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variant analytics

Chi-Hua Chen, Yunpeng Wang, Min-Tzu Lo, Andrew Schork, Chun-Chieh Fan, Dominic Holland, Karolina Kauppi, Olav B Smeland, Srdjan Djurovic, Nilotpal Sanyal, Derrek P Hibar, Paul M Thompson, Wesley K Thompson, Ole A Andreassen, Anders M Dale
Discovering genetic variants associated with human brain structures is an on-going effort. The ENIGMA consortium conducted genome-wide association studies (GWAS) with standard multi-study analytical methodology and identified several significant single nucleotide polymorphisms (SNPs). Here we employ a novel analytical approach that incorporates functional genome annotations (e.g., exon or 5'UTR), total linkage disequilibrium (LD) scores and heterozygosity to construct enrichment scores for improved identification of relevant SNPs...
November 16, 2017: Scientific Reports
Sung Eun Choi, Margaret L Brandeau, Sanjay Basu
OBJECTIVE: Personalised medicine seeks to select and modify treatments based on individual patient characteristics and preferences. We sought to develop an automated strategy to select and modify blood pressure treatments, incorporating the likelihood that patients with different characteristics would benefit from different types of medications and dosages and the potential severity and impact of different side effects among patients with different characteristics. DESIGN, SETTING AND PARTICIPANTS: We developed a Markov decision process (MDP) model to incorporate meta-analytic data and estimate the optimal treatment for maximising discounted lifetime quality-adjusted life-years (QALYs) based on individual patient characteristics, incorporating medication adjustment choices when a patient incurs side effects...
November 15, 2017: BMJ Open
Zdeněk Preisler, Barbara Saccà, Stephen Whitelam
DNA nanoparticles with three-fold coordination have been observed to self-assemble in experiment into a network equivalent to the hexagonal (6.6.6) tiling, and a network equivalent to the 4.8.8 Archimedean tiling. Both networks are built from a single type of vertex. Here we use analytic theory and equilibrium and dynamic simulation to show that a model particle, whose rotational properties lie between those of the vertices of the 6.6.6 and 4.8.8 networks, can self-assemble into a network built from three types of vertex...
November 13, 2017: Soft Matter
Hui-Min Zhang, Charlene Li, Ming Lei, Victor Lundin, Ho Young Lee, Milady Ninonuevo, Kevin Lin, Guanghui Han, Wendy Sandoval, Dongsheng Lei, Gang Ren, Jennifer Zhang, Hongbin Liu
Bispecific antibodies have great potential to be the next-generation biotherapeutics due to their ability to simultaneously recognize two different targets. Compared to conventional monoclonal antibodies, knob-into-hole bispecific antibodies face unique challenges in production and characterization due to the increase in variant possibilities, such as homodimerization in covalent and non-covalent forms. In this study, a storage- and pH-sensitive hydrophobic interaction chromatography (HIC) profile change was observed for the hole-hole homodimer, and the multiple HIC peaks were explored and shown to be conformational isomers...
November 12, 2017: Analytical Chemistry
Sarah Täuber, Lena Kunze, Oleg Grauberger, Armin Grundmann, Martina Viefhues
The efficient purification and analysis of topological DNA variants is mandatory for many state-of-the-art molecular medicine technologies, like gene- and cancer-therapy as well as plasmid vaccination. In this work, we exploit dielectrophoresis (DEP) for a fast and efficient continuous-flow separation and analysis that goes beyond the standard methods of gel electrophoresis and capillary electrophoresis. The aim of this work was to reach for the limits in dielectrophoretic analysis of DNA regarding the size resolution and the topological conformation...
November 9, 2017: Analyst
Nicolai J Wewer Albrechtsen
Towards the end of the 20th century, the number of subjects with diabetes and obesity rose exponentially. The discoveries of insulin- and appetite-modulating chemical signals, including glucagon-like peptide-1 (GLP-1), secreted from the gastrointestinal system, led to development of a new group of drugs which now are being used for glucose-lowering therapy and weight loss. Understanding of the physiology of gut derived signals and their pathophysiologi-cal importance requires accurate measurements of their circulat-ing levels...
