Author Archives: Peter Rogan

Sept. 7, 2019. Pan cancer article and database update

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We have published another revision to our pan-cancer splicing mutation database  paper: Shirley BC, Mucaki EJ and Rogan PK. Pan-cancer repository of validated natural and cryptic mRNA splicing mutations F1000Research 2019, 7:1908 (https://f1000research.com/articles/7-1908/v3). The paper is already indexed in PubMed.
In this version, we derive a simplified variant classification scheme with  ClinVar designations calibrated to the molecular phenotypes of mRNA splicing mutations. These are now indicated in the ValidspliceMut (https://validsplicemut.cytognomix.com) query results. The majority of variants cause aberrant splicing or are likely aberrant. Interestingly, a significant fraction of variants that have the same information, expression, population frequency properties as ClinVar variants designated as “benign” cause allele-specific alternative splicing.

Figure 1 of Pan-cancer repository of validated natural and cryptic mRNA splicing mutations. F1000Research 2019, 7:1908

Aug. 19, 2019. Review article about machine learning for predicting chemotherapy response

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New review article in Molecular Genetics and Metabolism about predicting responses to chemotherapy:

Multigene signatures of responses to chemotherapy derived by biochemically inspired machine learning

Published: https://doi.org/10.1016/j.ymgme.2019.08.005

Abstract:   Pharmacogenomic responses to chemotherapy drugs can be modeled by supervised machine learning of expression and copy number of relevant gene combinations. Such biochemical evidence can form the basis of derived gene signatures using cell line data, which can subsequently be examined in patients that have been treated with the same drugs. These gene signatures typically contain elements of multiple biochemical pathways which together comprise multiple origins of drug resistance or sensitivity. The signatures can capture variation in these responses to the same drug among different patients.

July 31, 2019. New preprint on biodosimetry in BioRxiv

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“Automated Cytogenetic Biodosimetry at Population-Scale”

PK Rogan, R Lu, E Mucaki, S Ali, B Shirley, Y Li, R Wilkins, F Norton, O Sevriukova, D Pham, E Ainsbury, J Moquat, R Cooke,

T Peerlaproulx, E Waller, JHM Knoll

https://www.biorxiv.org/content/10.1101/718973v1 (doi: https://doi.org/10.1101/718973)

Introduction The dicentric chromosome (DC) assay accurately quantifies exposure to radiation, however manual and semi-automated assignment of DCs has limited its use for a potential large-scale radiation incident. The Automated Dicentric Chromosome Identifier and Dose Estimator Chromosome (ADCI) software automates unattended DC detection and determines radiation exposures, fulfilling IAEA criteria for triage biodosimetry. We present high performance ADCI (ADCI-HT), with the requisite throughput to stratify exposures of populations in large scale radiation events.

Methods ADCI-HT streamlines dose estimation by optimal scheduling of DC detection, given that the numbers of samples and metaphase cell images in each sample vary. A supercomputer analyzes these data in parallel, with each processor handling a single image at a time. Processor resources are managed hierarchically to maximize a constant stream of sample and image analysis. Metaphase data from populations of individuals with clinically relevant radiation exposures after simulated large nuclear incidents were analyzed. Sample counts were derived from US Census data. Analysis times and exposures were quantified for 15 different scenarios.

Results Processing of metaphase images from 1,744 samples (500 images each) used 16,384 CPUs and was completed in 1hr 11min 23sec, with radiation dose of all samples determined in 32 sec with 1,024 CPUs. Processing of 40,000 samples with varying numbers of metaphase cells, 10 different exposures from 5 different biodosimetry labs met IAEA accuracy criteria (dose estimate differences were < 0.5 Gy; median = 0.07) and was completed in ~25 hours. Population-scale metaphase image datasets within radiation contours of nuclear incidents were defined by exposure levels (either >1 Gy or >2 Gy). The time needed to analyze samples of all individuals receiving exposures from a high yield airborne nuclear device ranged from 0.6-7.4 days, depending on the population density.

Conclusion ADCI-HT delivers timely and accurate dose estimates in a simulated population-scale radiation incident.

#nuclear #biodosimetry #radiationprotection #iaea #radiation #population#bioinformatics #highperformancecomputing

July 4, 2019. Presentations describing interlaboratory comparison of radiation exposure determination by automated cytogenetic biodosimetry

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We will be presenting:

Determination of radiation exposure levels by fully automated
dicentric chromosome analysis: Results from IAEA MEDBIODOSE
(CRP E35010) interlaboratory comparison

at both the 19th International Congress of Radiation Research (Aug. 25-29, 2019) and the 12th International Symposium on Chromosome Aberrations (Aug. 27, 2019)  in Manchester, UK. This study compared the performance of our Automated Dicentric Chromosome Identifier and Dose Estimator (ADCI) using data from 6 different laboratories.  Each of these members of the  IAEA-sponsored Cooperative Research Project E35010, submitted images for calibration curve construction and at least 2 samples of unknown exposure to CytoGnomix for analysis with ADCI. We will report the results of this analysis during this presentation.

