scholarly journals GRIDSS2: harnessing the power of phasing and single breakends in somatic structural variant detection

2020 ◽  
Author(s):  
Daniel L. Cameron ◽  
Jonathan Baber ◽  
Charles Shale ◽  
Jose Espejo Valle-Inclan ◽  
Nicolle Besselink ◽  
...  
Keyword(s):  
False Negative ◽  
False Negative Rate ◽  
High Sensitivity ◽  
General Purpose ◽  
Chromosome 1 ◽  
Structural Variants ◽  
Short Read ◽  
Structural Variant ◽  
Centromeric Sequence ◽  
Genomic Regions

AbstractHere we present GRIDSS2, a general purpose structural variant caller optimised for tumour/normal somatic calling. Using cell line, patient sample validation and cohort-level comparisons, we show GRIDSS2 outperforms recent state-of-the-art tools. We demonstrate GRIDSS2 retains high sensitivity and precision even for small events by identifying a small (32-100bp) duplication signature strongly associated with colorectal cancer using 3,782 metastatic cancers that have been deeply sequenced by the Hartwig Medical Foundation. Essential to the high precision achieved by GRIDSS2 is the novel reporting of single breakend variants: structural variants in which only one side can be unambiguously determined. We show that the inclusion of single breakends reduces the false negative rate from 10.4% to 3.4%. Demonstrating the power single breakend calling has in genomic regions traditionally considered inaccessible to short read callers, we find that 47% of somatic centromeric breaks are repaired to non-centromeric sequence, with chromosome 1 exhibiting a unique centromeric rearrangement signature. Finally, we show that somatic structural variants are highly clustered with GRIDSS2 able to phase 16% of somatic structural variants in the Hartwig cohort from short read sequencing alone.

scholarly journals GRIDSS2: comprehensive characterisation of somatic structural variation using single breakend variants and structural variant phasing

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Daniel L. Cameron ◽  
Jonathan Baber ◽  
Charles Shale ◽  
Jose Espejo Valle-Inclan ◽  
Nicolle Besselink ◽  
...  
Keyword(s):  
Copy Number ◽  
Structural Variation ◽  
False Negative ◽  
False Negative Rate ◽  
Structural Variants ◽  
Structural Variant ◽  
Complex Rearrangement ◽  
False Discovery ◽  
Copy Number Changes ◽  
Paired End Sequencing

AbstractGRIDSS2 is the first structural variant caller to explicitly report single breakends—breakpoints in which only one side can be unambiguously determined. By treating single breakends as a fundamental genomic rearrangement signal on par with breakpoints, GRIDSS2 can explain 47% of somatic centromere copy number changes using single breakends to non-centromere sequence. On a cohort of 3782 deeply sequenced metastatic cancers, GRIDSS2 achieves an unprecedented 3.1% false negative rate and 3.3% false discovery rate and identifies a novel 32–100 bp duplication signature. GRIDSS2 simplifies complex rearrangement interpretation through phasing of structural variants with 16% of somatic calls phasable using paired-end sequencing.

scholarly journals Novel low-delta value troponin algorithms have good precision for rule-out of NSTE-ACS

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
H Tjora ◽  
O.T Steiro ◽  
J Langorgen ◽  
T Omland ◽  
P Collinson ◽  
...  
Keyword(s):  
False Negative ◽  
False Negative Rate ◽  
High Sensitivity ◽  
Public Institution ◽  
University Hospital ◽  
P Value ◽  
Funding Source ◽  
Good Precision ◽  
Serum Samples ◽  
Rule Out

