3D genomic capture of regulatory immuno-genetic profiles in COVID-19 patients for prognosis of severe COVID disease outcome

Hunter, Ewan; Koutsothanasi, Christina; Wilson, Adam J.; Fc, Santos; Salter, Matthew; Powell, Ryan; Dring, Ann; Brajer, Paulina; Egan, Benedict; Jw, Westra; Ramadass, Aroul; Messer, William B.; Brunton, Amanda E; Lyski, Zoë L; Vancheeswaran, Rama; Barlow, Andrew; Pchejetski, Dmitri; Pa, Robbins; Mellor, Jane; Akoulitchev, Alexandre

doi:10.1101/2021.03.14.435295

Cited by 6 publications

(15 citation statements)

References 86 publications

(142 reference statements)

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“…EpiSwitch ® 3C libraries, with chromosome conformation analytes converted to sequence based tags, were prepared from frozen whole blood samples using EpiSwitch ® protocols following the manufacturer's instructions (Oxford BioDynamics Plc) [15]. All samples were processed under biological containment level CL2+.…”

Section: Preparation Of 3d Genomic Templatesmentioning

confidence: 99%

“…The top array-derived markers identified in our previous study were interrogated using OBD's proprietary primer design software package to identify genomic positions suitable for a hydrolysis probe based real time PCR (RT-PCR) assay [15]. Briefly, the top array-derived markers associated with prognostic potential to differentiate between mild and severe COVID disease outcomes were filtered on fold change and adjusted p value.…”

Section: Translation Of Array-based 3d Genomic Markers To Pcr Readoutsmentioning

confidence: 99%

“…As SARS-CoV-2 variants can spread faster than the original strain and some variants may be resistant to the neutralizing antibodies produced by individuals after vaccination, the risk of a widespread disease resurgence and the continued societal burdens of an extended pandemic are real[39][40][41].While many molecular tests have been developed to detect the presence of the SARS-CoV-2 virus, a reduced to practice molecular test with high prognostic accuracy for severe outcomes following a SARS-CoV-2 infection represents an unmet healthcare need. Here we extended on a previously published study and describe the validation of a blood-based biomarkers for the prediction of severe symptoms of COVID-19 disease, which can place individuals in the intensive care support[15]. We identified a set of six biomarkers associated with systemic immune-genetic dysregulation, that when processed and measured by qPCR on human blood samples provided an accurate predictive readout on likely COVID-19 disease severity.…”

mentioning

confidence: 94%

“…Recently, we reported on the use of EpiSwitch®, a chromosome conformation capture (3C) methodology that has been reduced to practice for the discovery of blood-based 3D genomic biomarkers and patient stratification in a variety of immune-related diseases, to identify prognostic profiles that could serve as a potential blood-based molecular classifier for the prediction of COVID-19 disease severity [15][16][17][18][19][20][21][22]. Specifically, we used EpiSwitch Explorer 3D whole genome arrays to identify changes at immune-related loci in blood samples from a multi-national cohort of COVID-19 patients.…”

Section: Introductionmentioning

confidence: 99%

“…The proteins encoded at the locations of the 3D genomic marker leads were involved in biological pathways with direct relevance to immune system function including T-cell signalling, macrophage-stimulating protein (MSP)-RON signalling, and calcium signalling [15]. The aim of this study was an extension of our previous work, using the established EpiSwitch platform to translate the array-derived 3D genomic biomarkers into a qPCR-based testing format, refine and reduce the biomarker panel, build a classification model and perform validation on independent COVID-19 patient cohorts.…”

Section: Introductionmentioning

confidence: 99%

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Development and validation of blood-based prognostic biomarkers for severity of COVID disease outcome using EpiSwitch 3D genomic regulatory immuno-genetic profiling

Hunter¹,

Koutsothanasi²,

Wilson³

et al. 2021

Preprint

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The COVID-19 pandemic has raised several global public health challenges to which the international medical community have responded. Diagnostic testing and the development of vaccines against the SARS-CoV-2 virus have made remarkable progress to date. As the population is now faced with the complex lifestyle and medical decisions that come with living in a pandemic, a forward-looking understanding of how a COVID-19 diagnosis may affect the health of an individual represents a pressing need. Previously we used whole genome microarray to identify 200 3D genomic marker leads that could predict mild or severe COVID-19 disease outcomes from blood samples in a multinational cohort of COVID-19 patients. Here, we focus on the development and validation of a qPCR assay to accurately predict severe COVID-19 disease requiring intensive care unit (ICU) support and/or mechanical ventilation. From 200 original biomarker leads we established a classification model containing six markers. The markers were qualified and validated on 38 COVID-19 patients from an independent cohort. Overall, the six-marker model obtained a positive predictive value of 93% and balanced accuracy of 88% across 116 patients for the prognosis of COVID-19 severity requiring ICU care/ventilation support. The six-marker signature identifies individuals at the highest risk of developing severe complications in COVID-19 with high predictive accuracy and can assist in patient prognosis and clinical management decisions.