November 2017: Danish Medical Journal
Susanne Deininger, Tilman Todenhöfer, Jörg Hennenlotter, Valentina Gerber, Jennifer Schwarz, Jens Bedke, Christian Schwentner, Arnulf Stenzl, Steffen Rausch
BACKGROUND: Urinary marker tests for bladder cancer (BC) detection and surveillance represent a desirable approach to diagnosis and follow-up. The SCIMEDX uCyt+ assay detects antigens expressed by BC cells (mucin glycoprotein and carcinoembryonic antigen) using green and red fluorescence and is interpreted according to specific manufacturer's recommendations. In the present study, we evaluated divergent approaches of numeric and morphological analysis of uCyt+ to generate a rationale for alternative test interpretation strategies...
November 8, 2017: Diagnostic Cytopathology
H Edward Wong, Chung-Jr Huang, Zhongqi Zhang
Proteins provide the molecular basis for cellular structure, catalytic activity, signal transduction, and molecular transport in biological systems. Recombinant protein expression is widely used to prepare and manufacture novel proteins that serve as the foundation of many biopharmaceutical products. However, protein translation bioprocesses are inherently prone to low-level errors. These sequence variants caused by amino acid misincorporation have been observed in both native and recombinant proteins. Protein sequence variants impact product quality, and their presence can be exacerbated through cellular stress, overexpression, and nutrient starvation...
October 26, 2017: Biotechnology Advances
Jeffrey S Phillips, Sandhitsu R Das, Corey T McMillan, David J Irwin, Emily E Roll, Fulvio Da Re, Ilya M Nasrallah, David A Wolk, Murray Grossman
Accumulation of paired helical filament tau contributes to neurodegeneration in Alzheimer's disease (AD). (18) F-flortaucipir is a positron emission tomography (PET) radioligand sensitive to tau in AD, but its clinical utility will depend in part on its ability to predict cognitive symptoms in diverse dementia phenotypes associated with selective, regional uptake. We examined associations between (18) F-flortaucipir and cognition in 14 mildly-impaired patients (12 with cerebrospinal fluid analytes consistent with AD pathology) who had amnestic (n = 5) and non-amnestic AD syndromes, including posterior cortical atrophy (PCA, n = 5) and logopenic-variant primary progressive aphasia (lvPPA, n = 4)...
November 6, 2017: Human Brain Mapping
Cecilia Vitali, Sumeet A Khetarpal, Daniel J Rader
PURPOSE OF REVIEW: Elevated high-density lipoprotein cholesterol levels in the blood (HDL-C) represent one of the strongest epidemiological surrogates for protection against coronary heart disease (CHD), but recent human genetic and pharmacological intervention studies have raised controversy about the causality of this relationship. Here, we review recent discoveries from human genome studies using new analytic tools as well as relevant animal studies that have both addressed, and in some cases, fueled this controversy...
November 4, 2017: Current Cardiology Reports
Dieter Galea, Paolo Inglese, Lidia Cammack, Nicole Strittmatter, Monica Rebec, Reza Mirnezami, Ivan Laponogov, James Kinross, Jeremy Nicholson, Zoltan Takats, Kirill A Veselkov
Hierarchical classification (HC) stratifies and classifies data from broad classes into more specific classes. Unlike commonly used data classification strategies, this enables the probabilistic prediction of unknown classes at different levels, minimizing the burden of incomplete databases. Despite these advantages, its translational application in biomedical sciences has been limited. We describe and demonstrate the implementation of a HC approach for "omics-driven" classification of 15 bacterial species at various taxonomic levels achieving 90-100% accuracy, and 9 cancer types into morphological types and 35 subtypes with 99% and 76% accuracy, respectively...
