Koy Chong Ng Kee Kwong

University of Edinburgh

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Co-Authors

Siddharthan Chandran

University of Edinburgh

Adam Waldman

University of Edinburgh

Daisy Mollison

University of Edinburgh

Elizabeth N. York

University of Edinburgh

Agniete Kampaite

University of Edinburgh

Rozanna Meijboom

University of Edinburgh

Michael J. Thrippleton

University of Edinburgh

Arpan R. Mehta

University of Edinburgh

Jenna M. Gregory

University of Aberdeen

Mark E. Bastin

University of Edinburgh

Cooperative Institutions

University of Birmingham

2,285

Institut de Virologie

1,688

Laboratoire des Sciences de l'Ingénieur, de l'Informatique et de l'Imagerie

1,468

NIHR Birmingham Biomedical Research Centre

1,439

Yorkshire Cancer Research

1,318

Urology Foundation

1,223

AstraZeneca (Brazil)

1,221

Association for Cancer Surgery

1,111

Stryker (United Kingdom)

1,076

Pfizer (United Kingdom)

857

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Leveraging molecular-QTL co-association to predict novel disease-associated genetic loci using a graph convolutional neural network

medRxiv (Cold Spring Harbor Laboratory) (2024)

Koy Chong Ng Kee Kwong Andrew D. Bretherick

Abstract Genome-wide association studies (GWAS) have successfully uncovered numerous associations between genetic variants and disease traits to date. Yet, identifying significantly associated loci remains a considerable challenge due to the concomitant multiple-testing burden of performing such analyses genome-wide. Here, we leverage the genetic associations of molecular traits – DNA CpG-site methylation status and RNA expression – to mitigate this problem. We encode their co-association across the genome using PinSage, a graph convolutional neural network-based recommender system previously deployed at Pinterest. We demonstrate, using this framework, that a model trained only on methylation quantitative trait locus (QTL) data could recapitulate over half (554,209/1,021,052) of possible SNP-RNA associations identified in a large expression QTL meta-analysis. Taking advantage of a recent ‘saturated’ map of height associations, we then show that height-associated loci predicted by a model trained on molecular-QTL data replicated comparably, following Bonferroni correction, to those that were genome-wide significant in UK Biobank (88% compared to 91%). On a set of 64 disease outcomes in UK Biobank, the same model identified 143 independent novel disease associations, with at least one additional association for 64% (41/64) of the disease outcomes examined. Excluding associations involving the MHC region, we achieve a total uplift of over 8% (128/1,548). We successfully replicated 38% (39/103) of the novel disease associations in an independent sample, with suggestive evidence for six additional associations from GWAS Catalog. Replicated associations included for instance that between rs10774625 (nearest gene: SH2B3/ATXN2) and coeliac disease, and that between rs12350420 (nearest gene: MVB12B) and glaucoma. For many GWAS, attaining such an enhancement by simply increasing sample size may be prohibitively expensive, or impossible depending on disease prevalence.

Genome-wide Association Study

Association (psychology)

Genetic architecture

Genetic Association

10.1101/2024.03.04.24303678

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Citations (0)

COVID-19, SARS and MERS: A neurological perspective

Journal of Clinical Neuroscience (2020)

Koy Chong Ng Kee Kwong Puja R. Mehta Garima Shukla Arpan R. Mehta

Highlights•COVID-19 is caused by a highly pathogenic coronavirus named "SARS-CoV-2".•COVID-19 pathophysiology is primarily defined by acute respiratory illness.•Several studies have revealed a possible neurological component to COVID-19.•Various neurological manifestations have also been reported for SARS and MERS.•Further research into the importance of neurological manifestations in COVID-19 is needed.AbstractCentral to COVID-19 pathophysiology is an acute respiratory infection primarily manifesting as pneumonia. Two months into the COVID-19 outbreak, however, a retrospective study in China involving more than 200 participants revealed a neurological component to COVID-19 in a subset of patients. The observed symptoms, the cause of which remains unclear, included impaired consciousness, skeletal muscle injury and acute cerebrovascular disease, and appeared more frequently in severe disease. Since then, findings from several studies have hinted at various possible neurological outcomes in COVID-19 patients. Here, we review the historical association between neurological complications and highly pathological coronaviruses including SARS-CoV, MERS-CoV and SARS-CoV-2. We draw from evidence derived from past coronavirus outbreaks, noting the similarities and differences between SARS and MERS, and the current COVID-19 pandemic. We end by briefly discussing possible mechanisms by which the coronavirus impacts on the human nervous system, as well as neurology-specific considerations that arise from the repercussions of COVID-19.

