The aim of this paper is to develop a weighted functional linear Cox regression model that accounts for the association between a failure time and a set of functional and scalar covariates. We ...formulate the weighted functional linear Cox regression by incorporating a comprehensive three-stage estimation procedure as a unified methodology. Specifically, the weighted functional linear Cox regression uses a functional principal component analysis to represent the functional covariates and a high-dimensional Cox regression model to capture the joint effects of both scalar and functional covariates on the failure time data. Then, we consider an uncensored probability for each subject by estimating the important parameter of a censoring distribution. Finally, we use such a weight to construct the pseudo-likelihood function and maximize it to acquire an estimator. We also show our estimation and testing procedures through simulations and an analysis of real data from the Alzheimer’s Disease Neuroimaging Initiative.
Schizophrenia is a neurodevelopmental disorder associated with subtle abnormal cortical thickness and cortical surface area. However, it is unclear whether these abnormalities exist in neonates ...associated with genetic risk for schizophrenia. To this end, this preliminary study was conducted to identify possible abnormalities of cortical thickness and surface area in the high-genetic-risk neonates. Structural magnetic resonance images were acquired from offspring of mothers (
N
= 21) who had schizophrenia (
N
= 12) or schizoaffective disorder (
N
= 9), and also matched healthy neonates of mothers who were free of psychiatric illness (
N
= 26). Neonatal cortical surfaces were reconstructed and parcellated as regions of interest (ROIs), and cortical thickness for each vertex was computed as the shortest distance between the inner and outer surfaces. Comparisons were made for the average cortical thickness and total surface area in each of 68 cortical ROIs. After false discovery rate (FDR) correction, it was found that the female high-genetic-risk neonates had significantly thinner cortical thickness in the right lateral occipital cortex than the female control neonates. Before FDR correction, the high-genetic-risk neonates had significantly thinner cortex in the left transverse temporal gyrus, left banks of superior temporal sulcus, left lingual gyrus, right paracentral cortex, right posterior cingulate cortex, right temporal pole, and right lateral occipital cortex, compared with the control neonates. Before FDR correction, in comparison with control neonates, male high-risk neonates had significantly thicker cortex in the left frontal pole, left cuneus cortex, and left lateral occipital cortex; while female high-risk neonates had significantly thinner cortex in the bilateral paracentral, bilateral lateral occipital, left transverse temporal, left pars opercularis, right cuneus, and right posterior cingulate cortices. The high-risk neonates also had significantly smaller cortical surface area in the right pars triangularis (before FDR correction), compared with control neonates. This preliminary study provides the first evidence that early development of cortical thickness and surface area might be abnormal in the neonates at genetic risk for schizophrenia.
Patients with Down syndrome (DS) are at risk for both obstructive sleep apnea (OSA) and central sleep apnea (CSA); however, it is unclear how these components evolve as patients age and whether ...patients are also at risk for hypoventilation. A retrospective review of 144 diagnostic polysomnograms (PSG) in a tertiary care facility over 10 years was conducted. Descriptive data and exploratory correlation analyses were performed. Sleep disordered breathing was common (seen in 78% of patients) with an average apnea-hypopnea index (AHI) = 10. The relative amount of obstructive apnea was positively correlated with age and body mass index (BMI). The relative amount of central sleep apnea was associated with younger age in the very youngest group (0-3 years). Hypoventilation was common occurring in more than 22% of patients and there was a positive correlation between the maximum CO₂ and BMI. Sleep disordered breathing, including hypoventilation, was common in patients with DS. The obstructive component increased significantly with age and BMI, while the central component occurred most in the very young age group. Due to the high risk of hypoventilation, which has not been previously highlighted, it may be helpful to consider therapies to target both apnea and hypoventilation in this population.
BackgroundThe characteristics of and relationship between sleep apnoea and hypoventilation in patients with muscular dystrophy (MD) remain to be fully understood.MethodsWe analysed 104 in-laboratory ...sleep studies of 73 patients with MD with five common types (DMD—Duchenne, Becker MD, CMD—congenital, LGMD—limb-girdle and DM—myotonic dystrophy). We used generalised estimating equations to examine differences among these types for outcomes.ResultsPatients in all five types had high risk of sleep apnoea with 53 of the 73 patients (73%) meeting the diagnostic criteria in at least one study. Patients with DM had higher risk of sleep apnoea compared with patients with LGMD (OR=5.15, 95% CI 1.47 to 18.0; p=0.003). Forty-three per cent of patients had hypoventilation with observed prevalence higher in CMD (67%), DMD (48%) and DM (44%). Hypoventilation and sleep apnoea were associated in those patients (unadjusted OR=2.75, 95% CI 1.15 to 6.60; p=0.03), but the association weakened after adjustment (OR=2.32, 95% CI 0.92 to 5.81; p=0.08). In-sleep average heart rate was about 10 beats/min higher in patients with CMD and DMD compared with patients with DM (p=0.0006 and p=0.02, respectively, adjusted for multiple testing).ConclusionSleep-disordered breathing is common in patients with MD but each type has its unique features. Hypoventilation was only weakly associated with sleep apnoea; thus, high clinical suspicion is needed for diagnosing hypoventilation. Identifying the window when respiratory muscle weakness begins to cause hypoventilation is important for patients with MD; it enables early intervention with non-invasive ventilation—a therapy that should both lengthen the expected life of these patients and improve its quality.Cite Now
Abstract The goal of this study was to assess whether magnetic resonance imaging (MRI) biomarkers can quantify disease progression in golden retriever muscular dystrophy (GRMD) via a natural history ...study. The proximal pelvic limbs of ten GRMD and eight normal dogs were scanned at 3, 6, and 9–12 months of age. Several MRI imaging and texture analysis biomarkers were quantified in seven muscles. Almost all MRI biomarkers readily distinguished GRMD from control dogs; however, only selected biomarkers tracked with longitudinal disease progression. The biomarkers that performed best were full-length muscle volume and a texture analysis biomarker, termed heterogeneity index. The biceps femoris, semitendinosus and cranial sartorius muscles showed differential progression in GRMD versus control dogs. MRI features in GRMD dogs showed dynamic progression that was most pronounced over the 3- to 6-month period. Volumetric biomarkers and water map values correlated with histopathological features of necrosis/regeneration at 6-months. In conclusion, selected MRI biomarkers (volume and heterogeneity index) in particular muscles (biceps femoris, semitendinosus, and cranial sartorius) adjusted for age effect allow distinction of differential longitudinal progression in GRMD dogs. These biomarkers may be used as surrogate outcome measures in preclinical GRMD trials.
Little is known about the temporospatial shape characteristics of human lateral ventricles (LVs) during the first two years of life. This study aimed to delineate the morphological growth ...characteristics of LVs during early infancy using longitudinally acquired MR images in normal healthy infants.
24 healthy infants were MR imaged starting from 2 weeks old every 3 months during the first and every 6 months during the second year. Bilateral LVs were segmented and longitudinal morphological and shape analysis were conducted using longitudinal mixed effect models.
A significant bilateral ventricular volume increase (p<0.0001) is observed in year one (Left: 126±51% and Right: 145±62%), followed by a significant reduction (p<0.02) during the second year of life (Left: -24±27% and Right: -20±18%) despite the continuing increase of intracranial volume. Morphological analysis reveals that the ventricular growth is spatially non-uniform, and that the most significant growth occurs during the first 6 months. The first 3 months of life exhibit a significant (p<0.01) bilateral lengthening of the anterior lateral ventricle and a significant increase of radius (p<0.01) and area (p<0.01) at the posterior portion of the ventricle. Shape analysis shows that the horns exhibit a faster growth rate than the mid-body. Finally, bilateral significant age effects (p<0.01) are observed for the growth of LVs whereas gender effects are more subtle and significant effects (p<0.01) only present at the left anterior and posterior horns. More importantly, both the age and gender effects are growth directionally dependent.
