Multi-Loop-Ring-Oscillator Design and Analysis for Sub-Micron CMOS

Ring oscillators provide a central role in timing circuits for today?s mobile devices and desktop computers. Increased integration in these devices exacerbates switching noise on the supply, necessitating improved supply resilience. Furthermore, reduced voltage headroom in submicron technologies limits the number of stacked transistors available in a delay cell. Hence, conventional single-loop oscillators offer relatively few design options to achieve desired specifications, such as supply rejection. Existing state-of-the-art supply-rejection- enhancement methods include actively regulating the supply with an LDO, employing a fully differential or current-starved delay cell, using a hi-Z voltage-to-current converter, or compensating/calibrating the delay cell. Multiloop ring oscillators (MROs) offer an additional solution because by employing a more complex ring-connection structure and associated delay cell, the designer obtains an additional degree of freedom to meet the desired specifications. Designing these more complex multiloop structures to start reliably and achieve the desired performance requires a systematic analysis procedure, which we attack on two fronts: (1) a generalized delay-cell viewpoint of the MRO structure to assist in both analysis and circuit layout, and (2) a survey of phase-noise analysis to provide a bank of methods to analyze MRO phase noise. We distill the salient phase-noise-analysis concepts/key equations previously developed to facilitate MRO and other non-conventional oscillator analysis. Furthermore, our proposed analysis framework demonstrates that all these methods boil down to obtaining three things: (1) noise modulation function (NMF), (2) noise transfer function (NTF), and (3) current-controlled-oscillator gain (KICO). As a case study, we detail the design, analysis, and measurement of a proposed multiloop ring oscillator structure that provides improved power-supply isolation (more than 20dB increase in supply rejection over a conventional-oscillator control case fabricated on the same test chip). Applying our general multi-loop-oscillator framework to this proposed MRO circuit leads both to design-oriented expressions for the oscillation frequency and supply rejection as well as to an efficient layout technique facilitating cross-coupling for improved quadrature accuracy and systematic, substantially simplified layout effort

Multi-Loop-Ring-Oscillator Design and Analysis for Sub-Micron CMOS

Ring oscillators provide a central role in timing circuits for today?s mobile devices and desktop computers. Increased integration in these devices exacerbates switching noise on the supply, necessitating improved supply resilience. Furthermore, reduced voltage headroom in submicron technologies limits the number of stacked transistors available in a delay cell. Hence, conventional single-loop oscillators offer relatively few design options to achieve desired specifications, such as supply rejection. Existing state-of-the-art supply-rejection- enhancement methods include actively regulating the supply with an LDO, employing a fully differential or current-starved delay cell, using a hi-Z voltage-to-current converter, or compensating/calibrating the delay cell. Multiloop ring oscillators (MROs) offer an additional solution because by employing a more complex ring-connection structure and associated delay cell, the designer obtains an additional degree of freedom to meet the desired specifications. Designing these more complex multiloop structures to start reliably and achieve the desired performance requires a systematic analysis procedure, which we attack on two fronts: (1) a generalized delay-cell viewpoint of the MRO structure to assist in both analysis and circuit layout, and (2) a survey of phase-noise analysis to provide a bank of methods to analyze MRO phase noise. We distill the salient phase-noise-analysis concepts/key equations previously developed to facilitate MRO and other non-conventional oscillator analysis. Furthermore, our proposed analysis framework demonstrates that all these methods boil down to obtaining three things: (1) noise modulation function (NMF), (2) noise transfer function (NTF), and (3) current-controlled-oscillator gain (KICO). As a case study, we detail the design, analysis, and measurement of a proposed multiloop ring oscillator structure that provides improved power-supply isolation (more than 20dB increase in supply rejection over a conventional-oscillator control case fabricated on the same test chip). Applying our general multi-loop-oscillator framework to this proposed MRO circuit leads both to design-oriented expressions for the oscillation frequency and supply rejection as well as to an efficient layout technique facilitating cross-coupling for improved quadrature accuracy and systematic, substantially simplified layout effort

Situating language register across the ages, languages, modalities, and cultural aspects: Evidence from complementary methods

In the present review paper by members of the collaborative research center “Register: Language Users' Knowledge of Situational-Functional Variation” (CRC 1412), we assess the pervasiveness of register phenomena across different time periods, languages, modalities, and cultures. We define “register” as recurring variation in language use depending on the function of language and on the social situation. Informed by rich data, we aim to better understand and model the knowledge involved in situation- and function-based use of language register. In order to achieve this goal, we are using complementary methods and measures. In the review, we start by clarifying the concept of “register”, by reviewing the state of the art, and by setting out our methods and modeling goals. Against this background, we discuss three key challenges, two at the methodological level and one at the theoretical level: (1) To better uncover registers in text and spoken corpora, we propose changes to established analytical approaches. (2) To tease apart between-subject variability from the linguistic variability at issue (intra-individual situation-based register variability), we use within-subject designs and the modeling of individuals' social, language, and educational background. (3) We highlight a gap in cognitive modeling, viz. modeling the mental representations of register (processing), and present our first attempts at filling this gap. We argue that the targeted use of multiple complementary methods and measures supports investigating the pervasiveness of register phenomena and yields comprehensive insights into the cross-methodological robustness of register-related language variability. These comprehensive insights in turn provide a solid foundation for associated cognitive modeling.Peer Reviewe

Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height

Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 × 10−6), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 × 10−8). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 × 10−11). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait

The Polygenic and Monogenic Basis of Blood Traits and Diseases

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation. Analysis of blood cell traits in the UK Biobank and other cohorts illuminates the full genetic architecture of hematopoietic phenotypes, with evidence supporting the omnigenic model for complex traits and linking polygenic burden with monogenic blood diseases

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

Genome-wide association meta-analysis identifies five novel loci for age-related hearing impairment

Previous research has shown that genes play a substantial role in determining a person's susceptibility to age-related hearing impairment. The existing studies on this subject have different results, which may be caused by difficulties in determining the phenotype or the limited number of participants involved. Here, we have gathered the largest sample to date (discovery n = 9,675; replication n = 10,963; validation n = 356,141), and examined phenotypes that represented low/mid and high frequency hearing loss on the pure tone audiogram. We identified 7 loci that were either replicated and/or validated, of which 5 loci are novel in hearing. Especially the ILDR1 gene is a high profile candidate, as it contains our top SNP, is a known hearing loss gene, has been linked to age-related hearing impairment before, and in addition is preferentially expressed within hair cells of the inner ear. By verifying all previously published SNPs, we can present a paper that combines all new and existing findings to date, giving a complete overview of the genetic architecture of age-related hearing impairment. This is of importance as age-related hearing impairment is highly prevalent in our ageing society and represents a large socio-economic burden

The Polygenic and Monogenic Basis of Blood Traits and Diseases

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.</p