Development and external evaluation of predictions models for mortality of COVID-19 patients using machine learning method.

To predict the mortality of patients with coronavirus disease 2019 (COVID-19). We collected clinical data of COVID-19 patients between January 18 and March 29 2020 in Wuhan, China . Gradient boosting decision tree (GBDT), logistic regression (LR) model, and simplified LR were built to predict the mortality of COVID-19. We also evaluated different models by computing area under curve (AUC), accuracy, positive predictive value (PPV), and negative predictive value (NPV) under fivefold cross-validation. A total of 2924 patients were included in our evaluation, with 257 (8.8%) died and 2667 (91.2%) survived during hospitalization. Upon admission, there were 21 (0.7%) mild cases, 2051 (70.1%) moderate case, 779 (26.6%) severe cases, and 73 (2.5%) critically severe cases. The GBDT model exhibited the highest fivefold AUC, which was 0.941, followed by LR (0.928) and LR-5 (0.913). The diagnostic accuracies of GBDT, LR, and LR-5 were 0.889, 0.868, and 0.887, respectively. In particular, the GBDT model demonstrated the highest sensitivity (0.899) and specificity (0.889). The NPV of all three models exceeded 97%, while their PPV values were relatively low, resulting in 0.381 for LR, 0.402 for LR-5, and 0.432 for GBDT. Regarding severe and critically severe cases, the GBDT model also performed the best with a fivefold AUC of 0.918. In the external validation test of the LR-5 model using 72 cases of COVID-19 from Brunei, leukomonocyte (%) turned to show the highest fivefold AUC (0.917), followed by urea (0.867), age (0.826), and SPO2 (0.704). The findings confirm that the mortality prediction performance of the GBDT is better than the LR models in confirmed cases of COVID-19. The performance comparison seems independent of disease severity. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at(10.1007/s00521-020-05592-1).

Immunogenicity of COVID-19 vaccines and levels of SARS-CoV-2 neutralising antibody in the Bruneian population: Protocol for a national longitudinal study.

INTRODUCTION: Neutralising antibodies (NAbs) have been shown to be correlative of immune protection against SARS-CoV-2. We report the protocol for a national longitudinal study to assess and compare the level of NAbs generated in response to COVID-19 vaccines in Brunei Darussalam in adults 2-6 weeks post primary series (BBIBP-CorV, AZD1222, or mRNA-1273 vaccines) and their subsequent follow-up after administration of a third (booster-1) dose (BBIBP-CorV, mRNA-1273, or BNT162b2). METHODS AND ANALYSIS: Participant data will be extracted and processed from the national electronic health record system (Bru-HIMS) and the national mobile health application (BruHealth) into a research data platform. Eligible adults who have received their primary or booster vaccine will be invited using a stratified random sampling strategy based on age, gender and vaccine type (baseline target population, n=3000; 2-6 weeks post last dose). Blood serum will be isolated, and NAb levels assessed using the cPass surrogate virus neutralisation test. Baseline participants will then be screened for eligibility for subsequent longitudinal analysis. Those who have received a third dose will be followed up at 1, 3, 6, 9 and up to 12 months. NAb levels will be evaluated across the participant population according to vaccine platform/booster type, time since the last dose and correlated with demographic data. The study period is from December 2021 to January 2023 and aims to evaluate how NAb levels wane following a third vaccine dose across different vaccine platforms and determine the impact and rate of breakthrough infections. ETHICS AND DISSEMINATION: This study has been approved by the Medical and Ethical Research Committee of Ministry of Health, Brunei Darussalam. Individual NAb test results will be shared with each participant by text message. The findings from this study will help policy-makers in Brunei develop future vaccination strategies and establish regulations across multiple agencies.

Technology-assisted adaptive recruitment strategy for a large nation-wide COVID-19 vaccine immunogenicity study in Brunei.

