Contact network uncertainty in individual level models of infectious disease transmission

Infectious disease transmission between individuals in a heterogeneous population is often best modelled through a contact network. This contact network can be spatial in nature, with connections between individuals closer in space being more likely. However, contact network data are often unobserved. Here, we consider the fit of an individual level model containing a spatially-based contact network that is either entirely, or partially, unobserved within a Bayesian framework, using data augmented Markov chain Monte Carlo (MCMC). We also incorporate the uncertainty about event history in the disease data. We also examine the performance of the data augmented MCMC analysis in the presence or absence of contact network observational models based upon either knowledge about the degree distribution or the total number of connections in the network. We find that the latter tend to provide better estimates of the model parameters and the underlying contact network.

Evaluating the power of the causal impact method in observational studies of HCV treatment as prevention

Objectives The causal impact method (CIM) was recently introduced for evaluation of binary interventions using observational time-series data. The CIM is appealing for practical use as it can adjust for temporal trends and account for the potential of unobserved confounding. However, the method was initially developed for applications involving large datasets and hence its potential in small epidemiological studies is still unclear. Further, the effects that measurement error can have on the performance of the CIM have not been studied yet. The objective of this work is to investigate both of these open problems. Methods Motivated by an existing dataset of HCV surveillance in the UK, we perform simulation experiments to investigate the effect of several characteristics of the data on the performance of the CIM. Further, we quantify the effects of measurement error on the performance of the CIM and extend the method to deal with this problem. Results We identify multiple characteristics of the data that affect the ability of the CIM to detect an intervention effect including the length of time-series, the variability of the outcome and the degree of correlation between the outcome of the treated unit and the outcomes of controls. We show that measurement error can introduce biases in the estimated intervention effects and heavily reduce the power of the CIM. Using an extended CIM, some of these adverse effects can be mitigated. Conclusions The CIM can provide satisfactory power in public health interventions. The method may provide misleading results in the presence of measurement error.

GLM based auto-regressive process to model Covid-19 pandemic in Turkey

Objectives: Our objective is to propose a robust approach to model daily new cases and daily new deaths due to covid-19 infection in Turkey. Methods: We consider the generalized linear model (GLM) approach for the autoregressive process (AR) with log link for modelling. We study the data between March 11, 2020 that is the date first confirmed case occurred and October 20, 2020. After a month of the first outbreak in Turkey, the first official curfew has been imposed during the weekend. Since then there have been curfews each weekend till June 1st. Hence, we include intervention effects as well as some outlying data points in the model where necessary. We use the data between March 11 and September 15 to build the models, and test the performance on the data from September 16 till October 20. We also study the consistency of the model statistics. Results: Estimated models fit data quite well. Results reveal that after the first curfew daily new Covid-19 cases decrease 18.5%. As expected, effect of the curfew gets more significant once a month is past, and daily new cases cut down 24.9%. Our approach also gives a robust estimate for the effective reproduction number that is approximately 2 meaning as of October 20, 2020 there is still a risk for an infected person to cause 2 secondary infections despite all the interventions, preventions, and rules. Conclusion: The GLM approach for AR process with log link produces consistent and robust estimates for the daily new cases and daily new deaths for the data covering almost the first year of the pandemic in Turkey. The proposed approach can also be used to model the cases in other countries.

Principal surrogates in context of high vaccine efficacy

Objectives The use of correlates of protection (CoPs) in vaccination trials offers significant advantages as useful clinical endpoint substitutes. Vaccines with very high vaccine efficacy (VE) are documented in the literature (95% or above). Callegaro, A., and F. Tibaldi. 2019. “Assessing Correlates of Protection in Vaccine Trials: Statistical Solutions in the Context of High Vaccine Efficacy.” BMC Medical Research Methodology 19: 47 showed that the rare infections observed in the vaccinated groups of these trials poses challenges when applying conventionally-used statistical methods for CoP assessment such as the Prentice criteria and meta-analysis. The objective of this work is to investigate the impact of this problem on another statistical method for the assessment of CoPs called Principal stratification. Methods We perform simulation experiments to investigate the effect of high vaccine efficacy on the performance of the Principal Stratification approach. Results Similarly to the Prentice framework, simulation results show that the power of the Principal Stratification approach decreases when the VE grows. Conclusions It can be challenging to validate principal surrogates (and statistical surrogates) for vaccines with very high vaccine efficacy.

