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The Multilayer Perceptron Model was developed for predicting organic matter removal from pulp and paper mill wastewater. The original database covered a period of 1,427 consecutive days and contained the most frequently measured parameters. Three models were constructed by applying the technique of Principal Component Analysis, which selected principal components, discarded original variables and excluded possible outliers. The data were randomized and divided into training, validation and testing sets. The training algorithm was the Levenberg–Marquardt type, which is an adaptation of the back-propagation algorithm. The learning rate was 0.05, and the evaluation criteria used were the mean square error and the linear correlation coefficient. A marked difference was observed in the predictive performance when the organic matter load was used as an input. The model M4, which was built by discarding the two variables pH and EC, proved to be the most suitable and the simplest model obtained. However, ...

P values linked to null hypothesis significance testing (NHST) is the most widely (mis)used method of statistical inference. Empirical data suggest that across the biomedical literature (1990–2015)...

The article by Muller, Quintana, and Page reviews a variety of Bayesian nonparametric models and demonstrates them in a few applications. They emphasize applications in spatial data on which our discussion focuses as well. In particular, we consider two types of mixture models based on species sampling models (SSM) for spatial clustering and apply them to the Chilean mathematics testing score data analyzed by the authors. We conclude that only the mixture model of SSM with spatial locations as part of observations renders spatially non-overlapping clusters.

We give some comments on the paper by Mendes and Yigit where some misleading statements on rank tests have been given. Also, we give some additional important references on the same topic, which are not cited in this paper. By extending the simulations presented in the Mendes and Yigit paper to larger and unequal sample sizes, we demonstrate that the main conclusions are misleading.

No abstract available.

RA Fisher introduced variance components in 1918. He synthesized Mendelian inheritance with Darwin's theory of evolution by showing that the genetic variance of a continuous trait could be decomposed into additive and non-additive components. The model can be extended to include environmental factors, interactions, covariation, and non-random mating. Identifiability depends critically on design. Methods of analysis include modelling the mean squares from a fixed effects analysis of variance, and covariance structure modelling, which can be extended to multivariate traits and has been used to study ordinal traits by reference to postulated, unmeasured, latent 'liabilities'. These methods operate on dependent observa tions within independent groups of the same size and structure, and therefore require balanced designs ('regular' pedigrees). A multivariate normal model handles data in its generic form, utilizes data efficiently from all members of pedigrees of unequal size or varying structure, accommodates individuals missing at random, and allows flexible modelling with tests of distributional assumptions and fit. Most analytical methods use least squares or maximum likelihood under normal theory. Robust methods, scale transforma tion, ascertainment, path diagrams and correlational path models (popular in behavioural genetics through addressing nonrandom mating and social interactions), 'heritability', and the contribution and limitations of statistical modelling to the 'nature-nurture' debate, are discussed.

The estimation of prevalence and incidence of parasitic infections is considered. As the detectability of such infections is not 100% and may furthermore depend on their intensity, statistical methods are often required to arrive at meaningful results. It appears to be essential to distinguish between parasities that multiply within the (human) host and those that do not. An overview of some models discussed in the literature is presented. These models can indeed be used in assessing detectability of infection, and they indicate that observations may lead to considerable misinterpretation of 'true' prevalences and incidences.

We construct confidence regions in high dimensions by inverting the globaltest statistics, and use them to choose the tuning parameter for penalized regression. The selected model corresponds to the point in the confidence region of the parameters that minimizes the penalty, making it the least complex model that still has acceptable fit according to the test that defines the confidence region. As the globaltest is particularly powerful in the presence of many weak predictors, it connects well to ridge regression, and we thus focus on ridge penalties in this paper. The confidence region method is quick to calculate, intuitive, and gives decent predictive potential. As a tuning parameter selection method it may even outperform classical methods such as cross‐validation in terms of mean squared error of prediction, especially when the signal is weak. We illustrate the method for linear models in simulation study and for Cox models in real gene expression data of breast cancer samples.

Two new Weibull probability plotting papers are presented. Their use is explained, and they are compared with other Weibull papers...

In this work, we developed a robust permutation test for the concordance correlation coefficient (ρ c) for testing the general hypothesis H 0 : ρ c = ρ c(0). The proposed test is based on an appropriately studentized statistic. Theoretically, the test is proven to be asymptotically valid in the general setting when two paired variables are uncorrelated but dependent. This desired property was demonstrated across a range of distributional assumptions and sample sizes in simulation studies, where the test exhibits robust type I error control in all settings tested, even when the sample size is small. We demonstrated the application of this test in two real world examples across cardiac output measurements and endocardiographic imaging.

