Extended two-stage adaptive designswith three target responses forphase II clinical trials

We develop a nature-inspired stochastic population-based algorithm and call it discrete particle swarm optimization tofind extended two-stage adaptive optimal designs that allow three target response rates for the drug in a phase II trial.Our proposed designs include the celebrated Simon’s two-stage design and its extension that allows two target responserates to be specified for the drug. We show that discrete particle swarm optimization not only frequently outperformsgreedy algorithms, which are currently used to find such designs when there are only a few parameters; it is also capableof solving design problems posed here with more parameters that greedy algorithms cannot solve. In stage 1 of ourproposed designs, futility is quickly assessed and if there are sufficient responders to move to stage 2, one tests one ofthe three target response rates of the drug, subject to various user-specified testing error rates. Our designs aretherefore more flexible and interestingly, do not necessarily require larger expected sample size requirements thantwo-stage adaptive designs. Using a real adaptive trial for melanoma patients, we show our proposed design requires onehalf fewer subjects than the implemented design in the study

Statistical identifiability and convergence evaluation for nonlinear pharmacokinetic models with particle swarm optimization

The statistical identifiability of nonlinear pharmacokinetic (PK) models with the Michaelis-Menten (MM) kinetic equation is considered using a global optimization approach, which is particle swarm optimization (PSO). If a model is statistically non-identifiable, the conventional derivative-based estimation approach is often terminated earlier without converging, due to the singularity. To circumvent this difficulty, we develop a derivative-free global optimization algorithm by combining PSO with a derivative-free local optimization algorithm to improve the rate of convergence of PSO. We further propose an efficient approach to not only checking the convergence of estimation but also detecting the identifiability of nonlinear PK models. PK simulation studies demonstrate that the convergence and identifiability of the PK model can be detected efficiently through the proposed approach. The proposed approach is then applied to clinical PK data along with a two-compartmental model

A new method of peak detection for analysis of comprehensive two-dimensional gas chromatography mass spectrometry data

We develop a novel peak detection algorithm for the analysis of comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry (GC$\times$GC-TOF MS) data using normal-exponential-Bernoulli (NEB) and mixture probability models. The algorithm first performs baseline correction and denoising simultaneously using the NEB model, which also defines peak regions. Peaks are then picked using a mixture of probability distribution to deal with the co-eluting peaks. Peak merging is further carried out based on the mass spectral similarities among the peaks within the same peak group. The algorithm is evaluated using experimental data to study the effect of different cutoffs of the conditional Bayes factors and the effect of different mixture models including Poisson, truncated Gaussian, Gaussian, Gamma and exponentially modified Gaussian (EMG) distributions, and the optimal version is introduced using a trial-and-error approach. We then compare the new algorithm with two existing algorithms in terms of compound identification. Data analysis shows that the developed algorithm can detect the peaks with lower false discovery rates than the existing algorithms, and a less complicated peak picking model is a promising alternative to the more complicated and widely used EMG mixture models.Comment: Published in at http://dx.doi.org/10.1214/14-AOAS731 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

SC VALL-E: Style-Controllable Zero-Shot Text to Speech Synthesizer

Expressive speech synthesis models are trained by adding corpora with diverse speakers, various emotions, and different speaking styles to the dataset, in order to control various characteristics of speech and generate the desired voice. In this paper, we propose a style control (SC) VALL-E model based on the neural codec language model (called VALL-E), which follows the structure of the generative pretrained transformer 3 (GPT-3). The proposed SC VALL-E takes input from text sentences and prompt audio and is designed to generate controllable speech by not simply mimicking the characteristics of the prompt audio but by controlling the attributes to produce diverse voices. We identify tokens in the style embedding matrix of the newly designed style network that represent attributes such as emotion, speaking rate, pitch, and voice intensity, and design a model that can control these attributes. To evaluate the performance of SC VALL-E, we conduct comparative experiments with three representative expressive speech synthesis models: global style token (GST) Tacotron2, variational autoencoder (VAE) Tacotron2, and original VALL-E. We measure word error rate (WER), F0 voiced error (FVE), and F0 gross pitch error (F0GPE) as evaluation metrics to assess the accuracy of generated sentences. For comparing the quality of synthesized speech, we measure comparative mean option score (CMOS) and similarity mean option score (SMOS). To evaluate the style control ability of the generated speech, we observe the changes in F0 and mel-spectrogram by modifying the trained tokens. When using prompt audio that is not present in the training data, SC VALL-E generates a variety of expressive sounds and demonstrates competitive performance compared to the existing models. Our implementation, pretrained models, and audio samples are located on GitHub