Refinement of newborn screening for cystic fibrosis with next generation sequencing.

BACKGROUND: Newborn screening for cystic fibrosis (CF) has been underway universally in the United States for more than a decade, as well in most European countries, and algorithms have been evolving throughout this period with quality improvement projects as immunoreactive trypsinogen (IRT) determinations alone have been transformed to a 2-tier strategy with DNA analyses. OBJECTIVE: To apply next generation sequencing (NGS) as a screening method to expand the DNA tier and identify substantially more variants in the CF transmembrane conductance regulator (CFTR) gene to enhance sensitivity and equity while minimizing incidental findings. DESIGN: Sequential evaluation and improvement plan in three phases using algorithm modifications coupled to statewide follow up and analysis of screening outcomes. RESULTS: After demonstrating feasibility in the first phase, we studied an IRT/NGS algorithm that included CFTR Variants with Varying Clinical Consequences (VVCCs). This revealed a high identification of CF patients with 2-variants detected through screening, but for every CF case there were 1.4 with CF metabolic syndrome/CF screen positive, inconclusive diagnosis (CRMS/CFSPID). This led us to a third phase of improvement in which the VVCCs were eliminated except for R117H, resulting in 94% 2-variant detection of patients and 0.44:1 ratio of CRMS/CFSPID to CF. CONCLUSION: NGS can be used with IRT as an effective method of identifying infants at risk for CF without an appreciable increase in detection of carriers. Its potential added value includes facilitating equity, enhancing sensitivity and detecting more CF patients with 2-variants during the screening process.

Defining and identifying early-onset lung disease in cystic fibrosis with cumulative clinical characteristics.

BACKGROUND: Because of the heterogeneity in cystic fibrosis (CF) lung disease among young children, a clinical method to identify early-onset lung disease is needed. OBJECTIVE: To develop a CF early-onset lung disease (CFELD) scoring system by utilizing prospectively collected longitudinal data on manifestations in the first 3 years of life. DESIGN: We studied 145 infants born during 2012-2017, diagnosed through newborn screening by age 3 months, and followed to 36 months of age. Cough severity, pulmonary exacerbations (PEx), respiratory cultures, and hospitalizations were collected at each CF center visit (every 1-2 months in infancy and quarterly thereafter). These data were used to construct the CFELD system and to classify lung disease into five categories: asymptomatic, minimal, mild, moderate, and severe. RESULTS: The most frequent manifestation of CF early lung disease was MD-reported PEx episodes, PEx hospitalizations, and positive Pseudomonas aeruginosa cultures. Parent-reported cough severity was correlated with the number of respiratory hospitalizations (r = 0.48, p < 0.0001). The distribution of CFELD categories was 10% asymptomatic, 17% minimal, 29% mild, 33% moderate, and 12% severe. The moderate and severe categories occurred threefold higher in pancreatic insufficient (PI, 49%) versus sufficient subjects (16%), p < 0.0001. In addition to PI, gastrointestinal and nutrition-related hospitalizations, plasma cytokines interleukin (IL)-6 and IL-10, duration of CFTR modulator therapy, and type of health insurance were significant predictors of CFELD scores. CONCLUSION: The CFELD scoring system is novel, allows systematic evaluation of lung disease prognosis early, and may aid in therapeutic decision-making particularly in the initiation of CFTR modulator therapy.

F1099L-CFTR (c.3297C>G) has Impaired Channel Function and Associates with Mild Disease Phenotypes in Two Pediatric Patients.

(1) Background: many rare cystic fibrosistransmembrane conductance regulator (CFTR) mutations remain poorly characterized with regard to functional consequences of the mutation. We present the clinical features of two pediatric cystic fibrosis (CF) subjects who are heterozygous for F1099L (c.3297C>G), one with G551D (a class III mutation) and one with 3849 + 10kbC->T (a class V mutation). We also identified the molecular defect(s) that are associated with F1099L mutation to correlate with the clinical features that we observed; (2) Methods: clinical findings and history were extracted from the electronic medical record and de-identified. F1099L-CFTR protein expression level and maturation status, channel function, and the effects of CFTR modulation on these characteristics were investigated using western blotting and iodide efflux assay; (3) Results: these two subjects have mild CF phenotypes when F1099L is combined with two known disease-causing mutations. F1099L-CFTR has a moderate defect in processing and maturation, causing fewer CFTR channels at the cell surface and, therefore, impaired channel activities. These defects could be effectively corrected using VX-809 (lumacaftor); and, (4) Conclusions: our biochemical data correlate with the disease manifestations and suggest that F1099L is potentially a CF-causing mutation. The study expands our knowledge of rare CFTR mutations and may help in developing effective therapies for subjects with F1099L mutation.

Newborn screening alone insufficient to improve pulmonary outcomes for cystic fibrosis.

BACKGROUND: The Wisconsin Cystic Fibrosis Neonatal Screening Project was a randomized clinical trial (RCT) revealing that children receiving an early diagnosis of CF via newborn screening (NBS) had improved nutritional outcomes but similar lung disease severity compared to those who presented clinically. Because the evaluations of these subjects by protocol ended in 2012, our objective was to assess long-term pulmonary and mortality outcomes. METHODS: Retrospective analysis of the RCT cohort utilized longitudinal outcome measures obtained from the Cystic Fibrosis Foundation Patient Registry (CFFPR). Data included screening assignment, clinical characteristics, percent predicted forced expiratory volume in 1 s (ppFEV1) and mortality. A random intercept model was used to compare the ppFEV1 decline of subjects between the two groups up to age 26 years. Mortality was analyzed using the Kaplan-Meier method. RESULTS: Of the 145 subjects who consented to the original study, 104 subjects met inclusion criteria and had adequate data in the CFFPR. Of 57 subjects in the screened group and 47 in the control group, the rates of ppFEV1 decline were 1.76%/year (95% CI 1.62 to 1.91%) and 1.43%/year (95% CI 1.26 to 1.60%), respectively (p<0.0002). Pseudomonas aeruginosa acquired before 2 years was partially responsible. There was no difference in mortality between the two groups. CONCLUSIONS: NBS alone does not improve pulmonary outcomes in CF, particularly when other risk factors supervene. In an era prior to strict infection control and current therapies, NBS for CF may be associated with worse pulmonary outcomes.

The Impact of the CFTR Gene Discovery on Cystic Fibrosis Diagnosis, Counseling, and Preventive Therapy.

Discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene was the long-awaited scientific advance that dramatically improved the diagnosis and treatment of cystic fibrosis (CF). The combination of a first-tier biomarker, immunoreactive trypsinogen (IRT), and, if high, DNA analysis for CF-causing variants, has enabled regions where CF is prevalent to screen neonates and achieve diagnoses within 1-2 weeks of birth when most patients are asymptomatic. In addition, IRT/DNA (CFTR) screening protocols simultaneously contribute important genetic data to determine genotype, prognosticate, and plan preventive therapies such as CFTR modulator selection. As the genomics era proceeds with affordable biotechnologies, the potential added value of whole genome sequencing will probably enhance personalized, precision care that can begin during infancy. Issues remain, however, about the optimal size of CFTR panels in genetically diverse regions and how best to deal with incidental findings. Because prospects for a primary DNA screening test are on the horizon, the debate about detecting heterozygote carriers will likely intensify, especially as we learn more about this relatively common genotype. Perhaps, at that time, concerns about CF heterozygote carrier detection will subside, and it will become recognized as beneficial. We share new perspectives on that issue in this article.

Impact of Intermediate Cystic Fibrosis Classification on Parents' Perceptions of Child Vulnerability and Protectiveness.

