Isometric Sliced Inverse Regression for Nonlinear Manifolds Learning

[[abstract]]Sliced inverse regression (SIR) was developed to find effective linear dimension-reduction directions for exploring the intrinsic structure of the high-dimensional data. In this study, we present isometric SIR for nonlinear dimension reduction, which is a hybrid of the SIR method using the geodesic distance approximation. First, the proposed method computes the isometric distance between data points; the resulting distance matrix is then sliced according to K-means clustering results, and the classical SIR algorithm is applied. We show that the isometric SIR (ISOSIR) can reveal the geometric structure of a nonlinear manifold dataset (e.g., the Swiss roll). We report and discuss this novel method in comparison to several existing dimension-reduction techniques for data visualization and classification problems. The results show that ISOSIR is a promising nonlinear feature extractor for classification applications.[[incitationindex]]SCI[[booktype]]紙本[[booktype]]電子

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Torrefied Cereals: The Future for Horse Nutrition?

No abstract available

Torrefied Cereals: The Future for Horse Nutrition?

No abstract available

Effect of insulin degludec versus sitagliptin in patients with type 2 diabetes uncontrolled on oral antidiabetic agents

Aim: The efficacy and safety of insulin degludec (IDeg), a new basal insulin with an ultra-long duration of action, was compared to sitagliptin (Sita) in a 26-week, open-label trial. Methods: Insulin-naïve subjects with type 2 diabetes [n=458, age: 56years, diabetes duration: 7.7years, glycosylated haemoglobin (HbA1c): 8.9% (74mmol/mol)] were randomized (1:1) to once-daily IDeg or Sita (100mg orally) as add-on to stable treatment with 1 or 2 oral antidiabetic drugs (OADs). Results: Superiority of IDeg to Sita in improving HbA1c and fasting plasma glucose (FPG) was confirmed [estimated treatment difference (ETD) IDeg-Sita for HbA1c: -0.43%-points [95% confidence interval (CI): -0.61; -0.24, p<0.0001] and for FPG: -2.17 mmol/l (95% CI: -2.59; -1.74, p<0.0001)]. HbA1c<7% (<53mmol/mol) was achieved by 41% (IDeg) versus 28% (Sita) of patients, estimated odds ratio IDeg/Sita: 1.60 (95% CI: 1.04; 2.47, p=0.034). There was no statistically significant difference in the rate of nocturnal confirmed hypoglycaemia between IDeg and Sita [0.52 vs. 0.30 episodes/patient-year, estimated rate ratio (ERR): IDeg/Sita: 1.93 (95% CI: 0.90; 4.10, p=0.09)]. Rates of overall confirmed hypoglycaemia were higher with IDeg than with Sita [3.1 vs. 1.3 episodes/patient-year, ERR IDeg/Sita: 3.81 (95% CI: 2.40; 6.05, p<0.0001)]. IDeg was associated with a greater change in body weight than Sita [ETD IDeg-Sita: 2.75kg (95% CI: 1.97; 3.54, p<0.0001)]. The overall rates of adverse events were low and similar for both groups. Conclusions: In patients unable to achieve good glycaemic control on OAD(s), treatment intensification with IDeg offers an effective, well-tolerated alternative to the addition of a second or third OAD. © 2013 John Wiley & Sons Ltd

Efficacy and safety of switching from the DPP-4 inhibitor sitagliptin to the human GLP-1 analog liraglutide after 52 weeks in metformin-treated patients with type 2 diabetes a randomized, open-label trial

OBJECTIVE - To assess the efficacy and safety of switching from sitagliptin to liraglutide in metformin-treated adults with type 2 diabetes. RESEARCH DESIGN AND METHODS - In an open-label trial, participants randomized to receive either liraglutide (1.2 or 1.8 mg/day) or sitagliptin (100 mg/day), each added to metformin, continued treatment for 52 weeks. In a 26-week extension, sitagliptin-treated participants were randomly allocated to receive instead liraglutide at either 1.2 or 1.8 mg/day, while participants originally randomized to receive liraglutide continued unchanged. RESULTS - Although 52 weeks of sitagliptin changed glycosylated hemoglobin (HbA1c) by -0.9% from baseline, additional decreases occurred after switching to liraglutide (1.2 mg/day, -0.2%, P = 0.006; 1.8 mg/day, -0.5%, P = 0.0001). Conversion to liraglutide was associated with reductions in fasting plasma glucose (FPG) (1.2 mg/day, -0.8 mmol/L, P = 0.0004; 1.8mg/ day, -1.4 mmol/L, P &lt; 0.0001) and body weight (1.2 mg/day, -1.6 kg; 1.8 mg/day, -2.5 kg; both P &lt; 0.0001) and with an increased proportion of patients reaching HbA1c &lt;7% (from ∼30% to ∼50%). Overall treatment satisfaction, assessed by the Diabetes Treatment Satisfaction Questionnaire, improved after switching to liraglutide (pooled 1.2 and 1.8 mg/day, 1.3; P = 0.0189). After switching, mostly transient nausea occurred in 21% of participants, and minor hypoglycemia remained low (3-4% of participants). Continuing liraglutide treatment at 1.2 mg/ day and 1.8 mg/day for 78 weeks reduced HbA1c (baseline 8.3 and 8.4%, respectively) by -0.9 and -1.3%, respectively; FPG by -1.3 and -1.7mmol/L, respectively; and weight by -2.6 and -3.1 kg, respectively, with 9-10% of participants reporting minor hypoglycemia. CONCLUSIONS - Glycemic control, weight, and treatment satisfaction improved after switching from sitagliptin to liraglutide, albeit with a transient increase in gastrointestinal reactions. © 2012 by the American Diabetes Association