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Evaluating the reproducibility or agreement of microbiome measurements is often a crucial step to ensure rigorous downstream analyses in microbiome studies. In this paper, we address this need by developing adaptations of Lin’s concordance correlation coefficient (CCC) tailored to microbiome studies. We introduce a general formulation of the new CCC measures upon the use of a distance function appropriately characterizing the discrepancy between microbiome compositional measurements. We thoroughly study the special cases that adopt the Euclidean distance and Aitchison distance. Our proposals appropriately account for the unique features of microbiome compositional data, including high-dimensionality, dependency among individual relative abundances and the presence of many zeros. We further investigate a practical compound approach to help better understand the sources of data inconsistency. Extensive simulation studies are conducted to evaluate the utility of the proposed methods in realistic scenarios. We also apply the proposed methods to a microbiome validation data set from the Feeding Infants Right.. from the STart (FIRST) study. Our analyses offer useful insight about the extent of data variations resulted from two different experiment procedures as well as their heterogeneous patterns across genera.

Because of the heterogeneity in cystic fibrosis (CF) lung disease among young children, a clinical method to identify early-onset lung disease is needed.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.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.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.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.

Children with cystic fibrosis (CF) are susceptible to fat-soluble vitamin deficiencies unless supplemented, but even large doses of vitamin D may not prevent low 25-hydroxyvitamin D (25OHD) concentrations. The explanation for these vitamin D non-responders has been elusive. We utilized data from whole genome sequencing (WGS) to test the hypothesis that genetic variations predict responsiveness to vitamin D supplementation in a prospective cohort study of children with CF in the first 3 years of life.One hundred and one infants born during 2012-2017 and diagnosed with CF through newborn screening were studied. Serum 25OHD concentrations and vitamin D supplement doses were assessed during early infancy and annually thereafter. WGS was performed, the resultant variant calling files processed, and the summary statistics from a recent genome-wide association study were utilized to construct a polygenic risk score (PRS) for each subject.Overall, the prevalence of vitamin D insufficiency (30 ng/mL) was 21% in the first 3 years of life. Among the 70 subjects who always adhered to vitamin D supplement doses recommended by the US CF Foundation guidelines, 89% were responders (achieved vitamin D sufficiency) by 3 years of age, while 11% were transient or non-responders. Multiple regression analysis revealed that PRS was a significant predictor of 25OHD concentrations (p 0.001) and the likelihood of being an earlier responder in the first 3 years of life (p 0.01). A limited SNP analysis revealed variants in four important genes (GC, LIPC, CYP24A1, and PDE3B) that were shown to be associated with 25OHD concentrations and vitamin D responder status. Other determinants included vitamin D supplement dose, season at 25OHD measurement, and pancreatic functional status.Applying WGS in conjunction with utilizing a PRS approach revealed genetic variations that partially explain the unresponsiveness of some children with CF to vitamin D supplementation. Our findings suggest that a nutrigenomics strategy could help promote personalized treatment in CF.

BACKGROUND: The variable response to fat-soluble vitamin supplementation in young children with CF, and factors contributing to this variability, remain under-investigated. OBJECTIVE: To determine if recommended supplement doses normalize serum vitamin A (retinol), D (25-hydroxy-vitamin D, 25OHD) and E (α-tocopherol), and identify factors predictive of achieving sufficiency, in children with CF in the first 3 years of life. DESIGN: We studied 144 infants born during 2012–2017 and diagnosed with CF through newborn screening. Serum retinol, 25OHD, α-tocopherol and plasma cytokines interleukin(IL)-6, IL-8, IL10 and tumor necrosis factor (TNF)-α were measured in early infancy and yearly thereafter. Vitamin supplement intakes and respiratory microbiology were assessed every 1–2 months in infancy and quarterly thereafter. RESULTS: The prevalence of vitamin D insufficiency (

BACKGROUND: Zinc deficiency is associated with poor growth in children without cystic fibrosis (CF), but its impact on growth in children with CF is unknown. OBJECTIVE: To determine the prevalence of low serum Zn (sZn) and its relationship with growth in the first three years of life in children with CF. METHODS: We utilized data from infants with CF who were enrolled in a longitudinal study of nutrition and lung health and had sZn measured as part of clinical care. Cross-sectional correlations between sZn levels and growth z-scores were assessed by Pearson’s correlation coefficient. To identify factors associated with sZn status and its association to longitudinal growth patterns, multiple regression analysis with repeated measures were performed using generalized estimating equations. RESULTS: A total of 106 sZn measurements from 53 infants were identified. Seventeen infants (32%) had intermittent Zn insufficiency, defined as at least one sZn

Recurrent events are commonly encountered in longitudinal studies. The observation of recurrent events is often stopped by a dependent terminal event in practice. For this data scenario, we propose two sensible adaptations of the generalized accelerated recurrence time (GART) model (J. Amer. Statist. Assoc. 111 (2016) 145–156) to provide useful alternative analyses that can offer physical interpretations while rendering extra flexibility beyond the existing work based on the accelerated failure time model. Our modeling strategies align with the rationale underlying the use of the survivors’ rate function or the adjusted rate function to account for the presence of the dependent terminal event. For the proposed models, we identify and develop estimation and inference procedures which can be readily implemented based on existing software. We establish the asymptotic properties of the new estimator. Simulation studies demonstrate good finite-sample performance of the proposed methods. An application to a dataset from the Cystic Fibrosis Foundation Patient Registry (CFFPR) illustrates the practical utility of the new methods.

Recurrent events data are frequently encountered in biomedical follow-up studies. The generalized accelerated recurrence time (GART) model (Sun et al., 2016), which formulates covariate effects on the time scale of the mean function of recurrent events (i.e., time to expected frequency), has arisen as a useful secondary analysis tool to provide meaningful physical interpretations. In this article, we investigate the GART model in a multivariate recurrent events setting, where subjects may experience multiple types of recurrent events and some event types may be missing. We propose methods for the GART model that utilize the inverse probability weighting technique or the estimating equation projection strategy to handle event types that are missing at random. The new methods do not require imposing any parametric model for the missing mechanism, and thus are robust; moreover, they enjoy easy and stable implementation. We establish the uniform consistency and weak convergence of the resulting estimators and develop appropriate inferential procedures. Extensive simulation studies and an application to a dataset from Cystic Fibrosis Foundation Patient Registry (CFFPR) illustrate the validity and practical utility of the proposed methods.

