Publications by authors named "Paul K S Chan"

352 Publications

A Bayesian method for synthesizing multiple diagnostic outcomes of COVID-19 tests.

R Soc Open Sci 2021 Sep 15;8(9):201867. Epub 2021 Sep 15.

JC School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong SAR, People's Republic of China.

The novel coronavirus disease 2019 (COVID-19) has spread worldwide and threatened human life. Diagnosis is crucial to contain the spread of SARS-CoV-2 infections and save lives. Diagnostic tests for COVID-19 have varying sensitivity and specificity, and the false-negative results would have substantial consequences to patient treatment and pandemic control. To detect all suspected infections, multiple testing is widely used. However, it may be challenging to build an assertion when the testing results are inconsistent. Considering the situation where there is more than one diagnostic outcome for each subject, we proposed a Bayesian probabilistic framework based on the sensitivity and specificity of each diagnostic method to synthesize a posterior probability of being infected by SARS-CoV-2. We demonstrated that the synthesized posterior outcome outperformed each individual testing outcome. A user-friendly web application was developed to implement our analytic framework with free access via http://www2.ccrb.cuhk.edu.hk/statgene/COVID_19/. The web application enables the real-time display of the integrated outcome incorporating two or more tests and calculated based on Bayesian posterior probability. A simulation-based assessment demonstrated higher accuracy and precision of the Bayesian probabilistic model compared with a single-test outcome. The online tool developed in this study can assist physicians in making clinical evaluations by effectively integrating multiple COVID-19 tests.
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http://dx.doi.org/10.1098/rsos.201867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441124PMC
September 2021

Mer Analyses Reveal Different Evolutionary Histories of Alpha, Beta, and Gamma Papillomaviruses.

Int J Mol Sci 2021 Sep 6;22(17). Epub 2021 Sep 6.

Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Papillomaviruses (PVs) are a heterogeneous group of DNA viruses that can infect fish, birds, reptiles, and mammals. PVs infecting humans (HPVs) phylogenetically cluster into five genera (Alpha-, Beta-, Gamma-, Mu- and Nu-PV), with differences in tissue tropism and carcinogenicity. The evolutionary features associated with the divergence of are not well understood. Using a combination of -mer distributions, genetic metrics, and phylogenetic algorithms, we sought to evaluate the characteristics and differences of Alpha-, Beta- and Gamma-PVs constituting the majority of HPV genomes. A total of 640 PVs including 442 HPV types, 27 non-human primate PV types, and 171 non-primate animal PV types were evaluated. Our analyses revealed the highest genetic diversity amongst Gamma-PVs compared to the Alpha and Beta PVs, suggesting reduced selective pressures on Gamma-PVs. Using a sequence alignment-free trimer ( = 3) phylogeny algorithm, we reconstructed a phylogeny that grouped most HPV types into a monophyletic clade that was further split into three branches similar to alignment-based classifications. Interestingly, a subset of low-risk Alpha HPVs (the species Alpha-2, 3, 4, and 14) split from other HPVs and were clustered with non-human primate PVs. Surprisingly, the trimer-constructed phylogeny grouped the Gamma-6 species types originally isolated from the cervicovaginal region with the main Alpha-HPV clade. These data indicate that characterization of papillomavirus heterogeneity via orthogonal approaches reveals novel insights into the biological understanding of HPV genomes.
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http://dx.doi.org/10.3390/ijms22179657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432194PMC
September 2021

Risk-adjusted zero-inflated Poisson CUSUM charts for monitoring influenza surveillance data.

BMC Med Inform Decis Mak 2021 07 30;21(Suppl 2):96. Epub 2021 Jul 30.

Department of Gynecology and Obstetrics, Luzhou People's Hospital, Luzhou, China.

Background: The influenza surveillance has been received much attention in public health area. For the cases with excessive zeroes, the zero-inflated Poisson process is widely used. However, the traditional control charts based on zero-inflated Poisson model, ignore the association between influenza cases and risk factors, and thus may lead to unexpected mistakes when implementing monitoring charts.

Method: In this paper, we proposed risk-adjusted zero-inflated Poisson cumulative sum control charts, in which the risk factors were put to adjust the risk of influenza and the adjustment was made by zero-inflated Poisson regression. We respectively proposed the control chart monitoring the parameters individually and simultaneously.

Results: The performance of our proposed risk-adjusted zero-inflated Poisson cumulative sum control chart was evaluated and compared with the unadjusted standard cumulative sum control charts in simulation studies. The results show that for different distribution of impact factors and different coefficients, the risk-adjusted cumulative sum charts can generate much less false alarm than the standard ones. Finally, the influenza surveillance data from Hong Kong is used to illustrate the application of the proposed chart.

Conclusions: Our results suggest that the adjusted cumulative sum control chart we proposed is more accurate and credible than the unadjusted standard control charts because of the lower false alarm rate of the adjusted ones. Even the unadjusted control charts may signal a little faster than the adjusted ones, the alarm they raise may have low credibility since they also raise alarm frequently even the processes are in control. Thus we suggest using the risk-adjusted cumulative sum control charts to monitor the influenza surveillance data to alert accurately, credibly and relatively quickly.
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http://dx.doi.org/10.1186/s12911-021-01443-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323201PMC
July 2021

Iris Depigmentation in the Prediction of Cytomegalovirus Anterior Uveitis.

Ocul Immunol Inflamm 2021 Jul 20:1-6. Epub 2021 Jul 20.

Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong.

Purpose: We hypothesize that the presence of iris depigmentation is associated with the prediction of cytomegalovirus (CMV) as the etiology of chronic or recurrent anterior uveitis.