Multiple primary outcomes are sometimes collected and analysed in randomised controlled trials (RCTs), and are used in favour of a single outcome. By collecting multiple primary outcomes, it is possible to fully evaluate the effect that an intervention has for a given disease process. A simple approach to analysing multiple outcomes is to consider each outcome separately, however, this approach does not account for any pairwise correlations between the outcomes. Any cases with missing values must be ignored, unless an additional imputation step is performed. Alternatively, multivariate methods that explicitly model the pairwise correlations between the outcomes may be more efficient when some of the outcomes have missing values. In this paper, we present an overview of relevant methods that can be used to analyse multiple outcome measures in RCTs, including methods based on multivariate multilevel (MM) models. We perform simulation studies to evaluate the bias in the estimates of the intervention effects and the power of detecting true intervention effects observed when using selected methods. Different simulation scenarios were constructed by varying the number of outcomes, the type of outcomes, the degree of correlations between the outcomes and the proportions and mechanisms of missing data. We compare multivariate methods to univariate methods with and without multiple imputation. When there are strong correlations between the outcome measures (ρ > .4), our simulation studies suggest that there are small power gains when using the MM model when compared to analysing the outcome measures separately. In contrast, when there are weak correlations (ρ < .4), the power is reduced when using univariate methods with multiple imputation when compared to analysing the outcome measures separately.

Most studies aiming to construct reference or standard charts use a cross‐sectional design, collecting one measurement per participant. Reference or standard charts can also be constructed using a longitudinal design, collecting multiple measurements per participant. The choice of appropriate statistical methodology is important as inaccurate centiles resulting from inferior methods can lead to incorrect judgements about fetal or newborn size, resulting in suboptimal clinical care. Reference or standard centiles should ideally provide the best fit to the data, change smoothly with age (eg, gestational age), use as simple a statistical model as possible without compromising model fit, and allow the computation of Z‐scores from centiles to simplify assessment of individuals and enable comparison with different populations. Significance testing and goodness‐of‐fit statistics are usually used to discriminate between models. However, these methods tend not to be useful when examining large data sets as very small differences are statistically significant even if the models are indistinguishable on actual centile plots. Choosing the best model from amongst many is therefore not trivial. Model choice should not be based on statistical considerations (or tests) alone as sometimes the best model may not necessarily offer the best fit to the raw data across gestational age. In this paper, we describe the most commonly applied methodologies available for the construction of age‐specific reference or standard centiles for cross‐sectional and longitudinal data: Fractional polynomial regression, LMS, LMST, LMSP, and multilevel regression methods. For illustration, we used data from the INTERGROWTH‐21st Project, ie, newborn weight (cross‐sectional) and fetal head circumference (longitudinal) data as examples.

Motivation The prediction performance of Cox proportional hazard model suffers when there are only few uncensored events in the training data. Results We propose a Sparse-Group regularized Cox regression method to improve the prediction performance of large-scale and high-dimensional survival data with few observed events. Our approach is applicable when there is one or more other survival responses that 1. has a large number of observed events; 2. share a common set of associated predictors with the rare event response. This scenario is common in the UK Biobank dataset where records for a large number of common and less prevalent diseases of the same set of individuals are available. By analyzing these responses together, we hope to achieve higher prediction performance than when they are analyzed individually. To make this approach practical for large-scale data, we developed an accelerated proximal gradient optimization algorithm as well as a screening procedure inspired by Qian et al. Availabilityandimplementation https://github.com/rivas-lab/multisnpnet-Cox

Observational longitudinal data on treatments and covariates are increasingly used to investigate treatment effects, but are often subject to time‐dependent confounding. Marginal structural models (MSMs), estimated using inverse probability of treatment weighting or the g‐formula, are popular for handling this problem. With increasing development of advanced causal inference methods, it is important to be able to assess their performance in different scenarios to guide their application. Simulation studies are a key tool for this, but their use to evaluate causal inference methods has been limited. This paper focuses on the use of simulations for evaluations involving MSMs in studies with a time‐to‐event outcome. In a simulation, it is important to be able to generate the data in such a way that the correct forms of any models to be fitted to those data are known. However, this is not straightforward in the longitudinal setting because it is natural for data to be generated in a sequential conditional manner, whereas MSMs involve fitting marginal rather than conditional hazard models. We provide general results that enable the form of the correctly specified MSM to be derived based on a conditional data generating procedure, and show how the results can be applied when the conditional hazard model is an Aalen additive hazard or Cox model. Using conditional additive hazard models is advantageous because they imply additive MSMs that can be fitted using standard software. We describe and illustrate a simulation algorithm. Our results will help researchers to effectively evaluate causal inference methods via simulation.