Recurrent events data are frequently encountered in biomedical follow-up studies. The generalized accelerated recurrence time (GART) model (Sun et al., 2016), which formulates covariate effects on the time scale of the mean function of recurrent events (i.e., time to expected frequency), has arisen as a useful secondary analysis tool to provide meaningful physical interpretations. In this article, we investigate the GART model in a multivariate recurrent events setting, where subjects may experience multiple types of recurrent events and some event types may be missing. We propose methods for the GART model that utilize the inverse probability weighting technique or the estimating equation projection strategy to handle event types that are missing at random. The new methods do not require imposing any parametric model for the missing mechanism, and thus are robust; moreover, they enjoy easy and stable implementation. We establish the uniform consistency and weak convergence of the resulting estimators and develop appropriate inferential procedures. Extensive simulation studies and an application to a dataset from Cystic Fibrosis Foundation Patient Registry (CFFPR) illustrate the validity and practical utility of the proposed methods.

We develop time-varying association analyses for onset ages of two lung infections to address the statistical challenges in utilizing registry data where onset ages are left-truncated by ages of entry and competing-risk censored by deaths. Two types of association estimators are proposed based on conditional cause-specific hazard function and cumulative incidence function that are adapted from unconditional quantities to handle left truncation. Asymptotic properties of the estimators are established by using the empirical process techniques. Our simulation study shows that the estimators perform well with moderate sample sizes. We apply our methods to the Cystic Fibrosis Foundation Registry data to study the relationship between onset ages of Pseudomonas aeruginosa and Staphylococcus aureus infections.

Objective To examine differences between use of World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) growth reference in children with cystic fibrosis (CF) up to 2 years of age. Study design Growth from 1-24 months in 2587 children, born 2003-2006 and recorded in the US CF Foundation Registry, was evaluated using WHO and CDC references. Results In both boys and girls with CF aged 1-24 months, use of WHO charts resulted in ∼8 percentile lower length-for-age and ∼13% higher short stature rate (length-for-age Conclusions Growth status in children with CF differed when using WHO and CDC references, particularly during the second year of life. These differences need to be considered for all uses of growth assessment in CF.

Background In children with cystic fibrosis (CF), recovery from growth faltering within 2 years of diagnosis ( Responders ) is associated with better growth and less lung disease at age 6 years. This study examined whether these benefits are sustained through 12 years of age. Methods Longitudinal growth from 76 children with CF enrolled in the Wisconsin CF Neonatal Screening Project was examined and categorized into 5 groups: R 12 , R 6 , and R 2 , representing Responders who maintained growth improvement to age 12, 6, and 2 years, respectively, and I 6 and N 6, representing Non-responders whose growth did and did not improve during ages 2–6 years, respectively. Lung disease was evaluated by % predicted forced expiratory volume in one second (FEV 1 ) and chest radiograph (CXR) scores. Results Sixty-two percent were Responders. Within this group, 47% were R 12 , 28% were R 6 , and 25% were R 2 . Among Non-responders, 76% were N 6 . CF children with meconium ileus (MI) had worse lung function and CXR scores compared to other CF children. Among 53 children with pancreatic insufficiency without MI, R 12 had significantly better FEV 1 (97–99% predicted) and CXR scores during ages 6–12 years than N 6 (89–93% predicted). Both R 6 and R 2 experienced a decline in FEV 1 by ages 10–12 years. Conclusions Early growth recovery in CF is critical, as malnutrition during infancy tends to persist and catch-up growth after age 2 years is difficult. The longer adequate growth was maintained after early growth recovery, the better the pulmonary outcomes at age 12 years.

Recurrent event data frequently arise in longitudinal studies when study subjects possibly experience more than one event during the observation period. Often, such recurrent events can be categorized. However, part of the categorization may be missing due to technical difficulties. If the event types are missing completely at random, then a complete case analysis may provide consistent estimates of regression parameters in certain regression models, but estimates of the baseline event rates are generally biased. Previous work on nonparametric estimation of these rates has utilized parametric missingness models. In this paper, we develop fully nonparametric methods in which the missingness mechanism is completely unspecified. Consistency and asymptotic normality of the nonparametric estimators of the mean event functions accommodate nonparametric estimators of the event category probabilities, which converge more slowly than the parametric rate. Plug-in variance estimators are provided and perform well in simulation studies, where complete case estimators may exhibit large biases and parametric estimators generally have a larger mean squared error when the model is misspecified. The proposed methods are applied to data from a cystic fibrosis registry. Copyright 2013, Oxford University Press.

Background Persistent Pseudomonas aeruginosa (PPA) infection promotes lung function deterioration in children with cystic fibrosis (CF). Although early CF diagnosis through newborn screening (NBS) has been shown to provide nutritional/growth benefit, it is unclear whether NBS lowers the risk of PPA infection and how the effect of NBS vary with age. Modeling the onset age of PPA infection is challenging because 1) the onset age of PPA infection is interval censored in patient registry data; and 2) some risk factors such as NBS may have time-varying effects. Methods This problem fits into the framework of a recently developed Bayesian dynamic Cox model for interval censored data, where each regression coefficient is allowed to be time-varying to an extent determined by the data. Results Application of the methodology to data from the CF Foundation Patient Registry revealed interesting findings. Compared with patients with meconium ileus or diagnosed through signs or symptoms, patients diagnosed through NBS had significantly lower risks of acquiring PPA infection between age 1 and 2 years, and the benefit in survival rate was found to last up to age 4 years. Two cohorts of five years apart were compared. Patients born in cohort 2003–2004 had significantly lower risks of the PPA infections at any age up to 4 years than those born in 1998–1999. Conclusions The study supports benefits of NBS on PPA infection in early childhood. In addition, our analyses demonstrate that patients in the more recent cohort had significantly lower risks of acquiring PPA infection up to age 4 years, which suggests improved CF treatment and care over time. Electronic supplementary material The online version of this article (doi:10.1186/s12874-016-0220-5) contains supplementary material, which is available to authorized users.

