7 results on '"Newton, Chad A."'
Search Results
2. The Role of Genetic Testing in Pulmonary Fibrosis: A Perspective From the Pulmonary Fibrosis Foundation Genetic Testing Work Group.
- Author
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Newton CA, Oldham JM, Applegate C, Carmichael N, Powell K, Dilling D, Schmidt SL, Scholand MB, Armanios M, Garcia CK, Kropski JA, and Talbert J
- Subjects
- Humans, United States, Genetic Testing, Idiopathic Pulmonary Fibrosis genetics
- Abstract
Patients with familial pulmonary fibrosis represent a subset of patients with pulmonary fibrosis in whom inherited gene variation predisposes them to disease development. In the appropriate setting, genetic testing allows for personalized assessment of disease, recognition of clinically relevant extrapulmonary manifestations, and assessing susceptibility in unaffected relatives. However currently, the use of genetic testing is inconsistent, partly because of the lack of guidance regarding high-yield scenarios in which the results of genetic testing can inform clinical decision-making. To address this, the Pulmonary Fibrosis Foundation commissioned a genetic testing work group comprising pulmonologists, geneticists, and genetic counselors from the United States to provide guidance on genetic testing in patients with pulmonary fibrosis. This CHEST special feature presents a concise review of these proceedings and reviews pulmonary fibrosis susceptibility, clinically available genetic testing methods, and clinical scenarios in which genetic testing should be considered., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
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3. Proteomic biomarkers of progressive fibrosing interstitial lung disease: a multicentre cohort analysis.
- Author
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Bowman WS, Newton CA, Linderholm AL, Neely ML, Pugashetti JV, Kaul B, Vo V, Echt GA, Leon W, Shah RJ, Huang Y, Garcia CK, Wolters PJ, and Oldham JM
- Subjects
- Biomarkers, Cohort Studies, Disease Progression, Female, Humans, Male, Proteomics, Idiopathic Pulmonary Fibrosis complications, Lung Diseases, Interstitial
- Abstract
Background: Progressive fibrosing interstitial lung disease (ILD) is characterised by parenchymal scar formation, leading to high morbidity and mortality. The ability to predict this phenotype remains elusive. We conducted a proteomic analysis to identify novel plasma biomarkers of progressive fibrosing ILD and developed a proteomic signature to predict this phenotype., Methods: Relative plasma concentrations for 368 biomarkers were determined with use of a semi-quantitative, targeted proteomic platform in patients with connective tissue disease-associated ILD, chronic hypersensitivity pneumonitis, or unclassifiable ILD who provided research blood draws at the University of California (discovery cohort) and the University of Texas (validation cohort). Univariable logistic regression was used to identify individual biomarkers associated with 1-year ILD progression, defined as death, lung transplant, or 10% or greater relative forced vital capacity (FVC) decline. A proteomic signature of progressive fibrosing ILD was then derived with use of machine learning in the University of California cohort and validated in the University of Texas cohort., Findings: The discovery cohort comprised 385 patients (mean age 63·6 years, 59% female) and the validation cohort comprised 204 patients (mean age 60·7 years, 61% female). 31 biomarkers were associated with progressive fibrosing ILD in the discovery cohort, with 17 maintaining an association in the validation cohort. Validated biomarkers showed a consistent association with progressive fibrosing ILD irrespective of ILD clinical diagnosis. A proteomic signature comprising 12 biomarkers was derived by machine learning and validated in the University of Texas cohort, in which it had a sensitivity of 0·90 and corresponding negative predictive value of 0·91, suggesting that approximately 10% of patients with a low-risk proteomic signature would experience ILD progression in the year after blood draw. Those with a low-risk proteomic signature experienced an FVC change of +85·7 mL (95% CI 6·9 to 164·4) and those with a high-risk signature experienced an FVC change of -227·1 mL (-286·7 to -167·5). A theoretical clinical trial restricted to patients with a high-risk proteomic signature would require 80% fewer patients than one designed without regard to proteomic signature., Interpretation: 17 plasma biomarkers of progressive fibrosing ILD were identified and showed consistent associations across ILD subtypes. A proteomic signature of progressive fibrosing ILD could enrich clinical trial cohorts and avoid the need for antecedent progression when defining progressive fibrosing ILD for clinical trial enrolment., Funding: National Heart Lung and Blood Institute., Competing Interests: Declaration of interests CAN reports personal fees from Boehringer Ingelheim, outside of the submitted work. CKG reports a grant from Boehringer Ingelheim and previous advisory board service for Pliant Therapeutics, both unrelated to the submitted work. PJW reports grants from Sanofi, grants and personal fees from Boehringer Ingelheim and Roche/Genentech, and personal fees from Gossamer Bio, Blade Therapeutics, and Pliant, unrelated to the submitted work. JMO reports an unrelated grant from Boehringer Ingelheim and personal fees from Genentech, United Therapeutics, Gatehouse Bio, and AmMax Bio, unrelated to the submitted work. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
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- 2022
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4. Familial Pulmonary Fibrosis: Genetic Features and Clinical Implications.
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Zhang D and Newton CA
- Subjects
- Genetic Predisposition to Disease, Genetic Variation, Humans, Research, Idiopathic Pulmonary Fibrosis genetics, Pulmonary Surfactant-Associated Proteins genetics, Telomere-Binding Proteins genetics
- Abstract
Pulmonary fibrosis comprises a wide range of fibrotic lung diseases with unknown pathogenesis and poor prognosis. Familial pulmonary fibrosis (FPF) represents a unique subgroup of patients in which at least one other relative is also affected. Patients with FPF exhibit a wide range of pulmonary fibrosis phenotypes, although idiopathic pulmonary fibrosis is the most common subtype. Despite variable disease manifestations, patients with FPF experience worse survival compared with their counterparts with the sporadic disease form. Therefore, ascertaining a positive family history not only provides prognostic value but should also raise suspicion for the inheritance of an underlying causative genetic variant within kindreds. By focusing on FPF kindreds, rare variants within surfactant metabolism and telomere maintenance genes have been discovered. However, such genetic variation is not solely restricted to FPF, as similar rare variants are found in patients with seemingly sporadic pulmonary fibrosis, further supporting the idea of genetic susceptibility underlying pulmonary fibrosis as a whole. Researchers are beginning to show how the presence of rare variants may inform clinical management, such as informing predisposition risk for yet unaffected relatives as well as informing prognosis and therapeutic strategy for those already affected. Despite these advances, rare variants in surfactant and telomere-related genes only explain the genetic basis in about one-quarter of FPF kindreds. Therefore, research is needed to identify the missing genetic contributors of pulmonary fibrosis, which would not only improve our understanding of disease pathobiology but may offer additional opportunities to improve the health of patients., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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5. Family History of Pulmonary Fibrosis Predicts Worse Survival in Patients With Interstitial Lung Disease.
