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It is often challenging to present the available evidence in a timely and comprehensible manner. We aimed to visualize the evolution of evidence about antidepressants for depression by conducting cumulative network meta-analyses (NMAs) and to examine whether it could have helped the selection of optimal drugs. We built a Shiny web application that performs and presents cumulative NMAs based on R netmeta. We used a comprehensive dataset of double-blind randomized controlled trials of 21 antidepressants in the acute treatment of major depression. The primary outcomes were efficacy (treatment response) and acceptability (all-cause discontinuation), and treatment effects were summarized via odds ratios. We evaluated the confidence in evidence using the CINeMA (Confidence in Network Meta-Analysis) framework for a series of consecutive NMAs. Users can change several conditions for the analysis, such as the period of synthesis, among the others. We present the league tables and two-dimensional plots that combine efficacy, acceptability and level of confidence in the evidence together, for NMAs conducted in 1990, 1995, 2000, 2005, 2010, and 2016. They reveal that through the past four decades, newly approved drugs often showed initially exaggerated results, which tended to diminish and stabilize after approximately a decade. Over the years, the drugs with relative superiority changed dramatically; but as the evidence network grew larger and better connected, the overall confidence improved. The Shiny app visualizes how evidence evolved over years, emphasizing the need for a careful interpretation of relative effects between drugs, especially for the potentially amplified performance of newly approved drugs. HIGHLIGHTS: Network meta-analysis is considered to be a proper way of demonstrating the available evidence, since it allows comparisons between multiple interventions, and has been proved to be statistically powerful. It is challenging to present the voluminous results of NMA in an efficient and comprehendible manner. Evidence evolution based on the relatively new method NMA has not been investigated yet. The results of NMA should not only include the effects but also the confidence in the evidence, which can help interpret the findings appropriately. Effective use of rapidly developing statistical analysis and presentation tools such as Shiny package in R, may facilitate and simplify the visualization of NMA output. We should stay conservative towards new drugs, as their performance was often shown to be exaggerated initially, and it took time to become stable.

Small and medium enterprises (SMEs) are a driving force for innovation. Stimulation of innovation in these SMEs is often the target of policy interventions, both regionally and nationally. Which technical areas should be in the focus and how to identify and monitor them? In this position paper, we propose hybrid AI methods for innovation monitoring, using natural language processing (NLP) and a dynamic knowledge graph that combines learning, reasoning and knowledge sharing in collaboration with innovation experts.

Effect direction (evidence to indicate improvement, deterioration, or no change in an outcome) can be used as a standardized metric which enables the synthesis of diverse effect measures in systematic reviews. The effect direction (ED) plot was developed to support the synthesis and visualization of effect direction data. Methods for the ED plot require updating in light of new Cochrane guidance on alternative synthesis methods. To update the ED plot, statistical significance was removed from the algorithm for within-study synthesis and use of a sign test was considered to examine whether patterns of ED across studies could be due to chance alone. The revised methods were applied to an existing Cochrane review of the health impacts of housing improvements. The revised ED plot provides a method of data visualization in synthesis without meta-analysis that incorporates information about study characteristics and study quality, using ED as a common metric, without relying on statistical significance to combine outcomes of single studies. The results of sign tests, when appropriate, suggest caution in over-interpreting apparent patterns in effect direction, especially when the number of included studies is small. The revised ED plot meets the need for alternative methods of synthesis and data visualization when meta-analysis is not possible, enabling a transparent link between the data and conclusions of a systematic review. ED plots may be particularly useful in reviews that incorporate nonrandomized studies, complex systems approaches, and diverse sources of evidence, due to the variety of study designs and outcomes in such reviews.

Graphic abstract Lack of data is an obvious limitation to what can be modelled. However, aggregate data in the form of means and possibly (co)variances, as well as previously published pharmacometric models, are often available. Being able to use all available data is desirable, and therefore this paper will outline several methods for using aggregate data as the basis of parameter estimation. The presented methods can be used for estimation of parameters from aggregate data, and as a computationally efficient alternative for the stochastic simulation and estimation procedure. They also allow for population PK/PD optimal design in the case when the data-generating model is different from the data-analytic model, a scenario for which no solutions have previously been available. Mathematical analysis and computational results confirm that the aggregate-data FO algorithm converges to the same estimates as the individual-data FO and yields near-identical standard errors when used in optimal design. The aggregate-data MC algorithm will asymptotically converge to the exactly correct parameter estimates if the data-generating model is the same as the data-analytic model. The performance of the aggregate-data methods were also compared to stochastic simulations and estimations (SSEs) when the data-generating model is different from the data-analytic model. The aggregate-data FO optimal design correctly predicted the sampling distributions of 200 models fitted to simulated datasets with the individual-data FO method. Supplementary Information The online version contains supplementary material available at 10.1007/s10928-021-09760-1.

Summary In this article, we first review the literature on dealing with missing values on a covariate in randomized studies and summarize what has been done and what is lacking to date. We then investigate the situation with a continuous outcome and a missing binary covariate in more details through simulations, comparing the performance of multiple imputation (MI) with various simple alternative methods. This is finally extended to the case of time‐to‐event outcome. The simulations consider five different missingness scenarios: missing completely at random (MCAR), at random (MAR) with missingness depending only on the treatment, and missing not at random (MNAR) with missingness depending on the covariate itself (MNAR1), missingness depending on both the treatment and covariate (MNAR2), and missingness depending on the treatment, covariate and their interaction (MNAR3). Here, we distinguish two different cases: (1) when the covariate is measured before randomization (best practice), where only MCAR and MNAR1 are plausible, and (2) when it is measured after randomization but before treatment (which sometimes occurs in nonpharmaceutical research), where the other three missingness mechanisms can also occur. The proposed methods are compared based on the treatment effect estimate and its standard error. The simulation results suggest that the patterns of results are very similar for all missingness scenarios in case (1) and also in case (2) except for MNAR3. Furthermore, in each scenario for continuous outcome, there is at least one simple method that performs at least as well as MI, while for time‐to‐event outcome MI is best.

Assessment of efficacy in important subgroups – such as those defined by sex, age, race and region – in confirmatory trials is typically performed using separate analysis of the specific subgroup. This ignores relevant information from the complementary subgroup. Bayesian dynamic borrowing uses an informative prior based on analysis of the complementary subgroup and a weak prior distribution centred on a mean of zero to construct a robust mixture prior. This combination of priors allows for dynamic borrowing of prior information; the analysis learns how much of the complementary subgroup prior information to borrow based on the consistency between the subgroup of interest and the complementary subgroup. A tipping point analysis can be carried out to identify how much prior weight needs to be placed on the complementary subgroup component of the robust mixture prior to establish efficacy in the subgroup of interest. An attractive feature of the tipping point analysis is that it enables the evidence from the source subgroup, the evidence from the target subgroup, and the combined evidence to be displayed alongside each other. This method is illustrated with an example trial in severe asthma where efficacy in the adolescent subgroup was assessed using a mixture prior combining an informative prior from the adult data in the same trial with a non‐informative prior.

