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A New Mixture Model With Cure Rate Applied to Breast Cancer Data 应用于乳腺癌数据的带有治愈率的新混合模型。
IF 1.3 3区 生物学 Q4 MATHEMATICAL & COMPUTATIONAL BIOLOGY Pub Date : 2024-08-05 DOI: 10.1002/bimj.202300257
Diego I. Gallardo, Márcia Brandão, Jeremias Leão, Marcelo Bourguignon, Vinicius Calsavara

We introduce a new modelling for long-term survival models, assuming that the number of competing causes follows a mixture of Poisson and the Birnbaum-Saunders distribution. In this context, we present some statistical properties of our model and demonstrate that the promotion time model emerges as a limiting case. We delve into detailed discussions of specific models within this class. Notably, we examine the expected number of competing causes, which depends on covariates. This allows for direct modeling of the cure rate as a function of covariates. We present an Expectation-Maximization (EM) algorithm for parameter estimation, to discuss the estimation via maximum likelihood (ML) and provide insights into parameter inference for this model. Additionally, we outline sufficient conditions for ensuring the consistency and asymptotic normal distribution of ML estimators. To evaluate the performance of our estimation method, we conduct a Monte Carlo simulation to provide asymptotic properties and a power study of LR test by contrasting our methodology against the promotion time model. To demonstrate the practical applicability of our model, we apply it to a real medical dataset from a population-based study of incidence of breast cancer in São Paulo, Brazil. Our results illustrate that the proposed model can outperform traditional approaches in terms of model fitting, highlighting its potential utility in real-world scenarios.

我们为长期生存模型引入了一种新的建模方法,假定竞争原因的数量服从泊松分布和伯恩鲍姆-桑德斯分布的混合分布。在此背景下,我们介绍了模型的一些统计特性,并证明晋升时间模型是一种极限情况。我们将详细讨论该类模型中的具体模型。值得注意的是,我们研究了竞争原因的预期数量,这取决于协变量。这样就可以将治愈率作为协变量的函数直接建模。我们提出了一种用于参数估计的期望最大化(EM)算法,以讨论通过最大似然法(ML)进行的估计,并为该模型的参数推断提供见解。此外,我们还概述了确保最大似然估计值一致性和渐近正态分布的充分条件。为了评估我们的估计方法的性能,我们进行了蒙特卡罗模拟,以提供渐近特性,并通过将我们的方法与晋升时间模型进行对比,对 LR 检验进行了功率研究。为了证明模型的实际应用性,我们将其应用于巴西圣保罗乳腺癌发病率人群研究的真实医疗数据集。我们的结果表明,所提出的模型在模型拟合方面优于传统方法,突出了其在现实世界中的潜在用途。
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引用次数: 0
Health Care Provider Clustering Using Fusion Penalty in Quasi-Likelihood 利用准可能性中的融合惩罚对医疗服务提供者进行聚类。
IF 1.3 3区 生物学 Q4 MATHEMATICAL & COMPUTATIONAL BIOLOGY Pub Date : 2024-08-05 DOI: 10.1002/bimj.202300185
Lili Liu, Kevin He, Di Wang, Shujie Ma, Annie Qu, Yihui Luan, J. Philip Miller, Yizhe Song, Lei Liu

There has been growing research interest in developing methodology to evaluate the health care providers' performance with respect to a patient outcome. Random and fixed effects models are traditionally used for such a purpose. We propose a new method, using a fusion penalty to cluster health care providers based on quasi-likelihood. Without any priori knowledge of grouping information, our method provides a desirable data-driven approach for automatically clustering health care providers into different groups based on their performance. Further, the quasi-likelihood is more flexible and robust than the regular likelihood in that no distributional assumption is needed. An efficient alternating direction method of multipliers algorithm is developed to implement the proposed method. We show that the proposed method enjoys the oracle properties; namely, it performs as well as if the true group structure were known in advance. The consistency and asymptotic normality of the estimators are established. Simulation studies and analysis of the national kidney transplant registry data demonstrate the utility and validity of our method.

