Nonlinear tests for genetic studies of complex disease

Linkage and association studies are major analytical tools to search for susceptibility genes for complex diseases. With the availability of large collection of single nucleotide polymorphisms (SNPs) and the rapid progresses for high throughput genotyping technologies, together with the ambitious goals of the International HapMap Project, genetic markers covering the whole genome will be available for genome-wide linkage and association studies. In order not to inflate the type I error rate in performing genome-wide linkage and association studies, multiple adjustment for the significant level for each independent linkage and/or association test is required, and this has led to the suggestion of genome-wide significant cut-off as low as 5 × 10 −7. Almost no linkage and/or association study can meet such a stringent threshold by the standard statistical methods. Developing new statistics with high power is urgently needed to tackle this problem. This dissertation proposes and explores a class of novel test statistics that can be used in both population-based and family-based genetic data by employing a completely new strategy, which uses nonlinear transformation of the sample means to construct test statistics for linkage and association studies. Extensive simulation studies are used to illustrate the properties of the nonlinear test statistics. Power calculations are performed using both analytical and empirical methods. Finally, real data sets are analyzed with the nonlinear test statistics. Results show that the nonlinear test statistics have correct type I error rates, and most of the studied nonlinear test statistics have higher power than the standard chi-square test. This dissertation introduces a new idea to design novel test statistics with high power and might open new ways to mapping susceptibility genes for complex diseases. ^

Outcome-based adaptive randomization for binary data in clinical trials---Compare and contrast

Monte Carlo simulation has been conducted to investigate parameter estimation and hypothesis testing in some well known adaptive randomization procedures. The four urn models studied are Randomized Play-the-Winner (RPW), Randomized Pôlya Urn (RPU), Birth and Death Urn with Immigration (BDUI), and Drop-the-Loses Urn (DL). Two sequential estimation methods, the sequential maximum likelihood estimation (SMLE) and the doubly adaptive biased coin design (DABC), are simulated at three optimal allocation targets that minimize the expected number of failures under the assumption of constant variance of simple difference (RSIHR), relative risk (ORR), and odds ratio (OOR) respectively. Log likelihood ratio test and three Wald-type tests (simple difference, log of relative risk, log of odds ratio) are compared in different adaptive procedures. ^ Simulation results indicates that although RPW is slightly better in assigning more patients to the superior treatment, the DL method is considerably less variable and the test statistics have better normality. When compared with SMLE, DABC has slightly higher overall response rate with lower variance, but has larger bias and variance in parameter estimation. Additionally, the test statistics in SMLE have better normality and lower type I error rate, and the power of hypothesis testing is more comparable with the equal randomization. Usually, RSIHR has the highest power among the 3 optimal allocation ratios. However, the ORR allocation has better power and lower type I error rate when the log of relative risk is the test statistics. The number of expected failures in ORR is smaller than RSIHR. It is also shown that the simple difference of response rates has the worst normality among all 4 test statistics. The power of hypothesis test is always inflated when simple difference is used. On the other hand, the normality of the log likelihood ratio test statistics is robust against the change of adaptive randomization procedures. ^

Apply response adaptive randomization to group sequential with early stopping

Group sequential methods and response adaptive randomization (RAR) procedures have been applied in clinical trials due to economical and ethical considerations. Group sequential methods are able to reduce the average sample size by inducing early stopping, but patients are equally allocated with half of chance to inferior arm. RAR procedures incline to allocate more patients to better arm; however it requires more sample size to obtain a certain power. This study intended to combine these two procedures. We applied the Bayesian decision theory approach to define our group sequential stopping rules and evaluated the operating characteristics under RAR setting. The results showed that Bayesian decision theory method was able to preserve the type I error rate as well as achieve a favorable power; further by comparing with the error spending function method, we concluded that Bayesian decision theory approach was more effective on reducing average sample size.^

Comparison of multiple comparison methods for identifying differential gene expression in simulated and real papillary thyroid cancer microarray data