BACKGROUND:To examine long-term growth benefit of newborn screening (NBS), adolescent peak height velocity (PHV), and adult height were compared between the screened (diagnosed early via NBS) and the control (identified generally by symptoms) in the Wisconsin Randomized Clinical Trial.METHODS:Data from 107 children born in 1985–1994 and followed through 2012 were analyzed. PHV was estimated by a semiparametric growth curve model and compared with Tanner reference.RESULTS:Meconium ileus (MI; n = 25) was associated with the worst pubertal growth and adult height, including 1 child who did not experience apparent PHV; children with pancreatic sufficiency (n = 18) achieved the best growth (normal PHV and adult height). In children with pancreatic insufficiency without meconium ileus (n = 64), the subgroup most likely to benefit from NBS, screened children had similar PHV but better adult height compared with controls. Specifically, in boys, the screened group (n = 22) achieved normal PHV (9.5 cm at 13.5 years); the control group (n = 19) had similar onset age (13.6 years) but 0.6-cm lower magnitude (P = .08). In girls, the screened group (n = 10) had somewhat later (12.5 years vs 11.7 years, P = .12) and lower PHV (7.3 cm vs 7.9 cm, P = .33) than the controls (n = 13), coinciding with later menarche (13.6 years vs 12.2 years, P = .10). Adult height was taller in the screened than the control (50th vs 29th percentile, P = .02), even after adjusted for genetic potential (32nd vs15th percentile, P = .006). Differences in adult height were primarily attributable to NBS and better prepubertal growth.CONCLUSIONS:Early linear growth benefits of NBS were sustained through puberty, leading to better adult height in cystic fibrosis.

In survival analysis, quantile regression has become a useful approach to account for covariate effects on the distribution of an event time of interest. In this article, we discuss how quantile regression can be extended to model counting processes and thus lead to a broader regression framework for survival data. We specifically investigate the proposed modeling of counting processes for recurrent events data. We show that the new recurrent events model retains the desirable features of quantile regression such as easy interpretation and good model flexibility, while accommodating various observation schemes encountered in observational studies. We develop a general theoretical and inferential framework for the new counting process model, which unifies with an existing method for censored quantile regression. As another useful contribution of this work, we propose a sample-based covariance estimation procedure, which provides a useful complement to the prevailing bootstrapping approach. We demonstrate the utility of our proposals via simulation studies and an application to a dataset from the U.S. Cystic Fibrosis Foundation Patient Registry (CFFPR). Supplementary materials for this article are available online.

BackgroundNewborn 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.MethodsWe 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).ResultsWe 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 2.3weeks versus 4.0weeks in IRT/IRT states, p

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

Background Obesity has been proposed to be a risk factor for the development of childhood asthma. Objective We sought to examine weight status from birth to age 5 years in relation to the occurrence of asthma at ages 6 and 8 years. Methods Two hundred eighty-five full-term high-risk newborns with at least 1 asthmatic/atopic parent enrolled in the Childhood Origin of Asthma project were studied from birth to age 8 years. Overweight was defined by weight-for-length percentiles of greater than the 85th percentile before the age of 2 years and a body mass index percentile of greater than the 85th percentile at ages 2 to 5 years. Results No significant concurrent association was found between overweight status and wheezing/asthma occurrence at each year of age. In contrast, longitudinal analyses revealed complex relationships between being overweight and asthma. Being overweight at age 1 year was associated with a decreased risk of asthma at age 6 (odds ratio [OR], 0.32; P = .02) and 8 (OR, 0.35; P = .04) years, as well as better lung function. However, being overweight beyond infancy was not associated with asthma occurrence. In fact, only children who were overweight at age 5 years but not at age 1 year had an increased risk of asthma at age 6 years (OR, 5.78; P = .05). Conclusion In children genetically at high risk of asthma, being overweight at age 1 year was associated with a decreased risk of asthma and better lung function at ages 6 and 8 years. However, being overweight beyond infancy did not have any protective effect and even could confer a higher risk for asthma.

BACKGROUND In 2005, the Cystic Fibrosis Foundation (CFF) revised the nutrition classification guidelines to eliminate the use of percentage of ideal body weight (%IBW) to define "nutritional failure"; the CFF also recommended that children with cystic fibrosis maintain a body mass index percentile (BMIp) > or = 50th. OBJECTIVE We assessed the effect of the 2005 CFF nutrition classification guidelines on evaluating the performance of nutritional care practices. DESIGN Data from 14,702 children reported to the 2002 CFF Patient Registry were analyzed to compare malnutrition rates in 113 cystic fibrosis centers in the United States. Nutritional failure was defined according to the 2002 CFF criteria--ie, height < 5th percentile, %IBW < 90%, or BMIp < 10th. "Below BMI goal" was defined according to the 2005 CFF criterion, ie BMIp < 50th. RESULTS Eliminating %IBW resulted in a 6% reduction (from 33% to 27%) in the nutritional failure rate in the United States. The use of BMIp < 50th led to the classification of 57% of children as below the BMI goal. Misclassification of nutritional failure according to %IBW ranged from 1% to 16% among 113 centers and was greater in the centers with a larger proportion of tall patients. After the elimination of %IBW, one-third of centers changed to a different tertile ranking for nutritional failure rates (kappa = 0.50, moderate-to-poor agreement). More than half the centers changed to a different tertile ranking, from nutritional failure to below BMI goal (kappa = 0.22, poor agreement). CONCLUSION Eliminating misclassification by %IBW and implementing the new BMI goal led to profound and unequal changes in malnutrition rates across cystic fibrosis centers.

Alcohol consumption is common on college campuses and is associated with negative consequences. Factors associated with availability of alcohol are not completely understood.To describe how proximity and density of alcohol outlets are associated with any drinking and binge drinking in students at the University of Wisconsin-Madison.Participants were full-time students enrolled in the Young Adults Eating and Active for Health, a multisite, randomized intervention that assessed a variety of health behaviors. Geographic information systems were used to calculate proximity and enumerate alcohol outlet densities. Participants were categorized as "drinkers" or "nondrinkers" based on self-reported alcohol consumption. Binge drinking was categorized as "non-binge drinker," "frequent binge drinker," and "excessive binge drinker." Analysis included regression, t tests, and chi-square tests. RESULTS. Among the 166 participants, 126 (76%) were drinkers. Among drinkers, 80 (63%) were either frequent or excessive binge drinkers. Drinkers lived closer to an alcohol outlet than non-drinkers (0.18 +/- 0.15 vs. 0.61 +/- 1.59 miles, respectively, P=0.005). Within a 1-mile walking radius, there were 47% more establishments for drinkers (153 +/- 47 compared to 104 +/- 55 outlets for nondrinkers, P0.0001). At distances of 0.10-0.25 and 0.25-0.50 miles, twice as many outlets were available to drinkers (19 +/- 19 and 43 +/- 25, respectively) compared to nondrinkers (7 +/- 11 and 20 +/- 22, respectively), P0.001. Proximity and density were hot associated with binge drinking frequency.Drinkers lived closer to alcohol outlets and had significantly more outlets available at a distance of up to 1 mile. Municipal and college administrators could consider limiting alcohol license distributions in municipalities with high alcohol consumption.