研究人员对开发评估医疗服务提供者在患者治疗结果方面表现的方法越来越感兴趣。传统上,随机效应和固定效应模型被用于此目的。我们提出了一种新方法,使用融合惩罚来根据准可能性对医疗服务提供者进行分组。在不预先了解分组信息的情况下,我们的方法提供了一种理想的数据驱动方法,可根据医疗服务提供者的表现自动将其分为不同的组别。此外,准似然法比常规似然法更灵活、更稳健,因为它不需要分布假设。为了实现所提出的方法,我们开发了一种高效的交替方向乘法算法。我们证明了所提出的方法具有神谕特性,即它的性能与事先已知的真实群体结构一样好。我们还确定了估计值的一致性和渐近正态性。模拟研究和全国肾移植登记数据分析证明了我们方法的实用性和有效性。
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引用次数: 0
Analysis of Nonconcurrent Controls in Adaptive Platform Trials: Separating Randomized and Nonrandomized Information 自适应平台试验中的非同期对照分析:分离随机和非随机信息。
IF 1.3 3区 生物学 Q4 MATHEMATICAL & COMPUTATIONAL BIOLOGY Pub Date : 2024-08-05 DOI: 10.1002/bimj.202300334
Ian C. Marschner, I. Manjula Schou

Adaptive platform trials allow treatments to be added or dropped during the study, meaning that the control arm may be active for longer than the experimental arms. This leads to nonconcurrent controls, which provide nonrandomized information that may increase efficiency but may introduce bias from temporal confounding and other factors. Various methods have been proposed to control confounding from nonconcurrent controls, based on adjusting for time period. We demonstrate that time adjustment is insufficient to prevent bias in some circumstances where nonconcurrent controls are present in adaptive platform trials, and we propose a more general analytical framework that accounts for nonconcurrent controls in such circumstances. We begin by defining nonconcurrent controls using the concept of a concurrently randomized cohort, which is a subgroup of participants all subject to the same randomized design. We then use cohort adjustment rather than time adjustment. Due to flexibilities in platform trials, more than one randomized design may be in force at any time, meaning that cohort-adjusted and time-adjusted analyses may be quite different. Using simulation studies, we demonstrate that time-adjusted analyses may be biased while cohort-adjusted analyses remove this bias. We also demonstrate that the cohort-adjusted analysis may be interpreted as a synthesis of randomized and indirect comparisons analogous to mixed treatment comparisons in network meta-analysis. This allows the use of network meta-analysis methodology to separate the randomized and nonrandomized components and to assess their consistency. Whenever nonconcurrent controls are used in platform trials, the separate randomized and indirect contributions to the treatment effect should be presented.

自适应平台试验允许在研究过程中增加或减少治疗,这意味着对照组的活动时间可能长于实验组。这就产生了非同期对照组,它们提供的非随机信息可能会提高效率,但也可能带来时间混杂和其他因素造成的偏差。人们提出了各种方法来控制来自非同期对照的混杂因素,这些方法基于对时间段的调整。我们证明,在自适应平台试验中存在非同期对照的某些情况下,时间调整不足以防止偏差,因此我们提出了一个更通用的分析框架,在这种情况下考虑非同期对照。首先,我们使用同期随机队列的概念来定义非同期对照组,即采用相同随机设计的参试者子群。然后,我们使用队列调整而不是时间调整。由于平台试验的灵活性,任何时候都可能有一种以上的随机设计在实施,这意味着队列调整分析和时间调整分析可能会有很大不同。通过模拟研究,我们证明了时间调整分析可能存在偏差,而队列调整分析可以消除这种偏差。我们还证明,队列调整分析可解释为随机和间接比较的综合,类似于网络荟萃分析中的混合治疗比较。这样就可以使用网络荟萃分析方法将随机和非随机成分分开,并评估其一致性。只要在平台试验中使用了非同期对照,就应分别列出随机和间接对治疗效果的贡献。
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引用次数: 0
MTML: An Efficient Multitrait Multilocus GWAS Method Based on the Cauchy Combination Test MTML:基于考奇组合检验的高效多特征多焦点 GWAS 方法
IF 1.3 3区 生物学 Q4 MATHEMATICAL & COMPUTATIONAL BIOLOGY Pub Date : 2024-07-30 DOI: 10.1002/bimj.202300130
Hongping Guo, Tong Li, Yao Shi, Xiao Wang