The difficulty of detecting differential gene expression in microarray data has existed for many years. Several correction procedures try to avoid the family-wise error rate in multiple comparison process, including the Bonferroni and Sidak single-step p-value adjustments, Holm's step-down correction method, and Benjamini and Hochberg's false discovery rate (FDR) correction procedure. Each multiple comparison technique has its advantages and weaknesses. We studied each multiple comparison method through numerical studies (simulations) and applied the methods to the real exploratory DNA microarray data, which detect of molecular signatures in papillary thyroid cancer (PTC) patients. According to our results of simulation studies, Benjamini and Hochberg step-up FDR controlling procedure is the best process among these multiple comparison methods and we discovered 1277 potential biomarkers among 54675 probe sets after applying the Benjamini and Hochberg's method to PTC microarray data.^

A hybrid method in combining treatment effects from matched and unmatched studies

In the biomedical studies, the general data structures have been the matched (paired) and unmatched designs. Recently, many researchers are interested in Meta-Analysis to obtain a better understanding from several clinical data of a medical treatment. The hybrid design, which is combined two data structures, may create the fundamental question for statistical methods and the challenges for statistical inferences. The applied methods are depending on the underlying distribution. If the outcomes are normally distributed, we would use the classic paired and two independent sample T-tests on the matched and unmatched cases. If not, we can apply Wilcoxon signed rank and rank sum test on each case. ^ To assess an overall treatment effect on a hybrid design, we can apply the inverse variance weight method used in Meta-Analysis. On the nonparametric case, we can use a test statistic which is combined on two Wilcoxon test statistics. However, these two test statistics are not in same scale. We propose the Hybrid Test Statistic based on the Hodges-Lehmann estimates of the treatment effects, which are medians in the same scale.^ To compare the proposed method, we use the classic meta-analysis T-test statistic on the combined the estimates of the treatment effects from two T-test statistics. Theoretically, the efficiency of two unbiased estimators of a parameter is the ratio of their variances. With the concept of Asymptotic Relative Efficiency (ARE) developed by Pitman, we show ARE of the hybrid test statistic relative to classic meta-analysis T-test statistic using the Hodges-Lemann estimators associated with two test statistics.^ From several simulation studies, we calculate the empirical type I error rate and power of the test statistics. The proposed statistic would provide effective tool to evaluate and understand the treatment effect in various public health studies as well as clinical trials.^

Bayesian adaptive designs in early phase clinical trials

There are two practical challenges in the phase I clinical trial conduct: lack of transparency to physicians, and the late onset toxicity. In my dissertation, Bayesian approaches are used to address these two problems in clinical trial designs. The proposed simple optimal designs cast the dose finding problem as a decision making process for dose escalation and deescalation. The proposed designs minimize the incorrect decision error rate to find the maximum tolerated dose (MTD). For the late onset toxicity problem, a Bayesian adaptive dose-finding design for drug combination is proposed. The dose-toxicity relationship is modeled using the Finney model. The unobserved delayed toxicity outcomes are treated as missing data and Bayesian data augment is employed to handle the resulting missing data. Extensive simulation studies have been conducted to examine the operating characteristics of the proposed designs and demonstrated the designs' good performances in various practical scenarios.^

DEVELOPMENT OF NOVEL METHODS TO MINIMIZE THE IMPACT OF SEQUENCING ERRORS IN THE NEXT-GENERATION SEQUENCING DATA ANALYSIS

Next-generation sequencing (NGS) technology has become a prominent tool in biological and biomedical research. However, NGS data analysis, such as de novo assembly, mapping and variants detection is far from maturity, and the high sequencing error-rate is one of the major problems. . To minimize the impact of sequencing errors, we developed a highly robust and efficient method, MTM, to correct the errors in NGS reads. We demonstrated the effectiveness of MTM on both single-cell data with highly non-uniform coverage and normal data with uniformly high coverage, reflecting that MTM’s performance does not rely on the coverage of the sequencing reads. MTM was also compared with Hammer and Quake, the best methods for correcting non-uniform and uniform data respectively. For non-uniform data, MTM outperformed both Hammer and Quake. For uniform data, MTM showed better performance than Quake and comparable results to Hammer. By making better error correction with MTM, the quality of downstream analysis, such as mapping and SNP detection, was improved. SNP calling is a major application of NGS technologies. However, the existence of sequencing errors complicates this process, especially for the low coverage (

