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https://www.readbyqxmd.com/read/28812537/leveraging-network-analytics-to-infer-patient-syndrome-and-identify-causal-genes-in-rare-disease-cases
#1
Andreas Krämer, Sohela Shah, Robert Anthony Rebres, Susan Tang, Daniel Rene Richards
BACKGROUND: Next-generation sequencing is widely used to identify disease-causing variants in patients with rare genetic disorders. Identifying those variants from whole-genome or exome data can be both scientifically challenging and time consuming. A significant amount of time is spent on variant annotation, and interpretation. Fully or partly automated solutions are therefore needed to streamline and scale this process. RESULTS: We describe Phenotype Driven Ranking (PDR), an algorithm integrated into Ingenuity Variant Analysis, that uses observed patient phenotypes to prioritize diseases and genes in order to expedite causal-variant discovery...
August 11, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28811102/high-resolution-separations-of-charge-variants-and-disulfide-isomers-of-monoclonal-antibodies-and-antibody-drug-conjugates-using-ultra-high-voltage-capillary-electrophoresis-with-high-electric-field-strength
#2
W Hampton Henley, Yan He, J Scott Mellors, Nicholas G Batz, J Michael Ramsey, James W Jorgenson
Ultra-high voltage capillary electrophoresis with high electric field strength has been applied to the separation of the charge variants, drug conjugates, and disulfide isomers of monoclonal antibodies. Samples composed of many closely related species are difficult to resolve and quantify using traditional analytical instrumentation. High performance instrumentation can often save considerable time and effort otherwise spent on extensive method development. Ideally, the resolution obtained for a given CE buffer system scales with the square root of the applied voltage...
July 29, 2017: Journal of Chromatography. A
https://www.readbyqxmd.com/read/28802831/validation-of-a-targeted-rna-sequencing-assay-for-kinase-fusion-detection-in-solid-tumors
#3
Julie W Reeser, Dorrelyn Martin, Jharna Miya, Esko A Kautto, Ezra Lyon, Eliot Zhu, Michele R Wing, Amy Smith, Matthew Reeder, Eric Samorodnitsky, Hannah Parks, Karan R Naik, Joseph Gozgit, Nicholas Nowacki, Kurtis D Davies, Marileila Varella-Garcia, Lianbo Yu, Aharon G Freud, Joshua Coleman, Dara L Aisner, Sameek Roychowdhury
Kinase gene fusions are important drivers of oncogenic transformation and can be inhibited with targeted therapies. Clinical grade diagnostics using RNA sequencing to detect gene rearrangements in solid tumors are limited, and the few that are available require prior knowledge of fusion break points. To address this, we have analytically validated a targeted RNA sequencing assay (OSU-SpARKFuse) for fusion detection that interrogates complete transcripts from 93 kinase and transcription factor genes. From a total of 74 positive and 36 negative control samples, OSU-SpARKFuse had 93...
August 8, 2017: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/28794230/analysis-of-factor-d-isoforms-in-malpuech-michels-mingarelli-carnevale-patients-highlights-the-role-of-masp-3-as-a-maturase-in-the-alternative-pathway-of-complement
#4
Rasmus Pihl, Lisbeth Jensen, Annette G Hansen, Ida B Thøgersen, Stephanie Andres, Frederik Dagnæs-Hansen, Konrad Oexle, Jan J Enghild, Steffen Thiel
Factor D (FD), which is also known as adipsin, is regarded as the first-acting protease of the alternative pathway (AP) of complement. It has been suggested that FD is secreted as a mature enzyme that does not require subsequent activation. This view was challenged when it was shown that mice lacking mannose-binding lectin (MBL)-associated serine protease-1 (MASP-1) and MASP-3 contain zymogenic FD (pro-FD), and it is becoming evident that MASP-3 is implicated in pro-FD maturation. However, the necessity of MASP-3 for pro-FD cleavage has been questioned, because AP activity is still observed in sera from MASP-1/3-deficient Malpuech-Michels-Mingarelli-Carnevale (3MC) patients...
August 9, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28792971/optimized-detection-of-insertions-deletions-indels-in-whole-exome-sequencing-data
#5
Bo-Young Kim, Jung Hoon Park, Hye-Yeong Jo, Soo Kyung Koo, Mi-Hyun Park
Insertion and deletion (INDEL) mutations, the most common type of structural variance, are associated with several human diseases. The detection of INDELs through next-generation sequencing (NGS) is becoming more common due to the decrease in costs, the increase in efficiency, and sensitivity improvements demonstrated by the various sequencing platforms and analytical tools. However, there are still many errors associated with INDEL variant calling, and distinguishing INDELs from errors in NGS remains challenging...