Genome-wide association study (GWAS) by measuring the joint effect of multiple loci on multiple traits, has recently attracted interest, due to the decreased costs of high-throughput genotyping and phenotyping technologies. Previous studies mainly focused on either multilocus models that identify associations with a single trait or multitrait models that scan a single marker at a time. Since these types of models cannot fully utilize the association information, the powers of the tests are usually low. To potentially address this problem, we present here a multitrait multilocus (MTML) modeling framework that implements in three steps: (1) simplify the complex calculation; (2) reduce the model dimension; (3) integrate the joint contribution of single markers to multiple traits by Cauchy combination. The performances of MTML are evaluated and compared with other three published methods by Monte Carlo simulations. Simulation results show that MTML is more powerful for quantitative trait nucleotide detection and robust for various numbers of traits. In the meanwhile, MTML can effectively control type I error rate at a reasonable level. Real data analysis of Arabidopsis thaliana shows that MTML identifies more pleiotropic genetic associations. Therefore, we conclude that MTML is an efficient GWAS method for joint analysis of multiple quantitative traits. The R package MTML, which facilitates the implementation of the proposed method, is publicly available on GitHub https://github.com/Guohongping/MTML.

全基因组关联研究(GWAS)通过测量多个基因位点对多个性状的联合效应,最近引起了人们的兴趣,原因是高通量基因分型和表型技术的成本降低了。以往的研究主要集中在确定与单个性状关联的多位点模型或一次扫描单个标记的多性状模型。由于这些类型的模型不能充分利用关联信息,因此检验的功率通常较低。为了有可能解决这个问题,我们在此提出了一个多性状多焦点(MTML)建模框架,该框架分三步实现:(1) 简化复杂的计算;(2) 减少模型维度;(3) 通过考奇组合整合单个标记对多个性状的联合贡献。通过蒙特卡罗模拟,对 MTML 的性能进行了评估,并与其他三种已发布的方法进行了比较。模拟结果表明,MTML 在定量性状核苷酸检测方面更强大,而且对不同数量的性状具有鲁棒性。同时,MTML 能有效地将 I 型错误率控制在合理水平。拟南芥的真实数据分析显示,MTML 能识别更多的多向遗传关联。因此,我们认为 MTML 是一种高效的 GWAS 方法,可用于多个数量性状的联合分析。MTML 的 R 软件包可在 GitHub https://github.com/Guohongping/MTML 上公开获取,该软件包有助于实现所提出的方法。
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引用次数: 0
Factor-Analytic Variance–Covariance Structures for Prediction Into a Target Population of Environments 用于预测目标环境人群的因子分析方差-协方差结构。
IF 1.3 3区 生物学 Q4 MATHEMATICAL & COMPUTATIONAL BIOLOGY Pub Date : 2024-07-25 DOI: 10.1002/bimj.202400008
Hans-Peter Piepho, Emlyn Williams

Finlay–Wilkinson regression is a popular method for modeling genotype–environment interaction in plant breeding and crop variety testing. When environment is a random factor, this model may be cast as a factor-analytic variance–covariance structure, implying a regression on random latent environmental variables. This paper reviews such models with a focus on their use in the analysis of multi-environment trials for the purpose of making predictions in a target population of environments. We investigate the implication of random versus fixed effects assumptions, starting from basic analysis-of-variance models, then moving on to factor-analytic models and considering the transition to models involving observable environmental covariates, which promise to provide more accurate and targeted predictions than models with latent environmental variables.

芬莱-威尔金森回归法是植物育种和作物品种测试中模拟基因型-环境交互作用的常用方法。当环境是一个随机因素时,该模型可被视为一个因素分析方差-协方差结构,意味着对随机潜在环境变量的回归。本文回顾了此类模型,重点介绍了它们在多环境试验分析中的应用,目的是对目标环境群体进行预测。我们从基本的方差分析模型入手,研究了随机效应假设与固定效应假设的影响,然后转向因子分析模型,并考虑向涉及可观测环境协变量的模型过渡,这些模型有望提供比潜在环境变量模型更准确、更有针对性的预测。
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引用次数: 0
Issue Information: Biometrical Journal 6'24 发行信息:生物计量学杂志 6'24
IF 1.3 3区 生物学 Q4 MATHEMATICAL & COMPUTATIONAL BIOLOGY Pub Date : 2024-07-22 DOI: 10.1002/bimj.202470006
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引用次数: 0
A Marginalized Zero-Inflated Negative Binomial Model for Spatial Data: Modeling COVID-19 Deaths in Georgia 空间数据的边际零膨胀负二项模型:佐治亚州 COVID-19 死亡建模。
IF 1.3 3区 生物学 Q4 MATHEMATICAL & COMPUTATIONAL BIOLOGY Pub Date : 2024-07-13 DOI: 10.1002/bimj.202300182
Fedelis Mutiso, John L. Pearce, Sara E. Benjamin-Neelon, Noel T. Mueller, Hong Li, Brian Neelon

