Statistics in Medicine最新文献

Many clinical trials involve partially clustered data, where some observations belong to a cluster and others can be considered independent. For example, neonatal trials may include infants from single or multiple births. Sample size and analysis methods for these trials have received limited attention. A simulation study was conducted to (1) assess whether existing power formulas based on generalized estimating equations (GEEs) provide an adequate approximation to the power achieved by mixed effects models, and (2) compare the performance of mixed models vs GEEs in estimating the effect of treatment on a continuous outcome. We considered clusters that exist prior to randomization with a maximum cluster size of 2, three methods of randomizing the clustered observations, and simulated datasets with uninformative cluster size and the sample size required to achieve 80% power according to GEE-based formulas with an independence or exchangeable working correlation structure. The empirical power of the mixed model approach was close to the nominal level when sample size was calculated using the exchangeable GEE formula, but was often too high when the sample size was based on the independence GEE formula. The independence GEE always converged and performed well in all scenarios. Performance of the exchangeable GEE and mixed model was also acceptable under cluster randomization, though under-coverage and inflated type I error rates could occur with other methods of randomization. Analysis of partially clustered trials using GEEs with an independence working correlation structure may be preferred to avoid the limitations of mixed models and exchangeable GEEs.

Research into vaccine hesitancy is a critical component of the public health enterprise, as rates of communicable diseases preventable by routine childhood immunization have been increasing in recent years. It is therefore important to estimate proportions of "never-vaccinators" in various subgroups of the population in order to successfully target interventions to improve childhood vaccination rates. However, due to privacy issues, it may be difficult to obtain individual patient data (IPD) needed to perform the appropriate time-to-event analyses: state-level immunization information services may only be willing to share aggregated data with researchers. We propose statistical methodology for the analysis of aggregated survival data that can accommodate a cured fraction based on a polynomial approximation of the mixture cure model log-likelihood function relying only on summary statistics. We study the performance of the method through simulation studies and apply it to a real-world data set from a study examining reminder/recall approaches to improve human papillomavirus (HPV) vaccination uptake. The proposed methods may be generalized for use when there is interest in fitting complex likelihood-based models but IPD is unavailable due to data privacy or other concerns.

Hypothetical strategy is a common strategy for handling intercurrent events (IEs). No current guideline or study considers treatment-IE interaction to target the estimand in any one IE-handling strategy. Based on the hypothetical strategy, we aimed to (1) assess the performance of three estimators with different considerations for the treatment-IE interaction in a simulation and (2) compare the estimation of these estimators in a real trial. Simulation data were generalized based on realistic clinical trials of Alzheimer's disease. The estimand of interest was the effect of treatment with no IE occurring under the hypothetical strategy. Three estimators, namely, G-estimation with and without interaction and IE-ignored estimation, were compared in scenarios where the treatment-IE interaction effect was set as -50% to 50% of the main effect. Bias was the key performance measure. The real case was derived from a randomized trial of methadone maintenance treatment. Only G-estimation with interaction exhibited unbiased estimations regardless of the existence, direction or magnitude of the treatment-IE interaction in those scenarios. Neglecting the interaction and ignoring the IE would introduce a bias as large as 0.093 and 0.241 (true value, -1.561) if the interaction effect existed. In the real case, compared with G-estimation with interaction, G-estimation without interaction and IE-ignored estimation increased the estimand of interest by 33.55% and 34.36%, respectively. This study highlights the importance of considering treatment-IE interaction in the estimand framework. In practice, it would be better to include the interaction in the estimator by default.

This work develops a generalized fused lasso (GFL) approach to fitting contrast-based network meta-analysis (NMA) models. The GFL method penalizes all pairwise differences between treatment effects, resulting in the pooling of treatments that are not sufficiently different. This approach offers an intriguing avenue for potentially mitigating biases in treatment rankings and reducing sparsity in networks. To fit contrast-based NMA models within the GFL framework, we formulate the models as generalized least squares problems, where the precision matrix depends on the standard error in the data, the estimated between-study heterogeneity and the correlation between contrasts in multi-arm studies. By utilizing a Cholesky decomposition of the precision matrix, we linearly transform the data vector and design matrix to frame NMA within the GFL framework. We demonstrate how to construct the GFL penalty such that every pairwise difference is penalized similarly. The model is straightforward to implement in R via the "genlasso" package, and runs instantaneously, contrary to other regularization approaches that are Bayesian. A two-step GFL-NMA approach is recommended to obtain measures of uncertainty associated with the (pooled) relative treatment effects. Two simulation studies confirm the GFL approach's ability to pool treatments that have the same (or similar) effects while also revealing when incorrect pooling may occur, and its potential benefits against alternative methods. The novel GFL-NMA method is successfully applied to a real-world dataset on diabetes where the standard NMA model was not favored compared to the best-fitting GFL-NMA model with AICc selection of the tuning parameter ( $\Delta AICc>13)$ .

Image based screening is now routinely available for early detection of cancer and other diseases. Quantitative analysis for effects of risk factors on digital images is important to extract biological insights for modifiable factors in prevention studies and understand pathways for targets in preventive drugs. However, current approaches are restricted to summary measures within the image with the assumption that all relevant features needed to characterize an image can be identified and appropriately quantified. Motivated by data challenges in breast cancer, we propose a nonparametric statistical framework for risk factor screening that uses the whole mammogram image as outcome. The proposed permutation test allows assessment of whether a set of scalar risk factors is associated with the whole image in the presence of correlated residuals across the spatial domain. We provide extensive simulation studies and illustrate an application to the Joanne Knight Breast Health Cohort using the mammogram imaging data.

