Integrative DNA copy number detection and genotyping from sequencing and array-based platforms.

Bioinformatics. 2018 Jul 15;34(14):2349-2355

Authors: Zhou Z, Wang W, Wang LS, Zhang NR

Abstract
Motivation: Copy number variations (CNVs) are gains and losses of DNA segments and have been associated with disease. Many large-scale genetic association studies are performing CNV analysis using whole exome sequencing (WES) and whole genome sequencing (WGS). In many of these studies, previous single-nucleotide polymorphism (SNP)-array data are available. An integrated cross-platform analysis is expected to improve resolution and accuracy, yet there is no tool for effectively combining data from sequencing and array platforms. The detection of CNVs using sequencing data alone can also be further improved by the utilization of allele-specific reads.
Results: We propose a statistical framework, integrated CNV (iCNV) detection algorithm, which can be applied to multiple study designs: WES only, WGS only, SNP array only, or any combination of SNP and sequencing data. iCNV applies platform-specific normalization, utilizes allele specific reads from sequencing and integrates matched NGS and SNP-array data by a hidden Markov model. We compare integrated two-platform CNV detection using iCNV to naïve intersection or union of platforms and show that iCNV increases sensitivity and robustness. We also assess the accuracy of iCNV on WGS data only and show that the utilization of allele-specific reads improve CNV detection accuracy compared to existing methods.
Availability and implementation: https://github.com/zhouzilu/iCNV.
Supplementary information: Supplementary data are available at Bioinformatics online.

PMID: 29992253 [PubMed - in process]

Evolutionary history of human colitis-associated colorectal cancer.

Gut. 2018 Jul 10;:

Authors: Baker AM, Cross W, Curtius K, Al Bakir I, Choi CR, Davis HL, Temko D, Biswas S, Martinez P, Williams MJ, Lindsay JO, Feakins R, Vega R, Hayes SJ, Tomlinson IPM, McDonald SAC, Moorghen M, Silver A, East JE, Wright NA, Wang LM, Rodriguez-Justo M, Jansen M, Hart AL, Leedham SJ, Graham TA

Abstract
OBJECTIVE: IBD confers an increased lifetime risk of developing colorectal cancer (CRC), and colitis-associated CRC (CA-CRC) is molecularly distinct from sporadic CRC (S-CRC). Here we have dissected the evolutionary history of CA-CRC using multiregion sequencing.
DESIGN: Exome sequencing was performed on fresh-frozen multiple regions of carcinoma, adjacent non-cancerous mucosa and blood from 12 patients with CA-CRC (n=55 exomes), and key variants were validated with orthogonal methods. Genome-wide copy number profiling was performed using single nucleotide polymorphism arrays and low-pass whole genome sequencing on archival non-dysplastic mucosa (n=9), low-grade dysplasia (LGD; n=30), high-grade dysplasia (HGD; n=13), mixed LGD/HGD (n=7) and CA-CRC (n=19). Phylogenetic trees were reconstructed, and evolutionary analysis used to reveal the temporal sequence of events leading to CA-CRC.
RESULTS: 10/12 tumours were microsatellite stable with a median mutation burden of 3.0 single nucleotide alterations (SNA) per Mb, ~20% higher than S-CRC (2.5 SNAs/Mb), and consistent with elevated ageing-associated mutational processes. Non-dysplastic mucosa had considerable mutation burden (median 47 SNAs), including mutations shared with the neighbouring CA-CRC, indicating a precancer mutational field. CA-CRCs were often near triploid (40%) or near tetraploid (20%) and phylogenetic analysis revealed that copy number alterations (CNAs) began to accrue in non-dysplastic bowel, but the LGD/HGD transition often involved a punctuated 'catastrophic' CNA increase.
CONCLUSIONS: Evolutionary genomic analysis revealed precancer clones bearing extensive SNAs and CNAs, with progression to cancer involving a dramatic accrual of CNAs at HGD. Detection of the cancerised field is an encouraging prospect for surveillance, but punctuated evolution may limit the window for early detection.

PMID: 29991641 [PubMed - as supplied by publisher]

The use of carbon dioxide insufflation to facilitate identification of intestinal injuries in patients undergoing cytoreductive surgery and intraperitoneal chemotherapy.

Tech Coloproctol. 2017 06;21(6):479-480

Authors: Kozman MA, Fisher OM, Valle SJ, Alzahrani N, Morris DL

PMID: 28616792 [PubMed - indexed for MEDLINE]

State-of-the-Art Metabolic Toxicity Screening and Pathway Evaluation.