To evaluate whether early diagnosis of cystic fibrosis (CF) through newborn screening (NBS) and early vitamin E status are associated with cognitive function.We assessed cognitive function for 71 children without meconium ileus (ages 7.3-16.9 years) enrolled in the screened (S) or control (C) group of the Wisconsin CF Neonatal Screening Project. The Test of Cognitive Skills, 2nd edition generated the cognitive skills index (CSI; mean = 100, SD = 16). Vitamin E deficiency at diagnosis was defined as plasma alpha-tocopherol (alpha-T) below 300 microg/dL (300E). Primary analyses evaluated CSI scores across the 4 levels of group (S or C) by using alpha-T status (300E or300E) with analysis of covariance.After adjusting for covariates, CSI in the C300E group was significantly lower than each of the other groups (C300E, S300E, and S300E; P.05). The highest proportion of CSI scores84 occurred in the C300E group (41%). Patients in this group also had the lowest mean head circumference z-scores at diagnosis.Our results show that prolonged alpha-T deficiency in infancy is associated with lower subsequent cognitive performance. Thus, diagnosis via NBS may benefit the cognitive development of children with CF, particularly in those prone to vitamin E deficiency during infancy.

Background: The Cystic Fibrosis Foundation (CFF) recommends using the percentage of ideal body weight (%IBWCFF) and body mass index percentiles (BMIp) to assess weight-for-height status and to screen for malnutrition. Objective: The objective was to examine the agreement and discrepancy between the use of %IBWCFF and BMIp for screening malnutrition. Design: Data from 13 021 children reported to the 2000 CFF Patient Registry were analyzed. Results: In children of average stature (ie, height-for-age between the 25th and 75th percentiles) and aged 10 y, %IBWCFF corresponded closely to BMIp, and the prevalence of underweight estimated by %IBWCFF 90% was similar to that by BMIp 15th percentile. However, in children with short stature (ie, height-forage 25th percentile), %IBWCFF reflected significantly better weight-for-height status than did the BMIp, whereas the opposite trend was observed in children with tall stature (ie, height-for-age 75th percentile). Such discrepancies averaged 8 –12 percentage points when BMIp was reexpressed to the same unit and scale as %IBWCFF. Consequently, the prevalence of underweight estimated by %IBWCFF 90% was significantly lower (7.3%) than that estimated by BMIp 15th percentile (25.7%) in children with short stature, whereas the opposite trend was found in children with tall stature (47.7% and 14.4%, respectively). Additional analyses showed that BMIp was more sensitive to, and had stronger associations with, the percentage of predicted forced expiratory volume in 1 s. Conclusion: Compared with BMIp, %IBWCFF underestimated the severity of malnutrition in children with short stature and overestimated the severity of malnutrition in children with tall stature. Am J Clin Nutr 2004;80:982–91.

This US study was conducted to determine whether mode of diagnosis and initial disease presentation influence lung disease and survival in patients with cystic fibrosis. The study population included 27,703 patients reported to the 1986-2000 Cystic Fibrosis Foundation Registry. Patients were segregated into four diagnostic categories: meconium ileus (MI), prenatal/neonatal screening (SCREEN), positive family history (FH), and symptoms other than meconium ileus (SYMPTOM). When compared with patients in the SCREEN group, those in the MI or SYMPTOM group were found to have significantly greater risks of shortened survival, Pseudomonas aeruginosa acquisition, and forced expiratory volume in 1 second (FEV(1)) below 70% of predicted. In the SYMPTOM group, the greatest risks of shortened survival, P. aeruginosa acquisition, and FEV(1)

Although early diagnosis of cystic fibrosis (CF) can lead to nutritional benefits, there has been uncertainty about pulmonary outcomes. Using a randomized controlled trial with unique unblinding/surveillance, we evaluated patients with CF who received similar treatment after being assigned to an early diagnosis (screened) group or to a standard diagnosis (control) group. When the youngest patient was 7 years of age, we compared outcomes using pulmonary function data and quantitative chest radiology. In the screened group (56 patients), diagnosis was made at a younger age of 12.4 weeks, compared with the diagnosis in control group (47 control patients) at the age of 95.8 weeks, but included a significantly greater proportion of patients with deltaF508 genotypes and pancreatic insufficiency. The first chest radiograph showed significantly fewer abnormalities in the screened group; but, over time, the two groups converged, and after 10 years of age the screened patients showed worse chest X-ray scores associated with earlier acquisition of Pseudomonas aeruginosa. No differences were detected in any measure of pulmonary dysfunction, which was generally mild in each group. Although CF neonatal screening provides a potential opportunity for better pulmonary outcomes, it appears that respiratory infections and pancreatic status are the dominant factors in pulmonary prognosis.

Children with cystic fibrosis (CF) develop bronchopulmonary disease at variable ages. Determining the epidemiology of chronic lung disease and quantifying its severity, however, have been difficult in infants and young children. As part of the Wisconsin CF Neonatal Screening Project, we were presented with an ideal opportunity to assess longitudinally the evolution of symptoms, signs, and quantitative measures of CF respiratory disease. After newborn screening test results led to early recognition, 64 patients diagnosed at a median age of 6.71 weeks were enrolled and studied systematically at a median age of 11.3 years to obtain clinical information, chest radiographs, and pulmonary function tests. Our observations revealed that a frequent cough by history is evident by 10.5 months of age in half the patients. Quantitative chest radiology (CXR scoring) demonstrated that potentially irreversible abnormalities are present in half the children by 2 years. The severity of Wisconsin and Brasfield CXR scores increased in association with respiratory infections. Longitudinal progression of Wisconsin CXR scores was related to age (P < 0.001), pancreatic insufficiency (P = 0.005), and respiratory secretion cultures positive for Staphylococus aureas (P = 0.039). In contrast, serial spirometry showed limited sensitivity, as did lung volume determinations; neither was satisfactory as repeated measures with acceptable quality control until after 7 years of age. Time to event analyses revealed that half the patients had % predicted FEF(25-75) and FEV(1)/FVC values greater than 80% until 10.7 and 9.9 years, respectively. We conclude that of the methods evaluated, quantitative chest radiology is currently the best procedure for frequent assessment of bronchopulmonary disease in CF, and that radiographic progression is evident in approximately 85% of patients by 5 years of age. Our results also suggest that bronchiectasis and other radiographic evidence of chronic infection are apparent prior to airways obstruction in young CF patients.