Abstract Background Rapid rule-out algorithms for non-ST-elevation infarction (NSTEMI) may be beneficial for logistics in the emergency room. Current algorithms are designed to rule-out NSTEMI, but do not differentiate between unstable angina (UAP) in need of revascularization and non-cardiac chest pain patients (NCCP) who could be discharged. Recent improvements in analytical precision of high sensitivity troponin (cTn) assays allow for trialing algorithms with very small delta values. Purpose Could the use of lower delta values produce rule-out algorithms for NSTE-ACS with a false negative rate of ≤5%, and a sufficient high rule-out rate of patients with NCCP. Method 927 patients with suspected NSTE-ACS were consecutively included. Serum samples were collected at 0, 3 and 8–12 hours. The final diagnosis was adjudicated by two independent cardiologists based on all clinical data including routine cTnT. The 0- and 3-hour samples were additionally measured for cTnIand cTnI from Singulex Clarity System (cTnI(sgx)). The diagnostic performance to rule-out NSTE-ACS was compared between one low-delta value algorithm from each assay (cTnT, cTnI and cTnT). Results The prevalence of NSTEMI was 13.4%, UAP 11.4% and NCCP 60%. Median age was 63 years, 60% males. Fig. 1 shows baseline and 3-hour delta cTn values for the UAP and NCCP patients for the three different assays. The baseline cTn value differed significantly between UAP and NCCP for all assays, p value <0.001. The novel low-delta cTnT algorithm (Table 1) ruled out 8 NSTE-ACS patients (3.5%), the cTnI algorithm and cTnI (sgx) algorithm ruled out 11 (4.8%) and 12 (5.2%) patients with NSTE-ACS, respectively. Moreover, the cTnT algorithm allocated 35.3% of the NCCP patients to discharge. Respective numbers for the cTnI(sgx) and cTnI algorithm were 30.6% and 33.5%. Comparing the ROC curves, the cTnT algorithm had significantly higher AUC compared to the cTnI(sgx) algorithm (p value =0.005, DeLong test). Conclusion The low-delta value algorithms correctly ruled in ≥95% of the NSTE-ACS patients whilst >30% of NCCP patients were ruled out. The cTnT algorithm had the best performance with a significant higher AUC compared to the cTnI(sgx) algorithm. Figure 1 Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Western Norway Regional Health Authority, Haukeland and Stavanger University hospital

scholarly journals Prioritisation of Structural Variant Calls in Cancer Genomes

2016 ◽  
Author(s):  
Miika J Ahdesmäki ◽  
Brad Chapman ◽  
Pablo E Cingolani ◽  
Oliver Hofmann ◽  
Aleksandr Sidoruk ◽  
...  
Keyword(s):  
Dna Sequence ◽  
Gene Fusion ◽  
Sequence Data ◽  
High Impact ◽  
Structural Variants ◽  
Short Read ◽  
Structural Variant ◽  
Dna Sequence Data ◽  
Cancer Genomes ◽  
Fusion Detection

AbstractSensitivity of short read DNA-sequencing for gene fusion detection is improving, but is hampered by the significant amount of noise composed of uninteresting or false positive hits in the data. In this paper we describe a tiered prioritisation approach to extract high impact gene fusion events. Using cell line and patient DNA sequence data we improve the annotation and interpretation of structural variant calls to best highlight likely cancer driving fusions. We also considerably improve on the automated visualisation of the high impact structural variants to highlight the effects of the variants on the resulting transcripts. The resulting framework greatly improves on readily detecting clinically actionable structural variants.

PD-L1 Expression in Esophageal Squamous Cell Carcinoma: A Comparative Analysis of 3 Different Antibodies

2020 ◽  
Author(s):  
Lei Guo ◽  
Ying Ji ◽  
Wei Guo ◽  
Huayu He ◽  
Peng Song ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
False Negative ◽  
False Negative Rate ◽  
High Sensitivity ◽  
Tissue Microarrays ◽  
Programmed Cell Death 1 ◽  
High Concordance

Abstract Background: Several studies have assessed the comparability of various immunohistochemical assays for programmed cell death 1 ligand 1 (PD-L1) expression in different kinds of tumours. However, there is a lack of relevant research on the detection efficacy of different PD-L1 clones in esophageal squamous cell carcinoma (ESCC). This study was performed to compare the PD-L1 expression results of three PD-L1 antibodies to assess their effectiveness.Methods: Three hundred and twenty-four cases of ESCC tissues in our medical institution were used to prepare tissue microarrays (TMAs). TMAs were stained with three validated assays (Ventana’s SP263 and Dako’s 28-8 and 22C3). Then, pathologists scored each tissue according to PD-L1 staining.Results: We found very high concordance when comparing 28-8 with SP263 at both the 1% (95.7%) and 50% (99.1%) cutoffs. Low overall concordance was found between 28-8 and 22C3 at the 1% cutoff (85.5%). Moreover, sensitivities of 91.2% and 87.5% were found for 28-8 compared with SP263 at the 1% and 50% cutoffs, respectively. Sensitivities of only 75.6% and 50% were found for 28-8 compared with 22C3 at the 1% and 50% cutoffs, respectively, which may result in more false negatives.Conclusions: We demonstrate that the PD-L1 SP263 shows high levels of overall agreement with 28-8 and relatively high sensitivity, with a low false negative rate. Thus, SP263 seems to be a reliable assay for PD-L1 testing in ESCC when considering pembrolizumab as immunotherapy.