This cross-sectional, mixed-method study examined factors associated with parent perceptions of child vulnerability and protectiveness in three groups: cystic fibrosis (CF-group, n = 40), intermediate CF classification (I-group, n = 20), and healthy (H-group, n = 50). A composite indicator structural equation (CISE) using Bayesian estimation tested two mediational models: psychological and biological. Significant results ( p < .05) from the psychological model showed I-group and CF-group parents perceived their children to be more vulnerable than H-group parents but reported lower levels of protectiveness than H-group parents. Perceptions of vulnerability mediated protectiveness for CF- and I-groups. The biological model showed I-group children had significantly less severe genotype and phenotype, and lower sweat chloride levels than the CF-group; I-group parents had lower expectations about children developing CF symptoms. Both models showed negative associations between children's ages and protectiveness. Psychological factors explained perceptions of child vulnerability and protectiveness; biological factors explained protectiveness. Parent perceptions of vulnerability and protectiveness are separate, independent constructs.

Effects of an Antioxidant-enriched Multivitamin in Cystic Fibrosis. A Randomized, Controlled, Multicenter Clinical Trial.

RATIONALE: Cystic fibrosis (CF) is characterized by dietary antioxidant deficiencies, which may contribute to an oxidant-antioxidant imbalance and oxidative stress. OBJECTIVES: Evaluate the effects of an oral antioxidant-enriched multivitamin supplement on antioxidant concentrations, markers of inflammation and oxidative stress, and clinical outcomes. METHODS: In this investigator-initiated, multicenter, randomized, double-blind, controlled trial, 73 pancreatic-insufficient subjects with CF 10 years of age and older with an FEV1 between 40% and 100% predicted were randomized to 16 weeks of an antioxidant-enriched multivitamin or control multivitamin without antioxidant enrichment. Endpoints included systemic antioxidant concentrations, markers of inflammation and oxidative stress, clinical outcomes (pulmonary exacerbations, anthropometric measures, pulmonary function), safety, and tolerability. MEASUREMENTS AND MAIN RESULTS: Change in sputum myeloperoxidase concentration over 16 weeks, the primary efficacy endpoint, was not significantly different between the treated and control groups. Systemic antioxidant (ß-carotene, coenzyme Q10, γ-tocopherol, and lutein) concentrations significantly increased in the antioxidant-treated group (P < 0.001 for each), whereas circulating calprotectin and myeloperoxidase decreased in the treated group compared with the control group at Week 4. The treated group had a lower risk of first pulmonary exacerbation requiring antibiotics than the control group (adjusted hazard ratio, 0.50; P = 0.04). Lung function and growth endpoints did not differ between groups. Adverse events and tolerability were similar between groups. CONCLUSIONS: Antioxidant supplementation was safe and well tolerated, resulting in increased systemic antioxidant concentrations and modest reductions in systemic inflammation after 4 weeks. Antioxidant treatment was also associated with a lower risk of first pulmonary exacerbation. Clinical trial registered with www.clinicaltrials.gov (NCT01859390).

Diagnosis of Cystic Fibrosis in Screened Populations.

OBJECTIVE: Cystic fibrosis (CF) can be difficult to diagnose, even when newborn screening (NBS) tests yield positive results. This challenge is exacerbated by the multitude of NBS protocols, misunderstandings about screening vs diagnostic tests, and the lack of guidelines for presumptive diagnoses. There is also confusion regarding the designation of age at diagnosis. STUDY DESIGN: To improve diagnosis and achieve standardization in definitions worldwide, the CF Foundation convened a committee of 32 experts with a mission to develop clear and actionable consensus guidelines on diagnosis of CF with an emphasis on screened populations, especially the newborn population. A comprehensive literature review was performed with emphasis on relevant articles published during the past decade. RESULTS: After reviewing the common screening protocols and outcome scenarios, 14 of 27 consensus statements were drafted that apply to screened populations. These were approved by 80% or more of the participants. CONCLUSIONS: It is recommended that all diagnoses be established by demonstrating dysfunction of the CF transmembrane conductance regulator (CFTR) channel, initially with a sweat chloride test and, when needed, potentially with newer methods assessing membrane transport directly, such as intestinal current measurements. Even in babies with 2 CF-causing mutations detected via NBS, diagnosis must be confirmed by demonstrating CFTR dysfunction. The committee also recommends that the latest classifications identified in the Clinical and Functional Translation of CFTR project [http://www.cftr2.org/index.php] should be used to aid with CF diagnosis. Finally, to avoid delays in treatment, we provide guidelines for presumptive diagnoses and recommend how to determine the age of diagnosis.