Methods: A prospective cohort study on patients with recurrent or chronic anterior uveitis. Pre-operative data on iris depigmentation and corneal endothelial cell densities were compared between eyes with and without CMV.

Results: Forty-one eyes of 38 subjects with a mean age of 61.1 ± 11.2 years old were recruited. Seventeen eyes were positive for CMV. A greater proportion of eyes with CMV showed severe or diffuse iris depigmentation than eyes without CMV, and possessed larger corneal endothelial cells ( = .028). When severe iris depigmentation was present with a reduced endothelial cell density, the positive and negative predictive values were raised to 100.0% and 64.9% from 41.5% and 58.5%, respectively.

Conclusion: Iris depigmentation is a potential clinical biomarker in predicting CMV in chronic or recurrent anterior uveitis.
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http://dx.doi.org/10.1080/09273948.2021.1952277DOI Listing
July 2021

Dissection of Aberration for Cervical Adenocarcinoma Outcomes.

Cancers (Basel) 2021 Jun 28;13(13). Epub 2021 Jun 28.

Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115, USA.

Personalized treatment of genetically stratified subgroups has the potential to improve outcomes in many malignant tumors. This study distills clinically meaningful prognostic/predictive genomic marker for cervical adenocarcinoma using signature genomic aberrations and single-point nonsynonymous mutation-specific droplet digital PCR (ddPCR). Mutations in E542K, E545K, or H1047R were detected in 41.7% of tumors. mutation detected in the patient's circulating DNA collected before treatment or during follow-up was significantly associated with decreased progression-free survival or overall survival. mutation in the circulating DNA during follow-up after treatment predicted recurrence with 100% sensitivity and 64.29% specificity. It is the first indication of the predictive power of mutations in cervical adenocarcinoma. The work contributes to the development of liquid biopsies for follow up surveillance and a possibility of tailoring management of this particular women's cancer.
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http://dx.doi.org/10.3390/cancers13133218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269188PMC
June 2021

Alterations in the Gut Virome in Obesity and Type 2 Diabetes Mellitus.

Gastroenterology 2021 Jun 25. Epub 2021 Jun 25.

Center for Gut Microbiota Research, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China; Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China; Institute of Digestive Disease, State Key Laboratory of Digestive Diseases, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China; Microbiota I-Center (MagIC) Limited, Hong Kong, China. Electronic address:

Background & Aims: Obesity and type 2 diabetes mellitus (T2DM) are associated with changes in the gut bacterial composition, but little is known about the role of the viral community (virome) in disease development. This study aims to characterize the gut virome alterations in obese subjects with or without T2DM.

Methods: There were 128 obese subjects (body mass index ≥28 kg/m) and 101 lean controls (body mass index ≥18.5 and <23 kg/m) recruited from 2 regions in China (Hong Kong and Kunming). Fecal virome and bacteriome were profiled by shotgun metagenomic sequencing. Gut virome, bacteriome, and viral-bacterial correlations were compared between obese subjects and lean controls.

Results: Obese subjects, especially those with T2DM (ObT2), had a decreased gut viral richness and diversity compared with lean controls in the Hong Kong cohort (P < .05), while no significant differences were observed in the Kunming cohort. Eleven viruses, including Escherichia phage, Geobacillus phage, and Lactobacillus phage were enriched in obese subjects (q < .1). Besides, 17 differentially abundant viruses were identified between ObT2 and lean controls (q < .1). Further ecologic analysis revealed that intensive transkingdom correlations between viruses and bacteria observed in lean controls were significantly decreased in ObT2 subjects (P < .001).

Conclusions: Obesity is characterized by altered viral taxonomic composition and weakened viral-bacterial correlations compared with lean controls. Obesity accompanied with T2DM may aggravate the obesity-associated virus signatures, signifying that the gut virome may play an important role in the development of obesity and T2DM. Geographic factors also contributed to the variations of gut virome in obesity and T2DM.
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http://dx.doi.org/10.1053/j.gastro.2021.06.056DOI Listing
June 2021

Current Updates on Cancer-Causing Types of Human Papillomaviruses (HPVs) in East, Southeast, and South Asia.

Cancers (Basel) 2021 May 30;13(11). Epub 2021 May 30.

Department of Microbiology, The Chinese University of Hong Kong, Hong Kong SAR 999077, China.

Human papillomavirus (HPV) infection remains one of the most prominent cancer-causing DNA viruses, contributing to approximately 5% of human cancers. While association between HPV and cervical cancers has been well-established, evidence on the attribution of head and neck cancers (HNC) to HPV have been increasing in recent years. Among the cancer-causing HPV genotypes, HPV16 and 18 remain the major contributors to cancers across the globe. Nonetheless, the distribution of HPV genotypes in ethnically, geographically, and socio-economically diverse East, Southeast, and South Asia may differ from other parts of the world. In this review, we garner and provide updated insight into various aspects of HPV reported in recent years (2015-2021) in these regions. We included: (i) the HPV genotypes detected in normal cancers of the uterine cervix and head and neck, as well as the distribution of the HPV genotypes by geography and age groups; (ii) the laboratory diagnostic methods and treatment regimens used within these regions; and (iii) the oncogenic properties of HPV prototypes and their variants contributing to carcinogenesis. More importantly, we also unveil the similarities and discrepancies between these aspects, the areas lacking study, and the challenges faced in HPV studies.
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http://dx.doi.org/10.3390/cancers13112691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198295PMC
May 2021

Inferring the Association between the Risk of COVID-19 Case Fatality and N501Y Substitution in SARS-CoV-2.