Anal Chem. 2016 05 03;88(9):4584-99

Authors: Hvastkovs EG, Rusling JF

Abstract
Routine in vitro bioassays and animal toxicity studies of drug and environmental chemical candidates fail to reveal toxicity in ∼30% of cases. This Feature article addresses research on new approaches to in vitro toxicity testing as well as our own efforts to produce high-throughput genotoxicity arrays and LC-MS/MS approaches to reveal possible chemical pathways of toxicity.

PMID: 27043322 [PubMed - indexed for MEDLINE]

15 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2018/07/12

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18 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

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6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2018/07/11

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

48 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2018/07/11

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Novel ETFDH mutations in four cases of riboflavin responsive multiple acyl-CoA dehydrogenase deficiency.

Mol Genet Metab Rep. 2018 Sep;16:15-19

Authors: Fan X, Xie B, Zou J, Luo J, Qin Z, D'Gama AM, Shi J, Yi S, Yang Q, Wang J, Luo S, Chen S, Agrawal PB, Li Q, Shen Y

Abstract
Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty acid, amino acid, and choline metabolism caused by mutations in EFTA, EFTB, or ETFDH. Many MADD patients are responsive to treatment with riboflavin, termed riboflavin-responsive MADD (RR-MADD). Here, we report three novel mutations and one previously reported mutation in ETFDH in four RR-MADD patients who presented at various ages, and characterize the corresponding changes in ETF-QO protein structure. Clinicians should consider MADD in the differential diagnosis when patients present with muscle weakness and biochemical abnormalities. Gene testing plays a critical role in confirming the diagnosis of MADD, and may not only prevent patients from invasive testing, but also allow timely initiation of riboflavin treatment. The novel variants in ETFDH and the corresponding clinical features reported here enrich the allelic heterogeneity of RR-MADD and provide insight into genotype-phenotype relationships.

PMID: 29988809 [PubMed]

The BabySeq project: implementing genomic sequencing in newborns.

BMC Pediatr. 2018 Jul 09;18(1):225

Authors: Holm IA, Agrawal PB, Ceyhan-Birsoy O, Christensen KD, Fayer S, Frankel LA, Genetti CA, Krier JB, LaMay RC, Levy HL, McGuire AL, Parad RB, Park PJ, Pereira S, Rehm HL, Schwartz TS, Waisbren SE, Yu TW, BabySeq Project Team, Green RC, Beggs AH

Abstract
BACKGROUND: The greatest opportunity for lifelong impact of genomic sequencing is during the newborn period. The "BabySeq Project" is a randomized trial that explores the medical, behavioral, and economic impacts of integrating genomic sequencing into the care of healthy and sick newborns.
METHODS: Families of newborns are enrolled from Boston Children's Hospital and Brigham and Women's Hospital nurseries, and half are randomized to receive genomic sequencing and a report that includes monogenic disease variants, recessive carrier variants for childhood onset or actionable disorders, and pharmacogenomic variants. All families participate in a disclosure session, which includes the return of results for those in the sequencing arm. Outcomes are collected through review of medical records and surveys of parents and health care providers and include the rationale for choice of genes and variants to report; what genomic data adds to the medical management of sick and healthy babies; and the medical, behavioral, and economic impacts of integrating genomic sequencing into the care of healthy and sick newborns.
DISCUSSION: The BabySeq Project will provide empirical data about the risks, benefits and costs of newborn genomic sequencing and will inform policy decisions related to universal genomic screening of newborns.
TRIAL REGISTRATION: The study is registered in ClinicalTrials.gov Identifier: NCT02422511 . Registration date: 10 April 2015.

PMID: 29986673 [PubMed - in process]

RNA helicase, DDX27 regulates skeletal muscle growth and regeneration by modulation of translational processes.

PLoS Genet. 2018 03;14(3):e1007226

Authors: Bennett AH, O'Donohue MF, Gundry SR, Chan AT, Widrick J, Draper I, Chakraborty A, Zhou Y, Zon LI, Gleizes PE, Beggs AH, Gupta VA

Abstract
Gene expression in a tissue-specific context depends on the combined efforts of epigenetic, transcriptional and post-transcriptional processes that lead to the production of specific proteins that are important determinants of cellular identity. Ribosomes are a central component of the protein biosynthesis machinery in cells; however, their regulatory roles in the translational control of gene expression in skeletal muscle remain to be defined. In a genetic screen to identify critical regulators of myogenesis, we identified a DEAD-Box RNA helicase, DDX27, that is required for skeletal muscle growth and regeneration. We demonstrate that DDX27 regulates ribosomal RNA (rRNA) maturation, and thereby the ribosome biogenesis and the translation of specific transcripts during myogenesis. These findings provide insight into the translational regulation of gene expression in myogenesis and suggest novel functions for ribosomes in regulating gene expression in skeletal muscles.