For continuous variables of randomized controlled trials, recently, longitudinal analysis of pre‐ and posttreatment measurements as bivariate responses is one of analytical methods to compare two treatment groups. Under random allocation, means and variances of pretreatment measurements are expected to be equal between groups, but covariances and posttreatment variances are not. Under random allocation with unequal covariances and posttreatment variances, we compared asymptotic variances of the treatment effect estimators in three longitudinal models. The data‐generating model has equal baseline means and variances, and unequal covariances and posttreatment variances. The model with equal baseline means and unequal variance–covariance matrices has a redundant parameter. In large sample sizes, these two models keep a nominal type I error rate and have high efficiency. The model with equal baseline means and equal variance–covariance matrices wrongly assumes equal covariances and posttreatment variances. Only under equal sample sizes, this model keeps a nominal type I error rate. This model has the same high efficiency with the data‐generating model under equal sample sizes. In conclusion, longitudinal analysis with equal baseline means performed well in large sample sizes. We also compared asymptotic properties of longitudinal models with those of the analysis of covariance (ANCOVA) and t‐test.

In confirmatory clinical trials, the pre-specification of the primary analysis model is a universally accepted scientific principle to allow strict control of the type-I-error. Accordingly both the ICH E9 guideline and the EMA guideline on missing data in confirmatory clinical trials require the explicit[for full text, please go to the a.m. URL], 64. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie e.V. (GMDS)

The standardized mean difference is a well‐known effect size measure for continuous, normally distributed data. In this paper we present a general basis for important other distribution families. As a general concept, usable for every distribution family, we introduce the relative effect, also called Mann–Whitney effect size measure of stochastic superiority. This measure is a truly robust measure, needing no assumptions about a distribution family. It is thus the preferred tool for assumption‐free, confirmatory studies. For normal distribution shift, proportional odds, and proportional hazards, we show how to derive many global values such as risk difference average, risk difference extremum, and odds ratio extremum. We demonstrate that the well‐known benchmark values of Cohen with respect to group differences—small, medium, large—can be translated easily into corresponding Mann–Whitney values. From these, we get benchmarks for parameters of other distribution families. Furthermore, it is shown that local measures based on binary data (2 × 2 tables) can be associated with the Mann–Whitney measure: The concept of stochastic superiority can always be used. It is a general statistical value in every distribution family. It therefore yields a procedure for standardizing the assessment of effect size measures. We look at the aspect of relevance of an effect size and—introducing confidence intervals—present some examples for use in statistical practice.

We propose methods to estimate sufficient reductions in matrix-valued predictors for regression or classification. We assume that the first moment of the predictor matrix given the response can be decomposed into a row and column component via a Kronecker product structure. We obtain least squares and maximum likelihood estimates of the sufficient reductions in the matrix predictors, derive statistical properties of the resulting estimates and present fast computational algorithms with assured convergence. The performance of the proposed approaches in regression and classification is compared in simulations.We illustrate the methods on two examples, using longitudinally measured serum biomarker and neuroimaging data.

The inclusion of covariates in population models during drug development is a key step to understanding drug variability and support dosage regimen proposal, but high correlation among covariates often complicates the identification of the true covariate. We compared three covariate selection methods balancing data information and prior knowledge: (1) full fixed effect modelling (FFEM), with covariate selection prior to data analysis, (2) simplified stepwise covariate modelling (sSCM), data driven selection only, and (3) Prior-Adjusted Covariate Selection (PACS) mixing both. PACS penalizes the a priori less likely covariate model by adding to its objective function value (OFV) a prior probability-derived constant: $$2*{\kern 1pt} \,{\ln}\left( {{\Pr}\left( X \right)/\left( {1 - {\Pr}\left( X \right)} \right)} \right)$$ 2 ∗ ln Pr X / 1 - Pr X , Pr(X) being the probability of the more likely covariate. Simulations were performed to compare their external performance (average OFV in a validation dataset of 10,000 subjects) in selecting the true covariate between two highly correlated covariates: 0.5, 0.7, or 0.9, after a training step on datasets of 12, 25 or 100 subjects (increasing power). With low power data no method was superior, except FFEM when associated with highly correlated covariates ($$r=0.9$$ r = 0.9 ), sSCM and PACS suffering both from selection bias. For high power data, PACS and sSCM performed similarly, both superior to FFEM. PACS is an alternative for covariate selection considering both the expected power to identify an anticipated covariate relation and the probability of prior information being correct. A proposed strategy is to use FFEM whenever the expected power to distinguish between contending models is 80% but

