Estimated Covid-19 burden in Spain: ARCH underreported non-stationary time series.

BACKGROUND: The problem of dealing with misreported data is very common in a wide range of contexts for different reasons. The current situation caused by the Covid-19 worldwide pandemic is a clear example, where the data provided by official sources were not always reliable due to data collection issues and to the high proportion of asymptomatic cases. In this work, a flexible framework is proposed, with the objective of quantifying the severity of misreporting in a time series and reconstructing the most likely evolution of the process. METHODS: The performance of Bayesian Synthetic Likelihood to estimate the parameters of a model based on AutoRegressive Conditional Heteroskedastic time series capable of dealing with misreported information and to reconstruct the most likely evolution of the phenomenon is assessed through a comprehensive simulation study and illustrated by reconstructing the weekly Covid-19 incidence in each Spanish Autonomous Community. RESULTS: Only around 51% of the Covid-19 cases in the period 2020/02/23-2022/02/27 were reported in Spain, showing relevant differences in the severity of underreporting across the regions. CONCLUSIONS: The proposed methodology provides public health decision-makers with a valuable tool in order to improve the assessment of a disease evolution under different scenarios.

Optimal Stein-type goodness-of-fit tests for count data.

Common count distributions, such as the Poisson (binomial) distribution for unbounded (bounded) counts considered here, can be characterized by appropriate Stein identities. These identities, in turn, might be utilized to define a corresponding goodness-of-fit (GoF) test, the test statistic of which involves the computation of weighted means for a user-selected weight function f. Here, the choice of f should be done with respect to the relevant alternative scenario, as it will have great impact on the GoF-test's performance. We derive the asymptotics of both the Poisson and binomial Stein-type GoF-statistic for general count distributions (we also briefly consider the negative-binomial case), such that the asymptotic power is easily computed for arbitrary alternatives. This allows for an efficient implementation of optimal Stein tests, that is, which are most powerful within a given class  F $\mathcal {F}$ of weight functions. The performance and application of the optimal Stein-type GoF-tests is investigated by simulations and several medical data examples.

Analysis of zero inflated dichotomous variables from a Bayesian perspective: application to occupational health.

BACKGROUND: Zero-inflated models are generally aimed to addressing the problem that arises from having two different sources that generate the zero values observed in a distribution. In practice, this is due to the fact that the population studied actually consists of two subpopulations: one in which the value zero is by default (structural zero) and the other is circumstantial (sample zero). METHODS: This work proposes a new methodology to fit zero inflated Bernoulli data from a Bayesian approach, able to distinguish between two potential sources of zeros (structural and non-structural). RESULTS: The proposed methodology performance has been evaluated through a comprehensive simulation study, and it has been compiled as an R package freely available to the community. Its usage is illustrated by means of a real example from the field of occupational health as the phenomenon of sickness presenteeism, in which it is reasonable to think that some individuals will never be at risk of suffering it because they have not been sick in the period of study (structural zeros). Without separating structural and non-structural zeros one would be studying jointly the general health status and the presenteeism itself, and therefore obtaining potentially biased estimates as the phenomenon is being implicitly underestimated by diluting it into the general health status. CONCLUSIONS: The proposed methodology is able to distinguish two different sources of zeros (structural and non-structural) from dichotomous data with or without covariates in a Bayesian framework, and has been made available to any interested researcher in the form of the bayesZIB R package ( https://cran.r-project.org/package=bayesZIB ).

Quantifying the under-reporting of uncorrelated longitudal data: the genital warts example.

BACKGROUND: Genital warts are a common and highly contagious sexually transmitted disease. They have a large economic burden and affect several aspects of quality of life. Incidence data underestimate the real occurrence of genital warts because this infection is often under-reported, mostly due to their specific characteristics such as the asymptomatic course. METHODS: Genital warts cases for the analysis were obtained from the Catalan public health system database (SIDIAP) for the period 2009-2016. People under 15 and over 94 years old were excluded from the analysis as the incidence of genital warts in this population is negligible. This work introduces a time series model based on a mixture of two distributions, capable of detecting the presence of under-reporting in the data. In order to identify potential differences in the magnitude of the under-reporting issue depending on sex and age, these covariates were included in the model. RESULTS: This work shows that only about 80% in average of genital warts incidence in Catalunya in the period 2009-2016 was registered, although the frequency of under-reporting has been decreasing over the study period. It can also be seen that this issue has a deeper impact on women over 30 years old. CONCLUSIONS: Although this study shows that the quality of the registered data has improved over the considered period of time, the Catalan public health system is underestimating genital warts real burden in almost 10,000 cases, around 23% of the registered cases. The total annual cost is underestimated in about 10 million Euros respect the 54 million Euros annually devoted to genital warts in Catalunya, representing 0.4% of the total budget.

