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Abstract Bayesian statistics plays a pivotal role in advancing medical science by enabling healthcare companies, regulators, and stakeholders to assess the safety and efficacy of new treatments, interventions, and medical procedures. The Bayesian framework offers a unique advantage over the classical framework, especially when incorporating prior information into a new trial with quality external data, such as historical data or another source of co-data. In recent years, there has been a significant increase in regulatory submissions using Bayesian statistics due to its flexibility and ability to provide valuable insights for decision-making, addressing the modern complexity of clinical trials where frequentist trials are inadequate. For regulatory submissions, companies often need to consider the frequentist operating characteristics of the Bayesian analysis strategy, regardless of the design complexity. In particular, the focus is on the frequentist type I error rate and power for all realistic alternatives. This tutorial review aims to provide a comprehensive overview of the use of Bayesian statistics in sample size determination, control of type I error rate, multiplicity adjustments, external data borrowing, etc., in the regulatory environment of clinical trials. Fundamental concepts of Bayesian sample size determination and illustrative examples are provided to serve as a valuable resource for researchers, clinicians, and statisticians seeking to develop more complex and innovative designs.

The hybrid frequentist-Bayesian approach to sample size determination is based on the expectation of the power function of a test with respect to a design prior for the unknown parameter value. In clinical trials this quantity is often called probability of success (PoS). Determination of the limiting value of PoS as the number of observations tends to infinity, that is crucial for well defined sample size criteria, has been considered in previous articles. Here, we focus on the asymptotic behavior of the whole distribution of the power function induced by the design prior. Under mild conditions, we provide asymptotic results for the three most common classes of hypotheses on a scalar parameter. The impact of the design parameters choice on the distribution of the power function and on its limit is discussed. [ABSTRACT FROM AUTHOR]

The expected value of the standard power function of a test, computed with respect to a design prior distribution, is often used to evaluate the probability of success of an experiment. However, looking only at the expected value might be reductive. Instead, the whole probability distribution of the power function induced by the design prior can be exploited. In this article we consider one‐sided testing for the scale parameter of exponential families and we derive general unifying expressions for cumulative distribution and density functions of the random power. Sample size determination criteria based on alternative summaries of these functions are discussed. The study sheds light on the relevance of the choice of the design prior in order to construct a successful experiment. [ABSTRACT FROM AUTHOR]

Bayesian statistics plays a pivotal role in advancing medical science by enabling healthcare companies, regulators, and stakeholders to assess the safety and efficacy of new treatments, interventions, and medical procedures. The Bayesian framework offers a unique advantage over the classical framework, especially when incorporating prior information into a new trial with quality external data, such as historical data or another source of co-data. In recent years, there has been a significant increase in regulatory submissions using Bayesian statistics due to its flexibility and ability to provide valuable insights for decision-making, addressing the modern complexity of clinical trials where frequentist trials are inadequate. For regulatory submissions, companies often need to consider the frequentist operating characteristics of the Bayesian analysis strategy, regardless of the design complexity. In particular, the focus is on the frequentist type I error rate and power for all realistic alternatives. This tutorial review aims to provide a comprehensive overview of the use of Bayesian statistics in sample size determination, control of type I error rate, multiplicity adjustments, external data borrowing, etc., in the regulatory environment of clinical trials. Fundamental concepts of Bayesian sample size determination and illustrative examples are provided to serve as a valuable resource for researchers, clinicians, and statisticians seeking to develop more complex and innovative designs. [ABSTRACT FROM AUTHOR]

We begin with a discussion of results on the asymptotic properties associated with purely sequential minimum risk point estimation (MRPE) methodology for an unknown mean when the distribution is unspecified, under squared error loss (SEL) plus the cost of sampling. We proceed to show that, given certain moment conditions, such properties can be extended to estimation problems under a broader class of loss functions, namely: first order risk-efficiency under powered absolute error loss (PAEL) plus the powered cost of sampling. In addition to purely sequential strategy, we also prove these asymptotic properties for a more operationally convenient, accelerated sequential procedure. We follow-up with extensive data analyses from simulations under mixture distributions. We conclude with illustrations using data from two cancer studies. [ABSTRACT FROM AUTHOR]

Over the past decades, the process of the traditional drug discovery study spent tremendous time and resources. More and more studies have shown that genetic determinants may mediate variability among persons in the response to a drug. In this article, the proposed method is considered for genetic heterogeneity in Simon's two-stage design for a phase II clinical trial. We try to propose the method to employ the phase II clinical trial based on the existence of the epidemiological evidence for genetic heterogeneity. For our proposed method, Simon's two-stage design is conditional on the probability of the genetic heterogeneity. The example is used to illustrate how to calculate sample size in given parameters. [ABSTRACT FROM AUTHOR]

Rank methods are well‐established tools for comparing two or multiple (independent) groups. Statistical planning methods for the computing the required sample size(s) to detect a specific alternative with predefined power are lacking. In the present paper, we develop numerical algorithms for sample size planning of pseudo‐rank‐based multiple contrast tests. We discuss the treatment effects and different ways to approximate variance parameters within the estimation scheme. We further compare pairwise with global rank methods in detail. Extensive simulation studies show that the sample size estimators are accurate. A real data example illustrates the application of the methods. [ABSTRACT FROM AUTHOR]

A sufficient number of participants should be included to adequately address the research interest in the surveys with sensitive questions. In this paper, sample size formulas/iterative algorithms are developed from the perspective of controlling the confidence interval width of the prevalence of a sensitive attribute under four non‐randomized response models: the crosswise model, parallel model, Poisson item count technique model and negative binomial item count technique model. In contrast to the conventional approach for sample size determination, our sample size formulas/algorithms explicitly incorporate an assurance probability of controlling the width of a confidence interval within the pre‐specified range. The performance of the proposed methods is evaluated with respect to the empirical coverage probability, empirical assurance probability and confidence width. Simulation results show that all formulas/algorithms are effective and hence are recommended for practical applications. A real example is used to illustrate the proposed methods. [ABSTRACT FROM AUTHOR]

In this study, we consider the sample size determination problem for clustered count data with many zeros. In general, zero-inflated Poisson and binomial models are commonly used for zero-inflated data; however, in real data the assumptions that should be satisfied when using each model might be violated. We calculate the required sample size based on a discrete Weibull regression model that can handle both underdispersed and overdispersed data types. We use the Monte Carlo simulation to compute the required sample size. With our proposed method, a unified model with a low failure risk can be used to cope with the dispersed data type and handle data with many zeros, which appear in groups or clusters sharing a common variation source. A simulation study shows that our proposed method provides accurate results, revealing that the sample size is affected by the distribution skewness, covariance structure of covariates, and amount of zeros. We apply our method to the pancreas disorder length of the stay data collected from Western Australia. [ABSTRACT FROM AUTHOR]

We discuss three issues. In the first part, we discuss the criteria emphasized by Maurer, Bretz, and Xun, warning that it modifies the per comparison error rate that does not address the concerns raised by multiple testing. In the second part, we strengthen the optimality results developed in the paper, based on our recent results. In the third part, we highlight the potentially important role that the use of weights may have in practice and discuss the difficulties in assigning weights that convey the importance in the gain and loss functions, especially as it pertains to multiple endpoints. [ABSTRACT FROM AUTHOR]

In this study we consider the problem of sample size determination for clustered count data based on clustered discrete Weibull regression model. Many papers that deal with sample size calculation for clustered count data have a strong assumption about the dispersion type of the data. Poisson, negative binomial are widely used models however their assumptions are hard to be met in real life. Here we propose to use discrete Weibull regression model which can handle both under and over dispersed type of data for clustered count data when calculating the sample size. We incorporate a random intercept to consider the correlation between the subjects in each cluster. We used the h-likelihood method and Monte Carlo simulation to estimate the required sample size for clustered count data. Extensive simulation study is also performed to examine the effect of the skewness of the data, variance of the random effect and the number of the clusters on calculating the required sample calculation. [ABSTRACT FROM AUTHOR]

Sample size calculations for two (independent) samples are well established and applied in (pre‐)clinical research. When planning several samples, which is common in, for example, preclinical studies, sample size planning tools based on analysis of variance methods are available. Since the underlying effect sizes of these methods are often hard to interpret and to provide for the sample size planning, we employ multiple contrast test procedures for sample size computations in both parametric (under normality assumption) and nonparametric designs using Steel‐type tests. Since the exact distributions of the test statistics are unknown under the alternative and variance heterogeneity, we use approximate solutions. Furthermore, since no closed formula for the sample size is available, we use numerical approximations for their computation. Extensive simulation studies are finally conducted to assess the quality of the approximations. It turns out that the methods are accurate in the sense that the multiple contrast test procedures reach the target power to detect the alternative of interest with the sample size computed. The developed procedures are a valuable tool to plan (pre‐)clinical trials with several samples and are easily accessible in publicly available software. [ABSTRACT FROM AUTHOR]

Abstract Prior research has suggested that clustered regression discontinuity designs are a formidable alternative to cluster randomized designs because they provide targeted treatment assignment while maintaining a high-quality basis for inferences on local treatment effects. However, methods for the design and analysis of clustered regression discontinuity designs have not been fully developed to address the array of core effects (e.g., main, moderation and mediation) typically examined in education studies. In this study, we complement prior design literature by developing principles of estimation, sampling variability, and closed-form expressions to predict the statistical power to detect mediation effects in clustered regression discontinuity designs. The results suggest that sample sizes typically seen in educational intervention studies (e.g., about 50 schools) can be sufficient to detect a mediation effect under some conditions when studies are carefully designed. We implement the results in software and a Shiny App (BLINDED FOR REVIEW). [ABSTRACT FROM AUTHOR]

Sample sizes of Phase 2 dose‐finding studies, usually determined based on a power requirement to detect a significant dose–response relationship, will generally not provide adequate precision for Phase 3 target dose selection. We propose to calculate the sample size of a dose‐finding study based on the probability of successfully identifying the target dose within an acceptable range (e.g., 80%–120% of the target) using the multiple comparison and modeling procedure (MCP‐Mod). With the proposed approach, different design options for the Phase 2 dose‐finding study can also be compared. Due to inherent uncertainty around an assumed true dose–response relationship, sensitivity analyses to assess the robustness of the sample size calculations to deviations from modeling assumptions are recommended. Planning for a hypothetical Phase 2 dose‐finding study is used to illustrate the main points. Codes for the proposed approach is available at https://github.com/happysundae/posMCPMod. [ABSTRACT FROM AUTHOR]

Randomized selection trials are frequently used to compare experimental treatments that have the potential to be beneficial, but they often do not include a control group. While time-to-event endpoints are commonly applied in clinical investigations, methodologies for determining the required sample size for such endpoints, except exponential distribution, are lacking. In recent times, there has been a shift in clinical trials, with a growing emphasis on progression-free survival as a primary endpoint. However, the utilization of this measure has typically been restricted to specific time points for both sample size determination and analysis. This alteration in approach could wield a substantial influence on the clinical trial process, potentially diminishing the capacity to discern variances between treatment groups. In the calculation of sample sizes for randomized trials, this investigation operates under the assumption that the time-to-event endpoint conforms to either an exponential, Weibull, or generalized exponential distribution.

