We present a nonparametric method for estimating the conditional future state entry probabilities and distributions of state entry time conditional on a past state visit when data are subject to dependent censorings in a progressive multistate model where Markovianity of the system is not assumed. These estimators are constructed using the competing risk techniques with risk sets consisting of fractional observations and inverse probability of censoring weights. The fractional observations correspond to estimates of the number of persons who ultimately enter a state from which the future state in question can be reached in one step. We then address the corresponding regression problem by combining these marginal estimators with the pseudo-value approach. The performance of our regression scheme is studied using a comprehensive simulation study. An analysis of existing data on graft-versus-host disease for bone marrow transplant individuals is presented using our novel methodology. A second analysis of another well-known data set on burn patients is also included.

A sequential multiple assignment randomized trial, which incorporates multiple stages of randomization, is a popular approach for collecting data to inform personalized and adaptive treatments. There is an extensive literature on statistical methods to analyze data collected in sequential multiple assignment randomized trials and estimate the optimal dynamic treatment regime. Q-learning with linear regression is widely used for this purpose due to its ease of implementation. However, model misspecification is a common problem with this approach, and little attention has been given to the impact of model misspecification when treatment effects are heterogeneous across subjects. This article describes the integrative impact of two possible types of model misspecification related to treatment effect heterogeneity: omitted early-stage treatment effects in late-stage main effect model, and violated linearity assumption between pseudo-outcomes and predictors despite non-linearity arising from the optimization operation. The proposed method, aiming to deal with both types of misspecification concomitantly, builds interactive models into modified parametric Q-learning with Murphy's regret function. Simulations show that the proposed method is robust to both sources of model misspecification. The proposed method is applied to a two-stage sequential multiple assignment randomized trial with embedded tailoring aimed at reducing binge drinking in first-year college students.

The effectiveness of a vaccine is measured by means of protective vaccine efficacy, defined by , where and are, respectively, the disease attack rates in the vaccinated and the unvaccinated population. For each of the cohoret and case-control designs, methods have been presented in the literature for calculating the required sample size when the desired width of the confidence interval and the probability of coverage are pre-specified, where an equal number of individuals were assumed to be allocated to the vaccine and placebo group. In this article, we present a method for calculating the required sample size with a specified degree of precision when there is an unequal allocation of individuals across the two groups. The sample size required to achieve a desired power for the relevant level test has also been explored, keeping the unequal allocation proportion in mind. The fraction of individuals allocated to the placebo group () can be so chosen that the total sample size or the expected number of people developing the disease or some other criteria of interest is minimized.

The success of preclinical research hinges on exploratory and confirmatory animal studies. Traditional null hypothesis significance testing is a common approach to eliminate the chaff from a collection of drugs, so that only the most promising treatments are funneled through to clinical research phases. Balancing the number of false discoveries and false omissions is an important aspect to consider during this process. In this paper, we compare several preclinical research pipelines, either based on null hypothesis significance testing or based on Bayesian statistical decision criteria. We build on a recently published large-scale meta-analysis of reported effect sizes in preclinical animal research and elicit a non-informative prior distribution under which both approaches are compared. After correcting for publication bias and shrinkage of effect sizes in replication studies, simulations show that (i) a shift towards statistical approaches which explicitly incorporate the minimum clinically important difference reduces the false discovery rate of frequentist approaches and (ii) a shift towards Bayesian statistical decision criteria can improve the reliability of preclinical animal research by reducing the number of false-positive findings. It is shown that these benefits hold while keeping the number of experimental units low which are required for a confirmatory follow-up study. Results show that Bayesian statistical decision criteria can help in improving the reliability of preclinical animal research and should be considered more frequently in practice.

In oncology, phase II clinical trials are often planned as single-arm two-stage designs with a binary endpoint, for example, progression-free survival after 12 months, and the option to stop for futility after the first stage. Simon's two-stage design is a very popular approach but depending on the follow-up time required to measure the patients' outcomes the trial may have to be paused undesirably long. To shorten this forced interruption, it was proposed to use a short-term endpoint for the interim decision, such as progression-free survival after 3 months. We show that if the assumptions for the short-term endpoint are misspecified, the decision-making in the interim can be misleading, resulting in a great loss of statistical power. For the setting of a binary endpoint with nested measurements, such as progression-free survival, we propose two approaches that utilize all available short-term and long-term assessments of the endpoint to guide the interim decision. One approach is based on conditional power and the other is based on Bayesian posterior predictive probability of success. In extensive simulations, we show that both methods perform similarly, when appropriately calibrated, and can greatly improve power compared to the existing approach in settings with slow patient recruitment. Software code to implement the methods is made publicly available.

