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1.  The Autism Simplex Collection: an international, expertly phenotyped autism sample for genetic and phenotypic analyses 
Molecular Autism  2014;5:34.
There is an urgent need for expanding and enhancing autism spectrum disorder (ASD) samples, in order to better understand causes of ASD.
In a unique public-private partnership, 13 sites with extensive experience in both the assessment and diagnosis of ASD embarked on an ambitious, 2-year program to collect samples for genetic and phenotypic research and begin analyses on these samples. The program was called The Autism Simplex Collection (TASC). TASC sample collection began in 2008 and was completed in 2010, and included nine sites from North America and four sites from Western Europe, as well as a centralized Data Coordinating Center.
Over 1,700 trios are part of this collection, with DNA from transformed cells now available through the National Institute of Mental Health (NIMH). Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule-Generic (ADOS-G) measures are available for all probands, as are standardized IQ measures, Vineland Adaptive Behavioral Scales (VABS), the Social Responsiveness Scale (SRS), Peabody Picture Vocabulary Test (PPVT), and physical measures (height, weight, and head circumference). At almost every site, additional phenotypic measures were collected, including the Broad Autism Phenotype Questionnaire (BAPQ) and Repetitive Behavior Scale-Revised (RBS-R), as well as the non-word repetition scale, Communication Checklist (Children’s or Adult), and Aberrant Behavior Checklist (ABC). Moreover, for nearly 1,000 trios, the Autism Genome Project Consortium (AGP) has carried out Illumina 1 M SNP genotyping and called copy number variation (CNV) in the samples, with data being made available through the National Institutes of Health (NIH). Whole exome sequencing (WES) has been carried out in over 500 probands, together with ancestry matched controls, and this data is also available through the NIH. Additional WES is being carried out by the Autism Sequencing Consortium (ASC), where the focus is on sequencing complete trios. ASC sequencing for the first 1,000 samples (all from whole-blood DNA) is complete and data will be released in 2014. Data is being made available through NIH databases (database of Genotypes and Phenotypes (dbGaP) and National Database for Autism Research (NDAR)) with DNA released in Dist 11.0. Primary funding for the collection, genotyping, sequencing and distribution of TASC samples was provided by Autism Speaks and the NIH, including the National Institute of Mental Health (NIMH) and the National Human Genetics Research Institute (NHGRI).
TASC represents an important sample set that leverages expert sites. Similar approaches, leveraging expert sites and ongoing studies, represent an important path towards further enhancing available ASD samples.
PMCID: PMC4228819  PMID: 25392729
2.  Influence of Low Tidal Volume Ventilation on Time to Extubation in Cardiac Surgical Patients 
Anesthesiology  2011;114(5):1102-1110.
Low tidal volumes have been associated with improved outcomes in patients with established acute lung injury. The role of low tidal volume ventilation in patients without lung injury is still unresolved. We hypothesized that such a strategy in patients undergoing elective surgery would reduce ventilator-associated lung injury and that this improvement would lead to a shortened time to extubation
A single-center randomized controlled trial was undertaken in 149 patients undergoing elective cardiac surgery. Ventilation with 6 versus 10 ml/kg tidal volume was compared. Ventilator settings were applied immediately after anesthesia induction and continued throughout surgery and the subsequent intensive care unit stay. The primary endpoint of the study was time to extubation. Secondary endpoints included the proportion of patients extubated at 6 h and indices of lung mechanics and gas exchange as well as patient clinical outcomes.
Median ventilation time was not significantly different in the low tidal volume group; a median (interquartile range) of 450 (264–1,044) min was achieved compared with 643 (417–1,032) min in the control group (P = 0.10). However, a higher proportion of patients in the low tidal volume group was free of any ventilation at 6 h: 37.3% compared with 20.3% in the control group (P = 0.02). In addition, fewer patients in the low tidal volume group required rein-tubation (1.3 vs. 9.5%; P = 0.03).
Although reduction of tidal volume in mechanically ventilated patients undergoing elective cardiac surgery did not significantly shorten time to extubation, several improvements were observed in secondary outcomes. When these data are combined with a lack of observed complications, a strategy of reduced tidal volume could still be beneficial in this patient population.