Funder: National Institute of Health Research (NIHR) Cambridge Biomedical Research Centre, A standard two-arm randomised controlled trial usually compares an intervention to a control treatment with equal numbers of patients randomised to each treatment arm and only data from within the current trial are used to assess the treatment effect. Historical data are used when designing new trials and have recently been considered for use in the analysis when the required number of patients under a standard trial design cannot be achieved. Incorporating historical control data could lead to more efficient trials, reducing the number of controls required in the current study when the historical and current control data agree. However, when the data are inconsistent, there is potential for biased treatment effect estimates, inflated type I error and reduced power. We introduce two novel approaches for binary data which discount historical data based on the agreement with the current trial controls, an equivalence approach and an approach based on tail area probabilities. An adaptive design is used where the allocation ratio is adapted at the interim analysis, randomising fewer patients to control when there is agreement. The historical data are down-weighted in the analysis using the power prior approach with a fixed power. We compare operating characteristics of the proposed design to historical data methods in the literature: the modified power prior; commensurate prior; and robust mixture prior. The equivalence probability weight approach is intuitive and the operating characteristics can be calculated exactly. Furthermore, the equivalence bounds can be chosen to control the maximum possible inflation in type I error.

Background Misdiagnosis, arbitrary charges, annoying queues, and clinic waiting times among others are long-standing phenomena in the medical industry across the world. These factors can contribute to patient anxiety about misdiagnosis by clinicians. However, with the increasing growth in use of big data in biomedical and health care communities, the performance of artificial intelligence (Al) techniques of diagnosis is improving and can help avoid medical practice errors, including under the current circumstance of COVID-19. Objective This study aims to visualize and measure patients’ heterogeneous preferences from various angles of AI diagnosis versus clinicians in the context of the COVID-19 epidemic in China. We also aim to illustrate the different decision-making factors of the latent class of a discrete choice experiment (DCE) and prospects for the application of AI techniques in judgment and management during the pandemic of SARS-CoV-2 and in the future. Methods A DCE approach was the main analysis method applied in this paper. Attributes from different dimensions were hypothesized: diagnostic method, outpatient waiting time, diagnosis time, accuracy, follow-up after diagnosis, and diagnostic expense. After that, a questionnaire is formed. With collected data from the DCE questionnaire, we apply Sawtooth software to construct a generalized multinomial logit (GMNL) model, mixed logit model, and latent class model with the data sets. Moreover, we calculate the variables’ coefficients, standard error, P value, and odds ratio (OR) and form a utility report to present the importance and weighted percentage of attributes. Results A total of 55.8% of the respondents (428 out of 767) opted for AI diagnosis regardless of the description of the clinicians. In the GMNL model, we found that people prefer the 100% accuracy level the most (OR 4.548, 95% CI 4.048-5.110, P Conclusions Latent class analysis was prominent and useful in quantifying preferences for attributes of diagnosis choice. People’s preferences for the “accuracy” and “diagnostic expenses” attributes are palpable. AI will have a potential market. However, accuracy and diagnosis expenses need to be taken into consideration.

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.

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.

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.

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.

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

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.

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.

[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

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.

In generalized linear modelling of responses and response times, the observed response time variables are commonly transformed to make their distribution approximately normal. A normal distribution for the transformed response times is desirable as it justifies the linearity and homoscedasticity assumptions in the underlying linear model. Past research has, however, shown that the transformed response times are not always normal. Models have been developed to accommodate this violation. In the present study, we propose a modelling approach for responses and response times to test and model non-normality in the transformed response times. Most importantly, we distinguish between non-normality due to heteroscedastic residual variances, and non-normality due to a skewed speed factor. In a simulation study, we establish parameter recovery and the power to separate both effects. In addition, we apply the model to a real data set.

SUMMARY In the analysis of survival times, the logrank test and the Cox model have been established as key tools, which do not require specific distributional assumptions. Under the assumption of proportional hazards, they are efficient and their results can be interpreted unambiguously. However, delayed treatment effects, disease progression, treatment switchers or the presence of subgroups with differential treatment effects may challenge the assumption of proportional hazards. In practice, weighted logrank tests emphasizing either early, intermediate or late event times via an appropriate weighting function may be used to accommodate for an expected pattern of non‐proportionality. We model these sources of non‐proportional hazards via a mixture of survival functions with piecewise constant hazard. The model is then applied to study the power of unweighted and weighted log‐rank tests, as well as maximum tests allowing different time dependent weights. Simulation results suggest a robust performance of maximum tests across different scenarios, with little loss in power compared to the most powerful among the considered weighting schemes and huge power gain compared to unfavorable weights. The actual sources of non‐proportional hazards are not obvious from resulting populationwise survival functions, highlighting the importance of detailed simulations in the planning phase of a trial when assuming non‐proportional hazards.We provide the required tools in a software package, allowing to model data generating processes under complex non‐proportional hazard scenarios, to simulate data from these models and to perform the weighted logrank tests.