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Section: Preparation Of 3d Genomic Templatesmentioning

confidence: 99%

Section: Translation Of Array-based 3d Genomic Markers To Pcr Readoutsmentioning

confidence: 99%

mentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Development and validation of blood-based prognostic biomarkers for severity of COVID disease outcome using EpiSwitch 3D genomic regulatory immuno-genetic profiling

Hunter¹,

Koutsothanasi²,

Wilson³

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

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When 3D genome technology meets viral infection, including SARS‐CoV‐2

Liang

Wang

Wang³

et al. 2022

Journal of Medical Virology

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Mammalian chromosomes undergo varying degrees of compression to form three‐dimensional genome structures. These three‐dimensional structures undergo dynamic and precise chromatin interactions to achieve precise spatial and temporal regulation of gene expression. Most eukaryotic DNA viruses can invade their genomes into the nucleus. However, it is still poorly understood how the viral genome is precisely positioned after entering the host cell nucleus to find the most suitable location and whether it can specifically interact with the host genome to hijack the host transcriptional factories or even integrate into the host genome to complete its transcription and replication rapidly. Chromosome conformation capture technology can reveal long‐range chromatin interactions between different chromosomal sites in the nucleus, potentially providing a reference for viral DNA‐host chromatin interactions. This review summarized the research progress on the three‐dimensional interaction between virus and host genome and the impact of virus integration into the host genome on gene transcription regulation, aiming to provide new insights into chromatin interaction and viral gene transcription regulation, laying the foundation for the treatment of infectious diseases.

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Development and validation of blood-based predictive biomarkers for response to PD-(L)-1 checkpoint inhibitors: evidence of a universal systemic core of 3D immunogenetic profiling across multiple oncological indications

Hunter¹,

Dizfouli²,

Koutsothanasi³

et al. 2021

Preprint

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Unprecedented advantages in cancer treatment with immune checkpoint inhibitors (ICI) remain limited to a subset of patients. Systemic analyses of the regulatory 3D genome architecture linked to individual epigenetics and immunogenetic controls associated with tumour immune evasion mechanisms and immune checkpoint pathways reveals a highly prevalent patient molecular profiles predictive of response to PD-(L)1 immune checkpoint inhibitors. A clinical blood test based on the set of 8 3D genomic biomarkers has been developed and validated on several independent cancer patient cohorts to predict response to PD-(L)1 immune checkpoint inhibition. The predictive 8 biomarker set is derived from prospective observational clinical trials, representing 229 treatments with Pembrolizumab, Atezolizumab, Durvalumab, in diverse indications: melanoma, non-small cell lung, urethral, hepatocellular, bladder, prostate cancer, head and neck, vulvar, colon, breast, bone, brain, lymphoma, larynx cancer, and cervix cancers. The 3D genomic 8 biomarker panel for response to immune checkpoint therapy achieved high accuracy up to 85%, sensitivity of 93% and specificity of 82%. This study demonstrates that a 3D genomic approach could be used to develop a predictive clinical assay for response to PD-(L)1 checkpoint inhibition in cancer patients.

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3D genomic capture of regulatory immuno-genetic profiles in COVID-19 patients for prognosis of severe COVID disease outcome

Cited by 6 publications

References 86 publications

Development and validation of blood-based prognostic biomarkers for severity of COVID disease outcome using EpiSwitch 3D genomic regulatory immuno-genetic profiling

Development and validation of blood-based prognostic biomarkers for severity of COVID disease outcome using EpiSwitch 3D genomic regulatory immuno-genetic profiling

When 3D genome technology meets viral infection, including SARS‐CoV‐2

Development and validation of blood-based predictive biomarkers for response to PD-(L)-1 checkpoint inhibitors: evidence of a universal systemic core of 3D immunogenetic profiling across multiple oncological indications

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