Objective. Despite its relative frequency among autosomal recessive diseases and the availability of the sweat test, cystic fibrosis (CF) has been difficult to diagnose in early childhood, and delays can lead to severe malnutrition, lung disease, or even death. The Wisconsin CF Neonatal Screening Project was designed as a randomized clinical trial to assess the benefits and risks of early diagnosis through screening. In addition, the incidence of CF was determined, and the validity of our randomization method assessed by comparing 16 demographic variables. Methodology. Immunoreactive trypsinogen analysis was applied to dried newborn blood specimens for recognition of CF risk from 1985 to 1991 and was coupled to DNA-based detection of the ΔF508 mutation from 1991 to 1994. Randomization of 650 341 newborns occurred when their blood specimens reached the Wisconsin screening laboratory. This created 2 groups—an early diagnosis, screened cohort and a standard diagnosis or control group. To avoid selection bias, we devised a unique unblinding method with a surveillance program to completely identify the control subjects. Because sequential analysis of nutritional outcome measures revealed significantly better growth in screened patients during 1996, we accelerated the unblinding and completely identified the control group by April 1998. Having each member of this cohort enrolled and evaluated for at least 1 year and having completed a comprehensive surveillance program, we performed another statistical analysis of anthropometric evaluated indices that includes all CF patients without meconium ileus. Results. The incidence of classical CF, ie, patients diagnosed in this trial with a sweat chloride of 60 mEq/L greater, was 1:4189. By incorporating other CF patients born during the randomization period, including 2 autopsy diagnosed patients and 8 probable patients, we calculate a maximum incidence of 1:3938 (95% confidence interval: 3402–4611). Although there were group differences in the proportion of patients with ΔF508 genotypes and with pancreatic insufficiency, validity of the randomization plan was demonstrated by analyzing 16 demographic variables and finding no significant difference after adjustment for multiple comparisons. Focusing on patients without meconium ileus, we found a marked difference in the mean ± standard deviation age of diagnosis for screened patients (13 ± 37 weeks), compared with the standard diagnosis group (100 ± 117). Anthropometric indices of nutritional status were significantly higher at diagnosis in the screened group, including length/height, weight, and head circumference. During 13 years of study, despite similar nutritional therapy and the inherently better pancreatic status of the control group, analysis of nutritional outcomes revealed significantly greater growth associated with early diagnosis. Most impressively, the screened group had a much lower proportion of patients with weight and height data below the 10th percentile throughout childhood. Conclusions. Although the screened group had a higher proportion of patients with pancreatic insufficiency, their growth indices were significantly better than those of the control group during the 13-year follow-up evaluation and, therefore, this randomized clinical trial of early CF diagnosis must be interpreted as unequivocally positive. Our conclusions did not change when the height and weight data before 4 years of age for the controls detected by unblinding were included in the analysis. Also, comparison of growth outcomes after 4 years of age in all subjects showed persistence of the significant differences. Therefore, selection bias has been eliminated as a potential explanation. In addition, the results show that severe malnutrition persists after delayed diagnosis of CF and that catch-up may not be possible. We conclude that early diagnosis of CF through neonatal screening combined with aggressive nutritional therapy can result in significantly enhanced long-term nutritional status.

It is uncertain whether the growth impairment that occurs in children during long-term treatment with glucocorticoids persists after the medication is discontinued and ultimately affects adult height.We evaluated growth six to seven years after alternate-day treatment with prednisone had been discontinued in 224 children 6 to 14 years of age with cystic fibrosis who had participated in a multicenter trial of this therapy from 1986 through 1991. Of the children, 151 had been randomly assigned to receive prednisone (either 1 or 2 mg per kilogram of body weight) and 73 to receive placebo. We obtained data on growth up to 1997 from the Cystic Fibrosis Foundation Patient Registry and standardized the data to sex- and age-specific norms from the National Center for Health Statistics. We used z scores to compare growth patterns among treatment groups.In 1997, 68 percent of the patients were 18 years of age or older. The z scores for height declined during prednisone therapy; catch-up growth began two years after treatment with prednisone was discontinued. Among the boys, the z scores for height in those treated with prednisone remained lower than the scores for those who received placebo (P=0.02). The mean heights for boys 18 years of age or older were 4 cm less in the prednisone groups than in the placebo group, an equivalent of 13 percentile points (P=0.03). Among the girls, differences in height between those who were treated with prednisone and those who received placebo were no longer present two to three years after prednisone therapy was discontinued.Among children with cystic fibrosis who have received alternate-day treatment with prednisone, boys, but not girls, have persistent growth impairment after treatment is discontinued.

Objective. This study was pursued as an extension of a randomized clinical investigation of neonatal screening for cystic fibrosis (CF). The objective was to determine if CF patients with meconium ileus (MI) were more likely to be malnourished compared with those without MI who were diagnosed during early infancy through neonatal screening. Methodology. Nutritional status was evaluated from early infancy to 13 years of age based on anthropometric, biochemical, and dietary assessments. Results. MI patients (n = 32) were smaller at birth (3117 g compared with 3413 g) and were shorter (22nd percentile compared with 48th percentile) and thinner (24th percentile compared with 49th percentile) compared with non-MI early diagnosed patients (n = 50) up to 13 years of age. Poor growth was particularly evident in 26 MI patients who required surgery for MI (height and weight at the 20th percentile), whereas those treated without surgery (n = 6) showed better height (45th percentile) and weight (37th percentile). Abnormal essential fatty acid profiles were significantly more prevalent in MI compared with non-MI early-diagnosed patients before 3 years of age. Daily intakes of calorie (130% compared with 111% recommended dietary allowances) and protein (339% compared with 279% recommended dietary allowances) were higher but the percentage of fat (37% compared with 38%) and linoleic acid (4.5% compared with 4.7%) in the diet were similar between the two groups. Conclusions. These results demonstrated a clear association of MI with malnutrition in CF. The observed poor growth among our MI patients was not because of poor dietary intakes, but was related to surgical treatment for MI and poor essential fatty acid status. These findings present new challenges regarding the optimal medical treatment and nutritional intervention for CF patients with MI.

Background: Differences in growth status of patients with cystic fibrosis (CF) between the United States and Canada were reported in the 1980s based on analysis of data from 2 regional CF centers. Objective: We evaluated the current growth status of the entire CF population in the United States and Canada in view of recent advances in the treatment of CF. Design: Growth data from the 1992-1994 CF Patient Registries were analyzed. Results: Mean height and weight were at approximately the 30th percentile for children with CF in the United States. Mean height and weight were 4-5 percentiles higher in children with CF in Canada than in those in the United States (P < 0.01), but percentages of ideal weight (104%) were similar in both populations. In adults with CF, mean height was similar at the 37th percentile; however, weight (26th compared with the 21st percentiles) and percentage of ideal weight (93% compared with 90%) were significantly higher in Canada than in the United States. Differences related to sex and age were similar in both countries for all indexes, which showed a high prevalence of underweight in infants and in older patients, but little sex discrepancy. Conclusion: We observed substantially smaller differences in the growth indexes of CF patients between the United States and Canada compared with results from the 1980s. These findings reflect significant improvements in the nutritional status of US patients in recent years. However, caution is required in the direct comparison of mean percentiles from reports using different growth standards because there are systematic differences in growth standards, which affect, in particular, the comparison of growth in males and females.