Contains fulltext : 232638.pdf (Publisher’s version ) (Open Access) In rare diseases, typically only a small number of patients are available for a randomized clinical trial. Nevertheless, it is not uncommon that more than one study is performed to evaluate a (new) treatment. Scarcity of available evidence makes it particularly valuable to pool the data in a meta-analysis. When the primary outcome is binary, the small sample sizes increase the chance of observing zero events. The frequentist random-effects model is known to induce bias and to result in improper interval estimation of the overall treatment effect in a meta-analysis with zero events. Bayesian hierarchical modeling could be a promising alternative. Bayesian models are known for being sensitive to the choice of prior distributions for between-study variance (heterogeneity) in sparse settings. In a rare disease setting, only limited data will be available to base the prior on, therefore, robustness of estimation is desirable. We performed an extensive and diverse simulation study, aiming to provide practitioners with advice on the choice of a sufficiently robust prior distribution shape for the heterogeneity parameter. Our results show that priors that place some concentrated mass on small τ values but do not restrict the density for example, the Uniform(-10, 10) heterogeneity prior on the log(τ(2) ) scale, show robust 95% coverage combined with less overestimation of the overall treatment effect, across varying degrees of heterogeneity. We illustrate the results with meta-analyzes of a few small trials.

Motivation Mendelian randomization is an epidemiological technique that uses genetic variants as instrumental variables to estimate the causal effect of a risk factor on an outcome. We consider a scenario in which causal estimates based on each variant in turn differ more strongly than expected by chance alone, but the variants can be divided into distinct clusters, such that all variants in the cluster have similar causal estimates. This scenario is likely to occur when there are several distinct causal mechanisms by which a risk factor influences an outcome with different magnitudes of causal effect. We have developed an algorithm MR-Clust that finds such clusters of variants, and so can identify variants that reflect distinct causal mechanisms. Two features of our clustering algorithm are that it accounts for differential uncertainty in the causal estimates, and it includes ‘null’ and ‘junk’ clusters, to provide protection against the detection of spurious clusters. Results Our algorithm correctly detected the number of clusters in a simulation analysis, outperforming methods that either do not account for uncertainty or do not include null and junk clusters. In an applied example considering the effect of blood pressure on coronary artery disease risk, the method detected four clusters of genetic variants. A post hoc hypothesis-generating search suggested that variants in the cluster with a negative effect of blood pressure on coronary artery disease risk were more strongly related to trunk fat percentage and other adiposity measures than variants not in this cluster. Availability and implementation MR-Clust can be downloaded from https://github.com/cnfoley/mrclust. Supplementary information Supplementary data are available at Bioinformatics online.

Although multicenter data are common, many prediction model studies ignore this during model development. The objective of this study is to evaluate the predictive performance of regression methods for developing clinical risk prediction models using multicenter data, and provide guidelines for practice. We compared the predictive performance of standard logistic regression, generalized estimating equations, random intercept logistic regression, and fixed effects logistic regression. First, we presented a case study on the diagnosis of ovarian cancer. Subsequently, a simulation study investigated the performance of the different models as a function of the amount of clustering, development sample size, distribution of center-specific intercepts, the presence of a center-predictor interaction, and the presence of a dependency between center effects and predictors. The results showed that when sample sizes were sufficiently large, conditional models yielded calibrated predictions, whereas marginal models yielded miscalibrated predictions. Small sample sizes led to overfitting and unreliable predictions. This miscalibration was worse with more heavily clustered data. Calibration of random intercept logistic regression was better than that of standard logistic regression even when center-specific intercepts were not normally distributed, a center-predictor interaction was present, center effects and predictors were dependent, or when themodel was applied in a new center. Therefore, to make reliable predictions in a specific center, we recommend random intercept logistic regression. ispartof: Biometrical Journal vol:62 issue:4 pages:932-944 ispartof: location:Germany status: published

