On optimal designs for clinical trials: An updated review

Optimization of clinical trial designs can help investigators achieve higher qualityresults for the given resource constraints. The present paper gives an overviewof optimal designs for various important problems that arise in different stages ofclinical drug development, including phase I dose–toxicity studies; phase I/II studiesthat consider early efficacy and toxicity outcomes simultaneously; phase IIdose–response studies driven by multiple comparisons (MCP), modeling techniques(Mod), or their combination (MCP–Mod); phase III randomized controlled multiarmmulti-objective clinical trials to test difference among several treatment groups;and population pharmacokinetics–pharmacodynamics experiments. We find thatmodern literature is very rich with optimal design methodologies that can be utilizedby clinical researchers to improve efficiency of drug development

Smart Sampling for Lightweight Verification of Markov Decision Processes

Markov decision processes (MDP) are useful to model optimisation problems in concurrent systems. To verify MDPs with efficient Monte Carlo techniques requires that their nondeterminism be resolved by a scheduler. Recent work has introduced the elements of lightweight techniques to sample directly from scheduler space, but finding optimal schedulers by simple sampling may be inefficient. Here we describe "smart" sampling algorithms that can make substantial improvements in performance.Comment: IEEE conference style, 11 pages, 5 algorithms, 11 figures, 1 tabl

Statistical Methods for Monte-Carlo based Multiple Hypothesis Testing

Statistical hypothesis testing is a key technique to perform statistical inference. The main focus of this work is to investigate multiple testing under the assumption that the analytical p-values underlying the tests for all hypotheses are unknown. Instead, we assume that they can be approximated by drawing Monte Carlo samples under the null. The first part of this thesis focuses on the computation of test results with a guarantee on their correctness, that is decisions on multiple hypotheses which are identical to the ones obtained with the unknown p-values. We present MMCTest, an algorithm to implement a multiple testing procedure which yields correct decisions on all hypotheses (up to a pre-specified error probability) based solely on Monte Carlo simulation. MMCTest offers novel ways to evaluate multiple hypotheses as it allows to obtain the (previously unknown) correct decision on hypotheses (for instance, genes) in real data studies (again up to an error probability pre-specified by the user). The ideas behind MMCTest are generalised in a framework for Monte Carlo based multiple testing, demonstrating that existing methods giving no guarantees on their test results can be modified to yield certain theoretical guarantees on the correctness of their outputs. The second part deals with multiple testing from a practical perspective. We assume that in practice, it might also be desired to sacrifice the additional computational effort needed to obtain guaranteed decisions and to invest it instead in the computation of a more accurate ad-hoc test result. This is attempted by QuickMMCTest, an algorithm which adaptively allocates more samples to hypotheses whose decisions are more prone to random fluctuations, thereby achieving an improved accuracy. This work also derives the optimal allocation of a finite number of samples to finitely many hypotheses under a normal approximation, where the optimal allocation is understood as the one minimising the expected number of erroneously classified hypotheses (with respect to the classification based on the analytical p-values). An empirical comparison of the optimal allocation of samples to the one computed by QuickMMCTest indicates that the behaviour of QuickMMCTest might not be too far away from being optimal.Open Acces

Multi-keyword multi-click advertisement option contracts for sponsored search

In sponsored search, advertisement (abbreviated ad) slots are usually sold by a search engine to an advertiser through an auction mechanism in which advertisers bid on keywords. In theory, auction mechanisms have many desirable economic properties. However, keyword auctions have a number of limitations including: the uncertainty in payment prices for advertisers; the volatility in the search engine's revenue; and the weak loyalty between advertiser and search engine. In this paper we propose a special ad option that alleviates these problems. In our proposal, an advertiser can purchase an option from a search engine in advance by paying an upfront fee, known as the option price. He then has the right, but no obligation, to purchase among the pre-specified set of keywords at the fixed cost-per-clicks (CPCs) for a specified number of clicks in a specified period of time. The proposed option is closely related to a special exotic option in finance that contains multiple underlying assets (multi-keyword) and is also multi-exercisable (multi-click). This novel structure has many benefits: advertisers can have reduced uncertainty in advertising; the search engine can improve the advertisers' loyalty as well as obtain a stable and increased expected revenue over time. Since the proposed ad option can be implemented in conjunction with the existing keyword auctions, the option price and corresponding fixed CPCs must be set such that there is no arbitrage between the two markets. Option pricing methods are discussed and our experimental results validate the development. Compared to keyword auctions, a search engine can have an increased expected revenue by selling an ad option.Comment: Chen, Bowei and Wang, Jun and Cox, Ingemar J. and Kankanhalli, Mohan S. (2015) Multi-keyword multi-click advertisement option contracts for sponsored search. ACM Transactions on Intelligent Systems and Technology, 7 (1). pp. 1-29. ISSN: 2157-690

Exploiting Homology Information in Nontemplate Based Prediction of Protein Structures

In this paper we describe a novel strategy for exploring the conformational space of proteins and show that this leads to better models for proteins the structure of which is not amenable to template based methods. Our strategy is based on the assumption that the energy global minimum of homologous proteins must correspond to similar conformations, while the precise profiles of their energy landscape, and consequently the positions of the local minima, are likely to be different. In line with this hypothesis, we apply a replica exchange Monte Carlo simulation protocol that, rather than using different parameters for each parallel simulation, uses the sequences of homologous proteins. We show that our results are competitive with respect to alternative methods, including those producing the best model for each of the analyzed targets in the CASP10 (10th Critical Assessment of techniques for protein Structure Prediction) experiment free modeling category