2019-20 coronavirus outbreak

Betacoronavirus

Coronavirus Infections

Sars virus

10.1016/j.jocn.2020.04.124

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Citations (161)

Supervised and unsupervised deep learning-based approaches for studying DNA replication spatiotemporal dynamics

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Koy Chong Ng Kee Kwong Ben Philps F. Smith Aleksandra Sobieska Naiming Chen

Abstract In eukaryotic cells, DNA replication is organised both spatially and temporally, as evidenced by the stage-specific spatial distribution of replication foci in the nucleus. Despite the genetic association of aberrant DNA replication with numerous human diseases, the labour-intensive methods employed to study DNA replication have hindered large-scale analyses of its roles in pathological processes. In this study, we first demonstrate that a convolutional neural network trained to classify S-phase stages based on DAPI and EdU patterns could identify altered replication dynamics in Rif1 -deficient mouse embryonic stem cells (mESCs), revealing a skewed distribution across the various S-phase stages. Given the possible practical limitations associated with a supervised framework, we proceed to show that the abnormal replication profile of Rif1 -deficient mESCs could further be detected by an unsupervised approach (based on self-supervised representation learning), which could additionally reconstruct progression through S-phase. Finally, we extend our approach to a well-characterised cellular model of inducible deregulated origin firing, involving cyclin E overexpression. Through parallel EdU- and PCNA-based analyses, we demonstrate the potential applicability of our method to patient samples, offering a means to identify the contribution of deregulated DNA replication to a plethora of pathogenic processes.

Replication

Dynamics

10.1101/2024.05.09.593366

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Death following pulmonary complications of surgery before and during the SARS-CoV-2 pandemic

British journal of surgery (2021)

Kenneth A McLean Sivesh K. Kamarajah Dhruva Chaudhry Rohan R Gujjuri Kyle Raubenheimer

This study aimed to determine the impact of pulmonary complications on death after surgery both before and during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic.

Pandemic

2019-20 coronavirus outbreak

Betacoronavirus

Coronavirus

Coronavirus Infections

10.1093/bjs/znab336

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Citations (35)

Rationale and design of the brain magnetic resonance imaging protocol for FutureMS: a longitudinal multi-centre study of newly diagnosed patients with relapsing-remitting multiple sclerosis in Scotland

Wellcome Open Research (2022)

Rozanna Meijboom Stewart Wiseman Elizabeth N. York Mark E. Bastin María del C. Valdés Hernández

Introduction: Multiple sclerosis (MS) is a chronic neuroinflammatory and neurodegenerative disease. MS prevalence varies geographically and is notably high in Scotland. Disease trajectory varies significantly between individuals and the causes for this are largely unclear. Biomarkers predictive of disease course are urgently needed to allow improved stratification for current disease modifying therapies and future targeted treatments aimed at neuroprotection and remyelination. Magnetic resonance imaging (MRI) can detect disease activity and underlying damage non-invasively in vivo at the micro and macrostructural level. FutureMS is a prospective Scottish longitudinal multi-centre cohort study, which focuses on deeply phenotyping patients with recently diagnosed relapsing-remitting MS (RRMS). Neuroimaging is a central component of the study and provides two main primary endpoints for disease activity and neurodegeneration. This paper provides an overview of MRI data acquisition, management and processing in FutureMS. FutureMS is registered with the Integrated Research Application System (IRAS, UK) under reference number 169955. Methods and analysis: MRI is performed at baseline (N=431) and 1-year follow-up, in Dundee, Glasgow and Edinburgh (3T Siemens) and in Aberdeen (3T Philips), and managed and processed in Edinburgh. The core structural MRI protocol comprises T1-weighted, T2-weighted, FLAIR and proton density images. Primary imaging outcome measures are new/enlarging white matter lesions (WML) and reduction in brain volume over one year. Secondary imaging outcome measures comprise WML volume as an additional quantitative structural MRI measure, rim lesions on susceptibility-weighted imaging, and microstructural MRI measures, including diffusion tensor imaging and neurite orientation dispersion and density imaging metrics, relaxometry, magnetisation transfer (MT) ratio, MT saturation and derived g-ratio measures. Conclusions: FutureMS aims to reduce uncertainty around disease course and allow for targeted treatment in RRMS by exploring the role of conventional and advanced MRI measures as biomarkers of disease severity and progression in a large population of RRMS patients in Scotland.