A central goal in designing clinical trials is to find the test that maximizes power (or equivalently minimizes required sample size) for finding a false null hypothesis subject to the constraint of type I error. When there is more than one test, such as in clinical trials with multiple endpoints, the issues of optimal design and optimal procedures become more complex. In this paper, we address the question of how such optimal tests should be defined and how they can be found. We review different notions of power and how they relate to study goals, and also consider the requirements of type I error control and the nature of the procedures. This leads us to an explicit optimization problem with objective and constraints that describe its specific desiderata. We present a complete solution for deriving optimal procedures for two hypotheses, which have desired monotonicity properties, and are computationally simple. For some of the optimization formulations this yields optimal procedures that are identical to existing procedures, such as Hommel's procedure or the procedure of Bittman et al. (2009), while for other cases it yields completely novel and more powerful procedures than existing ones. We demonstrate the nature of our novel procedures and their improved power extensively in a simulation and on the APEX study (Cohen et al., 2016). [ABSTRACT FROM AUTHOR]

Sequential analysis concerns statistical evaluation in which the number, pattern, or composition of the data is not determined at the start of the investigation, but instead depends on the information acquired during the investigation. Although sequential analysis originated in ballistics testing for the Department of Defense (DoD)and it is widely used in other disciplines, it is underutilized in the DoD. Expanding the use of sequential analysis may save money and reduce test time. In this paper, we introduce sequential analysis, describe its current and potential uses in operational test and evaluation (OT&E), and present a method for applying it to the test and evaluation of defense systems. We evaluate the proposed method by performing simulation studies and applying the method to a case study. Additionally, we discuss challenges to address for sequential analysis in OT&E. Lastly, while operational testing is the focus in this paper, the methodology presented is applicable to campaigns of experimentation and general testing across numerous disciplines. [ABSTRACT FROM AUTHOR]

Pragmatic trials evaluating health care interventions often adopt cluster randomization due to scientific or logistical considerations. Systematic reviews have shown that coprimary endpoints are not uncommon in pragmatic trials but are seldom recognized in sample size or power calculations. While methods for power analysis based on K (K≥2$K\ge 2$) binary coprimary endpoints are available for cluster randomized trials (CRTs), to our knowledge, methods for continuous coprimary endpoints are not yet available. Assuming a multivariate linear mixed model (MLMM) that accounts for multiple types of intraclass correlation coefficients among the observations in each cluster, we derive the closed‐form joint distribution of K treatment effect estimators to facilitate sample size and power determination with different types of null hypotheses under equal cluster sizes. We characterize the relationship between the power of each test and different types of correlation parameters. We further relax the equal cluster size assumption and approximate the joint distribution of the K treatment effect estimators through the mean and coefficient of variation of cluster sizes. Our simulation studies with a finite number of clusters indicate that the predicted power by our method agrees well with the empirical power, when the parameters in the MLMM are estimated via the expectation‐maximization algorithm. An application to a real CRT is presented to illustrate the proposed method. [ABSTRACT FROM AUTHOR]

Background: The intracluster correlation coefficient is a key input parameter for sample size determination in cluster-randomised trials. Sample size is very sensitive to small differences in the intracluster correlation coefficient, so it is vital to have a robust intracluster correlation coefficient estimate. This is often problematic because either a relevant intracluster correlation coefficient estimate is not available or the available estimate is imprecise due to being based on small-scale studies with low numbers of clusters. Misspecification may lead to an underpowered or inefficiently large and potentially unethical trial. Methods: We apply a Bayesian approach to produce an intracluster correlation coefficient estimate and hence propose sample size for a planned cluster-randomised trial of the effectiveness of a systematic voiding programme for post-stroke incontinence. A Bayesian hierarchical model is used to combine intracluster correlation coefficient estimates from other relevant trials making use of the wealth of intracluster correlation coefficient information available in published research. We employ knowledge elicitation process to assess the relevance of each intracluster correlation coefficient estimate to the planned trial setting. The team of expert reviewers assigned relevance weights to each study, and each outcome within the study, hence informing parameters of Bayesian modelling. To measure the performance of experts, agreement and reliability methods were applied. Results: The 34 intracluster correlation coefficient estimates extracted from 16 previously published trials were combined in the Bayesian hierarchical model using aggregated relevance weights elicited from the experts. The intracluster correlation coefficients available from external sources were used to construct a posterior distribution of the targeted intracluster correlation coefficient which was summarised as a posterior median with a 95% credible interval informing researchers about the range of plausible sample size values. The estimated intracluster correlation coefficient determined a sample size of between 450 (25 clusters) and 480 (20 clusters), compared to 500–600 from a classical approach. The use of quantiles, and other parameters, from the estimated posterior distribution is illustrated and the impact on sample size described. Conclusion: Accounting for uncertainty in an unknown intracluster correlation coefficient, trials can be designed with a more robust sample size. The approach presented provides the possibility of incorporating intracluster correlation coefficients from various cluster-randomised trial settings which can differ from the planned study, with the difference being accounted for in the modelling. By using expert knowledge to elicit relevance weights and synthesising the externally available intracluster correlation coefficient estimates, information is used more efficiently than in a classical approach, where the intracluster correlation coefficient estimates tend to be less robust and overly conservative. The intracluster correlation coefficient estimate constructed is likely to produce a smaller sample size on average than the conventional strategy of choosing a conservative intracluster correlation coefficient estimate. This may therefore result in substantial time and resources savings. [ABSTRACT FROM AUTHOR]

