Statistics in Medicine最新文献

In observational health services research, researchers often use clustered data to estimate the independent association between individual outcomes and several cluster-level covariates after adjusting for individual-level characteristics. Generalized estimating equations are a popular method for estimating generalized linear models using clustered data. The conventional Liang-Zeger variance estimator is known to result in estimated standard errors that are biased low when the number of clusters in small. Alternative variance estimators have been proposed for use when the number of clusters is low. Previous studies focused on these alternative variance estimators in the context of cluster randomized trials, which are often characterized by a small number of clusters and by an outcomes regression model that often consists of a single cluster-level variable (the treatment/exposure variable). We addressed the following questions: (i) which estimator is preferred for estimating the standard errors of cluster-level covariates for logistic regression models with multiple binary and continuous cluster-level variables in addition to subject-level variables; (ii) in such settings, how many clusters are required for the Liang-Zeger variance estimator to have acceptable performance for estimating the standard errors of cluster-level covariates. We suggest that when estimating standard errors: (i) when the number of clusters is < 15 use the Kauermann-Carroll estimator; (ii) when the number of clusters is between 15 and 40 use the Fay-Graubard estimator; (iii) when the number of clusters exceeds 40, use the Liang-Zeger estimator or the Fay-Graubard estimator. When estimating confidence intervals, we suggest using the Mancl-DeRouen estimator with a t-distribution.

This study presents a hybrid (Bayesian-frequentist) approach to sample size re-estimation (SSRE) for cluster randomised trials with continuous outcome data, allowing for uncertainty in the intra-cluster correlation (ICC). In the hybrid framework, pre-trial knowledge about the ICC is captured by placing a Truncated Normal prior on it, which is then updated at an interim analysis using the study data, and used in expected power control. On average, both the hybrid and frequentist approaches mitigate against the implications of misspecifying the ICC at the trial's design stage. In addition, both frameworks lead to SSRE designs with approximate control of the type I error-rate at the desired level. It is clearly demonstrated how the hybrid approach is able to reduce the high variability in the re-estimated sample size observed within the frequentist framework, based on the informativeness of the prior. However, misspecification of a highly informative prior can cause significant power loss. In conclusion, a hybrid approach could offer advantages to cluster randomised trials using SSRE. Specifically, when there is available data or expert opinion to help guide the choice of prior for the ICC, the hybrid approach can reduce the variance of the re-estimated required sample size compared to a frequentist approach. As SSRE is unlikely to be employed when there is substantial amounts of such data available (ie, when a constructed prior is highly informative), the greatest utility of a hybrid approach to SSRE likely lies when there is low-quality evidence available to guide the choice of prior.

Background: Outcome measures that are count variables with excessive zeros are common in health behaviors research. Examples include the number of standard drinks consumed or alcohol-related problems experienced over time. There is a lack of empirical data about the relative performance of prevailing statistical models for assessing the efficacy of interventions when outcomes are zero-inflated, particularly compared with recently developed marginalized count regression approaches for such data.

Methods: The current simulation study examined five commonly used approaches for analyzing count outcomes, including two linear models (with outcomes on raw and log-transformed scales, respectively) and three prevailing count distribution-based models (ie, Poisson, negative binomial, and zero-inflated Poisson (ZIP) models). We also considered the marginalized zero-inflated Poisson (MZIP) model, a novel alternative that estimates the overall effects on the population mean while adjusting for zero-inflation. Motivated by alcohol misuse prevention trials, extensive simulations were conducted to evaluate and compare the statistical power and Type I error rate of the statistical models and approaches across data conditions that varied in sample size ( $N=100$ to 500), zero rate (0.2 to 0.8), and intervention effect sizes.

Results: Under zero-inflation, the Poisson model failed to control the Type I error rate, resulting in higher than expected false positive results. When the intervention effects on the zero (vs. non-zero) and count parts were in the same direction, the MZIP model had the highest statistical power, followed by the linear model with outcomes on the raw scale, negative binomial model, and ZIP model. The performance of the linear model with a log-transformed outcome variable was unsatisfactory.

Conclusions: The MZIP model demonstrated better statistical properties in detecting true intervention effects and controlling false positive results for zero-inflated count outcomes. This MZIP model may serve as an appealing analytical approach to evaluating overall intervention effects in studies with count outcomes marked by excessive zeros.

Intercurrent events and estimands play a key role in defining the treatment effects of interest precisely. Sometimes the median or other quantiles of outcomes in a principal stratum according to potential occurrence of intercurrent events are of interest in randomized clinical trials. Naïve analyses such as those based on the observed occurrence of the intercurrent events lead to biased results. Therefore, we propose principal quantile treatment effect estimators that can nonparametrically estimate the distribution of potential outcomes by principal score weighting without relying on the exclusion restriction assumption. Our simulation studies show that the proposed method works in situations where the median or quantiles may be regarded as the preferred population-level summary over the mean. We illustrate our proposed method by using data from a randomized controlled trial conducted on patients with nonerosive reflux disease.

