Fernando Martinez

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• Zhai, J., Voraphani, N., Imboden, M., Keidel, D., Liu, C., Stern, D. A., Venker, C., Petersen, H., Bosco, A., Sherrill, D. L., Morgan, W. J., Tesfaigzi, Y., Probst-Hensch, N. M., Martinez, F. D., Halonen, M., & Guerra, S. (2024). Circulating biomarkers of airflow limitation across the life span. The Journal of allergy and clinical immunology.
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  Airflow limitation is a hallmark of COPD, which can develop through different lung function trajectories across the life span. There is a need for longitudinal studies aimed at identifying circulating biomarkers of airflow limitation across different stages of life.
• Marques Dos Santos, M., Pivniouk, V., Rankl, B., Walker, A., Pagani, G., Hertkorn, N., Schmitt-Kopplin, P., Müller, C., Bracher, F., Merl-Pham, J., Hauck, S. M., Schloter, M., Michael, A. N., Anderson, D., Honeker, L., Gozdz, J., Pivniouk, O., Ober, C., Holbreich, M., , Martinez, F. D., et al. (2023). Asthma-protective agents in dust from traditional farm environments. The Journal of allergy and clinical immunology, 152(3), 610-621.
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  Growing up on traditional European or US Amish dairy farms in close contact with cows and hay protects children against asthma, and airway administration of extracts from dust collected from cowsheds of those farms prevents allergic asthma in mice.
• McEvoy, C. T., Le Souef, P. N., & Martinez, F. D. (2023). The Role of Lung Function in Determining Which Children Develop Asthma. The journal of allergy and clinical immunology. In practice, 11(3), 677-683.
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  Longitudinal studies have demonstrated that altered indices of airway function, assessed shortly after birth, are a risk factor for the subsequent development of wheezing illnesses and asthma, and that these indices predict airway size and airway wall thickness in adult life. Pre- and postnatal factors that directly alter early airway function, such as extreme prematurity and cigarette smoke, may continue to affect airway function and, hence, the risks for wheeze and asthma. Early airway function and an associated asthma risk may also be indirectly influenced by immune system responses, respiratory viruses, the airway microbiome, genetics, and epigenetics, especially if they affect airway epithelial dysfunction. Few if any interventions, apart from smoking avoidance, have been proven to alter the risks of developing asthma, but vitamin C supplementation to pregnant smokers may help decrease the effects of in utero smoke on offspring lung function. We conclude that airway size and the factors influencing this play an important role in determining the risk for asthma across the lifetime. Progress in asthma prevention is long overdue and this may benefit from carefully designed interventions in well-phenotyped longitudinal birth cohorts with early airway function assessments monitored through to adulthood.
• Nenna, R., Stern, D. A., Carr, T. F., Spangenberg, A., Wright, A. L., Martinez, F. D., & Halonen, M. (2023). Prenatal exposure to RSV season influences first-year risk of RSV lower respiratory illness and RSV-specific immune responses assessed at birth. Journal of virology, 97(9), e0076723.
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  Maternal-to-fetal transmission of respiratory syncytial virus (RSV) has been shown to occur but whether late prenatal exposure to RSV season influences offspring postnatal RSV-lower respiratory illness (LRI) risk in early life or RSV immune status at birth is unclear. In this study, the duration of third trimester RSV season exposure was determined for 1,094 newborns of the Tucson Children's Respiratory Study (TCRS) and found to show an inverse relation to risk for first RSV-LRI in the first year. Cord blood anti-RSV antibody is related to third trimester RSV season exposure but not to first year RSV-LRI risk. In a separate birth cohort (the Infant Immune Study), supernatants from cord blood mononuclear cells stimulated with the recall antigen, UV-inactivated RSV, were assayed for IFN-γ and IL-4. The frequency of detectable IFN-γ (but not IL-4) was increased for those with at least 2 mo of third trimester RSV season exposure, suggestive of a fetal immune response to RSV. IMPORTANCE Our study found that duration of third trimester exposure to RSV season related inversely to subsequent risk of postnatal RSV-LRI in the first year, thus implicating this exposure as an important factor in reducing risk of postnatal RSV-LRIs, a risk reduction that appears to be independent of maternally transferred anti-RSV antibody level. The increase in frequency of detectable IFN-γ and not IL-4 in response to UV-inactivated RSV in cord blood immune cells for infants with greater third trimester exposure to RSV season is suggestive of a Type-1 immune response to RSV occurring .
• Nenna, R., Zhai, J., Spangenberg, A., Sherrill, D. L., Martinez, F. D., Halonen, M., & Guerra, S. (2023). Cytomegalovirus serology in young to mid-adult life and decline of lung function. The clinical respiratory journal, 17(5), 468-472.
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  Cytomegalovirus (CMV) seropositivity has been recently linked to severity and progression of asthma, cystic fibrosis, and chronic obstructive pulmonary disease (COPD). To date, no longitudinal study has addressed the relation of CMV serology to levels and decline of lung function in the general adult population.
• Polverino, F., Stern, D. A., Snyder, E. M., Wheatley-Guy, C., Bhatt, S. P., Martinez, F. D., Guerra, S., & Morgan, W. J. (2023). Lower respiratory illnesses in childhood are associated with the presence of air trapping in early adulthood. Respiratory medicine, 206, 107062.
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  Several factors occurring in early life, including lower respiratory tract illnesses (LRIs), are involved in determining lung structure and function in adulthood, but the effects of these factors on lung development remain largely unknown. Hereby, we evaluated the parameters from computed tomography (CT) scans performed at the age of 26 years in 39 subjects from the birth cohort of the Tucson Children's Respiratory Study (TCRS) in order to determine the relationship between early childhood factors and lung structural changes in young adult life. We found that participants with LRIs in childhood had increased air trapping at the age of 26 suggesting an association between childhood infections and lung development.
• Voraphani, N., Stern, D. A., Ledford, J. G., Spangenberg, A. L., Zhai, J., Wright, A. L., Morgan, W. J., Kraft, M., Sherrill, D. L., Curtin, J. A., Murray, C. S., Custovic, A., Kull, I., Hallberg, J., Bergström, A., Herrera-Luis, E., Halonen, M., Martinez, F. D., Simpson, A., , Melén, E., et al. (2023). Circulating CC16 and Asthma: A Population-based, Multicohort Study from Early Childhood through Adult Life. American journal of respiratory and critical care medicine, 208(7), 758-769.
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  Club cell secretory protein (CC16) is an antiinflammatory protein highly expressed in the airways. CC16 deficiency has been associated with lung function deficits, but its role in asthma has not been established conclusively. To determine ) the longitudinal association of circulating CC16 with the presence of active asthma from early childhood through adult life and ) whether CC16 in early childhood predicts the clinical course of childhood asthma into adult life. We assessed the association of circulating CC16 and asthma in three population-based birth cohorts: the Tucson Children's Respiratory Study (years 6-36; total participants, 814; total observations, 3,042), the Swedish Barn/Children, Allergy, Milieu, Stockholm, Epidemiological survey (years 8-24; total participants, 2,547; total observations, 3,438), and the UK Manchester Asthma and Allergy Study (years 5-18; total participants, 745; total observations, 1,626). Among 233 children who had asthma at the first survey in any of the cohorts, baseline CC16 was also tested for association with persistence of symptoms. After adjusting for covariates, CC16 deficits were associated with increased risk for the presence of asthma in all cohorts (meta-analyzed adjusted odds ratio per 1-SD CC16 decrease, 1.20; 95% confidence interval [CI], 1.12-1.28;  
• Welfley, H., Kylat, R., Zaghloul, N., Halonen, M., Martinez, F. D., Ahmed, M., & Cusanovich, D. A. (2023). Single-Cell Profiling of Premature Neonate Airways Reveals a Continuum of Myeloid Differentiation. American journal of respiratory cell and molecular biology, 69(6), 689-697.
