Combining evidence from clinical trials in conditional or accelerated approval

Conditional (European Medicines Agency) or accelerated (U.S. Food and Drug Administration) approval of drugs allows earlier access to promising new treatments that address unmet medical needs. Certain post-marketing requirements must typically be met in order to obtain full approval, such as conducting a new post-market clinical trial. We study the applicability of the recently developed harmonic mean ${\chi }^2$-test to this conditional or accelerated approval framework. The proposed approach can be used both to support the design of the post-market trial and the analysis of the combined evidence provided by both trials. Other methods considered are the two-trials rule, Fisher's criterion and Stouffer's method. In contrast to some of the traditional methods, the harmonic mean ${\chi }^2$-test always requires a post-market clinical trial. If the $p$-value from the pre-market clinical trial is $\ll 0.025$, a smaller sample size for the post-market clinical trial is needed than with the two-trials rule. For illustration, we apply the harmonic mean ${\chi }^2$-test to a drug which received conditional (and later full) market licensing by the EMA. A simulation study is conducted to study the operating characteristics of the harmonic mean ${\chi }^2$-test and two-trials rule in more detail. We finally investigate the applicability of these two methods to compute the power at interim of an ongoing post-market trial. These results are expected to aid in the design and assessment of the required post-market studies in terms of the level of evidence required for full approval.     

Alone,together: On the benefits of Bayesian borrowing in a meta-analytic setting

It is common practice to use hierarchical Bayesian model for the informing of a pediatric randomized controlled trial (RCT) by adult data, using a prespecified borrowing fraction parameter (BFP). This implicitly assumes that the BFP is intuitive and corresponds to the degree of similarity between the populations. Generalizing this model to any $K\ge 1$ historical studies, naturally leads to empirical Bayes meta-analysis. In this paper we calculate the Bayesian BFPs and study the factors that drive them. We prove that simultaneous mean squared error reduction relative to an uninformed model is always achievable through application of this model. Power and sample size calculations for a future RCT, designed to be informed by multiple external RCTs, are also provided. Potential applications include inference on treatment efficacy from independent trials involving either heterogeneous patient populations or different therapies from a common class.     

Daisee: Adaptive importance sampling by balancing exploration and exploitation

We study adaptive importance sampling (AIS) as an online learning problem and argue for the importance of the trade-off between exploration and exploitation in this adaptation. Borrowing ideas from the online learning literature, we propose Daisee, a partition-based AIS algorithm. We further introduce a notion of regret for AIS and show that Daisee has $𝒪(\sqrt{T}{(\log T)}^{\frac{3}{4}})$ cumulative pseudo-regret, where $T$ is the number of iterations. We then extend Daisee to adaptively learn a hierarchical partitioning of the sample space for more efficient sampling and confirm the performance of both algorithms empirically.     

Two-dimensional projection uniformity for space-filling designs

We investigate a space-filling criterion based on $L_2$-type discrepancies, namely the uniform projection criterion, aiming at improving designs' two-dimensional projection uniformity. Under a general reproducing kernel, we establish a formula for the uniform projection criterion function, which builds a connection between rows and columns of the design. For the commonly used discrepancies, we further use this formula to represent the two-dimensional projection uniformity in terms of the $L_p$-distances of U-type designs. These results generalize existing works and reveal new links between the two seemingly unrelated criteria of projection uniformity and the maximin $L_p$-distance for U-type designs. We also apply the obtained results to study several families of space-filling designs with appealing projection uniformity. Because of good projected space-filling properties, these designs are well adapted for computer experiments, especially for the case where not all the input factors are active.     

Sparse concordance-based ordinal classification

Ordinal classification is an important area in statistical machine learning, where labels exhibit a natural order. One of the major goals in ordinal classification is to correctly predict the relative order of instances. We develop a novel concordance-based approach to ordinal classification, where a concordance function is introduced and a penalized smoothed method for optimization is designed. Variable selection using the $L_1$ penalty is incorporated for sparsity considerations. Within the set of classification rules that maximize the concordance function, we find optimal thresholds to predict labels by minimizing a loss function. After building the classifier, we derive nonparametric estimation of class conditional probabilities. The asymptotic properties of the estimators as well as the variable selection consistency are established. Extensive simulations and real data applications show the robustness and advantage of the proposed method in terms of classification accuracy, compared with other existing methods.