Genetic Classification of Populations using Supervised Learning

There are many instances in genetics in which we wish to determine whether two candidate populations are distinguishable on the basis of their genetic structure. Examples include populations which are geographically separated, case--control studies and quality control (when participants in a study have been genotyped at different laboratories). This latter application is of particular importance in the era of large scale genome wide association studies, when collections of individuals genotyped at different locations are being merged to provide increased power. The traditional method for detecting structure within a population is some form of exploratory technique such as principal components analysis. Such methods, which do not utilise our prior knowledge of the membership of the candidate populations. are termed \emph{unsupervised}. Supervised methods, on the other hand are able to utilise this prior knowledge when it is available. In this paper we demonstrate that in such cases modern supervised approaches are a more appropriate tool for detecting genetic differences between populations. We apply two such methods, (neural networks and support vector machines) to the classification of three populations (two from Scotland and one from Bulgaria). The sensitivity exhibited by both these methods is considerably higher than that attained by principal components analysis and in fact comfortably exceeds a recently conjectured theoretical limit on the sensitivity of unsupervised methods. In particular, our methods can distinguish between the two Scottish populations, where principal components analysis cannot. We suggest, on the basis of our results that a supervised learning approach should be the method of choice when classifying individuals into pre-defined populations, particularly in quality control for large scale genome wide association studies.Comment: Accepted PLOS On

Empedoclean epic: how far can you go?

This paper attempts to take one step further the argument of P.R. Hardie’s 1995 article in Classical Quarterly, entitled ‘The Speech of Pythagoras in Ovid Metamorphoses 15: Empedoclean Epos’, by showing that Lucan can be fitted easily into a version of Latin literary history that privileges the presence of recurring Empedoclean influence

The Tuber Extract and Flour of Dioscorea Alatanormalize the Blood Lipid Profile of Rabbits Treated with High Cholesterol Diets

Background: Dioscorea alata(DA) tuber has potential to prevent the condition of hyperlipidemia due to the bioactive compound, such as anthocyanins, diosgenin, and dietary fiber that beneficial in normalizing blood lipid profiles. In this research, the effect of water extract and flour of DA tuber administration was examined on rabbits treated with high cholesterol diets.Methods:DA tuber extract and flour were administrated to the rabbits for 60 days using completely randomised design. The ration treatment are as follows: 1) Basal ration as negative control (K0), 2) Basal ration + 0.5% cholesterol, as positive control (K1), 3) Basal ration + 0.5% cholesterol + DA extract 1.8 g/100 g (KE1), 4) Basal ration + cholesterol 0.5% + DA extract 3.6 g/100 g (KE2), 5) Basal ration with 15% DA flour + 0.5% cholesterol (KT1) and 6) Basal ration with 30% DA flour + 0.5% cholesterol (KT2). The Total cholesterol, HDL, LDL cholesterol in serum were analysed at baseline, days 28, days 56 and at the end of study.Results:The administration of high cholesterol (1%) ration increased blood lipid levels by 16 fold compared to that of control. The administration of 15% and 30% of DA flour could maintain blood lipid profile to normal condition, in particular at 30% substitution DA flour. However the water extract of DA can not maintain a normal blood lipids of high cholesterol treated rabbitsConclusion: Dioscorea alata flour has suggested to have anti-hyperlipidemia effect. (Health Science Indones 2014;1:23-9

Cure of Helicobacter pylori infection in patients with reflux oesophagitis treated with long term omeprazole reverses gastritis without exacerbation of reflux disease: results of a randomised controlled trial

