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Sökning: WFRF:(Brueffer Christian)

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  • Brueffer, Christian, et al. (författare)
  • Abstract P4-09-03: On the development and clinical value of RNA-sequencing-based classifiers for prediction of the five conventional breast cancer biomarkers: A report from the population-based multicenter SCAN-B study
  • 2018
  • Ingår i: San Antonio Breast Cancer Symposium, 2017,San Antonio, United States,2017-12-05 - 2017-12-09. - American Association for Cancer Research Inc..
  • Konferensbidrag (refereegranskat)abstract
    • Background:In early breast cancer, five histopathological biomarkers are part of current clinical routines and used for determining prognosis and treatment: estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (ERBB2/HER2), Ki67, and Nottingham histological grade (NHG). We aimed to develop classifiers for these biomarkers based on tumor mRNA-sequencing (RNA-seq), compare classification performance to conventional histopathology, and test whether RNA-seq-based predictors could add value for patient risk-stratification.Patients and Methods:In total, 3678 breast tumors were studied. For 405 breast tumors in the training cohort, a comprehensive histopathological biomarker evaluation was performed by three pathology readings to estimate inter-pathologist variability on the original diagnostic slides as well as on repeat immunostains for this study, and the consensus biomarker status for all five conventional biomarkers was determined. Whole transcriptome gene expression profiling was performed by RNA-sequencing on the Illumina platform. Using RNA-seq-derived tumor gene expression data as input, single-gene classifiers (SGC) and multi-gene classifiers (MGC) were trained on the consensus pathology biomarker labels. The trained classifiers were tested on an independent prospective population-based series of 3273 primary breast cancer cases from the multicenter SCAN-B study with median 41 months follow-up (ClinicalTrials.gov identifier NCT02306096), and classifications were evaluated by agreement statistics and by Kaplan-Meier and Cox regression survival analyses.Results:For the histopathological evaluation, pathologist evaluation concordance was high for ER, PgR, and HER2 (average kappa values of .920, .891, and .899, respectively), but moderate for Ki67 and NHG (.734 and .581). Classification concordance between RNA-seq classifiers and histopathology for the independent 3273-cohort was similar to that within histopathology assessments, with SGCs slightly outperforming MGCs. Importantly, patients with discordant results, classified as hormone responsive (HoR+) by histopathology but non-hormone responsive by MGC, presented with significantly inferior overall survival compared to patients with concordant results. These results extended to patients with no adjuvant systemic therapy (hazard ratio, HR, 4.54; 95% confidence interval, CI, 1.42-14.5), endocrine therapy alone (HR 3.46; 95% CI, 2.01-5.95), or receiving chemotherapy (HR 2.57; 95% CI 1.13-5.86). For HoR+ cases receiving endocrine therapy alone, the MGC HoR classifier remained significant after multivariable adjustment (HR 3.14; 95% CI, 1.75-5.65).Conclusions:RNA-seq-based classifiers for the five key early breast cancer biomarkers were generally equivalent to conventional histopathology with regards to classification error rate. However, when benchmarked using overall survival, our RNA-seq classifiers provided added clinical value in particular for cases that are determined by histopathology to be hormone-responsive but by RNA-seq appear hormone-insensitive and have a significantly poorer outcome when treated with endocrine therapy alone
  • Brueffer, Christian, et al. (författare)
  • Biopython Project Update 2016
  • 2016
  • Ingår i: Bioinformatics Open Source Conference, 2016,Orlando, United States,2016-07-08 - 2016-07-09.