2017: PloS One
https://www.readbyqxmd.com/read/28791336/motility-of-active-nematic-films-driven-by-active-anchoring
#6
Matthew L Blow, Marco Aqil, Benno Liebchen, Davide Marenduzzo
We provide a minimal model for an active nematic film in contact with both a solid substrate and a passive isotropic fluid, and explore its dynamics in one and two dimensions using a combination of hybrid Lattice Boltzmann simulations and analytical calculations. By imposing nematic anchoring at the substrate while active flows induce a preferred alignment at the interface ("active anchoring"), we demonstrate that directed fluid flow spontaneously emerges in cases where the two anchoring types are opposing...
August 9, 2017: Soft Matter
https://www.readbyqxmd.com/read/28790422/spiral-form-of-the-human-cochlea-results-from-spatial-constraints
#7
M Pietsch, L Aguirre Dávila, P Erfurt, E Avci, T Lenarz, A Kral
The human inner ear has an intricate spiral shape often compared to shells of mollusks, particularly to the nautilus shell. It has inspired many functional hearing theories. The reasons for this complex geometry remain unresolved. We digitized 138 human cochleae at microscopic resolution and observed an astonishing interindividual variability in the shape. A 3D analytical cochlear model was developed that fits the analyzed data with high precision. The cochlear geometry neither matched a proposed function, namely sound focusing similar to a whispering gallery, nor did it have the form of a nautilus...
August 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28783153/pecan-library-free-peptide-detection-for-data-independent-acquisition-tandem-mass-spectrometry-data
#8
Ying S Ting, Jarrett D Egertson, James G Bollinger, Brian C Searle, Samuel H Payne, William Stafford Noble, Michael J MacCoss
Data-independent acquisition (DIA) is an emerging mass spectrometry (MS)-based technique for unbiased and reproducible measurement of protein mixtures. DIA tandem mass spectrometry spectra are often highly multiplexed, containing product ions from multiple cofragmenting precursors. Detecting peptides directly from DIA data is therefore challenging; most DIA data analyses require spectral libraries. Here we present PECAN (http://pecan.maccosslab.org), a library-free, peptide-centric tool that robustly and accurately detects peptides directly from DIA data...
August 7, 2017: Nature Methods
https://www.readbyqxmd.com/read/28780001/endocrinology-meets-metabolomics-achievements-pitfalls-and-challenges
#9
REVIEW
Janina Tokarz, Mark Haid, Alexander Cecil, Cornelia Prehn, Anna Artati, Gabriele Möller, Jerzy Adamski
The metabolome, although very dynamic, is sufficiently stable to provide specific quantitative traits related to health and disease. Metabolomics requires balanced use of state-of-the-art study design, chemical analytics, biostatistics, and bioinformatics to deliver meaningful answers to contemporary questions in human disease research. The technology is now frequently employed for biomarker discovery and for elucidating the mechanisms underlying endocrine-related diseases. Metabolomics has also enriched genome-wide association studies (GWAS) in this area by providing functional data...
August 2, 2017: Trends in Endocrinology and Metabolism: TEM
https://www.readbyqxmd.com/read/28776977/diffractive-protein-gratings-as-optically-active-transducers-for-high-throughput-label-free-immunosensing
#10
Miquel Avella-Oliver, Javier Carrascosa, Rosa Puchades, Angel Maquieira
: A novel label-free biosensing approach based on bioreceptor networks patterned as diffractive gratings (biogratings), has been developed. Nanogrooved structures were used as optically active scaffolds for producing arrays of functional BSA biogratings on low energy surfaces by a water-assisted variant of microcontact printing. An analytical scanner, comprising a LightScribe compact disk drive, was developed to measure the diffraction patterns of these biogratings, thus allowing bioin-teractions to be quantitatively sensed in a multiplex and label-free fashion by means of diffraction efficiency changes...
August 4, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28767674/versatile-ion-s5xl-sequencer-for-targeted-next-generation-sequencing-of-solid-tumors-in-a-clinical-laboratory
#11
Meenakshi Mehrotra, Dzifa Yawa Duose, Rajesh R Singh, Bedia A Barkoh, Jawad Manekia, Michael A Harmon, Keyur P Patel, Mark J Routbort, L Jeffrey Medeiros, Ignacio I Wistuba, Rajyalakshmi Luthra
BACKGROUND: Next generation sequencing based tumor tissue genotyping involves complex workflow and a relatively longer turnaround time. Semiconductor based next generation platforms varied from low throughput Ion PGM to high throughput Ion Proton and Ion S5XL sequencer. In this study, we compared Ion PGM and Ion Proton, with a new Ion S5XL NGS system for workflow scalability, analytical sensitivity and specificity, turnaround time and sequencing performance in a clinical laboratory. METHODS: Eighteen solid tumor samples positive for various mutations as detected previously by Ion PGM and Ion Proton were selected for study...