Background A lifelogs-based wellness index (LWI) is a function for calculating wellness scores based on health behavior lifelogs (eg, daily walking steps and sleep times collected via a smartwatch). A wellness score intuitively shows the users of smart wellness services the overall condition of their health behaviors. LWI development includes estimation (ie, estimating coefficients in LWI with data). A panel data set comprising health behavior lifelogs allows LWI estimation to control for unobserved variables, thereby resulting in less bias. However, these data sets typically have missing data due to events that occur in daily life (eg, smart devices stop collecting data when batteries are depleted), which can introduce biases into LWI coefficients. Thus, the appropriate choice of method to handle missing data is important for reducing biases in LWI estimations with panel data. However, there is a lack of research in this area. Objective This study aims to identify a suitable missing-data handling method for LWI estimation with panel data. Methods Listwise deletion, mean imputation, expectation maximization–based multiple imputation, predictive-mean matching–based multiple imputation, k-nearest neighbors–based imputation, and low-rank approximation–based imputation were comparatively evaluated by simulating an existing case of LWI development. A panel data set comprising health behavior lifelogs of 41 college students over 4 weeks was transformed into a reference data set without any missing data. Then, 200 simulated data sets were generated by randomly introducing missing data at proportions from 1% to 80%. The missing-data handling methods were each applied to transform the simulated data sets into complete data sets, and coefficients in a linear LWI were estimated for each complete data set. For each proportion for each method, a bias measure was calculated by comparing the estimated coefficient values with values estimated from the reference data set. Results Methods performed differently depending on the proportion of missing data. For 1% to 30% proportions, low-rank approximation–based imputation, predictive-mean matching–based multiple imputation, and expectation maximization–based multiple imputation were superior. For 31% to 60% proportions, low-rank approximation–based imputation and predictive-mean matching–based multiple imputation performed best. For over 60% proportions, only low-rank approximation–based imputation performed acceptably. Conclusions Low-rank approximation–based imputation was the best of the 6 data-handling methods regardless of the proportion of missing data. This superiority is generalizable to other panel data sets comprising health behavior lifelogs given their verified low-rank nature, for which low-rank approximation–based imputation is known to perform effectively. This result will guide missing-data handling in reducing coefficient biases in new development cases of linear LWIs with panel data.

We study the effect of delaying treatment in the presence of (unobserved) heterogeneity. In a homogeneous population and assuming a proportional treatment effect, a treatment delay period will result in notably lower cumulative recovery percentages. We show in theoretical scenarios using frailty models that if the population is heterogeneous, the effect of a delay period is much smaller. This can be explained by the selection process that is induced by the frailty. Patient groups that start treatment later have already undergone more selection. The marginal hazard ratio for the treatment will act differently in such a more homogeneous patient group. We further discuss modeling approaches for estimating the effect of treatment delay in the presence of heterogeneity, and compare their performance in a simulation study. The conventional Cox model that fails to account for heterogeneity overestimates the effect of treatment delay. Including interaction terms between treatment and starting time of treatment or between treatment and follow up time gave no improvement. Estimating a frailty term can improve the estimation, but is sensitive to misspecification of the frailty distribution. Therefore, multiple frailty distributions should be used and the results should be compared using the Akaike Information Criterion. Non‐parametric estimation of the cumulative recovery percentages can be considered if the dataset contains sufficient long term follow up for each of the delay strategies. The methods are demonstrated on a motivating application evaluating the effect of delaying the start of treatment with assisted reproductive techniques on time‐to‐pregnancy in couples with unexplained subfertility.

The Gini index is well-known for a single measure of inequality. The purpose of this article is to explore a matrix structure of the Gini index in a setting of multiple source income. Using matrices, we analyze the decomposition of the Gini index by income source and derive an explicit formula for the factors in terms of the associated percentile levels based on aggregated data reporting. Each factor is shown to be the sums of the two split off parts of the income within a percentile bracket. Both have unequalizing and equalizing contribution to the total inequality, respectively. We use R code and apply the methodology to several data sets including a sample of European aggregated income reporting in 2014 for illustration. A byproduct from the Gini decomposition provides a matrix approach to the decomposition of the associated Lorenz curve in terms of the density distribution matrix and a Toeplitz matrix.

The determination of the sample size required by a crossover trial typically depends on the specification of one or more variance components. Uncertainty about the value of these parameters at the design stage means that there is often a risk a trial may be under‐ or overpowered. For many study designs, this problem has been addressed by considering adaptive design methodology that allows for the re‐estimation of the required sample size during a trial. Here, we propose and compare several approaches for this in multitreatment crossover trials. Specifically, regulators favor reestimation procedures to maintain the blinding of the treatment allocations. We therefore develop blinded estimators for the within and between person variances, following simple or block randomization. We demonstrate that, provided an equal number of patients are allocated to sequences that are balanced for period, the proposed estimators following block randomization are unbiased. We further provide a formula for the bias of the estimators following simple randomization. The performance of these procedures, along with that of an unblinded approach, is then examined utilizing three motivating examples, including one based on a recently completed four‐treatment four‐period crossover trial. Simulation results show that the performance of the proposed blinded procedures is in many cases similar to that of the unblinded approach, and thus they are an attractive alternative.