BACKGROUND: Helicobacter pylori gastritis may progress to glandular atrophy and intestinal metaplasia, conditions that predispose to gastric cancer. Profound suppression of gastric acid is associated with increased severity of H pylori gastritis. This prospective randomised study aimed to investigate whether H pylori eradication can influence gastritis and its sequelae during long term omeprazole therapy for gastro-oesophageal reflux disease (GORD). METHODS: A total of 231 H pylori positive GORD patients who had been treated for > or =12 months with omeprazole maintenance therapy (OM) were randomised to either continuation of OM (OM only; n = 120) or OM plus a one week course of omeprazole, amoxycillin, and clarithromycin (OM triple; n = 111). Endoscopy with standardised biopsy sampling as well as symptom evaluation were performed at baseline and after one and two years. Gastritis was assessed according to the Sydney classification system for activity, inflammation, atrophy, intestinal metaplasia, and H pylori density. RESULTS: Corpus gastritis activity at entry was moderate or severe in 50% and 55% of the OM only and OM triple groups, respectively. In the OM triple group, H pylori was eradicated in 90 (88%) patients, and activity and inflammation decreased substantially in both the antrum and corpus (p<0.001, baseline v two years). Atrophic gastritis also improved in the corpus (p<0.001) but not in the antrum. In the 83 OM only patients with continuing infection, there was no change in antral and corpus gastritis activity or atrophy, but inflammation increased (p<0.01). H pylori eradication did not alter the dose of omeprazole required, or reflux symptoms. CONCLUSIONS: Most H pylori positive GORD patients have a corpus predominant pangastritis during omeprazole maintenance therapy. Eradication of H pylori eliminates gastric mucosal inflammation and induces regression of corpus glandular atrophy. H pylori eradication did not worsen reflux disease or lead to a need for increased omeprazole maintenance dose. We therefore recommend eradication of H pylori in GORD patients receiving long term acid suppression

An extensible framework for multicore response time analysis

In this paper, we introduce a multicore response time analysis (MRTA) framework, which decouples response time analysis from a reliance on context independent WCET values. Instead, the analysis formulates response times directly from the demands placed on different hardware resources. The MRTA framework is extensible to different multicore architectures, with a variety of arbitration policies for the common interconnects, and different types and arrangements of local memory. We instantiate the framework for single level local data and instruction memories (cache or scratchpads), for a variety of memory bus arbitration policies, including: Round-Robin, FIFO, Fixed-Priority, Processor-Priority, and TDMA, and account for DRAM refreshes. The MRTA framework provides a general approach to timing verification for multicore systems that is parametric in the hardware configuration and so can be used at the architectural design stage to compare the guaranteed levels of real-time performance that can be obtained with different hardware configurations. We use the framework in this way to evaluate the performance of multicore systems with a variety of different architectural components and policies. These results are then used to compose a predictable architecture, which is compared against a reference architecture designed for good average-case behaviour. This comparison shows that the predictable architecture has substantially better guaranteed real-time performance, with the precision of the analysis verified using cycle-accurate simulation

Empedoclean epic: how far can you go?

This paper attempts to take one step further the argument of P.R. Hardie’s 1995 article in Classical Quarterly, entitled ‘The Speech of Pythagoras in Ovid Metamorphoses 15: Empedoclean Epos’, by showing that Lucan can be fitted easily into a version of Latin literary history that privileges the presence of recurring Empedoclean influence

Whole Slide Imaging Versus Microscopy for Primary Diagnosis in Surgical Pathology: A Multicenter Blinded Randomized Noninferiority Study of 1992 Cases (Pivotal Study)

Most prior studies of primary diagnosis in surgical pathology using whole slide imaging (WSI) versus microscopy have focused on specific organ systems or included relatively few cases. The objective of this study was to demonstrate that WSI is noninferior to microscopy for primary diagnosis in surgical pathology. A blinded randomized noninferiority study was conducted across the entire range of surgical pathology cases (biopsies and resections, including hematoxylin and eosin, immunohistochemistry, and special stains) from 4 institutions using the original sign-out diagnosis (baseline diagnosis) as the reference standard. Cases were scanned, converted to WSI and randomized. Sixteen pathologists interpreted cases by microscopy or WSI, followed by a wash-out period of ≥4 weeks, after which cases were read by the same observers using the other modality. Major discordances were identified by an adjudication panel, and the differences between major discordance rates for both microscopy (against the reference standard) and WSI (against the reference standard) were calculated. A total of 1992 cases were included, resulting in 15,925 reads. The major discordance rate with the reference standard diagnosis was 4.9% for WSI and 4.6% for microscopy. The difference between major discordance rates for microscopy and WSI was 0.4% (95% confidence interval, -0.30% to 1.01%). The difference in major discordance rates for WSI and microscopy was highest in endocrine pathology (1.8%), neoplastic kidney pathology (1.5%), urinary bladder pathology (1.3%), and gynecologic pathology (1.2%). Detailed analysis of these cases revealed no instances where interpretation by WSI was consistently inaccurate compared with microscopy for multiple observers. We conclude that WSI is noninferior to microscopy for primary diagnosis in surgical pathology, including biopsies and resections stained with hematoxylin and eosin, immunohistochemistry and special stains. This conclusion is valid across a wide variety of organ systems and specimen types