A new method of sweat testing: the CF Quantum®sweat test.

BACKGROUND: Conventional methods of sweat testing are time consuming and have many steps that can and do lead to errors. This study compares conventional sweat testing to a new quantitative method, the CF Quantum® (CFQT) sweat test. This study tests the diagnostic accuracy and analytic validity of the CFQT. METHODS: Previously diagnosed CF patients and patients who required a sweat test for clinical indications were invited to have the CFQT test performed. Both conventional sweat testing and the CFQT were performed bilaterally on the same day. Pairs of data from each test are plotted as a correlation graph and Bland-Altman plot. Sensitivity and specificity were calculated as well as the means and coefficient of variation by test and by extremity. After completing the study, subjects or their parents were asked for their preference of the CFQT and conventional sweat testing. RESULTS: The correlation coefficient between the CFQT and conventional sweat testing was 0.98 (95% confidence interval: 0.97-0.99). The sensitivity and specificity of the CFQT in diagnosing CF was 100% (95% confidence interval: 94-100%) and 96% (95% confidence interval: 89-99%), respectively. In one center in this three center multicenter study, there were higher sweat chloride values in patients with CF and also more tests that were invalid due to discrepant values between the two extremities. The percentage of invalid tests was higher in the CFQT method (16.5%) compared to conventional sweat testing (3.8%) (p < 0.001). In the post-test questionnaire, 88% of subjects/parents preferred the CFQT test. CONCLUSIONS: The CFQT is a fast and simple method of quantitative sweat chloride determination. This technology requires further refinement to improve the analytic accuracy at higher sweat chloride values and to decrease the number of invalid tests.

Long-term follow-up of cystic fibrosis newborn screening: psychosocial functioning of adolescents and young adults.

BACKGROUND: Long-term psychosocial outcomes of cystic fibrosis (CF) patients diagnosed through newborn screening remain unknown. METHODS: This cross-sectional study compared three groups of youths (16 to 22 years): CF patients diagnosed through NBS (CF-NBS, n = 13), CF patients diagnosed through standard practice (CF-SP, n = 26) and healthy peers (H, n = 42), plus 72 of their parents. We hypothesized that adolescent psychological functioning would be mediated by parent depression and quality of parent-child communication and cohesiveness. RESULTS: A path analysis showed significantly more depression among CF-NBS group parents (p = .006-.008). Parent-child cohesiveness was related to communication (p < .001). Cohesiveness and communication were associated with youth Internalizing Problems (p = .037, p = .009), Emotional Symptoms (p = 0.018, p = 0.022), and Personal Adjustment (communication only, p = 0.009). Parent depression was related to youth Personal Adjustment (p = 0.022). CONCLUSIONS: CF patients report psychosocial function similar to healthy peers. Parents of children diagnosed with CF through NBS may be at risk for depressive symptoms when their children reach adolescence.

Risk factors for the progression of cystic fibrosis lung disease throughout childhood.

RATIONALE: Previous studies of risk factors for progression of lung disease in cystic fibrosis (CF) have suffered from limitations that preclude a comprehensive understanding of the determinants of CF lung disease throughout childhood. The epidemiologic component of the 27-year Wisconsin Randomized Clinical Trial of CF Neonatal Screening Project (WI RCT) afforded us a unique opportunity to evaluate the significance of potential intrinsic and extrinsic risk factors for lung disease in children with CF. OBJECTIVES: Describe the most important intrinsic and extrinsic risk factors for progression of lung disease in children with CF. METHODS: Variables hypothesized at the onset of the WI RCT study to be determinants of the progression of lung disease and potential risk factors previously identified in the WI RCT study were assessed with multivariable generalized estimating equation models for repeated measures of chest radiograph scores and pulmonary function tests in the WI RCT cohort. MEASUREMENTS AND MAIN RESULTS: Combining all patients in the WI RCT, 132 subjects were observed for a mean of 16 years and contributed 1,579 chest radiographs, and 1,792 pulmonary function tests. The significant determinants of lung disease include genotype, poor growth, hospitalizations, meconium ileus, and infection with mucoid Pseudomonas aeruginosa. The previously described negative effect of female sex was not seen. CONCLUSIONS: Modifiable extrinsic risk factors are the major determinants of progression of lung disease in children with CF. Better interventions to prevent or treat these risk factors may lead to improvements in lung health for children with CF.

Health-related quality of life in children and adolescents with cystic fibrosis: convergent validity with parent-reports and objective measures of pulmonary health.

OBJECTIVE: This study examined the convergent validity of health-related quality of life (HRQOL) reported by patients with cystic fibrosis compared with their parents' reports and objective pulmonary measures across 3 time points. METHODS: Ninety-two children (8-13 years) and adolescents (14-18 years) with cystic fibrosis and their parents completed Cystic Fibrosis Questionnaires to examine concordance with Wisconsin chest x-ray (WCXR) scores and pulmonary function tests, for example, forced expiratory volume at 1 second (FEV1), and parent-child/adolescent concordance across multiple HRQOL domains. Concordance was analyzed relative to patient age and gender. RESULTS: Parent-reports were closely aligned with WCXR scores, whereas patient reports were more closely aligned with FEV1. Adolescents and parents of both age groups had more HRQOL domains concordant with pulmonary health measures than did child self-reports. Parent-child concordance was inversely related to child age, particularly with male adolescents. Children generally reported better HRQOL than parents. Male adolescents and their parents were more likely to have significantly discordant HRQOL scores than female adolescents and their parents. Male and female adolescents reported higher HRQOL than their parents reported for all but vitality and health perception domains. Younger male children showed concordance with their parents on 5 of 7 domains. CONCLUSIONS: Parent-child/adolescent discordance on HRQOL was consistent with normative child development expectations. Findings underscore the value of enlisting perspectives from parents as well as children regarding HRQOL.

The sensitivity of lung disease surrogates in detecting chest CT abnormalities in children with cystic fibrosis.

RATIONALE: Chest CT scans detect structural abnormalities in children with cystic fibrosis (CF), even when pulmonary function tests (PFTs) are normal. The use of chest CT is limited in clinical practice, because of concerns over expense, increased resource utilization, and radiation exposure. Quantitative chest radiography scores are useful in detecting mild lung disease, but whether they are sensitive to the presence of CT scan abnormalities has not been evaluated. OBJECTIVE: To determine in a cross-sectional study if quantitative chest radiography is a more sensitive marker of chest CT abnormalities than other lung disease surrogates. METHODS: Brody chest CT scores were calculated for 81 children enrolled in the Wisconsin CF Neonatal Screening Project. We determined the sensitivity for Wisconsin (WCXR) and Brasfield (BCXR) chest radiography scores, PFTs, positive cultures for P. aeruginosa (PA), and parental report of symptoms to detect a Brody score worse than the median score for study participants. MEASUREMENTS AND MAIN RESULTS: The mean FEV(1) for the study population was 91% predicted. Abnormal WCXR and BCXR scores had the highest sensitivity to detect a chest CT score worse than the median; abnormal PFTs, parental report of symptoms, and the presence of PA had much lower sensitivity (P < 0.001). CONCLUSIONS: In this cross sectional study, quantitative chest radiography has excellent sensitivity to detect an abnormal chest CT and may have a role in monitoring lung disease progression in children with CF.

Regional differences in the evolution of lung disease in children with cystic fibrosis.

Progression of lung disease is a major event in children with cystic fibrosis (CF), but regional differences in its evolution are unclear. We hypothesized that regional differences occur beginning in early childhood. We examined this issue by evaluating 132 patients followed in the Wisconsin Neonatal Screening Project between 1985 and 2010. We scored chest X-rays obtained every 1-2 years with the Wisconsin chest X-ray system, in which we divided the lungs into quadrants, and gave special attention to ratings for bronchiectasis (BX) and nodular/branching opacities. We compared the upper and lower quadrant scores, and upper right and left quadrant scores, as patients aged using a multivariable generalized estimation equation (GEE) model. We did a confirmatory analysis for a subset of 81 patients with chest computerized tomography (CT) images obtained in 2000 and scored using the Brody scoring system. The chest X-ray analysis shows that the upper quadrants have higher BX (P<0.001) and nodular/branching opacities (P<0.001) scores than the lower quadrants. CT analysis likewise reveals that the upper quadrants have more BX (P=0.02). Patients positive for mucoid PA showed significantly higher BX scores than patients with non-mucoid PA (P=0.001). Chest X-ray scoring also revealed that the upper right quadrant has more BX (P<0.001) than the upper left quadrant, and CT analysis was again confirmatory (P<0.001). We conclude that pediatric patients with CF develop more severe lung disease in the upper lobes than the lower lobes in association with mucoid PA infections and also have more severe lung disease on the right side than on the left side in the upper quadrants. A variety of potential explanations such as aspiration episodes may be clinically relevant and provide insights regarding therapies.

Comparing age of cystic fibrosis diagnosis and treatment initiation after newborn screening with two common strategies.

BACKGROUND: Newborn screening (NBS) for CF has become widespread, although there are multiple strategies. Little is known about outcomes such as age of diagnosis after different NBS methods. METHODS: We used the U.S. Cystic Fibrosis Foundation Patient Registry to identify infants with CF born between 2001 and 2008 in states that utilized NBS. We compared ages at diagnosis, genotyping, sweat test, and first visit to a CF Centre between states that used serial immunoreactive trypsinogen (IRT/IRT) levels and states that used IRT and DNA analysis (IRT/DNA). RESULTS: We identified 1288 infants with CF. Compared to infants born in IRT/IRT states, infants born in IRT/DNA states were younger at the time of diagnosis (median 2.3 weeks versus 4.0 weeks in IRT/IRT states, p<0.001), genotyping (0.7 weeks versus 5.3 weeks, p<0.001), and initial CF Centre visit (5.9 weeks versus 7.7 weeks, p=0.008). CONCLUSIONS: Although there is room to improve outcomes with both strategies, infants born in IRT/DNA states have treatment initiated at a younger age than infants born in IRT/IRT states.

Factors accounting for a missed diagnosis of cystic fibrosis after newborn screening.

Newborn screening is a public health policy program involving the centralized testing laboratory, infant and their family, primary care provider, and subspecialist for confirmatory testing and follow-up of abnormal results. Cystic fibrosis (CF) newborn screening has now been enacted in all 50 states and the District of Columbia and throughout many countries in the world. Although CF neonatal screening will identify the vast majority of infants with CF, there are many factors in the newborn screening system that can lead to a missed diagnosis of CF. To inform clinicians, this article summarizes the CF newborn screening system and highlights 14 factors that can account for a missed diagnosis of CF. Care providers should maintain a high suspicion for CF if there are compatible symptoms, regardless of the results of the newborn screening test. These factors in newborn screening programs leading to a missed diagnosis of CF present opportunities for quality improvement in specimen collection, laboratory analysis of immunoreactive tryspinogen (IRT) and CF mutation testing, communication, and sweat testing.

Growth and pulmonary outcomes during the first 2 y of life of breastfed and formula-fed infants diagnosed with cystic fibrosis through the Wisconsin Routine Newborn Screening Program.