SUMMARY Subgroup analyses are a routine part of clinical trials to investigate whether treatment effects are homogeneous across the study population. Graphical approaches play a key role in subgroup analyses to visualise effect sizes of subgroups, to aid the identification of groups that respond differentially, and to communicate the results to a wider audience. Many existing approaches do not capture the core information and are prone to lead to a misinterpretation of the subgroup effects. In this work, we critically appraise existing visualisation techniques, propose useful extensions to increase their utility and attempt to develop an effective visualisation approach. We focus on forest plots, UpSet plots, Galbraith plots, subpopulation treatment effect pattern plot, and contour plots, and comment on other approaches whose utility is more limited. We illustrate the methods using data from a prostate cancer study.

The availability of intensive care beds during the COVID‐19 epidemic is crucial to guarantee the best possible treatment to severely affected patients. In this work we show a simple strategy for short‐term prediction of COVID‐19 intensive care unit (ICU) beds, that has proved very effective during the Italian outbreak in February to May 2020. Our approach is based on an optimal ensemble of two simple methods: a generalized linear mixed regression model, which pools information over different areas, and an area‐specific nonstationary integer autoregressive methodology. Optimal weights are estimated using a leave‐last‐out rationale. The approach has been set up and validated during the first epidemic wave in Italy. A report of its performance for predicting ICU occupancy at regional level is included.

To assess the current dynamic of an epidemic it is central to collect information on the daily number of newly diseased cases. This is especially important in real-time surveillance, where the aim is to gain situational awareness, e.g., if cases are currently increasing or decreasing. Reporting delays between disease onset and case reporting hamper our ability to understand the dynamic of an epidemic close to now when looking at the number of daily reported cases only. Nowcasting can be used to adjust daily case counts for occurred-but-not-yet-reported events. Here, we present a novel application of nowcasting to data on the current COVID–19 pandemic in Bavaria. It is based on a hierarchical Bayesian model that considers changes in the reporting delay distribution over time and associated with the weekday of reporting. Furthermore, we present a way to estimate the effective time-dependent case reproduction number Re(t) based on predictions of the nowcast. The approaches are based on previously published work, that we considerably extended and adapted to the current task of nowcasting COVID–19 cases. We provide methodological details of the developed approach, illustrate results based on data of the current epidemic, and evaluate the model based on synthetic and retrospective data on COVID–19 in Bavaria. Results of our nowcasting are reported to the Bavarian health authority and published on a webpage on a daily basis (https://corona.stat.uni-muenchen.de/). Code and synthetic data for the analysis is available from https://github.com/FelixGuenther/nc_covid19_bavaria and can be used for adaptions of our approach to different data.

This paper aims at investigating empirically whether and to what extent the containment measures adopted in Italy had an impact in reducing the diffusion of the COVID-19 disease across provinces. For this purpose, we extend the multivariate time-series model for infection counts proposed in Paul and Held (Stat Med 30(10):118–1136, 2011) by augmenting the model specification with B-spline regressors in order to account for complex nonlinear spatio-temporal dynamics in the propagation of the disease. The results of the model estimated on the time series of the number of infections for the Italian provinces show that the containment measures, despite being globally effective in reducing both the spread of contagion and its self-sustaining dynamics, have had nonlinear impacts across provinces. The impact has been relatively stronger in the northern local areas, where the disease occurred earlier and with a greater incidence. This evidence may be explained by the shared popular belief that the contagion was not a close-to-home problem but rather restricted to a few distant northern areas, which, in turn, might have led individuals to adhere less strictly to containment measures and lockdown rules.

In studies with recurrent event endpoints, misspecified assumptions of event rates or dispersion can lead to underpowered trials or overexposure of patients. Specification of overdispersion is often a particular problem as it is usually not reported in clinical trial publications. Changing event rates over the years have been described for some diseases, adding to the uncertainty in planning. To mitigate the risks of inadequate sample sizes, internal pilot study designs have been proposed with a preference for blinded sample size reestimation procedures, as they generally do not affect the type I error rate and maintain trial integrity. Blinded sample size reestimation procedures are available for trials with recurrent events as endpoints. However, the variance in the reestimated sample size can be considerable in particular with early sample size reviews. Motivated by a randomized controlled trial in paediatric multiple sclerosis, a rare neurological condition in children, we apply the concept of blinded continuous monitoring of information, which is known to reduce the variance in the resulting sample size. Assuming negative binomial distributions for the counts of recurrent relapses, we derive information criteria and propose blinded continuous monitoring procedures. The operating characteristics of these are assessed in Monte Carlo trial simulations demonstrating favourable properties with regard to type I error rate, power, and stopping time, ie, sample size.

Each year, the UK records 25,000 or more excess winter deaths, primarily among the elderly. A key policy response is the “Winter Fuel Payment” (WFP), a labelled but unconditional cash transfer to households with a member above the female state pension age. The WFP has been shown to raise fuel spending among eligible households. We examine the causal effect of the WFP on health outcomes, including self‐reports of chest infection, measured hypertension, and biomarkers of infection and inflammation. We find a robust, 6 percentage point reduction in the incidence of high levels of serum fibrinogen. Reductions in other disease markers point to health benefits, but the estimated effects are less robust.

A common challenge for the development of drugs in rare diseases and special populations, eg, paediatrics, is the small numbers of patients that can be recruited into clinical trials. Extrapolation can be used to support development and licensing in paediatrics through the structured integration of available data in adults and prospectively generated data in paediatrics to derive conclusions that support licensing decisions in the target paediatric population. In this context, Bayesian analyses have been proposed to obtain formal proof of efficacy of a new drug or therapeutic principle by using additional information (data, opinion, or expectation), expressed through a prior distribution. However, little is said about the impact of the prior assumptions on the evaluation of outcome and prespecified strategies for decision-making as required in the regulatory context. On the basis of examples, we explore the use of data-based Bayesian meta-analytic-predictive methods and compare these approaches with common frequentist and Bayesian meta-analysis models. Noninformative efficacy prior distributions usually do not change the conclusions irrespective of the chosen analysis method. However, if heterogeneity is considered, conclusions are highly dependent on the heterogeneity prior. When using informative efficacy priors based on previous study data in combination with heterogeneity priors, these may completely determine conclusions irrespective of the data generated in the target population. Thus, it is important to understand the impact of the prior assumptions and ensure that prospective trial data in the target population have an appropriate chance, to change prior belief to avoid trivial and potentially erroneous conclusions.

This paper introduces a gender specific model for the joint mortality projection of three countries (England and Wales combined, Scotland, and Northern Ireland) of the United Kingdom. The model, called 2-tier Augmented Common Factor model, extends the classical Lee and Carter [26] and Li and Lee [32] models, with a common time factor for the whole UK population, a sex specific period factor for males and females, and a specific time factor for each country within each gender. As death counts in each subpopulation are modelled directly, a Poisson framework is used. Our results show that the 2-tier ACF model improves the in-sample fitting compared to the use of independent LC models for each subpopulation or of independent Li and Lee models for each couple of genders within each country. Mortality projections also show that the 2-tier ACF model produces coherent forecasts for the two genders within each country and different countries within each gender, thus avoiding the divergence issues arising when independent projections are used. The 2-tier ACF is further extended to include a cohort term to take into account the faster improvements of the UK ‘golden generation’.