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  Single-cell genomic technologies hold great potential to advance our understanding of lung development and disease. A major limitation lies in accessing intact cells from primary lung tissues for profiling human airway health. Sampling methods such as endotracheal aspiration that are compatible with clinical interventions could enable longitudinal studies, the enrollment of large cohorts, and the development of novel diagnostics. To explore single-cell RNA sequencing profiling of the cell types present at birth in the airway lumen of extremely premature neonates (
• Carr, T. F., Granell, R., Stern, D. A., Guerra, S., Wright, A., Halonen, M., Henderson, J., & Martinez, F. D. (2022). High Insulin in Early Childhood Is Associated with Subsequent Asthma Risk Independent of Body Mass Index. The journal of allergy and clinical immunology. In practice, 10(3), 785-792.e5.
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  Asthma and obesity are major, interconnected public health challenges that usually have their origins in childhood, and for which the relationship is strengthened among those with insulin resistance.
• Carr, T. F., Stern, D. A., Morgan, W., Guerra, S., & Martinez, F. D. (2022). Elevated Childhood Insulin-related Asthma Is Risk Factor for Reduced Lung Function. American journal of respiratory and critical care medicine.
• Chang, E. H., Pouladi, N., Guerra, S., Jandova, J., Kim, A., Li, H., Li, J., Morgan, W., Stern, D. A., Willis, A. L., Lussier, Y. A., & Martinez, F. D. (2022). Epithelial cell responses to rhinovirus identify an early-life-onset asthma phenotype in adults. The Journal of allergy and clinical immunology, 150(3), 604-611.
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  The study of pathogenic mechanisms in adult asthma is often marred by a lack of precise information about the natural history of the disease. Children who have persistent wheezing (PW) during the first 6 years of life and whose symptoms start before age 3 years (PW) are much more likely to have wheezing illnesses due to rhinovirus (RV) in infancy and to have asthma into adult life than are those who do not have PW (PW).
• Guerra, S., Ledford, J. G., Melén, E., Lavi, I., Carsin, A. E., Stern, D. A., Zhai, J., Vidal, M., Bustamante, M., Addison, K. J., Vallecillo, R. G., Billheimer, D., Koppelman, G. H., Garcia-Aymerich, J., Lemonnier, N., Fitó, M., Dobaño, C., Kebede Merid, S., Kull, I., , McEachan, R. R., et al. (2022). Creatine Kinase is Decreased in Childhood Asthma. American journal of respiratory and critical care medicine.
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  The identification of novel molecules associated with asthma may provide insights into mechanisms of disease and their potential clinical implications.
• Harber, P., Furlong, M., Stern, D. A., Morgan, W. J., Wright, A. L., Guerra, S., & Martinez, F. D. (2022). Association of Childhood Respiratory Status with Adult Occupational Exposures in a Birth Cohort. Annals of the American Thoracic Society.
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  People with better early life respiratory health may be more likely to work in occupations with high workplace exposures in adult life, compared to people with poor respiratory health. This may manifest as a healthy worker effect bias potentially confounding the analysis of environmental exposure studies.
• Martinez, F. J., Agusti, A., Celli, B. R., Han, M. K., Allinson, J. P., Bhatt, S. P., Calverley, P., Chotirmall, S. H., Chowdhury, B., Darken, P., Da Silva, C. A., Donaldson, G., Dorinsky, P., Dransfield, M., Faner, R., Halpin, D. M., Jones, P., Krishnan, J. A., Locantore, N., , Martinez, F. D., et al. (2022). Treatment Trials in Young Patients with Chronic Obstructive Pulmonary Disease and Pre-Chronic Obstructive Pulmonary Disease Patients: Time to Move Forward. American journal of respiratory and critical care medicine, 205(3), 275-287.
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  Chronic obstructive pulmonary disease (COPD) is the end result of a series of dynamic and cumulative gene-environment interactions over a lifetime. The evolving understanding of COPD biology provides novel opportunities for prevention, early diagnosis, and intervention. To advance these concepts, we propose therapeutic trials in two major groups of subjects: "young" individuals with COPD and those with pre-COPD. Given that lungs grow to about 20 years of age and begin to age at approximately 50 years, we consider "young" patients with COPD those patients in the age range of 20-50 years. Pre-COPD relates to individuals of any age who have respiratory symptoms with or without structural and/or functional abnormalities, in the absence of airflow limitation, and who may develop persistent airflow limitation over time. We exclude from the current discussion infants and adolescents because of their unique physiological context and COPD in older adults given their representation in prior randomized controlled trials (RCTs). We highlight the need of RCTs focused on COPD in young patients or pre-COPD to reduce disease progression, providing innovative approaches to identifying and engaging potential study subjects. We detail approaches to RCT design, including potential outcomes such as lung function, patient-reported outcomes, exacerbations, lung imaging, mortality, and composite endpoints. We critically review study design components such as statistical powering and analysis, duration of study treatment, and formats to trial structure, including platform, basket, and umbrella trials. We provide a call to action for treatment RCTs in ) young adults with COPD and ) those with pre-COPD at any age.
• Pivniouk, V., Gimenes-Junior, J. A., Ezeh, P., Michael, A., Pivniouk, O., Hahn, S., VanLinden, S. R., Malone, S. P., Abidov, A., Anderson, D., Gozdz, J., DeVries, A., Martinez, F. D., Pasquali, C., & Vercelli, D. (2022). Airway administration of OM-85, a bacterial lysate, blocks experimental asthma by targeting dendritic cells and the epithelium/IL-33/ILC2 axis. The Journal of allergy and clinical immunology, 149(3), 943-956.
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  Microbial interventions against allergic asthma have robust epidemiologic underpinnings and the potential to recalibrate disease-inducing immune responses. Oral administration of OM-85, a standardized lysate of human airways bacteria, is widely used empirically to prevent respiratory infections and a clinical trial is testing its ability to prevent asthma in high-risk children. We previously showed that intranasal administration of microbial products from farm environments abrogates experimental allergic asthma.
• Voraphani, N., Stern, D. A., Zhai, J., Wright, A. L., Halonen, M., Sherrill, D. L., Hallberg, J., Kull, I., Bergström, A., Murray, C. S., Lowe, L., Custovic, A., Morgan, W. J., Martinez, F. D., Melén, E., Simpson, A., & Guerra, S. (2022). The role of growth and nutrition in the early origins of spirometric restriction in adult life: a longitudinal, multicohort, population-based study. The Lancet. Respiratory medicine, 10(1), 59-71.
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  Spirometric restriction, defined as a reduced forced vital capacity (FVC) with a preserved FEV/FVC ratio, is associated with increased respiratory and non-respiratory comorbidities and all-cause mortality in adulthood. Little is known about the early origins of this condition. We sought to identify early-life risk factors for spirometric restriction in adult life.
• Washington, C., Dapas, M., Biddanda, A., Magnaye, K. M., Aneas, I., Helling, B. A., Szczesny, B., Boorgula, M. P., Taub, M. A., Kenny, E., Mathias, R. A., Barnes, K. C., , C., Khurana Hershey, G. K., Kercsmar, C. M., Gereige, J. D., Makhija, M., Gruchalla, R. S., Gill, M. A., , Liu, A. H., et al. (2022). African-specific alleles modify risk for asthma at the 17q12-q21 locus in African Americans. Genome medicine, 14(1), 112.
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  Asthma is the most common chronic disease in children, occurring at higher frequencies and with more severe disease in children with African ancestry.
• Yang, C. X., Tomchaney, M., Landecho, M. F., Zamacona, B. R., Marin Oto, M., Zulueta, J., Malo, J., Knoper, S., Contoli, M., Papi, A., Vasilescu, D. M., Sauler, M., Straub, C., Tan, C., Martinez, F. D., Bhattacharya, D., Rosas, I. O., Kheradmand, F., Hackett, T. L., & Polverino, F. (2022). Lung Spatial Profiling Reveals a T Cell Signature in COPD Patients with Fatal SARS-CoV-2 Infection. Cells, 11(12).
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  People with pre-existing lung diseases such as chronic obstructive pulmonary disease (COPD) are more likely to get very sick from SARS-CoV-2 disease 2019 (COVID-19). Still, an interrogation of the immune response to COVID-19 infection, spatially throughout the lung structure, is lacking in patients with COPD. For this study, we characterized the immune microenvironment of the lung parenchyma, airways, and vessels of never- and ever-smokers with or without COPD, all of whom died of COVID-19, using spatial transcriptomic and proteomic profiling. The parenchyma, airways, and vessels of COPD patients, compared to control lungs had (1) significant enrichment for lung-resident CD45RO memory CD4 T cells; (2) downregulation of genes associated with T cell antigen priming and memory T cell differentiation; and (3) higher expression of proteins associated with SARS-CoV-2 entry and primary receptor ubiquitously across the ROIs and in particular the lung parenchyma, despite similar SARS-CoV-2 structural gene expression levels. In conclusion, the lung parenchyma, airways, and vessels of COPD patients have increased T-lymphocytes with a blunted memory CD4 T cell response and a more invasive SARS-CoV-2 infection pattern and may underlie the higher death toll observed with COVID-19.
• Zanobetti, A., Ryan, P. H., Coull, B., Brokamp, C., Datta, S., Blossom, J., Lothrop, N., Miller, R. L., Beamer, P. I., Visness, C. M., Andrews, H., Bacharier, L. B., Hartert, T., Johnson, C. C., Ownby, D., Khurana Hershey, G. K., Joseph, C., Yiqiang, S., Mendonça, E. A., , Jackson, D. J., et al. (2022). Childhood Asthma Incidence, Early and Persistent Wheeze, and Neighborhood Socioeconomic Factors in the ECHO/CREW Consortium. JAMA pediatrics, 176(8), 759-767.
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  In the United States, Black and Hispanic children have higher rates of asthma and asthma-related morbidity compared with White children and disproportionately reside in communities with economic deprivation.
• Agusti, A., Fabbri, L. M., Baraldi, E., Celli, B., Corradi, M., Faner, R., Martinez, F. D., Melén, E., & Papi, A. (2021). Spirometry: A practical lifespan predictor of global health and chronic respiratory and non-respiratory diseases. European journal of internal medicine, 89, 3-9.
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  1. To review and discuss available evidence supporting that spirometry is an overlooked global health marker, that could be used regularly through the lifespan to monitor human health and predict risk of chronic respiratory and other chronic non-communicable diseases (NCDs). 2. To discuss the challenges and opportunities that this proposal faces.Summary of key data. First, spirometry is essential to assess and monitor respiratory health. Second, spirometry adds prognostic value to other well-accepted health markers used in clinical practice, such as blood pressure, body mass index, glucose and blood lipids, by identifying individuals at risk, not only of respiratory diseases, but also of other NCDs, particularly cardiovascular and metabolic disorders.
• Boyce, W. T., Levitt, P., Martinez, F. D., McEwen, B. S., & Shonkoff, J. P. (2021). Genes, Environments, and Time: The Biology of Adversity and Resilience. Pediatrics, 147(2).
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  Exposures to adverse environments, both psychosocial and physicochemical, are prevalent and consequential across a broad range of childhood populations. Such adversity, especially early in life, conveys measurable risk to learning and behavior and to the foundations of both mental and physical health. Using an interactive gene-environment-time (GET) framework, we survey the independent and interactive roles of genetic variation, environmental context, and developmental timing in light of advances in the biology of adversity and resilience, as well as new discoveries in biomedical research. Drawing on this rich evidence base, we identify 4 core concepts that provide a powerful catalyst for fresh thinking about primary health care for young children: (1) all biological systems are inextricably integrated, continuously "reading" and adapting to the environment and "talking back" to the brain and each other through highly regulated channels of cross-system communication; (2) adverse environmental exposures induce alterations in developmental trajectories that can lead to persistent disruptions of organ function and structure; (3) children vary in their sensitivity to context, and this variation is influenced by interactions among genetic factors, family and community environments, and developmental timing; and (4) critical or sensitive periods provide unmatched windows of opportunity for both positive and negative influences on multiple biological systems. These rapidly moving frontiers of investigation provide a powerful framework for new, science-informed thinking about health promotion and disease prevention in the early childhood period.
• Clougherty, J. E., Kinnee, E. J., Cardet, J. C., Mauger, D., Bacharier, L., Beigelman, A., Blake, K. V., Cabana, M. D., Castro, M., Chmiel, J. F., Covar, R., Fitzpatrick, A., Gaffin, J. M., Gentile, D., Israel, E., Jackson, D. J., Kraft, M., Krishnan, J. A., Kumar, H. V., , Lang, J. E., et al. (2021). Geography, generalisability, and susceptibility in clinical trials. The Lancet. Respiratory medicine, 9(4), 330-332.
• Hallmark, B., Wegienka, G., Havstad, S., Billheimer, D., Ownby, D., Mendonca, E. A., Gress, L., Stern, D. A., Myers, J. B., Khurana Hershey, G. K., Hoepner, L., Miller, R. L., Lemanske, R. F., Jackson, D. J., Gold, D. R., O'Connor, G. T., Nicolae, D. L., Gern, J. E., Ober, C., , Wright, A. L., et al. (2021). Chromosome 17q12-21 Variants Are Associated with Multiple Wheezing Phenotypes in Childhood. American journal of respiratory and critical care medicine, 203(7), 864-870.
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  Birth cohort studies have identified several temporal patterns of wheezing, only some of which are associated with asthma. Whether 17q12-21 genetic variants, which are closely associated with asthma, are also associated with childhood wheezing phenotypes remains poorly explored. To determine whether wheezing phenotypes, defined by latent class analysis (LCA), are associated with nine 17q12-21 SNPs and if so, whether these relationships differ by race/ancestry. Data from seven U.S. birth cohorts ( = 3,786) from the CREW (Children's Respiratory Research and Environment Workgroup) were harmonized to represent whether subjects wheezed in each year of life from birth until age 11 years. LCA was then performed to identify wheeze phenotypes. Genetic associations between SNPs and wheeze phenotypes were assessed separately in European American (EA) ( = 1,308) and, for the first time, in African American (AA) ( = 620) children. The LCA best supported four latent classes of wheeze: infrequent, transient, late-onset, and persistent. Odds of belonging to any of the three wheezing classes (vs. infrequent) increased with the risk alleles for multiple SNPs in EA children. Only one SNP, rs2305480, showed increased odds of belonging to any wheezing class in both AA and EA children. These results indicate that 17q12-21 is a "wheezing locus," and this association may reflect an early life susceptibility to respiratory viruses common to all wheezing children. Which children will have their symptoms remit or reoccur during childhood may be independent of the influence of rs2305480.
• Johnson, C. C., Havstad, S. L., Ownby, D. R., Joseph, C. L., Sitarik, A. R., Biagini Myers, J., Gebretsadik, T., Hartert, T. V., Khurana Hershey, G. K., Jackson, D. J., Lemanske, R. F., Martin, L. J., Zoratti, E. M., Visness, C. M., Ryan, P. H., Gold, D. R., Martinez, F. D., Miller, R. L., Seroogy, C. M., , Wright, A. L., et al. (2021). Pediatric asthma incidence rates in the United States from 1980 to 2017. The Journal of allergy and clinical immunology, 148(5), 1270-1280.
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  Few studies have examined longitudinal asthma incidence rates (IRs) from a public health surveillance perspective.
• Johnson, M. D., Younis, U. S., Menghani, S. V., Addison, K. J., Whalen, M., Pilon, A. L., Cress, A. E., Polverino, F., Romanoski, C. E., Kraft, M., Martinez, F. D., Guerra, S., & Ledford, J. G. (2021). CC16 Binding to αβ Integrin Protects against Infection. American journal of respiratory and critical care medicine, 203(11), 1410-1418.
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  CC16 (club cell secretory protein) is a pneumoprotein produced predominantly by pulmonary club cells. Circulating CC16 is associated with protection from the inception and progression of the two most common obstructive lung diseases (asthma and chronic obstructive pulmonary disease). Although exact mechanisms remain elusive, studies consistently suggest a causal role of CC16 in mediating antiinflammatory and antioxidant functions in the lung. We sought to determine any novel receptor systems that could participate in CC16's role in obstructive lung diseases. Protein alignment of CC16 across species led to the discovery of a highly conserved sequence of amino acids, leucine-valine-aspartic acid (LVD), a known integrin-binding motif. Recombinant CC16 was generated with and without the putative integrin-binding site. A mouse model and a fluorescent cellular adhesion assay were used to determine the impact of the LVD site regarding CC16 function during live infection and on cellular adhesion during inflammatory conditions. CC16 bound to integrin αβ), also known as the adhesion molecule VLA-4 (very late antigen 4), dependent on the presence of the LVD integrin-binding motif. During infection, recombinant CC16 rescued lung function parameters both when administered to the lung and intravenously but only when the LVD integrin-binding site was intact; likewise, neutrophil recruitment during infection and leukocyte adhesion were both impacted by the loss of the LVD site. We discovered a novel receptor for CC16, VLA-4, which has important mechanistic implications for the role of CC16 in circulation as well as in the lung compartment.
• Martinez, F. D. (2021). Asthma in the Time of COVID-19. American journal of respiratory and critical care medicine, 203(7), 785-786.
• Ortega, V. E., Daya, M., Szefler, S. J., Bleecker, E. R., Chinchilli, V. M., Phipatanakul, W., Mauger, D., Martinez, F. D., Herrera-Luis, E., Pino-Yanes, M., Hawkins, G. A., Ampleford, E. J., Kunselman, S. J., Cox, C., Bacharier, L. B., Cabana, M. D., Cardet, J. C., Castro, M., Denlinger, L. C., , Eng, C., et al. (2021). Pharmacogenetic studies of long-acting beta agonist and inhaled corticosteroid responsiveness in randomised controlled trials of individuals of African descent with asthma. The Lancet. Child & adolescent health, 5(12), 862-872.
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  Pharmacogenetic studies in asthma cohorts, primarily made up of White people of European descent, have identified loci associated with response to inhaled beta agonists and corticosteroids (ICSs). Differences exist in how individuals from different ancestral backgrounds respond to long-acting beta agonist (LABA) and ICSs. Therefore, we sought to understand the pharmacogenetic mechanisms regulating therapeutic responsiveness in individuals of African descent.
• Ryan, P. H., Brokamp, C., Blossom, J., Lothrop, N., Miller, R. L., Beamer, P. I., Visness, C. M., Zanobetti, A., Andrews, H., Bacharier, L. B., Hartert, T., Johnson, C. C., Ownby, D., Lemanske, R. F., Gibson, H., Requia, W., Coull, B., Zoratti, E. M., Wright, A. L., , Martinez, F. D., et al. (2021). A distributed geospatial approach to describe community characteristics for multisite studies. Journal of clinical and translational science, 5(1), e86.
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  Understanding place-based contributors to health requires geographically and culturally diverse study populations, but sharing location data is a significant challenge to multisite studies. Here, we describe a standardized and reproducible method to perform geospatial analyses for multisite studies. Using census tract-level information, we created software for geocoding and geospatial data linkage that was distributed to a consortium of birth cohorts located throughout the USA. Individual sites performed geospatial linkages and returned tract-level information for 8810 children to a central site for analyses. Our generalizable approach demonstrates the feasibility of geospatial analyses across study sites to promote collaborative translational research.
• Tomchaney, M., Contoli, M., Mayo, J., Baraldo, S., Li, S., Cabel, C. R., Bull, D. A., Lick, S., Malo, J., Knoper, S., Kim, S. S., Tram, J., Rojas-Quintero, J., Kraft, M., Ledford, J. G., Tesfaigzi, Y., Martinez, F. D., Thorne, C. A., Kheradmand, F., , Campos, S. K., et al. (2021). Paradoxical effects of cigarette smoke and COPD on SARS-CoV-2 infection and disease. BMC pulmonary medicine, 21(1), 275.
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  How cigarette smoke (CS) and chronic obstructive pulmonary disease (COPD) affect severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection and severity is controversial. We investigated the effects of COPD and CS on the expression of SARS-CoV-2 entry receptor ACE2 in vivo in COPD patients and controls and in CS-exposed mice, and the effects of CS on SARS-CoV-2 infection in human bronchial epithelial cells in vitro.
• Wedzicha, J. A., Brochard, L., Donaldson, G. C., Martinez, F. D., & Martinez, F. J. (2021). Ending on a Crescendo: Reflections on Seven Years of a Successful Journal. American journal of respiratory and critical care medicine, 204(12), 1351-1352.
• Ledford, J., Guerra, S., Kraft, M., Martinez, F., ..., .., Addison, K., Insel, M., & Zhai, J. (2018). Club cell secretory protein deficiency leads to altered lung function. American Journal of Respiratory and Critical Care Medicine.
• Carr, T. F., Beamer, P. I., Rothers, J., Stern, D. A., Gerald, L. B., Rosales, C. B., Van Horne, Y. O., Pivniouk, O. N., Vercelli, D., Halonen, M., Gameros, M., Martinez, F. D., & Wright, A. L. (2017). Prevalence of Asthma in School Children on the Arizona-Sonora Border. The journal of allergy and clinical immunology. In practice, 5(1), 114-120.e2.
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  Mexican-born children living in the United States have a lower prevalence of asthma than other US children. Although children of Mexican descent near the Arizona (AZ)-Sonora border are genetically similar, differences in environmental exposures might result in differences in asthma prevalence across this region.
• Croteau-Chonka, D. C., Qiu, W., Martinez, F. D., Strunk, R. C., Lemanske, R. F., Liu, A. H., Gilliland, F. D., Millstein, J., Gauderman, W. J., Ober, C., Krishnan, J. A., White, S. R., Naureckas, E. T., Nicolae, D. L., Barnes, K. C., London, S. J., Barraza-Villarreal, A., Carey, V. J., Weiss, S. T., , Raby, B. A., et al. (2017). Gene Expression Profiling in Blood Provides Reproducible Molecular Insights into Asthma Control. American journal of respiratory and critical care medicine, 195(2), 179-188.
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  Maintaining optimal symptom control remains the primary objective of asthma treatment. Better understanding of the biologic underpinnings of asthma control may lead to the development of improved clinical and pharmaceutical approaches.
• Martinez, F. D. (2017). Bending the Twig Does the Tree Incline: Lung Function after Lower Respiratory Tract Illness in Infancy. American journal of respiratory and critical care medicine, 195(2), 154-155.
• Bacharier, L. B., Guilbert, T. W., & Martinez, F. D. (2016). Early Azithromycin Treatment to Prevent Severe Lower Respiratory Tract Illnesses in Children--Reply. JAMA, 315(19), 2122-3.
• Beamer, P. I., Klimecki, W. T., Loh, M., Van Horne, Y. O., Sugeng, A. J., Lothrop, N., Billheimer, D., Guerra, S., Lantz, R. C., Canales, R. A., & Martinez, F. D. (2016). Association of Children's Urinary CC16 Levels with Arsenic Concentrations in Multiple Environmental Media. International journal of environmental research and public health, 13(5).
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  Arsenic exposure has been associated with decreased club cell secretory protein (CC16) levels in adults. Further, both arsenic exposure and decreased levels of CC16 in childhood have been associated with decreased adult lung function. Our objective was to determine if urinary CC16 levels in children are associated with arsenic concentrations in environmental media collected from their homes. Yard soil, house dust, and tap water were taken from 34 homes. Urine and toenail samples were collected from 68 children. All concentrations were natural log-transformed prior to data analysis. There were associations between urinary CC16 and arsenic concentration in soil (b = -0.43, p = 0.001, R² = 0.08), water (b = -0.22, p = 0.07, R² = 0.03), house dust (b = -0.37, p = 0.07, R² = 0.04), and dust loading (b = -0.21, p = 0.04, R² = 0.04). In multiple analyses, only the concentration of arsenic in soil was associated with urinary CC16 levels (b = -0.42, p = 0.02, R² = 0.14 (full model)) after accounting for other factors. The association between urinary CC16 and soil arsenic may suggest that localized arsenic exposure in the lungs could damage the airway epithelium and predispose children for diminished lung function. Future work to assess this possible mechanism should examine potential associations between airborne arsenic exposures, CC16 levels, lung function, and other possible confounders in children in arsenic-impacted communities.
• Beamer, P. I., Klimecki, W. T., Loh, M., Van Horne, Y. O., Sugeng, A. J., Lothrop, N., Billheimer, D., Guerra, S., Lantz, R. C., Canales, R. A., & Martinez, F. D. (2016). Response to García-Nieto et al. Comments on Beamer et al. Association of Children's Urinary CC16 Levels with Arsenic Concentrations in Multiple Environmental Media. Int. J. Environ. Res. Public Health 2016, 13, 521. International journal of environmental research and public health, 13(10).
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  We would like to thank the editors for providing us with the opportunity to respond to the points raised by Dr. García Nieto.[...].
• Beamer, P., Klimecki, W., Loh, M., Van Horne, Y. O., Sugeng, A., Lothrop, N., Billheimer, D., Guerra, S., Lantz, R. C., & Martinez, F. (2016). Association of Children’s Urinary CC16 Levels with Arsenic Concentrations in Multiple Environmental Media. International Journal of Environmental Research and Public Health, 13(5), E521. doi:10.3390/ijerph13050521
• Beamer, P., Loh, M. M., Klimecki, W., Ornelas Van Horne, Y., Sugeng, A. J., Lothrop, N. Z., Billheimer, D. D., Guerra, S., Lantz, R. C., Canales, R. A., & Martinez, F. (2016). Association of children's urinary CC16 levels with arsenic concentrations in multiple environmental media. International Journal of Environmental Research and Public Health.
• Berry, C. E., Billheimer, D., Jenkins, I. C., Lu, Z. J., Stern, D. A., Gerald, L. B., Carr, T. F., Guerra, S., Morgan, W. J., Wright, A. L., & Martinez, F. D. (2016). A Distinct Low Lung Function Trajectory from Childhood to the Fourth Decade of Life. American journal of respiratory and critical care medicine, 194(5), 607-12.
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  Low maximally attained lung function increases the risk of chronic obstructive pulmonary disease irrespective of the subsequent rate of lung function decline.
• Chang, E. H., Willis, A. L., McCrary, H. C., Noutsios, G. T., Le, C. H., Chiu, A. G., Mansfield, C. J., Reed, D. R., Brooks, S. G., Adappa, N. D., Palmer, J. N., Cohen, N. G., Stern, D. A., Guerra, S., & Martinez, F. D. (2016). Association between the CDHR3 rs6967330 risk allele and chronic rhinosinusitis. The Journal of allergy and clinical immunology.
• Deshpande, D. R., & Martinez, F. D. (2016). The dilemma of systemic steroids in preschool children with recurrent wheezing exacerbations. Pediatric pulmonology, 51(8), 775-7.
• Fitzpatrick, A. M., Jackson, D. J., Mauger, D. T., Boehmer, S. J., Phipatanakul, W., Sheehan, W. J., Moy, J. N., Paul, I. M., Bacharier, L. B., Cabana, M. D., Covar, R., Holguin, F., Lemanske, R. F., Martinez, F. D., Pongracic, J. A., Beigelman, A., Baxi, S. N., Benson, M., Blake, K., , Chmiel, J. F., et al. (2016). Individualized therapy for persistent asthma in young children. The Journal of allergy and clinical immunology, 138(6), 1608-1618.e12.
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  Phenotypic presentations in young children with asthma are varied and might contribute to differential responses to asthma controller medications.
• Gerald, J. K., Gerald, L. B., Vasquez, M. M., Morgan, W. J., Boehmer, S. J., Lemanske, R. F., Mauger, D. T., Strunk, R. C., Szefler, S. J., Zeiger, R. S., Bacharier, L. B., Bade, E., Covar, R. A., Guilbert, T. W., Heidarian-Raissy, H., Kelly, H. W., Malka-Rais, J., Sorkness, C. A., Taussig, L. M., , Chinchilli, V. M., et al. (2016). Markers of Differential Response to Inhaled Corticosteroid Treatment Among Children with Mild Persistent Asthma. The journal of allergy and clinical immunology. In practice, 3(4), 540-6.e3.
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  Inhaled corticosteroids are recommended as first-line therapy for children with mild persistent asthma; however, specific patient characteristics may modify the treatment response.
• Gozdz, J., Holbreich, M., Metwali, N., Thorne, P. S., Sperling, A. I., Martinez, F. D., Ober, C., von Mutius, E., & Vercelli, D. (2016). Amish and Hutterite Environmental Farm Products Have Opposite Effects on Experimental Models of Asthma. Annals of the American Thoracic Society, 13 Suppl 1, S99.
• Martinez, F. D. (2016). Beyond the Paradigm of Asthma as an Inflammatory Disease. A Summary of the 2015 Aspen Lung Conference. Annals of the American Thoracic Society, 13 Suppl 1, S91-4.
• Martinez, F. D. (2016). Early-Life Origins of Chronic Obstructive Pulmonary Disease. The New England journal of medicine, 375(9), 871-8.
• Martinez, F. D. (2016). Safety of Fluticasone plus Salmeterol in Asthma--Reassuring Data, but No Final Answer. The New England journal of medicine, 374(19), 1887-8.
• Oren, E., Gerald, L., Stern, D. A., Martinez, F. D., & Wright, A. L. (2016). Self-Reported Stressful Life Events During Adolescence and Subsequent Asthma: A Longitudinal Study. The journal of allergy and clinical immunology. In practice.
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  Although exposure to stressful life events in adolescence has been associated with poor health as measured by number of physicians' visits and symptom scores, little is known regarding stress in adolescence and either concurrent or subsequent asthma.
• Sheehan, W. J., Mauger, D. T., Paul, I. M., Moy, J. N., Boehmer, S. J., Szefler, S. J., Fitzpatrick, A. M., Jackson, D. J., Bacharier, L. B., Cabana, M. D., Covar, R., Holguin, F., Lemanske, R. F., Martinez, F. D., Pongracic, J. A., Beigelman, A., Baxi, S. N., Benson, M., Blake, K., , Chmiel, J. F., et al. (2016). Acetaminophen versus Ibuprofen in Young Children with Mild Persistent Asthma. The New England journal of medicine, 375(7), 619-30.
