Publications by authors named "Li Hsu"

324 Publications

Duration and determinants of delayed tuberculosis diagnosis and treatment in high-burden countries: a mixed-methods systematic review and meta-analysis.

Respir Res 2021 Sep 23;22(1):251. Epub 2021 Sep 23.

Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore, Singapore.

Background: Thirty countries with the highest tuberculosis (TB) burden bear 87% of the world's TB cases. Delayed diagnosis and treatment are detrimental to TB prognosis and sustain TB transmission in the community, making TB elimination a great challenge, especially in these countries. Our objective was to elucidate the duration and determinants of delayed diagnosis and treatment of pulmonary TB in high TB-burden countries.

Methods: We conducted a systematic review and meta-analysis of quantitative and qualitative studies by searching four databases for literature published between 2008 and 2018 following PRISMA guidelines. We performed a narrative synthesis of the covariates significantly associated with patient, health system, treatment, and total delays. The pooled median duration of delay and effect sizes of covariates were estimated using random-effects meta-analyses. We identified key qualitative themes using thematic analysis.

Results: This review included 124 articles from 14 low- and lower-middle-income countries (LIC and LMIC) and five upper-middle-income countries (UMIC). The pooled median duration of delays (in days) were-patient delay (LIC/LMIC: 28 (95% CI 20-30); UMIC: 10 (95% CI 10-20), health system delay (LIC/LMIC: 14 (95% CI 2-28); UMIC: 4 (95% CI 2-4), and treatment delay (LIC/LMIC: 14 (95% CI 3-84); UMIC: 0 (95% CI 0-1). There was consistent evidence that being female and rural residence was associated with longer patient delay. Patient delay was also associated with other individual, interpersonal, and community risk factors such as poor TB knowledge, long chains of care-seeking through private/multiple providers, perceived stigma, financial insecurities, and poor access to healthcare. Organizational and policy factors mediated health system and treatment delays. These factors included the lack of resources and complex administrative procedures and systems at the health facilities. We identified data gaps in 11 high-burden countries.

Conclusions: This review presented the duration of delays and detailed the determinants of delayed TB diagnosis and treatment in high-burden countries. The gaps identified could be addressed through tailored approaches, education, and at a higher level, through health system strengthening and provision of universal health coverage to reduce delays and improve access to TB diagnosis and care. PROSPERO registration: CRD42018107237.
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http://dx.doi.org/10.1186/s12931-021-01841-6DOI Listing
September 2021

Public knowledge, attitudes and practices related to antibiotic use and resistance in Singapore: a cross-sectional population survey.

BMJ Open 2021 Sep 13;11(9):e048157. Epub 2021 Sep 13.

National University Singapore Saw Swee Hock School of Public Health, Singapore

Objectives: The WHO's Global Action Plan on Antimicrobial Resistance (AMR) includes increasing overall public awareness of appropriate antibiotic use and resistance as a key priority area. We aimed to measure public knowledge, attitudes and practices of antibiotics and antibiotic resistance in Singapore, as well as their healthcare-seeking behaviours relating to respiratory illnesses, providing baseline data against which to measure the progress of future interventions.

Design: A cross-sectional study.

Setting: The general population in Singapore.

Participants: Between May and June 2019, we conducted a survey via an online panel in Singapore with 706 respondents.

Results: Our findings indicated common misconceptions surrounding antibiotic effectiveness and mechanisms of antibiotic resistance-most participants thought that resistance occurs when our bodies become resistant to antibiotics (62.5%) or when antibiotics become less powerful (48.5%). In multivariable analyses, better knowledge scores were associated with more favourable antibiotic attitudes (β=0.29; 95% CI 0.20 to 0.37). In addition, more favourable attitude scores were associated with lower odds of both expecting (OR: 0.84, 95% CI 0.72 to 0.99) and being prescribed antibiotics by a primary care doctor (OR: 0.76, 95% CI 0.63 to 0.90).

Conclusions: This study presents important information about population perceptions towards antibiotics and antibiotic resistance in Singapore. Results from this study emphasise the importance of effective public communication strategies to promote responsible antibiotic use locally and should be used to inform future implementation of programmes and activities as laid out in Singapore's National Strategic Action Plan on AMR.
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http://dx.doi.org/10.1136/bmjopen-2020-048157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438872PMC
September 2021

Managing the COVID-19 pandemic in non-purpose-built dormitories.

Ann Acad Med Singap 2021 08;50(8):649-651

Department of Plastic Reconstructive and Aesthetic Surgery, Singapore General Hospital, Singapore.

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August 2021

Living with COVID-19: The road ahead.

Ann Acad Med Singap 2021 08;50(8):619-628

Communicable Diseases Division, Ministry of Health, Singapore.

Introduction: The COVID-19 pandemic has affected the world for more than a year, with multiple waves of infections resulting in morbidity, mortality and disruption to the economy and society. Response measures employed to control it have generally been effective but are unlikely to be sustainable over the long term.

Methods: We examined the evidence for a vaccine-driven COVID-19 exit strategy including academic papers, governmental reports and epidemiological data, and discuss the shift from the current pandemic footing to an endemic approach similar to influenza and other respiratory infectious diseases.

Results: A desired endemic state is characterised by a baseline prevalence of infections with a generally mild disease profile that can be sustainably managed by the healthcare system, together with the resumption of near normalcy in human activities. Such an endemic state is attainable for COVID-19 given the promising data around vaccine efficacy, although uncertainty remains around vaccine immunity escape in emergent variants of concern. Maintenance of non-pharmaceutical interventions remains crucial until high vaccination coverage is attained to avoid runaway outbreaks. It may also be worthwhile to de-escalate measures in phases, before standing down most measures for an endemic state. If a variant that substantially evades immunity emerges, it will need to be managed akin to a new disease threat, with pandemic preparedness and response plans.

Conclusion: An endemic state for COVID-19, characterised by sustainable disease control measures, is likely attainable through vaccination.
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August 2021

A COVARIANCE-ENHANCED APPROACH TO MULTI-TISSUE JOINT EQTL MAPPING WITH APPLICATION TO TRANSCRIPTOME-WIDE ASSOCIATION STUDIES.

Ann Appl Stat 2021 Jun 12;15(2):998-1016. Epub 2021 Jul 12.

Transcriptome-wide association studies based on genetically predicted gene expression have the potential to identify novel regions associated with various complex traits. It has been shown that incorporating expression quantitative trait loci (eQTLs) corresponding to multiple tissue types can improve power for association studies involving complex etiology. In this article, we propose a new multivariate response linear regression model and method for predicting gene expression in multiple tissues simultaneously. Unlike existing methods for multi-tissue joint eQTL mapping, our approach incorporates tissue-tissue expression correlation, which allows us to more efficiently handle missing expression measurements and more accurately predict gene expression using a weighted summation of eQTL genotypes. We show through simulation studies that our approach performs better than the existing methods in many scenarios. We use our method to estimate eQTL weights for 29 tissues collected by GTEx, and show that our approach significantly improves expression prediction accuracy compared to competitors. Using our eQTL weights, we perform a multi-tissue-based S-MultiXcan [2] transcriptome-wide association study and show that our method leads to more discoveries in novel regions and more discoveries overall than the existing methods. Estimated eQTL weights and code for implementing the method are available for download online at github.com/ajmolstad/MTeQTLResults.
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http://dx.doi.org/10.1214/20-aoas1432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372768PMC
June 2021

Random effect based tests for multinomial logistic regression in genetic association studies.

Genet Epidemiol 2021 Oct 17;45(7):736-740. Epub 2021 Aug 17.

Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

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http://dx.doi.org/10.1002/gepi.22427DOI Listing
October 2021

Re-calibrating pure risk integrating individual data from two-phase studies with external summary statistics.

Biometrics 2021 Aug 13. Epub 2021 Aug 13.

Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

Accurate risk assessment is critical in clinical decision-making. It entails the projected risk based on a risk prediction model agreeing with the observed risk in the target cohort. However, the model often over- or under-estimates the risk. Building a new model for the target cohort would be ideal but costly. It is therefore of great interest to recalibrate an existing model for the target cohort. Existing methods have been proposed to recalibrate the model by leveraging the disease incidence rates from the target cohort. However, they assume the same covariate distribution across cohorts and when the assumption is violated, the recalibrated model can be substantially biased. Further, recalibration is also complicated by the two-phase sampling design that is commonly used for developing risk prediction models. In this paper, we develop a weighted estimating-equation approach accounting for the two-phase design and combine it with a weighted empirical likelihood that leverages the summary information on both disease incidence rates and covariates from the target cohort. We provide a resampling-based inference procedure. Our extensive simulation results show that using the summary information from the target population, the proposed recalibration method yields nearly unbiased risk estimates under a wide range of scenarios. An application to a colorectal cancer study also illustrates that the proposed method yields a well-calibrated model in the target cohort.
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http://dx.doi.org/10.1111/biom.13543DOI Listing
August 2021

Association Between Smoking and Molecular Subtypes of Colorectal Cancer.

JNCI Cancer Spectr 2021 Aug 14;5(4):pkab056. Epub 2021 Jun 14.

Departments of Cancer Biology and Genetics and Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.

Background: Smoking is associated with colorectal cancer (CRC) risk. Previous studies suggested this association may be restricted to certain molecular subtypes of CRC, but large-scale comprehensive analysis is lacking.