Relapsing remitting

10.12688/wellcomeopenres.17731.1

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Citations (10)

40 Years of CSF Toxicity Studies in ALS: What Have We Learnt About ALS Pathophysiology?

Frontiers in Molecular Neuroscience (2021)

Koy Chong Ng Kee Kwong Pratap K. Harbham Bhuvaneish T. Selvaraj Jenna M. Gregory Suvankar Pal

Based on early evidence of in vitro neurotoxicity following exposure to serum derived from patients with amyotrophic lateral sclerosis (ALS), several studies have attempted to explore whether cerebrospinal fluid (CSF) obtained from people with ALS could possess similar properties. Although initial findings proved inconclusive, it is now increasingly recognized that ALS-CSF may exert toxicity both in vitro and in vivo . Nevertheless, the mechanism underlying CSF-induced neurodegeneration remains unclear. This review aims to summarize the 40-year long history of CSF toxicity studies in ALS, while discussing the various mechanisms that have been proposed, including glutamate excitotoxicity, proteotoxicity and oxidative stress. Furthermore, we consider the potential implications of a toxic CSF circulatory system in the pathophysiology of ALS, and also assess its significance in the context of current ALS research.

Excitotoxicity

Neurotoxicity

Proteotoxicity

Pathophysiology

10.3389/fnmol.2021.647895

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Citations (13)

Dual site proteomic analyses reveal potential drug targets for cardiovascular disease

medRxiv (Cold Spring Harbor Laboratory) (2024)

Christopher Aldous Oldnall Koy Chong Ng Kee Kwong Jimi Wills Anne Richmond Tim Regan

Background: While genome-wide association studies (GWAS) hold great promise for unravelling disease pathophysiology, the translation of disease-associated genetic loci into clinically actionable information remains a challenge. Mendelian randomisation (MR), using expressed proteins as exposures and disease as an outcome, stands as a powerful analytical approach for leveraging GWAS data to identify potential drug-targets--at scale--in a data-driven manner. Cardiovascular disease (CVD) is a major health burden worldwide, and therefore is an important outcome for which to establish and prioritise potential therapeutic targets. Methods: In this study, we utilised generalised summary-data-based MR (GSMR) with novel mass-spectrometry-based isoform-specific protein groups measured from peripheral-blood mononuclear cell (PBMC) obtained from Generation Scotland and antibody-based plasma protein measures from UK Biobank as exposures, and two CVD and three CVD-related risk-factors from UK Biobank as outcomes. Further, we used colocalisation to assess support for a shared causal variant between the proteins and the disease outcomes providing further evidence supporting a causal link. Results: We evaluate expression of 5,114 isoform-specific protein groups in PBMCs from 862 individuals. GSMR analysis, using this data, found 16 putative causal proteins across three of the CVD/CVD-related risk-factors with seven supported by colocalisation analysis. Within the plasma GSMR analysis, 761 putative causal proteins were identified, of which 145 were supported by colocalisation. In addition, we go on to examine enrichment amongst the results and find enrichment of pathways which relate to cholesterol metabolism and platelet function. There was an overlap of three proteins between significant GSMR results in PBMCs and plasma, with two proteins (COMT and SWAP70) identifying opposite directions of effect of the relevant outcome, and one identifying a concordant direction of effect (HLA-DRA). Discussion: This study identifies a number of proteins and pathways that may be involved in CVD pathogenesis. It also demonstrates the importance of the location of protein measurement and the methods by which it is quantified. Our research contributes to ongoing efforts to bridge the gap between genotype and phenotype.

