Characterizing phonetic transformations and fine-grained acoustic differences across dialects

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2011.Cataloged from PDF version of thesis.Includes bibliographical references (p. 169-175).This thesis is motivated by the gaps between speech science and technology in analyzing dialects. In speech science, investigating phonetic rules is usually manually laborious and time consuming, limiting the amount of data analyzed. Without sufficient data, the analysis could potentially overlook or over-specify certain phonetic rules. On the other hand, in speech technology such as automatic dialect recognition, phonetic rules are rarely modeled explicitly. While many applications do not require such knowledge to obtain good performance, it is beneficial to specifically model pronunciation patterns in certain applications. For example, users of language learning software can benefit from explicit and intuitive feedback from the computer to alter their pronunciation; in forensic phonetics, it is important that results of automated systems are justifiable on phonetic grounds. In this work, we propose a mathematical framework to analyze dialects in terms of (1) phonetic transformations and (2) acoustic differences. The proposed Phonetic based Pronunciation Model (PPM) uses a hidden Markov model to characterize when and how often substitutions, insertions, and deletions occur. In particular, clustering methods are compared to better model deletion transformations. In addition, an acoustic counterpart of PPM, Acoustic-based Pronunciation Model (APM), is proposed to characterize and locate fine-grained acoustic differences such as formant transitions and nasalization across dialects. We used three data sets to empirically compare the proposed models in Arabic and English dialects. Results in automatic dialect recognition demonstrate that the proposed models complement standard baseline systems. Results in pronunciation generation and rule retrieval experiments indicate that the proposed models learn underlying phonetic rules across dialects. Our proposed system postulates pronunciation rules to a phonetician who interprets and refines them to discover new rules or quantify known rules. This can be done on large corpora to develop rules of greater statistical significance than has previously been possible. Potential applications of this work include speaker characterization and recognition, automatic dialect recognition, automatic speech recognition and synthesis, forensic phonetics, language learning or accent training education, and assistive diagnosis tools for speech and voice disorders.by Nancy Fang-Yih Chen.Ph.D

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions

A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P <1 x 10(-6)) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P <5 x 10(-8) using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.Peer reviewe

A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure

Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P <5 x 10(-8), false discovery rate <0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.Peer reviewe

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

High-Performance Adaptive Decision Feedback Equalizer Designs for Ethernet Systems

隨著網際網路近年來的蓬勃發展，加上網路多媒體服務的崛起，通訊系統的傳輸頻寬需求也變得越來越高。西元2002年八月，國際電子電機工程師協會(Institute of Electrical and Electronics Engineers) 802.3a工作小組制訂了百億位元乙太網路的10G Base LX4系統的標準規格。當傳輸速度達到每秒百億位元符碼的數量級時，光纖已經不再是過往認定的理想傳輸介質。由於傳統的回饋等化器(Decision Feedback Equalizer)受限於謬誤延遲(Error Propagation)，因此無法達到10G Base LX4系統中位元錯誤率(Bit Error Rate)為10-12的標準。為了解決此問題，我們決定採用「軟基準多層級決策可適應性回饋等化器」(Soft-Threshold Multi-layer Adaptive Decision Feedback Equalizer)來降低位元錯誤率，藉以提高系統效能。軟基準多層級決策可適應性回饋等化器不但可提高系統效能，達到所要求之位元錯誤率，並且可降低類比/數位轉化器(Analog/Digital Converter)所需之位元精確度兩位元，降低了高速類比/數位轉化器設計的困難度。我們將軟基準多層級決策可適應性回饋等化器與前端類比等化器整合，亦大量化簡了數位等化器所需之硬體成本。本論文亦對軟基準多層級決策可適應性回饋等化器提出了管線化兩級前看式的超大積體電路設計架構來提昇系統之操作頻率。As the applications and prevalence of the world wide web (WWW) flourish over the past decade, the demand for higher bandwidth and data rate is skyrocketing. In August 2002, the IEEE 802.3ae task force finalized the 10-Gigabit Base LX4 Ethernet Standard. However, under multi-gigabit data rates, fiber is no longer an ideal transmission medium. This is especially the case for multi-mode fiber (MMF) used in 10G Base LX4 Ethernet systems, because it suffers from differential mode dispersion (DMD). However, conventional adaptive decision feedback equalizers (ADFE) cannot attain the bit error rate (BER) requirement of 10-12 in 10G Base LX4 Ethernet systems, because hard decision of slicers causes error propagation in the feedback loop. Soft threshold multi-layer adaptive decision feedback equalizer (STM-ADFE) designs are adopted to solve this problem. Our system simulation environment includes three representative channel impulses responses, trans-impedance amplifier (TIA), analog equalizer (AEQ), analog/digital converter (ADC), and STM-ADFE. Integration with the analog front end reduces the filter tap numbers needed in STM-ADFE. VLSI architectures of STM-ADFE are also presented. With low hardware overhead, STM-ADFE not only lowers the BER, but also reduces the bit resolution needed in the ADC from 8 to 6.Abstract I Table of Contents III List of Figures V List of Tables VII Chapter 1 Introduction 1 1.1 10G Base LX4 System Overview 1 1.2 Motivation and Goal 5 1.3 Thesis Organization 5 Chapter 2 Digital Equalization Techniques for 10G Base LX4 Systems 7 2.1 Introduction to Equalizers Decision Feedback Equalization 7 2.2 Soft-Threshold Multi-layer Adaptive Decision Feedback Equalizer 10 2.2.1 Maximum a Posteriori Probability Detection 11 2.2.2 Determination of Threshold Value 13 2.2.3 Simplified Algorithm for Low Cost Implementation 15 2.3 Summary 16 Chapter 3 Simulation Results of 10G Base LX4 Systems 17 3.1 Simulation Environment 17 3.1.1 Channel Model 17 3.1.2 Analog Equalization in 10G Base LX4 [11] 20 3.2 Parameter Assignment for Soft-Threshold Multi-layer Adaptive Decision Feedback Equalizer 23 3.2.1 Tap Number Determination 23 3.2.2 Floating-Point Analysis 27 3.2.3 Analog/Digital Converter Bit Number Determination 30 3.2.4 Fixed-Point Analysis 32 3.3 Simulation Results 34 3.4 Summary 38 Chapter 4 VLSI Architecture 39 4.1 Soft-Threshold Multi-layer Adaptive Decision Feedback Equalizer VLSI Architecture 39 4.2 Pipelined Soft-Threshold Multi-layer Adaptive Decision Feedback Equalizer 43 4.3 Register Transfer Level Simulation and Synthesis Results 45 Chapter 5 Conclusions 49 5.1 Summary 49 5.2 Future Work 49 Appendix 51 Reference 5

Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries

The authors have read the journal's policy and the authors of this manuscript have the following competing interests: Bruce M. Psaty (BMP) serves on the DSMB of a clinical trial funded by Zoll Lifecor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Barbara V. Howard (BVH) has a contract from National Heart, Lung, and Blood Institute (NHLBI). Brenda W.J.H. Penninx (BWJHP) has received research funding (non-related to the work reported here) from Jansen Research and Boehringer Ingelheim. Mike A. Nalls (MAN) is supported by a consulting contract between Data Tecnica International LLC and the National Institute on Aging (NIA), National Institutes of Health (NIH), Bethesda, MD, USA. MAN also consults for Illumina Inc., the Michael J. Fox Foundation, and the University of California Healthcare. MAN also has commercial affiliation with Data Tecnica International, Glen Echo, MD, USA. Mark J. Caulfield (MJC) has commercial affiliation and is Chief Scientist for Genomics England, a UK government company. OHF is supported by grants from Metagenics (on women's health and epigenetics) and from Nestlé (on child health). Peter S. Sever (PSS) is financial supported from several pharmaceutical companies which manufacture either blood pressure lowering or lipid lowering agents, or both, and consultancy fees. Paul W. Franks (PWF) has been a paid consultant in the design of a personalized nutrition trial (PREDICT) as part of a private-public partnership at Kings College London, UK, and has received research support from several pharmaceutical companies as part of European Union Innovative Medicines Initiative (IMI) projects. Terho Lehtimäki (TL) is employed by Fimlab Ltd. Ozren Polašek (OP) is employed by Gen‐info Ltd. There are no patents, products in development, or marked products to declare. All the other authors have declared no competing interests exist. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.International audienceHeavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension

Identification of four independent LD blocks in the 8p23.1 region <i>(~3</i>.<i>3 MBs</i>).

<p>Identification of four independent LD blocks in the 8p23.1 region <i>(~3</i>.<i>3 MBs</i>).</p

Novel SNVs/Genes associated with BP traits in Multi-ancestry meta-analysis in combined Stage 1 and Stage 2.

<p>Novel SNVs/Genes associated with BP traits in Multi-ancestry meta-analysis in combined Stage 1 and Stage 2.</p

Novel SNVs/Genes associated with BP traits from correlated meta-analysis in European ancestry in Stage 1.

<p>Novel SNVs/Genes associated with BP traits from correlated meta-analysis in European ancestry in Stage 1.</p