November 3, 2017: Scientific Reports
Michele R Wing, Julie W Reeser, Amy M Smith, Matthew Reeder, Dorrelyn Martin, Benjamin M Jewell, Jharna Datta, Jharna Miya, J Paul Monk, Amir Mortazavi, Gregory A Otterson, Richard M Goldberg, Jeffrey B VanDeusen, Sharon Cole, Kristin Dittmar, Sunny Jaiswal, Matthew Kinzie, Suraj Waikhom, Aharon G Freud, Xiao-Ping Zhou, Wei Chen, Darshna Bhatt, Sameek Roychowdhury
Multiplex somatic testing has emerged as a strategy to test patients with advanced cancer. We demonstrate our analytic validation approach for a gene hotspot panel and real-time prospective clinical application for any cancer type. The TruSight Tumor 26 assay amplifies 85 somatic hotspot regions across 26 genes. Using cell line and tumor mixes, we observed that 100% of the 14,715 targeted bases had at least 1000x raw coverage. We determined the sensitivity (100%, 95% CI: 96-100%), positive predictive value (100%, 95% CI: 96-100%), reproducibility (100% concordance), and limit of detection (3% variant allele frequency at 1000x read depth) of this assay to detect single nucleotide variants and small insertions and deletions...
September 29, 2017: Oncotarget
Šárka Moudříková, Andres Sadowsky, Sabine Metzger, Ladislav Nedbal, Tabea Mettler-Altmann, Peter Mojzes
Polyphosphates have occurred in living cells early in evolution and microalgae contain these important polymers in their cells. Progress in research of polyphosphate metabolism of these ecologically as well as biotechnologically important microorganisms is hampered by the lack of rapid quantification methods. Experiments with the green alga Chlorella vulgaris presented here compared polyphosphate extraction in water, methanol-chloroform, and phenol-chloroform followed by polyphosphate purification by binding to silica columns or ethanol precipitation...
November 3, 2017: Analytical Chemistry
Yu Annie Wang, Di Wu, Jared R Auclair, Joseph P Salisbury, Richa Sarin, Yang Tang, Nicholas Joseph Mozdzierz, Kartik Shah, Anna Fan Zhang, Shiaw-Lin Wu, Jeffrey Neil Agar, J Christopher Love, Kerry Routenberg Love, William S Hancock
With the advent of biosimilars to the US market, it is important to have better analytical tools to assure product quality from batch-to-batch. In addition, the recent popularity of using a continuous process for production of biopharmaceuticals, traditional bottom-up method, alone, for product characterization and quality analysis is no-longer sufficient. Bottom-up method requires large amounts of material for analysis, is labor-intensive and time consuming. Additionally, in this analysis, di-gestion of the protein with enzymes such as trypsin could induce artifacts and modifications which would increase the com-plexity of the analysis...
November 3, 2017: Analytical Chemistry
Shimaa Eissa, Nawal Alshehri, Anas M Abdel Rahman, Majed Dasouki, Khalid M Abu Salah, Mohammed Zourob
Spinal muscular atrophy is an untreatable potentially fatal hereditary disorder caused by loss-of-function mutations in the survival motor neuron (SMN) 1 gene which encodes the SMN protein. Currently, definitive diagnosis relies on the demonstration of biallelic pathogenic variants in SMN1 gene. Therefore, there is an urgent unmet need to accurately quantify SMN protein levels for screening and therapeutic monitoring of symptomatic newborn and SMA patients, respectively. Here, we developed a voltammetric immunosensor for the sensitive detection of SMN protein based on covalently functionalized carbon nanofiber-modified screen printed electrodes...
