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Evidence on improved outcomes with early diagnosis of cystic fibrosis through neonatal screening: enough is enough!
Farrell, PM, Lai, HJ, Li, Z, Kosorok, MR, Laxova, A, Green, CG, Collins, J, Hoffman, G, Laessig, R, Rock, MJ, et al
The Journal of pediatrics. 2005;(3 Suppl):S30-6
Abstract
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.
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Cognitive function of children with cystic fibrosis: deleterious effect of early malnutrition.
Koscik, RL, Farrell, PM, Kosorok, MR, Zaremba, KM, Laxova, A, Lai, HC, Douglas, JA, Rock, MJ, Splaingard, ML
Pediatrics. 2004;(6):1549-58
Abstract
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 alpha-tocopherol (alpha-T) levels at diagnosis. In addition, patients in the control group who also had vitamin E deficiency at diagnosis (alpha-T < 300 microg/dl) showed significantly lower CSI scores in comparison with alpha-T-sufficient control subjects and both deficient and sufficient alpha-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.
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Bronchopulmonary disease in children with cystic fibrosis after early or delayed diagnosis.
Farrell, PM, Li, Z, Kosorok, MR, Laxova, A, Green, CG, Collins, J, Lai, HC, Rock, MJ, Splaingard, ML
American journal of respiratory and critical care medicine. 2003;(9):1100-8
Abstract
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.
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Comparison of caloric intake and weight outcomes of an ad lib feeding regimen for preterm infants in two nurseries.
Pridham, KF, Kosorok, MR, Greer, F, Kayata, S, Bhattacharya, A, Grunwald, P
Journal of advanced nursing. 2001;(5):751-9
Abstract
BACKGROUND Effects on caloric intake and weight gain of an ad libitum (ad lib) feeding regimen for preterm infants may be specific to a special care nursery. OBJECTIVE To explore across two nurseries the similarity of effect on caloric intake and weight gain of an ad lib feeding regimen compared with a prescribed regimen and the similarity of effect of caloric intake on weight gain. METHODS All infants participating in the multi-site randomized clinical trial (RCT) of the ad lib feeding regimen were <35 weeks gestational age at birth and had birth weight appropriate for gestational age. Data on caloric intake and weight gain were collected at two nurseries (A, n=22; B, n=78) with the same feeding regimen protocols. Two strategies were used to explore similarity of regimen effect on caloric intake and weight gain. Repeated measures analysis of variance (ANOVA) was used to examine the effect on caloric intake and weight gain of time, feeding regimen, and time-by-regimen interaction for each nursery. RESULTS In both nurseries, regimen effects were reasonably consistent for caloric intake and weight gain. Caloric intake was lower across nurseries for infants fed ad lib. After accounting for caloric intake, the ad lib regimen did not affect weight gain. The time-by-regimen interaction effect on caloric intake was significant in both nurseries. Caloric intake for infants fed ad lib increased significantly over 5 days. CONCLUSIONS Despite differences between nurseries in infant characteristics and in protocol implementation, the feeding regimen effect was consistent for caloric intake and weight gain. Further support was found for the development of infant self-regulatory capacity.
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Early diagnosis of cystic fibrosis through neonatal screening prevents severe malnutrition and improves long-term growth. Wisconsin Cystic Fibrosis Neonatal Screening Study Group.
Farrell, PM, Kosorok, MR, Rock, MJ, Laxova, A, Zeng, L, Lai, HC, Hoffman, G, Laessig, RH, Splaingard, ML
Pediatrics. 2001;(1):1-13
Abstract
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 DeltaF508 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 DeltaF508 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