2017: PloS One
https://www.readbyqxmd.com/read/28763680/dysfunctional-metacognition-across-psychopathologies-a-meta-analytic-review
#12
X Sun, C Zhu, S H W So
BACKGROUND: Dysfunctions in metacognition have been reported in individuals with anxiety disorders. Although recent studies have examined metacognition in other disorders, how dysfunctional metacognition compares across disorders is not clear. This review aimed to ascertain the importance of dysfunctional metacognition in various psychopathologies, and to identify similarities and differences in metacognitive profiles across disorders. METHODS: Forty-seven studies were selected from 586 articles published between 1990 and August 2015, including a total sample of 3772 patients and 3376 healthy individuals...
June 7, 2017: European Psychiatry: the Journal of the Association of European Psychiatrists
https://www.readbyqxmd.com/read/28761347/genetic-and-epigenetic-mechanisms-of-epilepsy-a-review
#13
REVIEW
Tian Chen, Mohan Giri, Zhenyi Xia, Yadu Nanda Subedi, Yan Li
Epilepsy is a common episodic neurological disorder or condition characterized by recurrent epileptic seizures, and genetics seems to play a key role in its etiology. Early linkage studies have localized multiple loci that may harbor susceptibility genes to epilepsy, and mutational analyses have detected a number of mutations involved in both ion channel and nonion channel genes in patients with idiopathic epilepsy. Genome-wide studies of epilepsy have found copy number variants at 2q24.2-q24.3, 7q11.22, 15q11...
2017: Neuropsychiatric Disease and Treatment
https://www.readbyqxmd.com/read/28759653/high-resolution-physicochemical-characterization-of-different-intravenous-immunoglobulin-products
#14
Nathaniel Washburn, Robin Meccariello, Shaohui Hu, Maurice Hains, Naveen Bhatnagar, Hetal Sarvaiya, Bulbul Kapoor, John Schaeck, Ignacio Pino, Anthony Manning, Jonathan C Lansing, Carlos J Bosques
Intravenous immunoglobulin (IVIg) is a complex mixture drug comprising diverse immunoglobulins and non-IgG proteins purified from the plasma of thousands of healthy donors. Approved IVIg products on the market differ regarding source of plasma, isolation process, and formulation. These products are used widely, and often interchangeably, for the treatment of immunodeficiency and autoimmune and inflammatory diseases, but their mechanisms of action in different indications are not well understood. A primary limitation to understanding the therapeutic relevance of specific components within IVIg has been the limited resolution of analytics historically implemented to characterize its complex mixture...
2017: PloS One
https://www.readbyqxmd.com/read/28753643/pharmacogenetic-meta-analysis-of-baseline-risk-factors-pharmacodynamic-efficacy-and-tolerability-endpoints-from-two-large-global-cardiovascular-outcomes-trials-for-darapladib
#15
Astrid Yeo, Li Li, Liling Warren, Jennifer Aponte, Dana Fraser, Karen King, Kelley Johansson, Allison Barnes, Colin MacPhee, Richard Davies, Stephanie Chissoe, Elizabeth Tarka, Michelle L O'Donoghue, Harvey D White, Lars Wallentin, Dawn Waterworth
Darapladib, a lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor, failed to demonstrate efficacy for the primary endpoints in two large phase III cardiovascular outcomes trials, one in stable coronary heart disease patients (STABILITY) and one in acute coronary syndrome (SOLID-TIMI 52). No major safety signals were observed but tolerability issues of diarrhea and odor were common (up to 13%). We hypothesized that genetic variants associated with Lp-PLA2 activity may influence efficacy and tolerability and therefore performed a comprehensive pharmacogenetic analysis of both trials...