Genome-wide Association Study

Mendelian Randomization

Genetic Association

10.1101/2024.07.27.24311104

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Rim lesions are demonstrated in early relapsing–remitting multiple sclerosis using 3 T-based susceptibility-weighted imaging in a multi-institutional setting

Neuroradiology (2021)

Koy Chong Ng Kee Kwong Daisy Mollison Rozanna Meijboom Elizabeth N. York Agniete Kampaite

Abstract Purpose Rim lesions, characterised by a paramagnetic rim on susceptibility-based MRI, have been suggested to reflect chronic inflammatory demyelination in multiple sclerosis (MS) patients. Here, we assess, through susceptibility-weighted imaging (SWI), the prevalence, longitudinal volume evolution and clinical associations of rim lesions in subjects with early relapsing–remitting MS (RRMS). Methods Subjects ( n = 44) with recently diagnosed RRMS underwent 3 T MRI at baseline (M0) and 1 year (M12) as part of a multi-centre study. SWI was acquired at M12 using a 3D segmented gradient-echo echo-planar imaging sequence. Rim lesions identified on SWI were manually segmented on FLAIR images at both time points for volumetric analysis. Results Twelve subjects (27%) had at least one rim lesion at M12. A linear mixed-effects model, with ‘subject’ as a random factor, revealed mixed evidence for the difference in longitudinal volume change between rim lesions and non-rim lesions ( p = 0.0350 and p = 0.0556 for subjects with and without rim lesions, respectively). All 25 rim lesions identified showed T1-weighted hypointense signal. Subjects with and without rim lesions did not differ significantly with respect to age, disease duration or clinical measures of disability ( p > 0.05). Conclusion We demonstrate that rim lesions are detectable in early-stage RRMS on 3 T MRI across multiple centres, although their relationship to lesion enlargement is equivocal in this small cohort. Identification of SWI rims was subjective. Agreed criteria for defining rim lesions and their further validation as a biomarker of chronic inflammation are required for translation of SWI into routine MS clinical practice.

Susceptibility Weighted Imaging

Fluid-attenuated inversion recovery

Neuroradiology

10.1007/s00234-021-02768-x

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Citations (17)

Cerebrospinal fluid cytotoxicity in amyotrophic lateral sclerosis: a systematic review of in vitro studies

Brain Communications (2020)

Koy Chong Ng Kee Kwong Jenna M. Gregory Suvankar Pal Siddharthan Chandran Arpan R. Mehta

Abstract Various studies have suggested that a neurotoxic cerebrospinal fluid profile could be implicated in amyotrophic lateral sclerosis. Here, we systematically review the evidence for cerebrospinal fluid cytotoxicity in amyotrophic lateral sclerosis and explore its clinical correlates. We searched the following databases with no restrictions on publication date: PubMed, Embase and Web of Science. All studies that investigated cytotoxicity in vitro following exposure to cerebrospinal fluid from amyotrophic lateral sclerosis patients were considered for inclusion. Meta-analysis could not be performed, and findings were instead narratively summarized. Twenty-eight studies were included in our analysis. Both participant characteristics and study conditions including cerebrospinal fluid concentration, exposure time and culture model varied considerably across studies. Of 22 studies assessing cell viability relative to controls, 19 studies reported a significant decrease following exposure to cerebrospinal fluid from patients with amyotrophic lateral sclerosis, while three early studies failed to observe any difference. Seven of eight studies evaluating apoptosis observed significant increases in the levels of apoptotic markers following exposure to cerebrospinal fluid from patients with amyotrophic lateral sclerosis, with the remaining study reporting a qualitative difference. Although five studies investigated the possible relationship between cerebrospinal fluid cytotoxicity and patient characteristics, such as age, gender and disease duration, none demonstrated an association with any of the factors. In conclusion, our analysis suggests that cerebrospinal fluid cytotoxicity is a feature of sporadic and possibly also of familial forms of amyotrophic lateral sclerosis. Further research is, however, required to better characterize its underlying mechanisms and to establish its possible contribution to amyotrophic lateral sclerosis pathophysiology.

10.1093/braincomms/fcaa121

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A060 INNER CITY ASTHMA TELE-MEDICINE DURING COVID PANDEMIC

Annals of Allergy Asthma & Immunology (2020)

Koy Chong Ng Kee Kwong

Pandemic

2019-20 coronavirus outbreak

Asthma management

10.1016/j.anai.2020.08.054

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