A national study was conducted in Brunei to assess and compare the immunogenicity of the various brands of COVID-19 vaccines administered to the population as part of the National COVID-19 Vaccination Programme. Most of the population have had received at least 2 doses of BBIBP-CorV, AZD1222 or MRNA-1273 vaccines. Neutralising antibodies against SARS-CoV-2 induced by these vaccines will be analysed to infer population-level immune protection against COVID-19. During the 5-week recruitment period, 24,260 eligible individuals were invited to the study via SMS, out of which 2,712 participants were enrolled into the study. This paper describes the novel adaptive strategy used to recruit the study participants. Digital technology was leveraged to perform targeted online recruitment to circumvent the limitations of traditional recruitment methods. Technology also enabled stratified random selection of these eligible individuals who were stratified based on age, gender and vaccine brand. Data was extracted from the electronic health records, the national mobile health application and a third-party survey platform and integrated into a dedicated research platform called EVYDResearch. The instant availability and access to up-to-date data on EVYDResearch enabled the study team to meet weekly and adopt an adaptive recruitment strategy informed by behavioural science, where interventions could be quickly implemented to improve response rates. Some examples of these include incorporating nudge messaging into SMS invitations, involving the Minister of Health to make press announcements on this study, media coverage, setting up an enquiries hotline and reaching out to foreign language speaking expatriates of a local multinational company to participate in this study. Data integration from various data sources, real time information sharing and a strong teamwork led to good outcomes adaptable to the progress of recruitment, compared to the more time-consuming and static traditional recruitment methods.

Clinical and demographic characteristics of COVID-19 cases in Brunei Darussalam: comparison between the first and second waves, 2020 and 2021.

Objective: Differences in clinical manifestations between strains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been reported. This retrospective descriptive study compares the clinical and demographic characteristics of all confirmed coronavirus disease (COVID-19) cases admitted to the National Isolation Centre (NIC) in the first wave and at the beginning of the second wave of the pandemic in Brunei Darussalam. Methods: All COVID-19 cases admitted to the NIC between 9 March and 6 May 2020 (first wave) and 7-17 August 2021 (second wave) were included. Data were obtained from NIC databases and case characteristics compared using Student's t-tests and χ2 tests, as appropriate. Results: Cases from the first wave were significantly older than those from the second wave (mean 37.2 vs 29.7 years, P < 0.001), and a higher proportion reported comorbidities (30.5% vs 20.3%, P = 0.019). Cases from the second wave were more likely to be symptomatic at admission (77.7% vs 63.1%, P < 0.001), with a higher proportion reporting cough, anosmia, sore throat and ageusia/dysgeusia; however, myalgia and nausea/vomiting were more common among symptomatic first wave cases (all P < 0.05). There was no difference in the mean number of reported symptoms (2.6 vs 2.4, P = 0.890). Discussion: Our study showed clear differences in the profile of COVID-19 cases in Brunei Darussalam between the first and second waves, reflecting a shift in the predominating SARS-CoV-2 strain. Awareness of changes in COVID-19 disease manifestation can help guide adjustments to management policies such as duration of isolation, testing strategies, and criteria for admission and treatment.

Deconvoluting complex correlates of COVID-19 severity with a multi-omic pandemic tracking strategy.

The SARS-CoV-2 pandemic has differentially impacted populations across race and ethnicity. A multi-omic approach represents a powerful tool to examine risk across multi-ancestry genomes. We leverage a pandemic tracking strategy in which we sequence viral and host genomes and transcriptomes from nasopharyngeal swabs of 1049 individuals (736 SARS-CoV-2 positive and 313 SARS-CoV-2 negative) and integrate them with digital phenotypes from electronic health records from a diverse catchment area in Northern California. Genome-wide association disaggregated by admixture mapping reveals novel COVID-19-severity-associated regions containing previously reported markers of neurologic, pulmonary and viral disease susceptibility. Phylodynamic tracking of consensus viral genomes reveals no association with disease severity or inferred ancestry. Summary data from multiomic investigation reveals metagenomic and HLA associations with severe COVID-19. The wealth of data available from residual nasopharyngeal swabs in combination with clinical data abstracted automatically at scale highlights a powerful strategy for pandemic tracking, and reveals distinct epidemiologic, genetic, and biological associations for those at the highest risk.

COVID-19 patients with negative results on initial screening: Experience of Brunei Darussalam.

In any infectious disease outbreak, early diagnosis, isolation of cases and quarantine of contacts are central to disease containment. In Brunei Darussalam, suspected cases of coronavirus disease 2019 (COVID-19) were quarantined either at home or at designated centres and were tested immediately for severe acute respiratory syndrome coronavirus 2. We report on 10 cases of COVID-19 that initially tested negative for COVID-19 and were positive on re-testing after becoming symptomatic. These cases comprised 3.8% of the 266 total confirmed COVID-19 cases in Brunei Darussalam as of 9 July 2021, when this study was conducted. All the cases were in quarantine at home and were tested early during their quarantine period. Since then, home quarantine has been replaced by quarantine at designated centres only, with testing on the 12th day of quarantine.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Setting-specific Transmission Rates: A Systematic Review and Meta-analysis.

