Performance and robustness analysis for structured uncertainty

This paper introduces a nonconservative measure of performance for linear feedback systems in the face of structured uncertainty. This measure is based on a new matrix function, which we call the Structured Singular Value

Computation of p-Adic Heights and Log Convergence

This paper is about computational and theoretical questions regarding p-adic height pairings on elliptic curves over a global field K. The main stumbling block to computing them efficiently is in calculating, for each of the completions Kv at the places v of K dividing p, a single quantity: the value of the p-adic modular form E2 associated to the elliptic curve. Thanks to the work of Dwork, Katz, Kedlaya, Lauder and Monsky-Washnitzer we offer an efficient algorithm for computing these quantities, i.e., for computing the value of E2 of an elliptic curve. We also discuss the p-adic convergence rate of canonical expansions of the p-adic modular form E2 on the Hasse domain. In particular, we introduce a new notion of log convergence and prove that E2 is log convergent.Mathematic

Escape tactics used by bluegills and fathead minnows to avoid predation by tiger muskellunge

To explain why esocids prefer cylindrical, soft-rayed prey over compressed, spiny-rayed prey, we quantified behavioral interaction between tiger muskellunge (F1 hybrid of male northern pike Esox lucius and female muskellunge E. masquinongy) and fathead minnows (Pimephales promelas) and bluegills (Lepomis macrochirus). Tiger muskellunge required four times as many strikes and longer pursuits to capture bluegills than fathead minnows. Tiger muskellunge attacked each prey species differently; fathead minnows were grasped at midbody and bluegills were attacked in the caudal area. Each prey species exhibited different escape tactics. Fathead minnows remained in open water and consistently schooled; bluegills dispersed throughout the tank and sought cover by moving to corners and edges. Due to their antipredatory behavior (dispersing, cover seeking, and remaining motionless) and morphology (deep body and spines), bluegills were less susceptible to capture by tiger muskellunge than were fathead minnows.Funding for this project was provided by the Federal Aid in Fish Restoration Act under Dingell-Johnson Project F-57-R

Genome engineering of isogenic human ES cells to model autism disorders.

Isogenic pluripotent stem cells are critical tools for studying human neurological diseases by allowing one to study the effects of a mutation in a fixed genetic background. Of particular interest are the spectrum of autism disorders, some of which are monogenic such as Timothy syndrome (TS); others are multigenic such as the microdeletion and microduplication syndromes of the 16p11.2 chromosomal locus. Here, we report engineered human embryonic stem cell (hESC) lines for modeling these two disorders using locus-specific endonucleases to increase the efficiency of homology-directed repair (HDR). We developed a system to: (1) computationally identify unique transcription activator-like effector nuclease (TALEN) binding sites in the genome using a new software program, TALENSeek, (2) assemble the TALEN genes by combining golden gate cloning with modified constructs from the FLASH protocol, and (3) test the TALEN pairs in an amplification-based HDR assay that is more sensitive than the typical non-homologous end joining assay. We applied these methods to identify, construct, and test TALENs that were used with HDR donors in hESCs to generate an isogenic TS cell line in a scarless manner and to model the 16p11.2 copy number disorder without modifying genomic loci with high sequence similarity

‘Not clinically effective but cost-effective’ - paradoxical conclusions in randomised controlled trials with ‘doubly null’ results: a cross-sectional study

Objectives Randomised controlled trials in healthcare increasingly include economic evaluations. Some show small differences which are not statistically significant. Yet these sometimes come to paradoxical conclusions such as: 'the intervention is not clinically effective' but 'is probably cost-effective'. This study aims to quantify the extent of non-significant results and the types of conclusions drawn from them. Design Cross-sectional retrospective analysis of randomised trials published by the UK's National Institute for Health Research (NIHR) Health Technology Assessment programme. We defined as 'doubly null' those trials that found non-statistically significant differences in both primary outcome and cost per patient. Paradoxical was defined as concluding in favour of an intervention, usually compared with placebo or usual care. No human participants were involved. Our sample was 226 randomised trial projects published by the Health Technology Assessment programme 2004 to 2017. All are available free online. Results The 226 projects contained 193 trials with a full economic evaluation. Of these 76 (39%) had at least one 'doubly null' comparison. These 76 trials contained 94 comparisons. In these 30 (32%) drew economic conclusions in favour of an intervention. Overall report conclusions split roughly equally between those favouring the intervention (14), and those favouring either the control (7) or uncertainty (9). Discussion Trials with 'doubly null' results and paradoxical conclusions are not uncommon. The differences observed in cost and quality-adjustedlife year were small and non-statistically significant. Almost all these trials were also published in leading peer-reviewed journals. Although some guidelines for reporting economic results require cost-effectiveness estimates regardless of statistical significance, the interpretability of paradoxical results has nowhere been addressed. Conclusions Reconsideration is required of the interpretation of cost-effectiveness analyses in randomised controlled trials with 'doubly null' results, particularly when economics favours a novel intervention.</p

Exome sequencing identifies nonsegregating nonsense ATM and PALB2 variants in familial pancreatic cancer.

We sequenced 11 germline exomes from five families with familial pancreatic cancer (FPC). One proband had a germline nonsense variant in ATM with somatic loss of the variant allele. Another proband had a nonsense variant in PALB2 with somatic loss of the variant allele. Both variants were absent in a relative with FPC. These findings question the causal mechanisms of ATM and PALB2 in these families and highlight challenges in identifying the causes of familial cancer syndromes using exome sequencing

Genome-wide screening for DNA variants associated with reading and language traits

This research was funded by: Max Planck Society, the University of St Andrews - Grant Number: 018696, US National Institutes of Health - Grant Number: P50 HD027802, Wellcome Trust - Grant Number: 090532/Z/09/Z, and Medical Research Council Hub Grant Grant Number: G0900747 91070Reading and language abilities are heritable traits that are likely to share some genetic influences with each other. To identify pleiotropic genetic variants affecting these traits, we first performed a genome‐wide association scan (GWAS) meta‐analysis using three richly characterized datasets comprising individuals with histories of reading or language problems, and their siblings. GWAS was performed in a total of 1862 participants using the first principal component computed from several quantitative measures of reading‐ and language‐related abilities, both before and after adjustment for performance IQ. We identified novel suggestive associations at the SNPs rs59197085 and rs5995177 (uncorrected P ≈ 10–7 for each SNP), located respectively at the CCDC136/FLNC and RBFOX2 genes. Each of these SNPs then showed evidence for effects across multiple reading and language traits in univariate association testing against the individual traits. FLNC encodes a structural protein involved in cytoskeleton remodelling, while RBFOX2 is an important regulator of alternative splicing in neurons. The CCDC136/FLNC locus showed association with a comparable reading/language measure in an independent sample of 6434 participants from the general population, although involving distinct alleles of the associated SNP. Our datasets will form an important part of on‐going international efforts to identify genes contributing to reading and language skills.Publisher PDFPeer reviewe

Performance and robustness analysis for structured uncertainty

This paper introduces a nonconservative measure of performance for linear feedback systems in the face of structured uncertainty. This measure is based on a new matrix function, which we call the Structured Singular Value