Cumulated burden of COVID-19 in Spain from a Bayesian perspective.

BACKGROUND: The main goal of this work is to estimate the actual number of cases of COVID-19 in Spain in the period 31 January 2020 to 01 June 2020 by Autonomous Communities. Based on these estimates, this work allows us to accurately re-estimate the lethality of the disease in Spain, taking into account unreported cases. METHODS: A hierarchical Bayesian model recently proposed in the literature has been adapted to model the actual number of COVID-19 cases in Spain. RESULTS: The results of this work show that the real load of COVID-19 in Spain in the period considered is well above the data registered by the public health system. Specifically, the model estimates show that, cumulatively until 1 June 2020, there were 2 425 930 cases of COVID-19 in Spain with characteristics similar to those reported (95% credibility interval: 2 148 261-2 813 864), from which were actually registered only 518 664. CONCLUSIONS: Considering the results obtained from the second wave of the Spanish seroprevalence study, which estimates 2 350 324 cases of COVID-19 produced in Spain, in the period of time considered, it can be seen that the estimates provided by the model are quite good. This work clearly shows the key importance of having good quality data to optimize decision-making in the critical context of dealing with a pandemic.

Enhancing the monitoring of fallen stock at different hierarchical administrative levels: an illustration on dairy cattle from regions with distinct husbandry, demographical and climate traits.

BACKGROUND: The automated collection of non-specific data from livestock, combined with techniques for data mining and time series analyses, facilitates the development of animal health syndromic surveillance (AHSyS). An example of AHSyS approach relates to the monitoring of bovine fallen stock. In order to enhance part of the machinery of a complete syndromic surveillance system, the present work developed a novel approach for modelling in near real time multiple mortality patterns at different hierarchical administrative levels. To illustrate its functionality, this system was applied to mortality data in dairy cattle collected across two Spanish regions with distinct demographical, husbandry, and climate conditions. RESULTS: The process analyzed the patterns of weekly counts of fallen dairy cattle at different hierarchical administrative levels across two regions between Jan-2006 and Dec-2013 and predicted their respective expected counts between Jan-2014 and Jun- 2015. By comparing predicted to observed data, those counts of fallen dairy cattle that exceeded the upper limits of a conventional 95% predicted interval were identified as mortality peaks. This work proposes a dynamic system that combines hierarchical time series and autoregressive integrated moving average models (ARIMA). These ARIMA models also include trend and seasonality for describing profiles of weekly mortality and detecting aberrations at the region, province, and county levels (spatial aggregations). Software that fitted the model parameters was built using the R statistical packages. CONCLUSIONS: The work builds a novel tool to monitor fallen stock data for different geographical aggregations and can serve as a means of generating early warning signals of a health problem. This approach can be adapted to other types of animal health data that share similar hierarchical structures.

Online Cost-Effectiveness ANalysis (OCEAN): a user-friendly interface to conduct cost-effectiveness analyses for cervical cancer.

BACKGROUND: Most cost-effectiveness analyses in the context of cervical cancer prevention involve the use of mathematical models to simulate HPV infection, cervical disease and prevention strategies. However, it is common for professionals who would need to perform these analyses to not be familiar with the models. This work introduces the Online Cost-Effectiveness ANalysis tool, featuring an easy-to-use web interface providing health professionals, researchers and decision makers involved in cervical cancer prevention programmes with a useful instrument to conduct complex cost-effectiveness analyses, which are becoming an essential tool as an approach for supporting decision-making that involves important trade-offs. RESULTS: The users can run cost-effectiveness evaluations of cervical cancer prevention strategies without deep knowledge of the underlying mathematical model or any programming language, obtaining the most relevant costs and health outcomes in a user-friendly format. The results provided by the tool are consistent with the existing literature. CONCLUSIONS: Having such a tool will be an asset to the cervical cancer prevention community, providing researchers with an easy-to-use instrument to conduct cost-effectiveness analyses.