Viruses 2021 04 8;13(4). Epub 2021 Apr 8.

JC School of Public Health and Primary Care, Chinese University of Hong Kong, Hong Kong, China.

As COVID-19 is posing a serious threat to global health, the emerging mutation in SARS-CoV-2 genomes, for example, N501Y substitution, is one of the major challenges against control of the pandemic. Characterizing the relationship between mutation activities and the risk of severe clinical outcomes is of public health importance for informing the healthcare decision-making process. Using a likelihood-based approach, we developed a statistical framework to reconstruct a time-varying and variant-specific case fatality ratio (CFR), and to estimate changes in CFR associated with a single mutation empirically. For illustration, the statistical framework is implemented to the COVID-19 surveillance data in the United Kingdom (UK). The reconstructed instantaneous CFR gradually increased from 1.0% in September to 2.2% in November 2020 and stabilized at this level thereafter, which monitors the mortality risk of COVID-19 on a real-time basis. We identified a link between the SARS-CoV-2 mutation activity at molecular scale and COVID-19 mortality risk at population scale, and found that the 501Y variants may slightly but not significantly increase 18% of fatality risk than the preceding 501N variants. We found no statistically significant evidence of change in COVID-19 mortality risk associated with 501Y variants, and highlighted the real-time estimating potentials of the modelling framework.
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http://dx.doi.org/10.3390/v13040638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070306PMC
April 2021

Differential Influence of Age on the Relationship between Genetic Mismatch and A(H1N1)pdm09 Vaccine Effectiveness.

Viruses 2021 04 4;13(4). Epub 2021 Apr 4.

JC School of Public Health and Primary Care, Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China.

Assessment of influenza vaccine effectiveness (VE) and identification of relevant influencing factors are the current priorities for optimizing vaccines to reduce the impacts of influenza. To date, how the difference between epidemic strains and vaccine strains at genetic scale affects age-specific vaccine performance remains ambiguous. This study investigated the association between genetic mismatch on hemagglutinin and neuraminidase genes and A(H1N1)pdm09 VE in different age groups with a novel computational approach. We found significant linear relationships between VE and genetic mismatch in children, young adults, and middle-aged adults. In the children's group, each 3-key amino acid mutation was associated with an average of 10% decrease in vaccine effectiveness in a given epidemic season, and genetic mismatch exerted no influence on VE for the elderly group. We demonstrated that present vaccines were most effective for children, while protection for the elderly was reduced and indifferent to vaccine component updates. Modeling such relationships is practical to inform timely evaluation of VE in different groups of populations during mass vaccination and may inform age-specific vaccination regimens.
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http://dx.doi.org/10.3390/v13040619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065480PMC
April 2021

Temporal landscape of human gut RNA and DNA virome in SARS-CoV-2 infection and severity.

Microbiome 2021 04 14;9(1):91. Epub 2021 Apr 14.

Center for Gut Microbiota Research, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China.

Background: Coronavirus disease 2019 (COVID-19) caused by the enveloped RNA virus SARS-CoV-2 primarily affects the respiratory and gastrointestinal tracts. SARS-CoV-2 was isolated from fecal samples, and active viral replication was reported in human intestinal cells. The human gut also harbors an enormous amount of resident viruses (collectively known as the virome) that play a role in regulating host immunity and disease pathophysiology. Understanding gut virome perturbation that underlies SARS-CoV-2 infection and severity is an unmet need.

Methods: We enrolled 98 COVID-19 patients with varying disease severity (3 asymptomatic, 53 mild, 34 moderate, 5 severe, 3 critical) and 78 non-COVID-19 controls matched for gender and co-morbidities. All subjects had fecal specimens sampled at inclusion. Blood specimens were collected for COVID-19 patients at admission to test for inflammatory markers and white cell counts. Among COVID-19 cases, 37 (38%) patients had serial fecal samples collected 2 to 3 times per week from time of hospitalization until after discharge. Using shotgun metagenomics sequencing, we sequenced and profiled the fecal RNA and DNA virome. We investigated alterations and longitudinal dynamics of the gut virome in association with disease severity and blood parameters.

Results: Patients with COVID-19 showed underrepresentation of Pepper mild mottle virus (RNA virus) and multiple bacteriophage lineages (DNA viruses) and enrichment of environment-derived eukaryotic DNA viruses in fecal samples, compared to non-COVID-19 subjects. Such gut virome alterations persisted up to 30 days after disease resolution. Fecal virome in SARS-CoV-2 infection harbored more stress-, inflammation-, and virulence-associated gene encoding capacities including those pertaining to bacteriophage integration, DNA repair, and metabolism and virulence associated with their bacterial host. Baseline fecal abundance of 10 virus species (1 RNA virus, pepper chlorotic spot virus, and 9 DNA virus species) inversely correlated with disease COVID-19 severity. These viruses inversely correlated with blood levels of pro-inflammatory proteins, white cells, and neutrophils. Among the 10 COVID-19 severity-associated DNA virus species, 4 showed inverse correlation with age; 5 showed persistent lower abundance both during disease course and after disease resolution relative to non-COVID-19 subjects.

Conclusions: Both enteric RNA and DNA virome in COVID-19 patients were different from non-COVID-19 subjects, which persisted after disease resolution of COVID-19. Gut virome may calibrate host immunity and regulate severity to SARS-CoV-2 infection. Our observation that gut viruses inversely correlated with both severity of COVID-19 and host age may partly explain that older subjects are prone to severe and worse COVID-19 outcomes. Altogether, our data highlight the importance of human gut virome in severity and potentially therapeutics of COVID-19. Video Abstract.
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http://dx.doi.org/10.1186/s40168-021-01008-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044506PMC
April 2021

Microbiota engraftment after faecal microbiota transplantation in obese subjects with type 2 diabetes: a 24-week, double-blind, randomised controlled trial.