scholarly journals Comparison of Diagnostic Efficacy of Visual Inspection of Cervix with Acetic Acid and Pap Smear for Prevention of Cervical Cancer: Is VIA Superseding Pap Smear?

2011 ◽  
Vol 3 (3) ◽  
pp. 131-134 ◽  
Author(s):  
Kamal Patil ◽  
G Durdi ◽  
KS Lakshmi
Keyword(s):  
Acetic Acid ◽  
Visual Inspection ◽  
Pap Smear ◽  
False Positive Rate ◽  
False Negative ◽  
False Negative Rate ◽  
High Sensitivity ◽  
Cross Sectional Study ◽  
Diagnostic Efficacy ◽  
Cross Sectional

ABSTRACT Objectives To estimate diagnostic efficacy of visual inspection with acetic acid (VIA) in comparison to Pap smear. Methods This cross-sectional study was carried over a period of 24 months on 200 women attending colposcopy clinic at KLES Dr Prabhakar Kore Hospital and Medical Research Center, Belgaum, India. All women enrolled in study underwent Pap smear, VIA, colposcopy and biopsy. The sensitivity, specificity, PPV, NPV, false-positive rate and false-negative rate were calculated for VIA, Pap smear and colposcopy with biopsy as the reference standard. Results In our study, sensitivity and specificity of VIA were found to be 86.95% and 72.51% respectively, and that of Pap smear 37.68% and 92.36% respectively. Colposcopy showed higher sensitivity (94.20%) and specificity (94.65%). Conclusion VIA is a suitable primary screening procedure alternative to Pap smear as it has high sensitivity and negative predictive value.

scholarly journals Prioritisation of structural variant calls in cancer genomes

PeerJ ◽  
2017 ◽  
Vol 5 ◽  
pp. e3166 ◽  
Author(s):  
Miika J. Ahdesmäki ◽  
Brad A. Chapman ◽  
Pablo Cingolani ◽  
Oliver Hofmann ◽  
Aleksandr Sidoruk ◽  
...  
Keyword(s):  
Dna Sequence ◽  
Gene Fusion ◽  
Sequence Data ◽  
High Impact ◽  
Structural Variants ◽  
Short Read ◽  
Structural Variant ◽  
Dna Sequence Data ◽  
Cancer Genomes ◽  
Fusion Detection

Sensitivity of short read DNA-sequencing for gene fusion detection is improving, but is hampered by the significant amount of noise composed of uninteresting or false positive hits in the data. In this paper we describe a tiered prioritisation approach to extract high impact gene fusion events from existing structural variant calls. Using cell line and patient DNA sequence data we improve the annotation and interpretation of structural variant calls to best highlight likely cancer driving fusions. We also considerably improve on the automated visualisation of the high impact structural variants to highlight the effects of the variants on the resulting transcripts. The resulting framework greatly improves on readily detecting clinically actionable structural variants.

A deep learning approach for filtering structural variants in short read sequencing data

2020 ◽  
Author(s):  
Yongzhuang Liu ◽  
Yalin Huang ◽  
Guohua Wang ◽  
Yadong Wang
Keyword(s):  
Deep Learning ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Whole Genome ◽  
Structural Variants ◽  
Sequencing Data ◽  
Clinical Practices ◽  
Short Read ◽  
Structural Variant ◽  
Variant Detection

