans without asthma had significantly higher IgE levels and higher airway responsiveness than European American children. However, among subjects with asthma, they found no significant differences in IgE across racial groups. Overall, the mean IgE levels in all of our populations were higher than the mean IgE levels of subjects participating in the study by Joseph et al.¹¹ The difference in IgE levels between the different study populations likely reflects differences in ascertainment and exposure characteristics of their populations.

Although the major strengths of our study are the objective nature of the measurements (IgE levels and spirometry), the large sample size, and 3 separate populations, it has several important limitations that must be considered when interpreting our results. This was not a population-based study. Therefore, it is possible that we may have introduced bias. However, in these analyses, we have taken steps to adjust for potential confounding factors. In addition, there are no published pulmonary function reference values for Puerto Ricans. This limitation highlights the need for more research in minority populations. We used the predictive equations of Hankinson et al,²⁹ the most extensive data set of normal spirometric values for Latinos of all ages. These reference values, however, do not distinguish among the different Latino ethnicities. It has been shown that African Americans have smaller lungs than white subjects.³³, ³⁴, ³⁵, ³⁶ As such, there may be differences in lung size between Puerto Ricans, Mexicans, and African Americans that are not accounted for in our analysis. However, we found that FEV₁, FEF_25-75, and FEV₁/FVC ratio, the last of which is an index of airway obstruction adjusted for individual vital capacity, was lower among subjects with high IgE levels across all 3 ethnic groups. This consistency reinforces the validity of our results.

By evaluating a large sample of subjects with asthma, including a large number of children, the current study may improve the clinician's ability to predict long-term outcomes for children with asthma symptoms. We found that among the overall subject population, and in the subset of children under age 18 years, higher IgE levels are associated with an increase in symptom-based and pulmonary function–based asthma severity. This suggests that, among subjects with asthma with high IgE levels, the progression to more severe asthma may begin early in life. Although these results will need to be confirmed through additional investigation, we conclude that aggressive treatment of allergic patients with asthma may help prevent further decline in lung function over the lifetime of a subject with asthma. If validated, these results could have an important effect on the clinical management of individuals with and without allergy with asthma.

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We acknowledge the families and the patients for their participation. We also thank the numerous health care providers and community clinics for their support and participation in the GALA and SAGE studies. We thank especially Jeffrey M. Drazen, MD, Scott Weiss, MD, Ed Silverman, MD, PhD, Homer A. Boushey, MD, and Jean G. Ford, MD, for all of their effort towards the creation of the GALA study. Finally, we thank the Sandler Family Supporting Foundation, the primary sponsor of this investigation.

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Appendix. Supplementary data 

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