  • Konferensbidrag (övrigt vetenskapligt)abstract
    • The Biopython Project is a long-running distributed collaborative effort, supported by the Open Bioinformatics Foundation, which develops a freely available Python library for biological computation.We present here details of the latest Biopython release - version 1.66. New features include: extended Bio.KEGG and Bio.Graphics modules to support drawing KEGG pathways with transparency; extended “abi” Bio.SeqIO parser to decode almost all documented fields used by ABIF instruments; a QCPSuperimposer module using the Quaternion Characteristic Polynomial algorithm for superimposing structures to Bio.PDB; and an extended Bio.Entrez module to implement the NCBI Entrez Citation Matching function and to support NCBI XML files with XSD schemas. Additionally we fixed miscellaneous bugs, enhanced our test suite and continued our efforts to abide by the PEP8 coding style guidelines.We are currently preparing a new release – version 1.67 – that will deprecate the ability to compare SeqRecord objects with “==”, which sometimes lead to surprising results. In addition it will feature a new experimental Bio.phenotype module for working with Phenotype Microarray data; updates to Bio.Data toinclude NCBI genetic code table 25, covering Candidate Division SR1 and Gracilibacteria; an update to Bio.Restriction to include the REBASE May 2016 restriction enzyme list; updates to BioSQL to use foreign keys with SQLite3 databases; as well as corrections to the Bio.Entrez module and the MMCIF structure parser.Our website has been migrated from MediaWiki to GitHub Pages and is now under version control. The continuous integration process on GitHub has been enhanced by including external services like Landscape, Quantified Code and Codecov to perform quality review, test coverage analysis and generation of quality metrics.Finally, our range of Docker containers has been greatly enhanced. In addition to a basic container that includes Python 2 and 3 with Biopython and all its dependencies, as well as a BioSQL container, we now also provide two versions of Jupyter notebook containers: a basic one, and a version including the Biopython tutorial as notebooks.
  • Brueffer, Christian, et al. (författare)
  • Clinical Value of RNA Sequencing–Based Classifiers for Prediction of the Five Conventional Breast Cancer Biomarkers: A Report From the Population-Based Multicenter Sweden Cancerome Analysis Network—Breast Initiative
  • 2018
  • Ingår i: JCO Precision Oncology. - American Society of Clinical Oncology. - 2473-4284. ; 2, s. 1-18
  • Tidskriftsartikel (refereegranskat)abstract
    • PurposeIn early breast cancer (BC), five conventional biomarkers—estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), Ki67, and Nottingham histologic grade (NHG)—are used to determine prognosis and treatment. We aimed to develop classifiers for these biomarkers that were based on tumor mRNA sequencing (RNA-seq), compare classification performance, and test whether such predictors could add value for risk stratification.MethodsIn total, 3,678 patients with BC were studied. For 405 tumors, a comprehensive multi-rater histopathologic evaluation was performed. Using RNA-seq data, single-gene classifiers and multigene classifiers (MGCs) were trained on consensus histopathology labels. Trained classifiers were tested on a prospective population-based series of 3,273 BCs that included a median follow-up of 52 months (Sweden Cancerome Analysis Network—Breast [SCAN-B], ClinicalTrials.gov identifier: NCT02306096), and results were evaluated by agreement statistics and Kaplan-Meier and Cox survival analyses.ResultsPathologist concordance was high for ER, PgR, and HER2 (average κ, 0.920, 0.891, and 0.899, respectively) but moderate for Ki67 and NHG (average κ, 0.734 and 0.581). Concordance between RNA-seq classifiers and histopathology for the independent cohort of 3,273 was similar to interpathologist concordance. Patients with discordant classifications, predicted as hormone responsive by histopathology but non–hormone responsive by MGC, had significantly inferior overall survival compared with patients who had concordant results. This extended to patients who received no adjuvant therapy (hazard ratio [HR], 3.19; 95% CI, 1.19 to 8.57), or endocrine therapy alone (HR, 2.64; 95% CI, 1.55 to 4.51). For cases identified as hormone responsive by histopathology and who received endocrine therapy alone, the MGC hormone-responsive classifier remained significant after multivariable adjustment (HR, 2.45; 95% CI, 1.39 to 4.34).ConclusionClassification error rates for RNA-seq–based classifiers for the five key BC biomarkers generally were equivalent to conventional histopathology. However, RNA-seq classifiers provided added clinical value in particular for tumors determined by histopathology to be hormone responsive but by RNA-seq to be hormone insensitive.
  • Brueffer, Christian, et al. (författare)
  • TopHat-Recondition : A post-processor for TopHat unmapped reads
  • 2016
  • Ingår i: BMC Bioinformatics. - BioMed Central. - 1471-2105. ; 17:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: TopHat is a popular spliced junction mapper for RNA sequencing data, and writes files in the BAM format - the binary version of the Sequence Alignment/Map (SAM) format. BAM is the standard exchange format for aligned sequencing reads, thus correct format implementation is paramount for software interoperability and correct analysis. However, TopHat writes its unmapped reads in a way that is not compatible with other software that implements the SAM/BAM format. Results: We have developed TopHat-Recondition, a post-processor for TopHat unmapped reads that restores read information in the proper format. TopHat-Recondition thus enables downstream software to process the plethora of BAM files written by TopHat. Conclusions: TopHat-Recondition can repair unmapped read files written by TopHat and is freely available under a 2-clause BSD license on GitHub: https://github.com/cbrueffer/tophat-recondition.
