Browsing by Author "Forno, Erick"
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Item Evaluating Meta‐Learners to Analyze Treatment Heterogeneity in Survival Data: Application to Electronic Health Records of Pediatric Asthma Care in COVID‐19 Pandemic(Wiley, 2025) Bo, Na; Jeong, Jong-Hyeon; Forno, Erick; Ding, Ying; Pediatrics, School of MedicineAn important aspect of precision medicine focuses on characterizing diverse responses to treatment due to unique patient characteristics, also known as heterogeneous treatment effects (HTE) or individualized treatment effects (ITE), and identifying beneficial subgroups with enhanced treatment effects. Estimating HTE with right-censored data in observational studies remains challenging. In this paper, we propose a pseudo-ITE-based framework for analyzing HTE in survival data, which includes a group of meta-learners for estimating HTE, a variable importance metric for identifying predictive variables to HTE, and a data-adaptive procedure to select subgroups with enhanced treatment effects. We evaluate the finite sample performance of the framework under various observational study settings. Furthermore, we applied the proposed methods to analyze the treatment heterogeneity of a written asthma action plan (WAAP) on time-to-ED (Emergency Department) return due to asthma exacerbation using a large asthma electronic health records dataset with visit records expanded from pre- to post-COVID-19 pandemic. We identified vulnerable subgroups of patients with poorer asthma outcomes but enhanced benefits from WAAP and characterized patient profiles. Our research provides valuable insights for healthcare providers on the strategic distribution of WAAP, particularly during disruptive public health crises, ultimately improving the management and control of pediatric asthma.Item Historic Use of Race-Based Spirometry Values Lowered Transplant Priority for Black Patients(Elsevier, 2024) Colon Hidalgo, Daniel; Ramos, Kathleen J.; Harlan, Emily A.; Holguin, Fernando; Forno, Erick; Weiner, Daniel J.; Griffith, Matthew F.; Medicine, School of MedicineBackground: The lung allocation score (LAS) is a tool used to prioritize patients for lung transplantation. For patients with interstitial lung diseases (ILDs), spirometry data are used for the LAS calculation. Spirometry values such as a FVC are subjected to race-specific equations that determine expected values. The effect of race-specific equations in LAS score remains unknown. Research question: Did the use of a race-based spirometry equation lead to longer waitlist times for Black patients? Study design and methods: We performed a retrospective analysis of patients listed for lung transplantation from 2005 through 2020 using publicly available data from the United Network for Organ Sharing. We recalculated LAS scores for Black patients using White-specific equations with the available variables. The primary objective was to evaluate the effect of race-specific equations on LAS scores and time on the transplant waitlist. Results: A total of 33,845 patients listed for lung transplantation were included in the analysis. White patients were listed at lower LAS scores, a higher proportion of White patients underwent transplantation, and White patients died on the waitlist at lower rates. When recalculating LAS scores using White-specific equations, Black patients with ILD had up to a 1.9-point higher score, which resulted in additional waitlist time. Interpretation: Race-specific equations led to longer wait times in Black patients listed for lung transplantation. The use of race-based equations widened already known disparities in pulmonary transplantation.Item Management of the Pediatric Patient with Asthma and Obesity(Elsevier, 2024) Averill, Samantha H.; Forno, Erick; Pediatrics, School of MedicineAsthma and obesity are 2 of the most significant chronic diseases of childhood. Both are major public health problems that have been increasing in prevalence. Obesity increases the risk of developing asthma in children, and in children with asthma, obesity increases asthma severity and morbidity. The nature of this relationship is complex and not fully understood, but some pediatric patients with "obesity-related asthma" may represent a phenotype that differs from the more