To (a) explore the contribution of infant, environmental, and historical factors to the number of days from initiation to achievement of full nipple feeding (transition time) for premature infants with a history of lung disease; (b) examine differences in the contribution of infant and environmental factors to transition time made by historical era, either earlier (in the 1980s) or later (in the 1990s); and (c) compare, within eras, the contribution to transition time of infant and environmental factors for infants with each lung diagnosis, respiratory distress syndrome (RDS) without bronchopulmonary dysplasia (BPD) or BPD.Data were collected at two midwestern hospitals from the records of premature infants with a diagnosis of either RDS without BPD or BPD. The influence on transition time of infant, environmental and historical factors was assessed with the Cox proportional hazards model. This analytic model, a form of regression analysis, also was used to explore how era influenced the contribution to transition time of infant and environmental factors. Finally, the contribution to transition time of infant and environmental factors was examined within diagnostic group for each era.The hospital records audited were for infants who were 32 weeks gestational age or less with weight appropriate for gestational age. The number in each diagnostic group for each era was (a) BPD--Early, n = 35; (b) RDS--Early, n = 21; (c) BPD--Late, n = 21; and (d) RDS--Late, n = 15).All three types of factors (infant, environmental, and historical) contributed significantly (p.05) to shortening or lengthening transition time. A diagnosis of BPD lengthened transition time only in the early era. Across both eras, the number of days on tube feedings significantly lengthened transition time, and the older the infant in postconceptional age (PCA) at initiation of nipple feeding, the shorter the transition time.The contribution of infant, environmental, and historical factors to transition time confirmed the basic structure of the theoretical model of transition time for premature infants with a history of lung disease. The influence of era on the contributions to transition time of infant and environmental factors suggests that care policy and practice have shortened the transition time. Although the current findings support the basic structure of the theoretical model for infants with either RDS or BPD, the marginally significant (p.10) shortening effect of PCA on transition time for infants with BPD in both eras suggests that advancement to full nipple feeding may be limited by neurodevelopmental capacities, including respiratory control. How these capacities can be supported for advancement to full nipple feeding is a challenge for nursing practice and research.

The objectives of this study were to determine growth status and to identify malnutrition with various anthropometric indicators in children with cystic fibrosis (CF) based on cross-sectional analysis of the 1993 National CF Patient Registry data.Heights and weights of 13,116 children with CF were evaluated with percentile, percent of reference median, Z-score, and percent ideal weight-for-height based on National Center for Health Statistics/Centers for Disease Control growth references. Malnutrition was defined by four criteria: (1) height-for-age5th percentile ("stunting") or weight-for-age5th percentile ("wasting") (2) height-for-age90% of reference median or weight-for-age80% of reference median, (3) height-for-age5th percentile or percent ideal weight-for-height85%, and (4) height-for-age90% of reference median or weight-for-height85% of reference median.Mean and median height- and weight-for-age were found to be at the 30th and 20th percentiles in children with CF. Malnutrition (height- or weight-for-age5th percentile) was particularly pronounced in infants (47%) and adolescents (34%) and patients with newly diagnosed CF (44%). A significant sex difference (p0.01) in the occurrence of stunting (height-for-age5th percentile) was observed during adolescence: boys 11 to 14 years of age showed lower occurrence of stunting (19%) compared with girls (29%), whereas the opposite trend was observed at 15 to 18 years (34% in male patients vs 28% in female patients).Twenty percent of all children in the 1993 National CF Patient Registry were5th percentile for height- or weight-for-age. A significant discrepancy was found when different criteria were used to distinguish "stunting" versus "wasting" in malnourished children with CF.

BackgroundThe impact of improved nutritional status on health-related quality of life (HRQOL) is unknown for children with cystic fibrosis (CF).MethodsAssociations between nutritional status and HRQOL were examined over 2years in 95 children, aged 9–19years, who were followed in the Wisconsin Newborn Screening Project. HRQOL was assessed using the Cystic Fibrosis Questionnaire (CFQ). Associations between height z-score (HtZ), BMI z-score (BMIZ) and seven CFQ dimensions were evaluated.ResultsMean values of at least 80 were observed for all CFQ dimensions except respiratory symptoms and treatment burden. Treatment burden was significantly worse in patients with meconium ileus (57) compared to pancreatic insufficient (65) and sufficient (78) subjects, p

Section I: Basic Principles and Concepts Examining the Relationship between Diet, Nutrition and Disease: Dietary Assessment Methodology. Energy Requirement Methodology. Physical Assessment. Overview of Nutritional Epidemiology. Analysis, Presentation, and Interpretation of Dietary Data. Nutrition Intervention: Current Theoretical Bases for Nutrition Intervention and Their Uses. Nutrition Intervention: Lessons from Clinical Trials. Tools and Techniques to Facilitate Eating Behavior Change. Evaluation of Nutrition Interventions. Biomarkers and Biological Indicators of Change. Genetic Influence on Nutritional Health: Genetic Influences on Blood Lipids and Cardiovascular Disease Risk. Genetics of Human Obesity. Genetic Influence on Cancer Risk. Inborn Errors of Metabolism. Supplements and Food Replacements: Role of Liquid Dietary Supplements. Composite Foods and Formulas, Parenteral and Enteral Nutrition. Herbs and Other Botanical Supplements: Principles and Concepts. Section II: Disease-Specific Intervention: Prevention and Treatment Cardiovascular Disease: Dietary Macronutrients and Cardiovascular Risk. Other Dietary Components and Cardiovascular Risk. Nutrition, Diet & Hypertension. Nutrition and Congestive Heart Failure. Cancer Prevention and Therapy: Nutrition and Breast Cancer. Nutrition and Colon Cancer. Nutrition and Prostate Cancer. Nutrition and Lung Cancer. Nutrition and the Patient with Cancer. Diabetes Melitus: Obesity and the Risk for Diabetes. Nutrition Management for Type 1 Diabetes. Nutritional Management of Type 2 Diabetes. Nutrition Management for Gestational Diabetes. Obesity: Overview of Treatments and Interventions. Role of Physical Activity. Micronutrient Intake and Body Weight. Behavioral Risk Factors for Obesity: Diet and Physical Activity. Role of Taste and Appetite in Body Weight Regulation. Gastrointestinal Diseases: Nutrition in the Prevention and Treatment of Common Gastrointestinal Symptoms. Nutrient Considerations in Lactose Intolerance. Nutrient Considerations in Inflammatory Bowel Disease and Short Bowel Syndrome. Nutrition and Liver Disease. Other Major Diseases: Nutrition and Renal Disease. Nutritional Management of Parkinson's Disease and Other Conditions Like Alzheimer's Disease. Osteoporosis. Eating Disorders: Anorexia Nervosa, Bulimia Nervosa and Binge Eating Disorder. Nutrition and Food Allergy. Nutrition and Cystic Fibrosis. Osteomalacia. Nutrition and Immunodeficiency Syndromes. Disease Prevention Strategy: Nutrition Guidelines to Maintain Health. Epilogue.