Gut 2021 Mar 30. Epub 2021 Mar 30.

Center for Gut Microbiota Research, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China

Objective: The impact of faecal microbiota transplantation (FMT) on microbiota engraftment in patients with metabolic syndrome is uncertain. We aimed to study whether combining FMT with lifestyle modification could enhance the engraftment of favourable microbiota in obese patients with type 2 diabetes mellitus (T2DM).

Design: In this double-blind, randomised, placebo-controlled trial, 61 obese subjects with T2DM were randomly assigned to three parallel groups: FMT plus lifestyle intervention (LSI), FMT alone, or sham transplantation plus LSI every 4 weeks for up to week 12. FMT solution was prepared from six healthy lean donors. Faecal metagenomic sequencing was performed at baseline, weeks 4, 16 and 24. The primary outcome was the proportion of subjects acquiring ≥20% of microbiota from lean donors at week 24.

Results: Proportions of subjects acquiring ≥20% of lean-associated microbiota at week 24 were 100%, 88.2% and 22% in the FMT plus LSI, FMT alone, and sham plus LSI groups, respectively (p<0.0001). Repeated FMTs significantly increased the engraftment of lean-associated microbiota (p<0.05). FMT with or without LSI increased butyrate-producing bacteria. Combining LSI and FMT led to increase in and compared with FMT alone (p<0.05). FMT plus LSI group had reduced total and low-density lipoprotein cholesterol and liver stiffness at week 24 compared with baseline (p<0.05).

Conclusion: Repeated FMTs enhance the level and duration of microbiota engraftment in obese patients with T2DM. Combining lifestyle intervention with FMT led to more favourable changes in recipients' microbiota and improvement in lipid profile and liver stiffness.

Trial Registration Number: NCT03127696.
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http://dx.doi.org/10.1136/gutjnl-2020-323617DOI Listing
March 2021

Modelling the association between COVID-19 transmissibility and D614G substitution in SARS-CoV-2 spike protein: using the surveillance data in California as an example.

Theor Biol Med Model 2021 03 9;18(1):10. Epub 2021 Mar 9.

JC School of Public Health and Primary Care, Chinese University of Hong Kong, Hong Kong, China.

Background: The COVID-19 pandemic poses a serious threat to global health, and pathogenic mutations are a major challenge to disease control. We developed a statistical framework to explore the association between molecular-level mutation activity of SARS-CoV-2 and population-level disease transmissibility of COVID-19.

Methods: We estimated the instantaneous transmissibility of COVID-19 by using the time-varying reproduction number (R). The mutation activity in SARS-CoV-2 is quantified empirically depending on (i) the prevalence of emerged amino acid substitutions and (ii) the frequency of these substitutions in the whole sequence. Using the likelihood-based approach, a statistical framework is developed to examine the association between mutation activity and R. We adopted the COVID-19 surveillance data in California as an example for demonstration.

Results: We found a significant positive association between population-level COVID-19 transmissibility and the D614G substitution on the SARS-CoV-2 spike protein. We estimate that a per 0.01 increase in the prevalence of glycine (G) on codon 614 is positively associated with a 0.49% (95% CI: 0.39 to 0.59) increase in R, which explains 61% of the R variation after accounting for the control measures. We remark that the modeling framework can be extended to study other infectious pathogens.

Conclusions: Our findings show a link between the molecular-level mutation activity of SARS-CoV-2 and population-level transmission of COVID-19 to provide further evidence for a positive association between the D614G substitution and R. Future studies exploring the mechanism between SARS-CoV-2 mutations and COVID-19 infectivity are warranted.
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http://dx.doi.org/10.1186/s12976-021-00140-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941367PMC
March 2021

Understanding the Prevalence and Associated Factors of Behavioral Intention of COVID-19 Vaccination Under Specific Scenarios Combining Effectiveness, Safety, and Cost in the Hong Kong Chinese General Population.

Int J Health Policy Manag 2021 Jan 18. Epub 2021 Jan 18.

Department of Microbiology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.

Background: The prevalence of coronavirus disease 2019 (COVID-19) vaccination is very critical in controlling COVID-19. This study mainly aimed to (1) investigate behavioral intentions of COVID-19 vaccination under various specific scenarios, and (2) associated factors of the afore-mentioned vaccination intentions.

Methods: A random anonymous telephone survey interviewed 450 Chinese adults from September 16-30, 2020 in Hong Kong, China. Nine scenarios of behavioral intentions of COVID-19 vaccinations were measured combining effectiveness (80% versus 50%), safety (rare versus common mild side effect), and cost (free versus HK$ 500).

Results: The prevalence of behavioral intentions of COVID-19 vaccination under the 9 specific scenarios was very low and varied greatly (4.2% to 38.0%). The prospective countries of manufacture also influenced vaccination intention (eg, Japan: 55.8% vs China: 31.1%). Only 13.1% intended to take up COVID-19 vaccination at the soonest upon its availability. The attributes of effectiveness and side effect influenced vaccination intention most. Positively associated factors of behavioral intentions of COVID-19 vaccination included trust/satisfaction toward the government, exposure to positive social media information about COVID-19 vaccines, descriptive norms, perceived impact on the pandemic, perceived duration of protectiveness, and life satisfaction.

