Dataset Information

Median regression spline modeling of longitudinal FEV1 measurements in cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) patients.

ABSTRACT: Clinical phenotyping, therapeutic investigations as well as genomic, airway secretion metabolomic and metagenomic investigations can benefit from robust, nonlinear modeling of FEV1 in individual subjects. We demonstrate the utility of measuring FEV1 dynamics in representative cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) populations.Individual FEV1 data from CF and COPD subjects were modeled by estimating median regression splines and their predicted first and second derivatives. Classes were created from variables that capture the dynamics of these curves in both cohorts.Nine FEV1 dynamic variables were identified from the splines and their predicted derivatives in individuals with CF (n = 177) and COPD (n = 374). Three FEV1 dynamic classes (i.e. stable, intermediate and hypervariable) were generated and described using these variables from both cohorts. In the CF cohort, the FEV1 hypervariable class (HV) was associated with a clinically unstable, female-dominated phenotypes while stable FEV1 class (S) individuals were highly associated with the male-dominated milder clinical phenotype. In the COPD cohort, associations were found between the FEV1 dynamic classes, the COPD GOLD grades, with exacerbation frequency and symptoms.Nonlinear modeling of FEV1 with splines provides new insights and is useful in characterizing CF and COPD clinical phenotypes.

SUBMITTER: Conrad DJ

PROVIDER: S-EPMC5738083 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Median regression spline modeling of longitudinal FEV1 measurements in cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) patients.

Conrad Douglas J DJ Bailey Barbara A BA Hardie Jon A JA Bakke Per S PS Eagan Tomas M L TML Aarli Bernt B BB

PloS one 20171220 12

<h4>Rationale</h4>Clinical phenotyping, therapeutic investigations as well as genomic, airway secretion metabolomic and metagenomic investigations can benefit from robust, nonlinear modeling of FEV1 in individual subjects. We demonstrate the utility of measuring FEV1 dynamics in representative cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) populations.<h4>Methods</h4>Individual FEV1 data from CF and COPD subjects were modeled by estimating median regression splines and the ...[more]

PMID: 29261779

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Project description:To provide a more detailed survey of adaptive changes in the physiology of P. aeruginosa (PA) during long-term infection of the cystic fibrosis (CF) lung, we performed a comparative proteome and transcriptome analysis of a set of isogenic sequential non-mutator and mutator isolates from three selected CF patients. Recently, we showed that during CF lung persistence PA mutators converge to a virulence-attenuated phenotype. In this study, we demonstrate that besides virulence-associated traits (VATs) the adaptation process of PA predominantly comprises metabolic pathways. In end-stage mutator strains, transcripts of genes encoding VATs, chemotaxis, degradation of aromatic compounds and several two-component regulatory systems were decreased. In contrast, several transcripts of genes or proteins involved in metabolism of fatty acids, nucleotides, amino acids and the generation of energy were increased. Of particular interest is the increased expression level of genes involved in (i) the anaerobic arginine-deiminase pathway, (ii) the anaerobic respiration such as nitrate-uptake protein OprF, redox-active azurin and cytchrome c551 peroxidase, (iii) the micro-aerobic respiration such as high oxygen-affinity cytochrome oxidase cbb3 (iv) the tricarboxylic acid cycle (TCA), glyoxylate shunt and anaplerotic carboxylation reactions to oxaloacetate. Strikingly, an increased transcription of the anaerobic regulator gene anr correlates with the up-regulation of ANR-dependent genes. In conclusion, these changes in transcriptome and proteome indicate an adaptive shift towards constitutive expression of genes of metabolic pathways obviously required for growth under micro-aerobic and nutritional conditions of suppurative CF lung tissue. Finally, these results provide us with new targets for antimicrobial agents and biomarkers reflecting adaptation of PA towards progressive CF lung disease. Experiment Overall Design: P. aeruginosa isolates recovered from different time points of chronic cystic fibrosis lung disease were cultered in vitro, harvested for RNA extraction and hybridization on Affymetrix microarrays. We compared the transcriptome (triplicate microarrays) of early non-mutator P. aeruginosa isolates with late mutator isolates with high mutation frequency probably the driving force of an efficient adaptation to changing environements to conclude from differences in gene expression to the requirements of CF lung environment. Experiment Overall Design: Second publication of array data to be added later

