Approximate reasoning for real-time probabilistic processes

We develop a pseudo-metric analogue of bisimulation for generalized semi-Markov processes. The kernel of this pseudo-metric corresponds to bisimulation; thus we have extended bisimulation for continuous-time probabilistic processes to a much broader class of distributions than exponential distributions. This pseudo-metric gives a useful handle on approximate reasoning in the presence of numerical information -- such as probabilities and time -- in the model. We give a fixed point characterization of the pseudo-metric. This makes available coinductive reasoning principles for reasoning about distances. We demonstrate that our approach is insensitive to potentially ad hoc articulations of distance by showing that it is intrinsic to an underlying uniformity. We provide a logical characterization of this uniformity using a real-valued modal logic. We show that several quantitative properties of interest are continuous with respect to the pseudo-metric. Thus, if two processes are metrically close, then observable quantitative properties of interest are indeed close.Comment: Preliminary version appeared in QEST 0

Bioactive oat β-glucan reduces LDL cholesterol in Caucasians and non-Caucasians

<p>Abstract</p> <p>Background</p> <p>There is increasing global acceptance that viscous soluble fibers lower serum LDL cholesterol (LDL-C), but most evidence for this comes from studies in Caucasians. To see if oat β-glucan lowers LDL-C in Caucasians and non-Caucasians we conducted a post-hoc analysis of the results of a randomized, controlled, double-blind, multi-center clinical trial whose primary aim was to determine if molecular-weight (MW) influenced the LDL-C-lowering effect of oat β-glucan.</p> <p>Results</p> <p>Caucasian and non-Caucasian subjects with LDL-C-C ≥ 3.0 and ≤ 5.0 mmol/L (n = 786 screened, n = 400 ineligible, n = 19 refused, n = 367 randomized, n = 345 completed, n = 1 excluded for missing ethnicity) were randomly assigned to consume cereal containing wheat-fiber (Control, n = 74:13 Caucasian:non-Caucasian) or 3 g high-MW (3H, 2,250,000 g/mol, n = 67:19), 4 g medium-MW (4 M, 850,000 g/mol, n = 50:17), 3 g medium-MW (3M, 530,000 g/mol, n = 54:9) or 4 g low-MW (4 L, 210,000 g/mol, n = 51:12) oat β-glucan daily for 4 weeks. LDL-C after 4 weeks was influenced by baseline LDL-C (p < 0.001) and treatment (p = 0.003), but not ethnicity (p = 0.74). In all subjects, compared to control, 3 H, 4 M and 3 M reduced LDL-C significantly by 4.8 to 6.5%, but 4 L had no effect. Compared to control, the bioactive oat β-glucan treatments (3H, 4M and 3M) reduced LDL-C by a combined mean (95% CI) of 0.18 (0.06, 0.31) mmol/L (4.8%, n = 171, p = 0.004) in Caucasians, a value not significantly different from the 0.37 (0.09, 0.65) mmol/L (10.3%, n = 45, p = 0.008) reduction in non-Caucasians.</p> <p>Conclusion</p> <p>We conclude that oat β-glucan reduces LDL-C in both Caucasians and non-Caucasians; there was insufficient power to determine if the magnitude of LDL-C-lowering differed by ethnicity.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00981981">NCT00981981</a></p

Equivalent glycemic load (EGL): a method for quantifying the glycemic responses elicited by low carbohydrate foods

BACKGROUND: Glycemic load (GL) is used to quantify the glycemic impact of high-carbohydrate (CHO) foods, but cannot be used for low-CHO foods. Therefore, we evaluated the accuracy of equivalent-glycemic-load (EGL), a measure of the glycemic impact of low-CHO foods defined as the amount of CHO from white-bread (WB) with the same glycemic impact as one serving of food. METHODS: Several randomized, cross-over trials were performed by a contract research organization using overnight-fasted healthy subjects drawn from a pool of 63 recruited from the general population by newspaper advertisement. Incremental blood-glucose response area-under-the-curve (AUC) elicited by 0, 5, 10, 20, 35 and 50 g CHO portions of WB (WB-CHO) and 3, 5, 10 and 20 g glucose were measured. EGL values of the different doses of glucose and WB and 4 low-CHO foods were determined as: EGL = (F-B)/M, where F is AUC after food and B is y-intercept and M slope of the regression of AUC on grams WB-CHO. The dose-response curves of WB and glucose were used to derive an equation to estimate GL from EGL, and the resulting values compared to GL calculated from the glucose dose-response curve. The accuracy of EGL was assessed by comparing the GL (estimated from EGL) values of the 4 doses of oral-glucose with the amounts actually consumed. RESULTS: Over 0–50 g WB-CHO (n = 10), the dose-response curve was non-linear, but over the range 0–20 g the curve was indistinguishable from linear, with AUC after 0, 5, 10 and 20 g WB-CHO, 10 ± 1, 28 ± 2, 58 ± 5 and 100 ± 6 mmol × min/L, differing significantly from each other (n = 48). The difference between GL values estimated from EGL and those calculated from the dose-response curve was 0 g (95% confidence-interval, ± 0.5 g). The difference between the GL values of the 4 doses of glucose estimated from EGL, and the amounts of glucose actually consumed was 0.2 g (95% confidence-interval, ± 1 g). CONCLUSION: EGL, a measure of the glycemic impact of low-carbohydrate foods, is valid across the range of 0–20 g CHO, accurate to within 1 g, and at least sensitive enough to detect a glycemic response equivalent to that produced by 3 g oral-glucose in 10 subjects