Conclusion: Intention of COVID-19 vaccination was low in the Hong Kong general population, especially among younger people, females, and single people. Health promotion is warranted to enhance the intention. The significant factors identified in this study may be considered when designing such health promotion. Future research is required to confirm the findings in other countries. Such studies should pay attention to the specific context of cost, safety, and effectiveness, which would lead to different responses in the level of behavioral intention of COVID-19 vaccination (BICV).
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http://dx.doi.org/10.34172/ijhpm.2021.02DOI Listing
January 2021

Emergent human coronaviruses - History informs the future.

J Virol Methods 2021 04 2;290:114095. Epub 2021 Feb 2.

Department of Microbiology, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.

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http://dx.doi.org/10.1016/j.jviromet.2021.114095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955916PMC
April 2021

A global analysis of replacement of genetic variants of SARS-CoV-2 in association with containment capacity and changes in disease severity.

Clin Microbiol Infect 2021 Jan 30. Epub 2021 Jan 30.

Department of Microbiology, The Chinese University of Hong Kong, Hong Kong SAR, China. Electronic address:

Objectives: To examine severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant replacement in association with containment capacity and changes in case fatality at country level.

Methods: Altogether, 69 571 full SARS-CoV-2 genomes collected globally within the first 6 months of the pandemic were examined. The correlation between variant replacement and containment capacity was examined by logistic regression models using the WHO International Health Regulation (IHR) score, the Oxford COVID-19 Government Response Tracker (OxCGRT) and the vulnerability index INFORM as proxies, while correlation with changes in monthly crude case fatality ratios was examined by a mixed effect model.

Results: At the global level, variant lineage G∗, characterized by the S-D614G mutation, replaced the older lineages L and S in March 2020. European countries-including Finland, France and Italy-were the first to reach a 50% increment of G∗, whereas only Singapore and South Korea had non-G∗ persisting throughout the first 6 months. Countries with higher IHR scores (β-coefficient -0.001, 95%CI -0.016, -0.001; p 0.034) and higher stringency indexes (OxCGRT) (β-coefficient -0.011, 95%CI -0.020, -0.001; p 0.035) were associated with lower levels of G∗ replacement, whereas higher vulnerability indexes (INFORM) (β-coefficient 0.049, 95%CI 0.001, 0.097; p 0.044) were associated with higher replacement levels. Crude case fatality ratio showed a positive correlation with G∗ replacement (β-coefficient: 0.034, 95%CI 0.011, 0.058; p 0.004), even after adjusting for testing capacity and other country-specific characteristics.

Conclusions: SARS-CoV-2 variant lineage G∗ (S-D614G) replaced older lineages more efficiently in countries with lower containment capacity, and its possible association with increased disease severity deserves further investigation.
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http://dx.doi.org/10.1016/j.cmi.2021.01.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846470PMC
January 2021

In silico prediction of influenza vaccine effectiveness by sequence analysis.

Vaccine 2021 02 19;39(7):1030-1034. Epub 2021 Jan 19.

JC School of Public Health and Primary Care, Chinese University of Hong Kong, Shatin, N.T., Hong Kong Special Administrative Region; CUHK Shenzhen Research Institute, Shenzhen, China. Electronic address:

The effectiveness of seasonal influenza vaccines varies with the matching of vaccine strains to circulating strains. Based on the genetic distance of hemagglutinin and neuraminidase gene of the influenza viruses to vaccine strains, we statistically quantified the relationship between the genetic mismatch and vaccine effectiveness (VE) for influenza A/H1N1pdm09, A/H3N2 and B. We also proposed a systematic approach to integrate multiple genes and influenza types for overall VE estimation. Evident linear relationships were identified and validated in independent data. The modelling framework may enable in silico prediction for VE on a real-time basis and inform the influenza vaccine selection strategy.
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http://dx.doi.org/10.1016/j.vaccine.2021.01.006DOI Listing
February 2021

Acceptance of the COVID-19 vaccine based on the health belief model: A population-based survey in Hong Kong.

Vaccine 2021 02 6;39(7):1148-1156. Epub 2021 Jan 6.

Department of Microbiology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong. Electronic address:

Background: Vaccines for COVID-19 are anticipated to be available by 2021. Vaccine uptake rate is a crucial determinant for herd immunity. We examined factors associated with acceptance of vaccine based on (1). constructs of the Health Belief Model (HBM), (2). trust in the healthcare system, new vaccine platforms and manufacturers, and (3). self-reported health outcomes.

Methods: A population-based, random telephone survey was performed during the peak of the third wave of COVID-19 outbreak (27/07/2020 to 27/08/2020) in Hong Kong. All adults aged ≥ 18 years were eligible. The survey included sociodemographic details; self-report health conditions; trust scales; and self-reported health outcomes. Multivariable regression analyses were applied to examine independent associations. The primary outcome is the acceptance of the COVID-19 vaccine.

Results: We conducted 1200 successful telephone interviews (response rate 55%). The overall vaccine acceptance rate after adjustment for population distribution was 37.2% (95% C.I. 34.5-39.9%). The projected acceptance rates exhibited a "J-shaped" pattern with age, with higher rates among young adults (18-24 years), then increased linearly with age. Multivariable regression analyses revealed that perceived severity, perceived benefits of the vaccine, cues to action, self-reported health outcomes, and trust in healthcare system or vaccine manufacturers were positive correlates of acceptance; whilst perceived access barriers and harm were negative correlates. Remarkably, perceived susceptibility to infection carried no significant association, whereas recommendation from Government (aOR = 10.2, 95% C.I. 6.54 to 15.9, p < 0.001) was as the strongest driving factor for acceptance. Other key obstacles of acceptance included lack of confidence on newer vaccine platforms (43.4%) and manufacturers without track record (52.2%), which are of particular relevance to the current context.

Conclusions: Governmental recommendation is an important driver, whereas perceived susceptibility is not associated with acceptance of COVID-19 vaccine. These HBM constructs and independent predictors inform evidence-based formulation and implementation of vaccination strategies.
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http://dx.doi.org/10.1016/j.vaccine.2020.12.083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832076PMC
February 2021

Longitudinal dynamics of gut bacteriome, mycobiome and virome after fecal microbiota transplantation in graft-versus-host disease.

Nat Commun 2021 01 4;12(1):65. Epub 2021 Jan 4.

Center for Gut Microbiota Research, The Chinese University of Hong Kong, Hong Kong, China.

Fecal microbiota transplant (FMT) has emerged as a potential treatment for severe colitis associated with graft-versus-host disease (GvHD) following hematopoietic stem cell transplant. Bacterial engraftment from FMT donor to recipient has been reported, however the fate of fungi and viruses after FMT remains unclear. Here we report longitudinal dynamics of the gut bacteriome, mycobiome and virome in a teenager with GvHD after receiving four doses of FMT at weekly interval. After serial FMTs, the gut bacteriome, mycobiome and virome of the patient differ from compositions before FMT with variable temporal dynamics. Diversity of the gut bacterial community increases after each FMT. Gut fungal community initially shows expansion of several species followed by a decrease in diversity after multiple FMTs. In contrast, gut virome community varies substantially over time with a stable rise in diversity. The bacterium, Corynebacterium jeikeium, and Torque teno viruses, decrease after FMTs in parallel with an increase in the relative abundance of Caudovirales bacteriophages. Collectively, FMT may simultaneously impact on the various components of the gut microbiome with distinct effects.
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http://dx.doi.org/10.1038/s41467-020-20240-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782528PMC
January 2021

Genomic and evolutionary comparison between SARS-CoV-2 and other human coronaviruses.

J Virol Methods 2021 03 5;289:114032. Epub 2020 Dec 5.

Department of Microbiology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; Stanley Ho Centre for Emerging Infectious Diseases, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region.

Three highly pathogenic human coronaviruses can cause severe acute respiratory syndrome (SARS-CoV, SARS-CoV-2 and MERS-CoV). Although phylogenetic analyses have indicated ancient origin of human coronaviruses from animal relatives, their evolutionary history remains to be established. Using phylogenetics and "high order genomic structures" including trimer spectrums, codon usage and dinucleotide suppression, we observed distinct clustering of all human coronaviruses that formed phylogenetic clades with their closest animal relatives, indicating they have encompassed long evolutionary histories within specific ecological niches before jumping species barrier to infect humans. The close relationships between SARS-CoV and SARS-CoV-2 imply similar evolutionary origin. However, a lower Effective Codon Number (ENC) pattern and CpG dinucleotide suppression in SARS-CoV-2 genomes compared to SARS-CoV and MERS-CoV may imply a better host fitness, and thus their success in sustaining a pandemic. Characterization of coronavirus heterogeneity via complementary approaches enriches our understanding on the evolution and virus-host interaction of these emerging human pathogens while the underlying mechanistic basis in pathogenicity warrants further investigation.
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http://dx.doi.org/10.1016/j.jviromet.2020.114032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718587PMC
March 2021

The Intersection between Oral Microbiota, Host Gene Methylation and Patient Outcomes in Head and Neck Squamous Cell Carcinoma.

Cancers (Basel) 2020 Nov 18;12(11). Epub 2020 Nov 18.

Department of Otorhinolaryngology, Head and Neck Surgery, The Chinese University of Hong Kong, Hong Kong SAR, China.

The role of oral microbiota in head and neck squamous cell carcinoma (HNSCC) is poorly understood. Here we sought to evaluate the association of the bacterial microbiome with host gene methylation and patient outcomes, and to explore its potential as a biomarker for early detection or intervention. Here we performed 16S rRNA gene amplicon sequencing in sixty-eight HNSCC patients across both tissue and oral rinse samples to identify oral bacteria with differential abundance between HNSCC and controls. A subset of thirty-one pairs of HNSCC tumor tissues and the adjacent normal tissues were characterized for host gene methylation profile using bisulfite capture sequencing. We observed significant enrichments of and in HNSCC tumor tissues when compared to the adjacent normal tissues, and in HNSCC oral rinses when compared to healthy subjects, while ten other bacterial genera were largely depleted. These HNSCC-related bacteria were discriminative for HNSCC and controls with area under the receiver operating curves (AUCs) of 0.84 and 0.86 in tissue and oral rinse samples, respectively. Moreover, abundance in HNSCC cases was strongly associated with non-smokers, lower tumor stage, lower rate of recurrence, and improved disease-specific survival. An integrative analysis identified that enrichment of was associated with host gene promoter methylation, including hypermethylation of tumor suppressor genes and , for which gene expressions were downregulated in the HNSCC cohort from The Cancer Genome Atlas. In conclusion, we identified a taxonomically defined microbial consortium associated with HNSCC that may have clinical potential regarding biomarkers for early detection or intervention. Host-microbe interactions between enrichment and clinical outcomes or host gene methylation imply a potential role of as a pro-inflammatory driver in initiating HNSCC without traditional risk factors, which warrants further investigation for the underlying mechanisms.
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http://dx.doi.org/10.3390/cancers12113425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698865PMC
November 2020

SARS-CoV-2 detection by nasal strips: A superior tool for surveillance of paediatric population.