Background: Variable selection is an important issue when developing prognostic models. Missing data occur frequently in clinical research. Multiple imputation is increasingly used to address the presence of missing data in clinical research. The effect of different variable selection strategies with multiply imputed data on the external performance of derived prognostic models has not been well examined. Methods and Results: We used backward variable selection with 9 different ways to handle multiply imputed data in a derivation sample to develop logistic regression models for predicting death within 1 year of hospitalization with an acute myocardial infarction. We assessed the prognostic accuracy of each derived model in a temporally distinct validation sample. The derivation and validation samples consisted of 11 524 patients hospitalized between 1999 and 2001 and 7889 patients hospitalized between 2004 and 2005, respectively. We considered 41 candidate predictor variables. Missing data occurred frequently, with only 13% of patients in the derivation sample and 31% of patients in the validation sample having complete data. Regardless of the significance level for variable selection, the prognostic model developed using only the complete cases in the derivation sample had substantially worse performance in the validation sample than did the models for which variables were selected using the multiply imputed versions of the derivation sample. The other 8 approaches to handling multiply imputed data resulted in prognostic models with performance similar to one another. Conclusions: Ignoring missing data and using only subjects with complete data can result in the derivation of prognostic models with poor performance. Multiple imputation should be used to account for missing data when developing prognostic models.

Background Pain volatility is an important factor in chronic pain experience and adaptation. Previously, we employed machine-learning methods to define and predict pain volatility levels from users of the Manage My Pain app. Reducing the number of features is important to help increase interpretability of such prediction models. Prediction results also need to be consolidated from multiple random subsamples to address the class imbalance issue. Objective This study aimed to: (1) increase the interpretability of previously developed pain volatility models by identifying the most important features that distinguish high from low volatility users; and (2) consolidate prediction results from models derived from multiple random subsamples while addressing the class imbalance issue. Methods A total of 132 features were extracted from the first month of app use to develop machine learning–based models for predicting pain volatility at the sixth month of app use. Three feature selection methods were applied to identify features that were significantly better predictors than other members of the large features set used for developing the prediction models: (1) Gini impurity criterion; (2) information gain criterion; and (3) Boruta. We then combined the three groups of important features determined by these algorithms to produce the final list of important features. Three machine learning methods were then employed to conduct prediction experiments using the selected important features: (1) logistic regression with ridge estimators; (2) logistic regression with least absolute shrinkage and selection operator; and (3) random forests. Multiple random under-sampling of the majority class was conducted to address class imbalance in the dataset. Subsequently, a majority voting approach was employed to consolidate prediction results from these multiple subsamples. The total number of users included in this study was 879, with a total number of 391,255 pain records. Results A threshold of 1.6 was established using clustering methods to differentiate between 2 classes: low volatility (n=694) and high volatility (n=185). The overall prediction accuracy is approximately 70% for both random forests and logistic regression models when using 132 features. Overall, 9 important features were identified using 3 feature selection methods. Of these 9 features, 2 are from the app use category and the other 7 are related to pain statistics. After consolidating models that were developed using random subsamples by majority voting, logistic regression models performed equally well using 132 or 9 features. Random forests performed better than logistic regression methods in predicting the high volatility class. The consolidated accuracy of random forests does not drop significantly (601/879; 68.4% vs 618/879; 70.3%) when only 9 important features are included in the prediction model. Conclusions We employed feature selection methods to identify important features in predicting future pain volatility. To address class imbalance, we consolidated models that were developed using multiple random subsamples by majority voting. Reducing the number of features did not result in a significant decrease in the consolidated prediction accuracy.

In the absence of perfect reference standard, classical techniques result in biased diagnostic accuracy and prevalence estimates. By statistically defining the true disease status, latent class models (LCM) constitute a promising alternative. However, LCM is a complex method which relies on parametric assumptions, including usually a conditional independence between tests and might suffer from data sparseness. We carefully applied LCMs to assess new campylobacter infection detection tests for which bacteriological culture is an imperfect reference standard. Five diagnostic tests (culture, polymerase chain reaction and three immunoenzymatic tests) of campylobacter infection were collected in 623 patients from Bordeaux and Lyon Hospitals, France. Their diagnostic accuracy were estimated with standard and extended LCMs with a thorough examination of models goodness-of-fit. The model including a residual dependence specific to the immunoenzymatic tests best complied with LCM assumptions. Asymptotic results of goodness-of-fit statistics were substantially impaired by data sparseness and empirical distributions were preferred. Results confirmed moderate sensitivity of the culture and high performances of immunoenzymatic tests. LCMs can be used to estimate diagnostic tests accuracy in the absence of perfect reference standard. However, their implementation and assessment require specific attention due to data sparseness and limitations of existing software.