BACKGROUND: Understanding the drivers of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission is crucial for control policies, but evidence of transmission rates in different settings remains limited. METHODS: We conducted a systematic review to estimate secondary attack rates (SARs) and observed reproduction numbers (Robs) in different settings exploring differences by age, symptom status, and duration of exposure. To account for additional study heterogeneity, we employed a beta-binomial model to pool SARs across studies and a negative-binomial model to estimate Robs. RESULTS: Households showed the highest transmission rates, with a pooled SAR of 21.1% (95% confidence interval [CI]:17.4-24.8). SARs were significantly higher where the duration of household exposure exceeded 5 days compared with exposure of ≤5 days. SARs related to contacts at social events with family and friends were higher than those for low-risk casual contacts (5.9% vs 1.2%). Estimates of SARs and Robs for asymptomatic index cases were approximately one-seventh, and for presymptomatic two-thirds of those for symptomatic index cases. We found some evidence for reduced transmission potential both from and to individuals younger than 20 years of age in the household context, which is more limited when examining all settings. CONCLUSIONS: Our results suggest that exposure in settings with familiar contacts increases SARS-CoV-2 transmission potential. Additionally, the differences observed in transmissibility by index case symptom status and duration of exposure have important implications for control strategies, such as contact tracing, testing, and rapid isolation of cases. There were limited data to explore transmission patterns in workplaces, schools, and care homes, highlighting the need for further research in such settings.

Estimating the impact of physical distancing measures in containing COVID-19: an empirical analysis.

BACKGROUND: Epidemic modelling studies predict that physical distancing is critical in containing COVID-19. However, few empirical studies have validated this finding. Our study evaluates the effectiveness of different physical distancing measures in controlling viral transmission. METHODS: We identified three distinct physical distancing measures with varying intensity and implemented at different times-international travel controls, restrictions on mass gatherings, and lockdown-type measures-based on the Oxford COVID-19 Government Response Tracker. We also estimated the time-varying reproduction number (Rt) for 142 countries and tracked Rt temporally for two weeks following the 100th reported case in each country. We regressed Rt on the physical distancing measures and other control variables (income, population density, age structure, and temperature) and performed several robustness checks to validate our findings. FINDINGS: Complete travel bans and all forms of lockdown-type measures have been effective in reducing average Rt over the 14 days following the 100th case. Recommended stay-at-home advisories and partial lockdowns are as effective as complete lockdowns in outbreak control. However, these measures have to be implemented early to be effective. Based on the observed median timing across countries worldwide, lockdown-type measures are considered early if they were instituted about two weeks before the 100th case and travel bans a week before detection of the first case. INTERPRETATION: A combination of physical distancing measures, if implemented early, can be effective in containing COVID-19-tight border controls to limit importation of cases, encouraging physical distancing, moderately stringent measures such as working from home, and a full lockdown in the case of a probable uncontrolled outbreak.

Probable causes and risk factors for positive SARS-CoV-2 test in recovered patients: Evidence from Brunei Darussalam.

Case reports of patients with coronavirus disease-2019 (COVID-19) who have been discharged and subsequently report positive reverse transcription-polymerase chain reaction again (hereafter referred as "re-positive") do not fully describe the magnitude and significance of this issue. To determine the re-positive rate (proportion) and review probable causes and outcomes, we conduct a retrospective study of all 119 discharged patients in Brunei Darussalam up till April 23. Patients who were discharged are required to self-isolate at home for 14 days and undergo nasopharyngeal specimen collection postdischarge. Discharged patients found to be re-positive were readmitted. We reviewed the clinical and epidemiological records of all discharged patients and apply log-binomial models to obtain risk ratios for re-positive status. One in five recovered patients subsequently test positive again for severe acute respiratory syndrome coronavirus 2-this risk is more than six times higher in persons aged 60 years and above. The average Ct value of re-positive patients was lower predischarge compared with their readmission Ct value. Out of 111 close contacts tested, none were found to be positive as a result of exposure to a re-positive patient. Our findings support prolonged but intermittent viral shedding as the probable cause for this phenomenon. We did not observe infectivity potential in these patients.

Analysis of SARS-CoV-2 Transmission in Different Settings, Brunei.

We report the transmission dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) across different settings in Brunei. An initial cluster of SARS-CoV-2 cases arose from 19 persons who had attended the Tablighi Jama'at gathering in Malaysia, resulting in 52 locally transmitted cases. The highest nonprimary attack rates (14.8%) were observed from a subsequent religious gathering in Brunei and in households of attendees (10.6%). Household attack rates from symptomatic case-patients were higher (14.4%) than from asymptomatic (4.4%) or presymptomatic (6.1%) case-patients. Workplace and social settings had attack rates of <1%. Our analyses highlight that transmission of SARS-CoV-2 varies depending on environmental, behavioral, and host factors. We identify red flags for potential superspreading events, specifically densely populated gatherings with prolonged exposure in enclosed settings, persons with recent travel history to areas with active SARS-CoV-2 infections, and group behaviors. We propose differentiated testing strategies to account for differing transmission risk.