ObjectiveThe 2002 Cystic Fibrosis Foundation (CFF) practice guidelines recommend adjusting for genetic potential when evaluating height status in children with CF. However, there is paucity of data to support this recommendation. We compared three methods of classifying short stature: unadjusted height percentile

The growing availability of various disease registry data has brought precious opportunities to epidemiologists to understand the natural history of the registered diseases. It also presents challenges to the traditional data analysis techniques because of complicated censoring/truncation schemes and temporal dynamics of covariate influences. In a case study of the Cystic Fibrosis Foundation Patient Registry data, we propose analyses of progressive symptoms using temporal process regressions, as an alternative to the commonly employed proportional hazards models. Two endpoints are considered, the prevalence of ever positive and currently positive for Pseudomonas aeruginosa (PA) infection in the lungs, which capture different aspect of the disease process. The analysis of ever PA positive via a time-varying coefficient model demonstrates the lack of fit, as well as the potential loss of information, in the standard proportional hazards analysis. The analysis of currently PA positive yields results that are clinically meaningful and have not previously been reported in the cystic fibrosis literature. Our analyses demonstrate that prenatal/neonatal screening results in lower prevalence of PA infection compared to traditional diagnosis via signs and symptoms, but this benefit attenuates with age. Calendar years of diagnosis also affect the risk of PA infection; patients diagnosed in more recent cohort show higher prevalence of ever PA positive but lower prevalence of currently PA positive.

OBJECTIVE. We recently reported that 60% of children newly diagnosed with cystic fibrosis who had pancreatic insufficiency responded to treatment initiation and achieved catch-up weight gain to a level comparable with their birth weight z score within 2 years of diagnosis (“responders”), whereas the remaining 40% failed to do so (“nonresponders”). The present study examined the impact of this early weight recovery on subsequent growth pattern and pulmonary status at 6 years of age.PATIENTS AND METHODS. Sixty-three children with cystic fibrosis who had pancreatic insufficiency but no meconium ileus, and were enrolled in the Wisconsin Cystic Fibrosis Neonatal Screening Project, were studied. Responders were defined by a recovery of weight z score comparable with that at birth within 2 years of diagnosis. From ages 2 to 6, growth was measured by both height and BMI. Pulmonary status was evaluated by symptoms, spirometry, quantitative chest radiography, and respiratory microbiology.RESULTS. The majority (71%) of the responders maintained their early weight recovery through 6 years of age, whereas only 32% of the nonresponders achieved substantial growth improvement from 2 to 6 years of age. Proportionately fewer responders reported cough symptoms (10% daytime cough; 22% nighttime cough) compared with nonresponders (41% daytime cough; 45% nighttime cough) at age 6. The percentage of predicted forced expiratory volume in 1 second at age 6 was 11% higher in responders (99.5% ± 13.9%) compared with nonresponders (88.3% ± 18.5%). Responders had significantly better Brasfield (20.1 ± 1.4) and Wisconsin chest radiograph (8.3 ± 3.3) scores compared with nonresponders (Brasfield: 18.9 ± 1.8; Wisconsin: 12.3 ± 8.3). Respiratory microbiology results were not significantly different. Multiple regression analyses indicated that the positive association between responder and percent predicted forced expiratory volume in 1 second at 6 years of age remained statistically significant after controlling for infections with Pseudomonas aeruginosa and Staphylococcus aureus and chest radiograph scores. Growth patterns from 2 to 6 years of age were not associated with pulmonary measures at age 6.CONCLUSIONS. Patients with cystic fibrosis with pancreatic insufficiency who achieved early growth recovery within 2 years of diagnosis had fewer cough symptoms, higher lung function, and better chest radiograph scores at 6 years of age.

In 2005, the Cystic Fibrosis Foundation (CFF) revised the nutrition classification guidelines to eliminate the use of percentage of ideal body weight (%IBW) to define "nutritional failure"; the CFF also recommended that children with cystic fibrosis maintain a body mass index percentile (BMIp)or = 50th.We assessed the effect of the 2005 CFF nutrition classification guidelines on evaluating the performance of nutritional care practices.Data from 14,702 children reported to the 2002 CFF Patient Registry were analyzed to compare malnutrition rates in 113 cystic fibrosis centers in the United States. Nutritional failure was defined according to the 2002 CFF criteria--ie, height5th percentile, %IBW90%, or BMIp10th. "Below BMI goal" was defined according to the 2005 CFF criterion, ie BMIp50th.Eliminating %IBW resulted in a 6% reduction (from 33% to 27%) in the nutritional failure rate in the United States. The use of BMIp50th led to the classification of 57% of children as below the BMI goal. Misclassification of nutritional failure according to %IBW ranged from 1% to 16% among 113 centers and was greater in the centers with a larger proportion of tall patients. After the elimination of %IBW, one-third of centers changed to a different tertile ranking for nutritional failure rates (kappa = 0.50, moderate-to-poor agreement). More than half the centers changed to a different tertile ranking, from nutritional failure to below BMI goal (kappa = 0.22, poor agreement).Eliminating misclassification by %IBW and implementing the new BMI goal led to profound and unequal changes in malnutrition rates across cystic fibrosis centers.