The idea that medical treatment costs and outcomes might be connected is not new. Likewise, as long as researchers have been designing clinical trials and public opinion polls, there has been interest in the sample size necessary to obtain a desired level of precision and certainty before collecting the data. However, researchers continue to adapt cost-effectiveness models for scenarios of ever-increasing complexity, and equally adaptable sample size determination schemes are required. Of interest for the current study are those instances wherein a non-trivial proportion of patients incur zero costs associated with their treatment. We propose a sample size determination scheme for a cost-effectiveness model fit to such a scenario. Furthermore, we display our method's usefulness on multiple parameter configurations derived from applications presented in already published research. [ABSTRACT FROM AUTHOR]

Non-inferiority vaccine trials compare new candidates to active controls that provide clinically significant protection against a disease. Bayesian statistics allows to exploit pre-experimental information available from previous studies to increase precision and reduce costs. Here, historical knowledge is incorporated into the analysis through a power prior that dynamically regulates the degree of information-borrowing. We examine non-inferiority tests based on credible intervals for the unknown effects-difference between two vaccines on the log odds ratio scale, with an application to new Covid-19 vaccines. We explore the frequentist properties of the method and we address the sample size determination problem. [ABSTRACT FROM AUTHOR]

This paper derives analytic expressions for the expected value of sample information (EVSI), the expected value of distribution information, and the optimal sample size when data consists of independent draws from a bounded sequence of integers. Because of the challenges of creating tractable EVSI expressions, most existing work valuing data does so in one of three ways: (1) analytically through closed-form expressions on the upper bound of the value of data, (2) calculating the expected value of data using numerical comparisons of decisions made using simulated data to optimal decisions for which the underlying data distribution is known, or (3) using variance reduction as proxy for the uncertainty reduction that accompanies more data. For the very flexible case of modeling integer-valued observations using a multinomial data-generating process with Dirichlet prior, this paper develops expressions that (1) generalize existing beta-binomial computations, (2) do not require prior knowledge of some underlying "true" distribution, and (3) can be computed prior to the collection of any sample data. [ABSTRACT FROM AUTHOR]

In conceptual properties norming studies (CPNs), participants list properties that describe a set of concepts. From CPNs, many different parameters are calculated, such as semantic richness. A generally overlooked issue is that those values are only point estimates of the true unknown population parameters. In the present work, we present an R package that allows us to treat those values as population parameter estimates. Relatedly, a general practice in CPNs is using an equal number of participants who list properties for each concept (i.e., standardizing sample size). As we illustrate through examples, this procedure has negative effects on data's statistical analyses. Here, we argue that a better method is to standardize coverage (i.e., the proportion of sampled properties to the total number of properties that describe a concept), such that a similar coverage is achieved across concepts. When standardizing coverage rather than sample size, it is more likely that the set of concepts in a CPN all exhibit a similar representativeness. Moreover, by computing coverage the researcher can decide whether the CPN reached a sufficiently high coverage, so that its results might be generalizable to other studies. The R package we make available in the current work allows one to compute coverage and to estimate the necessary number of participants to reach a target coverage. We show this sampling procedure by using the R package on real and simulated CPN data. [ABSTRACT FROM AUTHOR]

Computational models that formalize complex human behaviors enable study and understanding of such behaviors. However, collecting behavior data required to estimate the parameters of such models is often tedious and resource intensive. Thus, estimating dataset size as part of data collection planning (also known as Sample Size Determination) is important to reduce the time and effort of behavior data collection while maintaining an accurate estimate of model parameters. In this article, we present a sample size determination method based on Uncertainty Quantification (UQ) for a specific Inverse Reinforcement Learning (IRL) model of human behavior, in two cases: (1) pre-hoc experiment design—conducted in the planning stage before any data is collected, to guide the estimation of how many samples to collect; and (2) post-hoc dataset analysis— performed after data is collected, to decide if the existing dataset has sufficient samples and whether more data is needed. We validate our approach in experiments with a realistic model of behaviors of people withMultiple Sclerosis (MS) and illustrate how to pick a reasonable sample size target. Our work enables model designers to perform a deeper, principled investigation of the effects of dataset size on IRL model parameters. [ABSTRACT FROM AUTHOR]

Abstract Background Bayesian methods are increasing in popularity in clinical research. The design of Bayesian clinical trials requires a prior distribution, which can be elicited from experts. In diseases with international differences in management, the elicitation exercise should recruit internationally, making a face-to-face elicitation session expensive and more logistically challenging. Thus, we used a remote, real-time elicitation exercise to construct prior distributions. These elicited distributions were then used to determine the sample size of the Bronchiolitis in Infants with Placebo Versus Epinephrine and Dexamethasone (BIPED) study, an international randomised controlled trial in the Pediatric Emergency Research Network (PERN). The BIPED study aims to determine whether the combination of epinephrine and dexamethasone, compared to placebo, is effective in reducing hospital admission for infants presenting with bronchiolitis to the emergency department. Methods We developed a Web-based tool to support the elicitation of the probability of hospitalisation for infants with bronchiolitis. Experts participated in online workshops to specify their individual prior distributions, which were aggregated using the equal-weighted linear pooling method. Experts were then invited to provide their comments on the aggregated distribution. The average length criterion determined the BIPED sample size. Results Fifteen paediatric emergency medicine clinicians from Canada, the USA, Australia and New Zealand participated in three workshops to provide their elicited prior distributions. The mean elicited probability of admission for infants with bronchiolitis was slightly lower for those receiving epinephrine and dexamethasone compared to supportive care in the aggregate distribution. There were substantial differences in the individual beliefs but limited differences between North America and Australasia. From this aggregate distribution, a sample size of 410 patients per arm results in an average 95% credible interval length of less than 9% and a relative predictive power of 90%. Conclusion Remote, real-time expert elicitation is a feasible, useful and practical tool to determine a prior distribution for international randomised controlled trials. Bayesian methods can then determine the trial sample size using these elicited prior distributions. The ease and low cost of remote expert elicitation mean that this approach is suitable for future international randomised controlled trials. Trial registration ClinicalTrials.gov NCT03567473