Methods: A total of 9789 CRC cases and 11 231 controls of European ancestry from 11 observational studies were included. We harmonized smoking variables across studies and derived sex study-specific quartiles of pack-years of smoking for analysis. Four somatic colorectal tumor markers were assessed individually and in combination, including mutation, mutation, CpG island methylator phenotype (CIMP), and microsatellite instability (MSI) status. A multinomial logistic regression analysis was used to assess the association between smoking and risk of CRC subtypes by molecular characteristics, adjusting for age, sex, and study. All statistical tests were 2-sided and adjusted for Bonferroni correction.

Results: Heavier smoking was associated with higher risk of CRC overall and stratified by individual markers ( < .001). The associations differed statistically significantly between all molecular subtypes, which was the most statistically significant for CIMP and . Compared with never-smokers, smokers in the fourth quartile of pack-years had a 90% higher risk of CIMP-positive CRC (odds ratio = 1.90, 95% confidence interval = 1.60 to 2.26) but only 35% higher risk for CIMP-negative CRC (odds ratio = 1.35, 95% confidence interval = 1.22 to 1.49; = 2.1 x 10). The association was also stronger in tumors that were positive, MSI high, or wild type when combined ( < .001).

Conclusion: Smoking was associated with differential risk of CRC subtypes defined by molecular characteristics. Heavier smokers had particularly higher risk of CRC subtypes that were CIMP positive and MSI high in combination, suggesting that smoking may be involved in the development of colorectal tumors via the serrated pathway.
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http://dx.doi.org/10.1093/jncics/pkab056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346704PMC
August 2021

An analysis of national action plans on antimicrobial resistance in Southeast Asia using a governance framework approach.

Lancet Reg Health West Pac 2021 Feb 23;7:100084. Epub 2021 Jan 23.

Saw Swee Hock School of Public Health, National University of Singapore, Tahir Foundation Building, 12 Science Drive 2, #10-01, Singapore 117549, Singapore.

The complex problem of antimicrobial resistance (AMR) is spread across human health, animal health, and the environment. The Global Action Plan (GAP) on AMR and context-specific national action plans (NAPs) were developed to combat this problem. To date, there is no systematic content analysis of NAPs from countries of the Association of Southeast Asia Nations (ASEAN). As the validity periods of most NAPs are ending, an analysis now will provide an opportunity to improve subsequent iterations of these NAPs. We analysed the current NAPs of ten ASEAN countries. We explored their objective alignment with GAP and performed content analysis using an AMR governance framework. Themes were broadly classified under five governance areas: policy design, implementation tools, monitoring and evaluation, sustainability, and One Health engagement. We identified policy priorities, useful features of NAPs, and specific areas that should be strengthened, including accountability, sustained engagement, equity, behavioural economics, sustainability plans and transparency, international collaboration, as well as integration of the environmental sector. Enhancement of these areas and adoption of best practices will drive improved policy formulation and its translation into effective implementation.
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http://dx.doi.org/10.1016/j.lanwpc.2020.100084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315476PMC
February 2021

Public knowledge, attitudes and practices surrounding antibiotic use and resistance in Cambodia.

JAC Antimicrob Resist 2021 Mar 3;3(1):dlaa115. Epub 2021 Feb 3.

Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore.

Background: WHO's Global Action Plan on Antimicrobial Resistance includes as a priority to increase public education surrounding antibiotic use and resistance. Monitoring population-level antibiotic behaviours is crucial for informing intervention strategies, but data from a broad range of settings, particularly lower-resourced countries, are lacking.

Objectives: We measured public knowledge, attitudes and practices regarding antibiotics and antibiotic resistance in Cambodia, providing baseline information against which to monitor the progress of future interventions.

Methods: Between September and October 2018, we conducted a household survey of knowledge, attitudes and practices related to antibiotic use in urban and rural populations of three Cambodian provinces: Phnom Penh, Siem Reap and Prey Veng. Response rates were respectively 79%, 86% and 86%.

Results: Among the 2005 participants, we found high levels of awareness of terms relating to antibiotics (86.5%) and antibiotic resistance; most participants also recognized that antibiotic resistance is a problem (58.4%). However, few understood that antibiotics are effective only against bacterial infections (1.2%). We also found province-specific differences in participants' sources of antibiotics and their sources of AMR-related information. In regression analyses, more favourable antibiotic practice scores were associated with higher knowledge (β = 0.18; 95% CI: 0.14-0.22) and attitude (β = 0.16; 95% CI: 0.11-0.22) scores, as well as trust in healthcare sources to obtain antibiotics and antibiotic information.

Conclusions: This study highlights the importance of interventions and public communication on antibiotic use and resistance that is effectively targeted to the local context through trusted healthcare providers.
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http://dx.doi.org/10.1093/jacamr/dlaa115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210153PMC
March 2021

Prevalence of MDR organism (MDRO) carriage in children and their household members in Siem Reap Province, Cambodia.

