Rhonda D. Szczesniak

Lymphangioleiomyomatosis Screening in Women With Tuberous Sclerosis

BACKGROUND Lymphangioleiomyomatosis (LAM) occurs in at least 40% of women with tuberous sclerosis complex (TSC), as diagnosed based on chest CT scan findings. Early identification may inform lifestyle choices and treatment decisions. Here we report LAM prevalence in a large TSC clinic and propose an approach to CT scan screening for LAM in women with TSC. METHODS We retrospectively reviewed initial chest CT scans of all female patients with TSC aged ≥ 15 years seen at our center over a 12-year period. Each CT image slice was manually scored for the presence or absence of characteristic thin-walled cysts, and the diagnosis of LAM was made if the sum of the cysts on all slices exceeded three cysts. RESULTS Of 133 female patients with TSC, 101 had chest CT scans available for review. Forty-eight (47.5%) met criteria for TSC-LAM on the initial CT scan. The risk of LAM was age dependent, rising by about 8% per year. The prevalence of LAM was 27% in subjects < 21 years of age and 81% in subjects > 40 years of age. Among asymptomatic subjects with LAM, 84% had cysts present in the single image at the level of the carina. Most subjects with LAM eventually developed pulmonary symptoms (63%), and 12.5% died from LAM. CONCLUSIONS These results suggest that most women with TSC ultimately develop cystic changes consistent with LAM and that most cases can be identified from a single CT imaging slice at the level of the carina. TSC-LAM was associated with appreciable morbidity and mortality in this referral population. An age-based approach using limited CT scanning methods may facilitate screening and subsequent treatment decisions with decreased radiation exposure in this at-risk population.

Regional Ventilation Changes in Severe Asthma after Bronchial Thermoplasty with 3He MR Imaging and CT

PURPOSE To quantify regional lung ventilation in healthy volunteers and patients with severe asthma (both before and after thermoplasty) by using a combination of helium 3 ((3)He) magnetic resonance (MR) imaging and computed tomography (CT), with the intention of developing more effective image-guided treatments for obstructive lung diseases. MATERIALS AND METHODS With approval of the local institutional review board, informed consent, and an Investigational New Drug Exemption, six healthy volunteers and 10 patients with severe asthma were imaged in compliance with HIPAA regulations by using both multidetector CT and (3)He MR imaging. Individual bronchopulmonary segments were labeled voxel by voxel from the CT images and then registered to the (3)He MR images by using custom software. The (3)He signal intensity was then analyzed by evaluating the volume-weighted fraction of total-lung signal intensity present in each segment (segmental ventilation percentage [ SVP segmental ventilation percentage ]) and by identifying the whole-lung defect percentage and the segmental defect percentage. Of the 10 patients with asthma, seven received treatment with bronchial thermoplasty and were imaged with (3)He MR a second time. Changes in segmental defect percentages and whole-lung defect percentages are presented. RESULTS Ventilation measures for healthy volunteers yielded smaller segment-to-segment variation (mean SVP segmental ventilation percentage , 100% ± 18 [standard deviation]) than did the measures for patients with severe asthma (mean SVP segmental ventilation percentage , 97% ± 23). Patients with asthma also demonstrated larger segmental defect percentages (median, 13.5%; interquartile range, 8.9%-17.8%) than healthy volunteers (median, 6%; interquartile range, 5.6%-6.3%). These quantitative results confirm what is visually observed on the (3)He images. A Spearman correlation of r = -0.82 was found between the change in whole-lung defect percentage and the number of days between final treatment and second (3)He imaging. CONCLUSION Regional quantification of lung ventilation is indeed feasible and may be a useful technique for image-guided treatment of obstructive lung diseases, such as bronchial thermoplasty for severe asthma. In these patients, ventilation defects decreased as a function of time after treatment.

Computational and statistical analysis of metabolomics data

Metabolomics is the comprehensive study of small molecule metabolites in biological systems. By assaying and analyzing thousands of metabolites in biological samples, it provides a whole picture of metabolic status and biochemical events happening within an organism and has become an increasingly powerful tool in the disease research. In metabolomics, it is common to deal with large amounts of data generated by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). Moreover, based on different goals and designs of studies, it may be necessary to use a variety of data analysis methods or a combination of them in order to obtain an accurate and comprehensive result. In this review, we intend to provide an overview of computational and statistical methods that are commonly applied to analyze metabolomics data. The review is divided into five sections. The first two sections will introduce the background and the databases and resources available for metabolomics research. The third section will briefly describe the principles of the two main experimental methods that produce metabolomics data: MS and NMR, followed by the fourth section that describes the preprocessing of the data from these two approaches. In the fifth and the most important section, we will review four main types of analysis that can be performed on metabolomics data with examples in metabolomics. These are unsupervised learning methods, supervised learning methods, pathway analysis methods and analysis of time course metabolomics data. We conclude by providing a table summarizing the principles and tools that we discussed in this review.

Multicenter Intestinal Current Measurements in Rectal Biopsies from CF and Non-CF Subjects to Monitor CFTR Function

Intestinal current measurements (ICM) from rectal biopsies are a sensitive means to detect cystic fibrosis transmembrane conductance regulator (CFTR) function, but have not been optimized for multicenter use. We piloted multicenter standard operating procedures (SOPs) to detect CFTR activity by ICM and examined key questions for use in clinical trials. SOPs for ICM using human rectal biopsies were developed across three centers and used to characterize ion transport from non-CF and CF subjects (two severe CFTR mutations). All data were centrally evaluated by a blinded interpreter. SOPs were then used across four centers to examine the effect of cold storage on CFTR currents and compare CFTR currents in biopsies from one subject studied simultaneously either at two sites (24 hours post-biopsy) or when biopsies were obtained by either forceps or suction. Rectal biopsies from 44 non-CF and 17 CF subjects were analyzed. Mean differences (µA/cm2; 95% confidence intervals) between CF and non-CF were forskolin/IBMX=102.6(128.0 to 81.1), carbachol=96.3(118.7 to 73.9), forskolin/IBMX+carbachol=200.9(243.1 to 158.6), and bumetanide=-44.6 (-33.7 to -55.6) (P<0.005, CF vs non-CF for all parameters). Receiver Operating Characteristic curves indicated that each parameter discriminated CF from non-CF subjects (area under the curve of 0.94-0.98). CFTR dependent currents following 18-24 hours of cold storage for forskolin/IBMX, carbachol, and forskolin/IBMX+carbachol stimulation (n=17 non-CF subjects) were 44%, 47.5%, and 47.3%, respectively of those in fresh biopsies. CFTR-dependent currents from biopsies studied after cold storage at two sites simultaneously demonstrated moderate correlation (n=14 non-CF subjects, Pearson correlation coefficients 0.389, 0.484, and 0.533). Similar CFTR dependent currents were detected from fresh biopsies obtained by either forceps or suction (within-subject comparisons, n=22 biopsies from three non-CF subjects). Multicenter ICM is a feasible CFTR outcome measure that discriminates CF from non-CF ion transport, offers unique advantages over other CFTR bioassays, and warrants further development as a potential CFTR biomarker.

A semiparametric approach to estimate rapid lung function decline in cystic fibrosis

PURPOSE Detecting the onset of rapid lung function decline is important to reduce mortality rates in cystic fibrosis (CF) and other lung diseases. The most common approach is conventional linear mixed modeling-estimating a population-level slope of lung function decline and using random effects to address serial correlation-but this ignores nonlinear features of disease progression and distinct sources of variability. The purpose of this article was to estimate patient-specific timing and degree of rapid decline while appropriately characterizing natural progression and variation in CF. METHODS We propose longitudinal semiparametric mixed modeling and contrast it with the conventional approach, which restricts lung function (measured as forced expiratory volume in 1 second as a percentage of predicted, FEV1%) to linear decline. Each approach is applied to clinical encounter data from the United States CF Foundation Patient Registry. RESULTS Timing and degree of rapid FEV1% decline vary across patients and as a function of key covariates. Patients experience maximal FEV1% loss by early adulthood more severe than indicated by conventional slope analysis. CONCLUSIONS Semiparametric mixed modeling provides a means to estimate patient-specific changes in CF disease progression and may be used to inform prognostic decisions in chronic care settings and clinical studies.