classical, atopic pediatric asthma. In this review, we investigate and discuss some of the currently available literature regarding treatment for asthma complicated by obesity in the pediatric population. We cover the importance of healthy lifestyle modifications, management of obesity-related comorbidities, and the potential role of nutritional supplementation or modification. We then review recent literature, mostly in adults, investigating the potential role of obesity or diabetes medications in the management of patients with asthma who have obesity. Finally, we discuss some of the necessary next steps before these potential new treatments can be considered as part of the standard clinical management of asthma.Item Metformin use is associated with decreased asthma exacerbations in adolescents and young adults(Wiley, 2024) Ararat, Erhan; Landes, Reid D.; Forno, Erick; Tas, Emir; Perry, Tamara T.; Medicine, School of MedicineRationale: Metformin is a commonly used antidiabetes medication with suggested anti-inflammatory and antioxidative effects. Metformin use has been associated with lower risk of asthma exacerbations and hospitalizations in adults. Here, we aimed to evaluate how asthma exacerbation rates changed after adolescents and young adults were prescribed metformin, and to learn if those changes were related to metformin prescription adherence. Methods: Using secondary data of patients between 12 and 20 years old with asthma diagnosis and a metformin prescription from the Arkansas All Payers Claim Database and Arkansas School body mass index (BMI) database, we estimated the change in annualized asthma exacerbation rates after metformin prescription. We also evaluated the association of prescription adherence to the changes in those rates using univariate and multivariate regression models. Results: A total of 464 patients met inclusion criteria. Outpatient exacerbation rates decreased after metformin prescription (13.4% only before vs. 7.8% only after, p = .009), and the annualized rate decreased more after metformin prescription as adherence increased (rank r = -.165, p < .001). After adjusting for potential confounders-age, sex, BMI, and inhaled corticoid steroid use-the strength of the association was attenuated. Conclusions: Asthma exacerbation rates decreased after metformin prescription, but a larger sample of patients who have experienced exacerbations and including patients with asthma who have not been prescribed metformin is needed to better know whether these decreases are driven by metformin use.Item Nasal Epithelium Transcriptomics Predict Clinical Response to Elexacaftor/Tezacaftor/Ivacaftor(American Thoracic Society, 2024) Yue, Molin; Weiner, Daniel J.; Gaietto, Kristina M.; Rosser, Franziska J.; Qoyawayma, Christopher M.; Manni, Michelle L.; Myerburg, Michael M.; Pilewski, Joseph M.; Celedón, Juan C.; Chen, Wei; Forno, Erick; Pediatrics, School of MedicineElexacaftor/tezacaftor/ivacaftor (ETI) has had a substantial positive impact for people living with cystic fibrosis (pwCF). However, there can be substantial variability in efficacy, and we lack adequate biomarkers to predict individual response. We thus aimed to identify transcriptomic profiles in nasal respiratory epithelium that predict clinical response to ETI treatment. We obtained nasal epithelial samples from pwCF before ETI initiation and performed a transcriptome-wide analysis of baseline gene expression to predict changes in forced expiratory volume in 1 second (ΔFEV1), year's best FEV1 (ΔybFEV1), and body mass index (ΔBMI). Using the top differentially expressed genes, we generated transcriptomic risk scores (TRSs) and evaluated their predictive performance. The study included 40 pwCF ≥6 years of age (mean, 27.7 [SD, 15.1] years; 40% female). After ETI initiation, FEV1 improved by ≥5% in 22 (61.1%) participants, and ybFEV1 improved by ≥5% in 19 (50%). TRSs were constructed using top overexpressed and underexpressed genes for each outcome. Adding the ΔFEV1 TRS to a model with age, sex, and baseline FEV1 increased the area under the receiver operating characteristic curve (AUC) from 0.41 to 0.88, the ΔybFEV1 TRS increased the AUC from 0.51 to 0.88, and the ΔBMI TRS increased the AUC from 0.46 to 0.92. Average accuracy was thus ∼85% in predicting the response to