October 10, 2017: Biosensors & Bioelectronics
Zirui Dong, Huilin Wang, Haixiao Chen, Hui Jiang, Jianying Yuan, Zhenjun Yang, Wen-Jing Wang, Fengping Xu, Xiaosen Guo, Ye Cao, Zhenzhen Zhu, Chunyu Geng, Wan Chee Cheung, Yvonne K Kwok, Huanming Yang, Tak Yeung Leung, Cynthia C Morton, Sau Wai Cheung, Kwong Wai Choy
PurposeRecent studies demonstrate that whole-genome sequencing enables detection of cryptic rearrangements in apparently balanced chromosomal rearrangements (also known as balanced chromosomal abnormalities, BCAs) previously identified by conventional cytogenetic methods. We aimed to assess our analytical tool for detecting BCAs in the 1000 Genomes Project without knowing which bands were affected.MethodsThe 1000 Genomes Project provides an unprecedented integrated map of structural variants in phenotypically normal subjects, but there is no information on potential inclusion of subjects with apparent BCAs akin to those traditionally detected in diagnostic cytogenetics laboratories...
November 2, 2017: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Sophie Hackinger, Eleftheria Zeggini
In recent years pleiotropy, the phenomenon of one genetic locus influencing several traits, has become a widely researched field in human genetics. With the increasing availability of genome-wide association study summary statistics, as well as the establishment of deeply phenotyped sample collections, it is now possible to systematically assess the genetic overlap between multiple traits and diseases. In addition to increasing power to detect associated variants, multi-trait methods can also aid our understanding of how different disorders are aetiologically linked by highlighting relevant biological pathways...
November 2017: Open Biology
Alexander H Li, Neil A Hanchard, Dieter Furthner, Susan Fernbach, Mahshid Azamian, Annarita Nicosia, Jill Rosenfeld, Donna Muzny, Lisa C A D'Alessandro, Shaine Morris, Shalini Jhangiani, Dhaval R Parekh, Wayne J Franklin, Mark Lewin, Jeffrey A Towbin, Daniel J Penny, Charles D Fraser, James F Martin, Christine Eng, James R Lupski, Richard A Gibbs, Eric Boerwinkle, John W Belmont
BACKGROUND: Left-sided lesions (LSLs) account for an important fraction of severe congenital cardiovascular malformations (CVMs). The genetic contributions to LSLs are complex, and the mutations that cause these malformations span several diverse biological signaling pathways: TGFB, NOTCH, SHH, and more. Here, we use whole exome sequence data generated in 342 LSL cases to identify likely damaging variants in putative candidate CVM genes. METHODS: Using a series of bioinformatics filters, we focused on genes harboring population-rare, putative loss-of-function (LOF), and predicted damaging variants in 1760 CVM candidate genes constructed a priori from the literature and model organism databases...
October 31, 2017: Genome Medicine
Alexandra J Mayhew, David Meyre
The goal of this review article is to provide a conceptual based summary of how heritability estimates for complex traits such as obesity are determined and to explore the future directions of research in the heritability field. The target audience are researchers who use heritability data rather than those conducting heritability studies. The article provides an introduction to key concepts critical to understanding heritability studies including: i) definitions of heritability: broad sense versus narrow sense heritability; ii) how data for heritability studies are collected: twin, adoption, family and population-based studies; and iii) analytical techniques: path analysis, structural equations and mixed or regressive models of complex segregation analysis...
August 2017: Current Genomics
Molly A Hall, John Wallace, Anastasia Lucas, Dokyoon Kim, Anna O Basile, Shefali S Verma, Cathy A McCarty, Murray H Brilliant, Peggy L Peissig, Terrie E Kitchner, Anurag Verma, Sarah A Pendergrass, Scott M Dudek, Jason H Moore, Marylyn D Ritchie
Genome-wide, imputed, sequence, and structural data are now available for exceedingly large sample sizes. The needs for data management, handling population structure and related samples, and performing associations have largely been met. However, the infrastructure to support analyses involving complexity beyond genome-wide association studies is not standardized or centralized. We provide the PLatform for the Analysis, Translation, and Organization of large-scale data (PLATO), a software tool equipped to handle multi-omic data for hundreds of thousands of samples to explore complexity using genetic interactions, environment-wide association studies and gene-environment interactions, phenome-wide association studies, as well as copy number and rare variant analyses...
October 27, 2017: Nature Communications
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