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  Studies have suggested an association between frequent acetaminophen use and asthma-related complications among children, leading some physicians to recommend that acetaminophen be avoided in children with asthma; however, appropriately designed trials evaluating this association in children are lacking.
• Stein, M. M., Hrusch, C. L., Gozdz, J., Igartua, C., Pivniouk, V., Murray, S. E., Ledford, J. G., Marques dos Santos, M., Anderson, R. L., Metwali, N., Neilson, J. W., Maier, R. M., Gilbert, J. A., Holbreich, M., Thorne, P. S., Martinez, F. D., von Mutius, E., Vercelli, D., Ober, C., & Sperling, A. I. (2016). Innate Immunity and Asthma Risk in Amish and Hutterite Farm Children. The New England journal of medicine, 375(5), 411-21.
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  The Amish and Hutterites are U.S. agricultural populations whose lifestyles are remarkably similar in many respects but whose farming practices, in particular, are distinct; the former follow traditional farming practices whereas the latter use industrialized farming practices. The populations also show striking disparities in the prevalence of asthma, and little is known about the immune responses underlying these disparities.
• Yan, X., Chu, J. H., Gomez, J., Koenigs, M., Holm, C., He, X., Perez, M. F., Zhao, H., Mane, S., Martinez, F. D., Ober, C., Nicolae, D. L., Barnes, K. C., London, S. J., Gilliland, F., Weiss, S. T., Raby, B. A., Cohn, L., & Chupp, G. L. (2016). Noninvasive Analysis of the Sputum Transcriptome Discriminates Clinical Phenotypes of Asthma. Annals of the American Thoracic Society, 13 Suppl 1, S104-5.
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  It is increasingly recognized that asthma is a heterogeneous disease. Therefore, it is possible that analysis of gene expression in the airway will reveal clinically meaningful transcriptional endotypes of asthma (TEA clusters).
• von Mutius, E., & Martinez, F. D. (2016). Inconclusive Results of Randomized Trials of Prenatal Vitamin D for Asthma Prevention in Offspring: Curbing the Enthusiasm. JAMA, 315(4), 347-8.
• Bacharier, L. B., Guilbert, T. W., Mauger, D. T., Boehmer, S., Beigelman, A., Fitzpatrick, A. M., Jackson, D. J., Baxi, S. N., Benson, M., Burnham, C. A., Cabana, M., Castro, M., Chmiel, J. F., Covar, R., Daines, M., Gaffin, J. M., Gentile, D. A., Holguin, F., Israel, E., , Kelly, H. W., et al. (2015). Early Administration of Azithromycin and Prevention of Severe Lower Respiratory Tract Illnesses in Preschool Children With a History of Such Illnesses: A Randomized Clinical Trial. JAMA, 314(19), 2034-44.
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  Many preschool children develop recurrent, severe episodes of lower respiratory tract illness (LRTI). Although viral infections are often present, bacteria may also contribute to illness pathogenesis. Strategies that effectively attenuate such episodes are needed.
• Beamer, P. I., Lothrop, N., Lu, Z., Ascher, R., Ernst, K., Stern, D. A., Billheimer, D., Wright, A. L., & Martinez, F. D. (2015). Spatial clusters of child lower respiratory illnesses associated with community-level risk factors. Pediatric pulmonology.
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  Identifying geographic areas with increased incidence of disease may elucidate community-level risk factors for intervention development. Lower respiratory illnesses (LRIs) are the leading cause of death in children and are associated with other morbidities. We assessed geographic clustering of LRIs and evaluated if these spatial patterns and associated risk factors differed by phenotype. Participants enrolled at birth in the Tucson Children's Respiratory Study were followed through age three for physician diagnosed LRIs. Spatial clustering analysis, based upon each participant's birth address, was performed for four LRI phenotypes. We conducted principal component analysis at the census tract level to generate indices for lower socioeconomic status (SES), poorer housing conditions, and increased air pollution. Enrollment addresses were mapped for 812 subjects, of whom 58.4%, 33.5%, 34.2%, and 23.4% had any LRI, a wheezing LRI, a viral LRI, and a respiratory syncytial virus (RSV) LRI, respectively. Patterns of spatial clustering and associated risk factors differed by LRI phenotype. Multivariable regression analyses showed that wheezing LRI clusters were associated with increased air pollution (OR = 1.18, P = 0.01). Being in a viral cluster was associated with poorer housing conditions (OR = 1.28, P = 0.01), while being in a RSV cluster was associated with increased air pollution (OR = 1.14, P = 0.006), poorer housing conditions (OR = 1.54, P = 0.003), and higher SES (OR = 0.77, P = 0.001). Our use of social and environmental indices allowed us to identify broad contextual factors that may contribute to increased incidence of LRIs in specific geographic regions. To reduce LRI incidence, multifaceted interventions should be developed at the community level. Pediatr Pulmonol. © 2015 Wiley Periodicals, Inc.
• Brehm, J. M., Ramratnam, S. K., Tse, S. M., Croteau-Chonka, D. C., Pino-Yanes, M., Rosas-Salazar, C., Litonjua, A. A., Raby, B. A., Boutaoui, N., Han, Y., Chen, W., Forno, E., Marsland, A. L., Nugent, N. R., Eng, C., Colón-Semidey, A., Alvarez, M., Acosta-Pérez, E., Spear, M. L., , Martinez, F. D., et al. (2015). Stress and Bronchodilator Response in Children with Asthma. American journal of respiratory and critical care medicine, 192(1), 47-56.
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  Stress is associated with asthma morbidity in Puerto Ricans (PRs), who have reduced bronchodilator response (BDR).
• Chan, J. Y., Stern, D. A., Guerra, S., Wright, A. L., Morgan, W. J., & Martinez, F. D. (2015). Pneumonia in childhood and impaired lung function in adults: a longitudinal study. Pediatrics, 135(4), 607-16.
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  Diminished lung function and increased prevalence of asthma have been reported in children with a history of early lower respiratory illnesses (LRIs), including pneumonia. Whether these associations persist up to adulthood has not been established.
• Croteau-Chonka, D. C., Rogers, A. J., Raj, T., McGeachie, M. J., Qiu, W., Ziniti, J. P., Stubbs, B. J., Liang, L., Martinez, F. D., Strunk, R. C., Lemanske, R. F., Liu, A. H., Stranger, B. E., Carey, V. J., & Raby, B. A. (2015). Expression Quantitative Trait Loci Information Improves Predictive Modeling of Disease Relevance of Non-Coding Genetic Variation. PloS one, 10(10), e0140758.
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  Disease-associated loci identified through genome-wide association studies (GWAS) frequently localize to non-coding sequence. We and others have demonstrated strong enrichment of such single nucleotide polymorphisms (SNPs) for expression quantitative trait loci (eQTLs), supporting an important role for regulatory genetic variation in complex disease pathogenesis. Herein we describe our initial efforts to develop a predictive model of disease-associated variants leveraging eQTL information. We first catalogued cis-acting eQTLs (SNPs within 100 kb of target gene transcripts) by meta-analyzing four studies of three blood-derived tissues (n = 586). At a false discovery rate < 5%, we mapped eQTLs for 6,535 genes; these were enriched for disease-associated genes (P < 10(-04)), particularly those related to immune diseases and metabolic traits. Based on eQTL information and other variant annotations (distance from target gene transcript, minor allele frequency, and chromatin state), we created multivariate logistic regression models to predict SNP membership in reported GWAS. The complete model revealed independent contributions of specific annotations as strong predictors, including evidence for an eQTL (odds ratio (OR) = 1.2-2.0, P < 10(-11)) and the chromatin states of active promoters, different classes of strong or weak enhancers, or transcriptionally active regions (OR = 1.5-2.3, P < 10(-11)). This complete prediction model including eQTL association information ultimately allowed for better discrimination of SNPs with higher probabilities of GWAS membership (6.3-10.0%, compared to 3.5% for a random SNP) than the other two models excluding eQTL information. This eQTL-based prediction model of disease relevance can help systematically prioritize non-coding GWAS SNPs for further functional characterization.