A nonparametric method of estimation of the population size in capture-recapture experiments.

A recent method for estimating a lower bound of the population size in capture-recapture samples is studied. Specifically, some asymptotic properties, such as strong consistency and asymptotic normality, are provided. The introduced estimator is based on the empirical probability generating function (pgf) of the observed data, and it is consistent for count distributions having a log-convex pgf ( LC -class). This is a large family that includes mixed and compound Poisson distributions, and their independent sums and finite mixtures as well. The finite-sample performance of the lower bound estimator is assessed via simulation showing a better behavior than some close competitors. Several examples of application are also analyzed and discussed.

Untangling serially dependent underreported count data for gender-based violence.

Underreporting in gender-based violence data is a worldwide problem leading to the underestimation of the magnitude of this social and public health concern. This problem deteriorates the data quality, providing poor and biased results that lead society to misunderstand the actual scope of this domestic violence issue. The present work proposes time series models for underreported counts based on a latent integer autoregressive of order 1 time series with Poisson distributed innovations and a latent underreporting binary state, that is, a first-order Markov chain. Relevant theoretical properties of the models are derived, and the moment-based and maximum-based methods are presented for parameter estimation. The new time series models are applied to the quarterly complaints of domestic violence against women recorded in some judicial districts of Galicia (Spain) between 2007 and 2017. The models allow quantifying the degree of underreporting. A comprehensive discussion is presented, studying how the frequency and intensity of underreporting in this public health concern are related to some interesting socioeconomic and health indicators of the provinces of Galicia (Spain).

Under-reported data analysis with INAR-hidden Markov chains.

In this work, we deal with correlated under-reported data through INAR(1)-hidden Markov chain models. These models are very flexible and can be identified through its autocorrelation function, which has a very simple form. A naïve method of parameter estimation is proposed, jointly with the maximum likelihood method based on a revised version of the forward algorithm. The most-probable unobserved time series is reconstructed by means of the Viterbi algorithm. Several examples of application in the field of public health are discussed illustrating the utility of the models. Copyright © 2016 John Wiley & Sons, Ltd.

Zero-inflated regression models for radiation-induced chromosome aberration data: A comparative study.

Within the field of cytogenetic biodosimetry, Poisson regression is the classical approach for modeling the number of chromosome aberrations as a function of radiation dose. However, it is common to find data that exhibit overdispersion. In practice, the assumption of equidispersion may be violated due to unobserved heterogeneity in the cell population, which will render the variance of observed aberration counts larger than their mean, and/or the frequency of zero counts greater than expected for the Poisson distribution. This phenomenon is observable for both full- and partial-body exposure, but more pronounced for the latter. In this work, different methodologies for analyzing cytogenetic chromosomal aberrations datasets are compared, with special focus on zero-inflated Poisson and zero-inflated negative binomial models. A score test for testing for zero inflation in Poisson regression models under the identity link is also developed.

radir package: an R implementation for cytogenetic biodosimetry dose estimation.

The Bayesian framework has been shown to be very useful in cytogenetic dose estimation. This approach allows description of the probability of an event in terms of previous knowledge, e.g. its expectation and/or its uncertainty. A new R package entitled radir (radiation inverse regression) has been implemented with the aim of reproducing a recent Bayesian-type dose estimation methodology. radir adopts the method of dose estimation under the Poisson assumption of the responses (the chromosomal aberrations counts) for the required dose-response curve (typically linear or quadratic). The individual commands are described in detail and relevant examples of the use of the methods and the corresponding radir software tools are given. The suitability of this methodology is highlighted and its application encouraged by providing a user-friendly command-type software interface within the R statistical software (version 3.1.1 or higher), which includes a complete manual.

Comparative analysis of the yields of dicentrics and chromosomal translocations.

