A Bayesian framework for incorporating multiple data sources and heterogeneity in the analysis of infectious disease outbreaks

When an outbreak of an infectious disease occurs, public health officials need to understand the dynamics of disease transmission in order to launch an effective response. Two quantities that are often used to describe transmission are the basic reproductive number and the distribution of the serial interval. The basic reproductive number, R0, is the average number of secondary cases a primary case will infect, assuming a completely susceptible population. The serial interval (SI) provides a measure of temporality, and is defined as the time between symptom onset between a primary case and its secondary case. Investigators typically collect outbreak data in the form of an epidemic curve that displays the number of cases by each day (or other time scale) of the outbreak. Occasionally the epidemic curve data is more expansive and includes demographic or other information. A contact trace sample may also be collected, which is based on a sample of the cases that have their contact patterns traced to determine the timing and sequence of transmission. In addition, numerous large scale social mixing surveys have been administered in recent years to collect information about contact patterns and infection rates among different age groups. These are readily available and are sometimes used to account for population heterogeneity. In this dissertation, we modify the methods presented in White and Pagano (2008) to account for additional data beyond the epidemic curve to estimate R0 and SI. We present two approaches that incorporate these data through the use of a Bayesian framework. First, we consider informing the prior distribution of the SI with contact trace data and examine implications of combining data that are in conflict. The second approach extends the first approach to account for heterogeneity in the estimation of R0. We derive a modification to the White and Pagano likelihood function and utilize social mixing surveys to inform the prior distributions of R0. Both approaches are assessed through a simulation study and are compared to alternative approaches, and are applied to real outbreak data from the 2003 SARS outbreak in Hong Kong and Singapore, and the influenza A(H1N1)2009pdm outbreak in South Africa

The impact of prior information on estimates of disease transmissibility using Bayesian tools

The basic reproductive number (R₀) and the distribution of the serial interval (SI) are often used to quantify transmission during an infectious disease outbreak. In this paper, we present estimates of R₀ and SI from the 2003 SARS outbreak in Hong Kong and Singapore, and the 2009 pandemic influenza A(H1N1) outbreak in South Africa using methods that expand upon an existing Bayesian framework. This expanded framework allows for the incorporation of additional information, such as contact tracing or household data, through prior distributions. The results for the R₀ and the SI from the influenza outbreak in South Africa were similar regardless of the prior information (R0 = 1.36-1.46, μ = 2.0-2.7, μ = mean of the SI). The estimates of R₀ and μ for the SARS outbreak ranged from 2.0-4.4 and 7.4-11.3, respectively, and were shown to vary depending on the use of contact tracing data. The impact of the contact tracing data was likely due to the small number of SARS cases relative to the size of the contact tracing sample

Associations of Circulating Dimethylarginines with the Metabolic Syndrome in the Framingham Offspring Study

BACKGROUND: Circulating levels of the endogenous inhibitor of nitric oxide synthase, asymmetric dimethylarginine (ADMA), are positively associated with the prevalence of metabolic syndrome (MetS) in cross-sectional investigations. It is unclear if circulating ADMA and other methylarginines are associated with incident MetS prospectively. METHODS: We related circulating ADMA, symmetric dimethylarginine (SDMA), L-arginine (ARG) concentrations (measured with a validated tandem mass spectrometry assay) and the ARG/ADMA ratio to MetS and its components in 2914 (cross-sectional analysis, logistic regression; mean age 58 years, 55% women) and 1656 (prospective analysis, Cox regression; mean age 56 years, 59% women) individuals from the Framingham Offspring Study who attended a routine examination. RESULTS: Adjusting for age, sex, smoking, and eGFR, we observed significant associations of ADMA (direct) and ARG/ADMA (inverse) with odds of MetS (N = 1461 prevalent cases; Odds Ratio [OR] per SD increment 1.13, 95%CI 1.04-1.22; and 0.89, 95%CI 0.82-0.97 for ADMA and ARG/ADMA, respectively). Upon further adjustment for waist circumference, systolic and diastolic blood pressure, glucose, high-density lipoprotein cholesterol, and triglycerides, we observed a positive relation between SDMA and MetS (OR per SD increment 1.15, 95% CI 1.01-1.30) but the other associations were rendered statistically non-significant. We did not observe statistically significant associations between any of the methylarginines and the risk of new-onset MetS (752 incident events) over a median follow-up of 11 years. CONCLUSION: It is unclear whether dimethylarginines play an important role in the incidence of cardiometabolic risk in the community, notwithstanding cross-sectional associations. Further studies of larger samples are needed to replicate our findings

Nasal and Plasma SARS-CoV-2 RNA Levels are Associated with Timing of Symptom Resolution in the ACTIV-2 Trial of Non-hospitalized Adults with COVID-19

Acute COVID-19 symptoms limit daily activities, but little is known about its association with SARS-CoV-2 viral burden. In this exploratory analysis of placebo recipients in the ACTIV-2/A5401 platform trial, we showed that high anterior nasal (AN) RNA levels and detectable plasma RNA were associated with delayed symptom improvement

Nasal and Plasma Severe Acute Respiratory Syndrome Coronavirus 2 RNA Levels Are Associated With Timing of Symptom Resolution in the ACTIV-2 Trial of Nonhospitalized Adults With Coronavirus Disease 2019

Acute Coronavirus Disease 2019 symptoms limit daily activities, but little is known about its association with severe acute respiratory syndrome coronavirus 2 viral burden. In this exploratory analysis of placebo recipients in the ACTIV-2/A5401 platform trial, we showed that high anterior nasal RNA levels and detectable plasma RNA were associated with delayed symptom improvement.Clinical Trials Registration.https://clinicaltrials.gov/ct2/show/NCT04518410