In a sequential hypothesis test, the analyst checks at multiple steps during data collection whether sufficient evidence has accrued to make a decision about the tested hypotheses. As soon as sufficient information has been obtained, data collection is terminated. Here, we compare two sequential hypothesis testing procedures that have recently been proposed for use in psychological research: Sequential Probability Ratio Test (SPRT; Psychological Methods, 25(2), 206–226, 2020) and the Sequential Bayes Factor Test (SBFT; Psychological Methods, 22(2), 322–339, 2017). We show that although the two methods have different philosophical roots, they share many similarities and can even be mathematically regarded as two instances of an overarching hypothesis testing framework. We demonstrate that the two methods use the same mechanisms for evidence monitoring and error control, and that differences in efficiency between the methods depend on the exact specification of the statistical models involved, as well as on the population truth. Our simulations indicate that when deciding on a sequential design within a unified sequential testing framework, researchers need to balance the needs of test efficiency, robustness against model misspecification, and appropriate uncertainty quantification. We provide guidance for navigating these design decisions based on individual preferences and simulation-based design analyses. [ABSTRACT FROM AUTHOR]

Studies with sensitive questions should include a sufficient number of respondents to adequately address the research interest. While studies with an inadequate number of respondents may not yield significant conclusions, studies with an excess of respondents become wasteful of investigators' budget. Therefore, it is an important step in survey sampling to determine the required number of participants. In this article, we derive sample size formulas based on confidence interval estimation of prevalence for four randomized response models, namely, the Warner's randomized response model, unrelated question model, item count technique model and cheater detection model. Specifically, our sample size formulas control, with a given assurance probability, the width of a confidence interval within the planned range. Simulation results demonstrate that all formulas are accurate in terms of empirical coverage probabilities and empirical assurance probabilities. All formulas are illustrated using a real-life application about the use of unethical tactics in negotiation. [ABSTRACT FROM AUTHOR]

In this article, we lay out the basic elements of Bayesian sample size determination (SSD) for the Bayesian design of a two-arm superiority clinical trial. We develop a flowchart of the Bayesian SSD that highlights the critical components of a Bayesian design and provides a practically useful roadmap for designing a Bayesian clinical trial in real world applications. We empirically examine the amount of borrowing, the choice of noninformative priors, and the impact of model misspecification on the Bayesian Type I error and power. A formal and statistically rigorous formulation of conditional borrowing within the decision rule framework is developed. Moreover, by extending the partial borrowing power priors, a new borrowing-by-parts power prior for incorporating historical data is proposed. Computational algorithms are also developed to calculate the Bayesian Type I error and power. Extensive simulation studies are carried out to explore the operating characteristics of the proposed Bayesian design of a superiority trial. [ABSTRACT FROM AUTHOR]

We address sampling design of population pharmacokinetics (popPK) experiments in the context of two phase 2b efficacy trials that evaluate the efficacy of VRC01 (vs. placebo) in reducing the rate of HIV infection among 4625 participants. Blood samples are collected at up to 22 study visits from all participants for immediate HIV diagnosis as the primary trial outcome, and stored for future outcome-dependent marker measurements. A key secondary objective of the trials is to evaluate correlates of prevention efficacy among a subcohort of VRC01 recipients in terms of whether the current value of VRC01 serum concentration is associated with the instantaneous rate of HIV infection. To accomplish this, concentrations on a daily grid are estimated via nonlinear mixed effects popPK modeling of observed 4-weekly concentrations. Given the impracticality of measuring concentrations in all stored blood samples, we devised a simulation-based sampling design framework to evaluate the impact of subcohort sample sizes (m) and sampling schemes of time-points on the accuracy and precision of the popPK model parameters. We accounted for specific study schedules and heterogeneity in participants' characteristics and study adherence patterns. We found that with m = 120, reasonably unbiased and consistent estimates of most fixed and random effect terms could be obtained without complete sampling of all 22 time-points, even under low study adherence (about half of the 4-weekly visits missing per participant). The described simulation framework is not only novel in its application to popPK sampling design for studying correlates of prevention efficacy in a subcohort of the parent trial, but also flexible in accommodating real-life study setup options, and can be generalized to other single- or multiple-dose PK sampling design settings. [ABSTRACT FROM AUTHOR]

A three-arm non-inferiority trial including a test treatment, a reference treatment, and a placebo is recommended to assess the assay sensitivity and internal validity of a trial when applicable. Existing methods for designing and analyzing three-arm trials with binary endpoints are mainly developed from a frequentist viewpoint. However, these methods largely depend on large sample theories. To alleviate this problem, we propose two fully Bayesian approaches, the posterior variance approach and Bayes factor approach, to determine sample size required in a three-arm non-inferiority trial with binary endpoints. Simulation studies are conducted to investigate the performance of the proposed Bayesian methods. An example is illustrated by the proposed methodologies. Bayes factor method always leads to smaller sample sizes than the posterior variance method, utilizing the historical data can reduce the required sample size, simultaneous test requires more sample size to achieve the desired power than the non-inferiority test, the selection of the hyperparameters has a relatively large effect on the required sample size. When only controlling the posterior variance, the posterior variance criterion is a simple and effective option for obtaining a rough outcome. When conducting a previous clinical trial, it is recommended to use the Bayes factor criterion in practical applications. [ABSTRACT FROM AUTHOR]

