Bioinformatics

National Institute Of Environmental Health Sciences

Investigators

Linked publications, trials & patents

Abstract

Project 1: Sleep Apnea and Hypoventilation in Patients with Five Major Types of Muscular Dystrophy What is already known on this topic? Sleep apnea and hypoventilation are common in patients with muscular dystrophy; however, the characteristics of sleep disordered breathing among patients with the five types are less known. This study looks into five major types of muscular dystrophy (DMD-Duchenne, BMD-Becker, CMD-Congenital, LGMD-Limb-Girdle, and DM-Myotonic dystrophy). What this study adds? Not all types of muscular dystrophy have the same degree and characteristics of sleep disordered breathing. Importantly, hypoventilation was only weakly associated with sleep apnea in muscular dystrophy patients. Moreover, DM is not well studied, and we found that DM patients had significantly higher risk for sleep apnea compared to LGMD patients. How this study might affect research, practice or policy? Specific attention should be paid to each type. Because of the weak association between sleep apnea and hypoventilation, high clinical suspicion is needed so that hypoventilation can be diagnosed early to allow for timely intervention with non-invasive ventilation and thus better outcome. Background: The characteristics of and relationship between sleep apnea and hypoventilation in patients with muscular dystrophy remain to be fully understood. Methods: We analyzed 97 in-laboratory sleep studies of 69 muscular dystrophy patients with five common types (DMD-Duchenne, BMD-Becker, CMD-Congenital, LGMD-Limb-Girdle, and DM-Myotonic dystrophy). We used generalized estimating equations to examine differences among these types for outcomes. Results: Patients in all five types had high risk for sleep apnea with 49 of the 69 patients (71% ) met the diagnostic criteria in at least one of the studies. DM patients had higher risk for sleep apnea compared to LGMD patients (OR=5.06, 95% CI 1.6215.8; p=0.001). Forty-three percentage of patients had hypoventilation with prevalence higher in CMD (67%), DMD (48%) and DM (44%). Hypoventilation and sleep apnea were associated in those patients (unadjusted OR=2.71, 95% CI 1.076.84; p=0.04); but the association weakened after adjustment (OR=2.30, 95% CI 0.866.22; p=0.10). In-sleep average heart rate was about 10 bpm higher in CMD and DMD patients compared to DM patients (p0.0001, adjusted for multiple testing). Conclusion: Sleep disordered breathing is common in muscular dystrophy patients but each type has its unique features. Hypoventilation was only weakly associated with sleep apnea, thus high clinical suspicion is needed for diagnosing hypoventilation. Routine cardiology follow-up for the risk of cardiomyopathy and early pharmacologic intervention should be considered. Identifying the critical window in which respiratory muscle weakness causes hypoventilation is important for intervention with non-invasive ventilation which should improve the quality and life expectancy for muscular dystrophy patients. Project 2:SSAVE: A Tool for Analysis and Visualization of Sleep Periods using Electroencephalography Data Sleep is essential for good physical and mental health, yet physical and mental conditions also affect sleep. In fact, sleep architecture can reflect human physiology. Sleep quantity and quality tend to differ with sex and age as well as among people who suffer from sleep disorders, stress, anxiety, neuropsychiatric disorders, or diabetes. Human sleep architecture is structured with repeated episodes of rapid-eye-movement (REM) and non-rapid-eye-movement (NREM) sleep. An overnight sleep study facilitates identification of macro and micro changes in the pattern and duration of sleep stages associated with sleep disorders and other aspects of human mental and physical health. Overnight sleep studies record, in addition to electroencephalography (EEG) and other electro-physiological signals, a sequence of sleep-stage annotations. SSAVE, introduced here, is open-source software that takes sleep-stage annotations and EEG signals as input, identifies and characterizes periods of NREM and REM sleep, and produces a hypnogram and its time-matched EEG spectrogram. SSAVE fills an important gap for the rapidly growing field of sleep medicine by providing an easy-to-use tool for sleep-period identification and visualization. SSAVE can be used as a Python package, a desktop standalone tool or through a web portal. All versions of the SSAVE tool can be found on: https://manticore.niehs.nih.gov/ssave. Project 3: Dnase1l3 enhances antitumor immunity and suppresses tumor progression This project lasts a few years and finally the manuscript for the project has been accepted for publication in JCI Insight. Deficiency of DNASE1L3, an enzyme highly expressed in dendritic cells, is associated with autoimmune diseases. However, the role of DNASE1L3 in the interplay between immune cells and cancer cells is unknown. Here we report that DNASE1L3 is a tumor suppressor associated with antitumor immunity. In humans, DNASE1L3 is downregulated in tumors and this downregulation is associated with poor prognosis in many cancer types. In mice, Dnase1l3 deficiency enhances tumor formation and growth in several colon tumor models, as evidenced by increased size and/or number of tumors. This finding is associated with impaired anti-tumor immunity, including a substantial reduction of a distinct subset of dendritic cells characterized by Xcr1loItgamloSirpalo. Cytotoxic T cells are also reduced in tumors of these mice. Collectively, our study unveils a previously unknown link between Dnase1l3 and anti-tumor immunity, and further suggests that restoration of Dnase1l3 activity may represent a potential therapeutic approach for anti-cancer therapy.