PURPOSE: Chromosomal dicentrics and translocations are commonly employed as biomarkers to estimate radiation doses. The main goal of this article is to perform a comparative analysis of yields of both types of aberrations. The objective is to determine if there are relevant distinctions between both yields, allowing for a comprehensive assessment of their respective suitability and accuracy in the estimation of radiation doses. MATERIALS AND METHODS: The analysis involved data from a partial-radiation simulation study with the calibration data obtained through two scoring methods: conventional and PAINT modified. Subsequently, a Bayesian bivariate zero-inflated Poisson model was employed to compare the posterior marginal density of the mean of dicentrics and translocations and assess the differences between them. RESULTS: When employing the conventional method of scoring, the findings indicate that there is no notable disparity between the yield of observed translocations and dicentrics. However, when utilizing the PAINT modified method, a notable discrepancy is observed for higher doses, indicating a relevant difference in the mean number of the two types of aberrations. CONCLUSIONS: The choice of scoring method significantly influences the analysis of radiation-induced aberrations, especially when distinguishing between complex and simple chromosomal formations. Further research and analysis are necessary to gain a deeper understanding of the factors and mechanisms impacting the formation of dicentrics and translocations.

A flexible count data model to fit the wide diversity of expression profiles arising from extensively replicated RNA-seq experiments.

BACKGROUND: High-throughput RNA sequencing (RNA-seq) offers unprecedented power to capture the real dynamics of gene expression. Experimental designs with extensive biological replication present a unique opportunity to exploit this feature and distinguish expression profiles with higher resolution. RNA-seq data analysis methods so far have been mostly applied to data sets with few replicates and their default settings try to provide the best performance under this constraint. These methods are based on two well-known count data distributions: the Poisson and the negative binomial. The way to properly calibrate them with large RNA-seq data sets is not trivial for the non-expert bioinformatics user. RESULTS: Here we show that expression profiles produced by extensively-replicated RNA-seq experiments lead to a rich diversity of count data distributions beyond the Poisson and the negative binomial, such as Poisson-Inverse Gaussian or Pólya-Aeppli, which can be captured by a more general family of count data distributions called the Poisson-Tweedie. The flexibility of the Poisson-Tweedie family enables a direct fitting of emerging features of large expression profiles, such as heavy-tails or zero-inflation, without the need to alter a single configuration parameter. We provide a software package for R called tweeDEseq implementing a new test for differential expression based on the Poisson-Tweedie family. Using simulations on synthetic and real RNA-seq data we show that tweeDEseq yields P-values that are equally or more accurate than competing methods under different configuration parameters. By surveying the tiny fraction of sex-specific gene expression changes in human lymphoblastoid cell lines, we also show that tweeDEseq accurately detects differentially expressed genes in a real large RNA-seq data set with improved performance and reproducibility over the previously compared methodologies. Finally, we compared the results with those obtained from microarrays in order to check for reproducibility. CONCLUSIONS: RNA-seq data with many replicates leads to a handful of count data distributions which can be accurately estimated with the statistical model illustrated in this paper. This method provides a better fit to the underlying biological variability; this may be critical when comparing groups of RNA-seq samples with markedly different count data distributions. The tweeDEseq package forms part of the Bioconductor project and it is available for download at http://www.bioconductor.org.

CytoBayesJ: software tools for Bayesian analysis of cytogenetic radiation dosimetry data.

A number of authors have suggested that a Bayesian approach may be most appropriate for analysis of cytogenetic radiation dosimetry data. In the Bayesian framework, probability of an event is described in terms of previous expectations and uncertainty. Previously existing, or prior, information is used in combination with experimental results to infer probabilities or the likelihood that a hypothesis is true. It has been shown that the Bayesian approach increases both the accuracy and quality assurance of radiation dose estimates. New software entitled CytoBayesJ has been developed with the aim of bringing Bayesian analysis to cytogenetic biodosimetry laboratory practice. CytoBayesJ takes a number of Bayesian or 'Bayesian like' methods that have been proposed in the literature and presents them to the user in the form of simple user-friendly tools, including testing for the most appropriate model for distribution of chromosome aberrations and calculations of posterior probability distributions. The individual tools are described in detail and relevant examples of the use of the methods and the corresponding CytoBayesJ software tools are given. In this way, the suitability of the Bayesian approach to biological radiation dosimetry is highlighted and its wider application encouraged by providing a user-friendly software interface and manual in English and Russian.

Distinguishing between a power law and a Pareto distribution.