Project description:BackgroundLung disease as major cause for morbidity in patients with cystic fibrosis (CF) starts early in life. Its large phenotypic heterogeneity is partially explained by the genotype but other contributing factors are not well delineated. The close relationship between mucus, inflammation and infection, drives morpho-functional alterations already early in pediatric CF disease, The TRACK-CF cohort has been established to gain insight to disease onset and progression, assessed by lung function testing and imaging to capture morpho-functional changes and to associate these with risk and protective factors, which contribute to the variation of the CF lung disease progression.Methods and designTRACK-CF is a prospective, longitudinal, observational cohort study following patients with CF from newborn screening or clinical diagnosis throughout childhood. The study protocol includes monthly telephone interviews, quarterly visits with microbiological sampling and multiple-breath washout and as well as a yearly chest magnetic resonance imaging. A parallel biobank has been set up to enable the translation from the deeply phenotyped cohort to the validation of relevant biomarkers. The main goal is to determine influencing factors by the combined analysis of clinical information and biomaterials. Primary endpoints are the lung clearance index by multiple breath washout and semi-quantitative magnetic resonance imaging scores. The frequency of pulmonary exacerbations, infection with pro-inflammatory pathogens and anthropometric data are defined as secondary endpoints.DiscussionThis extensive cohort includes children after diagnosis with comprehensive monitoring throughout childhood. The unique composition and the use of validated, sensitive methods with the attached biobank bears the potential to decisively advance the understanding of early CF lung disease.Ethics and trial registrationThe study protocol was approved by the Ethics Committees of the University of Heidelberg (approval S-211/2011) and each participating site and is registered at clinicaltrials.gov (NCT02270476).

Project description:To provide a more detailed survey of adaptive changes in the physiology of P. aeruginosa (PA) during long-term infection of the cystic fibrosis (CF) lung, we performed a comparative proteome and transcriptome analysis of a set of isogenic sequential non-mutator and mutator isolates from three selected CF patients. Recently, we showed that during CF lung persistence PA mutators converge to a virulence-attenuated phenotype. In this study, we demonstrate that besides virulence-associated traits (VATs) the adaptation process of PA predominantly comprises metabolic pathways. In end-stage mutator strains, transcripts of genes encoding VATs, chemotaxis, degradation of aromatic compounds and several two-component regulatory systems were decreased. In contrast, several transcripts of genes or proteins involved in metabolism of fatty acids, nucleotides, amino acids and the generation of energy were increased. Of particular interest is the increased expression level of genes involved in (i) the anaerobic arginine-deiminase pathway, (ii) the anaerobic respiration such as nitrate-uptake protein OprF, redox-active azurin and cytchrome c551 peroxidase, (iii) the micro-aerobic respiration such as high oxygen-affinity cytochrome oxidase cbb3 (iv) the tricarboxylic acid cycle (TCA), glyoxylate shunt and anaplerotic carboxylation reactions to oxaloacetate. Strikingly, an increased transcription of the anaerobic regulator gene anr correlates with the up-regulation of ANR-dependent genes. In conclusion, these changes in transcriptome and proteome indicate an adaptive shift towards constitutive expression of genes of metabolic pathways obviously required for growth under micro-aerobic and nutritional conditions of suppurative CF lung tissue. Finally, these results provide us with new targets for antimicrobial agents and biomarkers reflecting adaptation of PA towards progressive CF lung disease. Keywords: in vitro study/interstrain comparison/clinical isolates/early nonmutator vs. late mutator; variable time point of isolation from cf respiratory secretions

Dataset Information

Median regression spline modeling of longitudinal FEV1 measurements in cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) patients.

Publications

Median regression spline modeling of longitudinal FEV1 measurements in cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) patients.

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