Biometrics最新文献

Numerous statistical models have been proposed for conducting meta-analysis of diagnostic accuracy studies when a gold standard is available. However, in real-world scenarios, the gold standard test may not be perfect due to several factors such as measurement error, non-availability, invasiveness, or high cost. A generalized linear mixed model (GLMM) is currently recommended to account for an imperfect reference test. We propose vine copula mixed models for meta-analysis of diagnostic test accuracy studies with an imperfect reference standard. Our general models include the GLMM as a special case, can have arbitrary univariate distributions for the random effects, and can provide tail dependencies and asymmetries. Our general methodology is demonstrated with an extensive simulation study and illustrated by insightfully re-analyzing the data of a meta-analysis of the Papanicolaou test that diagnoses cervical neoplasia. Our study suggests that there can be an improvement on GLMM and makes the argument for moving to vine copula random effects models.

Covariate-adaptive randomization (CAR) is widely adopted in clinical trials to ensure balanced treatment allocations across key baseline covariates. Although much research has focused on analyzing average treatment effects, the inference of relative risk under CAR experiments has been less thoroughly explored. In this study, we examine a covariate-adjusted estimate of relative risk and investigate the properties of its associated hypothesis tests under CAR. We first derive the theoretical properties of the covariate-adjusted relative risk for a broad class of CAR procedures. Our findings indicate that conventional tests for relative risk tend to be conservative, leading to reduced type I error rates. To mitigate this issue, we introduce model-based and model-robust methods that enhance the estimation of standard errors. We demonstrate the validity and usage of model-robust and model-based adjusted tests. Extensive numerical studies have been conducted to demonstrate our theoretical findings and the favorable properties of the proposed adjustment methods.

Causal weighted quantile treatment effects (WQTEs) complement standard mean-focused causal contrasts when interest lies at the tails of the counterfactual distribution. However, existing methods for estimating and inferring causal WQTEs assume complete data on all relevant factors, which is often not the case in practice, particularly when the data are not collected for research purposes, such as electronic health records (EHRs) and disease registries. Furthermore, these data may be particularly susceptible to the outcome data being missing-not-at-random (MNAR). This paper proposes to use double sampling, through which the otherwise missing data are ascertained on a sub-sample of study units, as a strategy to mitigate bias due to MNAR data in estimating causal WQTEs. With the additional data, we present identifying conditions that do not require missingness assumptions in the original data. We then propose a novel inverse-probability weighted estimator and derive its asymptotic properties, both pointwise at specific quantiles and uniformly across quantiles over some compact subset of (0,1), allowing the propensity score and double-sampling probabilities to be estimated. For practical inference, we develop a bootstrap method that can be used for both pointwise and uniform inference. A simulation study is conducted to examine the finite sample performance of the proposed estimators. We illustrate the proposed method using EHR data examining the relative effects of 2 bariatric surgery procedures on BMI loss 3 years post-surgery.

Testing differences in mean vectors is a fundamental task in the analysis of high-dimensional microbiome compositional data. Existing methods may suffer from low power if the underlying signal pattern is in a situation that does not favor the deployed test. In this work, we develop 2-sample power-enhanced mean tests for high-dimensional compositional data based on the combination of $P$-values, which integrates strengths from 2 popular types of tests: the maximum-type test and the quadratic-type test. We provide rigorous theoretical guarantees on the proposed tests, showing accurate Type-I error rate control and enhanced testing power. Our method boosts the testing power toward a broader alternative space, which yields robust performance across a wide range of signal pattern settings. Our methodology and theory also contribute to the literature on power enhancement and Gaussian approximation for high-dimensional hypothesis testing. We demonstrate the performance of our method on both simulated data and real-world microbiome data, showing that our proposed approach improves the testing power substantially compared to existing methods.

Pharmacogenomics stands as a pivotal driver toward personalized medicine, aiming to optimize drug efficacy while minimizing adverse effects by uncovering the impact of genetic variations on inter-individual outcome variability. Despite its promise, the intricate landscape of drug metabolism introduces complexity, where the correlation between drug response and genes can be shaped by numerous nongenetic factors, often exhibiting heterogeneity across diverse subpopulations. This challenge is particularly pronounced in datasets such as the International Warfarin Pharmacogenetic Consortium (IWPC), which encompasses diverse patient information from multiple nations. To capture the between-patient heterogeneity in dosing requirement, we formulate a novel change surface model as a model-based approach for multiple subgroup identification in complex datasets. A key feature of our approach is its ability to accommodate nonlinear subgroup divisions, providing a clearer understanding of dynamic drug-gene associations. Furthermore, our model effectively handles high-dimensional data through a doubly penalized approach, ensuring both interpretability and adaptability. We propose an iterative 2-stage method that combines a change point detection technique in the first stage with a smoothed local adaptive majorize-minimization algorithm for surface regression in the second stage. Performance of the proposed methods is evaluated through extensive numerical studies. Application of our method to the IWPC dataset leads to significant new findings, where 3 subgroups subject to different pharmacogenomic relationships are identified, contributing valuable insights into the complex dynamics of drug-gene associations in patients.