The criteria used for sample size determination are generally developed based on applying averaging techniques to the possible values a variable can take on. This paper presented new methods for estimation of sample size, in particular for binomial distribution, when an observation on number of successes is available. In this paper, first, the general criteria for the determination of sample size were reviewed. Next, the BDLM process was concisely introduced and fit to the first real-world dataset. Then, based on the model, four new methods for the estimation of the missing total number of trials in binomial time series were developed with the illustrated small dataset, where number of successes at any specific time point was known. In addition, the worst outcome criterion was evaluated based on the highest probability density (HPD) confidence set by using the illustrated data and the results were compared with those of the new methods developed in the present paper. Later, an illustration of COVID-19 trinomial data was presented in which BDLM was fit to the time series of cured cases infected due to COVID-19 disease. Finally, the new methods of estimation of missing total confirmed cases evaluated by the relatively large dataset. [ABSTRACT FROM AUTHOR]

Stepped wedge cluster randomized trials enable rigorous evaluations of health intervention programs in pragmatic settings. In the present study, we aimed to update neurosurgeon scientists on the design of stepped wedge randomized trials. We have presented an overview of recent methodological developments for stepped wedge designs and included an update on the newer associated methodological tools to aid with future study designs. We defined the stepped wedge trial design and reviewed the indications for the design in depth. In addition, key considerations, including mainstream methods of analysis and sample size determination, were discussed. Stepped wedge designs can be attractive for study intervention programs aiming to improve the delivery of patient care, especially when examining a small number of heterogeneous clusters. [ABSTRACT FROM AUTHOR]

The paper addresses estimating and testing treatment effects with multivariate outcomes in clinical trials where imperfect diagnostic devices are used to assign subjects to treatment groups. The paper focuses on the pre‐post design and proposes two novel methods for estimating and testing treatment effects. In addition, methods for sample size and power calculations are developed. The methods are compared with each other and with a traditional method in a simulation study. The new methods show significant advantages in terms of power, coverage probability, and required sample size. The application of the methods is illustrated with data from electroencephalogram (EEG) recordings of alcoholic and control subjects. [ABSTRACT FROM AUTHOR]

Background: Bayesian methods are increasing in popularity in clinical research. The design of Bayesian clinical trials requires a prior distribution, which can be elicited from experts. In diseases with international differences in management, the elicitation exercise should recruit internationally, making a face-to-face elicitation session expensive and more logistically challenging. Thus, we used a remote, real-time elicitation exercise to construct prior distributions. These elicited distributions were then used to determine the sample size of the Bronchiolitis in Infants with Placebo Versus Epinephrine and Dexamethasone (BIPED) study, an international randomised controlled trial in the Pediatric Emergency Research Network (PERN). The BIPED study aims to determine whether the combination of epinephrine and dexamethasone, compared to placebo, is effective in reducing hospital admission for infants presenting with bronchiolitis to the emergency department.Methods: We developed a Web-based tool to support the elicitation of the probability of hospitalisation for infants with bronchiolitis. Experts participated in online workshops to specify their individual prior distributions, which were aggregated using the equal-weighted linear pooling method. Experts were then invited to provide their comments on the aggregated distribution. The average length criterion determined the BIPED sample size.Results: Fifteen paediatric emergency medicine clinicians from Canada, the USA, Australia and New Zealand participated in three workshops to provide their elicited prior distributions. The mean elicited probability of admission for infants with bronchiolitis was slightly lower for those receiving epinephrine and dexamethasone compared to supportive care in the aggregate distribution. There were substantial differences in the individual beliefs but limited differences between North America and Australasia. From this aggregate distribution, a sample size of 410 patients per arm results in an average 95% credible interval length of less than 9% and a relative predictive power of 90%.Conclusion: Remote, real-time expert elicitation is a feasible, useful and practical tool to determine a prior distribution for international randomised controlled trials. Bayesian methods can then determine the trial sample size using these elicited prior distributions. The ease and low cost of remote expert elicitation mean that this approach is suitable for future international randomised controlled trials.Trial Registration: ClinicalTrials.gov NCT03567473. [ABSTRACT FROM AUTHOR]

In Bayesian inference, prior distributions formalize preexperimental information and uncertainty on model parameters. Sometimes different sources of knowledge are available, possibly leading to divergent posterior distributions and inferences. Research has been recently devoted to the development of sample size criteria that guarantee agreement of posterior information in terms of credible intervals when multiple priors are available. In these articles, the goals of reaching consensus and evidence are typically kept separated. Adopting a Bayesian performance‐based approach, the present article proposes new sample size criteria for superiority trials that jointly control the achievement of both minimal evidence and consensus, measured by appropriate functions of the posterior distributions. We develop both an average criterion and a more stringent criterion that accounts for the entire predictive distributions of the selected measures of minimal evidence and consensus. Methods are developed and illustrated via simulation for trials involving binary outcomes. A real clinical trial example on Covid‐19 vaccine data is presented. [ABSTRACT FROM AUTHOR]

Abstract–It is common for clinical trials to include strata of patients with different risks of disease. In cancer trial settings, patients with different prior treatment history, tumor stages, metastatic sites may be included in a single trial. This is especially so for early phase studies that are exploratory in nature. In many cases, patient responses from these strata may be ordered. For example, earlier stage patients should have better outcomes than later stage patients. Incorporating such stratum information can lead to increased statistical efficiency and therefore possibly reduce sample sizes. Recent works have begun to deal with this issue for single-arm phase II cancer trials in terms of sample size determination. However, no approaches yet exist to explicitly consider the order constraint. In this article, we propose to use likelihood ratio tests with order constraints for both one-stage and two-stage designs. Our numerical results show that the proposed designs tend to have better power profiles compared with existing methods. A real application of our method to an ongoing phase II study is also included. [ABSTRACT FROM AUTHOR]