the three outcomes. Results were similar in models further adjusted for F508del zygosity and previous CFTR modulator use. In conclusion, we identified nasal epithelial transcriptomic profiles that help accurately predict changes in FEV1 and BMI with ETI treatment. These novel TRSs could serve as predictive biomarkers for clinical response to modulator treatment in pwCF.Item Nutritional Status and Lung Function in Children with Pancreatic-Sufficient Cystic Fibrosis(Elsevier, 2022) Madde, Ankitha; Okoniewski, Will; Sanders, Don B.; Ren, Clement L.; Weiner, Daniel J.; Forno, Erick; Pediatrics, School of MedicineBackground: There is a strong association between nutrition and long-term FEV1 in cystic fibrosis (CF), but studies have been driven by data from subjects with pancreatic insufficiency (PI-CF). We thus evaluated the association between body mass index (BMI) and FEV1 percent-predicted (FEV1pp) in children with pancreatic sufficiency (PS-CF) and contrasted it with the association in PI-CF. Methods: We utilized data from the CF Foundation Patient Registry. The cohort included children born 1995-2010, diagnosed <2 years of age, and who had annualized data on BMI percentile and FEV1pp at ages 6-16 years. Pancreatic status was defined based on pancreatic enzyme replacement therapy. The association between BMI and FEV1 was evaluated using linear and mixed-effects longitudinal regression. Results: There were 424 children with PS-CF and 7,849 with PI-CF. The association between BMI and FEV1 differed significantly by pancreatic status: each 10-pct higher BMI was associated with 2% [95%CI = 1.9-2.1] higher FEV1pp in PI-CF, compared to just 0.9% [0.5-1.3] in PS-CF (PINTERACTION < 0.001). Within the at-risk nutritional category (BMI <25pct), each 10-pct higher BMI was associated with 5% higher FEV1pp in PI-CF, but no significant increase in PS-CF. Moreover, in PS-CF, overweight/obesity (BMI ≥85pct) was associated with decreasing FEV1pp. In addition, FEV1pp decline through age 20 years in youth with PS-CF was modest (-0.6% per year) and independent of BMI (BMI*age PINTERACTION = 0.37). Conclusions: In children with PS-CF, BMI remains an important determinant of lung function. However, it may be less critical to attain a BMI >50th percentile; and BMI ≥85th percentile may be detrimental.Item Serum α-Klotho level, lung function, airflow obstruction and inflammatory markers in US adults(European Respiratory Society, 2023-11-06) Han, Yueh-Ying; Celedón, Juan C.; Forno, Erick; Pediatrics, School of MedicineBackground: α-Klotho is a pleiotropic protein that may have anti-oxidative and anti-inflammatory properties in the lung, but its role in airflow obstruction or lung function is largely unknown. Methods: This was a cross-sectional study of 6046 adults aged 40-79 years in the US National Health and Nutrition Examination Survey (NHANES) 2007-2012. We used multivariable logistic or linear regression to examine the relation between serum α-Klotho level and airflow obstruction, defined as forced expiratory volume in 1 s (FEV1) <80% of predicted and FEV1/forced vital capacity (FVC) ratio <0.70; FEV1, FVC and FEV1/FVC as percentage of predicted; and inflammatory markers in blood (white blood cell count, eosinophils, neutrophils and C-reactive protein (CRP)). Results: α-Klotho levels in the second to fourth quartiles (Q2-Q4) were associated with significantly decreased odds of airflow obstruction (adjusted OR for Q2-Q4 versus lowest quartile (Q1) 0.54 (95% CI 0.35-0.81)) in never-smokers and ex-smokers with <10 pack-years of smoking, but not in current smokers or ex-smokers with ≥10 pack-years of smoking. In all participants, each unit increment in log10-transformed α-Klotho level was significantly associated with 5.0% higher FEV1 % pred and 3.7% higher FVC % pred. Higher α-Klotho was also associated with lower eosinophils, neutrophils and CRP in participants both with and without airflow obstruction. Conclusions: Higher serum α-Klotho is associated with lower inflammatory markers and higher lung function in adults with and without airflow obstruction, and with decreased odds of airflow obstruction in never-smokers and ex-smokers with <10 pack-years of smoking. Further studies are warranted to replicate our findings and evaluate underlying mechanisms.Item Severe