Analysis of untyped SNPs: maximum likelihood and imputation methods

Analysis of untyped single nucleotide polymorphisms (SNPs) can facilitate the localization of disease-causing variants and permit meta-analysis of association studies with different genotyping platforms. We present two approaches for using the linkage disequilibrium structure of an external reference panel to infer the unknown value of an untyped SNP from the observed genotypes of typed SNPs. The maximum-likelihood approach integrates the prediction of untyped genotypes and estimation of association parameters into a single framework and yields consistent and efficient estimators of genetic effects and gene-environment interactions with proper variance estimators. The imputation approach is a two-stage strategy, which first imputes the untyped genotypes by either the most likely genotypes or the expected genotype counts and then uses the imputed values in a downstream association analysis. The latter approach has proper control of type I error in single-SNP tests with possible covariate adjustments even when the reference panel is misspecified; however, type I error may not be properly controlled in testing multiple-SNP effects or gene-environment interactions. In general, imputation yields biased estimators of genetic effects and gene-environment interactions, and the variances are underestimated. We conduct extensive simulation studies to compare the bias, type I error, power, and confidence interval coverage between the maximum likelihood and imputation approaches in the analysis of single-SNP effects, multiple-SNP effects, and gene-environment interactions under cross-sectional and case-control designs. In addition, we provide an illustration with genome-wide data from the Wellcome Trust Case-Control Consortium (WTCCC) [2007]

Analysis of 13 C and 14 C labeling in pyruvate and lactate in tumor and blood of lymphoma-bearing mice injected with 13 C- and 14 C-labeled pyruvate

Measurements of hyperpolarized 13C label exchange between injected [1‐13C]pyruvate and the endogenous tumor lactate pool can give an apparent first‐order rate constant for the exchange. The determination of the isotope flux, however, requires an estimate of the labeled pyruvate concentration in the tumor. This was achieved here by measurement of the tumor uptake of [1‐14C]pyruvate, which showed that <2% of the injected pyruvate reached the tumor site. Multiplication of this estimated labeled pyruvate concentration in the tumor with the apparent first‐order rate constant for hyperpolarized 13C label exchange gave an isotope flux that showed good agreement with a flux determined directly by the injection of non‐polarized [3‐13C]pyruvate, rapid excision of the tumor after 30 s and measurement of 13C‐labeled lactate concentrations in tumor extracts. The distribution of labeled lactate between intra‐ and extracellular compartments and the blood pool was investigated by imaging, by measurement of the labeled lactate concentration in blood and tumor, and by examination of the effects of a gadolinium contrast agent and a lactate transport inhibitor on the intensity of the hyperpolarized [1‐13C]lactate signal. These measurements showed that there was significant export of labeled lactate from the tumor, but that labeled lactate in the blood pool produced by the injection of hyperpolarized [1‐13C]pyruvate showed only relatively low levels of polarization. This study shows that measurements of hyperpolarized 13C label exchange between pyruvate and lactate in a murine tumor model can provide an estimate of the true isotope flux if the concentration of labeled pyruvate that reaches the tumor can be determined

The anti-caries efficacy of a dentifrice containing 1.5% arginine and 1450ppm fluoride as sodium monofluorophosphate assessed using Quantitative Light-induced Fluorescence (QLF)

AbstractObjectiveTo compare the efficacy of a new dentifrice containing 1.5% arginine, an insoluble calcium compound and 1450ppm fluoride to arrest and reverse naturally occurring buccal caries lesions in children relative to a positive control dentifrice containing 1450ppm fluoride alone.Study designParticipants from Chengdu, Sichuan Province, China tested three dentifrices: a new dentifrice containing 1.5% arginine, an insoluble calcium compound, and 1450ppm fluoride, as sodium monofluorophosphate, a positive control dentifrice containing 1450ppm fluoride, as sodium fluoride, in a silica base, and a matched negative control dentifrice without arginine and fluoride. Quantitative Light-induced Fluorescence (QLF) was used to assess buccal caries lesions at baseline and after 3 and 6 months of product use.Results438 participants (initial age 9–13 years (mean 11.1±0.78) and 48.6% female) completed the study. No adverse events attributable to the products were reported during the course of the study. The subject mean ΔQ (mm2%), representing lesion volume, was 27.26 at baseline. After 6 months of product use, the ΔQ values for the arginine-containing, positive and negative control dentifrices were 13.46, 17.99 and 23.70 representing improvements from baseline of 50.6%, 34.0% and 13.1%. After 6 months product use, the differences between the pair wise comparisons for all three groups were statistically significant (p<0.01). The arginine-containing dentifrice demonstrated an improvement after only 3 months that was almost identical to that achieved by the conventional 1450ppm fluoride dentifrice after 6 months.ConclusionThe new dentifrice containing 1.5% arginine, an insoluble calcium compound, and 1450ppm fluoride provides statistically significantly superior efficacy in arresting and reversing buccal caries lesions to a conventional dentifrice containing 1450ppm fluoride alone

Improving the power to establish clinical similarity in a Phase 3 efficacy trial by incorporating prior evidence of analytical and pharmacokinetic similarity