This paper introduces the location Pareto distribution as a natural extension of the power law distribution and gives a likelihood ratio test for choosing between the two models. Some properties of the distribution and test are thoroughly investigated, and applications to real data are provided. For large values of the observations the two models perform similarly; this explains why some classical approaches are very insensitive to the differentiation between them. The likelihood ratio test between the two models is simple to use and has a high level of discrimination power. It is recommended when the complementary cumulative distribution function exhibits linearity on a log-log scale.

Evaluation of γ-H2AX foci distribution among different peripheral blood mononucleated cell subtypes.

INTRODUCTION: The detection of γ-H2AX foci in peripheral blood mononucleated cells (PBMCs) has been incorporated as an early assay for biological dosimetry. However, overdispersion in the γ-H2AX foci distribution is generally reported. In a previous study from our group, it was suggested that overdispersion could be caused by the fact that when evaluating PBMCs, different cell subtypes are analyzed, and that these could differ in their radiosensitivity. This would cause a mixture of different frequencies that would result in the overdispersion observed. OBJECTIVES: The objective of this study was to evaluate both the possible differences in the radiosensitivities of the different cell subtypes present in the PBMCs and to evaluate the distribution of γ-H2AX foci in each cell subtype. MATERIALS AND METHODS: Peripheral blood samples from three healthy donors were obtained and total PBMCs, and CD3+, CD4+, CD8+, CD19+, and CD56+ cells were separated. Cells were irradiated with 1 and 2 Gy and incubated at 37 °C for 1, 2, 4, and 24 h. Sham-irradiated cells were also analyzed. γ-H2AX foci were detected after immunofluorescence staining and analyzed automatically using a Metafer Scanning System. For each condition, 250 nuclei were considered. RESULTS: When the results from each donor were compared, no observable significant differences between donors were observed. When the different cell subtypes were compared, CD8+ cells showed the highest mean of γ-H2AX foci in all post-irradiation time points. The cell type that showed the lowest γ-H2AX foci frequency was CD56+. The frequencies observed in CD4+ and CD19+ cells fluctuated between CD8+ and CD56+ without any clear pattern. For all cell types evaluated, and at all post-irradiation times, overdispersion in γ-H2AX foci distribution was significant. Independent of the cell type evaluated the value of the variance was four times greater than that of the mean. CONCLUSION: Although different PBMC subsets studied showed different radiation sensitivity, these differences did not explain the overdispersion observed in the γ-H2AX foci distribution after exposure to IR.

Biodose Tools: an R shiny application for biological dosimetry.

INTRODUCTION: In the event of a radiological accident or incident, the aim of biological dosimetry is to convert the yield of a specific biomarker of exposure to ionizing radiation into an absorbed dose. Since the 1980s, various tools have been used to deal with the statistical procedures needed for biological dosimetry, and in general those who made several calculations for different biomarkers were based on closed source software. Here we present a new open source program, Biodose Tools, that has been developed under the umbrella of RENEB (Running the European Network of Biological and retrospective Physical dosimetry). MATERIALS AND METHODS: The application has been developed using the R programming language and the shiny package as a framework to create a user-friendly online solution. Since no unique method exists for the different mathematical processes, several meetings and periodic correspondence were held in order to reach a consensus on the solutions to be implemented. RESULTS: The current version 3.6.1 supports dose-effect fitting for dicentric and translocation assay. For dose estimation Biodose Tools implements those methods indicated in international guidelines and a specific method to assess heterogeneous exposures. The app can include information on the irradiation conditions to generate the calibration curve. Also, in the dose estimate, information about the accident can be included as well as the explanation of the results obtained. Because the app allows generating a report in various formats, it allows traceability of each biological dosimetry study carried out. The app has been used globally in different exercises and training, which has made it possible to find errors and improve the app itself. There are some features that still need consensus, such as curve fitting and dose estimation using micronucleus analysis. It is also planned to include a package dedicated to interlaboratory comparisons and the incorporation of Bayesian methods for dose estimation. CONCLUSION: Biodose Tools provides an open-source solution for biological dosimetry laboratories. The consensus reached helps to harmonize the way in which uncertainties are calculated. In addition, because each laboratory can download and customize the app's source code, it offers a platform to integrate new features.