Funder: Cambridge Commonwealth, European and International Trust; doi: https://doi.org/10.13039/501100003343, Funder: Natural Sciences and Engineering Research Council of Canada (NSERC), We develop a resource theory of symmetric distinguishability, the fundamental objects of which are elementary quantum information sources, i.e., sources that emit one of two possible quantum states with given prior probabilities. Such a source can be represented by a classical-quantum state of a composite system $XA$, corresponding to an ensemble of two quantum states, with $X$ being classical and $A$ being quantum. We study the resource theory for two different classes of free operations: $(i)$ ${\rm{CPTP}}_A$, which consists of quantum channels acting only on $A$, and $(ii)$ conditional doubly stochastic (CDS) maps acting on $XA$. We introduce the notion of symmetric distinguishability of an elementary source and prove that it is a monotone under both these classes of free operations. We study the tasks of distillation and dilution of symmetric distinguishability, both in the one-shot and asymptotic regimes. We prove that in the asymptotic regime, the optimal rate of converting one elementary source to another is equal to the ratio of their quantum Chernoff divergences, under both these classes of free operations. This imparts a new operational interpretation to the quantum Chernoff divergence. We also obtain interesting operational interpretations of the Thompson metric, in the context of the dilution of symmetric distinguishability.

Motivation The human microbiota is the collection of microorganisms colonizing the human body, and plays an integral part in human health. A growing trend in microbiome analysis is to construct a network to estimate the co-occurrence patterns among taxa through precision matrices. Existing methods do not facilitate investigation into how these networks change with respect to covariates. Results We propose a new model called Microbiome Differential Network Estimation (MDiNE) to estimate network changes with respect to a binary covariate. The counts of individual taxa in the samples are modeled through a multinomial distribution whose probabilities depend on a latent Gaussian random variable. A sparse precision matrix over all the latent terms determines the co-occurrence network among taxa. The model fit is obtained and evaluated using Hamiltonian Monte Carlo methods. The performance of our model is evaluated through an extensive simulation study and is shown to outperform existing methods in terms of estimation of network parameters. We also demonstrate an application of the model to estimate changes in the intestinal microbial network topology with respect to Crohn’s disease. Availability and implementation MDiNE is implemented in a freely available R package: https://github.com/kevinmcgregor/mdine. Supplementary information Supplementary data are available at Bioinformatics online.

Motivation The use of human genome discoveries and other established factors to build an accurate risk prediction model is an essential step toward precision medicine. While multi-layer high-dimensional omics data provide unprecedented data resources for prediction studies, their corresponding analytical methods are much less developed. Results We present a multi-kernel penalized linear mixed model with adaptive lasso (MKpLMM), a predictive modeling framework that extends the standard linear mixed models widely used in genomic risk prediction, for multi-omics data analysis. MKpLMM can capture not only the predictive effects from each layer of omics data but also their interactions via using multiple kernel functions. It adopts a data-driven approach to select predictive regions as well as predictive layers of omics data, and achieves robust selection performance. Through extensive simulation studies, the analyses of PET-imaging outcomes from the Alzheimer’s Disease Neuroimaging Initiative study, and the analyses of 64 drug responses, we demonstrate that MKpLMM consistently outperforms competing methods in phenotype prediction. Availability and implementation The R-package is available at https://github.com/YaluWen/OmicPred. Supplementary information Supplementary data are available at Bioinformatics online.

Purpose The purpose of this report was to demonstrate the value of incorporating nonparametric item response theory in the development and refinement of patient- reported outcome measures for hearing. Conclusions Nonparametric item response theory can be useful in the development and refinement of patient-reported outcome measures for hearing. These methods are particularly useful as an alternative to exploratory factor analysis to determine the number of underlying abilities or traits represented by a scale when the items have ordered-categorical responses.

Motivation Recent microbiome association studies have revealed important associations between microbiome and disease/health status. Such findings encourage scientists to dive deeper to uncover the causal role of microbiome in the underlying biological mechanism, and have led to applying statistical models to quantify causal microbiome effects and to identify the specific microbial agents. However, there are no existing causal mediation methods specifically designed to handle high dimensional and compositional microbiome data. Results We propose a rigorous Sparse Microbial Causal Mediation Model (SparseMCMM) specifically designed for the high dimensional and compositional microbiome data in a typical three-factor (treatment, microbiome and outcome) causal study design. In particular, linear log-contrast regression model and Dirichlet regression model are proposed to estimate the causal direct effect of treatment and the causal mediation effects of microbiome at both the community and individual taxon levels. Regularization techniques are used to perform the variable selection in the proposed model framework to identify signature causal microbes. Two hypothesis tests on the overall mediation effect are proposed and their statistical significance is estimated by permutation procedures. Extensive simulated scenarios show that SparseMCMM has excellent performance in estimation and hypothesis testing. Finally, we showcase the utility of the proposed SparseMCMM method in a study which the murine microbiome has been manipulated by providing a clear and sensible causal path among antibiotic treatment, microbiome composition and mouse weight. Availability and implementation https://sites.google.com/site/huilinli09/software and https://github.com/chanw0/SparseMCMM. Supplementary information Supplementary data are available at Bioinformatics online.

Purpose We empirically assessed the results of computational optimization and prediction in communication interfaces that were designed to allow individuals with severe motor speech disorders to select phonemes and generate speech output. Method Interface layouts were either random or optimized, in which phoneme targets that were likely to be selected together were located in proximity. Target sizes were either static or predictive, such that likely targets were dynamically enlarged following each selection. Communication interfaces were evaluated by 36 users without motor impairments using an alternate access method. Each user was assigned to 1 of 4 interfaces varying in layout and whether prediction was implemented (random/static, random/predictive, optimized/static, optimized/predictive) and participated in 12 sessions over a 3-week period. Six participants with severe motor impairments used both the optimized/static and optimized/predictive interfaces in 1–2 sessions. Results In individuals without motor impairments, prediction provided significantly faster communication rates during training (Sessions 1–9), as users were learning the interface target locations and the novel access method. After training, optimization acted to significantly increase communication rates. The optimization likely became relevant only after training when participants knew the target locations and moved directly to the targets. Participants with motor impairments could use the interfaces with alternate access methods and generally rated the interface with prediction as preferred. Conclusions Optimization and prediction led to increases in communication rates in users without motor impairments. Predictive interfaces were preferred by users with motor impairments. Future research is needed to translate these results into clinical practice. Supplemental Material https://doi.org/10.23641/asha.8636948

There is growing interest in integrated Phase I/II oncology clinical trials involving molecularly targeted agents (MTA). One of the main challenges of these trials are nontrivial dose–efficacy relationships and administration of MTAs in combination with other agents. While some designs were recently proposed for such Phase I/II trials, the majority of them consider the case of binary toxicity and efficacy endpoints only. At the same time, a continuous efficacy endpoint can carry more information about the agent's mechanism of action, but corresponding designs have received very limited attention in the literature. In this work, an extension of a recently developed information‐theoretic design for the case of a continuous efficacy endpoint is proposed. The design transforms the continuous outcome using the logistic transformation and uses an information–theoretic argument to govern selection during the trial. The performance of the design is investigated in settings of single‐agent and dual‐agent trials. It is found that the novel design leads to substantial improvements in operating characteristics compared to a model‐based alternative under scenarios with nonmonotonic dose/combination–efficacy relationships. The robustness of the design to missing/delayed efficacy responses and to the correlation in toxicity and efficacy endpoints is also investigated.

A condenser was designed and developed for distillation of herbaceous oils. The performance of the condenser was evaluated by using two common refrigerants namely R12 and R134a to separate the water and essential oil molecules of spearmint (Mentha spicata) leaves from a vapor-air mixture flow. Three levels of air speed (1, 2 and 3 m/s) and temperature (180, 210 and 250 °C) were selected for the vapor-air mixture flow during the experiments. For this condenser, a better performance was observed for the R12 than the R134a refrigerant. The best performance of the condenser was obtained at lower air speeds and lower temperatures for the essential oil of spearmint leaves.

Motivation The flexibility of a Bayesian framework is promising for GWAS, but current approaches can benefit from more informative prior models. We introduce a novel Bayesian approach to GWAS, called Structured and Non-Local Priors (SNLPs) GWAS, that improves over existing methods in two important ways. First, we describe a model that allows for a marker’s gene-parent membership and other characteristics to influence its probability of association with an outcome. Second, we describe a non-local alternative model for differential minor allele rates at each marker, in which the null and alternative hypotheses have no common support. Results We employ a non-parametric model that allows for clustering of the genes in tandem with a regression model for marker-level covariates, and demonstrate how incorporating these additional characteristics can improve power. We further demonstrate that our non-local alternative model gives symmetric rates of convergence for the null and alternative hypotheses, whereas commonly used local alternative models have asymptotic rates that favor the alternative hypothesis over the null. We demonstrate the robustness and flexibility of our structured and non-local model for different data generating scenarios and signal-to-noise ratios. We apply our Bayesian GWAS method to single nucleotide polymorphisms data collected from a pool of Alzheimer’s disease and cognitively normal patients from the Alzheimer’s Database Neuroimaging Initiative. Availability and implementation R code to perform the SNLPs method is available at https://github.com/lockEF/BayesianScreening.

Background: Researchers studying health-related quality of life (HRQOL) in multiple sclerosis (MS) can choose from many instruments, but findings from studies which use different instruments cannot be easily combined. We aimed to develop a crosswalk that associates scores from the RAND-12 to scores on the Health Utilities Index—Mark III (HUI3) in persons with MS. Methods: In 2018, participants in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry completed the RAND-12 and the HUI3 to assess HRQOL. We used item-response theory (IRT) and equipercentile linking approaches to develop a crosswalk between instruments. We compared predicted scores for the HUI3 from each crosswalk to observed scores using Pearson correlations, intraclass correlation coefficients (ICCs), and Bland–Altman plots. Results: Of 11,389 invited participants, 7129 (62.6%) responded. Predicted and observed values of the HUI3 from the IRT-linking method were moderately correlated (Pearson r = 0.76) with good concordance (ICC = 0.72). However, the Bland–Altman plots suggested biased prediction. Predicted and observed values from the equipercentile linking method were also moderately correlated (Pearson r = 0.78, ICC = 0.78). The Bland–Altman plots suggested no bias. Conclusion: We developed a crosswalk between the RAND-12 and the HUI3 in the MS population which will facilitate data harmonization efforts.

To optimize sorbitol production through solid state fermentation (SSF) process using response surface methodology (RSM), the central composite design (CCD) was employed in this study in order to minimize the number of experiments needed for the determination of the best combination of parameters for the process optimization. The raw material used in this study was Meranti wood sawdust (MWS) obtained from Gambang Sawmill (M) Sdn Bhd, Gambang Kuantan, Pahang. The type of bacteria used for the study was Lactobacillus plantarum (BAA 793; NCIMB 8826), purchased from the America Type Culture Collection (ATCC). The physical and chemical pretreatment methods were used in the study to recover cellulose from the MSW, followed by the enzymatic hydrolysis process to produce glucose. The last phase of this work was the fermentation process using SSF to convert the produced glucose to sorbitol; this is the section of the study where the parameters were optimized using the RSM. The result of the RSM studies showed that the interactions between moisture content and temperature had a very significant effect with an F value of

Motivation It has been shown that the machine learning approach random forest can be successfully applied to omics data, such as gene expression data, for classification or regression and to select variables that are important for prediction. However, the complex relationships between predictor variables, in particular between causal predictor variables, make the interpretation of currently applied variable selection techniques difficult. Results Here we propose a new variable selection approach called surrogate minimal depth (SMD) that incorporates surrogate variables into the concept of minimal depth (MD) variable importance. Applying SMD, we show that simulated correlation patterns can be reconstructed and that the increased consideration of variable relationships improves variable selection. When compared with existing state-of-the-art methods and MD, SMD has higher empirical power to identify causal variables while the resulting variable lists are equally stable. In conclusion, SMD is a promising approach to get more insight into the complex interplay of predictor variables and outcome in a high-dimensional data setting. Availability and implementation https://github.com/StephanSeifert/SurrogateMinimalDepth. Supplementary information Supplementary data are available at Bioinformatics online.

Motivation Mammalian genomes can contain thousands of enhancers but only a subset are actively driving gene expression in a given cellular context. Integrated genomic datasets can be harnessed to predict active enhancers. One challenge in integration of large genomic datasets is the increasing heterogeneity: continuous, binary and discrete features may all be relevant. Coupled with the typically small numbers of training examples, semi-supervised approaches for heterogeneous data are needed; however, current enhancer prediction methods are not designed to handle heterogeneous data in the semi-supervised paradigm. Results We implemented a Dirichlet Process Heterogeneous Mixture model that infers Gaussian, Bernoulli and Poisson distributions over features. We derived a novel variational inference algorithm to handle semi-supervised learning tasks where certain observations are forced to cluster together. We applied this model to enhancer candidates in mouse heart tissues based on heterogeneous features. We constrained a small number of known active enhancers to appear in the same cluster, and 47 additional regions clustered with them. Many of these are located near heart-specific genes. The model also predicted 1176 active promoters, suggesting that it can discover new enhancers and promoters. Availability and implementation We created the ‘dphmix’ Python package: https://pypi.org/project/dphmix/. Supplementary information Supplementary data are available at Bioinformatics online.

Designs incorporating more than one endpoint have become popular in drug development. One of such designs allows for incorporation of short‐term information in an interim analysis if the long‐term primary endpoint has not been yet observed for some of the patients. At first we consider a two‐stage design with binary endpoints allowing for futility stopping only based on conditional power under both fixed and observed effects. Design characteristics of three estimators: using primary long‐term endpoint only, short‐term endpoint only, and combining data from both are compared. For each approach, equivalent cut‐off point values for fixed and observed effect conditional power calculations can be derived resulting in the same overall power. While in trials stopping for futility the type I error rate cannot get inflated (it usually decreases), there is loss of power. In this study, we consider different scenarios, including different thresholds for conditional power, different amount of information available at the interim, different correlations and probabilities of success. We further extend the methods to adaptive designs with unblinded sample size reassessments based on conditional power with inverse normal method as the combination function. Two different futility stopping rules are considered: one based on the conditional power, and one from P‐values based on Z‐statistics of the estimators. Average sample size, probability to stop for futility and overall power of the trial are compared and the influence of the choice of weights is investigated.

Total Mixed Ration (TMR), a system used in combining materials into feed for animals in the right proportion is a complex process especially when by-products are utilized. This involves several steps and unit machines. The current study focused on modeling a fermentation and storage system utilizing by-products for TMR feed production using the Arena V15 simulation program. Process time, operation rate, and bottleneck phenomenon were analyzed. The optimal capacities of unit machines were estimated using Opt-quest, an extension of the simulation program. Results showed the optimal operation rate of the mixer was 99% at 8.5 ton/h capacity and that of the steam sterilizer was 93% at 17.6 ton/h capacity. Moisture regulator was 89% at 7.0 ton/h capacity, while those of the vehicle loader and packaging device were 83.3 and 100% at 12.8 and 2.67 ton/h respectively. A field trial to verify the simulated results was conducted at Hwaseong Dairy Corporation. It shows mean square error and standard deviation between the simulated results and the field trial were within 5% range indicating a significant relationship. This work developed a livestock feed fermentation and storage model for cattle at an optimal performance.

Count data are common endpoints in clinical trials, for example magnetic resonance imaging lesion counts in multiple sclerosis. They often exhibit high levels of overdispersion, that is variances are larger than the means. Inference is regularly based on negative binomial regression along with maximum-likelihood estimators. Although this approach can account for heterogeneity it postulates a common overdispersion parameter across groups. Such parametric assumptions are usually difficult to verify, especially in small trials. Therefore, novel procedures that are based on asymptotic results for newly developed rate and variance estimators are proposed in a general framework. Moreover, in case of small samples the procedures are carried out using permutation techniques. Here, the usual assumption of exchangeability under the null hypothesis is not met due to varying follow-up times and unequal overdispersion parameters. This problem is solved by the use of studentized permutations leading to valid inference methods for situations with (i) varying follow-up times, (ii) different overdispersion parameters, and (iii) small sample sizes. peerReviewed

Background The major medical and social challenge of the 21st century is COVID-19, caused by the novel coronavirus SARS-CoV-2. Critical issues include the rate at which the coronavirus spreads and the effect of quarantine measures and population vaccination on this rate. Knowledge of the laws of the spread of COVID-19 will enable assessment of the effectiveness and reasonableness of the quarantine measures used, as well as determination of the necessary level of vaccination needed to overcome this crisis. Objective This study aims to establish the laws of the spread of COVID-19 and to use them to develop a mathematical model to predict changes in the number of active cases over time, possible human losses, and the rate of recovery of patients, to make informed decisions about the number of necessary beds in hospitals, the introduction and type of quarantine measures, and the required threshold of vaccination of the population. Methods This study analyzed the onset of COVID-19 spread in countries such as China, Italy, Spain, the United States, the United Kingdom, Japan, France, and Germany based on publicly available statistical data. The change in the number of COVID-19 cases, deaths, and recovered persons over time was examined, considering the possible introduction of quarantine measures and isolation of infected people in these countries. Based on the data, the virus transmissibility and the average duration of the disease at different stages were evaluated, and a model based on the principle of recursion was developed. Its key features are the separation of active (nonisolated) infected persons into a distinct category and the prediction of their number based on the average duration of the disease in the inactive phase and the concentration of these persons in the population in the preceding days. Results Specific values for SARS-CoV-2 transmissibility and COVID-19 duration were estimated for different countries. In China, the viral transmissibility was 3.12 before quarantine measures were implemented and 0.36 after these measures were lifted. For the other countries, the viral transmissibility was 2.28-2.76 initially, and it then decreased to 0.87-1.29 as a result of quarantine measures. Therefore, it can be expected that the spread of SARS-CoV-2 will be suppressed if 56%-64% of the total population becomes vaccinated or survives COVID-19. Conclusions The quarantine measures adopted in most countries are too weak compared to those previously used in China. Therefore, it is not expected that the spread of COVID-19 will stop and the disease will cease to exist naturally or owing to quarantine measures. Active vaccination of the population is needed to prevent the spread of COVID-19. Furthermore, the required specific percentage of vaccinated individuals depends on the magnitude of viral transmissibility, which can be evaluated using the proposed model and statistical data for the country of interest.

Background According to the World Health Organization, achieving targets for control of leprosy by 2030 will require disease elimination and interruption of transmission at the national or regional level. India and Brazil have reported the highest leprosy burden in the last few decades, revealing the need for strategies and tools to help health professionals correctly manage and control the disease. Objective The main objective of this study was to develop a cross-platform app for leprosy screening based on artificial intelligence (AI) with the goal of increasing accessibility of an accurate method of classifying leprosy treatment for health professionals, especially for communities further away from major diagnostic centers. Toward this end, we analyzed the quality of leprosy data in Brazil on the National Notifiable Diseases Information System (SINAN). Methods Leprosy data were extracted from the SINAN database, carefully cleaned, and used to build AI decision models based on the random forest algorithm to predict operational classification in paucibacillary or multibacillary leprosy. We used Python programming language to extract and clean the data, and R programming language to train and test the AI model via cross-validation. To allow broad access, we deployed the final random forest classification model in a web app via shinyApp using data available from the Brazilian Institute of Geography and Statistics and the Department of Informatics of the Unified Health System. Results We mapped the dispersion of leprosy incidence in Brazil from 2014 to 2018, and found a particularly high number of cases in central Brazil in 2014 that further increased in 2018 in the state of Mato Grosso. For some municipalities, up to 80% of cases showed some data discrepancy. Of a total of 21,047 discrepancies detected, the most common was “operational classification does not match the clinical form.” After data processing, we identified a total of 77,628 cases with missing data. The sensitivity and specificity of the AI model applied for the operational classification of leprosy was 93.97% and 87.09%, respectively. Conclusions The proposed app was able to recognize patterns in leprosy cases registered in the SINAN database and to classify new patients with paucibacillary or multibacillary leprosy, thereby reducing the probability of incorrect assignment by health centers. The collection and notification of data on leprosy in Brazil seem to lack specific validation to increase the quality of the data for implementations via AI. The AI models implemented in this work had satisfactory accuracy across Brazilian states and could be a complementary diagnosis tool, especially in remote areas with few specialist physicians.

A framework is developed using the Fisher information for information quantification in neutron reflectometry. The framework’s utility is demonstrated in the rapid estimation of model parameter uncertainties, as well as in experimental design to maximize information gain about given systems., An approach based on the Fisher information (FI) is developed to quantify the maximum information gain and optimal experimental design in neutron reflectometry experiments. In these experiments, the FI can be calculated analytically and used to provide sub-second predictions of parameter uncertainties. This approach can be used to influence real-time decisions about measurement angle, measurement time, contrast choice and other experimental conditions based on parameters of interest. The FI provides a lower bound on parameter estimation uncertainties, and these are shown to decrease with the square root of the measurement time, providing useful information for the planning and scheduling of experimental work. As the FI is computationally inexpensive to calculate, it can be computed repeatedly during the course of an experiment, saving costly beam time by signalling that sufficient data have been obtained or saving experimental data sets by signalling that an experiment needs to continue. The approach’s predictions are validated through the introduction of an experiment simulation framework that incorporates instrument-specific incident flux profiles, and through the investigation of measuring the structural properties of a phospholipid bilayer.