PMID: 29518074 [PubMed - indexed for MEDLINE]

Pediatric liver transplantation for hepatocellular cancer and rare liver malignancies: US multicenter and single-center experience (1981-2015).

Liver Transpl. 2017 Dec;23(12):1577-1588

Authors: Vinayak R, Cruz RJ, Ranganathan S, Mohanka R, Mazariegos G, Soltys K, Bond G, Tadros S, Humar A, Marsh JW, Selby RR, Reyes J, Sun Q, Haberman K, Sindhi R

Abstract
A tenth of all pediatric liver transplantations (LTs) are performed for unresectable liver malignancies, especially the more common hepatoblastoma (HBL). Less understood are outcomes after LT for the rare hepatocellular carcinoma, nonhepatoblastoma embryonal tumors (EMBs), and slow growing metastatic neuroendocrine tumors of childhood. Pediatric LT is increasingly performed for rare unresectable liver malignancies other than HBL. We performed a retrospective review of outcomes after LT for malignancy in the multicenter US Scientific Registry of Transplant Recipients (SRTR; n = 677; 1987-2015). We then reviewed the Children's Hospital of Pittsburgh (CHP; n = 74; 1981-2014) experience focusing on LT for unresectable hepatocellular cancer (HCC), EMBs, and metastatic liver tumors (METS). HBL was included to provide reference statistics. In the SRTR database, LT for HCC and HBL increased over time (P < 0.001). Compared with other malignancies, the 149 HCC cases received fewer segmental grafts (P < 0.001) and also experienced 10-year patient survival similar to 15,710 adult HCC LT recipients (51.6% versus 49.6%; P = 0.848, not significant [NS], log-rank test). For 22 of 149 cases with incidental HCC, 10-year patient survival was higher than 127 primary HCC cases (85% [95% confidence interval (CI), 70.6%-100%] versus 48.3% [95% CI, 38%-61%]; P = 0.168, NS) and similar to 3392 biliary atresia cases (89.9%; 95% CI, 88.7%-91%). Actuarial 10-year patient survival for 17 EMBs, 10 METS, and 6 leiomyosarcoma patients exceeded 60%. These survival outcomes were similar to those seen for HBL. At CHP, posttransplant recurrence-free and overall survival among 25 HCC, 17 (68%) of whom had preexisting liver disease, was 16/25 or 64%, and 9/25 or 36%, respectively. All 10 patients with incidental HCC and tumor-node-metastasis stage I and II HCC survived recurrence-free. Only vascular invasion predicted poor survival in multivariate analysis (P < 0.0001). A total of 4 of 5 EMB patients (80%) and all patients with METS (neuroendocrine-2, pseudopapillary pancreatic-1) also survived recurrence-free. Among children, LT can be curative for unresectable HCC confined to the liver and without vascular invasion, incidental HCC, embryonal tumors, and metastatic neuroendocrine tumors. Liver Transplantation 23 1577-1588 2017 AASLD.

PMID: 28834194 [PubMed - indexed for MEDLINE]

Meta-path methods for prioritizing candidate disease miRNAs.

IEEE/ACM Trans Comput Biol Bioinform. 2017 Nov 22;:

Authors: Zhang X, Zou Q, Rodruguez-Paton A, Zeng X

Abstract
MicroRNAs (miRNAs) play critical roles in regulating gene expression at post-transcriptional levels. Predicting potential miRNAdisease association is beneficial not only to explore the pathogenesis of diseases, but also to understand biological processes. In this work, we propose two methods that can effectively predict potential miRNAdisease associations using our reconstructed miRNA and disease similarity networks, which are based on the latest experimental data. We reconstruct a miRNA functional similarity network using the following biological information: the miRNA family information, miRNA cluster information, experimentally valid miRNA target association and disease miRNA information. We also reconstruct a disease similarity network using disease functional information and disease semantic information. We present Katz with specific weights and Katz with machine learning, on the comprehensive heterogeneous network. These methods, which achieve corresponding AUC values of 0.897 and 0.919, exhibit performance superior to the existing methods. Comprehensive data networks and reasonable considerations guarantee the high performance of our methods. Contrary to several methods, which cannot work in such situations, the proposed methods also predict associations for diseases without any known related miRNAs. A web service for the download and prediction of relationships between diseases and miRNAs is available at http://lab.malab.cn/soft/MDPredict/.

