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variant analytics

Jackie M Poos, Lize C Jiskoot, Janne M Papma, John C van Swieten, Esther van den Berg
OBJECTIVES: A meta-analysis of the extent, nature and pattern of memory performance in behavioral variant frontotemporal dementia (bvFTD). Multiple observational studies have challenged the relative sparing of memory in bvFTD as stated in the current diagnostic criteria. METHODS: We performed a meta-analytic review covering the period 1967 to February 2017 of case-control studies on episodic memory in bvFTD versus control participants (16 studies, 383 patients, 603 control participants), and patients with bvFTD versus those with Alzheimer's disease (AD) (20 studies, 452 bvFTD, 874 AD)...
March 19, 2018: Journal of the International Neuropsychological Society: JINS
Patricia L Hall, Christina Lam, John J Alexander, Ghazia Asif, Gerard T Berry, Carlos Ferreira, Hudson H Freeze, William A Gahl, Kim K Nickander, Jon D Sharer, Caroline M Watson, Lynne Wolfe, Kimiyo M Raymond
N-glycanase deficiency (NGLY1 deficiency, NGLY1-CDDG), the first autosomal recessive congenital disorder of N-linked deglycosylation (CDDG), is caused by pathogenic variants in NGLY1. The majority of affected individuals have been identified using exome or genome sequencing. To date, no reliable, clinically available biomarkers have been identified. Urine oligosaccharide analysis was included as part of a routine evaluation for possible biomarkers in patients with confirmed NGLY1-CDDG. During the qualitative review of oligosaccharide profiles by an experienced laboratory director an abnormal analyte with a proposed structure of Neu5Ac1Hex1GlcNAc1-Asn was identified in NGLY1-CDDG patient urine samples...
March 10, 2018: Molecular Genetics and Metabolism
Ana L Schaigorodsky, Juan I Perotti, Nahuel Almeira, Orlando V Billoni
In this work we introduce a variant of the Yule-Simon model for preferential growth by incorporating a finite kernel to model the effects of bounded memory. We characterize the properties of the model combining analytical arguments with extensive numerical simulations. In particular, we analyze the lifetime and popularity distributions by mapping the model dynamics to corresponding Markov chains and branching processes, respectively. These distributions follow power laws with well-defined exponents that are within the range of the empirical data reported in ecologies...
February 2018: Physical Review. E
Davina Gale, Andrew R J Lawson, Karen Howarth, Mikidache Madi, Bradley Durham, Sarah Smalley, John Calaway, Shannon Blais, Greg Jones, James Clark, Peter Dimitrov, Michelle Pugh, Samuel Woodhouse, Michael Epstein, Ana Fernandez-Gonzalez, Alexandra S Whale, Jim F Huggett, Carole A Foy, Gerwyn M Jones, Hadas Raveh-Amit, Karin Schmitt, Alison Devonshire, Emma Green, Tim Forshew, Vincent Plagnol, Nitzan Rosenfeld
INTRODUCTION: Detection and monitoring of circulating tumor DNA (ctDNA) is rapidly becoming a diagnostic, prognostic and predictive tool in cancer patient care. A growing number of gene targets have been identified as diagnostic or actionable, requiring the development of reliable technology that provides analysis of multiple genes in parallel. We have developed the InVision™ liquid biopsy platform which utilizes enhanced TAm-Seq™ (eTAm-Seq™) technology, an amplicon-based next generation sequencing method for the identification of clinically-relevant somatic alterations at low frequency in ctDNA across a panel of 35 cancer-related genes...
2018: PloS One
Vincent Plagnol, Samuel Woodhouse, Karen Howarth, Stefanie Lensing, Matt Smith, Michael Epstein, Mikidache Madi, Sarah Smalley, Catherine Leroy, Jonathan Hinton, Frank de Kievit, Esther Musgrave-Brown, Colin Herd, Katherine Baker-Neblett, Will Brennan, Peter Dimitrov, Nathan Campbell, Clive Morris, Nitzan Rosenfeld, James Clark, Davina Gale, Jamie Platt, John Calaway, Greg Jones, Tim Forshew
Circulating tumor DNA (ctDNA) analysis is being incorporated into cancer care; notably in profiling patients to guide treatment decisions. Responses to targeted therapies have been observed in patients with actionable mutations detected in plasma DNA at variant allele fractions (VAFs) below 0.5%. Highly sensitive methods are therefore required for optimal clinical use. To enable objective assessment of assay performance, detailed analytical validation is required. We developed the InVisionFirst™ assay, an assay based on enhanced tagged amplicon sequencing (eTAm-Seq™) technology to profile 36 genes commonly mutated in non-small cell lung cancer (NSCLC) and other cancer types for actionable genomic alterations in cell-free DNA...
2018: PloS One
Germano Orrù, Mauro Giovanni Carta
Background: Bipolar Disorder (BD), along with depression and schizophrenia, is one of the most serious mental illnesses, and one of the top 20 causes of severe impairment in everyday life. Recent molecular studies, using both traditional approaches and new procedures such as Whole-Genome Sequencing (WGS), have suggested that genetic factors could significantly contribute to the development of BD, with heritability estimates of up to 85%. However, it is assumed that BD is a multigenic and multifactorial illness with environmental factors that strongly contribute to disease development/progression, which means that progress in genetic knowledge of BD might be difficult to interpret in clinical practice...
2018: Clinical Practice and Epidemiology in Mental Health: CP & EMH
Katsuyuki Taguchi, Karl Stierstorfer, Christoph Polster, Okkyun Lee, Steffen Kappler
PURPOSE: The inter-pixel cross-talk of energy-sensitive photon counting x-ray detectors (PCDs) has been studied and an analytical model (version 2.1) has been developed for double-counting between neighboring pixels due to charge sharing and K-shell fluorescence x-ray emission followed by its re-absorption [Taguchi K, et al., Medical Physics 2016;43(12):6386-6404]. While the model version 2.1 simulated the spectral degradation well, it had the following problems that has been found to be significant recently: (1) The spectrum is inaccurate with smaller pixel sizes; (2) the charge cloud size must be smaller than the pixel size; (3) the model underestimates the spectrum/counts for 10-40 keV; and (4) the model version 2...
March 14, 2018: Medical Physics
Lorenzo Manganaro, Germano Russo, Faiza Bourhaleb, Federico Fausti, Simona Giordanengo, Vincenzo Monaco, Roberto Sacchi, Anna Vignati, Roberto Cirio, Andrea Attili
One major rationale for the application of heavy ion beams in tumour therapy is their increased relative biological effectiveness (RBE). The complex dependencies of the RBE on dose, biological endpoint, position in the field etc. require the use of biophysical models in treatment planning and clinical analysis. This study aims at introducing a new software, named "Survival", to facilitate the radiobiological computations needed in ion therapy. The simulation toolkit was written in C++ and it was developed with a modular architecture in order to easily incorporate different radiobiological models...
March 14, 2018: Physics in Medicine and Biology
Stanley Chung, Jun Tian, Zhijun Tan, Jie Chen, Jongchan Lee, Michael Borys, Zheng Jian Li
Controlling the charge profile of therapeutic protein is a critical challenge in the current quality-by-design (QbD) paradigm, throughout all phases of biologics process development (PD): cell line development, upstream cell culture, recovery process, downstream purification, and analytical characterization. Charge variant profiles may influence efficacy and/or lead to unintended side-effects. Thus, maintaining a consistent charge profile is of tremendous importance, and increasingly, researchers have focused efforts towards developing strategies to mitigate variability during cell culture and to improve separation and detection of charge variants...
March 13, 2018: Biotechnology and Bioengineering
Fuqiang Ma, Meng Ting Chung, Yuan Yao, Robert Nidetz, Lap Man Lee, Allen P Liu, Yan Feng, Katsuo Kurabayashi, Guang-Yu Yang
Directed evolution has long been a key strategy to generate enzymes with desired properties like high selectivity, but experimental barriers and analytical costs of screening enormous mutant libraries have limited such efforts. Here, we describe an ultrahigh-throughput dual-channel microfluidic droplet screening system that can be used to screen up to ~107 enzyme variants per day. As an example case, we use the system to engineer the enantioselectivity of an esterase to preferentially produce desired enantiomers of profens, an important class of anti-inflammatory drugs...
March 12, 2018: Nature Communications
Changshin Kim, Jinmo Yang, Su-Hyun Jeong, Hayoung Kim, Geun-Hee Park, Hwa Beom Shin, MyungJa Ro, Kyoung-Yeon Kim, YoungJoon Park, Keun Pil Kim, KyuBum Kwack
DNA repair mechanisms maintain genomic integrity upon exposure to various types of DNA damage, which cause either single- or double-strand breaks in the DNA. Here, we propose a strategy for the functional study of single nucleotide polymorphisms (SNPs) in the human DNA repair genes XPD/ERCC2, RAD18, and KU70/XRCC6 and the checkpoint activation gene ATR that are essentially involved in the cell cycle and DNA damage repair. We analyzed the mutational effects of the DNA repair genes under DNA-damaging conditions, including ultraviolet irradiation and treatment with genotoxic reagents, using a Saccharomyces cerevisiae system to overcome the limitations of the human cell-based assay...
2018: PloS One
Johanna C Herkert, Kristin M Abbott, Erwin Birnie, Martine T Meems-Veldhuis, Ludolf G Boven, Marloes Benjamins, Gideon J du Marchie Sarvaas, Daniela Q C M Barge-Schaapveld, J Peter van Tintelen, Paul A van der Zwaag, Yvonne J Vos, Richard J Sinke, Maarten P van den Berg, Irene M van Langen, Jan D H Jongbloed
PurposeWe evaluated the diagnostic yield in pediatric dilated cardiomyopathy (DCM) of combining exome sequencing (ES)-based targeted analysis and genome-wide copy-number variation (CNV) analysis. Based on our findings, we retrospectively designed an effective approach for genetic testing in pediatric DCM.MethodsWe identified 95 patients (in 85 families) with pediatric onset of DCM. We initially excluded 13 of these families because they already had a genetic diagnosis, leaving a total of 31 probands for single-nucleotide polymorphism (SNP) array and trio-ES...
March 8, 2018: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Mi-Jung Kim, Ji-Yeong Byeon, Young-Hoon Kim, Se-Hyung Kim, Choong-Min Lee, Eui Hyun Jung, Won Ki Chae, Yun Jeong Lee, Choon-Gon Jang, Seok-Yong Lee, Chang-Ik Choi
Clomiphene citrate, a selective estrogen receptor modulator, is metabolized into its 4-hydroxylated active metabolites, primarily by CYP2D6. In this study, we investigated the effects of the most common CYP2D6 variant allele in Asians, CYP2D6*10, on the pharmacokinetics of clomiphene and its two active metabolites (4-OH-CLO and 4-OH-DE-CLO) in healthy Korean subjects. A single 50-mg oral dose of clomiphene citrate was given to 22 Korean subjects divided into three genotype groups according to CYP2D6 genotypes, CYP2D6*wt/*wt (n = 8; *wt = *1 or *2), CYP2D6*wt/*10 (n = 8) and CYP2D6*10/*10 (n = 6)...
March 7, 2018: Archives of Pharmacal Research
Lu Wang, I King Jordan
A convergence of novel genome analysis technologies is enabling population genomic studies of human transposable elements (TEs). Population surveys of human genome sequences have uncovered thousands of individual TE insertions that segregate as common genetic variants, i.e. TE polymorphisms. These recent TE insertions provide an important source of naturally occurring human genetic variation. Investigators are beginning to leverage population genomic data sets to execute genome-scale association studies for assessing the phenotypic impact of human TE polymorphisms...
March 2, 2018: Current Opinion in Genetics & Development
Allison F Carey, Jeremy M Rock, Inna V Krieger, Michael R Chase, Marta Fernandez-Suarez, Sebastien Gagneux, James C Sacchettini, Thomas R Ioerger, Sarah M Fortune
Once considered a phenotypically monomorphic bacterium, there is a growing body of work demonstrating heterogeneity among Mycobacterium tuberculosis (Mtb) strains in clinically relevant characteristics, including virulence and response to antibiotics. However, the genetic and molecular basis for most phenotypic differences among Mtb strains remains unknown. To investigate the basis of strain variation in Mtb, we performed genome-wide transposon mutagenesis coupled with next-generation sequencing (TnSeq) for a panel of Mtb clinical isolates and the reference strain H37Rv to compare genetic requirements for in vitro growth across these strains...
March 2018: PLoS Pathogens
Jason D Merker, Geoffrey R Oxnard, Carolyn Compton, Maximilian Diehn, Patricia Hurley, Alexander J Lazar, Neal Lindeman, Christina M Lockwood, Alex J Rai, Richard L Schilsky, Apostolia M Tsimberidou, Patricia Vasalos, Brooke L Billman, Thomas K Oliver, Suanna S Bruinooge, Daniel F Hayes, Nicholas C Turner
Purpose Clinical use of analytical tests to assess genomic variants in circulating tumor DNA (ctDNA) is increasing. This joint review from ASCO and the College of American Pathologists summarizes current information about clinical ctDNA assays and provides a framework for future research. Methods An Expert Panel conducted a literature review on the use of ctDNA assays for solid tumors, including pre-analytical variables, analytical validity, interpretation and reporting, and clinical validity and utility. Results The literature search identified 1,338 references...
March 5, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Jason D Merker, Geoffrey R Oxnard, Carolyn Compton, Maximilian Diehn, Patricia Hurley, Alexander J Lazar, Neal Lindeman, Christina M Lockwood, Alex J Rai, Richard L Schilsky, Apostolia M Tsimberidou, Patricia Vasalos, Brooke L Billman, Thomas K Oliver, Suanna S Bruinooge, Daniel F Hayes, Nicholas C Turner
PURPOSE: - Clinical use of analytical tests to assess genomic variants in circulating tumor DNA (ctDNA) is increasing. This joint review from the American Society of Clinical Oncology and the College of American Pathologists summarizes current information about clinical ctDNA assays and provides a framework for future research. METHODS: - An Expert Panel conducted a literature review on the use of ctDNA assays for solid tumors, including preanalytical variables, analytical validity, interpretation and reporting, and clinical validity and utility...
March 5, 2018: Archives of Pathology & Laboratory Medicine
Holly Thurston, Sheridan Miyamoto
Child welfare agencies are tasked with investigating allegations of child maltreatment and intervening when necessary. Researchers are turning to the field of predictive analytics to optimize data analysis and data-driven decision making. To demonstrate the utility of statistical algorithms that preceded the current predictive analytics, we used Model Based (MOB) recursive partitioning, a variant of regression analysis known as decision trees, on a dataset of cases and controls with a binary outcome of serious maltreatment (defined as hospitalization or death)...
February 28, 2018: Child Abuse & Neglect
Yang Wu, Jian Zeng, Futao Zhang, Zhihong Zhu, Ting Qi, Zhili Zheng, Luke R Lloyd-Jones, Riccardo E Marioni, Nicholas G Martin, Grant W Montgomery, Ian J Deary, Naomi R Wray, Peter M Visscher, Allan F McRae, Jian Yang
The identification of genes and regulatory elements underlying the associations discovered by GWAS is essential to understanding the aetiology of complex traits (including diseases). Here, we demonstrate an analytical paradigm of prioritizing genes and regulatory elements at GWAS loci for follow-up functional studies. We perform an integrative analysis that uses summary-level SNP data from multi-omics studies to detect DNA methylation (DNAm) sites associated with gene expression and phenotype through shared genetic effects (i...
March 2, 2018: Nature Communications
Nurulamin Abu Bakar, Dirk J Lefeber, Monique van Scherpenzeel
Clinical glycomics comprises a spectrum of different analytical methodologies to analyze glycan structures, which provides insights into the mechanisms of glycosylation. Within clinical diagnostics, glycomics serves as a functional readout of genetic variants, and can form a basis for therapy development, as was described for PGM1-CDG. Integration of glycomics with genomics has resulted in the elucidation of previously unknown disorders of glycosylation, namely CCDC115-CDG, TMEM199-CDG, ATP6AP1-CDG, MAN1B1-CDG, and PGM1-CDG...
March 1, 2018: Journal of Inherited Metabolic Disease
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