Purpose Acoustic measurement of speech sounds requires first segmenting the speech signal into relevant units (words, phones, etc.). Manual segmentation is cumbersome and time consuming. Forced-alignment algorithms automate this process by aligning a transcript and a speech sample. We compared the phoneme-level alignment performance of five available forced-alignment algorithms on a corpus of child speech. Our goal was to document aligner performance for child speech researchers. Method The child speech sample included 42 children between 3 and 6 years of age. The corpus was force-aligned using the Montreal Forced Aligner with and without speaker adaptive training, triphone alignment from the Kaldi speech recognition engine, the Prosodylab-Aligner, and the Penn Phonetics Lab Forced Aligner. The sample was also manually aligned to create gold-standard alignments. We evaluated alignment algorithms in terms of accuracy (whether the interval covers the midpoint of the manual alignment) and difference in phone-onset times between the automatic and manual intervals. Results The Montreal Forced Aligner with speaker adaptive training showed the highest accuracy and smallest timing differences. Vowels were consistently the most accurately aligned class of sounds across all the aligners, and alignment accuracy increased with age for fricative sounds across the aligners too. Conclusion The best-performing aligner fell just short of human-level reliability for forced alignment. Researchers can use forced alignment with child speech for certain classes of sounds (vowels, fricatives for older children), especially as part of a semi-automated workflow where alignments are later inspected for gross errors. Supplemental Material https://doi.org/10.23641/asha.14167058

Funder: Johnson and Johnson; Id: http://dx.doi.org/10.13039/100004331, High‐dimensional hypothesis testing is ubiquitous in the biomedical sciences, and informative covariates may be employed to improve power. The conditional false discovery rate (cFDR) is a widely used approach suited to the setting where the covariate is a set of p‐values for the equivalent hypotheses for a second trait. Although related to the Benjamini–Hochberg procedure, it does not permit any easy control of type‐1 error rate and existing methods are over‐conservative. We propose a new method for type‐1 error rate control based on identifying mappings from the unit square to the unit interval defined by the estimated cFDR and splitting observations so that each map is independent of the observations it is used to test. We also propose an adjustment to the existing cFDR estimator which further improves power. We show by simulation that the new method more than doubles potential improvement in power over unconditional analyses compared to existing methods. We demonstrate our method on transcriptome‐wide association studies and show that the method can be used in an iterative way, enabling the use of multiple covariates successively. Our methods substantially improve the power and applicability of cFDR analysis.

Multiplicity is common in clinical studies and the current standard is to use the familywise error rate to ensure that the errors are kept at a prespecified level. In this paper, we will show that, in certain situations, familywise error rate control does not account for all errors made. To counteract this problem, we propose the use of the expected number of false claims (EFC). We will show that a (weighted) Bonferroni approach can be used to control the EFC, discuss how a study that uses the EFC can be powered for co‐primary, exchangeable, and hierarchical endpoints, and show how the weight for the weighted Bonferroni test can be determined in this manner. ©2016 The Authors. Pharmaceutical Statistics Published by John Wiley & Sons Ltd.

The analysis of adverse events plays an important role in the benefit assessment of drugs. Consequently, results on adverse events are an integral part of reimbursement dossiers submitted by pharmaceutical companies to health policy decision-makers. Methods applied in the analysis of adverse events commonly include simple standard methods for contingency tables. However, the results produced may be misleading if observations are censored at the time of discontinuation due to treatment switching or noncompliance, resulting in unequal follow-up periods. In this paper, we present examples to show that the application of inadequate methods for the analysis of adverse events in the reimbursement dossier can lead to a downgrading of the evidence on a drug's benefit in the subsequent assessment, as greater harm from the drug cannot be excluded with sufficient certainty. Legal regulations on the benefit assessment of drugs in Germany are presented, in particular, with regard to the analysis of adverse events. Differences in safety considerations between the drug approval process and the benefit assessment are discussed. We show that the naive application of simple proportions in reimbursement dossiers frequently leads to uninterpretable results if observations are censored and the average follow-up periods differ between treatment groups. Likewise, the application of incidence rates may be misleading in the case of recurrent events and unequal follow-up periods. To allow for an appropriate benefit assessment of drugs, adequate survival time methods accounting for time dependencies and duration of follow-up are required, not only for time-to-event efficacy endpoints but also for adverse events. © 2016 The Authors. Pharmaceutical Statistics published by John Wiley & Sons Ltd.

Background Transition to digital pathology usually takes months or years to be completed. We were familiarizing ourselves with digital pathology solutions at the time when the COVID-19 outbreak forced us to embark on an abrupt transition to digital pathology. Objective The aim of this study was to quantitatively describe how the abrupt transition to digital pathology might affect the quality of diagnoses, model possible causes by probabilistic modeling, and qualitatively gauge the perception of this abrupt transition. Methods A total of 17 pathologists and residents participated in this study; these participants reviewed 25 additional test cases from the archives and completed a final psychologic survey. For each case, participants performed several different diagnostic tasks, and their results were recorded and compared with the original diagnoses performed using the gold standard method (ie, conventional microscopy). We performed Bayesian data analysis with probabilistic modeling. Results The overall analysis, comprising 1345 different items, resulted in a 9% (117/1345) error rate in using digital slides. The task of differentiating a neoplastic process from a nonneoplastic one accounted for an error rate of 10.7% (42/392), whereas the distinction of a malignant process from a benign one accounted for an error rate of 4.2% (11/258). Apart from residents, senior pathologists generated most discrepancies (7.9%, 13/164). Our model showed that these differences among career levels persisted even after adjusting for other factors. Conclusions Our findings are in line with previous findings, emphasizing that the duration of transition (ie, lengthy or abrupt) might not influence the diagnostic performance. Moreover, our findings highlight that senior pathologists may be limited by a digital gap, which may negatively affect their performance with digital pathology. These results can guide the process of digital transition in the field of pathology.

Motivation An important goal of concentration–response studies in toxicology is to determine an ‘alert’ concentration where a critical level of the response variable is exceeded. In a classical observation-based approach, only measured concentrations are considered as potential alert concentrations. Alternatively, a parametric curve is fitted to the data that describes the relationship between concentration and response. For a prespecified effect level, both an absolute estimate of the alert concentration and an estimate of the lowest concentration where the effect level is exceeded significantly are of interest. Results In a simulation study for gene expression data, we compared the observation-based and the model-based approach for both absolute and significant exceedance of the prespecified effect level. Results show that, compared to the observation-based approach, the model-based approach overestimates the true alert concentration less often and more frequently leads to a valid estimate, especially for genes with large variance. Availability and implementation The code used for the simulation studies is available via the GitHub repository: https://github.com/FKappenberg/Paper-IdentificationAlertConcentrations. Supplementary information Supplementary data are available at Bioinformatics online.

