Josephine F. Reyes

Models of deletion for visualizing bacterial variation: an application to tuberculosis spoligotypes

BackgroundMolecular typing methods are commonly used to study genetic relationships among bacterial isolates. Many of these methods have become standardized and produce portable data. A popular approach for analyzing such data is to construct graphs, including phylogenies. Inferences from graph representations of data assist in understanding the patterns of transmission of bacterial pathogens, and basing these graph constructs on biological models of evolution of the molecular marker helps make these inferences. Spoligotyping is a widely used method for genotyping isolates of Mycobacterium tuberculosis that exploits polymorphism in the direct repeat region. Our goal was to examine a range of models describing the evolution of spoligotypes in order to develop a visualization method to represent likely relationships among M. tuberculosis isolates.ResultsWe found that inferred mutations of spoligotypes frequently involve the loss of a single or very few adjacent spacers. Using a second-order variant of Akaikes Information Criterion, we selected the Zipf model as the basis for resolving ambiguities in the ancestry of spoligotypes. We developed a method to construct graphs of spoligotypes (which we call spoligoforests). To demonstrate this method, we applied it to a tuberculosis data set from Cuba and compared the method to some existing methods.ConclusionWe propose a new approach in analyzing relationships of M. tuberculosis isolates using spoligotypes. The spoligoforest recovers a plausible history of transmission and mutation events based on the selected deletion model. The method may be suitable to study markers based on loci of similar structure from other bacteria. The groupings and relationships in the spoligoforest can be analyzed along with the clinical features of strains to provide an understanding of the evolution of spoligotypes.

Mutation rates of spoligotypes and variable numbers of tandem repeat loci in Mycobacterium tuberculosis

Variable numbers of tandem repeat (VNTR) loci and spoligotypes are molecular markers used to study genetic diversity of bacteria such as Mycobacterium tuberculosis. Knowledge about the rate at which molecular fingerprints change, or the mutation rate, is important for interpreting molecular epidemiological data and for studying quantitative models of the evolution and epidemiology of bacteria. In this paper we estimate the mutation rates of spoligotypes and VNTR loci of M. tuberculosis using published data sets from epidemiological studies. Our method makes use of a compound parameter: twice the product of the effective population size and the mutation rate. We use a standard procedure to estimate this population genetic parameter which describes genetic diversity. The ratio of estimated diversity parameters for different markers can be used to generate new estimates for markers with unknown mutation rates. We apply this method to generate new estimates along with confidence intervals. We found mutation rates for VNTR loci to be around 7x10(-4) to 1.5x10(-2) per locus per year, and for spoligotypes to be around 0.02-0.09 per year. The spoligotype rate is similar to previous estimates while the VNTR rates are at least an order of magnitude higher than previously reported. These findings confirm the high level of discrimination observed using multilocus VNTR typing, and suggest that caution should be taken not to underestimate the extent of recent transmission when using this marker.

A Model-Based Bayesian Estimation of the Rate of Evolution of VNTR Loci in Mycobacterium tuberculosis

Variable numbers of tandem repeats (VNTR) typing is widely used for studying the bacterial cause of tuberculosis. Knowledge of the rate of mutation of VNTR loci facilitates the study of the evolution and epidemiology of Mycobacterium tuberculosis. Previous studies have applied population genetic models to estimate the mutation rate, leading to estimates varying widely from around to per locus per year. Resolving this issue using more detailed models and statistical methods would lead to improved inference in the molecular epidemiology of tuberculosis. Here, we use a model-based approach that incorporates two alternative forms of a stepwise mutation process for VNTR evolution within an epidemiological model of disease transmission. Using this model in a Bayesian framework we estimate the mutation rate of VNTR in M. tuberculosis from four published data sets of VNTR profiles from Albania, Iran, Morocco and Venezuela. In the first variant, the mutation rate increases linearly with respect to repeat numbers (linear model); in the second, the mutation rate is constant across repeat numbers (constant model). We find that under the constant model, the mean mutation rate per locus is (95% CI: ,)and under the linear model, the mean mutation rate per locus per repeat unit is (95% CI: ,). These new estimates represent a high rate of mutation at VNTR loci compared to previous estimates. To compare the two models we use posterior predictive checks to ascertain which of the two models is better able to reproduce the observed data. From this procedure we find that the linear model performs better than the constant model. The general framework we use allows the possibility of extending the analysis to more complex models in the future.

Economic evaluations of implemented vaccination programmes: key methodological challenges in retrospective analyses.