Motivation Extreme phenotype sampling (EPS) is a broadly-used design to identify candidate genetic factors contributing to the variation of quantitative traits. By enriching the signals in extreme phenotypic samples, EPS can boost the association power compared to random sampling. Most existing statistical methods for EPS examine the genetic factors individually, despite many quantitative traits have multiple genetic factors underlying their variation. It is desirable to model the joint effects of genetic factors, which may increase the power and identify novel quantitative trait loci under EPS. The joint analysis of genetic data in high-dimensional situations requires specialized techniques, e.g. the least absolute shrinkage and selection operator (LASSO). Although there are extensive research and application related to LASSO, the statistical inference and testing for the sparse model under EPS remain unknown. Results We propose a novel sparse model (EPS-LASSO) with hypothesis test for high-dimensional regression under EPS based on a decorrelated score function. The comprehensive simulation shows EPS-LASSO outperforms existing methods with stable type I error and FDR control. EPS-LASSO can provide a consistent power for both low- and high-dimensional situations compared with the other methods dealing with high-dimensional situations. The power of EPS-LASSO is close to other low-dimensional methods when the causal effect sizes are small and is superior when the effects are large. Applying EPS-LASSO to a transcriptome-wide gene expression study for obesity reveals 10 significant body mass index associated genes. Our results indicate that EPS-LASSO is an effective method for EPS data analysis, which can account for correlated predictors. Availability and implementation The source code is available at https://github.com/xu1912/EPSLASSO. Supplementary information Supplementary data are available at Bioinformatics online.

SUMMARYAltered microbial communities are thought to play an important role in eosinophilic oesophagitis, an allergic inflammatory condition of the oesophagus. Identification of the majority of organisms present in human-associated microbial communities is feasible with the advent of high throughput sequencing technology. However, these data consist of non-negative, highly skewed sequence counts with a large proportion of zeros. In addition, hierarchical study designs are often performed with repeated measurements or multiple samples collected from the same subject, thus requiring approaches to account for within-subject variation, yet only a small number of microbiota studies have applied hierarchical regression models. In this paper, we describe and illustrate the use of a hierarchical regression-based approach to evaluate multiple factors for a small number of organisms individually. More specifically, the zero-inflated negative binomial mixed model with random effects in both the count and zero-inflated parts is applied to evaluate associations with disease state while adjusting for potential confounders for two organisms of interest from a study of human microbiota sequence data in oesophagitis.

Motivation: The construction of statistics for summarizing posterior samples returned by a Bayesian phylogenetic study has so far been hindered by the poor geometric insights available into the space of phylogenetic trees, and ad hoc methods such as the derivation of a consensus tree makeup for the ill-definition of the usual concepts of posterior mean, while bootstrap methods mitigate the absence of a sound concept of variance. Yielding satisfactory results with sufficiently concentrated posterior distributions, such methods fall short of providing a faithful summary of posterior distributions if the data do not offer compelling evidence for a single topology. Results: Building upon previous work of Billera et al., summary statistics such as sample mean, median and variance are defined as the geometric median, Fr\'echet mean and variance, respectively. Their computation is enabled by recently published works, and embeds an algorithm for computing shortest paths in the space of trees. Studying the phylogeny of a set of plants, where several tree topologies occur in the posterior sample, the posterior mean balances correctly the contributions from the different topologies, where a consensus tree would be biased. Comparisons of the posterior mean, median and consensus trees with the ground truth using simulated data also reveals the benefits of a sound averaging method when reconstructing phylogenetic trees., Comment: The original paper "Computing the posterior expectation of phylogenetic trees" was substantially rewritten, renamed to "Point estimates in phylogenetic reconstructions" and published in Bioinformatics

Identifying subgroups of patients with an enhanced response to a new treatment has become an area of increased interest in the last few years. When there is knowledge about possible subpopulations with an enhanced treatment effect before the start of a trial it might be beneficial to set up a testing strategy, which tests for a significant treatment effect not only in the full population, but also in these prespecified subpopulations. In this paper, we present a parametric multiple testing approach for tests in multiple populations for dose‐finding trials. Our approach is based on the MCP‐Mod methodology, which uses multiple comparison procedures (MCPs) to test for a dose–response signal, while considering multiple possible candidate dose–response shapes. Our proposed methods allow for heteroscedastic error variances between populations and control the family‐wise error rate over tests in multiple populations and for multiple candidate models. We show in simulations that the proposed multipopulation testing approaches can increase the power to detect a significant dose–response signal over the standard single‐population MCP‐Mod, when the specified subpopulation has an enhanced treatment effect.