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Beam A.L.,Center for Biomedical Informatics | Motsinger-Reif A.A.,North Carolina State University | Doyle J.,North Carolina State University
BioData Mining | Year: 2015

Background: Best practice for statistical methodology in cell-based dose-response studies has yet to be established. We examine the ability of MANOVA to detect trait-associated genetic loci in the presence of gene-gene interactions. We present a novel Bayesian nonparametric method designed to detect such interactions. Results: MANOVA and the Bayesian nonparametric approach show good ability to detect trait-associated genetic variants under various possible genetic models. It is shown through several sets of analyses that this may be due to marginal effects being present, even if the underlying genetic model does not explicitly contain them. Conclusions: Understanding how genetic interactions affect drug response continues to be a critical goal. MANOVA and the novel Bayesian framework present a trade-off between computational complexity and model flexibility. © 2015 Beam et al.; licensee BioMed Central.

Izumi K.,Childrens Hospital of Philadelphia | Izumi K.,University of Tokyo | Zhang Z.,Center for Biomedical Informatics | Kaur M.,Childrens Hospital of Philadelphia | And 2 more authors.
Chromosome Research | Year: 2014

Pallister-Killian syndrome is a multisystem sporadic genetic diagnosis characterized by facial dysmorphia, variable developmental delay and intellectual impairment, hypotonia, seizures, diaphragmatic hernia, and other systemic abnormalities. Pallister-Killian syndrome is typically caused by the presence of a supernumerary isochromosome that is always present in a tissue limited mosaic pattern, resulting in tetrasomy 12p due to the two extra copies of 12p. We evaluated the potential contribution of microRNAs located on 12p to the pathogenesis of Pallister-Killian syndrome phenotype. Using skin fibroblast cell lines from 13 probands with Pallister-Killian syndrome and 5 normal matched controls, the expression level of 5 microRNAs located on 12p and their target gene mRNA levels were measured. All measured micro RNAs located on 12p were overexpressed in Pallister-Killian syndrome fibroblasts, although the fold difference of the expression level was lower than copy number differences. Among the five microRNAs, miR-1244 had the highest fold difference. Many of computer-predicted target genes of miR-1244 were downregulated in Pallister-Killian syndrome skin fibroblasts. In particular, expression levels of MEIS2 and UQCRB were significantly decreased in Pallister-Killian syndrome samples, and an inverse linear correlation was seen between the level of miR-1244 and MEIS2 and UQCRB expression levels. Since many of computer-predicted miR-1244 target genes play roles in transcriptional regulation, overexpression of miR-1244 due to tetrasomy 12p may contribute to the pleiotropic phenotype of Pallister-Killian syndrome by modulating its downstream target genes including MEIS2 and UQCRB. © 2014, Springer Science+Business Media Dordrecht.

Glessner J.T.,Applied Genomics | Glessner J.T.,University of Pennsylvania | Bick A.G.,Harvard University | Ito K.,Harvard University | And 26 more authors.
Circulation Research | Year: 2014

Rationale: Congenital heart disease (CHD) is among the most common birth defects. Most cases are of unknown pathogenesis. Objective: To determine the contribution of de novo copy number variants (CNVs) in the pathogenesis of sporadic CHD. Methods and Results: We studied 538 CHD trios using genome-wide dense single nucleotide polymorphism arrays and whole exome sequencing. Results were experimentally validated using digital droplet polymerase chain reaction. We compared validated CNVs in CHD cases with CNVs in 1301 healthy control trios. The 2 complementary high-resolution technologies identified 63 validated de novo CNVs in 51 CHD cases. A significant increase in CNV burden was observed when comparing CHD trios with healthy trios, using either single nucleotide polymorphism array (P=7×10-5; odds ratio, 4.6) or whole exome sequencing data (P=6×10-4; odds ratio, 3.5) and remained after removing 16% of de novo CNV loci previously reported as pathogenic (P=0.02; odds ratio, 2.7). We observed recurrent de novo CNVs on 15q11.2 encompassing CYFIP1, NIPA1, and NIPA2 and single de novo CNVs encompassing DUSP1, JUN, JUP, MED15, MED9, PTPRE SREBF1, TOP2A, and ZEB2, genes that interact with established CHD proteins NKX2-5 and GATA4. Integrating de novo variants in whole exome sequencing and CNV data suggests that ETS1 is the pathogenic gene altered by 11q24.2-q25 deletions in Jacobsen syndrome and that CTBP2 is the pathogenic gene in 10q subtelomeric deletions. Conclusions: We demonstrate a significantly increased frequency of rare de novo CNVs in CHD patients compared with healthy controls and suggest several novel genetic loci for CHD. © 2014 American Heart Association, Inc.

Ogunyemi O.,Center for Biomedical Informatics | George S.,Center for Biomedical Informatics | Teklehaimanot S.,Drew University | Baker R.,Center for Biomedical Informatics
AMIA ... Annual Symposium proceedings / AMIA Symposium. AMIA Symposium | Year: 2013

In a previous paper, we presented initial findings from a study on the feasibility and challenges of implementing teleretinal screening for diabetic retinopathy in an urban safety net setting facing eyecare specialist shortages. This paper presents some final results from that study, which involved six South Los Angeles safety net clinics. A total of 2,732 unique patients were screened for diabetic retinopathy by three ophthalmologist readers, with 1035 receiving a recommendation for referral to specialty care. Referrals included 48 for proliferative diabetic retinopathy, 115 for severe non-proliferative diabetic retinopathy (NPDR), 247 for moderate NPDR, 246 for mild NPDR, 97 for clinically significant macular edema, and 282 for a non-diabetic condition, such as glaucoma. Image quality was also assessed, with ophthalmologist readers grading 4% to 13% of retinal images taken at the different clinics as being inadequate for any diagnostic interpretation.

Biagioli M.,Massachusetts General Hospital | Biagioli M.,Harvard University | Ferrari F.,Center for Biomedical Informatics | Mendenhall E.M.,University of Alabama in Huntsville | And 22 more authors.
Human Molecular Genetics | Year: 2015

The CAG repeat expansion in the Huntington's disease gene HTT extends a polyglutamine tract in mutant huntingtin that enhances its ability to facilitate polycomb repressive complex 2 (PRC2). To gain insight into this dominant gain of function, we mapped histone modifications genome-wide across an isogenic panel of mouse embryonic stem cell (ESC) and neuronal progenitor cell (NPC) lines, comparing the effects of Htt null and different size Htt CAG mutations.We found that Htt is required in ESC for the proper deposition of histone H3K27me3 at a subset of 'bivalent' loci but in NPC it is needed at 'bivalent' loci for both the proper maintenance and the appropriate removal of this mark. In contrast, Htt CAG size, though changing histone H3K27me3, is prominently associated with altered histone H3K4me3 at 'active' loci. The sets of ESC and NPC genes with altered histone marks delineated by the lack of huntingtin or the presence of mutant huntingtin, though distinct, are enriched in similar pathways with apoptosis specifically highlighted for the CAG mutation. Thus, the manner by which huntingtin function facilitates PRC2 may afford mutant huntingtin with multiple opportunities to impinge upon the broader machinery that orchestrates developmentally appropriate chromatin status. © The Author 2015.

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