We have demonstrated the temporospatial shape growth characteristics of human LVs during the first two years of life using a unique longitudinal MR data set. A temporally and spatially non-uniform growth pattern was reported. These normative results could provide invaluable information to discern abnormal growth patterns in patients with neurodevelopmental disorders.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Transient activation of the hypothalamic-pituitary-gonadal axis in early infancy plays an important role in male genital development and sexual differentiation of the brain, but factors contributing ...to individual variation in testosterone levels during this period are poorly understood. We measured salivary testosterone levels in 222 infants (119 males, 103 females, 108 singletons, 114 twins) between 2.70 and 4.80 months of age. We tested 16 major demographic and medical history variables for effects on inter-individual variation in salivary testosterone. Using the subset of twins, we estimated genetic and environmental contributions to salivary testosterone levels. Finally, we tested single nucleotide polymorphisms (SNPs) within ±5 kb of genes involved in testosterone synthesis, transport, signaling, and metabolism for associations with salivary testosterone using univariate tests and random forest (RF) analysis. We report an association between 5 min APGAR scores and salivary testosterone levels in males. Twin modeling indicated that individual variability in testosterone levels was primarily explained by environmental factors. Regarding genetic variation, univariate tests did not reveal any variants significantly associated with salivary testosterone after adjusting for false discovery rate. The top hit in males was rs10923844, an SNP of unknown function located downstream of HSD3B1 and HSD3B2. The top hits in females were two SNPs located upstream of ESR1 (rs3407085 and rs2295190). RF analysis, which reflects joint and conditional effects of multiple variants, indicated that genes involved in regulation of reproductive function, particularly LHCGR, are related to salivary testosterone levels in male infants, as are genes involved in cholesterol production, transport, and removal, while genes involved in estrogen signaling are related to salivary testosterone levels in female infants.
In this paper, we develop a variable selection framework with the spike-and-slab prior distribution via the hazard function of the Cox model. Specifically, we consider the transformation of the score ...and information functions for the partial likelihood function evaluated at the given data from the parameter space into the space generated by the logarithm of the hazard ratio. Thereby, we reduce the nonlinear complexity of the estimation equation for the Cox model and allow the utilization of a wider variety of stable variable selection methods. Then, we use a stochastic variable search Gibbs sampling approach via the spike-and-slab prior distribution to obtain the sparsity structure of the covariates associated with the survival outcome. Additionally, we conduct numerical simulations to evaluate the finite-sample performance of our proposed method. Finally, we apply this novel framework on lung adenocarcinoma data to find important genes associated with decreased survival in subjects with the disease.
Studies in rodents provide compelling evidence that microorganisms inhabiting the gut influence neurodevelopment. In particular, experimental manipulations that alter intestinal microbiota impact ...exploratory and communicative behaviors and cognitive performance. In humans, the first years of life are a dynamic time in gut colonization and brain development, but little is known about the relationship between these two processes.
We tested whether microbial composition at 1 year of age is associated with cognitive outcomes using the Mullen Scales of Early Learning and with global and regional brain volumes using structural magnetic resonance imaging at 1 and 2 years of age. Fecal samples were collected from 89 typically developing 1-year-olds. 16S ribosomal RNA amplicon sequencing was used for identification and relative quantification of bacterial taxa.
Cluster analysis identified 3 groups of infants defined by their bacterial composition. Mullen scores at 2 years of age differed significantly between clusters. In addition, higher alpha diversity was associated with lower scores on the overall composite score, visual reception scale, and expressive language scale at 2 years of age. Exploratory analyses of neuroimaging data suggest the gut microbiome has minimal effects on regional brain volumes at 1 and 2 years of age.
This is the first study to demonstrate associations between the gut microbiota and cognition in human infants. As such, it represents an essential first step in translating animal data into the clinic.
Abstract
Introduction
Patients with muscular dystrophies (dystrophinopathy, congenital muscular dystrophy and limb-girdle muscular dystrophy) are at greater risk of obstructive sleep apnea (OSA). ...However, few studies have examined if they are also at risk for hypoventilation and its relationship with OSA. We hypothesize that these two conditions occur independently of each other as an impaired ventilator drive and diaphragm weakness.
Methods
Retrospective review of diagnostic polysomnograms (PSG) in a tertiary care facility over 15 years was conducted. The polysomnography included either end tidal CO2 or transcutaneous CO2 measurements. Descriptive data analysis was performed on results described. We computed Pearson correlation coefficients to examine the relationships between PSG indices and other parameters. Pearson’s Chi-squared test with Yates’ continuity correction is used to test if hypoventilation is independent from OSA.
Results
42 PSG studies in patients with muscular dystrophies were included after excluding 2 studies due to insufficient sleep duration. The average age at the time of study was 14.2 yrs with 41 being male and average BMI of 24.1. 64% of the group met the definition for OSA with average AHI 8.0. 36% of the group met the criteria for hypoventilation, and 33% patients with hypoventilation did not have OSA. Chi squared analysis (p=1.0) shows that hypoventilation is independent of OSA.
Conclusion
Sleep disordered breathing is common in patients with muscular dystrophy. This study supports that OSA and CO2 retention may be independent processes.
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