To improve patients’ access to safe and effective biological medicines, abbreviated licensure pathways for biosimilar and interchangeable biological products have been established in the US, Europe, and other countries around the world. The US Food and Drug Administration and European Medicines Agency have published various guidance documents on the development and approval of biosimilars, which recommend a “totality-of-the-evidence” approach with a stepwise process to demonstrate biosimilarity. The approach relies on comprehensive comparability studies ranging from analytical and nonclinical studies to clinical pharmacokinetic/pharmacodynamic (PK/PD) and efficacy studies. A clinical efficacy study may be necessary to address residual uncertainty about the biosimilarity of the proposed product to the reference product and support a demonstration that there are no clinically meaningful differences. In this article, we propose a statistical strategy that takes into account the similarity evidence from analytical assessments and PK studies in the design and analysis of the clinical efficacy study in order to address residual uncertainty and enhance statistical power and precision. We assume that if the proposed biosimilar product and the reference product are shown to be highly similar with respect to the analytical and PK parameters, then they should also be similar with respect to the efficacy parameters. We show that the proposed methods provide correct control of the type I error and improve the power and precision of the efficacy study upon the standard analysis that disregards the prior evidence. We confirm and illustrate the theoretical results through simulation studies based on the biosimilars development experience of many different products

Effects of coarse-graining on the scaling behavior of long-range correlated and anti-correlated signals

We investigate how various coarse-graining methods affect the scaling properties of long-range power-law correlated and anti-correlated signals, quantified by the detrended fluctuation analysis. Specifically, for coarse-graining in the magnitude of a signal, we consider (i) the Floor, (ii) the Symmetry and (iii) the Centro-Symmetry coarse-graining methods. We find, that for anti-correlated signals coarse-graining in the magnitude leads to a crossover to random behavior at large scales, and that with increasing the width of the coarse-graining partition interval $\Delta$ this crossover moves to intermediate and small scales. In contrast, the scaling of positively correlated signals is less affected by the coarse-graining, with no observable changes when $\Delta1$ a crossover appears at small scales and moves to intermediate and large scales with increasing $\Delta$. For very rough coarse-graining ($\Delta>3$) based on the Floor and Symmetry methods, the position of the crossover stabilizes, in contrast to the Centro-Symmetry method where the crossover continuously moves across scales and leads to a random behavior at all scales, thus indicating a much stronger effect of the Centro-Symmetry compared to the Floor and the Symmetry methods. For coarse-graining in time, where data points are averaged in non-overlapping time windows, we find that the scaling for both anti-correlated and positively correlated signals is practically preserved. The results of our simulations are useful for the correct interpretation of the correlation and scaling properties of symbolic sequences.Comment: 19 pages, 13 figure

Regio- and stereoselective organocatalyzed relay glycosylations to synthesize 2-amino-2-deoxy-1,3-dithioglycosides

Herein, we describe a novel methodology for the regio-and stereoselectiveconvergent synthesis of 2-amino-2-deoxy-dithioglycosides via one-potrelay glycosylation of 3-O-acetyl-2-nitroglucal donors.This unique organo-catalysis relay glycosylation features excellentsite- and stereoselectivity, good to excellent yields, mild reactionconditions, and broad substrate scope. 2-Amino-2-deoxy-glucosides/mannosidesbearing 1,3-dithio-linkages were efficiently obtained from 3-O-acetyl-2-nitroglucal donors in both stepwise and one-potglycosylation protocols. The dithiolated O-antigen of E. coli serogroup 64 was successfully synthesizedusing this newly developed method.Bio-organic Synthesi

Measurements of the observed cross sections for exclusive light hadron production in e^+e^- annihilation at \sqrt{s}= 3.773 and 3.650 GeV

By analyzing the data sets of 17.3 pb$^{-1}$ taken at $\sqrt{s}=3.773$ GeV and 6.5 pb$^{-1}$ taken at $\sqrt{s}=3.650$ GeV with the BESII detector at the BEPC collider, we have measured the observed cross sections for 12 exclusive light hadron final states produced in $e^+e^-$ annihilation at the two energy points. We have also set the upper limits on the observed cross sections and the branching fractions for $\psi(3770)$ decay to these final states at 90% C.L.Comment: 8 pages, 5 figur

Hydrogen bond activated glycosylation under mild conditions

Herein, we report a new glycosylation system for the highly efficient and stereoselective formation of glycosidic bonds using glycosyl N-phenyl trifluoroacetimidate (PTFAI) donors and a charged thiourea hydrogen-bond-donor catalyst. The glycosylation protocol features broad substrate scope, controllable stereoselectivity, good to excellent yields and exceptionally mild catalysis conditions. Benefitting from the mild reaction conditions, this new hydrogen bond-mediated glycosylation system in combination with a hydrogen bond-mediated aglycon delivery system provides a reliable method for the synthesis of challenging phenolic glycosides. In addition, a chemoselective glycosylation procedure was developed using different imidate donors (trichloroacetimidates, N-phenyl trifluoroacetimidates, N-4-nitrophenyl trifluoroacetimidates, benzoxazolyl imidates and 6-nitro-benzothiazolyl imidates) and it was applied for a trisaccharide synthesis through a novel one-pot single catalyst strategy.Bio-organic Synthesi