Speaker Diarization Based on Intensity Channel Contribution

The time delay of arrival (TDOA) between multiple microphones has been used since 2006 as a source of information (localization) to complement the spectral features for speaker diarization. In this paper, we propose a new localization feature, the intensity channel contribution (ICC) based on the relative energy of the signal arriving at each channel compared to the sum of the energy of all the channels. We have demonstrated that by joining the ICC features and the TDOA features, the robustness of the localization features is improved and that the diarization error rate (DER) of the complete system (using localization and spectral features) has been reduced. By using this new localization feature, we have been able to achieve a 5.2% DER relative improvement in our development data, a 3.6% DER relative improvement in the RT07 evaluation data and a 7.9% DER relative improvement in the last year's RT09 evaluation data.

Influence of Current Pulse Shape on Directly Modulated Systems Performance in Metro Area Optical Networks

Due to the fact that a metro network market is very cost sensitive, direct modulated schemes appear attractive. In this paper a CWDM (Coarse Wavelength Division Multiplexing) system is studied in detail by means of an Optical Communication System Design Software; a detailed study of the modulated current shape (exponential, sine and gaussian) for 2.5 Gb/s CWDM Metropolitan Area Networks is performed to evaluate its tolerance to linear impairments such as signal-to-noise-ratio degradation and dispersion. Point-to-point links are investigated and optimum design parameters are obtained. Through extensive sets of simulation results, it is shown that some of these shape pulses are more tolerant to dispersion when compared with conventional gaussian shape pulses. In order to achieve a low Bit Error Rate (BER), different types of optical transmitters are considered including strongly adiabatic and transient chirp dominated Directly Modulated Lasers (DMLs). We have used fibers with different dispersion characteristics, showing that the system performance depends, strongly, on the chosen DML?fiber couple.

Factored Translation Models for improving a Speech into Sign Language Translation System

This paper proposes the use of Factored Translation Models (FTMs) for improving a Speech into Sign Language Translation System. These FTMs allow incorporating syntactic-semantic information during the translation process. This new information permits to reduce significantly the translation error rate. This paper also analyses different alternatives for dealing with the non-relevant words. The speech into sign language translation system has been developed and evaluated in a specific application domain: the renewal of Identity Documents and Driver’s License. The translation system uses a phrase-based translation system (Moses). The evaluation results reveal that the BLEU (BiLingual Evaluation Understudy) has improved from 69.1% to 73.9% and the mSER (multiple references Sign Error Rate) has been reduced from 30.6% to 24.8%.

A robustness verification system for mobile phone authentication based on gestures using Linear Discriminant Analysis

This article evaluates an authentication technique for mobiles based on gestures. Users create a remindful identifying gesture to be considered as their in-air signature. This work analyzes a database of 120 gestures of different vulnerability, obtaining an Equal Error Rate (EER) of 9.19% when robustness of gestures is not verified. Most of the errors in this EER come from very simple and easily forgeable gestures that should be discarded at enrollment phase. Therefore, an in-air signature robustness verification system using Linear Discriminant Analysis is proposed to infer automatically whether the gesture is secure or not. Different configurations have been tested obtaining a lowest EER of 4.01% when 45.02% of gestures were discarded, and an optimal compromise of EER of 4.82% when 19.19% of gestures were automatically rejected.