• Gardeux, V., Bosco, A., Li, J., Halonen, M. J., Jackson, D., Martinez, F. D., & Lussier, Y. A. (2015). Towards a PBMC "virogram assay" for precision medicine: Concordance between ex vivo and in vivo viral infection transcriptomes. Journal of biomedical informatics, 55, 94-103.
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  Understanding individual patient host-response to viruses is key to designing optimal personalized therapy. Unsurprisingly, in vivo human experimentation to understand individualized dynamic response of the transcriptome to viruses are rarely studied because of the obvious limitations stemming from ethical considerations of the clinical risk.
• Guerra, S., Halonen, M., Vasquez, M. M., Spangenberg, A., Stern, D. A., Morgan, W. J., Wright, A. L., Lavi, I., Tarès, L., Carsin, A., Dobaño, C., Barreiro, E., Zock, J., Martínez-Moratalla, J., Urrutia, I., Sunyer, J., Keidel, D., Imboden, M., Probst-Hensch, N., , Hallberg, J., et al. (2015). Relation between circulating CC16 concentrations, lung function, and development of chronic obstructive pulmonary disease across the lifespan: a prospective study. The Lancet. Respiratory medicine, 3(8), 613-20.
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  Low concentrations of the anti-inflammatory protein CC16 (approved symbol SCGB1A1) in serum have been associated with accelerated decline in forced expiratory volume in 1 s (FEV1) in patients with chronic obstructive pulmonary disease (COPD). We investigated whether low circulating CC16 concentrations precede lung function deficits and incidence of COPD in the general population.
• Igartua, C., Myers, R. A., Mathias, R. A., Pino-Yanes, M., Eng, C., Graves, P. E., Levin, A. M., Del-Rio-Navarro, B. E., Jackson, D. J., Livne, O. E., Rafaels, N., Edlund, C. K., Yang, J. J., Huntsman, S., Salam, M. T., Romieu, I., Mourad, R., Gern, J. E., Lemanske, R. F., , Wyss, A., et al. (2015). Ethnic-specific associations of rare and low-frequency DNA sequence variants with asthma. Nature communications, 6, 5965.
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  Common variants at many loci have been robustly associated with asthma but explain little of the overall genetic risk. Here we investigate the role of rare (
• Lange, P., Celli, B., Agustí, A., Boje Jensen, G., Divo, M., Faner, R., Guerra, S., Marott, J. L., Martinez, F. D., Martinez-Camblor, P., Meek, P., Owen, C. A., Petersen, H., Pinto-Plata, V., Schnohr, P., Sood, A., Soriano, J. B., Tesfaigzi, Y., & Vestbo, J. (2015). Lung-Function Trajectories Leading to Chronic Obstructive Pulmonary Disease. The New England journal of medicine, 373(2), 111-22.
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  Chronic obstructive pulmonary disease (COPD) is thought to result from an accelerated decline in forced expiratory volume in 1 second (FEV1) over time. Yet it is possible that a normal decline in FEV1 could also lead to COPD in persons whose maximally attained FEV1 is less than population norms.
• Li, H., Pouladi, N., Achour, I., Gardeux, V., Li, J., Li, Q., Zhang, H. H., Martinez, F. D., 'Skip' Garcia, J. G., & Lussier, Y. A. (2015). eQTL networks unveil enriched mRNA master integrators downstream of complex disease-associated SNPs. Journal of biomedical informatics, 58, 226-34.
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  The causal and interplay mechanisms of Single Nucleotide Polymorphisms (SNPs) associated with complex diseases (complex disease SNPs) investigated in genome-wide association studies (GWAS) at the transcriptional level (mRNA) are poorly understood despite recent advancements such as discoveries reported in the Encyclopedia of DNA Elements (ENCODE) and Genotype-Tissue Expression (GTex). Protein interaction network analyses have successfully improved our understanding of both single gene diseases (Mendelian diseases) and complex diseases. Whether the mRNAs downstream of complex disease genes are central or peripheral in the genetic information flow relating DNA to mRNA remains unclear and may be disease-specific. Using expression Quantitative Trait Loci (eQTL) that provide DNA to mRNA associations and network centrality metrics, we hypothesize that we can unveil the systems properties of information flow between SNPs and the transcriptomes of complex diseases. We compare different conditions such as naïve SNP assignments and stringent linkage disequilibrium (LD) free assignments for transcripts to remove confounders from LD. Additionally, we compare the results from eQTL networks between lymphoblastoid cell lines and liver tissue. Empirical permutation resampling (p
• McGeachie, M. J., Dahlin, A., Qiu, W., Croteau-Chonka, D. C., Savage, J., Wu, A. C., Wan, E. S., Sordillo, J. E., Al-Garawi, A., Martinez, F. D., Strunk, R. C., Lemanske, R. F., Liu, A. H., Raby, B. A., Weiss, S., Clish, C. B., & Lasky-Su, J. A. (2015). The metabolomics of asthma control: a promising link between genetics and disease. Immunity, inflammation and disease, 3(3), 224-38.
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  Short-acting β agonists (e.g., albuterol) are the most commonly used medications for asthma, a disease that affects over 300 million people in the world. Metabolomic profiling of asthmatics taking β agonists presents a new and promising resource for identifying the molecular determinants of asthma control. The objective is to identify novel genetic and biochemical predictors of asthma control using an integrative "omics" approach. We generated lipidomic data by liquid chromatography tandem mass spectrometry (LC-MS), - using plasma samples from 20 individuals with asthma. The outcome of interest was a binary indicator of asthma control defined by the use of albuterol inhalers in the preceding week. We integrated metabolomic data with genome-wide genotype, gene expression, and methylation data of this cohort to identify genomic and molecular indicators of asthma control. A Conditional Gaussian Bayesian Network (CGBN) was generated using the strongest predictors from each of these analyses. Integrative and metabolic pathway over-representation analyses (ORA) identified enrichment of known biological pathways within the strongest molecular determinants. Of the 64 metabolites measured, 32 had known identities. The CGBN model based on four SNPs (rs9522789, rs7147228, rs2701423, rs759582) and two metabolites-monoHETE_0863 and sphingosine-1-phosphate (S1P) could predict asthma control with an AUC of 95%. Integrative ORA identified 17 significantly enriched pathways related to cellular immune response, interferon signaling, and cytokine-related signaling, for which arachidonic acid, PGE2 and S1P, in addition to six genes (CHN1, PRKCE, GNA12, OASL, OAS1, and IFIT3) appeared to drive the pathway results. Of these predictors, S1P, GNA12, and PRKCE were enriched in the results from integrative and metabolic ORAs. Through an integrative analysis of metabolomic, genomic, and methylation data from a small cohort of asthmatics, we implicate altered metabolic pathways, related to sphingolipid metabolism, in asthma control. These results provide insight into the pathophysiology of asthma control.
• McGeachie, M. J., Wu, A. C., Tse, S. M., Clemmer, G. L., Sordillo, J., Himes, B. E., Lasky-Su, J., Chase, R. P., Martinez, F. D., Weeke, P., Shaffer, C. M., Xu, H., Denny, J. C., Roden, D. M., Panettieri, R. A., Raby, B. A., Weiss, S. T., & Tantisira, K. G. (2015). CTNNA3 and SEMA3D: Promising loci for asthma exacerbation identified through multiple genome-wide association studies. The Journal of allergy and clinical immunology, 136(6), 1503-10.