It is unclear why some patients with cystic fibrosis (CF) succeed ("responders") in recovering from malnutrition and growth faltering after treatment initiation whereas others fail to do so ("nonresponders"). We conducted a study to test the hypothesis that sustained high energy intake (increased EN) and normal plasma essential fatty acid status are critical determinants of treatment responsiveness within 2 years after diagnosis of CF.A total of 71 CF children who had pancreatic insufficiency but not meconium ileus and were enrolled in the Wisconsin CF Neonatal Screening Project were studied. Responders were defined by having achieved adequate weight gain, as indicated by a recovery of weight z score (Wtz) comparable to Wtz at birth (WtzBR) within 2 years of diagnosis. Increased EN and sustained normal plasma linoleic acid level (increased pLA) were defined by achieving energy intakeor =120% of estimated requirement foror =75% of the time and maintaining plasma LAor =26% of total fatty acids foror =75% of the time, respectively.Thirty-two (68%) screened patients and 13 (54%) patients whose CF was diagnosed conventionally recovered WtzBR within 2 years of diagnosis. Screened patients responded at significantly younger ages (mean/median: 6.3/4.3 months) than patients whose CF was diagnosed conventionally (mean/median: 15.8/11.8 months). Proportionately fewer screened patients (33%) achieved increased EN compared with patients whose CF was diagnosed conventionally (73%). However, more screened patients responded to increased EN and recovered WtzBR (91%) than patients whose CF was diagnosed conventionally (56%), although this difference was of borderline significance. Compared with having neither increased EN nor increased pLA, the likelihood of being a responder was greatest with combined increased EN and increased pLA, followed by increased EN only. The positive associations between increased EN and increased pLA to treatment responsiveness remained significant after adjustment for neonatal screening status, baseline height and weight status, and indices of pulmonary disease severity.Increased EN and increased pLA are critical in promoting adequate weight gain in children with newly diagnosed CF.

Objective To estimate the population impact of child mortality as a result of cystic fibrosis (CF) potentially preventable by newborn screening. Study design A systematic literature review of mortality in children with classic CF without meconium ileus (MI) in screened and unscreened cohorts was extended by contacting investigators for unpublished data. In addition, survival in US states with and without newborn screening (NBS) programs for CF was compared using data from the Cystic Fibrosis Foundation Patient Registry (CFFPR). Results Among non-US studies, CF-related mortality risk to approximately 10 years of age was lower by 5 to 10 per 100 in screened cohorts. Unpublished US data from a trial of NBS for CF indicate no CF-related deaths to 10 years of age in either cohort. CFFPR data suggest improved survival among children with CF born in US states with NBS, with a CF-related mortality difference to 10 years of age between the screened and unscreened groups between 1.5 and 2 per 100 children with CF without MI. Conclusion In addition to improving nutritional outcomes, newborn screening for CF may result in improved child survival. The absolute differential in mortality risk, although modest in size, appears comparable to NBS for certain other genetic disorders.

Objective To generate and examine evidence in support of diagnosing cystic fibrosis (CF) early through newborn screening (NBS). Study design Using a randomized controlled trial with unique unblinding/surveillance, we evaluated patients with CF receiving similar treatment after assignment to an early diagnosis (screened) group or to a control group. Outcomes studied at diagnosis and longitudinally included measures of nutritional status and lung disease. Results Assessment of patients with CF without meconium ileus who had pancreatic insufficiency revealed marked differences in age and condition at diagnosis—screened patients had significantly better length/height, weight, and head circumference. Follow-up evaluation for 16 years showed that height and weight differences persisted long term. Although screened patients had better chest x-ray scores at diagnosis, our trial suggests that the effects of confounders such as Pseudomonas aeruginosa infections led to deterioration of their scores after 10 years, but there were no significant differences between the 2 CF/pancreatic insufficiency subgroups. Conclusions Early diagnosis of CF and aggressive nutritional management can prevent malnutrition and growth failure. Although CF NBS provides a potential opportunity for better pulmonary outcomes, it appears that other factors can predominate over time in pulmonary prognosis. Overall, the Wisconsin trial is positive and provides enough evidence for routine CF NBS.

Objective. Patients who have cystic fibrosis (CF) and experience delayed diagnosis by traditional methods have greater nutritional insult compared with peers diagnosed via neonatal screening. The objective of this study was to evaluate cognitive function in children with CF and the influence of both early diagnosis through neonatal screening and the potential effect of early malnutrition. Methods. Cognitive assessment data were obtained for 89 CF patients (aged 7.3-17 years) during routine clinic visits. Patients had been enrolled in either the screened (N = 42) or traditional diagnosis (control) group (N = 47) of the Wisconsin CF Neonatal Screening Project. The Test of Cognitive Skills, Second Edition was administered to generate the Cognitive Skills Index (CSI) and cognitive factor scores (Verbal, Nonverbal, and Memory). Results. Cognitive scores in the overall study population were similar to normative data (CSI mean [standard deviation]: 102.5 [16.6]; 95% confidence interval: 99.1-105.9). The mean (standard deviation) CSI scores for the screened and control groups were 104.4 (14.4) and 99.8 (18.5), respectively. Significantly lower cognitive scores correlated with indicators of malnutrition and unfavorable family factors such as single parents, lower socioeconomic status, and less parental education. Our analyses revealed lower cognitive scores in patients with low plasma α-tocopherol (α-T) levels at diagnosis. In addition, patients in the control group who also had vitamin E deficiency at diagnosis (α-T < 300 μg/dl) showed significantly lower CSI scores in comparison with α-T–sufficient control subjects and both deficient and sufficient α-T subsets of screened patients. Conclusion. Results suggest that prevention of prolonged malnutrition by early diagnosis and nutritional therapy, particularly minimizing the duration of vitamin E deficiency, is associated with better cognitive functioning in children with CF.

This study was conducted to examine a patient's age and condition at the time of diagnosis as one potential factor contributing to the "gender gap" in cystic fibrosis. The study population consisted of 11,275 US patients diagnosed during 1986-1998 and reported to the Cystic Fibrosis Foundation Registry in the same or the following calendar year. Parallel analyses were performed for Wisconsin patients identified prospectively during 1985-1994 to obtain more detailed information on their condition at diagnosis. Analyses of the registry data showed that females identified because of symptoms other than meconium ileus were diagnosed at significantly older ages (median, 12.7 months) than were males (median, 8.7 months) (p < 0.001). The delay in diagnosis for females was most evident among patients presenting with respiratory symptoms only (median, 40.7 vs. 22.3 months; p < 0.001). Analyses of Wisconsin patients demonstrated no significant gender differences in cough and wheezing experiences or in chest radiographic severity scores between males and females during their first 10 years of life, although a disproportionately high number of males were referred for diagnostic sweat testing. A delay in diagnosis of females with cystic fibrosis was discovered, suggesting either differential recognition of respiratory symptoms or a gender bias.