Mutual Information and Perplexity based Clustering of Dialogue Information for Dynamic Adaptation of Language Models

We present two approaches to cluster dialogue-based information obtained by the speech understanding module and the dialogue manager of a spoken dialogue system. The purpose is to estimate a language model related to each cluster, and use them to dynamically modify the model of the speech recognizer at each dialogue turn. In the first approach we build the cluster tree using local decisions based on a Maximum Normalized Mutual Information criterion. In the second one we take global decisions, based on the optimization of the global perplexity of the combination of the cluster-related LMs. Our experiments show a relative reduction of the word error rate of 15.17%, which helps to improve the performance of the understanding and the dialogue manager modules.

Blind reconiliation

Information reconciliation is a crucial procedure in the classical post-processing of quantum key distribution (QKD). Poor reconciliation e?ciency, revealing more information than strictly needed, may compromise the maximum attainable distance, while poor performance of the algorithm limits the practical throughput in a QKD device. Historically, reconciliation has been mainly done using close to minimal information disclosure but heavily interactive procedures, like Cascade, or using less e?cient but also less interactive ?just one message is exchanged? procedures, like the ones based in low-density parity-check (LDPC) codes. The price to pay in the LDPC case is that good e?ciency is only attained for very long codes and in a very narrow range centered around the quantum bit error rate (QBER) that the code was designed to reconcile, thus forcing to have several codes if a broad range of QBER needs to be catered for. Real world implementations of these methods are thus very demanding, either on computational or communication resources or both, to the extent that the last generation of GHz clocked QKD systems are ?nding a bottleneck in the classical part. In order to produce compact, high performance and reliable QKD systems it would be highly desirable to remove these problems. Here we analyse the use of short-length LDPC codes in the information reconciliation context using a low interactivity, blind, protocol that avoids an a priori error rate estimation. We demonstrate that 2×103 bits length LDPC codes are suitable for blind reconciliation. Such codes are of high interest in practice, since they can be used for hardware implementations with very high throughput.

Improving automatic detection of obstructive sleep apnea through nonlinear analysis of sustained speech

We present a novel approach for the detection of severe obstructive sleep apnea (OSA) based on patients' voices introducing nonlinear measures to describe sustained speech dynamics. Nonlinear features were combined with state-of-the-art speech recognition systems using statistical modeling techniques (Gaussian mixture models, GMMs) over cepstral parameterization (MFCC) for both continuous and sustained speech. Tests were performed on a database including speech records from both severe OSA and control speakers. A 10 % relative reduction in classification error was obtained for sustained speech when combining MFCC-GMM and nonlinear features, and 33 % when fusing nonlinear features with both sustained and continuous MFCC-GMM. Accuracy reached 88.5 % allowing the system to be used in OSA early detection. Tests showed that nonlinear features and MFCCs are lightly correlated on sustained speech, but uncorrelated on continuous speech. Results also suggest the existence of nonlinear effects in OSA patients' voices, which should be found in continuous speech.

HF spectrum activity prediction model based on HMM for cognitive radio applications

Although most of the research on Cognitive Radio is focused on communication bands above the HF upper limit (30 MHz), Cognitive Radio principles can also be applied to HF communications to make use of the extremely scarce spectrum more efficiently. In this work we consider legacy users as primary users since these users transmit without resorting to any smart procedure, and our stations using the HFDVL (HF Data+Voice Link) architecture as secondary users. Our goal is to enhance an efficient use of the HF band by detecting the presence of uncoordinated primary users and avoiding collisions with them while transmitting in different HF channels using our broad-band HF transceiver. A model of the primary user activity dynamics in the HF band is developed in this work to make short-term predictions of the sojourn time of a primary user in the band and avoid collisions. It is based on Hidden Markov Models (HMM) which are a powerful tool for modelling stochastic random processes and are trained with real measurements of the 14 MHz band. By using the proposed HMM based model, the prediction model achieves an average 10.3% prediction error rate with one minute-long channel knowledge but it can be reduced when this knowledge is extended: with the previous 8 min knowledge, an average 5.8% prediction error rate is achieved. These results suggest that the resulting activity model for the HF band could actually be used to predict primary users activity and included in a future HF cognitive radio based station.