asthma in children: Description of a large multidisciplinary clinical cohort(Wiley, 2022) Forero Molina, Maria; Okoniewski, William; Puranik, Sandeep; Aujla, Shean; Celedón, Juan C.; Larkin, Allyson; Forno, Erick; Pediatrics, School of MedicineBackground: Children with severe asthma have substantial morbidity and healthcare utilization. Pediatric severe asthma is a heterogeneous disease, and a multidisciplinary approach can improve the diagnosis and management of these children. Methods: We reviewed the electronic health records for patients seen in the Severe Asthma Clinic (SAC) at UPMC Children's Hospital of Pittsburgh between August 2012 and October 2019. Results: Of the 110 patients in whom we extracted data, 46% were female, 48% were Black/African American, and 41% had ≥1 admission to the pediatric intensive care unit (PICU) for asthma. Compared to patients without a PICU admission, those with ≥1 PICU admission were more likely to be non-White (64.4% vs. 41.5%, p = 0.031) and more atopic (eosinophil count geometric mean = 673 vs. 319 cells/mm3 , p = 0.002; total IgE geometric mean = 754 vs. 303 KU/L, p = 0.003), and to have lower pre-bronchodilator FEV1 (58.6% [±18.1%] vs. 69.9% [±18.7%], p = 0.002) and elevated FeNO (60% vs. 22%, p = 0.02). In this cohort, 84% of patients were prescribed high-dose ICS/LABA and 36% were on biologics. Following enrollment in the SAC, severe exacerbations decreased from 3.2/year to 2.2/year (p < 0.0001); compared to the year before joining the SAC, in the following year the group had 106 fewer severe exacerbations. Conclusions: This large cohort of children with severe asthma had a high level of morbidity and healthcare utilization. Patients with a history of PICU admissions for asthma were more likely to be nonwhite and highly atopic, and to have lower lung function. Our data support a positive impact of a multidisciplinary clinic on patients with severe childhood asthma.Item The Impact of SARS-CoV-2 Infection on Symptom Control and Lung Function in Children with Asthma(American Thoracic Society, 2023) Gaietto, Kristina; Bergum, Nicholas; Acevedo-Torres, Natalia; Snyder, Oliver; DiCicco, Leigh Anne; Butler, Gabriella; Rauenswinter, Sherry; Iagnemma, Jennifer; Wolfson, David; Kazmerski, Traci M.; Forno, Erick; Pediatrics, School of MedicineRationale: Little is known about the long-term impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on children with asthma. Objectives: To determine whether SARS-CoV-2 infection affects symptom control and lung function in children with asthma. Methods: Using data from clinical registries and the electronic health record, we conducted a prospective case-control study of children with asthma aged 6–21 years who had (cases) or did not have (control subjects) SARS-CoV-2 infection, comparing baseline and follow-up asthma symptom control and spirometry within an ∼18-month time frame and, for cases, within 18 months of acute coronavirus disease (COVID-19). Results: A total of 171 cases had baseline and follow-up asthma symptom data, and 114 cases had baseline and follow-up spirometry measurements. There were no significant differences in asthma symptom control (P = 0.50), forced expiratory volume in 1 second (P = 0.47), forced vital capacity (P = 0.43), forced expiratory volume in 1 second/forced vital capacity (P = 0.43), or forced expiratory flow, midexpiratory phase (P = 0.62), after SARS-CoV-2 infection. Compared with control subjects (113 with symptom data and 237 with spirometry data), there were no significant differences in follow-up asthma symptom control or lung function. A similar proportion of cases and control subjects had poorer asthma symptom control (17.5% vs. 9.7%; P = 0.07) or worse lung function (29.0% vs. 32.5%; P = 0.50) at follow-up. Patients whose asthma control worsened after COVID-19 had a shorter time to follow-up (3.5 [1.5–7.5] vs. 6.1 [3.1–9.8] mo; P = 0.007) and were more likely to have presented with an asthma exacerbation during COVID-19 (46% vs. 26%; P = 0.04) than those without worse control. Conclusions: We found no significant differences in asthma symptom control or lung function in youth with asthma up to 18 months after acute COVID-19, suggesting that COVID-19 does not affect long-term asthma severity or control in the pediatric population.