In medical research, the accuracy of data from electronic medical records (EMRs) is critical, particularly when analyzing dense functional data, where anomalies can severely compromise research integrity. Anomalies in EMRs often arise from human errors in data measurement and entry, and increase in frequency with the volume of data. Despite the established methods in computer science, anomaly detection in medical applications remains underdeveloped. We address this deficiency by introducing a novel tool for identifying and correcting anomalies specifically in dense functional EMR data. Our approach utilizes studentized residuals from a mean-shift model, and therefore assumes that the data adheres to a smooth functional trajectory. Additionally, our method is tailored to be conservative, focusing on anomalies that signify actual errors in the data collection process while controlling for false discovery rates and type II errors. To support widespread implementation, we provide a comprehensive R package, ensuring that our methods can be applied in diverse settings. Our methodology's efficacy has been validated through rigorous simulation studies and real-world applications, confirming its ability to accurately identify and correct errors, thus enhancing the reliability and quality of medical data analysis.

Mild cognitive impairment (MCI) is a prodromal stage of Alzheimer's disease (AD) that causes a significant burden in caregiving and medical costs. Clinically, the diagnosis of MCI is determined by the impairment statuses of five cognitive domains. If one of these cognitive domains is impaired, the patient is diagnosed with MCI, and if two out of the five domains are impaired, the patient is diagnosed with AD. In medical records, most of the time, the diagnosis of MCI/AD is given, but not the statuses of the five domains. We may treat the domain statuses as missing variables. This diagnostic procedure relates MCI/AD status modeling to multiple-instance learning, where each domain resembles an instance. However, traditional multiple-instance learning assumes common predictors among instances, but in our case, each domain is associated with different predictors. In this article, we generalized the multiple-instance logistic regression to accommodate the heterogeneity in predictors among different instances. The proposed model is dubbed heterogeneous-instance logistic regression and is estimated via the expectation-maximization algorithm because of the presence of the missing variables. We also derived two variants of the proposed model for the MCI and AD diagnoses. The proposed model is validated in terms of its estimation accuracy, latent status prediction, and robustness via extensive simulation studies. Finally, we analyzed the National Alzheimer's Coordinating Center-Uniform Data Set using the proposed model and demonstrated its potential.

Subsampling is a practical strategy for analyzing vast survival data, which are progressively encountered across diverse research domains. While the optimal subsampling method has been applied to inferences for Cox models and parametric accelerated failure time (AFT) models, its application to semi-parametric AFT models with rank-based estimation have received limited attention. The challenges arise from the non-smooth estimating function for regression coefficients and the seemingly zero contribution from censored observations in estimating functions in the commonly seen form. To address these challenges, we develop optimal subsampling probabilities for both event and censored observations by expressing the estimating functions through a well-defined stochastic process. Meanwhile, we apply an induced smoothing procedure to the non-smooth estimating functions. As the optimal subsampling probabilities depend on the unknown regression coefficients, we employ a two-step procedure to obtain a feasible estimation method. An additional benefit of the method is its ability to resolve the issue of underestimation of the variance when the subsample size approaches the full sample size. We validate the performance of our estimators through a simulation study and apply the methods to analyze the survival time of lymphoma patients in the surveillance, epidemiology, and end results program.

Motivated by the experience of COVID-19 trials, we consider clinical trials in the setting of an emerging disease in which the uncertainty of natural disease course and potential treatment effects makes advance specification of a sample size challenging. One approach to such a challenge is to use a group sequential design to allow the trial to stop on the basis of interim analysis results as soon as a conclusion regarding the effectiveness of the treatment under investigation can be reached. As such a trial may be halted before a formal stopping boundary is reached, we consider the final analysis under such a scenario, proposing alternative methods for when the decision to halt the trial is made with or without knowledge of interim analysis results. We address the problems of ensuring that the type I error rate neither exceeds nor falls unnecessarily far below the nominal level. We also propose methods in which there is no maximum sample size, the trial continuing either until the stopping boundary is reached or it is decided to halt the trial.

Understanding the underlying causes of maternal death across all regions of the world is essential to inform policies and resource allocation to reduce the mortality burden. However, in many countries there exists very little data on the causes of maternal death, and data that do exist do not capture the entire population at risk. In this article, we present a Bayesian hierarchical multinomial model to estimate maternal cause of death distributions globally, regionally, and for all countries worldwide. The framework combines data from various sources to inform estimates, including data from civil registration and vital systems, smaller-scale surveys and studies, and high-quality data from confidential enquiries and surveillance systems. The framework accounts for varying data quality and coverage, and allows for situations where one or more causes of death are missing. We illustrate the results of the model on three case-study countries that have different data availability situations.

Regression analyses based on transformations of cumulative incidence functions are often adopted when modeling and testing for treatment effects in clinical trial settings involving competing and semi-competing risks. Common frameworks include the Fine-Gray model and models based on direct binomial regression. Using large sample theory we derive the limiting values of treatment effect estimators based on such models when the data are generated according to multiplicative intensity-based models, and show that the estimand is sensitive to several process features. The rejection rates of hypothesis tests based on cumulative incidence function regression models are also examined for null hypotheses of different types, based on which a robustness property is established. In such settings supportive secondary analyses of treatment effects are essential to ensure a full understanding of the nature of treatment effects. An application to a palliative study of individuals with breast cancer metastatic to bone is provided for illustration.