PMCID: PMC3500383  PMID: 21430518
3.  High-resolution analysis of DNA copy number alterations in patients with primary open-angle glaucoma 
Molecular Vision  2009;15:1594-1598.
To determine whether patients with isolated primary open-angle glaucoma (POAG) have evidence of chromosomal copy number alterations.
Twenty-seven Caucasian and African-American POAG patients and 12 ethnically matched controls were carefully screened for possible glaucoma and tested for chromosomal copy number alterations using high resolution array comparative genomic hybridization.
No POAG patient had evidence of chromosomal copy number alterations when compared to normal ethnically matched controls. Additionally, there was no evidence of somatic mosaicism in any tested POAG patient.
Chromosomal deletions and/or duplications were not detected in POAG patients as compared to controls. Other chromosomal imbalances such as translocations, inversions, and some ploidies cannot be detected by current array comparative genomic hybridization technology, and other nuclear genetic, mitochondrial abnormalities, or epigenetic factors cannot be excluded as a possible contributing factor to POAG pathogenesis.
PMCID: PMC2728570  PMID: 19693294
4.  Cell autonomous expression of inflammatory genes in biologically aged fibroblasts associated with elevated NF-kappaB activity 
Chronic inflammation is a well-known corollary of the aging process and is believed to significantly contribute to morbidity and mortality of many age-associated chronic diseases. However, the mechanisms that cause age-associated inflammatory changes are not well understood. Particularly, the contribution of cell stress responses to age-associated inflammation in 'non-inflammatory' cells remains poorly defined. The present cross-sectional study focused on differences in molecular signatures indicative of inflammatory states associated with biological aging of human fibroblasts from donors aged 22 to 92 years.
Gene expression profiling revealed elevated steady-state transcript levels consistent with a chronic inflammatory state in fibroblast cell-strains obtained from older donors. We also observed enhanced NF-κB DNA binding activity in a subset of strains, and the NF-κB profile correlated with mRNA expression levels characteristic of inflammatory processes, which include transcripts coding for cytokines, chemokines, components of the complement cascade and MHC molecules. This intrinsic low-grade inflammatory state, as it relates to aging, occurs in cultured cells irrespective of the presence of other cell types or the in vivo context.
Our results are consistent with the view that constitutive activation of inflammatory pathways is a phenomenon prevalent in aged fibroblasts. It is possibly part of a cellular survival process in response to compromised mitochondrial function. Importantly, the inflammatory gene expression signature described here is cell autonomous, i.e. occurs in the absence of prototypical immune or pro-inflammatory cells, growth factors, or other inflammatory mediators.
PMCID: PMC2483950  PMID: 18631391
5.  cis sequence effects on gene expression 
BMC Genomics  2007;8:296.
Sequence and transcriptional variability within and between individuals are typically studied independently. The joint analysis of sequence and gene expression variation (genetical genomics) provides insight into the role of linked sequence variation in the regulation of gene expression. We investigated the role of sequence variation in cis on gene expression (cis sequence effects) in a group of genes commonly studied in cancer research in lymphoblastoid cell lines. We estimated the proportion of genes exhibiting cis sequence effects and the proportion of gene expression variation explained by cis sequence effects using three different analytical approaches, and compared our results to the literature.
We generated gene expression profiling data at N = 697 candidate genes from N = 30 lymphoblastoid cell lines for this study and used available candidate gene resequencing data at N = 552 candidate genes to identify N = 30 candidate genes with sufficient variance in both datasets for the investigation of cis sequence effects. We used two additive models and the haplotype phylogeny scanning approach of Templeton (Tree Scanning) to evaluate association between individual SNPs, all SNPs at a gene, and diplotypes, with log-transformed gene expression. SNPs and diplotypes at eight candidate genes exhibited statistically significant (p < 0.05) association with gene expression. Using the literature as a "gold standard" to compare 14 genes with data from both this study and the literature, we observed 80% and 85% concordance for genes exhibiting and not exhibiting significant cis sequence effects in our study, respectively.
Based on analysis of our results and the extant literature, one in four genes exhibits significant cis sequence effects, and for these genes, about 30% of gene expression variation is accounted for by cis sequence variation. Despite diverse experimental approaches, the presence or absence of significant cis sequence effects is largely supported by previously published studies.
PMCID: PMC2077339  PMID: 17727713

Results 1-5 (5)