In Bayesian decision theory, the performance of an action is measured by its posterior expected loss. In some cases it may be convenient/necessary to use a non-optimal decision instead of the optimal one. In these cases it is important to quantify the additional loss we incur and evaluate whether to use the non-optimal decision or not. In this article we study the predictive probability distribution of a relative measure of the additional loss and its use to define sample size determination criteria in a general testing set-up. [ABSTRACT FROM AUTHOR]

The matching problem is known since the beginning of the eighteenth century and Bayesian solutions have been proposed. In this paper, we present a Bayesian analysis of an experiment that also leads to the matching problem. Since in this paper we consider the order in which assignments are made and not only the number of matches, our approach is different from the literature on this problem. Our approach also considers that it is possible to have different abilities for the different objects that will be guessed. Hence, we have a parameter that measures the matching ability for each specific object or assignment. As a consequence, we need to have some replicates of the experiment and a prior distribution for each of the parameters. Conjugate prior distributions for the parameters are discussed. The frequentist solution has a particular Bayesian interpretation under a non-informative prior distribution. A real data set is analyzed using the proposed methodology. [ABSTRACT FROM AUTHOR]

Mediation analyses supply a principal lens to probe the pathways through which a treatment acts upon an outcome because they can dismantle and test the core components of treatments and test how these components function as a coordinated system or theory of action. Experimental evaluation of mediation effects in addition to total effects has become increasingly common but literature has developed only limited guidance on how to plan mediation studies with multi-tiered hierarchical or clustered structures. In this study, we provide methods for computing the power to detect mediation effects in three-level cluster-randomized designs that examine individual- (level one), intermediate- (level two) or cluster-level (level three) mediators. We assess the methods using a simulation and provide examples of a three-level clinic-randomized study (individuals nested within therapists nested within clinics) probing an individual-, intermediate- or cluster-level mediator using the R package PowerUpR and its Shiny application. [ABSTRACT FROM AUTHOR]

Bayesian statistics has been widely utilized as an approach that can incorporate prior knowledge into statistical inference. Tolerance intervals (TI) are the most commonly used statistical methods for product quality assurance. There are two main Bayesian approaches for calculating statistical tolerance intervals: Hamada and Wolfinger. A simulation-based approach was implemented to compare two-sided Wolfinger, Hamada, and frequentist tolerance intervals which control the probability content at a specified level of confidence. As sample sizes increase, compared to frequentist, Hamada TI become more conservative while Wolfinger TI are more liberal. To address this issue, we propose an empirical weighted Bayesian TI approach that is a compromise between Hamada and Wolfinger approaches. The proposed Bayesian TI result in narrower limits in certain scenarios while ensuring the confidence content coverage remains comparable to frequentist. [ABSTRACT FROM AUTHOR]

Conceptual properties norming studies (CPNs) ask participants to produce properties that describe concepts. From that data, different metrics may be computed (e.g., semantic richness, similarity measures), which are then used in studying concepts and as a source of carefully controlled stimuli for experimentation. Notwithstanding those metrics' demonstrated usefulness, researchers have customarily overlooked that they are only point estimates of the true unknown population values, and therefore, only rough approximations. Thus, though research based on CPN data may produce reliable results, those results are likely to be general and coarse-grained. In contrast, we suggest viewing CPNs as parameter estimation procedures, where researchers obtain only estimates of the unknown population parameters. Thus, more specific and fine-grained analyses must consider those parameters' variability. To this end, we introduce a probabilistic model from the field of ecology. Its related statistical expressions can be applied to compute estimates of CPNs' parameters and their corresponding variances. Furthermore, those expressions can be used to guide the sampling process. The traditional practice in CPN studies is to use the same number of participants across concepts, intuitively believing that practice will render the computed metrics comparable across concepts and CPNs. In contrast, the current work shows why an equal number of participants per concept is generally not desirable. Using CPN data, we show how to use the equations and discuss how they may allow more reasonable analyses and comparisons of parameter values among different concepts in a CPN, and across different CPNs. [ABSTRACT FROM AUTHOR]

Summary: In assessing biosimilarity between two products, the question to ask is always "How similar is similar?" Traditionally, the equivalence of the means between products is the primary consideration in a clinical trial. This study suggests an alternative assessment for testing a certain percentage of the population of differences lying within a prespecified interval. In doing so, the accuracy and precision are assessed simultaneously by judging whether a two‐sided tolerance interval falls within a prespecified acceptance range. We further derive an asymptotic distribution of the tolerance limits to determine the sample size for achieving a targeted level of power. Our numerical study shows that the proposed two‐sided tolerance interval test controls the type I error rate and provides sufficient power. A real example is presented to illustrate our proposed approach. [ABSTRACT FROM AUTHOR]

This article investigates the homogeneity testing problem of binomial proportions for stratified partially validated data obtained by double-sampling method with two fallible classifiers. Several test procedures, including the weighted-least-squares test with/without log-transformation, logit-transformation and double log-transformation, and likelihood ratio test and score test, are developed to test the homogeneity under two models, distinguished by conditional independence assumption of two classifiers. Simulation results show that score test performs better than other tests in the sense that the empirical size is generally controlled around the nominal level, and hence be recommended to practical applications. Other tests also perform well when both binomial proportions and sample sizes are not small. Approximate sample sizes based on score test, likelihood ratio test and the weighted-least-squares test with double log-transformation are generally accurate in terms of the empirical power and type I error rate with the estimated sample sizes, and hence be recommended. An example from the malaria study is illustrated by the proposed methodologies. [ABSTRACT FROM AUTHOR]

