title: Refining the continuum of CFTR-associated disorders in the era of newborn screening.
abstract: Clinical heterogeneity in cystic fibrosis (CF) often causes diagnostic uncertainty in infants without symptoms and in older patients with milder phenotypes. We performed a cross-sectional evaluation of a comprehensive set of clinical and laboratory descriptors in a physician-defined cohort (N = 376; Children's Hospital of Wisconsin and the American Family Children's Hospital CF centers in Milwaukee and Madison, WI, USA) to determine the robustness of categorizing CF (N = 300), cystic fibrosis transmembrane conductance regulator (CFTR)-related disorder (N = 19), and CFTR-related (CRMS) metabolic syndrome (N = 57) according to current consensus guidelines. Outcome measures included patient demographics, clinical measures, sweat chloride levels, CFTR genotype, age at diagnosis, airway microbiology, pancreatic function, infection, and nutritional status. The CF cohort had a significantly higher median sweat chloride level (105 mmol/l) than CFTR-related disorder patients (43 mmol/l) and CFTR-related metabolic syndrome patients (35 mmol/l; p ≤ 0.001). Patient groups significantly differed in pancreatic sufficiency, immunoreactive trypsinogen levels, sweat chloride values, genotype, and positive Pseudomonas aeruginosa cultures (p ≤ 0.001). An automated classification algorithm using recursive partitioning demonstrated concordance between physician diagnoses and consensus guidelines. Our analysis suggests that integrating clinical information with sweat chloride levels, CFTR genotype, and pancreatic sufficiency provides a context for continued longitudinal monitoring of patients for personalized and effective treatment.
authors.affiliation: Children's Research Institute, Children's Hospital of Wisconsin and Medical College of Wisconsin, Milwaukee, WI, USA.|Division of Pulmonary and Sleep Medicine, Children's Hospital of Wisconsin, Milwaukee, WI, USA.
authors.forename: H
authors.initials: H
authors.lastname: Levy
authors.affiliation: Division of Quantitative Health Sciences, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: M
authors.initials: M
authors.lastname: Nugent
authors.affiliation: Children's Research Institute, Children's Hospital of Wisconsin and Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: K
authors.initials: K
authors.lastname: Schneck
authors.affiliation: Genetics Center, Children's Hospital and Health System of Wisconsin, Milwaukee, WI, USA.
authors.forename: D
authors.initials: D
authors.lastname: Stachiw-Hietpas
authors.affiliation: Department of Pediatrics and Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: A
authors.initials: A
authors.lastname: Laxova
authors.affiliation: Department of Pediatrics, Section of Pulmonary Medicine, Lurie's Children's Hospital and Northwestern University, Chicago, IL, USA.
authors.forename: O
authors.initials: O
authors.lastname: Lakser
authors.affiliation: Department of Pediatrics and Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: M
authors.initials: M
authors.lastname: Rock
authors.affiliation: Children's Research Institute, Children's Hospital of Wisconsin and Medical College of Wisconsin, Milwaukee, WI, USA.|Division of Pediatric Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: M K
authors.initials: MK
authors.lastname: Dahmer
authors.affiliation: Division of Pulmonary and Sleep Medicine, Children's Hospital of Wisconsin, Milwaukee, WI, USA.
authors.forename: J
authors.initials: J
authors.lastname: Biller
authors.affiliation: Division of Pediatric Pulmonary Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: S Z
authors.initials: SZ
authors.lastname: Nasr
authors.affiliation: Wisconsin State Lab of Hygiene, Madison, WI, USA.|Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: M
authors.initials: M
authors.lastname: Baker
authors.affiliation: Department of Pediatrics, Section of Pulmonary Medicine, Lurie's Children's Hospital and Northwestern University, Chicago, IL, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: McColley
authors.affiliation: Division of Quantitative Health Sciences, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: P
authors.initials: P
authors.lastname: Simpson
authors.affiliation: Department of Pediatrics and Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: P M
authors.initials: PM
authors.lastname: Farrell
mesh_terms: D000293:Adolescent; D002648:Child; D002712:Chlorides / Q000378:metabolism; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D003550:Cystic Fibrosis / Q000145:classification / Q000175:diagnosis / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D005260:Female; D005820:Genetic Testing / Q000379:methods*; D005838:Genotype; D006776:Hospitals, Pediatric; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D015997:Neonatal Screening / Q000379:methods*; D010179:Pancreas / Q000502:physiology / Q000503:physiopathology; D011550:Pseudomonas aeruginosa / Q000302:isolation & purification / Q000502:physiology; D013542:Sweat / Q000737:chemistry / Q000382:microbiology
chemical_list: D002712:Chlorides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: CFTR phenotype-genotype correlation; CFTR-opathies; cystic fibrosis; cystic fibrosis metabolic syndrome; cystic fibrosis-related disorder