Background The COVID-19 infodemic, a surge of information and misinformation, has sparked worry about the public’s perception of the coronavirus pandemic. Excessive information and misinformation can lead to belief in false information as well as reduce the accurate interpretation of true information. Such incorrect beliefs about the COVID-19 pandemic might lead to behavior that puts people at risk of both contracting and spreading the virus. Objective The objective of this study was two-fold. First, we attempted to gain insight into public beliefs about the novel coronavirus and COVID-19 in one of the worst hit countries: the United States. Second, we aimed to test whether a short intervention could improve people’s belief accuracy by empowering them to consider scientific consensus when evaluating claims related to the pandemic. Methods We conducted a 4-week longitudinal study among US citizens, starting on April 27, 2020, just after daily COVID-19 deaths in the United States had peaked. Each week, we measured participants’ belief accuracy related to the coronavirus and COVID-19 by asking them to indicate to what extent they believed a number of true and false statements (split 50/50). Furthermore, each new survey wave included both the original statements and four new statements: two false and two true statements. Half of the participants were exposed to an intervention aimed at increasing belief accuracy. The intervention consisted of a short infographic that set out three steps to verify information by searching for and verifying a scientific consensus. Results A total of 1202 US citizens, balanced regarding age, gender, and ethnicity to approximate the US general public, completed the baseline (T0) wave survey. Retention rate for the follow-up waves— first follow-up wave (T1), second follow-up wave (T2), and final wave (T3)—was high (≥85%). Mean scores of belief accuracy were high for all waves, with scores reflecting low belief in false statements and high belief in true statements; the belief accuracy scale ranged from –1, indicating completely inaccurate beliefs, to 1, indicating completely accurate beliefs (T0 mean 0.75, T1 mean 0.78, T2 mean 0.77, and T3 mean 0.75). Accurate beliefs were correlated with self-reported behavior aimed at preventing the coronavirus from spreading (eg, social distancing) (r at all waves was between 0.26 and 0.29 and all P values were less than .001) and were associated with trust in scientists (ie, higher trust was associated with more accurate beliefs), political orientation (ie, liberal, Democratic participants held more accurate beliefs than conservative, Republican participants), and the primary news source (ie, participants reporting CNN or Fox News as the main news source held less accurate beliefs than others). The intervention did not significantly improve belief accuracy. Conclusions The supposed infodemic was not reflected in US citizens’ beliefs about the COVID-19 pandemic. Most people were quite able to figure out the facts in these relatively early days of the crisis, calling into question the prevalence of misinformation and the public’s susceptibility to misinformation.

Motivation Machine learning in the biomedical sciences should ideally provide predictive and interpretable models. When predicting outcomes from clinical or molecular features, applied researchers often want to know which features have effects, whether these effects are positive or negative and how strong these effects are. Regression analysis includes this information in the coefficients but typically renders less predictive models than more advanced machine learning techniques. Results Here, we propose an interpretable meta-learning approach for high-dimensional regression. The elastic net provides a compromise between estimating weak effects for many features and strong effects for some features. It has a mixing parameter to weight between ridge and lasso regularization. Instead of selecting one weighting by tuning, we combine multiple weightings by stacking. We do this in a way that increases predictivity without sacrificing interpretability. Availability and implementation The R package starnet is available on GitHub (https://github.com/rauschenberger/starnet) and CRAN (https://CRAN.R-project.org/package=starnet).

Background The working environment of a suicide prevention helpline requires high emotional and cognitive awareness from chat counselors. A shared opinion among counselors is that as a chat conversation becomes more difficult, it takes more effort and a longer amount of time to compose a response, which, in turn, can lead to writer’s block. Objective This study evaluates and then designs supportive technology to determine if a support system that provides inspiration can help counselors resolve writer’s block when they encounter difficult situations in chats with help-seekers. Methods A content-based recommender system with sentence embedding was used to search a chat corpus for similar chat situations. The system showed a counselor the most similar parts of former chat conversations so that the counselor would be able to use approaches previously taken by their colleagues as inspiration. In a within-subject experiment, counselors’ chat replies when confronted with a difficult situation were analyzed to determine if experts could see a noticeable difference in chat replies that were obtained in 3 conditions: (1) with the help of the support system, (2) with written advice from a senior counselor, or (3) when receiving no help. In addition, the system’s utility and usability were measured, and the validity of the algorithm was examined. Results A total of 24 counselors used a prototype of the support system; the results showed that, by reading chat replies, experts were able to significantly predict if counselors had received help from the support system or from a senior counselor (P=.004). Counselors scored the information they received from a senior counselor (M=1.46, SD 1.91) as significantly more helpful than the information received from the support system or when no help was given at all (M=–0.21, SD 2.26). Finally, compared with randomly selected former chat conversations, counselors rated the ones identified by the content-based recommendation system as significantly more similar to their current chats (β=.30, P Conclusions Support given to counselors influenced how they responded in difficult conversations. However, the higher utility scores given for the advice from senior counselors seem to indicate that specific actionable instructions are preferred. We expect that these findings will be beneficial for developing a system that can use similar chat situations to generate advice in a descriptive style, hence helping counselors through writer’s block.

[Abstract:] Estimating the lengths-of-stay (LoS) of hospitalised COVID-19 patients is key for predicting the hospital beds’ demand and planning mitigation strategies, as overwhelming the healthcare systems has critical consequences for disease mortality. However, accurately mapping the time-to-event of hospital outcomes, such as the LoS in the intensive care unit (ICU), requires understanding patient trajectories while adjusting for covariates and observation bias, such as incomplete data. Standard methods, such as the Kaplan-Meier estimator, require prior assumptions that are untenable given current knowledge. Using real-time surveillance data from the first weeks of the COVID-19 epidemic in Galicia (Spain), we aimed to model the time-to-event and event probabilities of patients’ hospitalised, without parametric priors and adjusting for individual covariates. We applied a non-parametric mixture cure model and compared its performance in estimating hospital ward (HW)/ICU LoS to the performances of commonly used methods to estimate survival. We showed that the proposed model outperformed standard approaches, providing more accurate ICU and HW LoS estimates. Finally, we applied our model estimates to simulate COVID-19 hospital demand using a Monte Carlo algorithm. We provided evidence that adjusting for sex, generally overlooked in prediction models, together with age is key for accurately forecasting HW and ICU occupancy, as well as discharge or death outcomes. ALC was sponsored by the BEATRIZ GALINDO JUNIOR Spanish from MICINN (Ministerio de Ciencia, Innovación y Universidades) with reference BGP18/00154. ALC, MAJ and RC acknowledge partial support by the MINECO (Ministerio de Economía y Competitividad) Grant MTM2014-52876-R (EU ERDF support included) and the MICINN Grant MTM2017-82724-R (EU ERDF support included) and partial support of Xunta de Galicia (Centro Singular de Investigación de Galicia accreditation ED431G 2019/01 and Grupos de Referencia Competitiva ED431C-2020-14 and ED431C2016-015) and the European Union (European Regional Development Fund - ERDF). PMD is a current recipient of the Grant of Excellence for postdoctoral studies by the Ramón Areces Foundation Xunta de Galicia; ED431G 2019/01 Xunta de Galicia; ED431C 2020/14 Xunta de Galicia; ED431C 2016/015