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  Asthma exacerbations are a major cause of morbidity and medical cost.
• Yan, X., Chu, J., Gomez, J., Koenigs, M., Holm, C., He, X., Perez, M. F., Zhao, H., Mane, S., Martinez, F. D., Ober, C., Nicolae, D. L., Barnes, K. C., London, S. J., Gilliland, F., Weiss, S. T., Raby, B. A., Cohn, L., & Chupp, G. L. (2015). Noninvasive analysis of the sputum transcriptome discriminates clinical phenotypes of asthma. American journal of respiratory and critical care medicine, 191(10), 1116-25.
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  The airway transcriptome includes genes that contribute to the pathophysiologic heterogeneity seen in individuals with asthma.

Presentations

• Gerald, L. B., Martinez, F., Billheimer, D. D., Hallmark, B., & Gerald, J. K. (2018, May). Are hispanic children of mexican origin less responsive to ICS treatment than non-hispanic white children: A Meta-Analysis of CARE trials. American Thoracic Society International Conference. San Diego, CA: American Thoracic Society.
• Gerald, L. B., Martinez, F., Billheimer, D., Hallmark, B., & Gerald, J. K. (2018, May). Are Hispanic Children of Mexican Origin Less Responsive to ICS treatment than non-Hispanic White Children? A Meta-Analysis of CARE Trials.. American Thoracic Society International Conference. San Diego, California.
• Martinez, F., Wright, A. L., Halonen, M., Billheimer, D. D., Zhai, J., Stern, D. A., O'Rourke, M. K., Lothrop, N., Guerra, S., Furlong, M., & Beamer, P. (2018, August). CC16 levels into adult life are associated with nitrogen dioxide exposure at birth. Joint meeting of the International Society of Exposure Science and the International Society of Environmental Epidemiology. Ottawa, Canada.
• Oren, E., Gerald, L. B., Stern, D., Wright, A. L., & Martinez, F. (2015, May). Self-reported Stressful Life Events During Adolescence and Asthma. American Thoracic Society. Denver, CO.
• Li, H., Pouladi, N., Gardeux, V., Luo, Q., Li, Q., Li, J., Martinez, F., Garcia, J., & Lussier, Y. A. (2014, October). Centrality of complex disease genes unveiled by eQTL associations. Translational Bioinformatics Conference. Qingdao, China.

Poster Presentations

• Martinez, F., Martinez, F., Guerra, S., Guerra, S., Wright, A. L., Wright, A. L., Halonen, M., Halonen, M., Stern, D. A., Stern, D. A., Carr, T. F., & Carr, T. F. (2020, February). High Early Childhood Insulin Increases Asthma Risk Independent of Obesity.. American Academy of Allergy, Asthma & Immunology 2020 Annual Meeting, Virtual Congress.
• Wright, A. L., Stern, D., Martinez, F., & Cassell, H. (2018, March). Early Onset Eczema and the Association with Early Onset Asthma. American Academy of Allergy, Asthma, and Immunology. Orlando, FL.
• Mpody, C., Stern, D., Gerald, L. B., Morgan, W. J., Martinez, F., Wright, A. L., & Oren, E. (2017, April). Early caregiver stress and child's subsequent lung function through early adulthood: a longitudinal study from birth to 32 years of age. MEZCOPH Public Health Research Forum. Tucson, AZ: MEZCOPH.
• Carr, T. F., Mathur, A. K., Martinez, F., & Stern, D. A. (2016, March). Sensitivity and Specificity of a Clinical Diagnosis of Allergic Rhinitis in Childhood.. American Academy of Allergy, Asthma, and Immunology Annual Scientific Meeting , Los Angeles.
• Beamer, P., Guerra, S., Lothrop, N. Z., Stern, D., Lu, Z., Billheimer, D. D., Halonen, M., Wright, A. L., & Martinez, F. (2015, May). Levels are Associated with Diesel Exposure at Birth. American Thoracic Society. Denver, CO.
• Beamer, P., Guerra, S., Lothrop, N., Stern, D., Lu, Z., Billheimer, D. D., Halonen, M., Wright, A. L., & Martinez, F. (2015, May). Childhood CC16 Levels are Associated with Diesel Exposure at Birth. American Thoracic Society International Conference.
• Berry, C. E., Jenkins, I., Billheimer, D. D., Stern, D., Guerra, S., Wright, A. L., Morgan, W. J., & Martinez, F. (2015, May). Lung Function Trajectories in the Tucson Children’s Respiratory Study. American Thoracic Society. Denver, CO.
• Berry, C. E., Lu, Z. J., Jenkins, I. C., Billheimer, D., Stern, D. A., Gerald, L. B., Carr, T. F., Guerra, S., Wright, A. L., Morgan, W. J., Martinez, F. D., Berry, C. E., Lu, Z. J., Jenkins, I. C., Billheimer, D., Stern, D. A., Gerald, L. B., Carr, T. F., Guerra, S., , Wright, A. L., et al. (2015, May). Lung Function Trajectories in the Tucson Children's Respiratory Study. American Thoracic Society. Denver, CO: American Thoracic Society.
• Carr, T. F., Stern, D., Halonen, M., Wright, A. L., & Martinez, F. (2015, May). Active Rhinitis at Age 6 Predicts Subsequent Development of Asthma Independent of Atopy. American Thoracic Society. Denver, CO.
• Chan, J. Y., Stern, D., Wright, A. L., Halonen, M., & Martinez, F. (2015, May). Association Between Early Life Interleukin-5 and Childhood Eosinophilic Asthma. American Thoracic Society. Denver, CO.
• Gozdz, J., Holbreich, M., Metwali, N., Thorne, P., Sperling, A., Martinez, F., Ober, C., von Mutius, E., & Vercelli, D. (2015, Spring). Opposite effects of farming on asthma: mice exposed to Amish and Hutterite environmental products recapitulate asthma protection and risk. International Conference, American Thoracic Society. Denver, CO: American Thoracic Society.
• Hiranrattana, A., Stern, D., Guerra, S., Halonen, M., Wright, A. L., Martinez, F., & Morgan, W. J. (2015, May). Alternaria Sensitization is Associated with Increased Airway Reactivity in Overweight/Obese Non-Asthmatics. American Thoracic Society International Conference.
• Oren, E., Gerald, L. B., Stern, D., Wright, A. L., & Martinez, F. (2015, May). Self-reported Stressful Life Events During Adolescence and Asthma. American Thoracic Society. Denver, CO: American Thoracic Society.
• Parthasarathy, S., Vasquez, M., Halonen, M., Martinez, F., & Guerra, S. (2015, May). Insomnia is Independently Associated with Hospitalization. American Thoracic Society International Conference.
• Vasquez, M., Zhou, M., Hu, C., Martinez, F., & Guerra, S. (2015, May). Lung Function in Young Adult Life and Mortality Risk. American Thoracic Society International Conference.
• Voraphani, N., Guerra, S., Stern, D., Halonen, M., Wright, A. L., Morgan, W. J., & Martinez, F. (2015, May). Circulating CC16 In Childhood Differentiates Between Persistent And Remitting Severe Asthma In Adult Life. American Thoracic Society International Conference.
• Voraphani, N., Guerra, S., Stern, D., Halonen, M., Wright, A. L., Morgan, W. J., & Martinez, F. (2015, May). Circulating CC16 in Childhood Differentiates Between Persistent and Remitting Severe Asthma in Adult Life. American Thoracic Society. Denver, CO.