What do we know about SARS-CoV-2 transmission? A systematic review and meta-analysis of the secondary attack rate and associated risk factors.

INTRODUCTION: Current SARS-CoV-2 containment measures rely on controlling viral transmission. Effective prioritization can be determined by understanding SARS-CoV-2 transmission dynamics. We conducted a systematic review and meta-analyses of the secondary attack rate (SAR) in household and healthcare settings. We also examined whether household transmission differed by symptom status of index case, adult and children, and relationship to index case. METHODS: We searched PubMed, medRxiv, and bioRxiv databases between January 1 and July 25, 2020. High-quality studies presenting original data for calculating point estimates and 95% confidence intervals (CI) were included. Random effects models were constructed to pool SAR in household and healthcare settings. Publication bias was assessed by funnel plots and Egger's meta-regression test. RESULTS: 43 studies met the inclusion criteria for household SAR, 18 for healthcare SAR, and 17 for other settings. The pooled household SAR was 18.1% (95% CI: 15.7%, 20.6%), with significant heterogeneity across studies ranging from 3.9% to 54.9%. SAR of symptomatic index cases was higher than asymptomatic cases (RR: 3.23; 95% CI: 1.46, 7.14). Adults showed higher susceptibility to infection than children (RR: 1.71; 95% CI: 1.35, 2.17). Spouses of index cases were more likely to be infected compared to other household contacts (RR: 2.39; 95% CI: 1.79, 3.19). In healthcare settings, SAR was estimated at 0.7% (95% CI: 0.4%, 1.0%). DISCUSSION: While aggressive contact tracing strategies may be appropriate early in an outbreak, as it progresses, measures should transition to account for setting-specific transmission risk. Quarantine may need to cover entire communities while tracing shifts to identifying transmission hotspots and vulnerable populations. Where possible, confirmed cases should be isolated away from the household.

Epidemiological Investigation of the First 135 COVID-19 Cases in Brunei: Implications for Surveillance, Control, and Travel Restrictions.

Studies on the early introduction of SARS-CoV-2 in a naive population have important epidemic control implications. We report findings from the epidemiological investigation of the initial 135 COVID-19 cases in Brunei and describe the impact of control measures and travel restrictions. Epidemiological and clinical information was obtained for all confirmed COVID-19 cases, whose symptom onset was from March 9 to April 5, 2020. The basic reproduction number (R0), incubation period, and serial interval (SI) were calculated. Time-varying R was estimated to assess the effectiveness of control measures. Of the 135 cases detected, 53 (39.3%) were imported. The median age was 36 (range = 0.5-72) years. Forty-one (30.4%) and 13 (9.6%) were presymptomatic and asymptomatic cases, respectively. The median incubation period was 5 days (interquartile range [IQR] = 5, range = 1-11), and the mean SI was 5.4 days (SD = 4.5; 95% CI: 4.3, 6.5). The reproduction number was between 3.9 and 6.0, and the doubling time was 1.3 days. The time-varying reproduction number (Rt) was below one (Rt = 0.91; 95% credible interval: 0.62, 1.32) by the 13th day of the epidemic. Epidemic control was achieved through a combination of public health measures, with emphasis on a test-isolate-trace approach supplemented by travel restrictions and moderate physical distancing measures but no actual lockdown. Regular and ongoing testing of high-risk groups to supplement the existing surveillance program and a phased easing of physical distancing measures has helped maintain suppression of the COVID-19 outbreak in Brunei, as evidenced by the identification of only six additional cases from April 5 to August 5, 2020.

Containing COVID-19: Implementation of Early and Moderately Stringent Social Distancing Measures Can Prevent The Need for Large-Scale Lockdowns.

Guidance from many health authorities recommend that social distancing measures should be implemented in an epidemic when community transmission has already occurred. The clinical and epidemiological characteristics of COVID-19 suggest this is too late. Based on international comparisons of the timing and scale of the implementation of social distancing measures, we find that countries that imposed early stringent measures recorded far fewer cases than those that did not. Yet, such measures need not be extreme. We highlight the examples of Hong Kong and Brunei to demonstrate the early use of moderate social distancing measures as a practical containment strategy. We propose that such measures be a key part of responding to potential future waves of the epidemic.