PMID: 29990255 [PubMed - as supplied by publisher]

Peculiarities of Precocious Puberty in Boys and Girls With McCune-Albright Syndrome.

Front Endocrinol (Lausanne). 2018;9:337

Authors: Corica D, Aversa T, Pepe G, De Luca F, Wasniewska M

Abstract
McCune-Albright Syndrome (MAS; OMIM # 174800) is a rare, sporadic disease caused by a post-zygotic, activating mutation in the guanine-nucleotide binding protein α-subunit (GNAS1) gene. MAS is characterized by the clinical triad of polyostotic fibrous dysplasia of bone, café-au-lait skin pigmentation and peripheral precocious puberty. However, clinical presentation is highly variable depending on mosaic tissue distribution of mutant-bearing cells. Precocious puberty is the most common endocrine manifestation of MAS and is often the presenting, and sometimes the only, clinical sign of MAS. Due to the very low prevalence of MAS, data on course of precocious puberty, effectiveness of treatments and gonadal function during post-pubertal period are lacking. Our knowledge on this issue derives essentially from case reports and small cohorts of patients. The aim of this review is to report all available literature data on clinical aspects, therapeutic management and outcomes of precocious puberty in children with MAS. A systematic research was carried out through MEDLINE via PubMed, EMBASE, Web of Science, Semantic Scholar, Cochrane Library.

PMID: 29988390 [PubMed]

Relationship between out-of-home care placement history characteristics and educational achievement: A population level linked data study.

Child Abuse Negl. 2017 Aug;70:146-159

Authors: Maclean MJ, Taylor CL, O'Donnell M

Abstract
Studies generally show children who have entered out-of-home care have worse educational outcomes than the general population, although recent research suggests maltreatment and other adversities are major contributing factors. Children's out-of-home care experiences vary and may affect their outcomes. This study examined the influence of placement stability, reunification, type of care, time in care and age at entry to care on children's educational outcomes. We conducted a population-based record-linkage study of children born in Western Australia between 1990 and 2010 who sat State or national Year 3 reading achievement tests (N=235,045 children, including 2160 children with a history of out-of-home care). Children's educational outcomes varied with many aspects of their care experience. Children placed in residential care were particularly likely to have low scores, with an unadjusted OR 6.81, 95% CI[4.94, 9.39] for low reading scores, which was partially attenuated after adjusting for background risk factors but remained significant (OR=1.50, 95% CIs [1.08, 2.08]). Reading scores were also lower for children who had experienced changes in care arrangements in the year of the test. A dose-response effect for multiple placements was expected but not found. Older age at entering care was also associated with worse reading scores. Different characteristics of a child's care history were interwoven with each other as well as child, family and neighbourhood characteristics, highlighting a need for caution in attributing causality. Although the level of educational difficulties varied, the findings suggest a widespread need for additional educational support for children who have entered care, including after reunification.

PMID: 28609694 [PubMed - indexed for MEDLINE]

Effects of CYP2D6 genetic polymorphisms on the efficacy and safety of fluvoxamine in patients with depressive disorder and comorbid alcohol use disorder.

Pharmgenomics Pers Med. 2018;11:113-119

Authors: Zastrozhin MS, Grishina EA, Denisenko NP, Skryabin VY, Markov DD, Savchenko LM, Bryun EA, Sychev DA

Abstract
Background: Fluvoxamine therapy is used for treatment of patients with depressive disorder, but it is often ineffective, and some patients suffer from dose-dependent undesirable side effects such as vertigo, headache, indigestion, xerostomia, increased anxiety, etc. CYP2D6 is involved in the biotransformation of fluvoxamine. Meanwhile, the genes encoding these isoenzymes have a high level of polymorphism, which may affect the protein synthesis.
Objective: The primary objective of our study was to investigate the effects of CYP2D6 genetic polymorphisms on the efficacy and safety of fluvoxamine in patients with depressive disorder and comorbid alcohol use disorder, in order to develop the algorithms of optimization of fluvoxamine therapy for reducing the risk of dose-dependent undesirable side effects and pharmacoresistance.
Methods: The study involved 45 male patients (average age: 36.44±9.96 years) with depressive disorder and comorbid alcohol use disorder. A series of psychometric scales was used in the research. Genotyping of CYP2D6 (1846G>A) was performed using real-time polymerase chain reaction.
Results: According to results of Mann-Whitney U-test, statistically significant differences between the efficacy and safety of fluvoxamine were obtained on 9th and 16th days of therapy in patients with GG and GA genotypes (The Hamilton Rating Scale for Depression: 10.0 [10.0; 23.0] vs 25.0 [24.0; 16.0] (P<0.001) on the 9th day and 4.0 [2.0; 5.0] vs 6.0 [6.0; 7.0] on the 16th day; The UKU Side Effect Rating Scale: 6.0 [4.0; 6.0] vs 9.0 [9.0; 10.0] (P<0.001) on the 9th day and 5.0 [1.0; 9.0] vs 19.0 [18.0; 22.0] on the 16th day).
Conclusion: This study demonstrated the lower efficacy and safety of fluvoxamine in patients with depressive disorder and comorbid alcohol use disorders with GA genotype in CYP2D6 1846G>A polymorphic marker.