Predictors of SARS-CoV-2 RNA From Nasopharyngeal Swabs and Concordance With Other Compartments in Nonhospitalized Adults With Mild to Moderate COVID-19

Background Identifying characteristics associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA shedding may be useful to understand viral compartmentalization, disease pathogenesis, and risks for viral transmission. Methods Participants were enrolled August 2020 to February 2021 in ACTIV-2/A5401, a placebo-controlled platform trial evaluating investigational therapies for mild-to-moderate coronavirus disease 2019 (COVID-19), and underwent quantitative SARS-CoV-2 RNA testing on nasopharyngeal and anterior nasal swabs, oral wash/saliva, and plasma at entry (day 0, pretreatment) and days 3, 7, 14, and 28. Concordance of RNA levels (copies/mL) across compartments and predictors of nasopharyngeal RNA levels were assessed at entry (n = 537). Predictors of changes over time were evaluated among placebo recipients (n = 265) with censored linear regression models. Results Nasopharyngeal and anterior nasal RNA levels at study entry were highly correlated (r = 0.84); higher levels of both were associated with greater detection of RNA in plasma and oral wash/saliva. Older age, White non-Hispanic race/ethnicity, lower body mass index (BMI), SARS-CoV-2 immunoglobulin G seronegativity, and shorter prior symptom duration were associated with higher nasopharyngeal RNA at entry. In adjusted models, body mass index and race/ethnicity associations were attenuated, but the association with age remained (for every 10 years older, mean nasopharyngeal RNA was 0.27 log10 copies/mL higher; P < .001). Examining longitudinal viral RNA levels among placebo recipients, women had faster declines in nasopharyngeal RNA than men (mean change, −2.0 vs −1.3 log10 copies/mL, entry to day 3; P < .001). Conclusions SARS-CoV-2 RNA shedding was concordant across compartments. Age was strongly associated with viral shedding, and men had slower viral clearance than women, which could explain sex differences in acute COVID-19 outcomes

Phase 2 safety and antiviral activity of SAB-185, a novel polyclonal antibody therapy for non-hospitalized adults with COVID-19

SAB-185, a novel fully-human IgG polyclonal immunoglobulin product, underwent phase 2 evaluation for non-hospitalized adults with mild-moderate COVID-19.Participants received intravenous SAB-185 3,840 units/kg (low-dose) or placebo, or 10,240 units/kg (high-dose) or placebo. Primary outcome measures were nasopharyngeal SARS-CoV-2 RNA &lt;lower limit of quantification (LLoQ) at study days 3, 7, and 14, time to symptomatic improvement, and safety through day 28.Two-hundred thirteen participants received low-dose SAB-185/placebo (n=107/106) and 215 high-dose SAB-185/placebo (n=110/105). The proportions with SARS-CoV-2 RNA &lt;LLoQ were higher for SAB-185 versus placebo at days 3 and 7 and similar at day 14, and significantly higher at day 7 for high-dose SAB versus placebo only, relative risk (95% CI) 1.23 (1.01, 1.49). At day 3, SARS-CoV-2 RNA levels were lower with low-dose and high-dose SAB-185 versus placebo, differences in medians of -0.78 log10copies/mL (p=0.08) and -0.71 log10copies/mL (p=0.10), respectively. No difference was observed in time to symptom improvement: median 11/10 days (p=0.24) for low-dose SAB-185/placebo and 8/10 days (p=0.50) for high-dose SAB-185/placebo. Grade ≥3 adverse events occurred in 5%/13% of low-dose SAB-185/placebo and 9%/12% of high-dose SAB-185/placebo.SAB-185 was safe and generally well tolerated and demonstrated modest antiviral activity in predominantly low-risk non-hospitalized adults with COVID-19

Bamlanivimab therapy for acute COVID-19 does not blunt SARS-CoV-2-specific memory T cell responses

Despite the widespread use of SARS-CoV-2-specific monoclonal antibody (mAb) therapy for the treatment of acute COVID-19, the impact of this therapy on the development of SARS-CoV-2-specific T cell responses has been unknown, resulting in uncertainty as to whether anti-SARS-CoV-2 mAb administration may result in failure to generate immune memory. Alternatively, it has been suggested that SARS-CoV-2-specific mAb may enhance adaptive immunity to SARS-CoV-2 via a "vaccinal effect." Bamlanivimab (Eli Lilly) is a recombinant human IgG1 that was granted FDA emergency use authorization for the treatment of mild to moderate COVID-19 in those at high risk for progression to severe disease. Here, we compared SARS-CoV-2 specific CD4+ and CD8+ T cell responses of 95 individuals from the ACTIV-2/A5401 clinical trial 28 days after treatment with 700 mg bamlanivimab versus placebo. SARS-CoV-2-specific T cell responses were evaluated using activation induced marker (AIM) assays in conjunction with intracellular cytokine staining (ICS). We demonstrate that most individuals with acute COVID-19 develop SARS-CoV-2-specific T cell responses. Overall, our findings suggest that the quantity and quality of SARS-CoV-2-specific T cell memory was not diminished in individuals who received bamlanivimab for acute COVID-19. Receipt of bamlanivimab during acute COVID-19 neither diminished nor enhanced SARS-CoV-2-specific cellular immunity

B-type natriuretic peptide and C-reactive protein in the prediction of atrial fibrillation risk: the CHARGE-AF Consortium of community-based cohort studies

B-type natriuretic peptide (BNP) and C-reactive protein (CRP) predict atrial fibrillation (AF) risk. However, their risk stratification abilities in the broad community remain uncertain. We sought to improve risk stratification for AF using biomarker information