  • Chapman, Lesley M, et al. (författare)
  • SVCurator: A Crowdsourcing app to visualize evidence of structural variants for the human genome
  • 2019
  • Annan publikation (övrigt vetenskapligt)abstract
    • A high quality benchmark for small variants encompassing 88 to 90% of the reference genome has been developed for seven Genome in a Bottle (GIAB) reference samples. However a reliable benchmark for large indels and structural variants (SVs) is yet to be defined. In this study, we manually curated 1235 SVs which can ultimately be used to evaluate SV callers ortrain machine learning models. We developed a crowdsourcing app - SVCurator - to help curators manually review large indels and SVs within the human genome, and report their genotype and size accuracy.SVCurator is a Python Flask-based web platform that displays images from short, long, and linked read sequencing data from the GIAB Ashkenazi Jewish Trio son [NIST RM 8391/HG002]. We asked curators to assign labels describing SV type (deletion or insertion), size accuracy, and genotype for 1235 putative insertions and deletions sampled from different size bins between 20 and 892,149 bp. The crowdsourced results were highly concordant with 37 out ofthe 61 curators having at least 78% concordance with a set of ‘expert’ curators, where there was 93% concordance amongst ‘expert’ curators. This produced high confidence labels for 935 events. When compared to the heuristic-based draft benchmark SV callset from GIAB, the SVCurator crowdsourced labels were 94.5% concordant with the benchmark set. We found that curators can successfully evaluate putative SVs when given evidence from multiple sequencing technologies.
  • Förnvik, Daniel, et al. (författare)
  • Detection of circulating tumor cells and circulating tumor DNA before and after mammographic breast compression in a cohort of breast cancer patients scheduled for neoadjuvant treatment
  • 2019
  • Ingår i: Breast Cancer Research and Treatment. - Springer. - 1573-7217. ; 177:2, s. 447-455
  • Tidskriftsartikel (refereegranskat)abstract
    • PurposeIt is not known if mammographic breast compression of a primary tumor causes shedding of tumor cells into the circulatory system. Little is known about how the detection of circulating biomarkers such as circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) is affected by breast compression intervention.MethodsCTCs and ctDNA were analyzed in blood samples collected before and after breast compression in 31 patients with primary breast cancer scheduled for neoadjuvant therapy. All patients had a central venous access to allow administration of intravenous neoadjuvant chemotherapy, which enabled blood collection from superior vena cava, draining the breasts, in addition to sampling from a peripheral vein.ResultsCTC and ctDNA positivity was seen in 26% and 65% of the patients, respectively. There was a significant increase of ctDNA after breast compression in central blood (p = 0.01), not observed in peripheral testing. No increase related with breast compression was observed for CTC. ctDNA positivity was associated with older age (p = 0.05), and ctDNA increase after breast compression was associated with high Ki67 proliferating tumors (p = 0.04). CTCs were more abundant in central compared to peripheral blood samples (p = 0.04).ConclusionsThere was no significant release of CTCs after mammographic breast compression but more CTCs were present in central compared to peripheral blood. No significant difference between central and peripheral levels of ctDNA was observed. The small average increase in ctDNA after breast compression is unlikely to be clinically relevant. The results give support for mammography as a safe procedure from the point of view of CTC and ctDNA shedding to the blood circulation. The results may have implications for the standardization of sampling procedures for circulating tumor markers.
  • Grüning, Björn, et al. (författare)
  • Bioconda: A sustainable and comprehensive software distribution for the life sciences
  • 2017
  • Annan publikation (övrigt vetenskapligt)abstract
    • We present Bioconda (https://bioconda.github.io), a distribution of bioinformatics software for the lightweight, multi-platform and language-agnostic package manager Conda. Currently, Bioconda offers a collection of over 3000 software packages, which is continuously maintained, updated, and extended by a growing global community of more than 200 contributors. Bioconda improves analysis reproducibility by allowing users to define isolated environments with defined software versions, all of which are easily installed and managed without administrative privileges.
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