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Vandevanter D.R.,Case Western Reserve University | Pasta D.J.,ICON Clinical Research | Konstan M.W.,Case Western Reserve University
Journal of Pediatrics | Year: 2014

Objective To characterize spirometry and height changes in cohorts of 6-year-old children with cystic fibrosis (CF). Study design Global Lung Initiative forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC, and the Centers for Disease Control and Prevention height-for-age (HFA) z-scores were generated for 6-year-old children from the Cystic Fibrosis Foundation Patient Registry each year between 1994 and 2012. Z-score mean differences were analyzed by the t test, and time trends of means were analyzed by least squares regression for all children and for subgroups of sex, F508del mutation genotype, Medicaid insurance, and prenatal/newborn screening identification. Z-score distributions were compared using the 2-sample Kolmogorov-Smirnov test. Results A total of 11 670 children with CF were studied, of whom 50.5% were males, 50.2% had the F508del/F508del genotype, and 46.6% were insured by Medicaid. Mean HFA, FEV1, and FVC z-scores increased significantly over the period in the entire cohort and in all subgroups (P <.001), but FEV1/FVC z-scores were below normal and did not change significantly. In 2012, children identified by screening had significantly higher mean HFA (P =.002), FEV1 (P <.001), and FVC (P <.001) z-scores compared with children not screened, with 90% of FVC and 71.4% of FEV1 z-scores greater than predicted by the normal distribution. FEV1/FVC z-scores were not different between the children who were and were not screened. Conclusion Consistent, significant increases in HFA, FEV1, and FVC occurred between 1994 and 2012, but FEV1/FVC, a measure of airway obstruction, did not change appreciably during this period. FVC and FEV1 z-score distributions suggest that normative equation reference populations underpredict lung volumes of children with CF, but the reasons for this remain unclear. © 2014 Elsevier Inc. All rights reserved. Source


Sauzet O.,Bielefeld University | Wright K.C.,ICON Clinical Research | Marston L.,University College London | Brocklehurst P.,University College London | Peacock J.L.,Kings College London
Statistics in Medicine | Year: 2013

In cluster-randomised trials, the problem of non-independence within clusters is well known, and appropriate statistical analysis documented. Clusters typically seen in cluster trials are large in size and few in number, whereas datasets of preterm infants incorporate clusters of size two (twins), size three (triplets) and so on, with the majority of infants being in 'clusters' of size one. In such situations, it is unclear whether adjustment for clustering is needed or even possible. In this paper, we compared analyses allowing for clustering (linear mixed model) with analyses ignoring clustering (linear regression). Through simulations based on two real datasets, we explored estimation bias in predictors of a continuous outcome in different size datasets typical of preterm samples, with varying percentages of twins. Overall, the biases for estimated coefficients were similar for linear regression and mixed models, but the standard errors were consistently much less well estimated when using a linear model. Non-convergence was rare but was observed in approximately 5% of mixed models for samples below 200 and percentage of twins 2% or less. We conclude that in datasets with small clusters, mixed models should be the method of choice irrespective of the percentage of twins. If the mixed model does not converge, a linear regression can be fitted, but standard error will be underestimated, and so type I error may be inflated. © 2012 John Wiley & Sons, Ltd. Source


Van Devanter D.R.,Case Western Reserve University | Pasta D.J.,ICON Clinical Research | Konstan M.W.,Case Western Reserve University
Journal of Cystic Fibrosis | Year: 2015

Background: Pulmonary exacerbations (PEx) are important CF clinical events. Methods: We studied time to next PEx following intravenous (IV) antibiotic PEx treatment among Cleveland Ohio CF center patients occurring between January 2010 and September 2014. Patient demographics, clinical presentations, and treatments were modeled by Cox proportional hazards regression to identify covariates associated with time to next PEx. Results: 193 patients were treated for PEx; 155 had a subsequent IV-treated PEx. Six covariates were associated with future PEx hazard: number of PEx in the prior year (hazard ratio 25.1 for ≥. 3 and 4.4 for 1-2 prior-year PEx versus none; P. <. .0001), IV treatment duration in weeks (1.2; P. =. .0004), percent hospital treatment (1.1; P. =. .0018), and chronic inhaled aminoglycosides (2.5; P. <. .0001), leukotriene modifiers (1.8; P. =. .0031), and high dose ibuprofen (0.52; P. =. .0006). Conclusions: Time to next PEx was profoundly associated with prior-year PEx, suggestive of high-risk PEx phenotypes that warrant recognition and further study. © 2015 European Cystic Fibrosis Society.. Source


Rex D.K.,Indiana University | Katz P.O.,Albert Einstein Healthcare Network | Bertiger G.,Hillmont GI | Vanner S.,Queens University | And 3 more authors.
Gastrointestinal Endoscopy | Year: 2013

