A simulation study of methods for selecting subgroup‐specific doses in phase 1 trials

Patient heterogeneity may complicate dose‐finding in phase 1 clinical trials if the dose‐toxicity curves differ between subgroups. Conducting separate trials within subgroups may lead to infeasibly small sample sizes in subgroups having low prevalence. Alternatively,it is not obvious how to conduct a single trial while accounting for heterogeneity. To address this problem,we consider a generalization of the continual reassessment method on the basis of a hierarchical Bayesian dose‐toxicity model that borrows strength between subgroups under the assumption that the subgroups are exchangeable. We evaluate a design using this model that includes subgroup‐specific dose selection and safety rules. A simulation study is presented that includes comparison of this method to 3 alternative approaches,on the basis of nonhierarchical models,that make different types of assumptions about within‐subgroup dose‐toxicity curves. The simulations show that the hierarchical model‐based method is recommended in settings where the dose‐toxicity curves are exchangeable between subgroups. We present practical guidelines for application and provide computer programs for trial simulation and conduct.     

A Generalization of the Childs-Moran Result for Orthoscheme Probabilities

van der Vaart (1953, 1955) introduced the orthoscheme probability R_n (c ₁,..., c_n−1 ), meaning the orthant probability of an n -dimensional normal random vector with zero mean and tridiagonal correlation matrix with elements c ₁,..., c_n−1 on the upper diagonal. Childs (1967) conjectured and Moran (1983) proved that the generating function of { R_n (½,...,½)} equals tan z + sin z . This paper derives the generating function of { R_n (τ,½,...,½)}.     

The union-intersection principle applied to the test of dimensionality

In the first section Anderson-Rao-Fujikoshi's test statistics for testing the hypothesis of dimensionality are reviewed and then Olkin-Tomsky's generalized union-intersection principle is applied to show that a new class of test statistics for testing the hypothesis of dimensionality are derived which includes the likelihood ratio test statistics, the trace test statistics and a version of ROY'S maximum root test statistics.     

Fetal movement frequency and the effect of associated perinatal factors: Multicenter study

Background

Decreased fetal movements are associated with adverse perinatal outcomes, including stillbirth. Delayed maternal visits to a health care provider after perceiving decreased fetal movements are frequently observed in stillbirths. Informing pregnant women of the normal range of fetal movement frequency is essential in their earlier visits in order to prevent stillbirth.

TITE‐BOIN‐ET: Time‐to‐event Bayesian optimal interval design to accelerate dose‐finding based on both efficacy and toxicity outcomes

One of the primary purposes of an oncology dose‐finding trial is to identify an optimal dose (OD) that is both tolerable and has an indication of therapeutic benefit for subjects in subsequent clinical trials. In addition, it is quite important to accelerate early stage trials to shorten the entire period of drug development. However, it is often challenging to make adaptive decisions of dose escalation and de‐escalation in a timely manner because of the fast accrual rate, the difference of outcome evaluation periods for efficacy and toxicity and the late‐onset outcomes. To solve these issues, we propose the time‐to‐event Bayesian optimal interval design to accelerate dose‐finding based on cumulative and pending data of both efficacy and toxicity. The new design, named “TITE‐BOIN‐ET” design, is nonparametric and a model‐assisted design. Thus, it is robust, much simpler, and easier to implement in actual oncology dose‐finding trials compared with the model‐based approaches. These characteristics are quite useful from a practical point of view. A simulation study shows that the TITE‐BOIN‐ET design has advantages compared with the model‐based approaches in both the percentage of correct OD selection and the average number of patients allocated to the ODs across a variety of realistic settings. In addition, the TITE‐BOIN‐ET design significantly shortens the trial duration compared with the designs without sequential enrollment and therefore has the potential to accelerate early stage dose‐finding trials.     

Self-enforcing family rules,marriage and the (non)neutrality of public intervention

We demonstrate that the notion of a family ‘constitution’ (self-enforcing, renegotiation-proof norm) requiring adults to provide attention for their elderly parents carries over from a world where identical individuals reproduce asexually, to one where individuals differentiated by sex and preferences marry, have children and bargain over the allocation of domestic resources. In this heterogenous world, couples are sorted by their preferences. If a couple’s common preferences satisfy a certain condition, the couple have an interest in instilling those preferences into their children. Policies are generally nonneutral. In particular, wage redistribution may raise, and compulsory education will reduce, the share of the adult population that is governed by family constitutions, and thus the share of the elderly population who receive attention from their children.     

Excessively delayed maternal reaction after their perception of decreased fetal movements in stillbirths: Population-based study in Japan

Background

Fetal movement is the most common method to evaluate fetal well-being. Furthermore, maternal perception of decreased fetal movements is associated with perinatal demise. Previously, we showed that perception of decreased fetal movements was the most common reason for mothers visiting the outpatient department among those who had stillbirths in our region. Further investigation of stillbirths with decreased fetal movements is essential to find a possible way of preventing stillbirth.

Bayesian response adaptive randomization using longitudinal outcomes

The response adaptive randomization (RAR) method is used to increase the number of patients assigned to more efficacious treatment arms in clinical trials. In many trials evaluating longitudinal patient outcomes, RAR methods based only on the final measurement may not benefit significantly from RAR because of its delayed initiation. We propose a Bayesian RAR method to improve RAR performance by accounting for longitudinal patient outcomes (longitudinal RAR). We use a Bayesian linear mixed effects model to analyze longitudinal continuous patient outcomes for calculating a patient allocation probability. In addition, we aim to mitigate the loss of statistical power because of large patient allocation imbalances by embedding adjusters into the patient allocation probability calculation. Using extensive simulation we compared the operating characteristics of our proposed longitudinal RAR method with those of the RAR method based only on the final measurement and with an equal randomization method. Simulation results showed that our proposed longitudinal RAR method assigned more patients to the presumably superior treatment arm compared with the other two methods. In addition, the embedded adjuster effectively worked to prevent extreme patient allocation imbalances. However, our proposed method may not function adequately when the treatment effect difference is moderate or less, and still needs to be modified to deal with unexpectedly large departures from the presumed longitudinal data model. Copyright © 2015 John Wiley & Sons, Ltd.     

Characterization of probability models by an odds ratio in prospective and retrospective studies

It is shown that, when exposure variables are continuous, the odds ratios are functions of exposure differences if and only if Cox's binary logistic models hold in a prospective framework, and if and only if the underlying distribution belongs to a family of exponential type distributions in a retrospective framework.