J Infect 2021 04 12;82(4):84-123. Epub 2020 Nov 12.

Department of Paediatrics, Faculty of Medicine, The Chinese University of Hong Kong.; CUHK-UMCU Joint Research Laboratory of Respiratory Virus & Immunobiology, Faculty of Medicine, The Chinese University of Hong Kong. Electronic address:

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http://dx.doi.org/10.1016/j.jinf.2020.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658621PMC
April 2021

Serologic Responses in Healthy Adult with SARS-CoV-2 Reinfection, Hong Kong, August 2020.

Emerg Infect Dis 2020 12 22;26(12):3076-3078. Epub 2020 Oct 22.

In March 2020, mild signs and symptoms of coronavirus disease developed in a healthy 33-year-old man in Hong Kong. His first infection did not produce virus neutralizing antibodies. In August, he had asymptomatic reinfection, suggesting that persons without a robust neutralizing antibody response might be at risk for reinfection.
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http://dx.doi.org/10.3201/eid2612.203833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706979PMC
December 2020

Stringent containment measures without complete city lockdown to achieve low incidence and mortality across two waves of COVID-19 in Hong Kong.

BMJ Glob Health 2020 10;5(10)

Department of Microbiology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China

Introduction: An international city, Hong Kong, in proximity to the first epicentre of COVID- 19, experienced two epidemic waves with different importation pressure. We compared the epidemiological features of patients with COVID-19 in the context of containment policies between the first and second waves.

Methods: We retrieved information on the first 1038 cases detected in Hong Kong (23 January to 25 April 2020) to analyse the epidemiological characteristics including age/gender-specific incidence, clustering, reproduction number ( ) and containment delay; in relation to the containment measures implemented. Factors associated with containment delay were evaluated by multiple linear regression analysis with age, gender, epidemic wave and infection source as covariates. A time series of 5-day moving average was plotted to examine the changes across the two epidemic waves.

Results: The incidence and mortality (135.5 and 0.5 per 1 000 000 population) was among the lowest in the world. Aggressive escalation of border control correlated with reductions in from 1.35 to 0.57 and 0.92 to 0.18, and aversions of 450 and 1650 local infections during the first and second waves, respectively. Implementing COVID-19 tests for overseas returners correlated with an upsurge of asymptomatic case detection, and shortened containment delay in the second wave. Medium-sized cluster events in the first wave were family gatherings, whereas those in the second wave were leisure activities among youngsters. Containment delay was associated with older age (adjusted OR (AOR)=1.01, 95% CI 1.00 to 1.02, p=0.040), male gender (AOR=1.41, 95% CI 1.02 to 1.96, p=0.039) and local cases (AOR=11.18, 95% CI 7.43 to 16.83, p<0.001), and with significant improvement in the second wave compared with the first wave (average: 6.8 vs 3.7 days). A higher incidence rate was observed for males, raising possibility of gender predilection in susceptibility of developing symptoms.

Conclusion: Prompt and stringent all-round containment strategies represent successful measures in pandemic control. These findings could inform formulation and implementation of pandemic mitigation strategies.
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http://dx.doi.org/10.1136/bmjgh-2020-003573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542625PMC
October 2020

Population-Level Configurations of Gut Mycobiome Across 6 Ethnicities in Urban and Rural China.

Gastroenterology 2021 01 18;160(1):272-286.e11. Epub 2020 Sep 18.

Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Institute of Digestive Diseases, Kunming, Yunnan, China. Electronic address:

Background & Aims: Beyond bacteria, the human gastrointestinal tract is host to a vast diversity of fungi, collectively known as the gut mycobiome. Little is known of the impact of geography, ethnicity, and urbanization on the gut mycobiome at a large population level. We aim to delineate the variation of human gut mycobiome and its association with host factors, environmental factors, and diets.

Methods: Using shotgun metagenomic sequencing, we profiled and compared the fecal mycobiome of 942 healthy individuals across different geographic regions in China (Hong Kong and Yunnan), spanning 6 ethnicities: Han, Zang, Bai, Hani, Dai, and Miao (including both urban and rural residents of each ethnicity). In parallel to fecal sampling, we collected participant metadata (environmental exposure, bowel habits, anthropometrics, and medication), diet, and clinical blood measurement results (a total of 118 variables) and investigated their impact on the gut mycobiome variation in humans.

Results: The human gut mycobiome was highly variable across populations. Urbanization-related factors had the strongest impact on gut mycobiome variation, followed by geography, dietary habit, and ethnicity. The Hong Kong population (highly urbanized) had a significantly lower fungal richness compared with Yunnan population. Saccharomyces cerevisiae was highly enriched in urban compared with rural populations and showed significant inverse correlations with liver pathology-associated blood parameters, including aspartate transaminase, alanine transaminase, gamma-glutamyltransferase, and direct bilirubin. Candida dubliniensis, which was decreased in urban relative to rural populations, showed correlations with host metabolism-related parameters in blood, including a positive correlation with fasting high-density lipoprotein cholesterol levels and a negative correlation with fasting glucose levels. The fungal-blood parameter correlations were highly geography- and ethnicity-specific. Food choices had differential influences on gut mycobiome and bacterial microbiome, where taxa from the same genus tended to be coregulated by food and thereby cobloom. Ethnicity-specific fungal signatures were associated with distinct habitual foods in each ethnic group.

Conclusions: Our data highlight, for the first time to our knowledge, that geography, urbanization, ethnicity, and habitual diet play an important role in shaping the gut mycobiome composition. Gut fungal configurations in combination with population characteristics (such as residing region, ethnicity, diet, lifestyle) influence host metabolism and health.
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http://dx.doi.org/10.1053/j.gastro.2020.09.014DOI Listing
January 2021

Human-Gut-DNA Virome Variations across Geography, Ethnicity, and Urbanization.