Spatial count data with an abundance of zeros arise commonly in disease mapping studies. Typically, these data are analyzed using zero-inflated models, which comprise a mixture of a point mass at zero and an ordinary count distribution, such as the Poisson or negative binomial. However, due to their mixture representation, conventional zero-inflated models are challenging to explain in practice because the parameter estimates have conditional latent-class interpretations. As an alternative, several authors have proposed marginalized zero-inflated models that simultaneously model the excess zeros and the marginal mean, leading to a parameterization that more closely aligns with ordinary count models. Motivated by a study examining predictors of COVID-19 death rates, we develop a spatiotemporal marginalized zero-inflated negative binomial model that directly models the marginal mean, thus extending marginalized zero-inflated models to the spatial setting. To capture the spatiotemporal heterogeneity in the data, we introduce region-level covariates, smooth temporal effects, and spatially correlated random effects to model both the excess zeros and the marginal mean. For estimation, we adopt a Bayesian approach that combines full-conditional Gibbs sampling and Metropolis–Hastings steps. We investigate features of the model and use the model to identify key predictors of COVID-19 deaths in the US state of Georgia during the 2021 calendar year.

在疾病绘图研究中,经常会出现大量零点的空间计数数据。通常,这些数据使用零膨胀模型进行分析,该模型由零点质量和普通计数分布(如泊松分布或负二项分布)的混合物组成。然而,由于其混合物表示形式,传统的零膨胀模型在实际解释中具有挑战性,因为参数估计具有条件潜类解释。作为一种替代方法,一些学者提出了边际化零膨胀模型,即同时对多余零点和边际均值建模,从而得到与普通计数模型更接近的参数化。受一项关于 COVID-19 死亡率预测因素的研究的启发,我们建立了一个时空边际化零膨胀负二项模型,直接对边际均值建模,从而将边际化零膨胀模型扩展到空间环境。为了捕捉数据中的时空异质性,我们引入了地区级协变量、平滑时间效应和空间相关随机效应,以建立超额零点和边际均值模型。在估计时,我们采用贝叶斯方法,结合全条件吉布斯采样和 Metropolis-Hastings 步骤。我们研究了该模型的特征,并利用该模型确定了美国佐治亚州 2021 历年 COVID-19 死亡的关键预测因素。
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引用次数: 0
Years of Life Lost to COVID-19 and Related Mortality Indicators: An Illustration in 30 Countries COVID-19 及相关死亡率指标造成的生命损失年数:30 个国家的说明。
IF 1.3 3区 生物学 Q4 MATHEMATICAL & COMPUTATIONAL BIOLOGY Pub Date : 2024-07-13 DOI: 10.1002/bimj.202300386
Valentin Rousson, Isabella Locatelli

The concept of (potential) years of life lost is a measure of premature mortality that can be used to compare the impacts of different specific causes of death. However, interpreting a given number of years of life lost at face value is more problematic because of the lack of a sensible reference value. In this paper, we propose three denominators to divide an excess years of life lost, thus obtaining three indicators, called average life lost, increase of life lost, and proportion of life lost, which should facilitate interpretation and comparisons. We study the links between these three indicators and classical mortality indicators, such as life expectancy and standardized mortality rate, introduce the concept of weighted standardized mortality rate, and calculate them in 30 countries to assess the impact of COVID-19 on mortality in the year 2020. Using any of the three indicators, a significant excess loss is found for both genders in 18 of the 30 countries.