This poster presentation is now available on the Zenodo website (http://doi.org/10.5281/zenodo.4012749)

doi:  DOI 10.5281/zenodo.4012748

Authors:

Rogan P , Shirley B , Li Y , Guogyte K , Sevriukova O , Ngoc Duy P , Moquet J ,
Ainsbury E , Sudprasert W , Wilkins R , Norton F , Knoll J

Department of Biochemistry , University of Western Ontario, London Ontario, Canada
Department of Pathology and Laboratory Medicine, University of Western Ontario, London
Ontario, Canada
Radiation Protection Centre, Ministry of Health (L T -RPC), Vilnius, Lithuania
Dalat Nuclear Research Institute (VN-DNRI), Dalat, Vietnam
Public Health England (PHE), Oxford, Great Britain
Thai Biodosimetry Network, Kasetsart University (THA), Bangkok, Thailand
Health Canada, Ottawa Ontario, Canada
Canadian Nuclear Laboratories, Chalk River Ontario, Canada
Cytognomix, London Ontario, Canada

May 30, 2019. F1000Research splicing mutation database article now indexed in PubMed

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Large repository of human mRNA splicing mutations in TCGA and ICGC tumor exomes and genomes, with every mutation validated by transcriptome analysis of tumor vs controls:

Shirley BC, Mucaki EJ and Rogan PK. Pan-cancer repository of validated natural and cryptic mRNA splicing mutations. F1000Research 2019, 7:1908      (https://f1000research.com/articles/7-1908/v2)

 

April 11, 2019. New article about transcription factor binding site clusters, their role in target gene regulation and mutation analysis

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This article has now been accepted for publication and indexing in PubMed:

 Lu R and Rogan PK. Transcription factor binding site clusters identify target genes with similar tissue-wide expression and buffer against mutations [version 2; peer review: 2 approved]. F1000Research 2019, 7:1933 (https://doi.org/10.12688/f1000research.17363.2)

Pan-Cancer Splicing Web Beacon to be Presented at ACMG Meeting

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We’re giving a demonstration and a poster presentation of our new GA4GH-compliant web-based Beacon (https://validsplicemut.cytognomix.com) at the 2019 American College of Medical Genetics and Genomics annual conference this week.
Here are the details:

Pan-Cancer Repository of Validated Natural and Cryptic mRNA Splicing MutationsCategory: “Laboratory genetics and genomics”, Abstract Poster Number:  754 (link to abstract)

Where: Exhibit hall,  Washington Convention Center, ACMG Clinical Genetics Meeting in Seattle, Washington

When: April 2 – 6, 2019; Poster presentation time:  Friday, 4/5 from 10:30am-12:00pm

An e-poster is available on the CytoGnomix website (direct link to poster). The work has been published in F1000Research (link).

If you’d like to meet with Dr. Rogan, please contact him at info@cytognomix.com

This Beacon resource was created using the MutationForecaster system.

March 20, 2019. Presentation at the 2019 American College of Medical Genetics and Genomics annual conference

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The following  paper has been accepted for presentation:

 “Pan-Cancer Repository of Validated Natural and Cryptic mRNA Splicing Mutations”, 

Category: “Laboratory genetics and genomics”, Abstract Poster Number: 754     (link to Abstract)

Where: Exhibit hall, Washington Convention Center, ACMG Clinical Genetics Meeting in Seattle, Washington

When: April 2 – 6, 2019;  Poster presentation time: Friday, 4/5 from 10:30am-12:00pm

This work will be available as an ePoster AS WELL AS being presented in printed format on a poster board during the Annual Meeting.  Details to access the ePoster will be available soon.

 

 

 

 

Feb. 14, 2019. New article about targeted validation of mRNA splicing mutations

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New article in bioRxiv:
Expression changes confirm predicted single nucleotide variants affecting mRNA splicing. E. J. Mucaki and P.K. Rogan. (https://www.biorxiv.org/content/10.1101/549089v1)

This paper describes high quality qRT-PCR and microarray expression data of predicted splicing variants. The results confirm results of genome-wide TCGA and ICGC RNASeq findings (https://f1000research.com/articles/7-1908/v1). The genome scale results were obtained using CytoGnomix’s MutationForecaster (http://mutationforecaster.com ) system.

January 24, 2019. Updated version of CytoGnomix Visual Analytics (CytoVA) on MutationForecaster

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We have just updated the CytoVA software product. It now contains all PubMed references through Dec 2018 and the most recent version of the human phenotype ontology (HPO). With CytoVA (see below), you can query Shannon pipeline, Veridical or VEP output, the list of predicted deleterious variants, with this software  for HPO clinical phenotypes.  The software  reports the articles, and PubMed index codes that support the relationship between the gene variants and the queried phenotype. It’s a very effective way of filtering exome or complete genome sequencing results to limit the best candidate variants.

January 9, 2019. Article on fully automated interpretation of the dicentric chromosome assay for radiation quantification now available

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Our paper, “RADIATION DOSE ESTIMATION BY COMPLETELY AUTOMATED INTERPRETATION OF THE DICENTRIC CHROMOSOME ASSAY”  is now published in the journal Radiation Protection Dosimetry.

Unfortunately, the journal has not made the article open access. We have made it available on our ADCIWiki website, as permitted by the copyright agreement.

The link to the pdf full text is:

http://adcidewiki.cytognomix.com/files/pubs/LiRPD2019.pdf

November 28, 2018. New automated cytogenetic biodosimetry article accepted for publication

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RADIATION DOSE ESTIMATION BY COMPLETELY AUTOMATED INTERPRETATION OF THE

DICENTRIC CHROMOSOME ASSAY

Li, Yanxin; Shirley, Ben; Wilkins, Ruth; Norton, Farrah; Knoll, Joan; Rogan,Peter

Radiation Protection Dosimetry, in press

 

 

 

 

 

 

 

 

 

Figure 2 (from the article): Representative heat maps of chromosome object count distributions for Health Canada calibration (HC ##Gy.csv) and exercise (S##.csv) samples. Show: legend indicates significance of pairwise comparisons of object counts in (bottom panel) unselected vs. (top panel) Model B_C filter (5) selected images from each sample. Values close to 10^0 are not significant, whereas values such as 10^-20 are significant differences between samples. The legend displays probability thresholds of Wilcoxon signed rank tests of chromosome object counts between each pair of samples from the HC laboratory. Similar results were obtained for other chromosomal features.