A genome-wide association study identifies protein quantitative trait loci (pQTLs)

There is considerable evidence that human genetic variation influences gene expression. Genome-wide studies have revealed that mRNA levels are associated with genetic variation in or close to the gene coding for those mRNA transcripts - cis effects, and elsewhere in the genome - trans effects. The role of genetic variation in determining protein levels has not been systematically assessed. Using a genome-wide association approach we show that common genetic variation influences levels of clinically relevant proteins in human serum and plasma. We evaluated the role of 496,032 polymorphisms on levels of 42 proteins measured in 1200 fasting individuals from the population based InCHIANTI study. Proteins included insulin, several interleukins, adipokines, chemokines, and liver function markers that are implicated in many common diseases including metabolic, inflammatory, and infectious conditions. We identified eight Cis effects, including variants in or near the IL6R (p = 1.8×10 -57), CCL4L1 (p = 3.9×10-21), IL18 (p = 6.8×10-13), LPA (p = 4.4×10-10), GGT1 (p = 1.5×10-7), SHBG (p = 3.1×10-7), CRP (p = 6.4×10-6) and IL1RN (p = 7.3×10-6) genes, all associated with their respective protein products with effect sizes ranging from 0.19 to 0.69 standard deviations per allele. Mechanisms implicated include altered rates of cleavage of bound to unbound soluble receptor (IL6R), altered secretion rates of different sized proteins (LPA), variation in gene copy number (CCL4L1) and altered transcription (GGT1). We identified one novel trans effect that was an association between ABO blood group and tumour necrosis factor alpha (TNF-alpha) levels (p = 6.8×10-40), but this finding was not present when TNF-alpha was measured using a different assay , or in a second study, suggesting an assay-specific association. Our results show that protein levels share some of the features of the genetics of gene expression. These include the presence of strong genetic effects in cis locations. The identification of protein quantitative trait loci (pQTLs) may be a powerful complementary method of improving our understanding of disease pathways. © 2008 Melzer et al

Genome sequencing of the extinct Eurasian wild aurochs, Bos primigenius, illuminates the phylogeography and evolution of cattle

Background Domestication of the now-extinct wild aurochs, Bos primigenius, gave rise to the two major domestic extant cattle taxa, B. taurus and B. indicus. While previous genetic studies have shed some light on the evolutionary relationships between European aurochs and modern cattle, important questions remain unanswered, including the phylogenetic status of aurochs, whether gene flow from aurochs into early domestic populations occurred, and which genomic regions were subject to selection processes during and after domestication. Here, we address these questions using whole-genome sequencing data generated from an approximately 6,750-year-old British aurochs bone and genome sequence data from 81 additional cattle plus genome-wide single nucleotide polymorphism data from a diverse panel of 1,225 modern animals. Results Phylogenomic analyses place the aurochs as a distinct outgroup to the domestic B. taurus lineage, supporting the predominant Near Eastern origin of European cattle. Conversely, traditional British and Irish breeds share more genetic variants with this aurochs specimen than other European populations, supporting localized gene flow from aurochs into the ancestors of modern British and Irish cattle, perhaps through purposeful restocking by early herders in Britain. Finally, the functions of genes showing evidence for positive selection in B. taurus are enriched for neurobiology, growth, metabolism and immunobiology, suggesting that these biological processes have been important in the domestication of cattle. Conclusions This work provides important new information regarding the origins and functional evolution of modern cattle, revealing that the interface between early European domestic populations and wild aurochs was significantly more complex than previously thought

Appraisal of quality and analysis of the similarities and differences between osteoarthritis Clinical Practice Guideline recommendations: A systematic review

Objective: Clinical Practice Guidelines (CPGs) aim to support management of hip and knee osteoarthritis (OA), but recommendations are often conflicting and implementation is poor, contributing to evidence-to-practice gaps. This systematic review investigated the contextual and methodological factors contributing to conflicting recommendations for hip and knee OA. Method: Our systematic review appraised CPGs for managing hip and knee OA in adults ≥18 years (PROSPERO CRD42021276635). We used AGREE-II and AGREE-REX to assess quality and extracted data on treatment gaps, conflicts, biases, and consensus. Heterogeneity of recommendations was determined using Weighted Fleiss Kappa (K). The relationship between (K) and AGREE-II/AGREE-REX scores was explored. Results: We identified 25 CPGs across eight countries and four international organisations. The ACR, EULAR, NICE, OARSI and RACGP guidelines scored highest for overall AGREE-II quality (83%). The highest overall AGREE-REX scores were for BMJ Arthroscopy (80%), RACGP (78%) and NICE (76%). CPGs with the least agreement for pharmacological recommendations were ESCEO and NICE (−0.14), ACR (−0.08), and RACGP (−0.01). The highest agreements were between RACGP and NICE (0.53), RACGP and ACR (0.61), and NICE and ACR (0.91). Decreased internal validity determined by low-quality AGREE scores(<60%) in editorial independence were associated with less agreement for pharmacological recommendations. Conclusion: There were associations between guideline quality and agreement scores. Future guideline development should be informed by robust evidence, editorial independence and methodological rigour to ensure a harmonisation of recommendations. End-users of CPGs must recognise the contextual factors associated with the development of OA CPGs and balance these factors with available evidence

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts