Standardized benchmarking approaches are required to assess the accuracy of variants called from sequence data. Although variant-calling tools and the metrics used to assess their performance ...continue to improve, important challenges remain. Here, as part of the Global Alliance for Genomics and Health (GA4GH), we present a benchmarking framework for variant calling. We provide guidance on how to match variant calls with different representations, define standard performance metrics, and stratify performance by variant type and genome context. We describe limitations of high-confidence calls and regions that can be used as truth sets (for example, single-nucleotide variant concordance of two methods is 99.7% inside versus 76.5% outside high-confidence regions). Our web-based app enables comparison of variant calls against truth sets to obtain a standardized performance report. Our approach has been piloted in the PrecisionFDA variant-calling challenges to identify the best-in-class variant-calling methods within high-confidence regions. Finally, we recommend a set of best practices for using our tools and evaluating the results.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Accurately calling indels with next-generation sequencing (NGS) data is critical for clinical application. The precisionFDA team collaborated with the U.S. Food and Drug Administration's (FDA's) ...National Center for Toxicological Research (NCTR) and successfully completed the NCTR Indel Calling from Oncopanel Sequencing Data Challenge, to evaluate the performance of indel calling pipelines. Top performers were selected based on precision, recall, and F1-score. The performance of many other pipelines was close to the top performers, which produced a top cluster of performers. The performance was significantly higher in high confidence regions and coding regions, and significantly lower in low complexity regions. Oncopanel capture and other issues may have occurred that affected the recall rate. Indels with higher variant allele frequency (VAF) may generally be called with higher confidence. Many of the indel calling pipelines had good performance. Some of them performed generally well across all three oncopanels, while others were better for a specific oncopanel. The performance of indel calling can further be improved by restricting the calls within high confidence intervals (HCIs) and coding regions, and by excluding low complexity regions (LCR) regions. Certain VAF cut-offs could be applied according to the applications.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
In the version of this article initially published online, two pairs of headings were switched with each other in Table 4: "Recall (PCR free)" was switched with "Recall (with PCR)," and "Precision ...(PCR free)" was switched with "Precision (with PCR)." The error has been corrected in the print, PDF and HTML versions of this article.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Chromosome rearrangement, a hallmark of cancer, has profound effects on carcinogenesis and tumor phenotype. We used a panel
of 60 human cancer cell lines (the NCI-60) as a model system to identify ...relationships among DNA copy number, mRNA expression
level, and drug sensitivity. For each of 64 cancer-relevant genes, we calculated all 4,096 possible Pearson's correlation
coefficients relating DNA copy number (assessed by comparative genomic hybridization using bacterial artificial chromosome
microarrays) and mRNA expression level (determined using both cDNA and Affymetrix oligonucleotide microarrays). The analysis
identified an association of ERBB2 overexpression with 3p copy number, a finding supported by data from human tumors and a mouse model of ERBB2-induced carcinogenesis.
When we examined the correlation between DNA copy number for all 353 unique loci on the bacterial artificial chromosome microarray
and drug sensitivity for 118 drugs with putatively known mechanisms of action, we found a striking negative correlation (−0.983;
95% bootstrap confidence interval, −0.999 to −0.899) between activity of the enzyme drug l -asparaginase and DNA copy number of genes near asparagine synthetase in the ovarian cancer cells. Previous analysis of drug
sensitivity and mRNA expression had suggested an inverse relationship between mRNA levels of asparagine synthetase and l -asparaginase sensitivity in the NCI-60. The concordance of pharmacogenomic findings at the DNA and mRNA levels strongly suggests
further study of l -asparaginase for possible treatment of a low-synthetase subset of clinical ovarian cancers. The DNA copy number database
presented here will enable other investigators to explore DNA transcript-drug relationships in their own domains of research
focus. Mol Cancer Ther 2006;5(4):853–67
Domestic goats in Syria may provide an interesting source of genetic variability due to its proximity to the centers of domestication. This study aimed to assess the morphological variation, genetic ...diversity and population substructure of the Syrian goat populations. Commonly, three goat genotypes are distinguished in Syria, namely Jabali or mountain goat, Baladi or local goat and Shami or Damascus (a well-known dairy goat). A pre-tested semi-structured questionnaire was used in recording both qualitative (coat color, eye color, horn length, horn orientation, nose profile) and quantitative (height at wither, chest girth, cannon length, body length, ear length and ear width) morphological data. Data from a total of 5,730 individual goats of the three goat populations reared in ten representative provinces of Syria were collected and analyzed using GenStat version 14 statistical packages. Results of the morphological analysis confirmed that there were clear morphological variations among the three goat populations. The three goat populations are mainly distinguished by their straight (Baladi, 71.1% and Jabali, 82.8%) and curved (Shami, 89.5%) nose profiles. Substantial phenotypic variability was found among and within the breeds suggesting that these goat breeds have not yet undergone an organized breeding program. The genetic variability and population substructures from 398 individual animals of the three breeds were genotyped using 12 DNA microsatellite markers from Food and Agricultural Organization (FAO) panel. All microsatellites typed were found to be polymorphic and a total of 41 distinct alleles were detected on Baladi, Jabali and Shami goat populations. The Syrian goat populations had observed and expected heterozygosity values that ranged from 0.50 to 0.62 and 0.74 to 0.85, respectively, and an average of 13.97 alleles per locus across breeds. For all loci, an average inbreeding values (F sub(IS)) of low to moderate level was obtained across the three goat breeds, which ranged from 0.29 (Shami goats) to 0.34 (Baladi goats) indicating the absence of mating between close relatives within these populations. The observed positive F sub(IS )coefficients among the studied goat breeds also suggested heterozygote deficiencies. The analyses of the molecular data using STRUCURE program indicated there were two primary populations, which did support the results based on morphological data of the same goat populations that clustered these goat populations into two main groups and confirmed the admixture nature of the Baladi and Jabali goat populations, while the Shami goat breed was well differentiated and grouped into a separate cluster that suggests its evolutionary and genetic uniqueness. The analysis of molecular variance (AMOVA) results detected genetic variations within individuals in a population (96%). The high genetic variability within individuals in a population provides a good base for designing genetic improvement programs under the existing goat management systems.
In silico Analysis of Vaccination Adverse Events Baraniuk, James N., MD; McGarvey, Peter, PhD; Suzek, Baris E., PhD ...
Journal of allergy and clinical immunology,
02/2015, Volume:
135, Issue:
2
Journal Article
Peer reviewed
Results Rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Guillain-Barre syndrome (GBS), and idiopathic thrombocytopenic purpura (ITP) were the most frequently reported vaccine-related ...autoimmune adverse events.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We have developed GoMiner, a program package that organizes lists of 'interesting' genes (for example, under- and overexpressed genes from a microarray experiment) for biological interpretation in ...the context of the Gene Ontology. GoMiner provides quantitative and statistical output files and two useful visualizations. The first is a tree-like structure analogous to that in the AmiGO browser and the second is a compact, dynamically interactive 'directed acyclic graph'. Genes displayed in GoMiner are linked to major public bioinformatics resources.
Chromosomal instability—a hallmark of epithelial cancers—is an ongoing process that results in aneuploidy and karyotypic heterogeneity of a cancer cell population. Previously, we stratified cancer ...cell lines in the NCI-60 drug discovery panel based on their karyotypic complexity and heterogeneity. Using this stratification in conjunction with drug response data for the cell lines allowed us to identify classes of chemical compounds whose growthinhibitory activity correlates with karyotypic complexity and chromosomal instability. In this article, we asked the question: What are the biological processes, pathways, or genes associated with chromosomal instability of cancer cells? We found that increased instability of the chromosomal content in a cancer cell population, particularly, persistent gains and losses of chromosomes, is associated with elevated expression of genes involved with aggressive cellular behavior, including invasion- and metastasis-associated changes in cell communication, adhesion, motility, and migration. These same karyotypic features are negatively correlated with the expression of genes involved in cell cycle checkpoints, DNA repair, and chromatin maintenance.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Purpose: The cytochrome P-450 (CYP) and glutathione S -transferase (GST) enzyme systems may influence the biological effects of carcinogens, including estrogens. As such, these
enzymes may predict ...the developmental risk of breast cancer, as well as be potential targets for chemoprevention. The purpose
of this study was to compare the expression of GST-Pi and CYPs 1A1, 2B6, 2E1, and 3A4 in paired samples of normal and malignant
breast tissue from patients with breast cancer and women undergoing reduction mammoplasty.
Experimental design: Expression of CYPs 1A1, 2B6, 2E1, 3A4, and GST-Pi was quantified in breast tissue from 33 patients with breast cancer and
in 17 women without history of cancer who underwent reduction mammoplasty. The expression of CYP 1A1, 2B6, 2E1, 3A4, and GST-Pi
was quantified by immunoblotting.
Results: CYP 1A1, 2E1, and 3A4 expression was significantly lower ( P < 0.05) in malignant tissue as compared with morphologically normal adjacent tissue. Conversely, GST-Pi expression was marginally
lower in the normal tissue ( P = 0.08). No significant difference in enzyme expression was seen between the tissue from reduction mammoplasty and normal
tissue from breast cancer patients. There was a trend for higher expression of CYP 2B6 and GST-Pi in the estrogen receptor
expressing tumors than those tumors without expression ( P > 0.28).
Conclusion: The expression of these enzymes was similar in morphologically normal breast tissue from patients with or without breast
cancer. The expression of CYPs was down-regulated in the tumor tissue. The clinical significance of CYP alterations in breast
cancer will need further characterization.
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