JAC Antimicrob Resist 2020 Dec 4;2(4):dlaa097. Epub 2020 Dec 4.

Cambodia Oxford Medical Research Unit, Angkor Hospital for Children, Siem Reap, Cambodia.

Background: The rising incidence of infections caused by MDR organisms (MDROs) poses a significant public health threat. However, little has been reported regarding community MDRO carriage in low- and middle-income countries.

Methods: We conducted a cross-sectional study in Siem Reap, Cambodia comparing hospital-associated households, in which an index child (age: 2-14 years) had been hospitalized for at least 48 h in the preceding 2-4 weeks, with matched community households on the same street, in which no other child had a recent history of hospitalization. Participants were interviewed using a survey questionnaire and tested for carriage of MRSA, ESBL-producing Enterobacterales (ESBL-E) and carbapenemase-producing Enterobacterales (CPE) by culture followed by antibiotic susceptibility testing. We used logistic regression analysis to analyse associations between collected variables and MDRO carriage.

Results: Forty-two pairs of households including 376 participants with 376 nasal swabs and 290 stool specimens were included in final analysis. MRSA was isolated from 26 specimens (6.9%). ESBL-producing was detected in 269 specimens (92.8%) whereas ESBL-producing was isolated from 128 specimens (44.1%), of which 123 (42.4%) were co-colonized with ESBL-producing Six (2.1%) specimens tested positive for CPE (4 and 2 ). The prevalence ratios for MRSA, ESBL-producing and ESBL-producing carriage did not differ significantly in hospital-associated households and hospitalized children compared with their counterparts.

Conclusions: The high prevalence of ESBL-E across both household types suggests that MDRO reservoirs are common in the community. Ongoing genomic analyses will help to understand the epidemiology and course of MDRO spread.
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http://dx.doi.org/10.1093/jacamr/dlaa097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210010PMC
December 2020

Vaccinating undocumented migrants against covid-19.

BMJ 2021 06 25;373:n1608. Epub 2021 Jun 25.

Health Intervention and Technology Assessment Program (HITAP), Department of Health, Muang, Nonthaburi 11000, Thailand

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http://dx.doi.org/10.1136/bmj.n1608DOI Listing
June 2021

Author Correction: Saliva is more sensitive than nasopharyngeal or nasal swabs for diagnosis of asymptomatic and mild COVID-19 infection.

Sci Rep 2021 Jun 9;11(1):12538. Epub 2021 Jun 9.

Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, #10-01, 12 Science Drive 2, Singapore, 117549, Singapore.

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http://dx.doi.org/10.1038/s41598-021-89880-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188150PMC
June 2021

Nongenetic Determinants of Risk for Early-Onset Colorectal Cancer.

JNCI Cancer Spectr 2021 Jun 20;5(3):pkab029. Epub 2021 May 20.

Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.

Background: Incidence of early-onset (younger than 50 years of age) colorectal cancer (CRC) is increasing in many countries. Thus, elucidating the role of traditional CRC risk factors in early-onset CRC is a high priority. We sought to determine whether risk factors associated with late-onset CRC were also linked to early-onset CRC and whether association patterns differed by anatomic subsite.

Methods: Using data pooled from 13 population-based studies, we studied 3767 CRC cases and 4049 controls aged younger than 50 years and 23 437 CRC cases and 35 311 controls aged 50 years and older. Using multivariable and multinomial logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) to assess the association between risk factors and early-onset CRC and by anatomic subsite.

Results: Early-onset CRC was associated with not regularly using nonsteroidal anti-inflammatory drugs (OR = 1.43, 95% CI = 1.21 to 1.68), greater red meat intake (OR = 1.10, 95% CI = 1.04 to 1.16), lower educational attainment (OR = 1.10, 95% CI = 1.04 to 1.16), alcohol abstinence (OR = 1.23, 95% CI = 1.08 to 1.39), and heavier alcohol use (OR = 1.25, 95% CI = 1.04 to 1.50). No factors exhibited a greater excess in early-onset compared with late-onset CRC. Evaluating risks by anatomic subsite, we found that lower total fiber intake was linked more strongly to rectal (OR = 1.30, 95% CI = 1.14 to 1.48) than colon cancer (OR = 1.14, 95% CI = 1.02 to 1.27;  = .04).

Conclusion: In this large study, we identified several nongenetic risk factors associated with early-onset CRC, providing a basis for targeted identification of those most at risk, which is imperative in mitigating the rising burden of this disease.
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http://dx.doi.org/10.1093/jncics/pkab029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134523PMC
June 2021

Estimating the excess bed days and economic burden of healthcare-associated infections in Singapore public acute-care hospitals.

Infect Control Hosp Epidemiol 2021 May 21:1-4. Epub 2021 May 21.

Program in Health Services and Systems Research, Duke-NUS Medical School, Singapore.