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Cutting CC, Bowman WS, Dao N, Pugashetti JV, Garcia CK, Oldham JM, and Newton CA
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- Aged, California epidemiology, Female, Follow-Up Studies, Humans, Idiopathic Pulmonary Fibrosis epidemiology, Longitudinal Studies, Lung Diseases, Interstitial epidemiology, Male, Middle Aged, Prevalence, Retrospective Studies, Survival Analysis, Texas epidemiology, Idiopathic Pulmonary Fibrosis complications, Lung Diseases, Interstitial genetics, Lung Diseases, Interstitial mortality
- Abstract
Background: A number of genetic markers linked to familial pulmonary fibrosis predict differential survival in interstitial lung disease (ILD) patients. Although genetic testing is not performed routinely for ILD, family history commonly is obtained and may inform outcome risk., Research Question: Does survival vary between patients with and without self-reported familial pulmonary fibrosis?, Methods: Family history was acquired systematically for consecutive ILD patients who consented to clinical registry enrollment at the University of Texas Southwestern and the University of California at Davis. Patients were stratified by idiopathic pulmonary fibrosis (IPF) and non-IPF ILD diagnosis and were substratified by presence or absence of familial pulmonary fibrosis, defined as one or more additional affected family members. Transplant-free survival was compared using multilevel, mixed-effects Cox proportional hazards regression., Results: Of the 1,262 patients included, 534 (42%) had IPF ILD and 728 (58%) had non-IPF ILD. Of those with non-IPF ILD, 18.5% had connective tissue disease, 15.6% had chronic hypersensitivity pneumonitis, and 23.5% had unclassifiable ILD. Familial pulmonary fibrosis was reported in 134 IPF ILD patients (25.1%) and 90 non-IPF ILD patients (12.4%). Those with familial IPF showed an 80% increased risk of death or transplantation compared with those with sporadic IPF (hazard ratio [HR], 1.8; 95% CI, 1.37-2.37; P < .001), whereas those with familial non-IPF ILD showed a twofold increased risk compared with their counterparts with sporadic disease (HR, 2.08; 95% CI, 1.46-2.96; P < .001). Outcome risk among those with familial non-IPF ILD was no different than for those with sporadic IPF ILD (HR, 1.27; 95% CI, 0.89-1.84; P = .19)., Interpretation: Patient-reported familial pulmonary fibrosis is predictive of reduced transplant-free survival in IPF and non-IPF ILD patients. Because survival among patients with familial non-IPF ILD approximates that of sporadic IPF ILD, early intervention should be considered for such patients. Until clinical genetic testing is widely available and provides actionable results, family history should be ascertained and considered in risk stratification., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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6. Telomere length in patients with pulmonary fibrosis associated with chronic lung allograft dysfunction and post-lung transplantation survival.
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Newton CA, Kozlitina J, Lines JR, Kaza V, Torres F, and Garcia CK
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- Chronic Disease, DNA genetics, Female, Follow-Up Studies, Humans, Incidence, Male, Middle Aged, Polymerase Chain Reaction, Postoperative Period, Primary Graft Dysfunction epidemiology, Primary Graft Dysfunction genetics, Prospective Studies, Pulmonary Fibrosis epidemiology, Pulmonary Fibrosis etiology, Risk Factors, Survival Rate trends, Texas epidemiology, Graft Survival, Lung Transplantation, Postoperative Complications, Primary Graft Dysfunction complications, Pulmonary Fibrosis genetics, Telomere genetics, Telomere Homeostasis genetics
- Abstract
Background: Prior studies have shown that patients with pulmonary fibrosis with mutations in the telomerase genes have a high rate of certain complications after lung transplantation. However, few studies have investigated clinical outcomes based on leukocyte telomere length., Methods: We conducted an observational cohort study of all patients with pulmonary fibrosis who underwent lung transplantation at a single center between January 1, 2007, and December 31, 2014. Leukocyte telomere length was measured from a blood sample collected before lung transplantation, and subjects were stratified into 2 groups (telomere length <10th percentile vs ≥10th percentile). Primary outcome was post-lung transplant survival. Secondary outcomes included incidence of allograft dysfunction, non-pulmonary organ dysfunction, and infection., Results: Approximately 32% of subjects had a telomere length <10th percentile. Telomere length <10th percentile was independently associated with worse survival (hazard ratio 10.9, 95% confidence interval 2.7-44.8, p = 0.001). Telomere length <10th percentile was also independently associated with a shorter time to onset of chronic lung allograft dysfunction (hazard ratio 6.3, 95% confidence interval 2.0-20.0, p = 0.002). Grade 3 primary graft dysfunction occurred more frequently in the <10th percentile group compared with the ≥10th percentile group (28% vs 7%; p = 0.034). There was no difference between the 2 groups in incidence of acute cellular rejection, cytopenias, infection, or renal dysfunction., Conclusions: Telomere length <10th percentile was associated with worse survival and shorter time to onset of chronic lung allograft dysfunction and thus represents a biomarker that may aid in risk stratification of patients with pulmonary fibrosis before lung transplantation., (Copyright © 2017 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
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7. The MUC5B promoter polymorphism and telomere length in patients with chronic hypersensitivity pneumonitis: an observational cohort-control study.