PMID: 29988737 [PubMed]

DNA methylation landscapes in the pathogenesis of type 2 diabetes mellitus.

Nutr Metab (Lond). 2018;15:47

Authors: Zhou Z, Sun B, Li X, Zhu C

Abstract
Although genetic variations and environmental factors are vital to the development and progression of type 2 diabetes mellitus (T2DM), emerging literature suggest that epigenetics, especially DNA methylation, play a key role in the pathogenesis of T2DM by affecting insulin secretion of pancreatic β cells and the body's resistance to insulin. Previous studies have elucidated how DNA methylation interacted with various factors in T2DM pathogenesis. This review summarized the role of related methylation genes in insulin-sensitive organs, such as pancreatic islets, skeletal muscle, liver, brain and adipose tissue, as well as peripheral blood cells, comparing the tissue similarity and specificity of methylated genes, aiming at a better understanding of the pathogenesis of T2DM and providing new ideas for the personalized treatment of this metabolism-associated disease.

PMID: 29988495 [PubMed]

Genotype-guided versus traditional clinical dosing of warfarin in patients of Asian ancestry: a randomized controlled trial.

BMC Med. 2018 Jul 10;16(1):104

Authors: Syn NL, Wong AL, Lee SC, Teoh HL, Yip JWL, Seet RC, Yeo WT, Kristanto W, Bee PC, Poon LM, Marban P, Wu TS, Winther MD, Brunham LR, Soong R, Tai BC, Goh BC

Abstract
BACKGROUND: Genotype-guided warfarin dosing has been shown in some randomized trials to improve anticoagulation outcomes in individuals of European ancestry, yet its utility in Asian patients remains unresolved.
METHODS: An open-label, non-inferiority, 1:1 randomized trial was conducted at three academic hospitals in South East Asia, involving 322 ethnically diverse patients newly indicated for warfarin (NCT00700895). Clinical follow-up was 90 days. The primary efficacy measure was the number of dose titrations within the first 2 weeks of therapy, with a mean non-inferiority margin of 0.5 over the first 14 days of therapy.
RESULTS: Among 322 randomized patients, 269 were evaluable for the primary endpoint. Compared with traditional dosing, the genotype-guided group required fewer dose titrations during the first 2 weeks (1.77 vs. 2.93, difference -1.16, 90% CI -1.48 to -0.84, P < 0.001 for both non-inferiority and superiority). The percentage of time within the therapeutic range over 3 months and median time to stable international normalized ratio (INR) did not differ between the genotype-guided and traditional dosing groups. The frequency of dose titrations (incidence rate ratio 0.76, 95% CI 0.67 to 0.86, P = 0.001), but not frequency of INR measurements, was lower at 1, 2, and 3 months in the genotype-guided group. The proportions of patients who experienced minor or major bleeding, recurrent venous thromboembolism, or out-of-range INR did not differ between both arms. For predicting maintenance doses, the pharmacogenetic algorithm achieved an R2 = 42.4% (P < 0.001) and mean percentage error of -7.4%.
CONCLUSIONS: Among Asian adults commencing warfarin therapy, a pharmacogenetic algorithm meets criteria for both non-inferiority and superiority in reducing dose titrations compared with a traditional dosing approach, and performs well in prediction of actual maintenance doses. These findings imply that clinicians may consider applying a pharmacogenetic algorithm to personalize initial warfarin dosages in Asian patients.
TRIAL REGISTRATION: ClinicalTrials.gov NCT00700895 . Registered on June 19, 2008.

PMID: 29986700 [PubMed - in process]