Technological advancements have made it possible to deliver mobile health interventions to individuals. A novel framework that has emerged from such advancements is the just-in-time adaptive intervention, which aims to suggest the right support to the individuals when their needs arise. The micro-randomized trial design has been proposed recently to test the proximal effects of the components of these just-in-time adaptive interventions. However, the extant micro-randomized trial framework only considers components with a fixed number of categories added at the beginning of the study. We propose a more flexible micro-randomized trial design which allows addition of more categories to the components during the study. Note that the number and timing of the categories added during the study need to be fixed initially. The proposed design is motivated by collaboration on the Diabetes and Mental Health Adaptive Notification Tracking and Evaluation study, which learns to deliver effective text messages to encourage physical activity among patients with diabetes and depression. We developed a new test statistic and the corresponding sample size calculator for the flexible micro-randomized trial using an approach similar to the generalized estimating equation for longitudinal data. Simulation studies were conducted to evaluate the sample size calculators and an R shiny application for the calculators was developed.

Cure rate models have been widely studied to analyze time-to-event data with a cured fraction of patients. In this type of model, the number of concurrent causes is assumed to be a random variable. However, in practice, it is natural to admit that the distribution of the number of competing causes is different from individual to individual. Our proposal is to assume that the number of competing causes belongs to a class of a finite mixture of competing causes distributions. We assume the number of malignant cells follow a mixture of two power series distributions and suppose that the time to the event of interest follows a Weibull distribution. We consider the proportion of the cured number of competing causes depending on covariates, allowing direct modeling of the cure rate. The proposed model includes several well-known models as special cases and defines many new special models. An expectation-maximization algorithm is proposed for parameter estimation, where the expectation step involves the computation of the expected number of concurrent causes for each individual. A Monte Carlo simulation is performed to assess the behavior of the estimation method. In order to show the potential for the practice of our model, we apply it to the real medical data set from a population-based study of incident cases of cutaneous melanoma diagnosed in the state of São Paulo, Brazil, illustrating that the model proposed can outperform traditional models in terms of model fitting.

Parallel design and crossover design are two of the most frequently used designs for studying drug-gene interactions. Due to the concerns of statistical power and ethics, it is often more prudent to use the crossover design while allowing the patients to have choices of not switching the treatment if the first stage treatment is effective. This complicates the calculation of the required sample size to achieve pre-specified statistical power. We propose a method to determine the required sample size with a closed-form formula. The proposed approach is applied to determine the sample size of an adaptive crossover trial in studying gene-drug interaction in treating atrial fibrillation, the most common cardiac arrhythmia in clinical practice. Our simulation study confirms the power achieved by the sample size determined using the proposed approach. Issues related to the adaptive crossover trial are also discussed and practical guidelines are provided.

Mixed panel count data have attracted increasing attention in medical research based on event history studies. When such data arise, one either observes the number of event occurrences or only knows whether the event has happened or not over an observation period. In this article, we discuss variable selection in event history studies given such complex data, for which there does not seem to exist an established procedure. For the problem, we propose a penalized likelihood variable selection procedure and for the implementation, an expectation-maximization algorithm is developed with the use of the coordinate descent algorithm in the M-step. Furthermore, the oracle property of the proposed method is established, and a simulation study is performed and indicates that the proposed method works well in practical scenarios. Finally, the method is applied to identify the risk factors associated with medical non-adherence arising from the Sequenced Treatment Alternatives to Relieve Depression Study.

Real-world data sources offer opportunities to compare the effectiveness of treatments in practical clinical settings. However, relevant outcomes are often recorded selectively and collected at irregular measurement times. It is therefore common to convert the available visits to a standardized schedule with equally spaced visits. Although more advanced imputation methods exist, they are not designed to recover longitudinal outcome trajectories and typically assume that missingness is non-informative. We, therefore, propose an extension of multilevel multiple imputation methods to facilitate the analysis of real-world outcome data that is collected at irregular observation times. We illustrate multilevel multiple imputation in a case study evaluating two disease-modifying therapies for multiple sclerosis in terms of time to confirmed disability progression. This survival outcome is derived from repeated measurements of the Expanded Disability Status Scale, which is collected when patients come to the healthcare center for a clinical visit and for which longitudinal trajectories can be estimated. Subsequently, we perform a simulation study to compare the performance of multilevel multiple imputation to commonly used single imputation methods. Results indicate that multilevel multiple imputation leads to less biased treatment effect estimates and improves the coverage of confidence intervals, even when outcomes are missing not at random.