潜在)寿命损失年数的概念是衡量过早死亡率的一个指标,可用来比较不同具体死因的影响。然而,由于缺乏合理的参考值,从表面价值来解释给定的生命损失年数问题较大。在本文中,我们提出了三个分母来划分一个超额寿命损失年数,从而得到三个指标,即平均寿命损失、寿命损失增加和寿命损失比例,这三个指标应有助于解释和比较。我们研究了这三个指标与传统死亡率指标(如预期寿命和标准化死亡率)之间的联系,引入了加权标准化死亡率的概念,并在 30 个国家进行了计算,以评估 COVID-19 对 2020 年死亡率的影响。使用这三个指标中的任何一个,都会发现在 30 个国家中的 18 个国家中,男女两性的超额损失都很大。
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引用次数: 0
Robust Regression Techniques for Multiple Method Comparison and Transformation 用于多种方法比较和转换的稳健回归技术。
IF 1.3 3区 生物学 Q4 MATHEMATICAL & COMPUTATIONAL BIOLOGY Pub Date : 2024-07-13 DOI: 10.1002/bimj.202400027
Florian Dufey

A generalization of Passing–Bablok regression is proposed for comparing multiple measurement methods simultaneously. Possible applications include assay migration studies or interlaboratory trials. When comparing only two methods, the method boils down to the usual Passing–Bablok estimator. It is close in spirit to reduced major axis regression, which is, however, not robust. To obtain a robust estimator, the major axis is replaced by the (hyper-)spherical median axis. This technique has been applied to compare SARS-CoV-2 serological tests, bilirubin in neonates, and an in vitro diagnostic test using different instruments, sample preparations, and reagent lots. In addition, plots similar to the well-known Bland–Altman plots have been developed to represent the variance structure.

为同时比较多种测量方法,提出了 Passing-Bablok 回归的一般化方法。可能的应用包括化验迁移研究或实验室间试验。当只比较两种方法时,该方法可归结为通常的 Passing-Bablok 估计器。它在精神上接近于还原主轴回归,但不稳健。为了获得稳健的估计器,主轴被(超)球面中轴取代。这项技术已被应用于比较 SARS-CoV-2 血清学检测、新生儿胆红素以及使用不同仪器、样品制备和试剂批次的体外诊断检测。此外,还绘制了与著名的布兰-阿尔特曼图类似的图来表示方差结构。
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引用次数: 0
A Shared-Frailty Spatial Scan Statistic Model for Time-to-Event Data 时间-事件数据的共享-弱点空间扫描统计模型。
IF 1.3 3区 生物学 Q4 MATHEMATICAL & COMPUTATIONAL BIOLOGY Pub Date : 2024-07-11 DOI: 10.1002/bimj.202300200
Camille Frévent, Mohamed-Salem Ahmed, Sophie Dabo-Niang, Michaël Genin

Spatial scan statistics are well-known methods widely used to detect spatial clusters of events. Furthermore, several spatial scan statistics models have been applied to the spatial analysis of time-to-event data. However, these models do not take account of potential correlations between the observations of individuals within the same spatial unit or potential spatial dependence between spatial units. To overcome this problem, we have developed a scan statistic based on a Cox model with shared frailty and that takes account of the spatial dependence between spatial units. In simulation studies, we found that (i) conventional models of spatial scan statistics for time-to-event data fail to maintain the type I error in the presence of a correlation between the observations of individuals within the same spatial unit and (ii) our model performed well in the presence of such correlation and spatial dependence. We have applied our method to epidemiological data and the detection of spatial clusters of mortality in patients with end-stage renal disease in northern France.

空间扫描统计是众所周知的方法,被广泛用于检测事件的空间集群。此外,一些空间扫描统计模型已被应用于时间到事件数据的空间分析。然而,这些模型并没有考虑到同一空间单位内个体观测数据之间的潜在相关性,也没有考虑到空间单位之间的潜在空间依赖性。为了解决这个问题,我们开发了一种基于具有共同脆弱性的 Cox 模型的扫描统计量,它考虑到了空间单位之间的空间依赖性。在模拟研究中,我们发现:(i) 用于时间到事件数据的传统空间扫描统计模型,在同一空间单元内的个体观测值之间存在相关性的情况下,无法保持 I 型误差;(ii) 我们的模型在存在这种相关性和空间依赖性的情况下表现良好。我们已将我们的方法应用于流行病学数据和法国北部终末期肾病患者死亡率空间集群的检测。
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引用次数: 0
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Biometrical Journal
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