Background: New bowel cleansers for colonoscopy that lead to improved efficacy, safety, and tolerability are needed. Objective: This study evaluated a nonphosphate, dual-action, low-volume, orange-flavored preparation containing sodium picosulfate and magnesium citrate (P/MC). Design: Multicenter, assessor-blinded, randomized, noninferiority study. Setting: University hospitals, academic medical centers, and private clinics across the United States. Patients: Adults preparing for colonoscopy. Interventions: P/MC versus 2 L of polyethylene glycol solution (2L PEG-3350) and two 5-mg bisacodyl tablets. Main Outcome Measurements: This phase 3 study investigated the efficacy, safety, and tolerability of split-dose administration of P/MC versus day-before dosing of 2L PEG-3350 and two 5-mg bisacodyl tablets (SEE CLEAR I study). Efficacy was evaluated by using the Aronchick and Ottawa scales; noninferiority and superiority analyses were performed. Safety was assessed by monitoring adverse events (AEs). Tolerability was measured via a patient questionnaire. Results: The intent-to-treat population consisted of 601 patients who self-administered P/MC (n = 304) or 2L PEG-3350 and bisacodyl tablets (n = 297). P/MC was superior to 2L PEG-3350 and bisacodyl tablets in overall colon cleansing (84.2% vs 74.4%; 1-sided 97.5% confidence interval [CI], 3.4) (Aronchick scores of excellent or good) and in cleansing of the ascending (89.5% vs 78.8%; 1-sided 97.5% CI, 4.9), mid (transverse and descending) (92.4% vs 85.9%; 1-sided 97.5% CI, 1.6), and rectosigmoid (92.4% vs 87.2%; 1-sided 97.5% CI, 0.4) segments of the colon (Ottawa scores of excellent, good, or fair). Commonly reported AEs related to the bowel preparations were nausea, vomiting, headache, and chills. Patient-reported tolerability, including ease of consumption and taste, was significantly higher for P/MC than 2L PEG-3350 and bisacodyl tablets (P <.0001). Limitations: Because of differences in administration and volume of the bowel preparations, the study was designed to be a single-assessor, blinded study. Conclusions: The bowel-cleansing effects and patient acceptability of split-dose P/MC were superior to day-before dosing with 2L PEG-3350 and bisacodyl tablets. © 2013 by the American Society for Gastrointestinal Endoscopy. Source


Katz P.O.,Albert Einstein Healthcare Network | Rex D.K.,Indiana University | Epstein M.,Annapolis flyer cab | Grandhi N.K.,Gastroenterology Research Consultants of Greater Cincinnati | And 4 more authors.
American Journal of Gastroenterology | Year: 2013

OBJECTIVES:Optimal bowel preparation is vital for the efficacy and safety of colonoscopy. The inconvenience, discomfort, required consumption of large volumes of product, and potential adverse effects associated with some bowel preparations deter patients from colonoscopy and may provide inadequate cleansing. A dual-action, non-phosphate, natural orange-flavored, low-volume preparation containing sodium picosulfate and magnesium citrate (P/MC) is currently being reviewed for bowel cleansing.METHODS:This was a phase 3, randomized, multicenter, assessor-blinded, prespecified non-inferiority, head-to-head study to investigate the efficacy, safety, and tolerability of day-before administration of P/MC vs. 2L polyethylene glycol solution and two 5-mg bisacodyl tablets (2L PEG-3350 and bisacodyl tablets (HalfLytely and Bisacodyl Tablets Bowel Prep Kit)) in adult patients preparing for colonoscopy (SEE CLEAR II Study). The primary objective of the study was to demonstrate the non-inferiority of P/MC to 2L PEG-3350 and bisacodyl tablets in overall colon cleansing using a modified Aronchick scale. In addition, efficacy in the ascending, mid (transverse and descending), and recto-sigmoid segments of colon was evaluated using a modified Ottawa scale. Patient acceptability and tolerability of the bowel preparations were assessed via a standard questionnaire. Safety was assessed based on the monitoring of adverse events (AEs) and meaningful findings on clinical evaluations including physical examinations, vital sign measurements, and electrocardiograms (ECGs).RESULTS:A total of 603 patients were randomized to receive either P/MC (n=300) or 2L PEG-3350 and bisacodyl tablets (n=303). Based on the Aronchick scale, successful overall cleansing was similar in patients receiving P/MC (83.0%) and patients receiving 2L PEG-3350 and bisacodyl tablets (79.7%). P/MC demonstrated non-inferiority to 2L PEG-3350 and bisacodyl tablets in overall cleansing of the colon, as measured by the Aronchick scale. Similarly, the efficacy of P/MC, as measured by the Ottawa scale, was non-inferior to 2L PEG-3350 and bisacodyl tablets in cleansing the ascending, mid, and recto-sigmoid segments of the colon. Patient-reported acceptability and tolerability for each item examined on the questionnaire was significantly greater for P/MC compared with 2L PEG-3350 and bisacodyl tablets (P<0.0001).Treatment-emergent AEs related to the bowel preparation reported by 1% of patients receiving P/MC or 2L PEG-3350 and bisacodyl tablets were nausea (3.0% vs. 4.3%), vomiting (1.4% vs. 2.0%), and headache (2.7% vs. 1.7%). No clinically meaningful changes were noted in either treatment arm in data collected from physical examinations, vital sign measurements, and ECGs.CONCLUSIONS:When administered as a day-before dose, the bowel cleansing effects of P/MC were non-inferior compared with 2L PEG-3350 and bisacodyl tablets using the clinician-rated Aronchick and Ottawa scales. Treatment acceptability was significantly more favorable in patients receiving P/MC than in patients receiving 2L PEG-3350 and bisacodyl tablets. Source

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