BACKGROUND: The optimal feeding (breast milk, formula, or a combination) for infants with cystic fibrosis (CF) is unknown. Recommendations from the CF Foundation are based on limited data. OBJECTIVE: We compared growth and pulmonary outcomes between breastfed and formula-fed infants through the age of 2 y. DESIGN: A total of 103 CF infants born in 1994-2006 and diagnosed through newborn screening in Wisconsin were studied. Breastfed infants were classified by the duration of exclusive breastfeeding (ExBF). Exclusive formula-feeding (ExFM) was classified by the formula's caloric density (ie, standard [0.67 kcal/mL (20 kcal/oz) (ExFM20)] throughout infancy or high density [≥0.74 kcal/mL (22 kcal/oz) (ExFM22+)] for some duration of infancy). RESULTS: Fifty-three infants (51% of infants) were breastfed and 50 infants (49% of infants) were ExFM. In breastfed infants, the duration of ExBF was <1 mo (53% of infants), 1-1.9 mo (21% of infants), 2-3 mo (17% of infants), and 4-9 mo (9% of infants). In ExFM infants, 23 infants (46%) received a formula with a high caloric density; approximately half (n = 13) of the ExFM infants received the formula by 6 mo of age. Proportionately more infants with pancreatic sufficiency (n = 9) were ExBF ≥1 mo (44% of infants), and none of the infants were ExFM22+, compared with infants with meconium ileus (n = 24; 13% of infants were ExBF ≥1 mo, and 38% of infants were ExFM22+) or pancreatic insufficiency (n = 70; 25% of infants were ExBF ≥1 mo, and 20% of infants were ExFM22+) (P = 0.02). In infants with pancreatic insufficiency, weight z scores declined from birth to 6 mo (P < 0.0001) in infants who were ExBF ≥2 mo, and the number of Pseudomonas aeruginosa infections through the age of 2 y was fewer in breastfed than in ExFM infants (P = 0.003) but did not differ by the duration of ExBF. CONCLUSION: For infants with CF, ExBF <2 mo does not compromise growth and is associated with a respiratory benefit.

Relationships among health-related quality of life, pulmonary health, and newborn screening for cystic fibrosis.

BACKGROUND: The objective of this study was to examine relationships between pulmonary health and health-related quality of life (HRQOL) in patients with cystic fibrosis (CF) evaluated longitudinally in the Wisconsin Newborn Screening Project. METHODS: Patients aged 8 to 18 years (mean ± SD, 13.5 ± 2.8) in early diagnosis (n = 45) and control (n = 50) groups completed Cystic Fibrosis Questionnaires (CFQs) to measure HRQOL at three data points over a 2-year period. Pulmonary health was evaluated concurrently by the Wisconsin chest x-ray scoring system (WCXR) and pulmonary function tests (PFTs). RESULTS: WCXR showed significant group differences (P ≤ .023), with the early diagnosis group showing more-severe lung disease. When adjusted for group differences in mucoid Pseudomonas aeruginosa status and pancreatic status, however, WCXR differences and PFT data were not significant. Most patients (74%) had FEV(1) values ≥ 80% predicted (within normal range). For patients aged < 14 years, as WCXR scores worsened CFQ respiratory and physical domain scores decreased (both P ≤ .007). FEV(1)/FVC showed a positive relationship with the respiratory and physical domains (both P ≤ .006). WCXR scores for patients aged ≥ 14 years were associated with CFQ weight, respiratory, and health domains (all P ≤ .011). FEV(1) was associated with CFQ weight, respiratory, health, and physical domains (all P ≤ .003). Changes in pulmonary health were not associated with changes in CFQ over time. Significant group differences on the CFQ-Child social functioning domain favored the control group. CONCLUSIONS: To our knowledge, this study is the first to compare pulmonary outcomes with HRQOL indicators assessed by serial, standardized, patient-reported outcome measures for patients with CF identified either through newborn screening or diagnosed by use of traditional methods. This study found no benefits of newborn screening for pulmonary health or HRQOL after controlling for risk factors. Using WCXR and PFT data collectively helped to identify associations between pulmonary health and HRQOL.