We estimated the annual bed days lost and economic burden of healthcare-associated infections to Singapore hospitals using Monte Carlo simulation. The mean (standard deviation) cost of a single healthcare-associated infection was S$1,809 (S$440) [or US$1,362 (US$331)]. This translated to annual lost bed days and economic burden of 55,978 (20,506) days and S$152.0 million (S$37.1 million) [or US$114.4 million (US$27.9 million)], respectively.
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http://dx.doi.org/10.1017/ice.2021.165DOI Listing
May 2021

Updated APLAR consensus statements on care for patients with rheumatic diseases during the COVID-19 pandemic.

Int J Rheum Dis 2021 Jun 4;24(6):733-745. Epub 2021 May 4.

Department of Rheumatology, BSM Medical University, Dhaka, Bangladesh.

Aim: To update previous guidance of the Asia Pacific League of Associations for Rheumatology (APLAR) on the management of patients with rheumatic and musculoskeletal diseases (RMD) during the coronavirus disease 2019 (COVID-19) pandemic.

Methods: Research questions were formulated focusing on diagnosis and treatment of adult patients with RMD within the context of the pandemic, including the management of RMD in patients who developed COVID-19. MEDLINE was searched for eligible studies to address the questions, and the APLAR COVID-19 task force convened 2 meetings through video conferencing to discuss its findings and integrate best available evidence with expert opinion. Consensus statements were finalized using the modified Delphi process.

Results: Agreement was obtained around key aspects of screening for or diagnosis of COVID-19; management of patients with RMD without confirmed COVID-19; and management of patients with RMD with confirmed COVID-19. The task force achieved consensus on 25 statements covering the potential risk of acquiring COVID-19 in RMD patients, advice on RMD medication adjustment and continuation, the roles of telemedicine and vaccination, and the impact of the pandemic on quality of life and on treatment adherence.

Conclusions: Available evidence primarily from descriptive research supported new recommendations for aspects of RMD care not covered in the previous document, particularly with regard to risk factors for complicated COVID-19 in RMD patients, modifications to RMD treatment regimens in the context of the pandemic, and COVID-19 vaccination in patients with RMD.
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http://dx.doi.org/10.1111/1756-185X.14124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206920PMC
June 2021

Personalised randomised controlled trial designs-a new paradigm to define optimal treatments for carbapenem-resistant infections.

Lancet Infect Dis 2021 06 21;21(6):e175-e181. Epub 2021 Apr 21.

Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK; and Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam. Electronic address:

Antimicrobial resistance is impacting treatment decisions for, and patient outcomes from, bacterial infections worldwide, with particular threats from infections with carbapenem-resistant Enterobacteriaceae, Acinetobacter baumanii, or Pseudomonas aeruginosa. Numerous areas of clinical uncertainty surround the treatment of these highly resistant infections, yet substantial obstacles exist to the design and conduct of treatment trials for carbapenem-resistant bacterial infections. These include the lack of a widely acceptable optimised standard of care and control regimens, varying antimicrobial susceptibilities and clinical contraindications making specific intervention regimens infeasible, and diagnostic and recruitment challenges. The current single comparator trials are not designed to answer the urgent public health question, identified as a high priority by WHO, of what are the best regimens out of the available options that will significantly reduce morbidity, costs, and mortality. This scenario has an analogy in network meta-analysis, which compares multiple treatments in an evidence synthesis to rank the best of a set of available treatments. To address these obstacles, we propose extending the network meta-analysis approach to individual randomisation of patients. We refer to this approach as a Personalised RAndomised Controlled Trial (PRACTical) design that compares multiple treatments in an evidence synthesis, to identify, overall, which is the best treatment out of a set of available treatments to recommend, or how these different treatments rank against each other. In this Personal View, we summarise the design principles of personalised randomised controlled trial designs. Specifically, of a network of different potential regimens for life-threatening carbapenem-resistant infections, each patient would be randomly assigned only to regimens considered clinically reasonable for that patient at that time, incorporating antimicrobial susceptibility, toxicity profile, pharmacometric properties, availability, and physician assessment. Analysis can use both direct and indirect comparisons across the network, analogous to network meta-analysis. This new trial design will maximise the relevance of the findings to each individual patient, and enable the top-ranked regimens from any personalised randomisation list to be identified, in terms of both efficacy and safety.
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http://dx.doi.org/10.1016/S1473-3099(20)30791-XDOI Listing
June 2021

Causal Effects of Lifetime Smoking on Breast and Colorectal Cancer Risk: Mendelian Randomization Study.

Cancer Epidemiol Biomarkers Prev 2021 05 2;30(5):953-964. Epub 2021 Mar 2.

Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.

Background: Observational evidence has shown that smoking is a risk factor for breast and colorectal cancer. We used Mendelian randomization (MR) to examine causal associations between smoking and risks of breast and colorectal cancer.