Sleep Disordered Breathing in Young Boys with Duchenne Muscular Dystrophy

OBJECTIVES To describe sleep-disordered breathing (SDB) in young boys with Duchenne muscular dystrophy (DMD) and its relationship with pulmonary function tests (PFTs). STUDY DESIGN This retrospective study examined diagnostic polysomnogram and PFT data of boys younger than 18 years with DMD and treated with steroids. Spirometry, respiratory muscle strength, body mass index (BMI), sleep architecture variables, and indices of SDB were analyzed. We examined the effect of PFT measures on the risk of each type of respiratory event using logistic regression and have reported results as OR (95% CI). RESULTS Subjects included 110 boys with DMD, mean age 11.5 (5.6-17.9) years. Mean (±SD) percent forced vital capacity predicted was 79.5% ± 29.1%. Mean BMI for all subjects was 21.9 ± 7.0 kg/m(2), and mean BMI z-score was 0.65 ± 1.93. Seventy (63.6%) subjects had obstructive sleep apnea; 37 (33.6%) subjects had central sleep apnea; 18 (17%) subjects had hypoventilation. Median (IQR) Apnea Hypopnea Index was 2.9 (1.6-6.9) and median Obstructive Index was 1.5 (0.5-3.8). Obstructive Index during rapid eye movement sleep positively correlated with BMI (r = 0.33, P = .002), BMI z-score (r = 0.22, P = .04), and age (r = 0.31, P = .004). Lower forced vital capacity was associated with increased risk of hypoventilation (OR 0.8, P = .001). CONCLUSION SDB is common in young boys with DMD treated with steroids. It is manifest with rapid eye movement-obstructive sleep apnea, often severe, and strongly influenced by BMI.

Behavioral and nutritional treatment for preschool-aged children with cystic fibrosis a randomized clinical trial

IMPORTANCE Evidence-based treatments that achieve optimal energy intake and improve growth in preschool-aged children with cystic fibrosis (CF) are a critical need. OBJECTIVE To test whether behavioral and nutritional treatment (intervention) was superior to an education and attention control treatment in increasing energy intake, weight z (WAZ) score, and height z (HAZ) score. DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial included 78 children aged 2 to 6 years (mean age, 3.8 years) with CF and pancreatic insufficiency (intervention, n = 36 and control, n = 42). The study was conducted at 7 CF centers between January 2006 and November 2012; all 78 participants who met intent-to-treat criteria completed through follow-up. INTERVENTIONS Behavioral intervention combined individualized nutritional counseling targeting increased energy intake and training in behavioral child management skills. The control arm provided education and served as a behavioral placebo controlling for attention and contact frequency. Both treatments were delivered in person or telehealth (via telephone). Sessions occurred weekly for 8 weeks then monthly for 4 months (6 months). Participants then returned to standard care for 1 year, with 12-month follow-up thereafter. MAIN OUTCOMES AND MEASURES Changes in energy intake and WAZ score were examined from pretreatment to posttreatment (6 months) and change in HAZ score was assessed pretreatment to follow-up (18 months). Covariates included sex, Pseudomonas aeruginosa status at baseline, and treatment modality (in person vs telehealth). RESULTS At baseline, mean (SD) energy intake was 1462 (329) kcals/d, WAZ score was -0.44 (0.81), and HAZ score was -0.55 (0.84). From pretreatment to posttreatment, the intervention increased daily energy intake by 485 calories vs 58 calories for the control group (adjusted difference, 431 calories; 95% CI, 282 to 581; P < .001) and increased the WAZ score by 0.12 units vs 0.06 for the control (adjusted difference, 0.09; 95% CI, -0.06 to 0.24; P = .25). From pretreatment to follow-up, the intervention increased the HAZ score by 0.09 units vs -0.02 for the control (adjusted difference, 0.14 units; 95% CI, 0.001 to 0.27; P = .049). Measured treatment integrity and credibility were high for both groups. CONCLUSIONS AND RELEVANCE Behavioral and nutritional intervention improved energy intake and HAZ score outcomes but not WAZ score outcomes. Our results provide evidence that behavioral and nutritional treatment may be efficacious as a nutritional intervention for preschoolers aged 2 to 6 years with CF and pancreatic insufficiency. TRIAL REGISTRATION clinicaltrials.gov Identifier:NCT00241969.

Chest imaging in cystic fibrosis studies: What counts, and can be counted?

BACKGROUND The dawn of precision medicine and CFTR modulators require more detailed assessment of lung structure in cystic fibrosis (CF) clinical studies. Various imaging markers have emerged and are measurable, but clarity is needed to identify what markers should count for clinical studies. High-resolution chest computed tomography (CT) scoring has yielded sensitive markers for the study of CF disease progression. Once completed, CT scores from ongoing randomized controlled trials can be used to examine relationships between imaging endpoints and therapeutic effectiveness. Similarly, Magnetic Resonance Imaging (MRI) is in development to generate structural as well as functional markers. RESULTS The aim of this review is to characterize the role of currently available CT and MRI markers in clinical studies, and to discuss study design, data processing and statistical challenges unique to these endpoints in CF studies. Suggestions to overcome these challenges in CF studies are included. CONCLUSIONS To maximize the potential of CT and MRI markers in clinical studies and advance treatment of CF disease progression, efforts should be made to conduct longitudinal randomized controlled trials including these modalities, develop data repositories, promote standardization and conduct reproducible research.

Insulin secretion abnormalities in exocrine pancreatic sufficient cystic fibrosis patients.

BACKGROUND The aim of this study is to assess insulin secretion in pediatric cystic fibrosis (CF) patients with exocrine pancreatic sufficiency. METHODS Glucose and insulin responses during an oral glucose tolerance test (OGTT) were measured in 146 CF patients. Patients were divided into exocrine sufficient (CF-PS) and insufficient (CF-PI) groups based on pancreatic enzyme usage and fecal elastase. A reference group included healthy, non-diabetic subjects. RESULTS All CF groups showed reduced insulin secretion as measured by insulinogenic index. The CF-PS patients had normal glucose tolerance. There was a direct correlation between BMI z-score and insulin area under the curve. CONCLUSION Patients with CF have reduced insulin secretion during an OGTT regardless of exocrine pancreatic status. The abnormal insulin secretion in all CF patients may predispose them for glucose intolerance, particularly when challenged by inflammation, infection, or nutritional deficiency. In addition, the diminished insulin secretion may contribute to increased catabolism. Lastly, the CF-related diabetes (CFRD) screening guidelines should be followed by all CF patients regardless of pancreatic status.

Use of FEV1 in cystic fibrosis epidemiologic studies and clinical trials: A statistical perspective for the clinical researcher

BACKGROUND Forced expiratory volume in 1s (FEV1) is an established marker of cystic fibrosis (CF) disease progression that is used to capture clinical course and evaluate therapeutic efficacy. The research community has established FEV1 surveillance data through a variety of observational data sources such as patient registries, and there is a growing pipeline of new CF therapies demonstrated to be efficacious in clinical trials by establishing improvements in FEV1. RESULTS In this review, we summarize from a statistical perspective the clinical relevance of FEV1 based on its association with morbidity and mortality in CF, its role in epidemiologic studies of disease progression and comparative effectiveness, and its utility in clinical trials. In addition, we identify opportunities to advance epidemiologic research and the clinical development pipeline through further statistical considerations. CONCLUSIONS Our understanding of CF disease course, therapeutics, and clinical care has evolved immensely in the past decades, in large part due to the thoughtful application of rigorous research methods and meaningful clinical endpoints such as FEV1. A continued commitment to conduct research that minimizes the potential for bias, maximizes the limited patient population, and harmonizes approaches to FEV1 analysis while maintaining clinical relevance, will facilitate further opportunities to advance CF care.