MONEY DEMAND, FINANCIAL DISTRESS, AND EXCHANGE-RATE UNCERTAINTY IN INDONESIA

This paper examines the demand for currency and quasi-money in Indonesia with linear and neural network models. The goal is to predict better the recent financial distress, reflected by the flight into currency and decline of quasi-money. The results show that neural network approaches, much more than linear models, are capable of accurate out-of-sample predictions for both monetary aggregates. However, for the very turbulent period of November and December of 1997, even the neural network models show large out-of-sample forecast errors.  When a proxy for exchange-rate uncertainty supplements the network models, the out-of-sample currency demand becomes quite accurate, even for the last month of 1997. The quasi-money demand forecast also improve, although not as dramatically as those of currency demand.  The analysis shows that a credible program, which reduces uncertainty in exchange-rate expectations, may mitigate the flight into currency from broad money, and the ensuing demonetization of the financial sector

Empirical Distributions of F-ST from Large-Scale Human Polymorphism Data

Studies of the apportionment of human genetic variation have long established that most human variation is within population groups and that the additional variation between population groups is small but greatest when comparing different continental populations. These studies often used Wright’s FST that apportions the standardized variance in allele frequencies within and between population groups. Because local adaptations increase population differentiation, high-FST may be found at closely linked loci under selection and used to identify genes undergoing directional or heterotic selection. We re-examined these processes using HapMap data. We analyzed 3 million SNPs on 602 samples from eight worldwide populations and a consensus subset of 1 million SNPs found in all populations. We identified four major features of the data: First, a hierarchically FST analysis showed that only a paucity (12%) of the total genetic variation is distributed between continental populations and even a lesser genetic variation (1%) is found between intra-continental populations. Second, the global FST distribution closely follows an exponential distribution. Third, although the overall FST distribution is similarly shaped (inverse J), FST distributions varies markedly by allele frequency when divided into non-overlapping groups by allele frequency range. Because the mean allele frequency is a crude indicator of allele age, these distributions mark the time-dependent change in genetic differentiation. Finally, the change in mean-FST of these groups is linear in allele frequency. These results suggest that investigating the extremes of the FST distribution for each allele frequency group is more efficient for detecting selection. Consequently, we demonstrate that such extreme SNPs are more clustered along the chromosomes than expected from linkage disequilibrium for each allele frequency group. These genomic regions are therefore likely candidates for natural selection

Genome-wide analysis of BMI in adolescents and young adults reveals additional insight into the effects of genetic loci over the life course

Genetic loci for body mass index (BMI) in adolescence and young adulthood, a period of high risk for weight gain, are understudied, yet may yield important insight into the etiology of obesity and early intervention. To identify novel genetic loci and examine the influence of known loci on BMI during this critical time period in late adolescence and early adulthood, we performed a two-stage meta-analysis using 14 genome-wide association studies in populations of European ancestry with data on BMI between ages 16 and 25 in up to 29 880 individuals. We identified seven independent loci (P < 5.0 × 10−8) near FTO (P = 3.72 × 10−23), TMEM18 (P = 3.24 × 10−17), MC4R (P = 4.41 × 10−17), TNNI3K (P = 4.32 × 10−11), SEC16B (P = 6.24 × 10−9), GNPDA2 (P = 1.11 × 10−8) and POMC (P = 4.94 × 10−8) as well as a potential secondary signal at the POMC locus (rs2118404, P = 2.4 × 10−5 after conditioning on the established single-nucleotide polymorphism at this locus) in adolescents and young adults. To evaluate the impact of the established genetic loci on BMI at these young ages, we examined differences between the effect sizes of 32 published BMI loci in European adult populations (aged 18-90) and those observed in our adolescent and young adult meta-analysis. Four loci (near PRKD1, TNNI3K, SEC16B and CADM2) had larger effects and one locus (near SH2B1) had a smaller effect on BMI during adolescence and young adulthood compared with older adults (P < 0.05). These results suggest that genetic loci for BMI can vary in their effects across the life course, underlying the importance of evaluating BMI at different age