Methods: Genome-Wide Association Study summary data were used to identify genetic variants associated with lifetime amount of smoking ( = 126 variants) and ever having smoked regularly ( = 112 variants). Using two-sample MR, we examined these variants in relation to incident breast (122,977 cases/105,974 controls) and colorectal cancer (52,775 cases/45,940 controls).

Results: In inverse-variance weighted models, a genetic predisposition to higher lifetime amount of smoking was positively associated with breast cancer risk [OR per 1-SD increment: 1.13; 95% confidence interval (CI): 1.00-1.26; = 0.04]; although heterogeneity was observed. Similar associations were found for estrogen receptor-positive and estrogen receptor-negative tumors. Higher lifetime amount of smoking was positively associated with colorectal cancer (OR per 1-SD increment, 1.21; 95% CI, 1.04-1.40; = 0.01), colon cancer (OR, 1.31; 95% CI, 1.11-1.55; < 0.01), and rectal cancer (OR, 1.36; 95% CI, 1.07-1.73; = 0.01). Ever having smoked regularly was not associated with risks of breast (OR, 1.01; 95% CI, 0.90-1.14; = 0.85) or colorectal cancer (OR, 0.97; 95% CI, 0.86-1.10; = 0.68).

Conclusions: These findings are consistent with prior observational evidence and support a causal role of higher lifetime smoking amount in the development of breast and colorectal cancer.

Impact: The results from this comprehensive MR analysis indicate that lifetime smoking is a causal risk factor for these common malignancies.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611442PMC
May 2021

Highly functional virus-specific cellular immune response in asymptomatic SARS-CoV-2 infection.

J Exp Med 2021 05;218(5)

Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore.

The efficacy of virus-specific T cells in clearing pathogens involves a fine balance between antiviral and inflammatory features. SARS-CoV-2-specific T cells in individuals who clear SARS-CoV-2 without symptoms could reveal nonpathological yet protective characteristics. We longitudinally studied SARS-CoV-2-specific T cells in a cohort of asymptomatic (n = 85) and symptomatic (n = 75) COVID-19 patients after seroconversion. We quantified T cells reactive to structural proteins (M, NP, and Spike) using ELISpot and cytokine secretion in whole blood. Frequencies of SARS-CoV-2-specific T cells were similar between asymptomatic and symptomatic individuals, but the former showed an increased IFN-γ and IL-2 production. This was associated with a proportional secretion of IL-10 and proinflammatory cytokines (IL-6, TNF-α, and IL-1β) only in asymptomatic infection, while a disproportionate secretion of inflammatory cytokines was triggered by SARS-CoV-2-specific T cell activation in symptomatic individuals. Thus, asymptomatic SARS-CoV-2-infected individuals are not characterized by weak antiviral immunity; on the contrary, they mount a highly functional virus-specific cellular immune response.
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http://dx.doi.org/10.1084/jem.20202617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927662PMC
May 2021

Genetic architectures of proximal and distal colorectal cancer are partly distinct.

Gut 2021 Jul 25;70(7):1325-1334. Epub 2021 Feb 25.

Cancer Prevention and Control Program, Catalan Institute of Oncology - IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.

Objective: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined.

Design: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling.

Results: We identified 13 loci that reached genome-wide significance (p<5×10) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer.

Conclusion: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.
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http://dx.doi.org/10.1136/gutjnl-2020-321534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223655PMC
July 2021

Antimicrobial stewardship capacity and manpower needs in the Asia Pacific.

J Glob Antimicrob Resist 2021 03 3;24:387-394. Epub 2021 Feb 3.

Asia Pacific Foundation for Infectious Diseases, Seoul, Republic of Korea; CHA Bio Group, Gyeonggi-do, Republic of Korea.

Objectives: Antimicrobial stewardship is a strategy to combat antimicrobial resistance in hospitals. Given the burden and impact of antimicrobial resistance in the Asia Pacific, it is important to document capacity and gaps in antimicrobial stewardship programmes (ASP). We aimed to understand existing capacities and practices, and define the resources needed to establish antimicrobial stewardship where it is lacking.

Methods: An anonymous online survey, consisting of questions on antimicrobial control at country, hospital and programme levels, was circulated to healthcare providers in the field of infectious diseases and microbiology through Asian Network for Surveillance of Resistant Pathogens, ReAct Group and the Australasian Society for infectious Diseases.

Results: 139 participants from 16 countries or regions completed the survey. The majority of participants were adult infectious diseases physicians (61/139, 43.9%) and microbiologists (31/139, 22.3%). Participants from 7 countries reported that antimicrobials can be obtained without prescriptions. Despite the high percentage (75.5%) of respondents working in large hospitals, only 22/139 participants (15.8%) from Australia, China, Singapore, Taiwan, Thailand and Vietnam reported having more than 10 infectious diseases physicians. Hospital empiric antimicrobial guidelines for common infections were available according to 110/139 (79.1%) participants. Pre-authorisation of antimicrobials was reported by 88/113 (77.9%) respondents while prospective audit and feedback was reported by 93/114 (81.6%). Automatic stop orders and culture-guided de-escalation were reported by only 52/113 (46.0%) and 27/112 (24.1%) respectively.

Conclusion: The survey reveals a wide range of ASP development in Asia Pacific. Establishing national workgroups and guidelines will help advance antimicrobial stewardship in this diverse region.
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http://dx.doi.org/10.1016/j.jgar.2021.01.013DOI Listing
March 2021

Saliva is more sensitive than nasopharyngeal or nasal swabs for diagnosis of asymptomatic and mild COVID-19 infection.

Sci Rep 2021 02 4;11(1):3134. Epub 2021 Feb 4.

Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, #10-01, 12 Science Drive 2, Singapore, 117549, Singapore.

We aimed to test the sensitivity of naso-oropharyngeal saliva and self-administered nasal (SN) swab compared to nasopharyngeal (NP) swab for COVID-19 testing in a large cohort of migrant workers in Singapore. We also tested the utility of next-generation sequencing (NGS) for diagnosis of COVID-19. Saliva, NP and SN swabs were collected from subjects who presented with acute respiratory infection, their asymptomatic roommates, and prior confirmed cases who were undergoing isolation at a community care facility in June 2020. All samples were tested using RT-PCR. SARS-CoV-2 amplicon-based NGS with phylogenetic analysis was done for 30 samples. We recruited 200 subjects, of which 91 and 46 were tested twice and thrice respectively. In total, 62.0%, 44.5%, and 37.7% of saliva, NP and SN samples were positive. Cycle threshold (Ct) values were lower during the earlier period of infection across all sample types. The percentage of test-positive saliva was higher than NP and SN swabs. We found a strong correlation between viral genome coverage by NGS and Ct values for SARS-CoV-2. Phylogenetic analyses revealed Clade O and lineage B.6 known to be circulating in Singapore. We found saliva to be a sensitive and viable sample for COVID-19 diagnosis.
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http://dx.doi.org/10.1038/s41598-021-82787-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862309PMC
February 2021

A Method for Subtype Analysis with Somatic Mutations.

Bioinformatics 2021 Jan 8. Epub 2021 Jan 8.

Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, U.S.A.

Motivation: Cancer is a highly heterogeneous disease, and virtually all types of cancer have subtypes. Understanding the association between cancers subtypes and genetic variations is fundamental to the development of targeted therapies for patients. Somatic mutation plays important roles in tumor development and has emerged as a new type of genetic variations for studying the association with cancer subtypes. However, the low prevalence of individual mutations poses a tremendous challenge to the related statistical analysis.

Results: In this article, we propose an approach, SASOM, for the association analysis of cancer subtypes with somatic mutations. Our approach tests the association between a set of somatic mutations (from a genetic pathway) and subtypes, while incorporating functional information of the mutations into the analysis. We further propose a robust p-value combination procedure, DAPC, to synthesize statistical significance from different sources. Simulation studies show that the proposed approach has correct type I error and tends to be more powerful than possible alternative methods. In a real data application, we examine the somatic mutations from a cutaneous melanoma dataset, and identify a genetic pathway that is associated with immune-related subtypes.

Availability And Implementation: The SASOM R package is available at https://github.com/rksyouyou/SASOM-pkg. R scripts and data are available at https://github.com/rksyouyou/SASOM-analysis.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btaa1090DOI Listing
January 2021

Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study.

BMC Med 2020 12 17;18(1):396. Epub 2020 Dec 17.

Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood.

Methods: We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models.

Results: In sex-specific MR analyses, higher BMI (per 4.2 kg/m) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles.

Conclusions: Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.
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http://dx.doi.org/10.1186/s12916-020-01855-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745469PMC
December 2020

Whole genome sequencing analysis of multidrug-resistant tuberculosis in Singapore, 2006-2018.

Eur J Clin Microbiol Infect Dis 2021 May 15;40(5):1079-1083. Epub 2020 Nov 15.

TB Control Unit, Tan Tock Seng Hospital, Singapore, Singapore.

There were 290 multidrug-resistant (MDR)-TB cases diagnosed in Singapore from 2006 to 2018. Eighty-one percent were foreign-born. Spoligotyping and MIRU-VNTR methods identified 108 patients in 24 clusters. The Beijing spoligotype accounted for 22 clusters. Whole genome sequencing (WGS) analysis reduced the number of clustered patients and clusters to 43 and nine respectively. One MIRU cluster was redefined into three WGS clusters. All the clusters had foreign-born source cases. Forty percent of local-born, versus 9% of foreign-born, MDR-TB cases belonged to WGS clusters. WGS more accurately elucidated potential MDR-TB transmission which was overestimated by conventional genotyping methods in Singapore.
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http://dx.doi.org/10.1007/s10096-020-04100-6DOI Listing
May 2021

COVID-19 and Singapore: From Early Response to Circuit Breaker.