Background: Work stress affects individual health and well-being. These negative effects could be mitigated through regular monitoring of employees’ stress. Such monitoring becomes even more important as the digital transformation of the economy implies profound changes in working conditions. Objective: The goal of this study was to investigate the association between computer mouse movements and work stress in the field. Methods: We hypothesized that stress is associated with a speed-accuracy trade-off in computer mouse movements. To test this hypothesis, we conducted a longitudinal field study at a large business organization, where computer mouse movements from regular work activities were monitored over 7 weeks; the study included 70 subjects and 1829 observations. A Bayesian regression model was used to estimate whether self-reported acute work stress was associated with a speed-accuracy trade-off in computer mouse movements. Results: There was a negative association between stress and the two-way interaction term of mouse speed and accuracy (mean −0.32, 95% highest posterior density interval −0.58 to −0.08), which means that stress was associated with a speed-accuracy trade-off. The estimated association was not sensitive to different processing of the data and remained negative after controlling for the demographics, health, and personality traits of subjects. Conclusions: Self-reported acute stress is associated with computer mouse movements, specifically in the form of a speed-accuracy trade-off. This finding suggests that the regular analysis of computer mouse movements could indicate work stress., Journal of Medical Internet Research, 23 (4), ISSN:1438-8871

The purpose of this study was to evaluate the feasibility and module content of a brief online self-help program for concerned gamblers, i.e., gamblers who perceived a need to change their gambling habits, in the context of a gambling helpline. The program consisted of four modules based on Motivational Interviewing (MI) and Cognitive Behavioral Therapy (CBT), covering motivation to change, logging gambling behaviors, planning and implementing gambling-free activities, and managing risk situations. Gambling expenditures were also logged in the program, and their development over time were analyzed as longitudinal data using marginalized two-part models. Out of 4655 gamblers recruited via the helpline’s webpage, 92% completed content in at least one module, and 23% were active in all four modules. Attrition was in general high, with only 10% retention in the gambling log for longer than 14 days. Gambling expenditures decreased for those who logged them for a shorter time period, whereas it increased for those who logged expenditures for a longer time period. This study shows that it is relatively easy to recruit participants to an online program for concerned gamblers in the context of a gambling helpline. However, since few users logged in to the program more than once, we suggest future online programs to have open modules with all content accessible at once. Supplementary Information The online version contains supplementary material available at(10.1007/s10899-021-10005-6).

Providing support outside the household can be considered an actual sign of an active social life for the elderly. Adopting an ego–network perspective, we study support Italian elders provide to kin or non–kin. More specifically, using Italian survey data, we build the ego–centered networks of social contacts elders entertain and the ego–networks of support elders provide to other non–cohabitant kin or non–kin. Since ego–network data are inherently multilevel, we use Bayesian multilevel models to analyze variation in support ties, controlling for the characteristics of elders and their contacts. This modeling strategy enables dealing with sparseness and alter–alter overlap in the ego support network data and to disentangle the effects related to the ego (the elder), the dyad ego–alter, the kind of support provided, as well as social contacts and contextual variables. The results suggest that the elderly in Italy who provide support outside their household — compared to all elders in the sample — are younger, healthier, more educated, and embedded in a more diversified ego–network of social contacts. The latter also conveys both the type and the recipient of the support, with the elderly who entertain few relationships with kin being more prone to provide aid to non–kin. Further, a “peer homophily” effect in directing elder support to a non–kin is also found.

Motivation With the growth of big data, variable selection has become one of the critical challenges in statistics. Although many methods have been proposed in the literature, their performance in terms of recall (sensitivity) and precision (predictive positive value) is limited in a context where the number of variables by far exceeds the number of observations or in a highly correlated setting. Results In this article, we propose a general algorithm, which improves the precision of any existing variable selection method. This algorithm is based on highly intensive simulations and takes into account the correlation structure of the data. Our algorithm can either produce a confidence index for variable selection or be used in an experimental design planning perspective. We demonstrate the performance of our algorithm on both simulated and real data. We then apply it in two different ways to improve biological network reverse-engineering. Availability and implementation Code is available as the SelectBoost package on the CRAN, https://cran.r-project.org/package=SelectBoost. Some network reverse-engineering functionalities are available in the Patterns CRAN package, https://cran.r-project.org/package=Patterns. Supplementary information Supplementary data are available at Bioinformatics online.

We analyze the Covid-19 epidemic curve from March to end of April 2020 in Germany. We use statistical models to estimate the number of cases with disease onset on a given day and use back-projection techniques to obtain the number of new infections per day. The respective time series are analyzed by a Poisson trend regression model with change points. The change points are estimated directly from the data without further assumptions. We carry out the analysis for the whole of Germany and the federal state of Bavaria, where we have more detailed data. Both analyses show a major change between March 9th and 13th for the time series of infections: from a strong increase to a stagnation or a slight decrease. Another change was found between March 24th and March 31st, where the decline intensified. These two major changes can be related to different governmental measures. On March, 11th, Chancellor Merkel appealed for social distancing in a press conference with the Robert Koch Institute (RKI) and a ban on major events with more than 1000 visitors (March 10th) was issued. The other change point at the end of March could be related to the shutdown in Germany. Our results differ from those by other authors as we take into account the reporting delay, which turned out to be time dependent and therefore changes the structure of the epidemic curve compared to the curve of newly reported cases.

Advancement of gene expression measurements in longitudinal studies enables the identification of genes associated with disease severity over time. However, problems arise when the technology used to measure gene expression differs between time points. Observed differences between the results obtained at different time points can be caused by technical differences. Modeling the two measurements jointly over time might provide insight into the causes of these different results. Our work is motivated by a study of gene expression data of blood samples from Huntington disease patients, which were obtained using two different sequencing technologies. At time point 1, DeepSAGE technology was used to measure the gene expression, with a subsample also measured using RNA‐Seq technology. At time point 2, all samples were measured using RNA‐Seq technology. Significant associations between gene expression measured by DeepSAGE and disease severity using data from the first time point could not be replicated by the RNA‐Seq data from the second time point. We modeled the relationship between the two sequencing technologies using the data from the overlapping samples. We used linear mixed models with either DeepSAGE or RNA‐Seq measurements as the dependent variable and disease severity as the independent variable. In conclusion, (1) for one out of 14 genes, the initial significant result could be replicated with both technologies using data from both time points; (2) statistical efficiency is lost due to disagreement between the two technologies, measurement error when predicting gene expressions, and the need to include additional parameters to account for possible differences.

Population model-based (pharmacometric) approaches are widely used for the analyses of phase IIb clinical trial data to increase the accuracy of the dose selection for phase III clinical trials. On the other hand, if the analysis is based on one selected model, model selection bias can potentially spoil the accuracy of the dose selection process. In this paper, four methods that assume a number of pre-defined model structure candidates, for example a set of dose–response shape functions, and then combine or select those candidate models are introduced. The key hypothesis is that by combining both model structure uncertainty and model parameter uncertainty using these methodologies, we can make a more robust model based dose selection decision at the end of a phase IIb clinical trial. These methods are investigated using realistic simulation studies based on the study protocol of an actual phase IIb trial for an oral asthma drug candidate (AZD1981). Based on the simulation study, it is demonstrated that a bootstrap model selection method properly avoids model selection bias and in most cases increases the accuracy of the end of phase IIb decision. Thus, we recommend using this bootstrap model selection method when conducting population model-based decision-making at the end of phase IIb clinical trials. Electronic supplementary material The online version of this article (doi:10.1007/s10928-017-9550-0) contains supplementary material, which is available to authorized users.