When many participants in a randomized trial do not comply with their assigned intervention, the randomized encouragement design is a possible solution. In this design, the causal effects of the intervention can be estimated among participants who would have experienced the intervention if encouraged. For many policy interventions, encouragements cannot be randomized and investigators need to rely on observational data. To address this, we propose a cross-temporal design, which uses time to mimic a randomized encouragement experiment. However, time may be confounded with temporal trends that influence the outcomes. To disentangle these trends from the intervention effects, we replace the commonly used exclusion restrictions with temporal assumptions. We develop Bayesian procedures to estimate the causal effects and compare it to instrumental variables and matching approaches in simulations. The Bayesian approach outperforms the other 2 approaches in terms of estimation accuracy, and it is relatively robust to various violations of the common trends assumption. Taking advantage of the expansion of the Medicare Advantage (MA) program between 2011 and 2017, we implement the proposed method to estimate the effects of MA enrollment on the risk of skilled nursing facility residents being re-hospitalized within 30 days after discharge from the hospital.

Effect modification occurs when the impact of the treatment on an outcome varies based on the levels of other covariates known as effect modifiers. Modeling these effect differences is important for etiological goals and for purposes of optimizing treatment. Structural nested mean models (SNMMs) are useful causal models for estimating the potentially heterogeneous effect of a time-varying exposure on the mean of an outcome in the presence of time-varying confounding. A data-adaptive selection approach is necessary if the effect modifiers are unknown a priori and need to be identified. Although variable selection techniques are available for estimating the conditional average treatment effects using marginal structural models or for developing optimal dynamic treatment regimens, all of these methods consider a single end-of-follow-up outcome. In the context of an SNMM for repeated outcomes, we propose a doubly robust penalized G-estimator for the causal effect of a time-varying exposure with a simultaneous selection of effect modifiers and prove the oracle property of our estimator. We conduct a simulation study for the evaluation of its performance in finite samples and verification of its double-robustness property. Our work is motivated by the study of hemodiafiltration for treating patients with end-stage renal disease at the Centre Hospitalier de l'Université de Montréal. We apply the proposed method to investigate the effect heterogeneity of dialysis facility on the repeated session-specific hemodiafiltration outcomes.

Dynamic treatment regimes (DTRs) formalize medical decision-making as a sequence of rules for different stages, mapping patient-level information to recommended treatments. In practice, estimating an optimal DTR using observational data from electronic medical record (EMR) databases can be complicated by nonignorable missing covariates resulting from informative monitoring of patients. Since complete case analysis can provide consistent estimation of outcome model parameters under the assumption of outcome-independent missingness, Q-learning is a natural approach to accommodating nonignorable missing covariates. However, the backward induction algorithm used in Q-learning can introduce challenges, as nonignorable missing covariates at later stages can result in nonignorable missing pseudo-outcomes at earlier stages, leading to suboptimal DTRs, even if the longitudinal outcome variables are fully observed. To address this unique missing data problem in DTR settings, we propose 2 weighted Q-learning approaches where inverse probability weights for missingness of the pseudo-outcomes are obtained through estimating equations with valid nonresponse instrumental variables or sensitivity analysis. The asymptotic properties of the weighted Q-learning estimators are derived, and the finite-sample performance of the proposed methods is evaluated and compared with alternative methods through extensive simulation studies. Using EMR data from the Medical Information Mart for Intensive Care database, we apply the proposed methods to investigate the optimal fluid strategy for sepsis patients in intensive care units.

As a commonly employed method for analyzing time-to-event data involving functional predictors, the functional Cox model assumes a linear relationship between the functional principal component (FPC) scores of the functional predictors and the hazard rates. However, in practical scenarios, such as our study on the survival time of kidney transplant recipients, this assumption often fails to hold. To address this limitation, we introduce a class of high-dimensional partially linear functional Cox models, which accommodates the non-linear effects of functional predictors on the response and allows for diverging numbers of scalar predictors and FPCs as the sample size increases. We employ the group smoothly clipped absolute deviation method to select relevant scalar predictors and FPCs, and use B-splines to obtain a smoothed estimate of the non-linear effect. The finite sample performance of the estimates is evaluated through simulation studies. The model is also applied to a kidney transplant dataset, allowing us to make inferences about the non-linear effects of functional predictors on patients' hazard rates, as well as to identify significant scalar predictors for long-term survival time.

In longitudinal data analyses, the within-individual repeated measurements often exhibit large variations and these variations appear to change over time. Understanding the nature of the within-individual systematic and random variations allows us to conduct more efficient statistical inferences. Motivated by human immunodeficiency virus (HIV) viral dynamic studies, we considered a nonlinear mixed effects model for modeling the longitudinal means, together with a model for the within-individual variances which also allows us to address outliers in the repeated measurements. Statistical inference was then based on a joint model for the mean and variance, implemented by a computationally efficient approximate method. Extensive simulations evaluated the proposed method. We found that the proposed method produces more efficient estimates than the corresponding method without modeling the variances. Moreover, the proposed method provides robust inference against outliers. The proposed method was applied to a recent HIV-related dataset, with interesting new findings.