Abstract Short read whole genome sequencing has become widely used to detect structural variants in human genetic studies and clinical practices. However, accurate detection of structural variants is a challenging task. Especially existing structural variant detection approaches produce a large proportion of incorrect calls, so effective structural variant filtering approaches are urgently needed. In this study, we propose a novel deep learning-based approach, DeepSVFilter, for filtering structural variants in short read whole genome sequencing data. DeepSVFilter encodes structural variant signals in the read alignments as images and adopts the transfer learning with pre-trained convolutional neural networks as the classification models, which are trained on the well-characterized samples with known high confidence structural variants. We use two well-characterized samples to demonstrate DeepSVFilter’s performance and its filtering effect coupled with commonly used structural variant detection approaches. The software DeepSVFilter is implemented using Python and freely available from the website at https://github.com/yongzhuang/DeepSVFilter.

scholarly journals An Iterative Algorithm for Semisupervised Classification of Hotspots on Bone Scintigraphies of Patients with Prostate Cancer

2021 ◽  
Vol 7 (8) ◽  
pp. 148
Author(s):  
Laura Providência ◽  
Inês Domingues ◽  
João Santos
Keyword(s):  
Prostate Cancer ◽  
Bone Scintigraphy ◽  
False Negative ◽  
False Negative Rate ◽  
High Sensitivity ◽  
Response To Treatment ◽  
Disease Evolution ◽  
Semisupervised Classification ◽  
Bone Scans ◽  
Sensitivity Specificity

Prostate cancer (PCa) is the second most diagnosed cancer in men. Patients with PCa often develop metastases, with more than 80% of this metastases occurring in bone. The most common imaging technique used for screening, diagnosis and follow-up of disease evolution is bone scintigraphy, due to its high sensitivity and widespread availability at nuclear medicine facilities. To date, the assessment of bone scans relies solely on the interpretation of an expert physician who visually assesses the scan. Besides this being a time consuming task, it is also subjective, as there is no absolute criteria neither to identify bone metastases neither to quantify them by a straightforward and universally accepted procedure. In this paper, a new algorithm for the false positives reduction of automatically detected hotspots in bone scintigraphy images is proposed. The motivation relies in the difficulty of building a fully annotated database. In this way, our algorithm is a semisupervised method that works in an iterative way. The ultimate goal is to provide the physician with a fast, precise and reliable tool to quantify bone scans and evaluate disease progression and response to treatment. The algorithm is tested in a set of bone scans manually labeled according to the patient’s medical record. The achieved classification sensitivity, specificity and false negative rate were 63%, 58% and 37%, respectively. Comparison with other state-of-the-art classification algorithms shows superiority of the proposed method.

scholarly journals Stroke Prehospital Informed Decision-Making Using EEG Recordings (SPIDER)

2019 ◽  
Vol 34 (s1) ◽  
pp. s87-s88
Author(s):  
Wayne Loudon ◽  
Andrew Wong ◽  
Simon Finnigan ◽  
Vivienne Tippett
Keyword(s):  
Decision Making ◽  
Acute Stroke ◽  
False Negative ◽  
False Negative Rate ◽  
Hospital Setting ◽  
High Sensitivity ◽  
Cost Effective ◽  
Large Vessel ◽  
Assessment Scores ◽  
Eeg Recordings

Introduction:The acute care of stroke involves the administration of a clot-dissolving drug (thrombolysis) and/or its removal using endovascular clot retrieval. Earlier intervention results in significantly improved patient outcomes. Clinical assessment scores have limitations, and studies have shown that even the most robust scores have a reported false-negative rate of >20% for large vessel occlusive strokes that may be eligible for clot retrieval, while inappropriate bypass may delay delivery of thrombolysis.1 Quantitative Electroencephalography (QEEG) has been shown to have a very high sensitivity and specificity in the identification of acute stroke versus matched controls in an in-hospital setting.(2,3)Aim:The SPIDER study commenced in Brisbane, Queensland on September 3, 2018, and is investigating the use of an EEG recorder to gather data on acute stroke patients presenting to a metropolitan ambulance service.Discussion:The data collected will guide the development of a simple numerical output reference to guide decision making. The data may aid in identifying large vessel occlusive stroke and patients eligible for endovascular intervention. The QEEG will provide a more accurate and cost-effective tool for the prehospital clinician over other imaging technologies and can guide early destination decisions. This presentation discusses the implementation of a pre-hospital research platform, integration with the clinical dispatch matrix, staff engagement, patient recruitment, and the success of the project so far.

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