2017: PloS One
https://www.readbyqxmd.com/read/28751446/gene-copy-number-estimation-from-targeted-next-generation-sequencing-of-prostate-cancer-biopsies-analytic-validation-and-clinical-qualification
#16
George Seed, Wei Yuan, Joaquin Mateo, Suzanne Carreira, Claudia Bertan, Maryou Lambros, Gunther Boysen, Roberta Ferraldeschi, Susana Miranda, Ines Figueiredo, Ruth Riisnaes, Mateus Crespo, Daniel Nava Rodrigues, Eric Talevich, Dan R Robinson, Lakshmi P Kunju, Yi-Mi Wu, Robert Lonigro, Shahneen Sandhu, Arul Chinnayan, Johann S de Bono
Abstract <p>Purpose</p> <p>Precise detection of copy number aberrations (CNAs) from tumor biopsies is critically important to the treatment of metastatic prostate cancer. The use of targeted panel next generation sequencing (NGS) is inexpensive, high throughput and easily feasible, allowing single nucleotide variant calls, but CNA estimation from this remains challenging..</p> <p>Experimental Design</p> <p>We evaluated CNVkit for CNA identification from amplicon-based targeted NGS in a cohort of 110 fresh castration resistant prostate cancer biopsies, and used capture based whole exome sequencing (WES), array comparative genomic hybridization (aCGH), and fluorescent in situ hybridization (FISH) to explore the viability of this approach...
July 27, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28745059/near-infrared-neodymium-tag-for-quantifying-targeted-biomarker-and-counting-its-host-circulating-tumor-cells
#17
Chunlan Liu, Shu Lu, Limin Yang, Peijie Chen, Peiming Bai, Qiuquan Wang
Quantitative information on a targeted analyte in a complex biological system is the most basic premise for understanding its involved mechanisms, and thus precise diagnosis of a disease if it is a so-called biomarker. Here, we designed and synthesized a neodymium (Nd)-cored tag [1,4,7,10-tetraazacyclododecane-1,4,7-trisacetic acid (DOTA)-Nd complex together with a light-harvesting antenna aminofluorescein (AMF, λex/em = 494/520 nm), AMF-DOTA-Nd] with duplex signals, second near-infrared (NIR) window luminescence (λem = 1065 nm, 2...
August 9, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28742963/the-spin-flip-variant-of-the-algebraic-diagrammatic-construction-yields-the-correct-topology-of-s1-s0-conical-intersections
#18
Daniel Lefrancois, Deniz Tuna, Todd J Martínez, Andreas Dreuw
While the conventional variants of the algebraic-diagrammatic construction (ADC) scheme for the polarization propagator are generally incapable of correctly describing the topology of S1/S0 conical intersections (CIs), its corresponding spin-flip (SF) variant of third-order ADC (ADC(3)) is herein demonstrated to successfully reproduce the S1/S0 minimum-energy CI (MECI) of twisted formaldinium (H2CNH2(+)). Analytical nuclear excited-state gradients of ADC have been used in combination with the CIOpt program for the optimization of the MECI without the need for nonadiabatic-coupling vectors...
July 25, 2017: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/28742912/association-of-genetic-variants-related-to-serum-calcium-levels-with-coronary-artery-disease-and-myocardial-infarction
#19
Susanna C Larsson, Stephen Burgess, Karl Michaëlsson
Importance: Serum calcium has been associated with cardiovascular disease in observational studies and evidence from randomized clinical trials indicates that calcium supplementation, which raises serum calcium levels, may increase the risk of cardiovascular events, particularly myocardial infarction. Objective: To evaluate the potential causal association between genetic variants related to elevated serum calcium levels and risk of coronary artery disease (CAD) and myocardial infarction using mendelian randomization...
July 25, 2017: JAMA: the Journal of the American Medical Association
https://www.readbyqxmd.com/read/28740869/comparing-sequencing-assays-and-human-machine-analyses-in-actionable-genomics-for-glioblastoma
#20
Kazimierz O Wrzeszczynski, Mayu O Frank, Takahiko Koyama, Kahn Rhrissorrakrai, Nicolas Robine, Filippo Utro, Anne-Katrin Emde, Bo-Juen Chen, Kanika Arora, Minita Shah, Vladimir Vacic, Raquel Norel, Erhan Bilal, Ewa A Bergmann, Julia L Moore Vogel, Jeffrey N Bruce, Andrew B Lassman, Peter Canoll, Christian Grommes, Steve Harvey, Laxmi Parida, Vanessa V Michelini, Michael C Zody, Vaidehi Jobanputra, Ajay K Royyuru, Robert B Darnell
OBJECTIVE: To analyze a glioblastoma tumor specimen with 3 different platforms and compare potentially actionable calls from each. METHODS: Tumor DNA was analyzed by a commercial targeted panel. In addition, tumor-normal DNA was analyzed by whole-genome sequencing (WGS) and tumor RNA was analyzed by RNA sequencing (RNA-seq). The WGS and RNA-seq data were analyzed by a team of bioinformaticians and cancer oncologists, and separately by IBM Watson Genomic Analytics (WGA), an automated system for prioritizing somatic variants and identifying drugs...
August 2017: Neurology. Genetics
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