A therapeutic product is usually not suitable for all patients but for only a subpopulation. The safe and effective use of such a therapeutic product requires the co-approval of a companion diagnostic device which can be used to identify suitable patients. While the first-of-a-kind companion diagnostic device is often developed in conjunction with its intended therapeutic product and simultaneously validated through a randomized clinical trial, there remains room for the innovation of new and improved follow-on companion diagnostic devices designed for the same therapeutic product. However, conducting a new randomized trial or a bridging study for the follow on companion devices may be unethical, expensive or unpractical. Hence, there arises a need for an external study to evaluate the concordance between the FDA-approved comparator companion diagnostic device (CCD) and the subsequent follow-on companion diagnostic devices (FCD), indirectly validating the latter. In this article, we introduce a novel external study design, referred to as the targeted treatment design, as an extension of the existing concordance design. Additionally, we present corresponding statistical analysis methods. Our approach combines the CCD randomized trial data and the FCD external study data, enabling the estimation of drug efficacy within the FCD+ and FCD- subpopulations-the parameters crucial for the validation of the FCD. Theoretical results and simulation studies validate the proposed methods and we further illustrate the proposed methods through an application in a real example of non-small-cell lung cancer.

For phase II clinical trials that determine the acceptability of an experimental treatment based on ordinal toxicity and ordinal response, most monitoring methods require each ordinal outcome to be dichotomized using a selected cut-point. This allows two early stopping rules to be constructed that compare marginal probabilities of toxicity and response to respective upper and lower limits. Important problems with this approach are loss of information due to dichotomization, dependence of treatment acceptability decisions on precisely how each ordinal variable is dichotomized, and ignoring association between the two outcomes. To address these problems, we propose a new Bayesian method, which we call U-Bayes, that exploits elicited numerical utilities of the joint ordinal outcomes to construct one early stopping rule that compares the mean utility to a lower limit. U-Bayes avoids the problems noted above by using the entire joint distribution of the ordinal outcomes, and not dichotomizing the outcomes. A step-by-step algorithm is provided for constructing a U-Bayes rule based on elicited utilities and elicited limits on marginal outcome probabilities. A simulation study shows that U-Bayes greatly improves the probability of determining treatment acceptability compared to conventional designs that use two monitoring rules based on marginal probabilities.

Sparse data bias, where there is a lack of sufficient cases, is a common problem in data analysis, particularly when studying rare binary outcomes. Although a two-step meta-analysis approach may be used to lessen the bias by combining the summary statistics to increase the number of cases from multiple studies, this method does not completely eliminate bias in effect estimation. In this paper, we propose a one-shot distributed algorithm for estimating relative risk using a modified Poisson regression for binary data, named ODAP-B. We evaluate the performance of our method through both simulation studies and real-world case analyses of postacute sequelae of SARS-CoV-2 infection in children using data from 184 501 children across eight national academic medical centers. Compared with the meta-analysis method, our method provides closer estimates of the relative risk for all outcomes considered including syndromic and systemic outcomes. Our method is communication-efficient and privacy-preserving, requiring only aggregated data to obtain relatively unbiased effect estimates compared with two-step meta-analysis methods. Overall, ODAP-B is an effective distributed learning algorithm for Poisson regression to study rare binary outcomes. The method provides inference on adjusted relative risk with a robust variance estimator.

Iterated conditional expectation (ICE) g-computation is an estimation approach for addressing time-varying confounding for both longitudinal and time-to-event data. Unlike other g-computation implementations, ICE avoids the need to specify models for each time-varying covariate. For variance estimation, previous work has suggested the bootstrap. However, bootstrapping can be computationally intense. Here, we present ICE g-computation as a set of stacked estimating equations. Therefore, the variance for the ICE g-computation estimator can be consistently estimated using the empirical sandwich variance estimator. Performance of the variance estimator was evaluated empirically with a simulation study. The proposed approach is also demonstrated with an illustrative example on the effect of cigarette smoking on the prevalence of hypertension. In the simulation study, the empirical sandwich variance estimator appropriately estimated the variance. When comparing runtimes between the sandwich variance estimator and the bootstrap for the applied example, the sandwich estimator was substantially faster, even when bootstraps were run in parallel. The empirical sandwich variance estimator is a viable option for variance estimation with ICE g-computation.

Broadening eligibility criteria in cancer trials has been advocated to represent the intended patient population more accurately. The advantages are clear in terms of generalizability and recruitment, however there are some important considerations in terms of design for efficiency and patient safety. While toxicity may be expected to be homogeneous across these subpopulations, designs should be able to recommend safe and precise doses if subpopulations with different toxicity profiles exist. Dose-finding designs accounting for patient heterogeneity have been proposed, but existing methods assume that the source of heterogeneity is known. We propose a broadened eligibility dose-finding design to address the situation of unknown patient heterogeneity in phase I cancer clinical trials where eligibility is expanded, and multiple eligibility criteria could potentially lead to different optimal doses for patient subgroups. The design offers a two-in-one approach to dose-finding by simultaneously selecting patient criteria that differentiate the maximum tolerated dose (MTD), using stochastic search variable selection, and recommending the subpopulation-specific MTD if needed. Our simulation study compares the proposed design to the naive approach of assuming patient homogeneity and demonstrates favorable operating characteristics across a wide range of scenarios, allocating patients more often to their true MTD during the trial, recommending more than one MTD when needed, and identifying criteria that differentiate the patient population. The proposed design highlights the advantages of adding more variability at an early stage and demonstrates how assuming patient homogeneity can lead to unsafe or sub-therapeutic dose recommendations.