Traditionally, asymptotic tests are studied and applied under local alternative. There exists a widespread opinion that the Wald, likelihood ratio, and score tests are asymptotically equivalent. We dispel this myth by showing that These tests have different statistical power in the presence of nuisance parameters. The local properties of the tests are described in terms of the first and second derivative evaluated at the null hypothesis. The comparison of the tests are illustrated with two popular regression models: linear regression with random predictor and logistic regression with binary covariate. We study the aberrant behavior of the tests when the distance between the null and alternative does not vanish with the sample size. We demonstrate that these tests have different asymptotic power. In particular, the score test is generally asymptotically biased but slightly superior for linear regression in a close neighborhood of the null. The power approximations are confirmed through simulations. [ABSTRACT FROM AUTHOR]

Abstract Background Sample size planning for longitudinal data is crucial when designing mediation studies because sufficient statistical power is not only required in grant applications and peer-reviewed publications, but is essential to reliable research results. However, sample size determination is not straightforward for mediation analysis of longitudinal design. Methods To facilitate planning the sample size for longitudinal mediation studies with a multilevel mediation model, this article provides the sample size required to achieve 80% power by simulations under various sizes of the mediation effect, within-subject correlations and numbers of repeated measures. The sample size calculation is based on three commonly used mediation tests: Sobel’s method, distribution of product method and the bootstrap method. Results Among the three methods of testing the mediation effects, Sobel’s method required the largest sample size to achieve 80% power. Bootstrapping and the distribution of the product method performed similarly and were more powerful than Sobel’s method, as reflected by the relatively smaller sample sizes. For all three methods, the sample size required to achieve 80% power depended on the value of the ICC (i.e., within-subject correlation). A larger value of ICC typically required a larger sample size to achieve 80% power. Simulation results also illustrated the advantage of the longitudinal study design. The sample size tables for most encountered scenarios in practice have also been published for convenient use. Conclusions Extensive simulations study showed that the distribution of the product method and bootstrapping method have superior performance to the Sobel’s method, but the product method was recommended to use in practice in terms of less computation time load compared to the bootstrapping method. A R package has been developed for the product method of sample size determination in mediation longitudinal study design.

Specific plasma proteins serve as valuable markers for various diseases and are in many cases routinely measured in clinical laboratories by fully automated systems. For safe diagnostics and monitoring using these markers, it is important to ensure an analytical quality in line with clinical needs. For this purpose, information on the analytical and the biological variation of the measured plasma protein, also in the context of the discovery and validation of novel, disease protein biomarkers, is important, particularly in relation to for sample size calculations in clinical studies. Nevertheless, information on the biological variation of the majority of medium-to-high abundant plasma proteins is largely absent. In this study, we hypothesized that it is possible to generate data on inter-individual biological variation in combination with analytical variation of several hundred abundant plasma proteins, by applying LC-MS/MS in combination with relative quantification using isobaric tagging (10-plex TMT-labeling) to plasma samples. Using this analytical proteomic approach, we analyzed 42 plasma samples prepared in doublets, and estimated the technical, inter-individual biological, and total variation of 265 of the most abundant proteins present in human plasma thereby creating the prerequisites for power analysis and sample size determination in future clinical proteomics studies. Our results demonstrated that only five samples per group may provide sufficient statistical power for most of the analyzed proteins if relative changes in abundances >1.5-fold are expected. Seventeen of the measured proteins are present in the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Biological Variation Database, and demonstrated remarkably similar biological CV’s to the corresponding CV’s listed in the EFLM database suggesting that the generated proteomic determined variation knowledge is useful for large-scale determination of plasma protein variations.

SUMMARY: The feasibility of a new clinical trial may be increased by incorporating historical data of previous trials. In the particular case where only data from a single historical trial are available, there exists no clear recommendation in the literature regarding the most favorable approach. A main problem of the incorporation of historical data is the possible inflation of the type I error rate. A way to control this type of error is the so‐called power prior approach. This Bayesian method does not "borrow" the full historical information but uses a parameter 0 ≤ δ ≤ 1 to determine the amount of borrowed data. Based on the methodology of the power prior, we propose a frequentist framework that allows incorporation of historical data from both arms of two‐armed trials with binary outcome, while simultaneously controlling the type I error rate. It is shown that for any specific trial scenario a value δ > 0 can be determined such that the type I error rate falls below the prespecified significance level. The magnitude of this value of δ depends on the characteristics of the data observed in the historical trial. Conditionally on these characteristics, an increase in power as compared to a trial without borrowing may result. Similarly, we propose methods how the required sample size can be reduced. The results are discussed and compared to those obtained in a Bayesian framework. Application is illustrated by a clinical trial example. [ABSTRACT FROM AUTHOR]

A disease prevalence can be estimated by classifying subjects according to whether they have the disease. When gold-standard tests are too expensive to be applied to all subjects, partially validated data can be obtained by double-sampling in which all individuals are classified by a fallible classifier, and some of individuals are validated by the gold-standard classifier. However, it could happen in practice that such infallible classifier does not available. In this article, we consider two models in which both classifiers are fallible and propose four asymptotic test procedures for comparing disease prevalence in two groups. Corresponding sample size formulae and validated ratio given the total sample sizes are also derived and evaluated. Simulation results show that (i) Score test performs well and the corresponding sample size formula is also accurate in terms of the empirical power and size in two models; (ii) the Wald test based on the variance estimator with parameters estimated under the null hypothesis outperforms the others even under small sample sizes in Model II, and the sample size estimated by this test is also accurate; (iii) the estimated validated ratios based on all tests are accurate. The malarial data are used to illustrate the proposed methodologies. [ABSTRACT FROM AUTHOR]