Cell Host Microbe 2020 11 9;28(5):741-751.e4. Epub 2020 Sep 9.

Center for Gut Microbiota Research, Faculty of Medicine, The Chinese University of Hong Kong, China; Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China; Li Ka Shing Institute of Health Science, State Key Laboratory of Digestive Diseases, The Chinese University of Hong Kong, Hong Kong, China. Electronic address:

The human-gut-DNA virome is highly diverse and individual specific, but little is known of its variation at a population level. Here, we report the fecal DNA virome of 930 healthy adult subjects from two regions in China (Hong Kong and Yunnan) spanning six ethnicities (Han, Zang, Miao, Bai, Dai, and Hani), and including urban and rural residents for each ethnicity. Twenty host factors were found to significantly correlate with the human-gut virome variation, with geography carrying the strongest impact and ethnicity-distinct diets associating with certain viral species. Urbanization enhances interindividual dissimilarities between gut viromes, with the duration of urban residence associating with multiple bacteriophages, including Lactobacillus phage and Lactococcus phage. Overall, the gut virome presents more heterogeneity relative to the bacterial microbiome across the examined Chinese populations. This study highlights population-based variations and the importance of host and environmental factors in shaping the DNA virome in the human gut.
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http://dx.doi.org/10.1016/j.chom.2020.08.005DOI Listing
November 2020

Development of an Ordinal Scale Treatment Endpoint for Adults Hospitalized With Influenza.

Clin Infect Dis 2020 Jun 17. Epub 2020 Jun 17.

School of Public Health, University of Alberta, Edmonton, Canada.

Background: An obstacle in influenza therapeutics development is the lack of clinical endpoints, especially in hospitalized patients. A single time-point binary outcome measure is limited by patients' diverse clinical trajectories and low event rates.

Methods: A 6-point ordinal scale with ascending clinical status severity (scoring: discharged; subacute care; acute care without/with respiratory failure; intensive care unit [ICU]; death) was proposed to study outcomes of adults hospitalized with influenza. Individual patient data from 2 active surveillance cohorts' datasets (2015/2016-2017/2018; Edmonton, Hong Kong) was used for evaluation. The impact of neuraminidase inhibitor (NAI) treatment on longitudinal ordinal outcome changes over 30 days was analyzed using mixed-effects ordinal logistic regression and group-based trajectory models.

Results: Patient (n = 1226) baseline characteristics included age (mean 68.0 years), virus-type (A 78.1%, B 21.9%), respiratory failure (57.2%), ICU admittance (14.4%), and NAI treatment within 5 days of illness (69.2%). Outcomes at 30 days included discharged (75.2%), subacute care (13.7%), acute care (4.5%), and death (6.6%). Two main clinical trajectories were identified, predictive by baseline scoring (mean ± SD, 4.3 ± 0.6 vs 3.5 ± 0.6, P < .001). Improved outcomes with NAI treatment within 5 days were indicated by significantly lower clinical status scores over time (unadjusted odds ratio [OR], 0.53; 95% confidence interval [CI], .41-.69; P < .001; adjusted OR, 0.62; 95% CI, .50-.77; P < .001, for baseline score, age, and within-patient correlations). In subanalysis, influenza vaccination was also associated with lower scores (adjusted OR, 0.67; 95% CI, .50-.90; P = .007). Analyses of binary endpoints showed insignificant results.

Conclusions: The ordinal outcome scale is a potentially useful clinical endpoint for influenza therapeutic trials, which could account for the diverse clinical trajectories of hospitalized patients, warranting further development.
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http://dx.doi.org/10.1093/cid/ciaa777DOI Listing
June 2020

Prospective Study Comparing Deep Throat Saliva With Other Respiratory Tract Specimens in the Diagnosis of Novel Coronavirus Disease 2019.

J Infect Dis 2020 10;222(10):1612-1619

Department of Microbiology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region (SAR), China.

Background: Self-collected specimens have been advocated to avoid infectious exposure to healthcare workers. Self-induced sputum in those with a productive cough and saliva in those without a productive cough have been proposed, but sensitivity remains uncertain.

Methods: We performed a prospective study in 2 regional hospitals in Hong Kong.

Results: We prospectively examined 563 serial samples collected during the virus shedding periods of 50 patients: 150 deep throat saliva (DTS), 309 pooled-nasopharyngeal (NP) and throat swabs, and 104 sputum. Deep throat saliva had the lowest overall reverse-transcriptase polymerase chain reaction (RT-PCR)-positive rate (68.7% vs 89.4% [sputum] and 80.9% [pooled NP and throat swabs]) and the lowest viral ribonucleic acid (RNA) concentration (mean log copy/mL 3.54 vs 5.03 [sputum] and 4.63 [pooled NP and throat swabs]). Analyses with respect to time from symptom onset and severity also revealed similar results. Virus yields of DTS correlated with that of sputum (Pearson correlation index 0.76; 95% confidence interval, 0.62-0.86). We estimated that the overall false-negative rate of DTS could be as high as 31.3% and increased 2.7 times among patients without sputum.

Conclusions: Deep throat saliva produced the lowest viral RNA concentration and RT-PCR-positive rate compared with conventional respiratory specimens in all phases of illness. Self-collected sputum should be the choice for patients with sputum.
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http://dx.doi.org/10.1093/infdis/jiaa487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454747PMC
October 2020
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