Sample size calculation for active-arm trial with counterfactual incidence based on recency assay

Objectives The past decade has seen tremendous progress in the development of biomedical agents that are effective as pre-exposure prophylaxis (PrEP) for HIV prevention. To expand the choice of products and delivery methods, new medications and delivery methods are under development. Future trials of non-inferiority, given the high efficacy of ARV-based PrEP products as they become current or future standard of care, would require a large number of participants and long follow-up time that may not be feasible. This motivates the construction of a counterfactual estimate that approximates incidence for a randomized concurrent control group receiving no PrEP. Methods We propose an approach that is to enroll a cohort of prospective PrEP users and aug-ment screening for HIV with laboratory markers of duration of HIV infection to indicate recent infections. We discuss the assumptions under which these data would yield an estimate of the counterfactual HIV incidence and develop sample size and power calculations for comparisons to incidence observed on an investigational PrEP agent. Results We consider two hypothetical trials for men who have sex with men (MSM) and transgender women (TGW) from different regions and young women in sub-Saharan Africa. The calculated sample sizes are reasonable and yield desirable power in simulation studies. Conclusions Future one-arm trials with counterfactual placebo incidence based on a recency assay can be conducted with reasonable total screening sample sizes and adequate power to determine treatment efficacy.

Confidence limits for the averted infections ratio estimated via the counterfactual placebo incidence rate

Objectives The averted infections ratio (AIR) is a novel measure for quantifying the preservation-of-effect in active-control non-inferiority clinical trials with a time-to-event outcome. In the main formulation, the AIR requires an estimate of the counterfactual placebo incidence rate. We describe two approaches for calculating confidence limits for the AIR given a point estimate of this parameter, a closed-form solution based on a Taylor series expansion (delta method) and an iterative method based on the profile-likelihood. Methods For each approach, exact coverage probabilities for the lower and upper confidence limits were computed over a grid of values of (1) the true value of the AIR (2) the expected number of counterfactual events (3) the effectiveness of the active-control treatment. Results Focussing on the lower confidence limit, which determines whether non-inferiority can be declared, the coverage achieved by the delta method is either less than or greater than the nominal coverage, depending on the true value of the AIR. In contrast, the coverage achieved by the profile-likelihood method is consistently accurate. Conclusions The profile-likelihood method is preferred because of better coverage properties, but the simpler delta method is valid when the experimental treatment is no less effective than the control treatment. A complementary Bayesian approach, which can be applied when the counterfactual incidence rate can be represented as a prior distribution, is also outlined.

Evaluating the relative contribution of data sources in a Bayesian analysis with the application of estimating the size of hard to reach populations

ObjectivesWhen using multiple data sources in an analysis, it is important to understand the influence of each data source on the analysis and the consistency of the data sources with each other and the model. We suggest the use of a retrospective value of information framework in order to address such concerns.MethodsValue of information methods can be computationally difficult. We illustrate the use of computational methods that allow these methods to be applied even in relatively complicated settings. In illustrating the proposed methods, we focus on an application in estimating the size of hard to reach populations. Specifically, we consider estimating the number of injection drug users in Ukraine by combining all available data sources spanning over half a decade and numerous sub-national areas in the Ukraine. This application is of interest to public health researchers as this hard to reach population that plays a large role in the spread of HIV.Results and conclusionsWe apply a Bayesian hierarchical model and evaluate the contribution of each data source in terms of absolute influence, expected influence, and level of surprise. Finally we apply value of information methods to inform suggestions on future data collection.

Pre-selected class-level testing of longitudinal biomarkers reduces required multiple testing corrections to yield novel insights in longitudinal small sample human studies

ObjectivesExploratory studies that aim to evaluate novel therapeutic strategies in human cohorts often involve the collection of hundreds of variables measured over time on a small sample of individuals. Stringent error control for testing hypotheses in this setting renders it difficult to identify statistically signification associations. The objective of this study is to demonstrate how leveraging prior information about the biological relationships among variables can increase power for novel discovery.MethodsWe apply the class level association score statistic for longitudinal data (CLASS-LD) as an analysis strategy that complements single variable tests. An example is presented that aims to evaluate the relationships among 14 T-cell and monocyte activation variables measured with CD4 T-cell count over three time points after antiretroviral therapy (n=62).ResultsCLASS-LD using three classes with emphasis on T-cell activation with either classical vs. intermediate/inflammatory monocyte subsets detected associations in two of three classes, while single variable testing detected only one out of the 14 variables considered.ConclusionsApplication of a class-level testing strategy provides an alternative to single immune variables by defining hypotheses based on a collection of variables that share a known underlying biological relationship. Broader use of class-level analysis is expected to increase the available information that can be derived from limited sample clinical studies.

Estimation of time-dependent arbovirus infection risk in blood and tissue donations

West Nile virus (WNV) outbreaks raise the concern of WNV infection in donated blood and blood products destined for transfusion. We describe methods we developed to estimate time-dependent risk of WNV infection in donated blood, including improvements not previously detailed. The methods are then extended for use in estimation of the risk of WNV infection in donated cadaveric tissues by introducing stratification and stratum-specific weighting to address novel aspects of this application. Data from the WNV outbreak in Colorado in 2003 are used to estimate risk for donated cardiac tissue.