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Ley B, Newton CA, Arnould I, Elicker BM, Henry TS, Vittinghoff E, Golden JA, Jones KD, Batra K, Torrealba J, Garcia CK, and Wolters PJ
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- Aged, Alveolitis, Extrinsic Allergic blood, Alveolitis, Extrinsic Allergic mortality, California, Case-Control Studies, Cohort Studies, Female, Humans, Idiopathic Pulmonary Fibrosis blood, Idiopathic Pulmonary Fibrosis mortality, Intracellular Signaling Peptides and Proteins, Male, Middle Aged, Mucin-5B blood, Promoter Regions, Genetic genetics, Risk Factors, Texas, White People genetics, Alveolitis, Extrinsic Allergic genetics, Idiopathic Pulmonary Fibrosis genetics, Mucin-5B genetics, Polymorphism, Single Nucleotide, Telomere
- Abstract
Background: Patients with hypersensitivity pneumonitis are at risk of developing pulmonary fibrosis, which is associated with reduced survival. In families with multiple affected members, individuals might be diagnosed as having idiopathic pulmonary fibrosis (IPF) or chronic (fibrotic) hypersensitivity pneumonitis, which suggests these disorders share risk factors. We aimed to test whether the genomic risk factors associated with the development and progression of IPF are also associated with the development of fibrosis and reduced survival in people with chronic hypersensitivity pneumonitis., Methods: We did an observational study of two independent cohorts of patients with chronic hypersensitivity pneumonitis, one from the University of California San Francisco, CA, USA (UCSF), and one from the University of Texas Southwestern, TX, USA (UTSW). We measured two common single-nucleotide polymorphisms associated with IPF (MUC5B rs35705950 and TOLLIP rs5743890) and telomere length in peripheral blood leucocytes, and assessed their associations with chronic hypersensitivity pneumonitis risk, survival, and clinical, radiographic, and pathological features. We compared findings with those in patients with IPF from the UCSF and UTSW cohorts, and healthy controls from the European population of the 1000 Genomes Project Phase 3, version 1., Findings: The cohorts included 145 patients from UCSF and 72 from UTSW. The minor allele frequency (MAF) was greater for MUC5B rs35705950 in patients with chronic hypersensitivity pneumonitis than in healthy controls (24·4% in UCSF and 32·3% in UTSW vs 10·7%, both p<0·0001), but not for TOLLIP rs5743890. The MAFs were similar to those for IPF (UCSF 33·3%, p=0·09; UTSW 32·0%, p=0·95). In the combined UCSF and UTSW chronic hypersensitivity pneumonitis cohort, we saw associations between extent of radiographic fibrosis and MUC5B rs35705950 minor alleles (adjusted odds ratio [OR] 1·91, 95% CI 1·02-3·59, p=0·045) and short telomere length (adjusted OR per unit change in mean natural logarithm-transformed ratio of telomere repeat copy number to single gene copy number 0·23, 0·09-0·59, p=0·002). Telomere length less than the tenth percentile for age was also significantly associated with reduced survival (log-rank p=0·006)., Interpretation: The associations between MUC5B rs35705950 and short telomere length with extent of fibrosis, histopathological features of usual interstitial pneumonia, and reduced survival in patients with chronic hypersensitivity pneumonitis suggest shared pathobiology with IPF, and might help to stratify risk., Funding: National Institutes of Health and Nina Ireland Program for Lung Health., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
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