Ann Acad Med Singap 2020 08;49(8):561-572

Saw Swee Hock School of Public Health, National University of Singapore, Singapore.

Singapore, an island country with 5.6 million population and a large volume of tourists from mainland China, was one of the first countries to report imported COVID-19 cases and had the highest number of cases outside mainland China for a time in February 2020. The government responded with a series of broadscale public health measures and managed to contain this first wave of infection. Notwithstanding that, an evolving pandemic situation in other countries eventually triggered a second, and much larger, wave of infection. This case study narrates the developments, influencing factors, and outcomes related to events starting from Singapore's first response to COVID-19 and up to the point of its entry into Circuit Breaker. It serves as a reference for the understanding and analysis of developments in an evolving pandemic and a nation's response from a systems level perspective.
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August 2020

Characterizing and Measuring Tuberculosis Stigma in the Community: A Mixed-Methods Study in Cambodia.

Open Forum Infect Dis 2020 Oct 16;7(10):ofaa422. Epub 2020 Sep 16.

Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore.

Background: Stigma is a significant barrier to healthcare and a factor that drives the global burden of tuberculosis (TB). However, there is a scarcity of information on TB stigma in developing countries. We aimed to characterize, measure, and explore the determinants of TB stigma among people with TB in Cambodia.

Methods: We conducted a mixed-methods study between February and August 2019 using a triangulation convergent design-a cross-sectional survey ( = 730) and nested in-depth interviews ( = 31) among people with TB. Quantitative data were analyzed using descriptive statistics and generalized linear regression models. Qualitative transcripts were thematically analyzed.

Results: A total of 56% and 51% of participants experienced self-stigma and perceived stigma by the community, respectively. We found rural dwellers, knowledge of how TB is transmitted, and knowledge that anybody can get TB were associated with higher levels of self-stigma and perceived stigma by the community. Higher scores on knowledge of TB symptoms were inversely associated with both self-stigma and community stigma. Thematic analyses revealed accounts of experienced stigma, acts of intentional distancing and hiding TB diagnosis from others, and feelings of embarrassment and shame.

Conclusions: Tuberculosis stigma was prevalent, suggesting a need for the incorporation of stigma-reduction strategies in the national TB responses. These strategies should be contextualized and developed through community engagement. Future research should continue to measure the levels and dimensions of TB stigma among people with TB through behavioral surveillance using standardized tools.
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http://dx.doi.org/10.1093/ofid/ofaa422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585330PMC
October 2020

Identifying Novel Susceptibility Genes for Colorectal Cancer Risk From a Transcriptome-Wide Association Study of 125,478 Subjects.

Gastroenterology 2021 03 12;160(4):1164-1178.e6. Epub 2020 Oct 12.

Department of Cancer Biology and Genetics and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.

Background And Aims: Susceptibility genes and the underlying mechanisms for the majority of risk loci identified by genome-wide association studies (GWAS) for colorectal cancer (CRC) risk remain largely unknown. We conducted a transcriptome-wide association study (TWAS) to identify putative susceptibility genes.

Methods: Gene-expression prediction models were built using transcriptome and genetic data from the 284 normal transverse colon tissues of European descendants from the Genotype-Tissue Expression (GTEx), and model performance was evaluated using data from The Cancer Genome Atlas (n = 355). We applied the gene-expression prediction models and GWAS data to evaluate associations of genetically predicted gene-expression with CRC risk in 58,131 CRC cases and 67,347 controls of European ancestry. Dual-luciferase reporter assays and knockdown experiments in CRC cells and tumor xenografts were conducted.

Results: We identified 25 genes associated with CRC risk at a Bonferroni-corrected threshold of P < 9.1 × 10, including genes in 4 novel loci, PYGL (14q22.1), RPL28 (19q13.42), CAPN12 (19q13.2), MYH7B (20q11.22), and MAP1L3CA (20q11.22). In 9 known GWAS-identified loci, we uncovered 9 genes that have not been reported previously, whereas 4 genes remained statistically significant after adjusting for the lead risk variant of the locus. Through colocalization analysis in GWAS loci, we additionally identified 12 putative susceptibility genes that were supported by TWAS analysis at P < .01. We showed that risk allele of the lead risk variant rs1741640 affected the promoter activity of CABLES2. Knockdown experiments confirmed that CABLES2 plays a vital role in colorectal carcinogenesis.

Conclusions: Our study reveals new putative susceptibility genes and provides new insight into the biological mechanisms underlying CRC development.
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http://dx.doi.org/10.1053/j.gastro.2020.08.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956223PMC
March 2021
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