Post-implementation evaluation should play an important role in assessing the success of public health programmes; however, the value for money achieved by vaccine programmes after introduction has received relatively little attention to date. In this article we explore the methodological challenges in these analyses and offer direction for future evaluations in the area. We identify alternative approaches to addressing these challenges, which include the estimation of disease changes attributable to vaccination efforts, the hypothetical no vaccination comparator scenario and the full benefit achieved by implemented vaccination programmes. We also outline other important considerations such as the evolution of prices over time. Further work needs to be done to explore these issues and to determine how the application of different approaches may impact on the results of evaluations in various circumstances. As retrospective analyses are likely to become more frequent and influential, it is important that both the benefits and the limitations of post-implementation evaluations are recognised and understood. We argue that it would be useful to establish a methodological framework to provide standards and guidance on how to undertake such analyses in the future.

Beyond expectations: Post-implementation data shows rotavirus vaccination is likely cost-saving in Australia

BACKGROUND Universal vaccination against rotavirus was included in the funded Australian National Immunisation Program in July 2007. Predictive cost-effectiveness models assessed the program before introduction. METHODS We conducted a retrospective economic evaluation of the Australian rotavirus program using national level post-implementation data on vaccine uptake, before-after measures of program impact and published estimates of excess intussusception cases. These data were used as inputs into a multi-cohort compartmental model which assigned cost and quality of life estimates to relevant health states, adopting a healthcare payer perspective. The primary outcome was discounted cost per quality adjusted life year gained, including or excluding unspecified acute gastroenteritis (AGE) hospitalisations. RESULTS Relative to the baseline period (1997-2006), over the 6years (2007-2012) after implementation of the rotavirus program, we estimated that ∼77,000 hospitalisations (17,000 coded rotavirus and 60,000 unspecified AGE) and ∼3 deaths were prevented, compared with an estimated excess of 78 cases of intussusception. Approximately 90% of hospitalisations prevented were in children <5years, with evidence of herd protection in older age groups. The program was cost-saving when observed changes (declines) in both hospitalisations coded as rotavirus and as unspecified AGE were attributed to the rotavirus vaccine program. The adverse impact of estimated excess cases of intussusception was far outweighed by the benefits of the program. CONCLUSION The inclusion of herd impact and declines in unspecified AGE hospitalisations resulted in the value for money achieved by the Australian rotavirus immunisation program being substantially greater than predicted bypre-implementation models, despite the potential increased cases of intussusception. This Australian experience is likely to be relevant to high-income countries yet to implement rotavirus vaccination programs.

Cost-effectiveness of 13-valent pneumococcal conjugate vaccine (PCV13) in older Australians

BACKGROUND The 23-valent pneumococcal polysaccharide vaccine (PPV23) has been funded under the Australia National Immunisation Program (NIP) since January 2005 for those aged >65years and other risk groups. In 2016, PCV13 was accepted by the Pharmaceutical Benefits Advisory Committee (PBAC) as a replacement for a single dose of PPV23 in older Australian adults. METHODS A single-cohort deterministic multi-compartment (Markov) model was developed describing the transition of the population between different invasive and non-invasive pneumococcal disease related health states. We applied a healthcare system perspective with costs (Australian dollars, A

Retrospective economic evaluation of childhood 7-valent pneumococcal conjugate vaccination in Australia: Uncertain herd impact on pneumonia critical.

) and health effects (measured in quality adjusted life-years, QALYs) attached to model states and discounted at 5% annually. We explored replacement of PPV23 with PCV13 at 65years as well as other age based vaccination strategies. Parameter uncertainty was explored using deterministic and probabilistic sensitivity analysis. RESULTS In a single cohort, we estimated PCV13 vaccination at the age of 65years to cost ∼A

Cost-effectiveness of antiretroviral therapy expansion strategies in Vietnam

11,120,000 and prevent 39 hospitalisations and 6 deaths from invasive pneumococcal disease and 180 hospitalisations and 10 deaths from community acquired pneumonia. The PCV13 program had an incremental cost-effectiveness ratio of ∼A

The role of timeliness in the cost-effectiveness of older adult vaccination: A case study of pneumococcal conjugate vaccine in Australia

88,100 per QALY gained when compared to a no-vaccination, whereas PPV23 was ∼A

spolTools: online utilities for analyzing spoligotypes of the Mycobacterium tuberculosis complex

297,200 per QALY gained. To fall under a cost-effectiveness threshold of A